In the article "Active Immunization Targeting Amyloid β for the Treatment of Alzheimer's Disease" [Neurodegener Dis. 2025; <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="https://doi.org/10.1159/000546287">https://doi.org/10.1159/000546287</ext-link>] by Triplett et al., the wrong copyright license was displayed. It has been corrected to a CC-BY 4.0 license. The section title was also corrected to Review Article.The original online article has been updated to reflect this.</sec></body>.}, } @article {pmid41165744, year = {2025}, author = {Xiong, S and Cui, M and Liu, H and Wu, L and Xiong, X and Zhang, S and Yang, J and Wang, P}, title = {Rational Design of a Dual-Channel Fluorescent Probe for the Simultaneous Imaging of Brain Amyloid-β Plaques and HClO/ClO[-] in Alzheimer's Disease.}, journal = {Analytical chemistry}, volume = {97}, number = {44}, pages = {24656-24667}, doi = {10.1021/acs.analchem.5c04718}, pmid = {41165744}, issn = {1520-6882}, mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; *Fluorescent Dyes/chemistry/chemical synthesis ; Animals ; *Hypochlorous Acid/analysis/metabolism ; PC12 Cells ; *Amyloid beta-Peptides/metabolism/analysis ; Rats ; *Brain/metabolism/diagnostic imaging ; Mice ; *Plaque, Amyloid/metabolism/diagnostic imaging ; Optical Imaging ; Humans ; Coumarins/chemistry ; }, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia. The pathological hallmarks of AD are characterized by the presence of amyloid-β (Aβ) plaques and elevated production of hypochlorous acid (HClO/ClO[-]) in the brain. However, there is a lack of effective tools to image the biological functions of Aβ aggregates and HClO/ClO[-] in the AD brain. In this study, we presented the first single-molecule fluorescent probe, CTAD-MB, capable of detecting both Aβ aggregates and HClO/ClO[-]. The design strategy for this probe combines an N,N-dimethyl-phenylcoumarin moiety, which has high affinity for Aβ aggregates, with a methylene blue derivative that specifically responds to hypochlorite. This bifunctional fluorescent probe provided distinct fluorescent signals for Aβ aggregates and HClO/ClO[-]. CTAD-MB demonstrated completely independent spectral responses to Aβ and HClO/ClO[-], offering high selectivity, sensitivity, and rapid response. The probe was successfully employed in imaging the HClO/ClO[-] stimulated by Aβ aggregates in PC12 cells. Also, it was effectively applied for dual-channel detection of Aβ and HClO/ClO[-] in the live AD mouse, which could be used to distinguish from the brain inflammation mouse. This insight not only advances our understanding of AD but also provides new avenues for its diagnosis and treatment.}, } @article {pmid41165739, year = {2025}, author = {Dalal, N and Jaiswal, J and Kushwaha, M and Verma, H and Rana, P and Gupta, S and Panwar, R and Janmeda, P and Jain, P and Singh, AK and Mohan, A and Kumar, A}, title = {Implications of Gut Microbiota-Derived Metabolites in Neurological Disorders.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {22}, pages = {4315-4326}, doi = {10.1021/acschemneuro.5c00414}, pmid = {41165739}, issn = {1948-7193}, mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Nervous System Diseases/metabolism/microbiology ; Animals ; Methylamines/metabolism ; Blood-Brain Barrier/metabolism ; Cresols/metabolism ; Oxidative Stress/physiology ; Brain/metabolism ; Neuroinflammatory Diseases/metabolism ; }, abstract = {Neurological disorders (NDs) represent a significant global health challenges, with neurodegeneration being a common pathological feature. Recent investigations indicate the involvement of gut microbiota-derived metabolites in these disorders, such as neuroinflammation, oxidative stress, and cognitive decline. The gut-brain axis, a communication network between the gut and the central nervous system (CNS), is influenced by microbial metabolites, which can cross the blood-brain barrier and impact brain function. Key metabolites such as trimethylamine N-oxide (TMAO), para-cresol sulfate (pCS), 4-ethylphenyl sulfate (4-EPS), and indoxyl sulfate (IS) have been linked with the progression of neurological disorders. TMAO disrupts blood-brain barrier integrity, promotes oxidative stress, and activates microglial cells, which lead to the apoptosis of neurons, resulting in neuroinflammation. This could also result in psychiatric changes and behavioral disorders. pCS produced from gut bacteria metabolizing dietary proteins is correlated with amplified oxidative stress, neuroinflammation, and cognitive impairments in disorders like Parkinson's disease and Alzheimer's disease. Similarly, elevated 4-EPS levels are linked to autism spectrum disorder, contributing to anxiety-like behavior and blood-brain barrier disruption. Understanding the mechanisms by which gut-derived metabolites affect neurological health could lead to novel therapeutic strategies that can target gut microbiota for the medication and treatment of neurological disorders. Dietary precursors and gut microbiota metabolites, modulated by probiotics, prebiotics, postbiotics, and synbiotics, play a critical role in maintaining microbiota homeostasis and influencing neurological health, needing sophisticated biosensors to enable real-time monitoring and early intervention in disorders linked to gut metabolite imbalances.}, } @article {pmid41165158, year = {2025}, author = {Hao, J and Wan, Q and Chen, C}, title = {Atractylenolide III Promotes Astrocyte Aβ Clearance by Up-regulating AQP4 to Improve Alzheimer's Disease.}, journal = {Folia biologica}, volume = {71}, number = {3}, pages = {140-148}, doi = {10.14712/fb2025071030140}, pmid = {41165158}, issn = {0015-5500}, support = {D202303076913//Health Commission of Hunan Province/ ; D202304017019//Health Commission of Hunan Province/ ; }, mesh = {*Astrocytes/metabolism/drug effects ; Animals ; *Aquaporin 4/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Sesquiterpenes/pharmacology/therapeutic use/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Lactones/pharmacology/therapeutic use/chemistry ; Mice ; *Up-Regulation/drug effects ; Molecular Docking Simulation ; Male ; Disease Models, Animal ; Cell Survival/drug effects ; Mice, Inbred C57BL ; Peptide Fragments/metabolism ; }, abstract = {Astrocytes actively phagocytose amyloid beta (Aβ), enhancing cerebral clearance and positioning themselves as viable therapeutic targets for Alz-heimer's disease (AD). Atractylenolide III (ATL-III), the primary bioactive compound in the traditional Chinese herb Baizhu, demonstrates established neuroprotective properties. However, the research on its effects on astrocytes has not yet been elaborated. To induce an astrocyte-based AD model, Aβ1-42 was utilized. Cell viability assays were conducted to screen for the optimal concentration of ATL-III treatment. Molecular docking was performed to investigate the binding between ATL-III and aquaporin 4 (AQP4). Additionally, an Aβ1-42-induced AD mouse model was adopted. In this study, ATL-III effectively reduced the accumulation level of Aβ1-42 in the cell supernatant, and at the same time, significantly enhanced the internalization of Aβ by astrocytes. Of interest, the study reveals that ATL-III not only has the property of binding to AQP4 but also up-regulates the expression level of this protein. Mechanistic probes suggest that the role of ATL-III in promoting Aβ clearance by astrocytes may be partially dependent on its regulation of AQP4 expression. Animal behavioural experiments confirmed that the compound ameliorated Aβ1-42-induced cognitive dysfunction, and pathological analyses revealed significantly elevated AQP4 expression in the hippocampus. The combined findings suggest that ATL-III may play a role in ameliorating the pathological process of AD by enhancing the efficiency of astrocyte-mediated Aβ clearance through the up-regulation of AQP4 expression.}, } @article {pmid41165142, year = {2025}, author = {Chen, YN and Xiong, ZE and Wen, X and He, SJ and Zhang, XL and Zhang, R and Wang, T and Zou, J}, title = {Anthocyanins in the treatment of Alzheimer's disease: a systematic review and meta-analysis of animal studies.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/1028415X.2025.2578641}, pmid = {41165142}, issn = {1476-8305}, abstract = {BACKGROUND: To comprehensively evaluate the therapeutic potential of anthocyanins in animal models of Alzheimer's disease (AD). METHODS: The PubMed, Web of Science, and Embase databases were searched for preclinical animal studies investigating anthocyanin intervention in AD models up to June 2025. Studies reporting outcomes related to cognitive behavior, neuropathological changes such as amyloid-β (Aβ) deposition, or molecular mechanisms including oxidative stress and inflammatory markers, were included in the analysis. Data analysis was performed using RevMan 5.4 software. The SYRCLE tool was used to assess the risk of bia. RESULTS: Anthocyanin intervention significantly improved cognitive function in animal models of AD. Meta-analysis revealed that in the Morris water maze test, the anthocyanin treatment group exhibited a significantly higher number of crossings in the target quadrant compared to the control group (SMD = 1.83, 95% CI: 1.48 -2.18, p < 0.00001). Regarding pathological indicators, anthocyanin administration was associated with a significant reduction in Aβ protein deposition (SMD = -5.39, 95% CI: - 6.89 to - 3.88, p < 0.00001). Furthermore, anthocyanin effectively alleviated oxidative stress, as evidenced by a significant decrease in malondialdehyde (MDA) levels (SMD = -4.19, 95% CI: - 6.76 to - 1.63, p = 0.001). In terms of neuroinflammatory markers, anthocyanin treatment significantly reduced the expression levels of tumor necrosis factor-alpha (TNF-α) (SMD = -3.30, 95% CI: - 4.91 to - 1.68, p < 0.0001) and interleukin-1 beta (IL-1β) (SMD = -2.23, 95% CI: - 3.12 to - 1.34, p < 0.00001). CONCLUSION: This systematic review and meta-analysis suggest that anthocyanins could improve cognitive function and mitigate neuropathology in animal models of AD.}, } @article {pmid41164883, year = {2025}, author = {André, C and Stankeviciute, L and Michaelian, JC and Antonsdottir, IM and Benca, RM and Coulthard, EJ and D'Rozario, AL and Dijk, DJ and Gimenez, S and Gorgoni, M and Leng, Y and Lucey, BP and Pase, MP and Rainey-Smith, SR and Rosenzweig, I and Spira, AP and Winer, JR and Rauchs, G and Naismith, SL and , }, title = {International recommendations for sleep and circadian research in aging and Alzheimer's disease: A Delphi consensus study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70742}, pmid = {41164883}, issn = {1552-5279}, support = {//Alzheimer's Association International Society/ ; //Advance Alzheimer's Research and Treatment/ ; //Sleep and Circadian Rhythms/ ; //PIA membership, ISTAART,/ ; /ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Alzheimer Disease/physiopathology ; Delphi Technique ; *Aging/physiology ; *Circadian Rhythm/physiology ; Consensus ; *Sleep/physiology ; *Sleep Wake Disorders ; *Biomedical Research ; }, abstract = {INTRODUCTION: Research in the field of sleep, aging, and dementia is rapidly growing. Consensus guidance is needed to facilitate high-quality research, comparability, and consistency. METHODS: A modified Delphi consensus study was conducted by the Sleep and Circadian Rhythms Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment (ISTAART) and an international panel of experts to establish recommendations for future research. RESULTS: After two voting rounds, the group (1) determined by consensus the most relevant sleep and circadian features to assess in the context of aging and dementia research, (2) established recommendations on data acquisition and report for future studies, and (3) identified high-priority future directions. DISCUSSION: This expert consensus study provides guidance to develop high-quality sleep and circadian research in the context of aging and dementia. Similar recommendations will need to be established for clinical practice. HIGHLIGHTS: We report the results of an international expert consensus study. Sleep and circadian rhythms features relevant to aging and dementia were identified. Recommendations on data acquisition and reporting were established. High-priority future research directions were identified.}, } @article {pmid41164820, year = {2025}, author = {Summanwar, D and Owora, AH and Ben Miled, Z and Dexter, PR and Kulshreshtha, A and Strunk, S and Jiang, B and Coppedge, K and Disla, S and Galvin, JE and Boustani, M and Fowler, NR}, title = {Prevalence of Multiple Chronic Conditions in Older Adults with Undiagnosed Mild Cognitive Impairment and Alzheimer's Disease and Related Dementias in Primary Care.}, journal = {Clinical interventions in aging}, volume = {20}, number = {}, pages = {1799-1809}, pmid = {41164820}, issn = {1178-1998}, support = {R01 AG069765/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Aged ; *Cognitive Dysfunction/epidemiology/diagnosis ; Male ; Female ; Cross-Sectional Studies ; *Primary Health Care/statistics & numerical data ; *Alzheimer Disease/epidemiology/diagnosis ; Aged, 80 and over ; Prevalence ; *Multiple Chronic Conditions/epidemiology ; Indiana/epidemiology ; Florida/epidemiology ; *Dementia/epidemiology/diagnosis ; }, abstract = {BACKGROUND: Most adults aged ≥65 years live with multiple chronic conditions (MCC), and nearly one in four have recognized or unrecognized Alzheimer's disease and related dementias (ADRD), including an estimated 7.2 million Americans. Together, MCC and ADRD increase treatment complexity, medication burden, and the risk of adverse outcomes. Among patients who meet clinical criteria for mild cognitive impairment (MCI) or ADRD but lack a formal diagnosis, MCC burden remains unclear. This study examined the association between MCC burden and undiagnosed MCI and ADRD in a diverse cohort of older adults in primary care. METHODS: We conducted a cross-sectional analysis of 324 adults aged ≥65 from primary care clinics in Indiana and South Florida (2021-2023), as part of a larger ADRD detection study. Patients without documented MCI or ADRD completed standardized cognitive assessments. Cognitive status (normal, MCI, ADRD) was determined by interdisciplinary consensus. Chronic conditions and medications were extracted from electronic health records. Multinomial logistic regression was used to examine the association between MCC profiles and cognitive status. RESULTS: Among 324 older adults, 51.9% were determined to have MCI and 8% ADRD. Patients with MCI and ADRD had more chronic conditions (mean = 5-6) and medications (mean = 4-5) than those with normal cognition (p < 0.001). Anticholinergic use was more common in the MCI (23.8%) and ADRD (23.1%) groups than in those with normal cognition (10.8%). In adjusted models, MCI and ADRD were associated with higher odds of having more chronic conditions. Cerebrovascular disease was associated with both MCI and ADRD; diabetes, sleep apnea, and insomnia with MCI; and ischemic heart disease and insomnia with ADRD. CONCLUSION: Older adults with unrecognized MCI and ADRD experience substantial MCC and medication burden. These findings highlight the need for targeted primary care interventions that integrate cognitive screening, support MCC management, optimize self-management capacity, and promote safer prescribing.}, } @article {pmid41164318, year = {2025}, author = {Yaghmaei, E and Dillard, A and Rezaei, M and Rezaie, A and Pierce, A and Lu, H and Adams, E and Todorov, N and Ehwerhemuepha, L and Zheng, J and Sajjadi, SA and Bazargan, M and Rakovski, C}, title = {Comprehensive descriptive analysis of large Alzheimer's disease patient cohorts.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251385560}, pmid = {41164318}, issn = {2542-4823}, support = {R25 MD007610/MD/NIMHD NIH HHS/United States ; U54 MD007598/MD/NIMHD NIH HHS/United States ; }, abstract = {BACKGROUND: Precise estimates of the prevalence of Alzheimer's disease (AD), the distribution of demographic characteristics, comorbidities, treatment plans, insurance types, cost of treatment and survival probabilities at various time points are crucially important to advancing our understanding and for improving future AD research studies. OBJECTIVE: We analyzed two of the largest and high-quality medical databases, Oracle EHR Real-World Data and IQVIA. The results provide the most complete description of the AD patients in the US. METHODS: We present high-accuracy summary statistics of many important variables related to AD patients. Proportions, means and 95% confidence intervals were provided for all levels of the categorical and quantitative variables. RESULTS: We report high accuracy estimates of the overall survival probabilities for the first five years after initial diagnosis, drug treatments and patterns of use, demographics, insurance types, hospitalization duration, number of hospital visits, and a detailed list of comorbidities. We also report estimates of the annual total average cost of treatment per patient as well as itemized allocations for drugs, hospitalizations, surgery, and management costs. CONCLUSIONS: We present the most complete, detailed and high-accuracy descriptive analysis of AD patients to date.}, } @article {pmid41164084, year = {2025}, author = {Zhu, L and Cai, M and Lu, Z and Wang, Q and Zhai, T and Hu, J}, title = {The impact of high-intensity interval training on cerebrovascular function in the APP/PS1 mice.}, journal = {Frontiers in aging}, volume = {6}, number = {}, pages = {1647628}, pmid = {41164084}, issn = {2673-6217}, abstract = {ABSTRACT: Alzheimer's disease (AD), the most commonly diagnosed form of senile dementia worldwide, is closely associated with aging and distinct neuropathological features. Recent studies highlight that up to 90% of individuals, either preclinical or clinical, diagnosed with vascular pathology in the context of AD exhibit thickening and hyalinization of the media in small and medium-sized cerebral vessels. Exercise has emerged as a potential, non-pharmaceutical, and cost-effective intervention for the prevention and treatment of AD. However, there is limited research exploring the effects of high-intensity interval training (HIIT) on cerebrovascular function in AD. METHODS: Four-month-old female C57BL/6 J mice and APP/PS1 transgenic mice were initially acclimated to a standard diet for 1 week. The two groups were then divided into sedentary and exercise cohorts, with the exercise group engaging in a 6-week HIIT regimen. Post-intervention, hippocampal specimens were collected for analysis. Aβ and Tau protein levels were measured to assess AD pathology, while cognitive function was evaluated using the eight-arm radial maze and BDNF mRNA expression. Additionally, markers of cerebrovascular function-including VEGF, EPO, eNOS, GPR68, and ET-1-were examined, and HIF-1α was utilized to assess the hippocampal response to AD pathology. RESULTS: HIIT significantly reduced reference memory errors (p = 0.025) and markedly upregulated Bdnf mRNA expression (p < 0.001) specifically in APP/PS1 mice. Furthermore, HIIT significantly decreased protein levels of AD pathological markers p-TAU (p = 0.001) and APP (p = 0.002) in APP/PS1 mice. HIIT significantly increased the mRNA (p < 0.001) and protein (p = 0.003) levels of EPO and Vegfa mRNA (p < 0.001) levels to stimulate pro-angiogenic signal in APP/PS1 mice. HIIT also significantly increased both the mRNA and proteins levels of eNOS expression (p < 0.001) while decreasing the mRNA and proteins levels of ET-1 (p < 0.001) and GPR68 (p < 0.001) to enhance vasodilation in APP/PS1 mice. Finally, HIIT significantly increased HIF-1α expression at both protein and mRNA levels (p < 0.001), independent of genotype. CONCLUSION: HIIT ameliorates cognitive function and reduces hallmark AD pathology. This positive effect is potentially mediated through cerebral microangiogenesis, cerebrovascular function regulation, and hypoxic metabolism. HIIT represents a promising non-pharmacological strategy for targeting multiple aspects of AD pathophysiology.}, } @article {pmid41163934, year = {2025}, author = {Jafari, M and Alipour, M and Zamani, S and Mohtasham Amiri, A and Pourabbas, P and Hasannejad-Bibalan, M}, title = {Probiotics as a Complementary Medicine in Neurologic Disorders.}, journal = {Health science reports}, volume = {8}, number = {11}, pages = {e71422}, pmid = {41163934}, issn = {2398-8835}, abstract = {BACKGROUND AND AIMS: Today, neurological and neuropsychiatric disorders, including depression, anxiety, Parkinson's disease (PD), Alzheimer's disease (AS), autism spectrum disorder (ASD), and multiple sclerosis (MS), contribute significantly to global disability and healthcare burden. Most current treatment options only provide symptomatic relief and are limited by challenges such as drug resistance, systemic side effects, and poor blood-brain barrier permeability. The growing interest in the gut-brain axis has encouraged exploration of the gut microbiota as a potential therapeutic target. Probiotics-live microorganisms that may confer health benefits to the host-have been proposed to modulate the gut-brain axis through immune, metabolic, and neurochemical pathways. METHODS: In this narrative review, a targeted search was performed across multiple databases to identify relevant articles, from which the key relationships and strategies were extracted. Then, we represented the findings to provide a comprehensive overview of the topic and highlight emerging trends and gaps in the literature. RESULTS: Emerging preclinical and clinical studies suggest that specific probiotic strains can improve neurological symptoms by reducing neuroinflammation, supporting gut barrier integrity, and influencing neurotransmitter production. However, findings remain heterogeneous due to strain specificity, individual microbiome diversity, and methodological differences across studies. Preclinical and clinical studies suggest that specific probiotic strains can improve neurological symptoms by reducing neuroinflammation, enhancing gut barrier integrity, and influencing neurotransmitter production. Evidence supports their potential as adjunctive treatments for major neurological and neuropsychiatric disorders, including depression, anxiety, ASD, PD, AD, and MS, particularly in patients with gut dysbiosis or gastrointestinal comorbidities. However, findings remain heterogeneous due to strain specificity, individual microbiome variability, and methodological differences across studies. CONCLUSION: This brief review summarizes the current evidence on the use of probiotics in neurological disorders, discusses potential mechanisms of action, and highlights safety considerations and limitations. Future directions include personalized probiotic therapies, large-scale randomized controlled trials, and integration with conventional neurological therapies. Overall, probiotics could be a low-risk, complementary option in the evolving field of neurotherapy, but more rigorous evidence is needed before definitive clinical recommendations can be made.}, } @article {pmid41163844, year = {2025}, author = {Kurban, B and Sağlık Özkan, BN and Osmaniye, D and Levent, S and Özkay, Y and Kaplancıklı, ZA}, title = {Structure-based design, synthesis, and biological activity evaluation of chalcone-piperazine derivatives as dual AChE and MAO B inhibitors.}, journal = {RSC advances}, volume = {15}, number = {48}, pages = {40897-40911}, pmid = {41163844}, issn = {2046-2069}, abstract = {The development of pharmaceutical compounds for the treatment of Alzheimer's Disease (AD) and other neurodegenerative diseases is crucial, as the pathophysiology of AD remains incompletely understood and effective treatments are still lacking. In this study, a series of novel compounds based on Donepezil, incorporating piperazine and chalcone structures, were designed, synthesized, and characterized. The structures of the compounds were confirmed using IR, [1]H-NMR, [13]C-NMR, and HRMS techniques. Biological activities of the compounds were evaluated against cholinesterase enzymes and monoamine oxidase enzymes. The most potent derivative against acetylcholinesterase (AChE) was compound 4g, with an IC50 value of 0.027 ± 0.001 μM, and the most potent against monoamine oxidase B (MAO B) was also 4g, with an IC50 value of 0.114 ± 0.003 μM. In silico studies further elucidated the interaction of compound 4g with AChE. Molecular docking revealed key interactions between 4g and amino acids in the AChE active site. A 100 ns molecular dynamics simulation confirmed the stability of the 4g-AChE complex.}, } @article {pmid41163274, year = {2025}, author = {Sanghvi, G and Deepak, A and R, R and Ariffin, IA and Kashyap, A and Chahar, M and Nanda, A and Ray, S and Joshi, KK}, title = {Chondroitinase ABC in Neural Regeneration: Advances in CNS and Peripheral Nerve Repair.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128392818251012115510}, pmid = {41163274}, issn = {1873-4286}, abstract = {Chondroitinase ABC (ChABC) is a bacterial enzyme that can potentially address the inhibitory effects of Chondroitin Sulfate Proteoglycans (CSPGs) in various neurological disorders and injuries. CSPGs are key components of the extracellular matrix that, when accumulated after Central Nervous System (CNS) injury or neurodegenerative diseases, inhibit axonal growth and tissue repair. This review explores the therapeutic potential of ChABC in Spinal Cord Injury (SCI), Traumatic Brain Injury (TBI), stroke, Parkinson's Disease (PD), Alzheimer's Disease (AD), and peripheral nerve regeneration. ChABC's mechanism of action involves the degradation of CSPGs, promoting neural plasticity, axonal regeneration, and functional recovery in SCI and other CNS injuries. In stroke and TBI, ChABC treatment has been shown to enhance neurogenesis, reduce glial scar formation, and support neuronal survival. In neurodegenerative conditions like PD and AD, ChABC's ability to modify the inhibitory extracellular environment offers novel strategies for promoting neuronal repair and cognitive function. Additionally, ChABC has been explored in cancer therapy, where its ability to degrade the tumor extracellular matrix facilitates improved drug delivery and tumor infiltration. While ChABC holds promise, challenges remain in its clinical application, particularly regarding stability, targeted delivery, and long-term effects. This review discusses the mechanism of action of ChABC and various delivery strategies, including viral vectors and localized infusion, and emphasizes the need for further research to optimize ChABC's potential. The future of ChABC in regenerative medicine depends on overcoming these barriers, improving delivery methods, and exploring synergistic treatments for enhanced recovery outcomes.}, } @article {pmid41163120, year = {2025}, author = {Juan, Y and Wei, T and Weiwei, Z and Dongdong, S and Mengjie, Z and Xuefeng, W and Xianglong, L and Yuelong, S and Jinhua, Z and Xiumei, L}, title = {Regulation on microbial composition,serotonergic synapse, and apoptotic signaling pathway by extracts fromSonchus brachyotus DC. (SBE) to improve ethanol-induced acute oxidative stress in mice.}, journal = {Microbiome}, volume = {13}, number = {1}, pages = {221}, pmid = {41163120}, issn = {2049-2618}, support = {CAAS-IFR-ZDRW202406//The Agricultural Science and Technology Innovation Program/ ; }, mesh = {Animals ; *Oxidative Stress/drug effects ; Mice ; *Gastrointestinal Microbiome/drug effects ; *Apoptosis/drug effects ; Signal Transduction/drug effects ; *Plant Extracts/pharmacology ; Ethanol/toxicity/adverse effects ; Male ; *Synapses/drug effects/metabolism ; Bacteria/classification/genetics/drug effects/isolation & purification ; Antioxidants/pharmacology ; *Sonchus/chemistry ; RNA, Ribosomal, 16S/genetics ; }, abstract = {BACKGROUND: Oxidative stress has been firmly established as a pivotal contributor to the pathogenesis of inflammatory bowel disease, diabetes mellitus, Alzheimer's disease, and other multifactorial disorders. Our previous findings have demonstrated the extracts from Sonchus brachyotus DC. (SBE) mitigates intestinal oxidative stress through interactions between the oxidative stress biomarkers and gut microbiota. However, we did not focus on the mechanism by which SBE exerts antioxidant stress effects through regulating metabolites and genes, nor the correlation between the two and gut microbiota. Therefore, this study aimed to elucidate the underlying mechanism by which SBE mitigates oxidative stress through the gut microbiota, metabolites, and genes. RESULTS: Supplementation with SBE exerts a promising regulatory effect on oxidative stress by modulating key oxidative stress biomarkers (e.g., GSH, SOD, etc.) in serum, intestine, liver, and brain tissues in ethanol-model mice. And the SBE treatment exhibited a notable reparative effect on intestine, liver, and brain tissue damage. Concomitantly, 16S rRNA and ITS sequencing revealed significant alterations in the composition of intestinal bacteria and fungi in SBE-treated mice, suggesting the restoration of gut microbiota homeostasis. Spearman correlation analysis further indicated significant associations (p < 0.05) between gut microbes, particularly fungal genera, and oxidative stress biomarkers. Notably, the abundance of specific fungal genera (Alternaria and Pichia), the levels of 14,15-DiHETrE, 5-Hydroxyindole-3-acetic acid, and prostaglandin C2 key metabolites of the serotonergic synapse pathway, and the expression of Fas and Tnfsf10 key genes of apoptosis signaling pathway were significantly correlated (p < 0.05) based on the constructed correlation network. This mechanism likely triggers coordinated changes in metabolites and gene expression associated with the serotonergic synapse and apoptosis signaling pathways, ultimately leading to multi-targeted amelioration of oxidative stress. Molecular docking further revealed that trigonelline, mesaconic acid, and salicylic acid, bioactive components of SBE, may exhibit considerable binding affinity with Fas and Tnfsf10, providing a potential structural basis for SBE's regulatory effects on oxidative stress via modulation of the apoptotic signaling. CONCLUSIONS: The antioxidant effects of SBE likely involve multi-pathway and multi-target mechanisms, consistent with the combinatorial properties of its herbs constituents. These findings lays a foundation for subsequent research. Video Abstract.}, } @article {pmid41162940, year = {2025}, author = {Arif, M and Musleh, S and Alam, T}, title = {DeepB[3]Pred: blood-brain barrier peptide predictor using stacked BiGRU model with novel features.}, journal = {BMC biology}, volume = {23}, number = {1}, pages = {325}, pmid = {41162940}, issn = {1741-7007}, mesh = {*Blood-Brain Barrier/metabolism ; *Deep Learning ; *Computational Biology/methods ; *Cell-Penetrating Peptides/chemistry ; *Peptides/chemistry ; }, abstract = {BACKGROUND: The blood-brain barrier (B[3]) acts as a membrane that is a major concern in treating central nervous system (CNS) disorders. The B[3] penetrating peptides (B[3]PPs) play a significant role in delivering therapeutic drugs to a wide range of disorder diseases such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Therefore, the correct identification of drug agents is important for the disease treatment. Generally, the computational methods are more cost effective and faster than conventional wet-lab methods in predicting B[3]PPs. Consequently, we have developed a novel deep learning-based predictor called DeepB[3]Pred that accurately predicts the B[3]PPs and non-B[3]PPs from sequence data. RESULTS: In the proposed method, we used three types of novel features namely Pseduo residue energy content matric (PseRECM), graphical and statistical-based feature engineering (GSFE), and composition-transition and distribution (CTD)-based features. These features capture the energy-, graphical-, and compositional-based properties of from the primary peptide sequences. The data skewness is recognized as an inevitable issue that was tackled by employing a random under sampling technique. The extracted data were fed into various deep learning, i.e., stacked bidirectional gated recurrent unit (BiGRU), Deep Forest, and machine learning models, i.e., CatBoost, Support Vector Machine. BiGRU-based DeepB[3]Pred model attained better results than the other state-of-the-art B[3]PPs predictors. The prediction efficacy of the proposed model on fivefold cross-validation in terms of accuracy is 0.945, MCC of 0.877, and area under the curve (AUC) of 0.965. The generalization performance on the unseen data is reported as 0.869 for accuracy, 0.635 for MCC, and 0.933 for AUC. CONCLUSION: We believe our research will accelerate the peptide-based drug discovery for neurological diseases in particular.}, } @article {pmid41161455, year = {2025}, author = {Ishaq, K and Arputharaj, E and Khan, MB and Dahms, HU and Delattre, C and Chao, YY and Huang, YL}, title = {Turning an adversary into an ally: Self-assembled amyloid-like fibril aerogel packed 3D-printed microfluidic sample pre-treatment device for elemental analysis.}, journal = {International journal of biological macromolecules}, volume = {332}, number = {Pt 1}, pages = {148590}, doi = {10.1016/j.ijbiomac.2025.148590}, pmid = {41161455}, issn = {1879-0003}, mesh = {*Printing, Three-Dimensional ; *Amyloid/chemistry ; Gels/chemistry ; Muramidase/chemistry ; *Lab-On-A-Chip Devices ; Polyethyleneimine/chemistry ; Graphite/chemistry ; Limit of Detection ; Humans ; Nitrogen Compounds ; }, abstract = {In this study, we transformed well-known disease-causing amyloid fibrils into a functional ally. Instead of using Alzheimer's disease associated amyloid-beta fibrils we employed synthetic lysozyme derived amyloid-like fibrillar aggregates. We developed a simple and effective method for enriching and detecting various toxic elements in complex serum samples. This method employs a reusable 3D-printed microfluidic sample pre-treatment device, packed with a bio-based aerogel elemental ion extractant composed of self-assembled amyloid-like lysozyme fibrillar aggregates (AF), graphitic carbon nitride nanosheets (g-C3N4 NSs), and polyethyleneimine (PEI). The developed setup is integrated with inductively coupled plasma mass spectrometry (ICP-MS), enabling accurate elemental analysis without interference from the sample matrix. The synthesized elemental ion extractant aerogel is rich in diverse functional groups, significantly enhances the element extraction efficiency compared to conventional toxic element sorbents lacking structured amyloid-like networks. The established method yielded significant detection limits ranging from 1 to 100 μg L[-1] for Ag[+], Cr[3+] and Se IV over other elements with relative standard deviations (RSDs) between 2.1 and 4.6 %. Specifically, the approach achieved a limit of detection (LOD) of 0.2 μg L[-][1] for Cr, 0.4 μg L[-][1] for Se, and 1.1 μg L[-][1] for Ag. High recovery rates ranging from 85 to 102 % were achieved in spiked complex serum matrices. Moreover, the proposed multifunctional 3D-printed microfluidic approach significantly enhanced the selective extraction and detection of toxic elements in complex serum samples, demonstrating robust performance over seven adsorption-desorption cycles and representing a sustainable and significant analytical advancement.}, } @article {pmid41161293, year = {2025}, author = {Sahoo, SS and Paidesetty, SK and Sahu, PK and Pattanaik, S and Dandela, R}, title = {Therapeutic innovation through drug repurposing: A multidimensional approach toward treating Parkinson's disease.}, journal = {Bioorganic chemistry}, volume = {166}, number = {}, pages = {109129}, doi = {10.1016/j.bioorg.2025.109129}, pmid = {41161293}, issn = {1090-2120}, mesh = {Animals ; Humans ; *Antiparkinson Agents/chemistry/therapeutic use/pharmacology ; *Drug Repositioning ; Molecular Structure ; *Neuroprotective Agents/chemistry/therapeutic use/pharmacology ; *Parkinson Disease/drug therapy ; Rifaximin/chemistry/pharmacology ; }, abstract = {Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease, primarily affecting the aging population. Despite the introduction of levodopa in the 1960s and significant progress in managing PD symptoms, no treatment has yet demonstrated neuroprotective efficacy. The complexity and multifactorial nature of PD continue to present substantial therapeutic challenges, prompting researchers to explore alternative approaches such as drug repurposing. This strategy offers a time- and cost-efficient route to drug development. Recent efforts have focused on repurposing agents originally developed for metabolic and other non-neurological disorders. Ongoing research is actively investigating several repurposed drugs originally intended for different conditions, including anti-hypertensives (isradipine, dexmedetomidine), anti-asthmatics (montelukast), phosphodiesterase5 inhibitors (sildenafil), antimicrobials (rifaximin), and various CNS-active agents (aripiprazole, escitalopram, paroxetine, venlafaxine, duloxetine, caffeine). While drug repurposing holds considerable promise, comprehensive preclinical and clinical studies are essential to validate these candidates for PD-specific therapeutic applications. This review aims to provide an in-depth overview of PD, encompassing its pathological and molecular characteristics, and to critically evaluate the current landscape of drug repurposing strategies to develop effective therapies for PD.}, } @article {pmid41160917, year = {2025}, author = {Rößler, H and Hamzehpour, L and Grimm, O}, title = {Transdiagnostic neuroanatomical risk in schizophrenia: integrating regional vulnerability indices with anthropometric and fitness-based markers of cardiometabolic health.}, journal = {NeuroImage. Clinical}, volume = {48}, number = {}, pages = {103897}, pmid = {41160917}, issn = {2213-1582}, mesh = {Humans ; *Schizophrenia/diagnostic imaging/physiopathology/pathology/epidemiology ; Male ; Female ; Middle Aged ; Adult ; Magnetic Resonance Imaging ; *Physical Fitness/physiology ; Anthropometry ; Hand Strength/physiology ; *Cardiorespiratory Fitness/physiology ; Neuroimaging/methods ; }, abstract = {Schizophrenia is a multisystem disorder affecting both brain and body, with patients exhibiting substantial somatic comorbidities including obesity, reduced physical fitness, and elevated cardiometabolic risk. While neuroimaging-derived Regional Vulnerability Indices (RVIs) have quantified brain structural deviations from disorder-specific patterns, their relationship to physical health in schizophrenia remains largely unexplored. In this study, we combined RVIs with detailed anthropometric and fitness assessments in 42 schizophrenia patients and 43 matched healthy controls. Participants underwent MRI-based cortical thickness analyses to derive RVIs for nine psychiatric, neurological, and metabolic disorders, alongside measurements of body composition, cardiorespiratory fitness, handgrip strength, and jump performance. Patients exhibited significantly higher RVIs for schizophrenia (Cohen's D = -1.1), bipolar disorder (Cohen's D = -0.9), Alzheimer's (Cohen's D = -0.6) and Parkinson's disease (Cohen's D = -0.7), and type 2 diabetes (Cohen's D = -0.9). These overlapping neuroanatomical vulnerabilities across psychiatric, neurodegenerative, and metabolic conditions might reflect shared underlying genetic and physiological mechanisms. Principal component analysis revealed three latent dimensions: (1) general risk factors, (2) physical fitness deficits, and (3) psychosis-spectrum vulnerability, with the latter two showing significant differences between groups. These findings highlight that metabolic impairment and reduced physical fitness in schizophrenia are not merely secondary phenomena but constitute distinct dimensions of systemic vulnerability. Overall, our results support a brain-body conceptualization of schizophrenia, suggesting that RVIs may serve as biomarkers to guide precision medicine interventions integrating neuroprotective strategies with lifestyle management. Future research should incorporate longitudinal and multimodal assessments to clarify causal relationships and optimize individualized treatment approaches.}, } @article {pmid41160464, year = {2026}, author = {Kim, M and Kwon, H and Sohn, S and Lee, WJ and Cho, K and Kim, GW}, title = {Alzheimer's disease diagnosis and treatment: From pathophysiological insights to therapeutic advances in the era of precision neurology (2025 review).}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {1}, pages = {17-33}, doi = {10.1177/13872877251391820}, pmid = {41160464}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/physiopathology ; *Precision Medicine/methods/trends ; Biomarkers/cerebrospinal fluid ; Neuroimaging ; *Neurology/trends/methods ; Artificial Intelligence ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder marked by progressive cognitive decline, functional impairment, and ultimately, loss of independence. Traditional models centered on amyloid-β and tau pathology have expanded to encompass interconnected processes such as neuroinflammation, synaptic dysfunction, and gut-brain axis disruption, underscoring the multifactorial nature of the disease. In this review, we delivered that advances in diagnosis now integrate fluid biomarkers within the A/T/N/X framework, high-resolution neuroimaging, and artificial intelligence, enabling earlier and more precise disease characterization. On the therapeutic front, the approval of anti-amyloid monoclonal antibodies marks a paradigm shift toward disease-modifying approaches, yet challenges remain regarding efficacy, safety, and accessibility. Complementary strategies, including cognitive interventions and innovative drug delivery systems, highlight the need for multidimensional care that extends beyond pharmacology to improve patient quality of life. Furthermore, emerging avenues such as stem cell therapy, multitarget drug development, and precision medicine approaches illustrate a field in transition-shifting from symptomatic management toward personalized strategies aimed at altering the course of AD.}, } @article {pmid41160460, year = {2025}, author = {Cury, RM and da Silva, T and Cezar-Dos-Santos, F and Fakih, YRC and Narvaez, KAR and Gouvea, MC and Espínola, C and Ferreira, CF and de Castro, WAC and Pamplona, FA and Silva, EGD and Bicca, MA and Nascimento, FP}, title = {A randomized clinical trial of low-dose cannabis extract in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1602-1613}, doi = {10.1177/13872877251389608}, pmid = {41160460}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Double-Blind Method ; Male ; Female ; Aged, 80 and over ; Aged ; *Dronabinol/therapeutic use/administration & dosage ; *Plant Extracts/therapeutic use/administration & dosage ; Middle Aged ; Treatment Outcome ; *Cannabidiol/therapeutic use/administration & dosage ; Mental Status and Dementia Tests ; *Cannabis ; }, abstract = {BackgroundPreclinical and clinical evidence suggest that low-dose cannabinoids could ameliorate Alzheimer's disease (AD) signs and symptoms. We designed this trial to evaluate the safety and efficacy of low-dose THC-CBD balanced cannabinoid extract in the treatment of patients with AD-associated dementia.ObjectiveThe objective of this phase 2 trial was to evaluate the safety and efficacy of a balanced THC-CBD cannabinoid extract for symptomatic patients with AD.MethodsA Phase 2, randomized, double-blind, placebo-controlled, clinical trial including patients between 60 and 80 years-old diagnosed with AD-associated dementia. For 26 weeks, participants orally received either placebo or THC-CBD extract (0.350 mg/THC and 0.245 mg/CBD), daily.ResultsAt week 26, Mini-Mental State Exam total score was significantly higher in cannabis- when compared to placebo-treated patients, which was assessed using the mixed model analysis. No significant difference was detected between placebo and cannabis groups in terms of secondary outcomes and adverse events incidence.ConclusionsTo this date, this is the longest clinical trial evaluating cannabinoids effects on AD patients. We initially demonstrate that low-dose THC-CBD potentially can be an effective and safe therapeutic option for AD-related dementia. Nonetheless, larger and longer trials are necessary to confirm this finding and establish cannabinoid administration as therapy for AD dementia.Trial RegistrationThe Brazilian Registry of Clinical Trials (ReBEC) registration #U1111-1258-2058 - REBEC (ensaiosclinicos.gov.br).}, } @article {pmid41160443, year = {2025}, author = {Lim, MJ and Cheung, CY and Chong, JR and Chua, J and Hilal, S and Lai, MK and Maier, AB and Schmetterer, L and Tan, BY and Venketasubramanian, N and Wong, TY and Xu, X and Yeo, BT and Zhou, JH and Chen, CL}, title = {HARMONISATION - A multimodal prospective study of vascular cognitive impairment in multi-ethnic Asians: Cohort profile, progress, current contributions, and future impact.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1452-1474}, doi = {10.1177/13872877251389006}, pmid = {41160443}, issn = {1875-8908}, mesh = {Aged ; Female ; Humans ; Male ; Asian People/ethnology ; Biomarkers ; *Cerebrovascular Disorders/complications ; *Cognitive Dysfunction/ethnology/diagnostic imaging ; Cohort Studies ; *Dementia, Vascular/ethnology ; Prospective Studies ; Observational Studies as Topic ; Middle Aged ; Aged, 80 and over ; }, abstract = {Vascular cognitive impairment (VCI) describes cerebrovascular disease (CeVD)-associated cognitive disorders regardless of pathogenesis, ranging from a prodrome to dementia. Heterogeneity in the etiology and severity of CeVD, and significant co-occurrence with Alzheimer's disease (AD) pathology has hampered investigations. Research into VCI is especially relevant in Asia, where cognitive impairment and dementia, often due to VCI, grows due to rapidly aging populations and high prevalence of vascular risk factors. This manuscript reviewed the rationale, unique positioning, design, methodology, and findings from the HARMONISATION study, a prospective observational study of VCI and AD in multi-ethnic Asians. HARMONISATION aimed to discover and validate novel biomarkers as effective diagnostic and prognostic tools, and translate findings into improved patient care, disease management and treatment-utilizing comprehensive multimodal clinical, neuroimaging, retinal, and blood biomarker data to address critical research gaps such as the etiology and clinical importance of mixed dementia, relationships between AD and CeVD pathology, and challenges of heterogenous CeVD pathology. HARMONIZATION recruited and deeply phenotyped 700 older multi-ethnic Asians with no cognitive impairment, mild cognitive impairment, and dementia for up to 5 years of follow-up. It has yielded developments in biomarker identification, validation, interactions and analysis methods; disease mechanisms and progression; clinical prognostics for VCI and AD; improved patient care and management; and enabled future development of novel interventions in Asians, and globally. An ongoing extension study will allow up to 10 years follow-up to further explore specific modifiable processes of VCI and the contributions of vascular events to cognitive impairment.}, } @article {pmid41160347, year = {2025}, author = {Brixner, DI and Zhao, C and Toyosaki, H and Frech, FH and Rosenbloom, MH}, title = {Initial Real-World Evidence for Lecanemab in the United States.}, journal = {Drugs & aging}, volume = {}, number = {}, pages = {}, pmid = {41160347}, issn = {1179-1969}, abstract = {BACKGROUND: Lecanemab is the first anti-amyloid monoclonal antibody with full approval in the US for the treatment of early Alzheimer's disease (AD). This observational study aimed to provide information about patient demographics, clinical characteristics, provider specialty, and lecanemab utilization patterns. METHODS: This observational study used open administrative claims from the PurpleLab, a database encompassing medical and pharmacy claims derived from diverse sources, such as clearinghouses and Pharmacies. We included patients receiving one or more lecanemab doses between January 6, 2023 and October 31, 2024, and having continuous clinical activity ≥ 6 months prior to the first lecanemab infusion. The observation period ran from the first lecanemab infusion to the latest clinical activity or data availability. Treatment gaps were calculated as the number of gap days in lecanemab supply between consecutive infusions. RESULTS: Among the study population (n = 4261), mean age was 75.2 years, 77.8% were White, 98.4% lived in urban settings, 81.7% were treated by neurologists, 77.3% had AD, and 31.7% had mild cognitive impairment. Mean follow-up period was 171.1 days. Lecanemab infusions averaged 1.9 per patient per month (SD 1.0), 16.3 days apart (SD 11.0), and 2.8% of patients experienced a treatment interruption ≥90 days. CONCLUSIONS: Lecanemab utilization followed US FDA-approved prescribing information. Disparities for minority and rural-based populations were observed suggesting opportunities to improve access for underserved populations.}, } @article {pmid41160319, year = {2025}, author = {Sarikamis Johnson, B and Ercin, N and Kalkan Cakmak, R and Besli, N and Beker, M and Beker, MC and Celik, U}, title = {Exploring the effects of squalene in the PERK/ATF4/eIF2α/CHOP signalling pathway in an in vitro Alzheimer Disease model and in silico approach.}, journal = {Metabolic brain disease}, volume = {40}, number = {8}, pages = {300}, pmid = {41160319}, issn = {1573-7365}, support = {123Z925//Scientific and Technological Research Council of Türkiye/ ; 2021-067//University of Health Sciences, Türkiye/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; Activating Transcription Factor 4/metabolism ; eIF-2 Kinase/metabolism ; *Signal Transduction/drug effects ; Eukaryotic Initiation Factor-2/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Transcription Factor CHOP/metabolism ; *Squalene/pharmacology/therapeutic use ; Unfolded Protein Response/drug effects ; Reactive Oxygen Species/metabolism ; Molecular Docking Simulation ; Amyloid beta-Peptides ; Oxidative Stress/drug effects ; Mesenchymal Stem Cells/drug effects/metabolism ; Cells, Cultured ; Peptide Fragments ; }, abstract = {Recent studies emphasize the pivotal role of endoplasmic reticulum (ER) stress in Alzheimer's disease (AD), highlighting the need for further investigation into this critical link. In response to ER stress, cells increase reactive oxygen species (ROS) production, leading to heightened oxidative stress. This interplay has sparked interest in antioxidant molecules such as squalene (SQ) as potential therapeutic agents. The primary objective of this study was to examine the impact of SQ on the unfolded protein response (UPR) pathway triggered by ER stress in an in vitro AD model. Herein, molecular docking analysis was performed to evaluate SQ interactions with target proteins, followed by in vitro assays. Human bone marrow-derived mesenchymal stem cells were differentiated into neuronal-like cells and characterized via immunostaining. The cells were then exposed to Aβ1-42 toxicity to establish an in vitro AD model. To assess the effects of SQ treatment following Aβ1-42 exposure, UPR-related proteins (BIP, p-PERK, PERK, eIF2α, p-eIF2α, ATF4, CHOP) were analysed by Western blotting; ROS levels were quantified to evaluate oxidative stress, and a TUNEL assay was performed to assess apoptosis. Our findings indicate that SQ alters protein expression within the UPR pathway in the AD experimental model. Notably, amyloid-β levels were significantly reduced in the SQ-treated group (p˂0.001). Furthermore, SQ reduced ROS levels. These results suggest that SQ holds potential as a therapeutic agent for mitigating amyloid-β toxicity.}, } @article {pmid41160288, year = {2025}, author = {Motamedzadeh, A and Karimzad, Y and Ferdosi, F and Nabavizadeh, F and Rahmati-Dehkordi, F and Dadgostar, E and Aschner, M and Validad, A and Kazemi, B and Tamtaji, OR}, title = {Potential of Benfotiamine in the treatment of neuropsychological disorders.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {26}, pmid = {41160288}, issn = {1573-4978}, mesh = {Humans ; *Thiamine/analogs & derivatives/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Mental Disorders/drug therapy/metabolism ; Signal Transduction/drug effects ; Thiamine Deficiency/drug therapy/metabolism ; }, abstract = {Neuropsychiatric disorders pose significant health challenges. Current drug therapies are often inadequate, highlighting the urgent need for new and effective treatments. Thiamine deficiency has been implicated in the pathophysiology of various neuropsychiatric disorders. In this context, benfotiamine, a synthetic thiamine derivative, has gained increasing attention for its potential therapeutic effects across a range of neuropsychiatric conditions. Emerging evidence supports the neuroprotective effects of benfotiamine, which are mediated through its modulation of diverse cellular and molecular pathways, i.e., Tau phosphorylation, amyloid β, oxidative stress, neuroinflammation, as well as synaptic plasticity via the glycogen synthase kinase-3β (GSK3β) signaling pathway. In this narrative review, we provide a comprehensive overview of the cellular and molecular pathways modulated by benfotiamine in the context of neuropsychiatric disorders. Specifically, we highlight its effects on oxidative stress, inflammatory signaling, mitochondrial function, glucose metabolism, and advanced glycation end-product (AGE) formation, all of which contribute to its neuroprotective and potentially therapeutic properties.}, } @article {pmid41158654, year = {2025}, author = {Chiba, T and Hattori, Y and Asakura, K and Sano, Y and Saito, S and Minami, M and Yamamoto, H and Ihara, M}, title = {Taxifolin for prevention of COGnitive impairment (T-COG trial): a study protocol for a randomized, double-blind, placebo-controlled trial.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1686381}, pmid = {41158654}, issn = {2296-861X}, abstract = {BACKGROUND: In 2023 and 2024, the novel anti-β-amyloid antibodies lecanemab and donanemab have been approved for treatment of mild cognitive impairment and mild dementia in several countries, including Japan and the United States. Although they successfully eliminate accumulated β-amyloid, they merely delay cognitive deterioration and do not improve cognitive function. This suggests that β-amyloid elimination is insufficient for cognitive improvement. Therefore, novel treatments with pleiotropic neuroprotective effects are warranted. Taxifolin, a bioactive flavonoid, shows pleiotropic effects, such as inhibition of amyloid-β aggregation and oligomerization and hippocampal neuroinflammation, as well as stimulation of brain lymphatic vessel formation in our previous experimental studies. Furthermore, our preliminary observational study showed that oral administration of taxifolin was associated with cognitive improvement in patients with mild cognitive impairment or mild dementia. METHODS: This is a randomized, double-blind, placebo-controlled, crossover trial involving 60 patients with mild cognitive impairment or mild dementia. All participants will take 100-mg taxifolin or placebo capsules orally once daily for 12 weeks. The washout period will be 6 weeks. The primary objective is to determine the effect of taxifolin on cognitive impairment using the Montreal Cognitive Assessment. The main secondary objectives are to evaluate the impact of taxifolin on (i) prevention further cognitive decline, as evaluated by changes in the scores for total Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 and trail making test and (ii) changes in white matter hyperintensity volume and number of cerebral microbleeds on brain magnetic resonance imaging. DISCUSSION: This T-COG trial may provide valuable insights into new therapeutic approaches, considering that taxifolin has multitarget neuroprotection, which could prevent further cognitive decline, along with its highly safe profile and inexpensive cost. CLINICAL TRIAL REGISTRATION: https://jrct.mhlw.go.jp, jRCTs051250004.}, } @article {pmid41157961, year = {2025}, author = {Cruz-Aguilar, MA and Hernández-Arteaga, E and Ramírez-Salado, I and Hernández-González, M and Guevara, MA}, title = {Melatonin reorganizes the sleep EEG spectral power in Alzheimer's disease: a preliminary principal component analysis-based comparison of placebo and treatment effects.}, journal = {Neurological research}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/01616412.2025.2578344}, pmid = {41157961}, issn = {1743-1328}, abstract = {OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaque accumulation, tau pathology, and cortical atrophy, leading to widespread synaptic dysfunction and cognitive decline. Sleep disturbances are highly prevalent in AD and are thought to both reflect and exacerbate underlying neurodegenerative processes. Melatonin, an indoleamine synthesized by the pineal gland, is central to the regulation of circadian rhythms and sleep - wake cycles. In healthy individuals, melatonin enhances non-rapid eye movement (NREM) sleep and attenuates beta activity during wakefulness. In AD populations, it has been associated with improved sleep quality and potential neuroprotective effects against amyloid-related pathology. Electroencephalography (EEG) offers a non-invasive method to monitor neurophysiological changes associated with AD. Principal component analysis (PCA), a dimensionality reduction technique, enables the identification of latent neural patterns within complex EEG data. METHODS: In this preliminary study, PCA was applied to EEG recordings from eight individuals with mild-to-moderate AD during both wakefulness and sleep under placebo and melatonin conditions. EEG derivations included bipolar (F7-T3, F8-T4, F3-F4, O1-O2) and referential (C3-A1, C4-A2) configurations. RESULTS: Preliminary PCA suggests that melatonin administration may induce a stage-dependent reorganization of EEG spectral activity, characterized by a relative enhancement of slow-frequency activity and an apparent increase in spectral segregation during NREM sleep. DISCUSSION: These preliminary findings suggest that melatonin could optimize stage-specific neural dynamics, supporting its therapeutic potential in AD-related sleep disruption.}, } @article {pmid41156471, year = {2025}, author = {Zhang, J and Zhang, J}, title = {Natural Small-Molecule Bergapten Ameliorates Amyloid-β Pathology and Neuroinflammation in Alzheimer's Disease.}, journal = {Nutrients}, volume = {17}, number = {20}, pages = {}, pmid = {41156471}, issn = {2072-6643}, support = {2022QH2300//Fujian Medical University/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Amyloid beta-Peptides/metabolism ; Microglia/drug effects/metabolism ; Molecular Docking Simulation ; *Neuroinflammatory Diseases/drug therapy ; Disease Models, Animal ; Male ; Maze Learning/drug effects ; MAP Kinase Signaling System/drug effects ; Memory/drug effects ; *Anti-Inflammatory Agents/pharmacology ; }, abstract = {BACKGROUND: The pathogenesis of Alzheimer's disease (AD) is complex, and effective treatments remain elusive. Growing evidence suggests that dietary factors may play a significant role in preventing or alleviating AD. Bergapten (BG), a natural compound with anti-inflammatory properties, has been studied; however, its specific role in neuroinflammation and AD pathogenesis remains unclear. METHODS: Through public databases and bioinformatics tools, the possible molecular mechanisms of BG's effects on AD were analyzed. Six-month-old 5×FAD mice underwent intragastric administration of BG for 30 consecutive days. Learning and memory abilities were assessed using the novel object recognition (NOR) test and the Morris water maze (MWM) test. Immunofluorescence staining, Western blot and q-PCR was conducted to assess the underlying mechanisms. In vitro experiments used Aβ-stimulated BV2 microglial cells for BG intervention. RESULTS: Bioinformatics analysis revealed the MAPK signaling pathway as the top-ranked pathway. Molecular docking studies further demonstrated strong binding interactions between BG and key proteins within the MAPK pathway. In behavioral studies, NOR test and MWM test demonstrated that BG treatment improved learning and memory abilities in 5×FAD mice. Additionally, BG treatment significantly reduced Aβ deposition, pro-inflammatory cytokine levels, and inhibited excessive microglial activation in these mice. Consistent with in vivo findings, BG effectively decreased pro-inflammatory cytokines in Aβ-stimulated BV2 microglial cells. Mechanistic studies revealed that BG attenuates neuroinflammatory responses by inhibiting the MAPK signaling pathway both in vivo and in vitro. CONCLUSIONS: Our findings suggest that BG mitigates AD pathological features by suppressing MAPK-mediated neuroinflammation and represents a promising natural small molecule for the prevention and treatment of AD.}, } @article {pmid41155570, year = {2025}, author = {Atanasova, M}, title = {Small-Molecule Inhibitors of Amyloid Beta: Insights from Molecular Dynamics-Part B: Natural Compounds.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {10}, pages = {}, pmid = {41155570}, issn = {1424-8247}, support = {Grant No BG16RFPR002-1.014-0018//the Centre of Excellence in Informatics and ICT funded by the Research, Innovation and Digitalization for Smart Transformation Programme 2021-2027 and co-financed by the European Union/ ; agreement D01-98/26.06.2025//the National Road Map/ ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive decline. Its key pathological hallmarks include extracellular amyloid plaques composed of amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. Although numerous studies have investigated the complex pathology of AD, its underlying mechanisms remain incompletely understood. The amyloid cascade hypothesis continues to be the leading model of AD pathogenesis. It suggests that Aβ aggregation is the initial trigger of neurotoxicity, setting off a cascade of pathological events including inflammation, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, and, ultimately, dementia. Molecular dynamics (MD) is a powerful tool in structure-based drug design (SBDD). By simulating biomolecular motions at the atomic level, MD provides unique insights into molecular properties, functions, and inhibition mechanisms-insights often inaccessible through other experimental or computational techniques. When integrated with experimental data, MD further deepens our understanding of molecular interactions and biological processes. Natural compounds, known for their pleiotropic pharmacological activities, favorable safety profiles, and general tolerability (despite occasional side effects), are increasingly explored for their potential in both the treatment and prevention of various diseases, including AD. In this review, we summarize current findings from MD simulations of natural compounds with anti-amyloidogenic potential. This work builds upon our previous publication, which focused on endogenous compounds and repurposed drugs. The review is structured as follows: an overview of the amyloid cascade hypothesis; a discussion of Aβ oligomeric structures and their stabilizing interactions; a section on molecular dynamics, including its challenges and future directions; and a comprehensive analysis of the inhibitory mechanisms of natural compounds, categorized by their shared structural features.}, } @article {pmid41155541, year = {2025}, author = {Perez, DM}, title = {α1A-Adrenergic Receptor as a Target for Neurocognition: Cautionary Tale from Nicergoline and Quinazoline Non-Selective Blockers.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {10}, pages = {}, pmid = {41155541}, issn = {1424-8247}, support = {R01 AG066627/AG/NIA NIH HHS/United States ; RO1AG066627/GF/NIH HHS/United States ; }, abstract = {Decades ago, previous studies that used non-selective ergot derivatives suggested that blockage of the α1A-adrenergic receptor mildly increased cognition through increased blood flow to the brain due to vasodilation and, thus, could be used as a treatment for dementia. However, further studies indicated that nicergoline was non-specific and hit many different targets. Today, a similar scenario is developing with the use of non-selective α1-AR antagonists of the quinazoline class, referred to as "osins", as potential treatments for COVID-19/SARS, post-traumatic stress disorder, cancer, and neurodegenerative disorders, such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. While there is extensive evidence of neuroprotection from many clinical trials, the mechanism of action of quinazolines is often not α1-AR-mediated but keyed to its glycolysis-enhancing effects through activation of the enzyme phosphoglycerate kinase 1 (PGK1). These studies have incorrectly labeled the α1A-adrenergic receptor as an "old target" to treat Alzheimer's and other neurocognitive diseases, hampering drug development. This review will summarize these and other studies to indicate that activation, not blockage, of norepinephrine's actions, through α1A-AR, mediates cognitive, memory, and neuroprotective functions that may reverse the progression of neurocognitive diseases.}, } @article {pmid41155525, year = {2025}, author = {Lin, GB and Liu, HH and Kuo, YY and Chen, YM and Hsu, FT and Wang, YW and Kung, Y and Ching, C and Chao, CY}, title = {Thermal Cycling Stimulation via Nasal Inhalation Attenuates Aβ25-35-Induced Cognitive Deficits in C57BL/6 Mice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155525}, issn = {1422-0067}, support = {NSTC 113-2112-M-002-024//National Science and Technology Council/ ; NSTC 112-2112-M-002-033//National Science and Technology Council/ ; MOST 110-2112-M-002-004//Ministry of Science and Technology/ ; }, mesh = {Animals ; *Amyloid beta-Peptides/metabolism/toxicity ; Mice ; Mice, Inbred C57BL ; *Cognitive Dysfunction/therapy/metabolism/chemically induced ; Male ; *Peptide Fragments/toxicity ; Hippocampus/metabolism ; Disease Models, Animal ; Alzheimer Disease/therapy/metabolism ; *Hyperthermia, Induced/methods ; Administration, Inhalation ; Maze Learning ; }, abstract = {Alzheimer's disease (AD) remains a significant public health challenge, with current treatments limited partly due to the difficulty of delivering therapeutics across the blood-brain barrier (BBB). The nose-to-brain (N-2-B) pathway offers a promising alternative to circumvent the BBB, but no drugs have yet been clinically applied via this route for AD. Mild stress is thought to activate intrinsic protective mechanisms against neurodegeneration, but traditional methods lack specificity and practicality. To address this, we propose the inhalation of mildly heated air as thermal stimulation, which utilizes the N-2-B pathway to induce mild stress and stimulate cerebral activity. This study employs thermal cycling-hyperthermia (TC-HT) in developing thermal cycling-stimulation via nasal inhalation (TCSNI), providing cyclic stimulation to maintain pathway activity while minimizing thermal injury. In C57BL/6 mice, TCSNI showed no adverse olfactory effects. In β-amyloid (Aβ)-treated mice, TCSNI significantly enhanced cognitive performance in Y-maze and novel object recognition (NOR) assessments, suggesting cognitive improvement. Mice hippocampal protein analyses indicated a reduction in Aβ accumulation, alongside increased expression of heat shock protein 70 (HSP70), insulin-degrading enzyme (IDE), and phosphorylated Akt (p-Akt). These results suggest that N-2-B-delivered TCSNI effectively modulates protein expression and enhances cognitive function, highlighting its potential for further exploration in AD treatment.}, } @article {pmid41155356, year = {2025}, author = {Trifonova, EA and Pashchenko, AA and Ivanov, RA and Kochetov, AV and Lashin, SA}, title = {Genetic and Pathogenic Overlaps Between Autism Spectrum Disorder and Alzheimer's Disease: Evolutionary Features and Opportunities for Drug Repurposing.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155356}, issn = {1422-0067}, mesh = {*Autism Spectrum Disorder/genetics/drug therapy ; Humans ; *Alzheimer Disease/genetics/drug therapy/metabolism ; *Drug Repositioning ; Gene Regulatory Networks ; TOR Serine-Threonine Kinases/metabolism/genetics ; Genetic Predisposition to Disease ; Evolution, Molecular ; Signal Transduction ; }, abstract = {Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are neurodevelopmental and neurodegenerative disorders, respectively. While exome sequencing is routinely employed during the early stages of ASD diagnosis, it rarely influences therapeutic strategies. To address this gap, we have reconstructed and analyzed the gene networks linking autism spectrum disorders, Alzheimer's disease, and mTOR signaling. In addition, we have performed a phylostratigraphic analysis that reveals similarities and differences in the evolution of both ASD and Alzheimer's disease predisposition genes. We have shown that almost half of the genes predisposing to autism and two-fifths of the genes predisposing to Alzheimer's disease are directly related to the mTOR signaling pathway. Analysis of Phylostratigraphic Age Index (PAI) value distributions revealed a significant enrichment of evolutionarily ancient genes in both ASD- and AD-related gene sets. When studying the distribution of ASD predisposition genes by Divergence Index (DI) values, a significant enrichment with genes having extremely low DI = 0 has been found. Such low DI values indicate that most likely these genes are under stabilizing selection. Using the ANDVisio tool, both pharmacological and natural mTOR regulators with potential for ASD treatment were selected, such as propofol, dexamethasone, celecoxib, statins, berberine, resveratrol, quercetin, myricetin, mio-inositol, and several amino acids.}, } @article {pmid41155218, year = {2025}, author = {Lee, J and Lee, E and Kwon, H and Moon, S and Bae, HJ and Hwang, JH and Cho, GH and Kong, H and Park, MH and Kim, SK and Kim, DH and Jung, JW}, title = {Synaptic Plasticity-Enhancing and Cognitive-Improving Effects of Standardized Ethanol Extract of Perilla frutescens var. acuta in a Scopolamine-Induced Mouse Model.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155218}, issn = {1422-0067}, support = {S3400191//Ministry of SMEs and Startups/ ; }, mesh = {Animals ; Scopolamine/toxicity ; Mice ; Male ; *Plant Extracts/pharmacology/chemistry ; *Perilla frutescens/chemistry ; *Neuronal Plasticity/drug effects ; Disease Models, Animal ; Mice, Inbred ICR ; Hippocampus/drug effects/metabolism ; Long-Term Potentiation/drug effects ; Ethanol/chemistry ; *Cognition/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism ; *Cognitive Dysfunction/drug therapy/chemically induced ; Maze Learning/drug effects ; }, abstract = {In our previous study, we demonstrated that a standardized ethanol extract of Perilla frutescens var. acuta (PE) alleviates memory deficits in an Alzheimer's disease mouse model by inhibiting amyloid β (Aβ) aggregation and promoting its disaggregation. However, the extent to which PE exerts additional cognitive benefits independent of Aβ pathology remained unclear. Here, we aimed to evaluate the effects of PE on synaptic plasticity and learning and memory functions. Male ICR mice were used, and cognitive impairment was induced by scopolamine administration. PE was orally administered at doses determined from previous studies, and cognitive performance was assessed using the passive avoidance, Y-maze, and Morris water maze tests. In parallel, hippocampal slices were employed to examine the effects of PE on synaptic plasticity. PE (100 and 300 μg/mL) significantly enhanced long-term potentiation (LTP) in a concentration-dependent manner without altering basal synaptic transmission. This facilitation of LTP was blocked by scopolamine (1 μM), a muscarinic acetylcholine receptor (mAChR) antagonist, and IEM-1460 (50 μM), a calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) inhibitor, indicating the involvement of mAChR and CP-AMPAR pathways. In vivo, PE (100, 250, and 500 mg/kg) treatment improved memory performance across all behavioral tasks and upregulated hippocampal synaptic proteins including GluN2B, PSD-95, and CaMKII. Collectively, these results demonstrate that PE ameliorates scopolamine (1 mg/kg)-induced cognitive impairment by enhancing synaptic plasticity, likely through modulation of mAChR, CP-AMPAR, and NMDA receptor signaling. These findings highlight the therapeutic potential of PE for memory deficits associated with cholinergic dysfunction.}, } @article {pmid41155192, year = {2025}, author = {Kowalczyk, T and Muskała, M and Piekarski, J and Kowalski, M and Staszewski, M and Konuklugil, B and Rijo, P and Sitarek, P}, title = {Therapeutic Promise and Biotechnological Prospects of Dendroaspis polylepis Venom Proteins: Mambalgins, Fasciculins, and Dendrotoxins.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155192}, issn = {1422-0067}, mesh = {Humans ; Animals ; *Snake Venoms/chemistry/therapeutic use/pharmacology ; *Neurotoxins/therapeutic use/pharmacology/chemistry ; Neoplasms/drug therapy ; Biotechnology/methods ; }, abstract = {Animal toxins contain various bioactive peptides and proteins which have evolved to interact in specific ways. As such, they are a good starting point for developing new drugs and vaccines. This paper examines three natural neurotoxins derived from the black mamba (Dendroaspis polylepis), which show significant pharmacological potential: mambalgins, fasciculins and dendrotoxins. All three may be of value in the treatment of pain, cancer and neurodegenerative disease. Mambalgins provide similar pain relief to opioids but without the risk of addiction; they act by selectively blocking acid-sensitive ion channels (ASICs), especially ASIC1a. Thanks to this inhibitory activity they also demonstrate selective activity against glioblastoma, melanoma and leukemia cells as innovative anticancer drugs. Fasciculins are very strong inhibitors of acetylcholinesterase (AChE) and hence offer promise in multi-target drugs and as treatments for treating Alzheimer's disease. Dendrotoxins such as DTX-K and DTX-I are able to modulate neuronal excitability and synaptic transmission by blocking voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.6); both have been shown to be effective against cancer cells, and to influence the cardiovascular, immune, and digestive systems. Recent advances in recombinant biotechnology and protein engineering have allowed their safe production with increased therapeutic value. The review examines the translational potential of D. polylepis venom proteins and highlights the need for additional preclinical research on bioactive molecules of toxin origin.}, } @article {pmid41155149, year = {2025}, author = {Frei, M and Wirawan, R and Wein, T and Bracher, F}, title = {Lead Structure-Based Hybridization Strategy Reveals Major Potency Enhancement of SirReal-Type Sirt2 Inhibitors.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155149}, issn = {1422-0067}, support = {project ID: 325871075-SFB1309//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) with funds from SFB1309 (Chemical Biology of Epigenetic Modifications)/ ; }, mesh = {*Sirtuin 2/antagonists & inhibitors/chemistry/metabolism ; Molecular Docking Simulation ; Humans ; Structure-Activity Relationship ; *Histone Deacetylase Inhibitors/chemistry/pharmacology ; }, abstract = {Selective and potent inhibitors of the NAD[+]-dependent deacetylase Sirt2 represent a valuable epigenetic strategy for the treatment of currently incurable diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, and multiple sclerosis. Guided by molecular docking and MM/GBSA validation studies, a lead structure-based hybridization strategy was developed, resulting in a series of very effective Sirt2 inhibitors. With RW-93, we present a highly potent and subtype selective Sirt2 inhibitor (IC50 = 16 nM), which as a next generation SirReal-type inhibitor significantly surpasses established Sirt2 inhibitors and contributes to the extension of the current SAR profile. The structural modification strategy employed in this study proved to be highly promising, resulting in the identification of the most potent low-molecular-weight Sirt2 inhibitor reported to date, providing a promising target for further medicinal chemistry-driven SAR studies.}, } @article {pmid41155106, year = {2025}, author = {Rahman, S and Rahman, MM and Bhatt, S and Sundararajan, R and Faezipour, M}, title = {NeuroNet-AD: A Multimodal Deep Learning Framework for Multiclass Alzheimer's Disease Diagnosis.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {41155106}, issn = {2306-5354}, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia. This disease significantly impacts cognitive functions and daily activities. Early and accurate diagnosis of AD, including the preliminary stage of mild cognitive impairment (MCI), is critical for effective patient care and treatment development. Although advancements in deep learning (DL) and machine learning (ML) models improve diagnostic precision, the lack of large datasets limits further enhancements, necessitating the use of complementary data. Existing convolutional neural networks (CNNs) effectively process visual features but struggle to fuse multimodal data effectively for AD diagnosis. To address these challenges, we propose NeuroNet-AD, a novel multimodal CNN framework designed to enhance AD classifcation accuracy. NeuroNet-AD integrates Magnetic Resonance Imaging (MRI) images with clinical text-based metadata, including psychological test scores, demographic information, and genetic biomarkers. In NeuroNet-AD, we incorporate Convolutional Block Attention Modules (CBAMs) within the ResNet-18 backbone, enabling the model to focus on the most informative spatial and channel-wise features. We introduce an attention computation and multimodal fusion module, named Meta Guided Cross Attention (MGCA), which facilitates effective cross-modal alignment between images and meta-features through a multi-head attention mechanism. Additionally, we employ an ensemble-based feature selection strategy to identify the most discriminative features from the textual data, improving model generalization and performance. We evaluate NeuroNet-AD on the Alzheimer's Disease Neuroimaging Initiative (ADNI1) dataset using subject-level 5-fold cross-validation and a held-out test set to ensure robustness. NeuroNet-AD achieved 98.68% accuracy in multiclass classification of normal control (NC), MCI, and AD and 99.13% accuracy in the binary setting (NC vs. AD) on the ADNI dataset, outperforming state-of-the-art models. External validation on the OASIS-3 dataset further confirmed the model's generalization ability, achieving 94.10% accuracy in the multiclass setting and 98.67% accuracy in the binary setting, despite variations in demographics and acquisition protocols. Further extensive evaluation studies demonstrate the effectiveness of each component of NeuroNet-AD in improving the performance.}, } @article {pmid41154564, year = {2025}, author = {Wei, C and Chen, X and Sun, M and Cao, J and Liao, D and Cheng, Z and Wang, H}, title = {α-Asarone Maintains Protein Homeostasis Through SKN-1-Mediated Proteasome and Autophagy Pathways to Mitigate Aβ-Associated Toxicity in Caenorhabditis elegans.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {41154564}, issn = {2076-3921}, support = {32370420//National Natural Science Foundation of China/ ; 31670347//National Natural Science Foundation of China/ ; 23ZR1467200//Natural Science Foundation of Shanghai/ ; }, abstract = {Acorus tatarinowii Schott (A. tatarinowii), a traditional Chinese medicine, has been widely used in the treatment of dementia, particularly AD. α-Asarone is the main active component of A. tatarinowii oil, and its neuroprotective effects and underlying molecular mechanism in AD remain unclear. In this study, we utilized different transgenic Caenorhabditis elegans (C. elegans) AD models to investigate the neuroprotective mechanism of α-asarone in vivo. Our findings revealed that α-asarone significantly ameliorated Aβ- and tau-induced phenotypic abnormalities, including deficits in chemotaxis-related learning, hyposensitivity to exogenous serotonin, and impaired neuronal integrity. Furthermore, the α-asarone treatment effectively reduced Aβ-induced oxidative stress. Mechanistically, α-asarone reduced Aβ accumulation and maintained protein homeostasis by stimulating proteasome degradation and autophagy in an SKN-1/Nrf2-dependent manner. Our study highlights the potential of α-asarone as an SKN-1/Nrf2 activator and its capability to facilitate proteostasis, supporting its therapeutic potential for AD treatment.}, } @article {pmid41154171, year = {2025}, author = {Zou, J and Liao, R and Zhang, W and Kuang, Z}, title = {Acupuncture Modulation of the Lung-Brain Axis in Alzheimer's Disease: Mechanisms and Therapeutic Perspectives.}, journal = {Brain sciences}, volume = {15}, number = {10}, pages = {}, pmid = {41154171}, issn = {2076-3425}, support = {2025A1515012049//Natural Science Foundation of Guangdong Province/ ; 20251096//the Research Project of the Traditional Chinese Medicine Bureau of Guangdong Province/ ; 2023A1515110788//Basic and Applied Basic Research Foundation of Guangdong Province/ ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and an impaired quality of life, for which no curative treatment is currently available. Recent research indicates that chronic pulmonary conditions-including chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA)-exhibit significant epidemiological associations with AD pathogenesis, suggesting that the lung-brain axis may contribute to AD development. Acupuncture, a core TCM intervention, shows promise for modulating multisystem functions and enhancing cognitive performance. This review synthesizes the current evidence regarding pulmonary diseases influencing AD through the lung-brain axis, elucidates potential mechanisms by which acupuncture may modulate pulmonary function and mitigate AD pathology, and explores future directions for lung-brain axis-targeted acupuncture interventions. Our overarching aim is to propose integrative, evidence-based strategies that combine Chinese and Western medicine for the prevention and management of AD.}, } @article {pmid41153730, year = {2025}, author = {Danesin, L and D'Este, G and Barresi, R and Piazzalunga, E and Di Garbo, A and Giustiniani, A and Semenza, C and Bottini, G and Oliveri, M and Burgio, F}, title = {Preliminary Evidence of Biological and Cognitive Efficacy of Prismatic Adaptation Combined with Cognitive Training on Patients with Mild Cognitive Impairment.}, journal = {Biomedicines}, volume = {13}, number = {10}, pages = {}, pmid = {41153730}, issn = {2227-9059}, support = {Ricerca Corrente//Ministero della Salute/ ; }, abstract = {Background/Objectives: This study evaluated a novel rehabilitation tool that combines prismatic adaptation (PA) and cognitive training through serious games (SGs) in patients with mild cognitive impairment (MCI) due to prodromal Alzheimer's dementia or consequent to Parkinson's disease. While non-pharmacological interventions have been shown to improve cognition or delay dementia onset, their underlying neurobiological mechanisms, such as brain plasticity, remain unclear. Leveraging studies suggesting neuromodulatory effects of PA, we investigated whether the combined PA+SGs treatment could influence plasticity-related mechanisms, assessed through brain-derived neurotrophic factor (BDNF) serum levels, compared to cognitive training with only SGs and standard cognitive rehabilitation (SCR). Methods: Twenty three MCI patients were randomized into three intervention groups: PA+SGs (experimental group), SG-only (control group), and SCR (control group), completing ten treatment sessions. Patients underwent neuropsychological assessments and blood sampling pre- and post-treatment. Results: At baseline, demographic, clinical, and biological characteristics were comparable across groups. Post-treatment, though differences from control groups were not statistically significant, the PA+SGs group showed significant within-group improvements in memory, with trend-level changes also in executive function and visuospatial abilities, which, however, did not reach the significance threshold. Notably, only the PA+SGs group exhibited increased BDNF levels, which positively correlated with memory and language performance. Conclusions: Our findings suggest that combining PA with cognitive training may enhance cognitive functioning in MCI patients, yielding results comparable to SCR. Furthermore, PA appears to enhance neuroplasticity mechanisms that may support the behavioral improvements observed in cognitive training. Future research should validate these findings and further explore the relationship between cognitive impairment and its rehabilitation, while also considering the underlying neurobiological mechanisms.}, } @article {pmid41152946, year = {2025}, author = {Bali, ZK and Bruszt, N and Göntér, K and Hernádi, I}, title = {Differential cognitive enhancer effects of acetylcholinesterase inhibitors and memantine on age-related deficits in vigilance and sustained attention: a preclinical validation study.}, journal = {Behavioral and brain functions : BBF}, volume = {21}, number = {1}, pages = {35}, pmid = {41152946}, issn = {1744-9081}, support = {KK/492/2019//Gedeon Richter Plc., Budapest, Hungary/ ; RRF-2.3.1-21-2022-00015//National Research, Development and Innovation Office/ ; K 143816//National Research, Development, and Innovation Office of the Hungarian Government/ ; }, mesh = {Animals ; *Memantine/pharmacology ; Donepezil/pharmacology ; *Cholinesterase Inhibitors/pharmacology ; Galantamine/pharmacology ; *Attention/drug effects ; Rats ; Male ; *Nootropic Agents/pharmacology ; Psychomotor Performance/drug effects ; Reaction Time/drug effects ; *Aging/drug effects/psychology ; Cognition/drug effects ; *Arousal/drug effects ; Indans/pharmacology ; Cognitive Dysfunction/drug therapy ; }, abstract = {BACKGROUND: The psychomotor vigilance task (PVT) is a cognitive test commonly used to measure sustained attention and vigilance in humans in healthy and diseased states. Here, we aimed to utilize a recently designed rat version of the PVT to assess potential cognitive enhancer effects of various pharmacological compounds in a natural model of age-related cognitive decline. Therefore, we treated aged rats (> 28 months old) with different doses of three approved Alzheimer's disease drugs: donepezil, galantamine, and memantine. RESULTS: Aged rats made significantly slower responses to the cue stimuli compared to young animals and fewer correct responses, mainly because of an increased number of missed trials (i.e., when the trial was not initiated by the rat). Donepezil improved the performance of aged rats by accelerating their responses at a dose of 0.03 mg/kg. However, galantamine treatment showed no beneficial effects on either reaction time or the number of correct trials. Furthermore, both donepezil (0.3 and 1.0 mg/kg) and galantamine (3.0 mg/kg) increased the reaction time and number of missed trials at high doses. Memantine did not affect the reaction time of aged rats, but it increased the number of correct responses at 0.1 and 0.3 mg/kg doses. CONCLUSIONS: Here, we showed that PVT is suitable for addressing pharmacological effects on various cognitive domains in a single behavioral paradigm. Our findings also indicate that different cognitive enhancer compounds (even when their targets are thought to be the same) may differentially influence distinct cognitive domains and modulate task performance.}, } @article {pmid41152341, year = {2025}, author = {Fujii, K and Koshidaka, Y and Yanagibashi, Y and Adachi, M and Matsuo, M and Kimura, K and Saito, T and Saido, TC and Takao, K}, title = {Ovariectomy attenuates phenotypes related to Alzheimer's disease in a preclinical mouse model and in C57BL/6 J mice.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {36995}, pmid = {41152341}, issn = {2045-2322}, support = {22H04922//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology/physiopathology ; *Ovariectomy ; Disease Models, Animal ; Female ; Mice ; Mice, Inbred C57BL ; Phenotype ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice, Transgenic ; Behavior, Animal ; Mutation ; Amyloid beta-Peptides/metabolism ; Fear ; Anxiety ; Gene Knock-In Techniques ; Memory ; }, abstract = {Women are at higher risk for Alzheimer's disease (AD) than men and hormonal changes during perimenopause are considered a risk factor. The relationship between ovarian hormones and AD has been explored using AD animal models, especially through ovariectomy (OVX) in established AD models. The link between early-stage AD and ovarian hormones, however, remains unclear, largely due to the lack of suitable animal models. Appropriate models for studying early-stage AD pathology, treatment, and prevention are critically needed. The App knock-in mouse model, which carries a single amyloid precursor protein (App) gene mutation, effectively reproduces early amyloid AD pathology. To elucidate the relationship between ovarian hormone deficiency and the behavioral phenotypes of a preclinical AD model, we applied a comprehensive behavioral test battery to this mouse model with bilateral OVX. The App mutation reduced anxiety-like behavior and impaired performance in the fear memory task. OVX restored the anxiety-like behavior of the App mutation mice to a level comparable to that in wild-type (WT) mice. Furthermore, OVX enhanced performance in a fear memory task in both genotypes and reduced amyloid-β staining in WT mice. Together, these findings suggest that OVX attenuates AD-related phenotypes in a preclinical AD model and in C57BL/6 J WT mice.}, } @article {pmid41152189, year = {2025}, author = {Snyder, A and Samra, K and Wu, T and Russell, LL and Farren, J and Crook, J and Haselhuhn, T and Porter, K and Szabo, M and Duckett, A and Lin, F and Danielian, L and Traynor, BJ and Scholz, SW and Boeve, BF and Rosen, HJ and Rohrer, JD and Kwan, JY}, title = {Integrating a motor domain enhances disease severity scales in an FTD-ALS spectrum cohort.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70786}, pmid = {41152189}, issn = {1552-5279}, support = {U19 AG063911/AG/NIA NIH HHS/United States ; U19AG063911//The National Institute on Aging/ ; U01AG045390//The National Institute on Aging/ ; U54NS092089//The National Institute on Aging/ ; U01 AG045390/AG/NIA NIH HHS/United States ; //The Intramural Research Program of the National Institutes of Health/ ; U54 NS092089/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; *Severity of Illness Index ; Female ; *Frontotemporal Dementia/diagnosis/physiopathology ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Aged ; Longitudinal Studies ; Cohort Studies ; Neuropsychological Tests ; }, abstract = {INTRODUCTION: The Genetic Frontotemporal Initiative (GENFI) and Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Longitudinal Frontotemporal Lobar Degeneration Study (ALLFTD) consortia developed Clinical Dementia Rating (CDR)-derived scales with a motor domain to overcome systematic underestimation of disease severity by the CDR. We calculated disease severity scores using these scales in a mixed neurodegenerative cohort and correlated them with objective motor measures. METHODS: The CDR plus National Alzheimer's Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD), CDR + NACC FTLD-M (Motor), and Multidomain Impairment Rating (MIR) scores and motor measures were determined and correlated in 242 participants. RESULTS: Both CDR + NACC FTLD-M and MIR showed increased disease severity scores and correlated with motor measures. These findings were held in 81 amyotrophic lateral sclerosis (ALS) participants and correlated with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Including a motor domain required fewer study participants in a simulated clinical trial sample size calculation. DISCUSSION: With a motor domain, CDR + NACC FTLD-M and MIR improve disease severity classification and correlate with quantitative motor assessments. This addition more fully captures the extent of symptoms across the FTD-ALS spectrum and improves clinical trial efficiency. HIGHLIGHTS: CDR + NACC FTLD-M and MIR strongly correlate with objective motor measures. The enhanced scales improve disease severity classification in FTD and ALS. Greater clinical trial efficiency is achieved using these enhanced scales.}, } @article {pmid41151846, year = {2025}, author = {Kuzuya, A and Ohara, T and Akamatsu, N}, title = {Pathogenesis of comorbid epilepsy in Alzheimer's disease and use of perampanel, an AMPA receptor inhibitor.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {12}, pages = {1399-1409}, doi = {10.1080/14737175.2025.2581758}, pmid = {41151846}, issn = {1744-8360}, mesh = {Humans ; Nitriles ; *Pyridones/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/complications/epidemiology ; *Epilepsy/drug therapy/epidemiology/complications ; *Receptors, AMPA/antagonists & inhibitors ; *Anticonvulsants/therapeutic use/pharmacology ; Comorbidity ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) and epilepsy frequently co-occur and are risk factors for each other's onset. In patients with AD-comorbid epilepsy, seizure control with appropriate anti-seizure medications (ASMs) is crucial, yet no established treatment guidelines exist. Recent studies indicate that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) are involved in the pathogenesis of both diseases. Perampanel, an AMPAR antagonist, has been approved as an ASM. AREAS COVERED: This review explains the relationship between AD and epilepsy and discusses the involvement of AMPARs. Furthermore, it focuses on and presents opinions regarding the role of AMPAR inhibitors in the treatment of AD-comorbid epilepsy. The authors searched for clinical studies that were published and identifiable in PubMed and Scopus (Jan 2015-Dec 2024) including the terms 'Alzheimer's disease' or 'dementia' with 'epilepsy' or 'seizure'. EXPERT OPINION: Considering the hypothesis that AD and epilepsy are linked, creating a cycle that progresses both diseases via AMPARs, AMPAR inhibition may have beneficial effects in treatment of epilepsy in AD. Although evidence is limited, studies of perampanel have demonstrated symptomatic improvement in patients with AD-comorbid epilepsy. Perampanel may be particularly useful for specific subgroups of patients with AD-comorbid epilepsy, such as those with myoclonus, sleep disturbances, or poor medication adherence.}, } @article {pmid41151285, year = {2025}, author = {Song, J and Ding, X and Li, M and Xin, Y and Lu, Y and Yang, X and Lu, X}, title = {N[6]-methyladenosine reader YTHDF1 mediates neuronal apoptosis induced by aluminum via m[6]A/Bcl-2 manner.}, journal = {Ecotoxicology and environmental safety}, volume = {306}, number = {}, pages = {119270}, doi = {10.1016/j.ecoenv.2025.119270}, pmid = {41151285}, issn = {1090-2414}, mesh = {*Apoptosis/drug effects ; Animals ; *Adenosine/analogs & derivatives/metabolism ; *RNA-Binding Proteins/metabolism/genetics ; *Neurons/drug effects ; *Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Aluminum/toxicity ; Mice ; Male ; Humans ; }, abstract = {Aluminum (Al) has emerged as a pervasive environmental and industrial risk factor for cognitive impairment and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Nowadays, N6-methyladenosine (m[6]A) modification mechanism contributing to aluminum toxicity is gradually gaining attention. m[6]A modification determines the fate of RNA through m[6]A "readers". Novel findings indicate that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1, a kind of "readers") participates in various pathological processes induced by some toxic chemicals. Here, we investigated the function of YTHDF1 in neuronal apoptosis induced by aluminum and explored the molecular mechanisms. We first observed the YTHDF1 expression both in vivo and in vitro neuronal apoptosis model induced by aluminum, as well as the reversal effect of YTHDF1 overexpression by lentivirus transfection in vitro. Further, we explored Bcl-2 as a target gene of YTHDF1 and probed their m[6]A modification manner and molecular mechanism using RIP assay, Me-RIP assay, and Actinomycin D (ActD) assay. Finally, we examined the regulatory role of YTHDF1/m[6]A/Bcl-2 axis in aluminum neurotoxicity in vitro and in vivo. Functionally, Al(mal)3 treatment decreased YTHDF1 expression, which negatively regulates apoptosis via m[6]A modification manner. Mechanistically, Bcl-2 acted as the target of YTHDF1, and YTHDF1 regulated Bcl-2 by enhancing its mRNA stability. Collectively, Al(mal)3 treatment inhibited the YTHDF1/m[6]A/Bcl-2 axis, thereby promoting neuronal apoptosis and subsequent cognitive impairment. This study provides a novel protective strategy against aluminum toxicity.}, } @article {pmid41151129, year = {2026}, author = {Yang, F and Guo, Q and Chen, M and Wang, W and Chen, X and Zhang, S and Bian, H and Li, J and Jiao, Z and Wang, Q and Xiong, W and Huang, YY and Liu, Y and Xu, C and Huang, L}, title = {Discovery of novel 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one derivatives as PDE2 inhibitors with Alzheimer's disease therapeutic potential.}, journal = {European journal of medicinal chemistry}, volume = {302}, number = {Pt 1}, pages = {118302}, doi = {10.1016/j.ejmech.2025.118302}, pmid = {41151129}, issn = {1768-3254}, mesh = {*Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors/metabolism ; Animals ; Humans ; Structure-Activity Relationship ; Mice ; Molecular Structure ; *Drug Discovery ; Male ; Dose-Response Relationship, Drug ; *Phosphodiesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Microsomes, Liver/metabolism ; *Pyridines/chemistry/pharmacology/chemical synthesis ; *Pyrazoles/chemistry/pharmacology/chemical synthesis ; }, abstract = {Phosphodiesterase 2 (PDE2), a dual-substrate cyclic nucleotide hydrolase, represents a potential therapeutic target for cognitive impairment. This study aims to develop 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one-based PDE2 inhibitors with favorable drug-like properties for the treatment of Alzheimer's disease. Through scaffold hopping and cocrystal structure analysis, compound 14c was identified as an effective PDE2 inhibitor (IC50 = 0.6 μM, aqueous solubility = 60.36 μg/mL). Moreover, 14c demonstrated favorable hepatic microsomal stability, pharmacokinetic properties (t1/2 = 4.4 h, F% = 95.66 %) and promising safety both in vitro and in vivo. In the OKA-induced AD mice models, administration of 14c significantly improved memory deficits and cognitive impairment. Molecular mechanism studies revealed that the neuroprotective effects of 14c were mediated through the PKA/CREB/BDNF signaling pathway. Collectively, these findings represent significant advances in developing PDE2 inhibitors with favorable drug-like properties and establish a solid foundation for their therapeutic application in AD.}, } @article {pmid41149051, year = {2025}, author = {Valdez Gayosso, N and Omaña Covarrubias, A and Nez Castro, AT and López Pontigo, L and Acuña Gurrola, MDR and Pimentel Pérez, BM}, title = {The Effect of Bacteria Modulation with Probiotic Consumption in Neurodegeneration During Aging: A Narrative Review of the Literature.}, journal = {Diseases (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, pmid = {41149051}, issn = {2079-9721}, support = {NA//Universidad Autónoma del Estado de Hidalgo/ ; }, abstract = {Aging is the result of the accumulation of a great variety of molecular and cellular damage over time. During aging, the brain undergoes changes and diseases such as depression, dementia, anxiety, Alzheimer's, delirium, behavioral disorders and aggression, and prolonged mourning, among others, appear. The gut-brain axis suggests that the gut and the brain have a bidirectional communication, so it is important to maintain proper intestinal health to strengthen the neurological changes of this age group. The intestinal microbiota is a dynamic and highly complex ecosystem of microorganisms residing in the gastrointestinal tract. The bidirectional and dynamic communication between the homeostatic systems, such as the endocrine and immune systems, as well as the nervous system, allow us to face problems associated with several diseases. Probiotics are defined as non-pathogenic live microorganisms that provide beneficial effects to the organism and participate in the prevention and treatment of diseases, which is the reason why it is important to promote interventions that keep intestinal microbiota in eubiosis (microbiota balance). The concentration and balance of the intestinal microbiota depend on several conditions, such as diet, antibiotic consumption, and lifestyle, to mentioned a few. However, interventions with probiotics have shown improvements in both cognitive function and processes that promote neurodegeneration. It is such that the research has been directed on designing strategies that improve not only oral bioavailability but also intestinal adhesion and retention, to clarify the frequency and dosage that should be consumed.}, } @article {pmid41148458, year = {2025}, author = {Goel, F and Kumar, D and Singh, P and Rai, SN and Yadav, DK}, title = {Molecular crosstalk between miRNAs and lncRNAs in neurodegenerative disease pathways.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {16}, pmid = {41148458}, issn = {1573-4978}, mesh = {Humans ; *RNA, Long Noncoding/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/therapy ; Gene Expression Regulation ; Animals ; Signal Transduction ; Gene Regulatory Networks ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal degeneration and dysfunction. Of recent interest, a series of studies have been targeting the role of non-coding RNAs, particularly miRNAs and lncRNAs, in regulating gene expression and influencing cellular pathways that may play a critical role in the pathogenesis of these diseases. miRNAs regulate many biological processes by degrading or repressing the translation of target mRNAs, whereas lncRNAs act as scaffolds, sponges, and guides to control gene expression and cellular activities. Both miRNAs and lncRNAs participate in neurodegenerative mechanisms such as protein aggregation, inflammation, oxidative stress, and neuroinflammation. While targeting miRNAs and lncRNAs holds promise for potential therapeutic benefits, problems persist with their efficient delivery, specificity, and off-target effects. New techniques like viral vectors, lipid nanoparticles, and CRISPR-based gene editing will further enhance the development of therapies based on miRNA and lncRNA. Moreover, their interaction with regulatory networks may present new avenues toward understanding disease mechanisms and guiding therapeutic design. This review covers the role of miRNAs and lncRNAs in neurodegenerative disorders, their therapeutic potential, challenges, and future directions in ncRNA-based treatment approaches.}, } @article {pmid41147168, year = {2025}, author = {Hu, D and Li, X and Li, Y and Zhang, Q and Dai, Y and Teng, X and Hou, H and Li, J}, title = {A Drug Screening Targeting Upregulation of Syk Gene Identifies Neochlorogenic Acid and L-Arabinitol Capable of Inducing the M2 Phenotype of Microglia in Alzheimer's Disease.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {26}, number = {23}, pages = {e202500515}, doi = {10.1002/cbic.202500515}, pmid = {41147168}, issn = {1439-7633}, support = {2023000CA0050//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024100CA0080//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024101RPIA02//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024501QPIC05//Beijing Life Science Academy Initiative Scientific Research Program/ ; }, mesh = {*Syk Kinase/genetics/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Up-Regulation/drug effects ; *Microglia/drug effects/metabolism/pathology ; Animals ; Phagocytosis/drug effects ; Amyloid beta-Peptides/metabolism ; Humans ; Drug Evaluation, Preclinical ; Mice ; Phenotype ; }, abstract = {Despite numerous therapeutic attempts of Alzheimer's disease (AD), treatment options remain limited. Targeting microglia (MG) polarization from M1 to M2 is considered a promising approach, yet no drug specifically modulating this transition has been identified. The spleen tyrosine kinase (Syk) has emerged as a potential therapeutic target due to its role in regulating AD risk genes and promoting Amyloid-β (Aβ) clearance. Herein, a microglial reporter gene screening model targeting Syk is developed and two small molecules, neochlorogenic acid (NCGA) and L-arabinitol (L-Ara), that can upregulate Syk gene expression, leading to the activation of MG M2 phenotype, are identified. Furthermore, these compounds markedly enhance the capacity of MG to migrate toward Aβ and phagocytose Aβ. However, when Syk expression is silenced using shRNA, the ability of these small molecules to induce the MG M2 phenotype and promote Aβ phagocytosis by MG is substantially attenuated. These findings offer new insights into AD therapy development.}, } @article {pmid41145342, year = {2025}, author = {Dickson, SP and Mallinckrodt, C and Burstein, AH and Nisenbaum, L and Fillit, HM and Zhang, C and Hendrix, SB}, title = {The impact of recent approvals on future alzheimer's disease clinical development: Statistical considerations for combination trials.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {10}, pages = {100391}, pmid = {41145342}, issn = {2426-0266}, mesh = {*Alzheimer Disease/drug therapy/prevention & control ; Humans ; Drug Therapy, Combination ; *Research Design ; *Antibodies, Monoclonal/therapeutic use ; *Clinical Trials as Topic ; *Drug Approval ; *Drug Development ; Sample Size ; Disease Progression ; }, abstract = {BACKGROUND: A new era of Alzheimer's disease (AD) research is beginning with multiple approved anti-amyloid monoclonal antibodies (mABs). These drugs are currently not widely used, but may be soon, especially at clinical trial sites. Putative disease-modifying therapies (DMTs) may alter the progression rate, potentially reducing our ability to detect effects on top of mABs. Co-administration of amyloid-targeted agents may diminish benefit (antagonism, due to the overlapping mechanism of action); alternatively, complementary treatment mechanisms may increase benefit (synergy). METHOD: We consider several clinical trial design scenarios: a 2-arm trial added-on to a mAB, a 2-arm combination compared to double placebo, and a 4-arm full factorial trial. We calculate the required sample sizes for the shortest practical study for secondary prevention (prevention of AD clinical diagnosis in biomarker positive individuals, 2-year study), early AD (18-months), and mild-to-moderate AD (1-year). We consider additivity, antagonism, and synergy. RESULT: The expected interaction between investigational and mAB treatment can have a large effect on power and study design. Antagonistic treatment effects often require double the sample size of synergistic effects. The 4-arm scenario required ∼10-fold increase compared to a 2-arm combination study. CONCLUSION: Studies evaluating investigational therapies as add-on to mABs are complex, and their cost will depend on the interaction between treatments. An inescapable fact in add-on trials is the slower progression of the control arm; and it is difficult to further slow already slow progression. Treatments that are likely to work better with amyloid removal will be easier to study due to their complementary MOA. Symptomatic treatments may require fewer additional subjects than disease-modifying treatments since they are less affected by the presence or absence of mABs.}, } @article {pmid41145339, year = {2025}, author = {Ballard, C and Sultana, J and Doherty, P and Williams, G and Corbett, A}, title = {Identifying synergistic combinations of repurposed treatments for Alzheimer's Disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {10}, pages = {100329}, pmid = {41145339}, issn = {2426-0266}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Drug Repositioning ; Drug Therapy, Combination ; Drug Synergism ; Delphi Technique ; }, abstract = {There is considerable opportunity to fast-track novel treatments for Alzheimer's Disease (AD) through repurposing of existing licensed medications as a way of complementing ongoing drug discovery efforts. Given the complex interplay between AD neuropathological mechanisms, there is also a strong rationale that treatment benefits may be enhanced by examining combinations of treatments to identify potential synergies that would address multiple disease-modifying mechanisms. A Delphi consensus programme combined with a pragmatic analysis of primary care data has identified a series of individual and combined therapies that warrant further investigation in pre-clinical and clinical trials. These include treatments which target well-established neurodegeneration pathways and more explorative agents, including hormonal and anti-infective agents, which align to emerging hypotheses relating to endocrine and immune pathways in AD. Whilst caution is critical when considering combined therapy due to the risks of interaction and polypharmacy, this study provides valuable indications of potential synergistic drug pairs that warrant further investigation.}, } @article {pmid41145338, year = {2025}, author = {Cummings, J and Burstein, AH and Fillit, H}, title = {Add-on combination therapy with monoclonal antibodies: Implications for drug development.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {10}, pages = {100359}, pmid = {41145338}, issn = {2426-0266}, support = {P20 GM109025/GM/NIGMS NIH HHS/United States ; R01 NS139383/NS/NINDS NIH HHS/United States ; R25 AG083721/AG/NIA NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Development ; *Antibodies, Monoclonal/therapeutic use ; Drug Therapy, Combination ; Amyloid beta-Peptides ; Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {Three anti-amyloid monoclonal antibodies (MABs) including aducanumab, lecanemab, and donanemab have been approved by the FDA and lecanemab and donanemab are available in the US market and a variety of other national markets. The increasing use of anti-amyloid MABs to treat early AD will require that development of novel agents occur as add-on treatment to MABs. There is limited experience with add-on therapy to anti-amyloid agents. In most cases, it is prudent to initiate novel agents after at least six-months exposure to the MAB at the highest dose. Agents with extensive data on pharmacokinetics and pharmacodynamics and well-known safety may employ alternative approaches. Anti-amyloid MABs have different mechanisms of action, titration, and side effect profiles suggesting that add-on trials include only one type of MAB if possible. Demonstration of clinical benefit with add-on therapy will require showing additional slowing beyond that provided by the anti-amyloid MAB. Anti-amyloid therapies have profound effects on biomarkers including amyloid positron emission tomography and plasma p-tau and plasma GFAP measures. Definition of the biomarker profile of a novel agent prior to initiation of add-on therapies, inclusion of target engagement biomarkers specific to the novel intervention, assessment of biomarkers not known to be affected by anti-amyloid MABs, and interrogation of the magnitude, timing, and trajectory of biomarker change in the add-on context compared to monotherapy with MABs will provide insight into the biological impact of the novel therapy on AD. Patient convenience in terms of formulation and timing of add-on therapies will be important to successful clinical implementation. Add-on therapies are an important step in addressing the complexity of AD and optimizing patient outcomes.}, } @article {pmid41145337, year = {2025}, author = {Cummings, JL and Burstein, AH and Fillit, H}, title = {Alzheimer Combination Therapies: Overview and Scenarios.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {10}, pages = {100328}, pmid = {41145337}, issn = {2426-0266}, mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; Drug Therapy, Combination ; Combined Modality Therapy ; Animals ; }, abstract = {Progress in understanding the complexity of Alzheimer's disease informs the search for combination therapies that can successfully prevent or substantially slow the progression of the disease. Anti-amyloid monoclonal antibodies are the first approved disease targeted therapies; they slow disease progression by approximately 30 %. Building on these agents in add-on therapies is one avenue to designing combination treatments. Development of combination drugs consisting of two or more novel interventions is an alternate pathway for combination treatment development. Combination therapies can involve small molecule drugs, biological agents, devices, stem cells, gene therapies, lifestyle interventions, or cognitive training. Nonclinical assessment of drug combinations may involve animal models or new approach methodologies such as induced pluripotent stem cells or organoids. Phase 1 trials are required to characterize each member of a novel combination. Phase 2 trials may use a 2-by-2 factorial design comparing each drug to placebo and the drug combination. In Phase 3, comparison of the novel combination to standard of care may be sufficient or more complex designs may be required. Targets for combination therapies beyond amyloid-related processes include tau abnormalities, inflammation, neurodegeneration, and co-pathologies such as alpha-synuclein and TDP-43. The choice of combination therapies will depend on the strength of the information regarding the target, biomarkers to guide clinical trials, and a candidate agent with the appropriate mechanism of action. Computational strategies based on network analysis of disease and drugs, validation in non-clinical models, and use of real-world data may facilitate prioritization of candidates for combination treatments.}, } @article {pmid41144509, year = {2025}, author = {Morden, NE and Chyn, D and Meara, E}, title = {Falls and Fractures Among Medicare Beneficiaries Concurrently Receiving Anti-Dementia Drugs and Potentially Risky Medications.}, journal = {Medical care}, volume = {63}, number = {12}, pages = {941-948}, doi = {10.1097/MLR.0000000000002229}, pmid = {41144509}, issn = {1537-1948}, mesh = {Humans ; *Accidental Falls/statistics & numerical data ; United States/epidemiology ; Female ; Male ; *Medicare/statistics & numerical data ; Aged, 80 and over ; Aged ; *Dementia/drug therapy ; *Cholinesterase Inhibitors/adverse effects/therapeutic use ; Analgesics, Opioid/adverse effects ; Memantine/adverse effects/therapeutic use ; Hip Fractures/epidemiology ; }, abstract = {BACKGROUND: Patients with Alzheimer disease and related dementias (ADRD) face risks from medications labeled "potentially inappropriate in older adults" (risky); concurrent receipt of anti-dementia drugs may amplify risk. We studied adverse events among older adults concurrently receiving anti-dementia and risky medications. METHODS: Using 2016-2019 administrative data from a random 40% sample of fee-for-service Medicare beneficiaries receiving anti-dementia medications (acetylcholinesterase inhibitors (AChEI) and/or memantine), we identified days with concurrent receipt of select, risky medications (benzodiazepines, sedative hypnotics, opioids). We measured diagnosed falls, hip fractures, and deaths among person-days with anti-dementia drug receipt comparing person-days with versus without concurrent risky drug receipt. We stratified regression analyses on long-term care (LTC) residence. RESULTS: We studied 633,528 beneficiaries; 64.3% were women, 33.7% met LTC residence criteria. Mean (SD) age was 80.9 (7.6) years. Each beneficiary contributed a mean (SD) of 551.7 (449.2) anti-dementia drug receipt days. Overall, 4.5% of person-days involved receipt of AChEI plus benzodiazepines; 3.8% involved AChEI plus an opioid. Falls, the most common outcome, affected 22.5% of our beneficiaries. Concurrent receipt of AChEI and opioids was associated with the greatest fall risk increase. Among community-dwelling beneficiaries, AChEI and opioid receipt (vs. AChEI alone) was associated with a hazard ratio for falls of 2.25 (95% CI: 2.19, 2.32); among LTC residents the corresponding hazard ratio was 1.46 (95% CI: 1.42, 1.51). CONCLUSIONS: Assessment and treatment of symptoms among people with ADRD is complex; concurrent receipt of opioids and dementia medications is uncommon but seems risky. Efforts to eliminate avoidable opioids may decrease adverse events and associated suffering in this population.}, } @article {pmid41143926, year = {2025}, author = {Shi, Y and Ma, H and Li, H and Wang, Y and Wang, C and Zhang, N and Luo, G and Wang, Y and Gao, X}, title = {Sennoside A alleviating cognitive impairment in APP/PS1 mice via balancing microbiome metabolism.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1659-1676}, doi = {10.1177/13872877251389922}, pmid = {41143926}, issn = {1875-8908}, mesh = {Animals ; *Gastrointestinal Microbiome/drug effects ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism ; *Sennosides/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; Male ; Mice, Transgenic ; Disease Models, Animal ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/genetics ; Brain/drug effects/pathology/metabolism ; }, abstract = {BackgroundThe progression of Alzheimer's disease (AD) is associated with constipation, potentially mediated by gut microbiota. Laxatives have shown potential in improving the cognitive function of AD, but the specific mechanism remains underexplored. Sennoside A (SA), a well-established laxative, is commonly used for treating constipation.ObjectiveThis work used SA as a probe to explore the therapeutic effects and potential mechanisms of laxatives on AD via the gut-brain axis.MethodsFollowing a two-month treatment, behavioral experiments were used to assess the cognitive function. The central pathologies and neuroinflammation were evaluated by histopathology and ELISA. 16S rRNA sequencing, fecal microbiota transplantation and antibiotic treatment were conducted to verify whether SA exerts anti-AD effects via gut microbiota. Further, non-targeted metabolomics coupled with Spearman correlation analysis was employed to elucidate the underlying mechanisms.ResultsSA significantly countered cognitive dysfunction and central pathological damage in APP/PS1 mice. Besides, SA ameliorated gut dysbiosis and affected the metabolic functions of the flora. Furthermore, the therapeutic effects of SA decrease with the depletion of gut microbes and could be transferred with the microbiota. Intriguingly, amino acid metabolism and aminoacyl-tRNA biosynthesis were the main metabolic pathways regulated by SA, consistent with the predicted functions of gut bacteria. Finally, correlation analysis revealed a strong correlation between gut microbes, fecal metabolites, and cognitive ability affected by SA.ConclusionsThe study investigated the efficacy and mechanisms of laxatives represented by SA for AD from the perspective of the gut-brain axis.}, } @article {pmid41143875, year = {2025}, author = {Saak, TM and Tervo, JP and Motter, JN and Overdevest, JB}, title = {Expanding the scope of olfactory evaluation in Alzheimer's disease and related dementias (ADRD): A narrative review of the role for odor memory and recognition in AD/ADRD.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251389113}, doi = {10.1177/13872877251389113}, pmid = {41143875}, issn = {1875-8908}, abstract = {Olfactory dysfunction (OD) is a well-characterized feature of Alzheimer's disease (AD) and is often one of the earliest functional biomarkers in the disease course. As such, olfactory evaluation shows promise as an important tool in AD screening and may provide insight into pathologic underpinnings and potential treatment pathways. The National Plan to Address Alzheimer's Disease emphasizes the importance of including Alzheimer's disease related dementias (ADRD) in research efforts, and while olfaction is also associated with ADRD, this association is relatively understudied. Additionally, there have been efforts to expand the evaluation of olfactory function to include assessments beyond key domains, such as odor threshold, odor discrimination, and odor identification, which have been the primary focus of most olfaction research in AD/ADRD. Odor recognition memory assessments have been developed primarily for their utility in identifying and stratifying individuals along the AD continuum, although a wide variety of methods have been reported in the literature. In this narrative review, we provide an overview of odor identification, odor threshold, and odor discrimination in AD/ADRD with a specific focus on providing a centralized guide detailing odor recognition memory methods and their utility in AD/ADRD.}, } @article {pmid41143243, year = {2025}, author = {Allué, JA and Sarasa, L and Fandos, N and Gonzalo, R and Sabido-Vera, R and Loscos, J and Romero, J and Sánchez, A and Terencio, J and Matias-Guiu, JA and Piñol-Ripoll, G and Pascual-Lucas, M}, title = {Clinical validation of a plasma-based antibody-free LC-MS method for identifying CSF amyloid positivity in mild cognitive impairment.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1681516}, pmid = {41143243}, issn = {1663-4365}, abstract = {BACKGROUND: The recent approval of monoclonal antibodies for the treatment of Alzheimer's disease (AD) in several countries has accelerated the need for affordable, simple and scalable methods to identify patients who are eligible for treatment with the new disease-modifying therapies (DMT). Blood-based biomarkers offer less invasive alternatives to established gold standards. We have clinically validated a predictive model combining plasma Aβ42/Aβ40, apolipoprotein E (APOE) genotype and age, in two independent real-world cohorts to identify brain amyloid deposition. METHODS: We conducted a clinical validation study involving 450 patients with mild cognitive impairment (MCI) from two real-world cohorts (HCSC, Madrid, Spain and HUSM, Lleida, Spain). Plasma Aβ42/Aβ40 was measured by ABtest-MS, an antibody-free liquid chromatography-mass spectrometry method. CSF Aβ42/Aβ40 and p-tau181/Aβ42 (gold standards) were quantified with the Lumipulse[®] platform. The model was trained in the HCSC cohort and validated in the HUSM cohort. Finally, an overall analysis in the combined population was performed. A dual cutoff approach was used to classify the patients as positive or negative. Statistical analysis included bootstrap resampling and model calibration. RESULTS: In the HCSC, HUSM, external validation and combined analysis, AUCs were 0.89 (95% confidence intervals-CI: 0.84-0.93), 0.88 (0.84-0.93), 0.88 (0.83-0.92) and 0.88 (0.84-0.91), with corresponding accuracies of 82.3, 81.6, 82.3, and 81.1%, respectively. After the combined analysis, positive and negative predictive values (PPV and NPV) were established at 87.5%, resulting in cutoff values of 0.30 and 0.67 for the likelihood of amyloid negativity and positivity, respectively, for a prevalence of 62%. Probability values lower than 0.30 indicate low probability of brain amyloid deposition, while values greater than 0.67 indicate high probability. Less than 28% of the participants fell into the intermediate zone. Additional cutoffs were derived for different prevalence values. Predictive model calibration showed excellent agreement with observed data, confirming accurate predictions (slope = 0.98, intercept = -0.01). CONCLUSION: This predictive model has demonstrated high accuracy for the identification of brain amyloid deposition in patients with MCI. Derived cutoffs enabled over 70% reduction in invasive testing, supporting efficient and cost-effective identification of candidates for DMTs.}, } @article {pmid41141907, year = {2025}, author = {Blazquez-Folch, J and Limones Andrade, M and Calm, B and Auñón García, JM and Alegret, M and Muñoz, N and Cano, A and Fernández, V and García-Gutiérrez, F and De Rojas, I and García-González, P and Olivé, C and Puerta, R and Capdevila-Bayo, M and Muñoz-Morales, Á and Bayón-Buján, P and Miguel, A and Montrreal, L and Espinosa, A and Sanz-Cartagena, P and Rosende-Roca, M and Zaldua, C and Gabirondo, P and Cantero-Fortiz, Y and Gurruchaga, MJ and Tarraga, L and Boada, M and Ruiz, A and Marquié, M and Valero, S}, title = {Federated learning for cognitive impairment detection using speech data.}, journal = {Frontiers in artificial intelligence}, volume = {8}, number = {}, pages = {1662859}, pmid = {41141907}, issn = {2624-8212}, abstract = {INTRODUCTION: In Alzheimer's disease (AD) research, clinical, neuroimaging, genetic, and biomarker data are vital for advancing its understanding and treatment. However, privacy concerns and limited datasets complicate data sharing. Federated learning (FL) offers a solution by enabling collaborative research while preserving data privacy. METHODS: This study analyzed data from patients assessed at the Memory Unit of the Ace Alzheimer Center Barcelona who completed a standardized digital speech protocol. Acoustic features extracted from these recordings were used to distinguish between cognitively unimpaired (CU) and cognitively impaired (CI) individuals. The aim was to evaluate how data heterogeneity impacted the FL model performance across three scenarios: (1) equal contributions and class ratios, (2) unequal contributions, and (3) imbalanced class ratios. In each scenario, the performance of local models trained using an MLP feed-forward neural network on institutional data was analyzed and compared to a global model created by aggregating these local models using Federated Averaging (FedAvg) and Iterative Data Aggregation (IDA). RESULTS: The cohort included 2,239 participants: 221 CU individuals (mean age 66.8, 64.7% female) and 2,018 CI subjects, comprising 1,219 with mild cognitive impairment (mean age 74.3, 61.9% female) and 799 with mild AD dementia (mean age 80.8, 64.8% female). In scenarios 1 and 3, FL provided modest gains in accuracy and AUC. In scenario 2, FL markedly improved performance for the smaller dataset (balanced accuracy rising from 0.51 to 0.80) while preserving 0.86 accuracy in the larger dataset, highlighting scalability across heterogeneous conditions. CONCLUSION: These findings demonstrate the potential of FL to enable collaborative modeling of speech-based biomarkers for cognitive impairment detection, even under conditions of data imbalance and institutional disparity. This work highlights FL as a scalable and privacy-preserving approach for advancing digital health research in neurodegenerative diseases.}, } @article {pmid41141199, year = {2025}, author = {Sorod, P and Chen, GI}, title = {Hearing All About Donepezil: Its Role in the Field of Auditory Processing.}, journal = {Cureus}, volume = {17}, number = {9}, pages = {e93143}, pmid = {41141199}, issn = {2168-8184}, abstract = {Donepezil is a central-acting acetylcholinesterase inhibitor aimed at increasing acetylcholine availability at the neuron synapses to enhance cholinergic transmission. It is often used to assist with cognitive function and is well-known as the first-line treatment for mild to severe dementia of several etiologies. However, its mechanism of action within "top-down" and "bottom-up" neurological pathways continues to be explored. This case reports on a 93-year-old woman in an ambulatory geriatrics clinic with moderate-to-severe dementia. Her significant history of hearing loss with auditory hallucination impressively responded to the initiation of donepezil. There may be potential benefits of donepezil within the peripheral pathways of neuro-cortical reorganization in the field of hearing loss and auditory processing.}, } @article {pmid41140221, year = {2025}, author = {Mastrostefano, A and Alborghetti, M and Tiso, D and Davinelli, S and Medoro, A and Scapagnini, G}, title = {Pleiotropic Actions of Gastrodia Elata Glucosides in the Treatment of Painful Neuropathies and CNS Disorders: Focus on Mitochondrial Dysfunction and Modulation of Ion Channels.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X402568251002112117}, pmid = {41140221}, issn = {1875-6190}, abstract = {Glycosides contained in Gastrodia elata have consistently shown neuroprotective and antiinflammatory activity in preclinical models of neurological disorders, including peripheral neuropathies, cerebrovascular disorders, and chronic neurodegenerative disorders. In a commercial product used in Italy, gastrodin has replaced α-lipoic, the use of which is now limited by unexpected adverse effects, such as severe hypoglycemia. The clinical efficacy of gastrodin in traditional Chinese medicine has been ascribed to a plethora of mechanisms, which involve the modulation of intracellular signaling pathways and membrane ion channels. Moving from the pathophysiology of diabetic neuropathy, Alzheimer's disease, and Parkinson's disease, we now focus on what we consider a key mechanism in the action of gastrodin, i.e., the regulation of mitochondrial quality control. Gastrodin is able to enhance mitochondrial fusion and biogenesis, as shown by the induction of specific biochemical markers, such as mitofusins and mitochondrial transcription factors. This supports mitochondrial health, preventing the loss of energy production and formation of reactive oxygen species associated with disorders of the central and peripheral nervous system. In addition, gastrodin physically interacts with, and restrains the expression and activity of, voltage-sensitive ion channels and acid-sensing ion channels, which play a central role in pain transmission and nociceptive sensitization. Thus, gastrodin and other constituents of Gastrodia elata show promising potential to support first-line treatments, based on preclinical evidence in models of neurological disease.}, } @article {pmid41140219, year = {2025}, author = {Devi, S and Singh, AP}, title = {Novel Therapeutic Approaches to Neuroinflammation in Neurodegenerative Disorders: Aptamers as Central Nervous System Agents.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249392444251002135338}, pmid = {41140219}, issn = {1875-6166}, abstract = {INTRODUCTION: Neurodegenerative disorders (NDDs) like Alzheimer's, Parkinson's, and multiple sclerosis all begin with neuroinflammation. Neuroinflammation targeting has recently gained attention as a potential approach to treating several diseases affecting the central nervous system. The objective of this review is to explore the potential of aptamers as innovative therapeutic agents for targeting neuroinflammation in neurodegenerative disorders, offering a novel approach to CNS treatment. METHODS: The use of aptamers, which are single-stranded nucleic acids, in diagnostic and therapeutic contexts may one day help overcome these obstacles. Myotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders are linked to neuroinflammation. Important regulators of CNS inflammatory responses include microglia and astrocytes. RESULTS: Neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) and neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes) activation of microglia and astrocytes, respectively, is a diverse and complex process. There may be a lack of reflection of the diverse morphologies of microglia and astrocytes in this binary categorisation. In addition to the complexity of the relationships between these activated glial cells, the phenotypic distribution can vary as neurodegenerative illnesses progress. DISCUSSION: To create effective treatments for neurodegenerative illnesses, a deeper knowledge of microglia and astrocyte functions is required. Drug efficacy, safety concerns, and pharmacokinetics are only a few of the topics covered, along with the enormous possibilities and enormous hurdles of employing aptamers as therapeutic agents. CONCLUSION: This review highlights aptamers as a promising genetic tool for treating neuroinflammation and neurodegenerative diseases through targeted delivery to the central nervous system.}, } @article {pmid41140213, year = {2025}, author = {Zhao, R and Che, M and Cui, Y and Peng, J and Chen, M}, title = {The Role of Lipoprotein and Gut Microbiome in Alzheimer's Disease: A Review of Novel Findings and Potential Applications.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050407276251014113234}, pmid = {41140213}, issn = {1875-5828}, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is inadequately comprehended, with hypotheses implicating amyloid-β, tau pathology, mitochondrial dysfunction, and epigenetic factors. Recent research underscores the significance of lipoproteins and the gut microbiota in the etiology of AD. Apolipoprotein E (ApoE), particularly the E4 subtype, emerges as a key genetic risk factor, influencing oxidative stress, synaptic defects, glucose metabolism, and amyloid-β clearance. Lipoprotein receptors, such as LRP-1, also influence the integrity of the blood-brain barrier, indicating potential for therapeutic applications. Novel therapies targeting lipoproteins, such as ALZ-801 and IDOL inhibitors, show promise in preclinical and clinical trials. Concurrently, the gut microbiome's impact on AD is increasingly recognized. Dysbiosis correlates with inflammation, mitochondrial oxidative stress, impaired autophagy, and neurotransmitter imbalances. Gut-derived metabolites, including phenylalanine and isoleucine, promote Th1 cell activation and microglial dysfunction, exacerbating AD pathology. Interventions, like probiotics, GV-971, and polyphenols, demonstrate efficacy in restoring microbial balance and mitigating cognitive decline. Crucially, bidirectional interactions between lipoproteins and the gut microbiome are implicated in AD. ApoE genotypes influence gut microbial composition, while microbiota- derived short-chain fatty acids and endotoxins modulate lipid metabolism and neuroinflammation. These interactions, mediated via the gut-brain axis, highlight novel therapeutic avenues. Current FDA-approved AD drugs face limitations in efficacy and side effects, underscoring the need for innovative strategies targeting lipoprotein-gut microbiome crosstalk. Integrating insights into lipoprotein biology and gut microbiota dynamics may offer transformative potential for AD treatment, emphasizing combinatorial approaches to modulate these interconnected pathways. Further research is warranted to elucidate mechanistic links and translate preclinical findings into clinical applications.}, } @article {pmid41140062, year = {2025}, author = {Abdel-Lah, ES and Hamad, N and Taha, AF and Mohamed, WH and Fawy, MA and Attaai, AH and Abbas, FYA and Sherkawy, HS and Abdelwarith, A and Gamea, MG}, title = {Neuroprotective Effect of Empagliflozin/Rivastigmine in Alzheimer's Disease Rat Model: Optimization of Multifaceted Mechanism of Action.}, journal = {Drug development research}, volume = {86}, number = {7}, pages = {e70180}, doi = {10.1002/ddr.70180}, pmid = {41140062}, issn = {1098-2299}, support = {//The authors received no specific funding for this work./ ; }, mesh = {Animals ; *Rivastigmine/pharmacology/administration & dosage ; *Glucosides/pharmacology/administration & dosage/therapeutic use ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Male ; *Benzhydryl Compounds/pharmacology/administration & dosage/therapeutic use ; Rats ; Disease Models, Animal ; Oxidative Stress/drug effects ; Acetylcholinesterase/metabolism ; Glucose/metabolism ; Brain/drug effects/pathology/metabolism ; Rats, Wistar ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; tau Proteins/metabolism ; Drug Therapy, Combination ; Lipid Peroxidation/drug effects ; }, abstract = {This study assessed the neuroprotective potential of empagliflozin (EMPA) as antidiabetic drug on glucose metabolism, comparing it to rivastigmine (RIVA) as standard treatment for Alzheimer's disease (AD), and their combination. Male rats were sorted into five groups. Group I served as the control, while groups II, III, IV, and V received the scopolamine plus heavy metal mixture for AD induction. Groups III and IV were administered RIVA and EMPA, respectively, and group V received both treatments. Cognitive function was evaluated behaviorally. Subsequently, glucose levels, acetylcholinesterase, oxidative stress, and inflammatory markers were assessed. Alongside the brain histopathological changes, the expression of phosphorylated tau protein was assessed. Moreover, glycolytic enzymes and glucose transporters were assessed using PCR analysis. The findings were attributed to a notable suppressive impact of EMPA on lipid peroxidation, acetylcholinesterase, glucose levels, phosphorylated tau protein, pro-inflammatory cytokines, and neuropathological changes, while enhancing antioxidant and interleukin-10 levels. It also improves glucose metabolism. The findings suggest that EMPA may be a viable candidate for future therapeutic exploration in AD, which has a multifaceted mechanism of action encompassing anti-neuroinflammation, antioxidant stress, and enhanced glucose metabolism, as well as decreased acetylcholinesterase activity and phosphorylated tau protein levels. Interestingly, combined treatment showed a superior effect than EMPA alone.}, } @article {pmid41139687, year = {2025}, author = {Li, X and Singh, S and DeVries, A and Gurwitz, JH}, title = {Lecanemab Therapy Use Patterns for Alzheimer's Disease Among Early Initiators in a Large National Health Plan.}, journal = {Journal of the American Geriatrics Society}, volume = {73}, number = {10}, pages = {3203-3207}, pmid = {41139687}, issn = {1532-5415}, support = {K01 AG073651/AG/NIA NIH HHS/United States ; R33 AG057806/AG/NIA NIH HHS/United States ; K01AG073651/AG/NIA NIH HHS/United States ; 3R33AG057806-07S1/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Female ; Aged ; Male ; United States ; Medicare Part C/statistics & numerical data ; Magnetic Resonance Imaging ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage ; Aged, 80 and over ; }, abstract = {BACKGROUND: Lecanemab, an anti-amyloid monoclonal antibody, has been approved for treatment of early Alzheimer's disease. However, real-world data remain limited regarding use. METHODS: Using data from a large national health plan with primarily Medicare Advantage enrollees, we characterized demographic and clinical characteristics in the 6 months preceding the initial infusion among individuals who initiated lecanemab between 1/1/2023 and 06/30/2024. We also characterized the patterns of infusions and the timing of MRIs for safety monitoring following the initial infusion among initiators who had ≥ 3 months of follow-up. We further assessed trends in lecanemab use between 1/1/2023 and 12/31/2024. RESULTS: Of the 195 lecanemab initiators, the average age was 74.6 (SD = 5.5) years, 62.1% were female, 87.7% were White, 4.1% were Black, 1.5% were Hispanic, and 98.5% were on a Medicare Advantage plan. Almost all initiators resided in nonrural areas (96.4%); 2.6% used anticoagulants, and 1.5% used antiplatelets. Among the 119 initiators who had ≥ 3 months of follow-up, 40 (33.6%) received 7 total infusions, the expected number of infusions based on the recommended schedule of every 2 weeks. From the initial infusion, the average number of days to the first MRI was 47.1 (SD = 15.8), and to the second MRI scan was 73.4 (SD = 12.0) days, consistent with the recommended schedule. During 2023-2024, there were 526 patients who had ever received lecanemab. The increase in new initiators was modest over 2024, with only 43 more initiators during the final (n = 137) versus the first quarter (n = 94) of 2024. CONCLUSIONS: This study demonstrated slow uptake of lecanemab among Medicare Advantage beneficiaries. Adherence to the ideal treatment schedule was less than recommended. Early lecanemab users were not representative of the population likely eligible for treatment nationally. Further research is warranted to track longer-term trends in utilization, as well as reasons for treatment interruption or discontinuation in real-world populations.}, } @article {pmid41139428, year = {2025}, author = {Justo-Henriques, SI and Lemos, R and Rahmatpour, P and Silva, RCG and Carvalho, JO and Ribeiro, O}, title = {Effectiveness of Individual Cognitive Stimulation on Cognition in Mild Alzheimer's Disease: A Multicenter RCT.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {25}, number = {6}, pages = {e70109}, pmid = {41139428}, issn = {1479-8301}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; Male ; Aged ; *Executive Function/physiology ; Neuropsychological Tests ; Treatment Outcome ; *Cognition/physiology ; Aged, 80 and over ; *Cognitive Behavioral Therapy/methods ; Memory ; Portugal ; *Cognitive Dysfunction/therapy ; }, abstract = {BACKGROUND: Alzheimer's Disease (AD) is characterised by impairments across several neurocognitive domains, including memory and executive function. The study explored the effectiveness of a 3-month individual Cognitive Stimulation (iCS) program in older adults with mild AD. METHODS: A multicenter randomised controlled trial was conducted with 62 Portuguese older adults with mild AD. Participants were randomly assigned to either iCS (n = 33; 53%) or treatment as usual (TAU, n = 29; 47%). Cognitive outcomes were assessed at baseline, post-intervention, and 12-week follow-up using standardised tests for global cognition, memory and executive function. RESULTS: The iCS group showed a significant improvement in memory and executive function compared to the TAU group. The analysis of subscales revealed significant improvements in encoding and semantic memory (Memory Alteration Test) and free delayed recall (Free and Cued Selective Reminding Test). Adherence and engagement with the intervention were high. CONCLUSIONS: A 3-month iCS program showed preliminary benefits in specific cognitive domains (memory and executive function) in older adults with mild AD, warranting further research with larger samples and longer follow-up. TRAIL REGISTRATION: Clinicaltrials.gov ID: NCT05433493; Effect of Individual Cognitive Stimulation on Memory and Executive Function in Older Adults With Alzheimer's Disease.}, } @article {pmid41139132, year = {2026}, author = {Sonwani, A and Pathak, A and Jain, K}, title = {Development and characterization of multifunctional dendrimeric nanoconjugates for delivery of rutin: in vitro characterization for potential neuroprotective application.}, journal = {Nanomedicine (London, England)}, volume = {21}, number = {1}, pages = {1-14}, pmid = {41139132}, issn = {1748-6963}, mesh = {*Rutin/chemistry/administration & dosage/pharmacology ; *Dendrimers/chemistry ; *Neuroprotective Agents/chemistry/administration & dosage/pharmacology ; *Nanoconjugates/chemistry ; Humans ; Antioxidants/chemistry/pharmacology ; Animals ; Folic Acid/chemistry ; Drug Liberation ; Cell Survival/drug effects ; Particle Size ; Acetylcysteine/chemistry ; Drug Delivery Systems ; *Drug Carriers/chemistry ; }, abstract = {AIM: In the present research work, multifunctional dendrimeric nanoconjugates were developed, where poly(amidoamine) dendrimer generation 4.0 (G4.0) was conjugated with folic acid and N-acetyl cysteine simultaneously to deliver rutin for potential neuroprotective applications. METHODS: G4.0 was functionalized with folic acid and N-acetyl cysteine by carbodiimide coupling chemistry, and the conjugation was confirmed using [1]H NMR and FTIR spectroscopy. Further, rutin was incorporated within the conjugate, and the rutin-loaded dendrimeric conjugate was evaluated for size, drug release, cytotoxicity, cellular uptake, and antioxidant activity. RESULTS: The results of FTIR and [1]H NMR confirmed the conjugation of folic acid and N-acetyl cysteine over the dendrimeric surface. The particle size of NAC-FA-G4.0 was 163.4 ± 16.63 nm, which was increased to 229.76 ± 14.05 nm following the rutin incorporation. The in vitro drug release study showed an initial burst release of rutin, i.e. 44.27 ± 6.4% from dendrimeric conjugate within 4 h, followed by sustained release up to 72 h. The safety and biocompatibility of the developed nanoconjugate were confirmed by the hemolytic toxicity and cytotoxicity studies. CONCLUSION: The developed rutin-loaded dendrimeric conjugate showed improved antioxidant activity and acetylcholinesterase inhibition, suggesting promising neuroprotection properties and hence may be further explored for the treatment of neurodegenerative diseases, including Alzheimer's disease.}, } @article {pmid41139043, year = {2026}, author = {Yu, C and Liu, L and Lu, Z and Chen, M and Yang, N and Li, Z and Bai, L and Li, C and Zhou, X}, title = {A new approach for treating AD: Guifu Dihuang Pills improves brain insulin resistance by promoting NrCAM to activate the EGFR/PI3K/Akt signaling pathway.}, journal = {Journal of ethnopharmacology}, volume = {356}, number = {}, pages = {120642}, doi = {10.1016/j.jep.2025.120642}, pmid = {41139043}, issn = {1872-7573}, mesh = {Animals ; *Insulin Resistance ; Proto-Oncogene Proteins c-akt/metabolism ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Male ; ErbB Receptors/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; Humans ; Hippocampus/drug effects/metabolism ; Brain/drug effects/metabolism ; Streptozocin ; Mice, Inbred C57BL ; }, abstract = {Guifu Dihuang Pills (GFDHP), a classical Chinese herbal formula originally recorded in the Synopsis of the Golden Chamber (Jingui Yaolüe), significantly ameliorate cognitive dysfunction in patients with Alzheimer's disease (AD). However, the precise molecular mechanisms underlying its therapeutic effects, particularly those involving the regulation of cerebral insulin resistance (IR), are not yet fully elucidated. AIM OF THE STUDY: This study systematically investigated the neuroprotective mechanism of the traditional Chinese medicine (TCM) compound GFDHP in alleviating AD by integrating RNA-seq transcriptomics, surface plasmon resonance (SPR) analysis, and bioinformatic analysis. The aim was to clarify its key targets and signaling pathways involved in the modulation of cerebral IR by in vitro and in vivo experiments. METHODS: The chemical components of GFDHP were characterized using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). An AD model with cerebral IR was established by an intracerebroventricular streptozotocin (ICV-STZ) injection. Cognitive function was assessed using the Morris water maze (MWM) test, while hippocampal damage was evaluated by histological staining. The insulin level in hippocampal tissues was quantified using enzyme-linked immunosorbent assay (ELISA). AD-related proteins were analyzed using immunohistochemistry and Western blot. Integrated transcriptome sequencing, AlphaFold3 prediction, and SPR analysis confirmed the interaction between neuronal cell adhesion molecule (NrCAM) and epidermal growth factor receptor (EGFR). In vitro experiments were performed using HT22 cells treated with dexamethasone (DXM) to induce an IR model, followed by evaluation of IR and AD-related markers. Lentivirus-mediated shRNA knockdown of NrCAM was performed to systematically examine its regulatory effect on the EGFR/PI3K/Akt signaling pathway and GFDHP's therapeutic intervention. RESULTS: GFDHP significantly attenuated ICV-STZ-induced IR and AD-related neuropathological alterations. SPR analysis further revealed that NrCAM mediated the neuroprotective effect through the specific binding to EGFR, thereby activating the downstream PI3K/Akt signaling cascade. NrCAM silencing not only exacerbated both IR and AD pathology but also suppressed the EGFR/PI3K/Akt pathway and reduced the therapeutic effect of GFDHP. CONCLUSIONS: This study demonstrated that GFDHP alleviated IR by upregulating NrCAM expression and subsequently activating the EGFR/PI3K/Akt signaling pathway, thereby ameliorating AD. This is the first report identifying NrCAM as the key molecular target mediating the neuroprotective effect of this herbal formulation, providing a novel therapeutic strategy for AD treatment.}, } @article {pmid41138654, year = {2025}, author = {Ha, TY and Kim, Y and Lim, SM and Hong, Y and Chang, KA}, title = {GPR40 agonist ameliorates neurodegeneration by regulating mitochondria dysfunction and NLRP3 inflammasome in Alzheimer's disease animal models.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {192}, number = {}, pages = {118678}, doi = {10.1016/j.biopha.2025.118678}, pmid = {41138654}, issn = {1950-6007}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Receptors, G-Protein-Coupled/agonists/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; Disease Models, Animal ; *Inflammasomes/metabolism/drug effects ; Mice ; Amyloid beta-Peptides/metabolism ; Male ; Mice, Transgenic ; Neurons/drug effects/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Hippocampus/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; *Phenethylamines/pharmacology ; Autophagy/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction and chronic neuroinflammation. G-protein coupled receptor 40 (GPR40), primarily known for its role in metabolic regulation, has recently emerged as a modulator of neuronal activity and inflammatory signaling. In this study, we investigated the therapeutic potential of the selective GPR40 agonist TUG469 in both in vitro and in vivo models of AD. Treatment with amyloid-β oligomers (AβO) induced mitochondrial dysfunction in primary hippocampal neurons, as evidenced by disrupted mitochondrial morphology and membrane potential. TUG469 treatment restored mitochondrial integrity and membrane potential. Moreover, TUG469 significantly reduced AβO-induced reactive oxygen species (ROS) production. In the 5xFAD mouse model of AD, TUG469 administration improved cognitive performance and reduced Aβ plaque burden. Furthermore, TUG469 rescued impaired autophagy flux, as demonstrated by the regulation of LC3, p62, and LAMP1 expression, and attenuated neuroinflammatory responses by inhibiting NLRP3 inflammasome activation and modulating microglial reactivity. These findings indicate that GPR40 activation mitigates mitochondrial dysfunction and neuroinflammation, thereby alleviating AD-related pathology. Our results highlight the therapeutic potential of TUG469 as a multi-target modulator for AD.}, } @article {pmid41138336, year = {2026}, author = {Waheed, R and Mostafa, Z and Emad, M and Darwish, SS and Purgatorio, R and Miniero, DV and De Palma, A and Cheng, TP and Wang, TY and Chen, YC and El Kerdawy, AM and Gabr, M and Catto, M and Abadi, AH and Hwang, TL and Abdel-Halim, M}, title = {Revisiting COX-2 inhibitors for Alzheimer's disease as multitargeted ligands: Development of 4-hydrazono-pyrazolidinediones with tuned COX selectivity profile and improved cellular potency.}, journal = {European journal of medicinal chemistry}, volume = {302}, number = {Pt 1}, pages = {118261}, doi = {10.1016/j.ejmech.2025.118261}, pmid = {41138336}, issn = {1768-3254}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Cyclooxygenase 2 Inhibitors/pharmacology/chemistry/chemical synthesis ; Structure-Activity Relationship ; *Cyclooxygenase 2/metabolism ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Molecular Structure ; Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Ligands ; Dose-Response Relationship, Drug ; Animals ; *Hydrazones/chemistry/pharmacology/chemical synthesis ; Dogs ; *Pyrazoles/chemistry/pharmacology/chemical synthesis ; Cyclooxygenase 1/metabolism ; }, abstract = {Herein, we expand on our previously synthesized 4-hydrazono-pyrazolidinedione COX-2 inhibitors as multitargeted agents for Alzheimer's disease (AD). Structural modifications of the 4-phenylhydrazono group led to the identification of several highly potent COX-2 inhibitors, with compound 3 exhibiting the strongest COX-2 inhibition (IC50 = 0.07 μM), with a balanced COX-2/COX-1 profile, suggesting lower cardiovascular risk. Compounds 2 and 9 showed high potency and selectivity shift toward COX-1 and displayed strong antiplatelet activity. Several derivatives showed 4-7 times improved submicromolar cellular potency, significantly inhibiting PGE2 release in LPS-stimulated THP-1 cells. Compounds 2, 3, 7, and 9 maintained the multitarget profile and inhibited Aβ and tau aggregation. Compounds 2, 3, and 7 protected against Amyloid-beta (Aβ)- and H2O2-induced cytotoxicity, confirming their neuroprotective activity with high potential for BBB permeability demonstrated via PAMPA and MDCK-MDR1 assays. These results support the potential of multitargeted COX-2 inhibitors as AD therapeutics and suggest a re-evaluation of their role in neurodegenerative disease treatment.}, } @article {pmid41138018, year = {2025}, author = {Hu, L and Qi, L and Lin, Z and Zhu, J and Zhang, M}, title = {Research progress of single cell RNA sequencing in nervous system.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {9}, pmid = {41138018}, issn = {1573-4978}, support = {82271747//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Single-Cell Analysis/methods ; *Sequence Analysis, RNA/methods ; *Nervous System/metabolism ; Transcriptome/genetics ; *Nervous System Diseases/genetics ; Animals ; Gene Expression Profiling/methods ; }, abstract = {Single-cell RNA sequencing (scRNA-seq) and its integration with multi-omics technologies such as epigenomics and spatial transcriptomics are revolutionizing our traditional understanding of cellular heterogeneity and the microenvironment in the nervous system. While technical reviews abound, translating multi-omics data into biological and clinical insights remains a challenge. This review comprehensively outlines the latest advancements in scRNA-seq technology and its integration with multi-omics approaches and artificial intelligence. We systematically summarize its applications across neuroscience, from unraveling neurodevelopment and evolution to deciphering the mechanisms of neurological diseases such as Alzheimer's disease, Parkinson's disease, and gliomas. By deeply resolving cell-specific expression differences in neurological disorders, scRNA-seq has enabled the discovery of novel cell subtypes and revealed intercellular regulatory mechanisms, thereby facilitating the deconstruction of disease pathogenesis and the identification of new potential therapeutic targets. Furthermore, this technology has demonstrated significant value in drug screening, efficacy evaluation, and the development of novel treatment strategies. However, scRNA-seq still faces multiple technical limitations. Future efforts should focus on reducing its application costs, addressing clinical ethical concerns, and progressively advancing the clinical translation of scRNA-seq technology.}, } @article {pmid41137894, year = {2025}, author = {Gu, X and Yu, SP and Jiang, MQ and Zhong, W and Sastry, A and Wei, L}, title = {Preventive Memantine Treatment at the Preclinical Stage in the Alzheimer's Disease Model of the 5xFAD Mouse.}, journal = {Neuroscience bulletin}, volume = {}, number = {}, pages = {}, pmid = {41137894}, issn = {1995-8218}, abstract = {Neuronal and NMDA receptor (NMDAR) hyperactivities are common pathophysiology in Alzheimer's disease (AD). We recently identified that the deficiency of NMDAR regulatory subunit GluN3A (NR3A) cultivated early psychological and olfactory symptoms, followed by cognitive decline and deferred endogenous amyloid/tau pathologies. NMDAR antagonist memantine (MEM) prevented AD-like progression in GluN3A knockout (KO) mice. We tested the hypothesis that AD development of the 5xFAD mouse can be antagonized by the preemptive MEM treatment. MEM (10 or 20 mg/kg per day in drinking water for 3 months) was started in wild-type (WT) and 5xFAD mice at 3 months old. In this preclinical stage, the 5xFAD mouse displayed psychological and olfactory symptoms, yet exhibited no significant cognitive deficits or Aβ42 deposition. The MEM treatment antagonized early symptoms, abated cognitive decline, and amyloid/tau pathology. Early and persistent maintenance of normal neuronal/NMDAR activities in individuals carrying AD risk factors should be considered as a preventive and a possible disease-modifying therapy.}, } @article {pmid41137616, year = {2025}, author = {Chan, D and de Weck, G and Jackson, BL and Suk, HJ and Milman, NP and Kitchener, E and Avalos, VSF and Quay, MJ and Aoki, K and Ruiz, E and Becker, A and Zheng, M and Philips, R and Firenze, R and Geigenmüller, U and Hammerschlag, B and Arnold, S and Kivisäkk, P and Brickhouse, M and Touroutoglou, A and Brown, EN and Boyden, ES and Dickerson, BC and Klerman, EB and Tsai, LH}, title = {Gamma sensory stimulation in mild Alzheimer's dementia: An open-label extension study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70792}, pmid = {41137616}, issn = {1552-5279}, support = {//Freedom Together Foundation/ ; //Robert A. and Renee E. Belfer Family Foundation/ ; //Eleanor Schwartz Charitable Foundation/ ; //The Dolby Family/ ; //Che King Leo/ ; //Amy Wong and Calvin Chin/ ; //Kathleen and Miguel Octavio/ ; //the Degroof-VM Foundation/ ; //Halis Family Foundation/ ; //Chijen Lee/ ; //Eduardo Eurnekian/ ; //Larry and Debora Hilibrand/ ; //Gary Hua and Li Chen/ ; //Ko Han Family/ ; //Lester Gimpelson/ ; //David B. Emmes/ ; //Joseph P. DiSabato and Nancy E. Sakamoto/ ; //Donald A. and Glenda G. Mattes/ ; //Alan and Susan Patricof/ ; //Carol and Gene Ludwig Family Foundation/ ; //Alex Hu and Anne Gao/ ; //Elizabeth K. and Russell L. Siegelman/ ; //Marc Haas Foundation/ ; //Dave and Mary Wargo/ ; //James D. Cook, and the Nobert H. Hardner Foundation/ ; UDIW8172//NIH Loan Repayment Program/ ; 15367//Doris Duke Clinical Scientist Development Award/ ; //Picower Clinical Fellowship/ ; UL1 TR002541/TR/NCATS NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Acoustic Stimulation/methods ; *Alzheimer Disease/therapy/physiopathology/diagnostic imaging ; Biomarkers/blood ; Brain/diagnostic imaging/physiopathology ; Cognition/physiology ; Electroencephalography ; Magnetic Resonance Imaging ; Mental Status and Dementia Tests ; Neuropsychological Tests ; *Photic Stimulation/methods ; tau Proteins/blood ; }, abstract = {INTRODUCTION: We evaluated the long-term effects of daily 40 Hz (gamma frequency) audiovisual stimulation on cognition and biomarkers in five patients with mild Alzheimer's disease (AD). METHODS: Over 2 years, patients received 1-h daily stimulation. Electroencephalography (EEG) was used to assess neural entrainment; magnetic resonance imaging (MRI) measured brain volumes; actigraphy monitored activity patterns; neuropsychological tests evaluated cognition; and S-PLEX assay measured plasma pTau217. RESULTS: No adverse events occurred over the study period. Three female patients with late-onset AD (LOAD) retained strong EEG entrainment and showed less decline in Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Functional Assessment Scale (FAS) scores compared to matched controls from National Alzheimer's Coordinating Center (NACC), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). Plasma samples were available for only two of five participants - both with LOAD - and both showed pTau217 reductions of 47% and 19%. DISCUSSION: These findings suggest that long-term 40 Hz audiovisual stimulation is safe, feasible, and may offer cognitive and biomarker benefits in some individuals with mild AD, supporting further investigation. ClinicalTrials.gov (NCT04055376). HIGHLIGHTS: Five mild Alzheimer's disease (AD) patients safely used daily 40 Hz audiovisual stimulation for 2 years. Late-onset AD (LOAD) patients showed increased 40 Hz electroencephalography (EEG) power and improved cognitive scores. National Alzheimer's Coordinating Center (NACC) data enhanced early-phase analysis and support precision medicine in AD studies. Plasma pTau217 declined in 2 LOAD patients after 2 years of daily use. This small pilot is the first to link long-term 40 Hz therapy to AD biomarker change.}, } @article {pmid41137085, year = {2025}, author = {Zhang, W and Song, J and Zhong, F and Yu, W and Qin, Z and Yang, Z and Liu, J and Wang, X and Chen, L and Lü, W and Xing, D and Liu, J and Huang, C and Wu, J and Liu, X and Yu, W and Lü, Y}, title = {Computerized cognitive training enhances cognitive function in Alzheimer's disease by downregulating Ruminococcus-TMAO pathway.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {1173}, pmid = {41137085}, issn = {1479-5876}, support = {2022YSZX-JSX0002CSTB//grants from Innovation Programs Led by the Academicians in Chongqing under Project/ ; cstc2022ycjh-bgzxm0184//Chongqing Talent Plan/ ; CSTC2021jscx-gksb-N0020//Jiangsu Provincial Agricultural Science and Technology Independent Innovation Fund/ ; 2021ZD0201802//STI2030-Major Projects/ ; 2018YFC2001700//National Key R&D Program of China/ ; 0201[2023]160 202412//Chongqing Medical Key Discipline and Regional Medical Key Discipline Development Project/ ; }, mesh = {Humans ; Male ; *Alzheimer Disease/microbiology/physiopathology/therapy/blood ; Female ; *Cognition/physiology ; Aged ; *Methylamines/blood/metabolism ; *Down-Regulation ; Gastrointestinal Microbiome ; Cognitive Dysfunction/physiopathology ; Cognitive Training ; }, abstract = {BACKGROUND: The microbiota-gut-brain (MGB) axis is implicated in Alzheimer's disease (AD), but evidence for interventional strategies targeting this axis remains limited. METHODS: In a 24-week, single-blind, randomized controlled trial, 84 individuals with mild cognitive impairment (MCI) or mild AD received either computerized cognitive training (CCT) or treatment as usual (TAU). Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) was the primary outcome. We also assessed functional connectivity (fNIRS), plasma trimethylamine N-oxide (TMAO) levels, and gut microbiota at baseline and 24 weeks. RESULTS: Seventy-four participants completed the study. The CCT group showed significant improvement in ADAS-cog scores compared to controls (Cohen's d = 1.57 by week 24). Notably, CCT also induced a distinct reorganization of prefrontal functional connectivity and significantly reduced plasma TMAO levels. Microbiome analysis revealed that CCT mitigated the expansion of Ruminococcus torques group (R.torques), which was observed in the control group. Crucially, R.torques was the only genus significantly correlated with improvements in cognition (ADAS-cog, r = 0.407), neuropsychiatric symptoms (NPI, r = 0.395), TMAO reduction (r = 0.443), and functional connectivity changes (r = 0.449). CONCLUSION: A 24-week CCT program improves cognitive function in MCI and mild AD, potentially through downregulating the R.torques-TMAO pathway within the MGB axis. This pathway represents a promising novel target for multi-domain intervention in AD.}, } @article {pmid41136359, year = {2025}, author = {Pan, X and Su, Z and Huang, Z and Chen, Y and Li, X and Zheng, X}, title = {N-acetylcysteine (NAC) ameliorates ethanol-induced oxidative stress, neuroinflammation, and cognitive dysfunction in APP/PS1 mouse model.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {435}, pmid = {41136359}, issn = {2158-3188}, mesh = {Animals ; *Acetylcysteine/pharmacology ; *Ethanol/toxicity/adverse effects ; Mice ; *Oxidative Stress/drug effects ; Disease Models, Animal ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroinflammatory Diseases/chemically induced/drug therapy ; Mice, Transgenic ; Male ; Microglia/drug effects ; *Antioxidants/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects ; Disks Large Homolog 4 Protein/metabolism/drug effects ; Amyloid beta-Protein Precursor/genetics ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder that predominantly affects the elderly, leading to a progressive decline in cognitive function. Accumulating evidence suggests that many environmental and dietary factors, especially chronic ethanol exposure, aggravate the risk of this disease. However, its precise influence on AD has not yet been clarified. Here, we show that ethanol exposure caused earlier and severer cognitive behavioral impairments, more beta amyloid (Aβ) depositions, microglia activation, decreased total antioxidant capacity (T-AOC). Moreover, inflammatory mediators, such as Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and Tumor necrosis factor-alpha (TNF-α) increased, while pivotal proteins involved in dendritic and synaptic development, such as Synaptophysin (SYP), postsynaptic density protein 95 (PSD95) and brain-derived neurotrophic factor (BDNF) decreased in APP/PS1 mice. N-acetylcysteine (NAC), a well-known antioxidant, could attenuate cognitive behavioral impairments and neuroinflammatory damage by restoring inflammatory and neurodevelopmental mediators. In general, our study uncovered that chronic ethanol exposure may exacerbate AD progress at the pathological and molecular levels and NAC may act as a potential drug for the treatment of AD patients with chronic ethanol exposure.}, } @article {pmid41135777, year = {2026}, author = {Zhang, S and Fan, Z and Ji, D}, title = {Advances in eye-brain axis: Anatomy, immunity, and association with visual dysfunction.}, journal = {Ageing research reviews}, volume = {113}, number = {}, pages = {102925}, doi = {10.1016/j.arr.2025.102925}, pmid = {41135777}, issn = {1872-9649}, mesh = {Humans ; *Brain/immunology/anatomy & histology/pathology ; Animals ; *Eye/anatomy & histology/immunology ; *Vision Disorders/physiopathology/immunology/pathology ; Glaucoma/physiopathology ; }, abstract = {The "eye-brain axis" refers to the dynamic system of interactions between the eyes and the brain, collectively encompassing the visual signal transmission and integration pathways. The eyes and the brain exhibit structural and functional synergy, and visual dysfunction not only impairs information processing within the eye but also induces structural and functional remodeling of the central nervous system (CNS) via the eye-brain axis. For instance, the effects of glaucoma on the visual cortex are manifested as reduced blood perfusion and decreased efficiency of mitochondrial adenosine triphosphate (ATP) synthesis. Moreover, the eye can serve as an important window and biomarker for the early diagnosis and intervention of neurodegenerative diseases of the CNS. Relevant research findings include the parallelism of beta amyloid (Aβ) and phosphorylated Tau (p-Tau) between the retina and Alzheimer's disease (AD), glaucomatous neurodegeneration with AD-like features, and the role of vascular endothelial growth factor C (VEGF-C) expression along the eye-brain lymphatic pathway in regulating intraocular pressure (IOP) and correcting macular edema. Therefore, eye-brain axis research provides novel perspectives for understanding the pathophysiological mechanisms underlying visual dysfunction and related disorders, while simultaneously supporting the development of cross-organ neuroprotective strategies. This review explores the anatomical foundations, immune regulation, and bidirectional interactions of the eye-brain axis, and evaluates its relevance to the diagnosis and treatment of visual dysfunction and degenerative diseases of the CNS.}, } @article {pmid41135742, year = {2025}, author = {Hu, T and Xi, J and Xie, N and Zhang, X and Huang, N and Cheng, Y}, title = {Multi-omics analysis reveals the protective role of transcriptional enhancer factor and the pathogenic mechanism of monocytes in Parkinson's disease.}, journal = {Brain research bulletin}, volume = {232}, number = {}, pages = {111594}, doi = {10.1016/j.brainresbull.2025.111594}, pmid = {41135742}, issn = {1873-2747}, mesh = {Animals ; *Parkinson Disease/genetics/metabolism ; Humans ; *Monocytes/metabolism/pathology ; Mice ; Mendelian Randomization Analysis ; *Transcription Factors/metabolism/genetics ; Male ; Mice, Inbred C57BL ; Cell Line, Tumor ; Multiomics ; }, abstract = {Parkinson's disease (PD) is a multifactorial neurodegenerative disorder whose pathogenic mechanisms remain incompletely elucidated. This study aimed to systematically identify key regulatory factors involved in PD at the genetic, cellular, and molecular levels. Using univariate Mendelian randomization (UVMR), we identified plasma proteins and genes associated with Alzheimer's disease (AD), PD, and amyotrophic lateral sclerosis (ALS), and validated their causal relationships through colocalization analysis. Cross-validation across multi-omics datasets revealed transcriptional enhancer factor (TEF) as a protective factor for PD, whereas increased counts of CD14[+]CD16[+] monocytes were identified as a risk factor. Single-cell analysis and multivariate Mendelian randomization (MVMR) further suggested potential mediating roles of these factors in PD pathogenesis. In vitro experiments demonstrated that TEF overexpression significantly enhanced the resistance of neuroblastoma cells to rotenone-induced damage, inhibited apoptosis, and preserved tyrosine hydroxylase (TH) expression. In vivo, TEF notably improved motor coordination and exploratory behavior in PD mouse models. Collectively, these findings suggest that TEF may exert neuroprotective effects by modulating immune and neuronal pathways, offering a novel therapeutic target for the prevention and treatment of Parkinson's disease.}, } @article {pmid41134994, year = {2025}, author = {Mullins, CA and Gannaban, RB and Kramer, A and Shah, H and Haque, ZF and Ramezan, M and Dehghani, F and Palaniyappan, AK and Bowers, F and MohanKumar, SM and MohanKumar, PS and Shin, AC}, title = {Early branched-chain amino acid reduction delays the onset of cognitive decline in a mouse model of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1567-1583}, doi = {10.1177/13872877251389236}, pmid = {41134994}, issn = {1875-8908}, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *Amino Acids, Branched-Chain/metabolism/blood ; *Cognitive Dysfunction/prevention & control/metabolism ; Mice ; Male ; Disease Models, Animal ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Peptides/metabolism ; }, abstract = {BackgroundMany Alzheimer's disease (AD) treatments focus on a single variable of AD that have yet demonstrated clinically meaningful and perceived benefits by the patients. We recently showed that lowering plasma branched-chain amino acids (BCAAs) can deliver multiple pro-neuronal effects in APP/PS1 and 5xFAD mouse models.ObjectiveThe main aim was to determine the optimal point in time for the disease-modifying effects of BCAA reduction during AD development.Methods12-month-old, cognitively impaired male WT and APP/PS1 mice were injected with either vehicle or BCAA-lowering compound BT2 (40 mg/kg/day ip) for 30 days. To test if early BT2 during AD progression would have long-lasting beneficial effects, 2-month-old, cognitively intact male 5xFAD mice were treated with BT2 after which they were left alone for a month.ResultsPlasma BCAAs were reduced in BT2-treated APP/PS1 mice. Despite Aβ42 reduction, BT2 did not modify proteins or genes related to AD-related pathology, dendritic density and neurotransmitters in the cortex and hippocampus, or alleviate cognitive deficit. In another experiment, BT2-treated 5xFAD mice had lower plasma BCAAs. Importantly, early BT2, even after treatment cessation for a month, was able to effectively delay cognitive impairment which was associated with a complete restoration of cortical neurotransmitters. These results were observed without any changes in pathology markers in the brain.ConclusionsOur findings suggest that BT2-induced BCAA reduction is a novel strategy to delay AD progression possibly through enhanced neurotransmission. The efficacy is time-dependent such that treating with BT2 before the onset of AD can successfully rescue cognitive function.}, } @article {pmid41134991, year = {2025}, author = {Tseng, P}, title = {Does weak gamma entrainment still work? Rethinking the comfort-efficacy trade-off in 40 Hz sensory stimulation.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1517-1519}, doi = {10.1177/13872877251389153}, pmid = {41134991}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology ; *Gamma Rhythm/physiology ; Electroencephalography ; *Photic Stimulation/methods ; }, abstract = {As 40 Hz sensory stimulation gains attention as a potential treatment for Alzheimer's disease, comfort-focused designs such as invisible spectral flicker and multi-luminaire are increasingly used to promote long-term compliance. However, these systems often produce significantly weaker electroencephalographic entrainment than traditional stroboscopic lights. It is therefore important to question the common assumption that any level of entrainment is sufficient, and consider the possibility of nonlinear or threshold-based mechanisms that may require a minimum entrainment strength for therapeutic effects. The field needs to empirically test the relationship between entrainment strength and outcome, to ensure efficacy is not compromised for comfort.}, } @article {pmid41134085, year = {2026}, author = {Xu, YJ and Wu, T and Lo, LT and Ko, CC and Wang, X and Ma, CHE}, title = {Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {2}, pages = {e05421}, pmid = {41134085}, issn = {2198-3844}, support = {ITS/099/23FP//Innovation and Technology Commission of the Hong Kong Special Administrative Region (HKSAR) Government/ ; R1005-24F//Research Grant Council of the HKSAR Government/ ; CityU11100424//Research Grant Council of the HKSAR Government/ ; 08193956//Health and Medical Research Fund, Food and Health Bureau, HKSAR Government/ ; 32400807//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *Microglia/metabolism ; *Amyloid beta-Peptides/metabolism ; Mice ; *Phagocytosis/genetics ; *tau Proteins/metabolism/genetics ; Disease Models, Animal ; Mice, Transgenic ; Humans ; Male ; }, abstract = {Amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low-dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg-AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H4R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg-AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p-tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF-β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF-β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H4R/cAMP/TGF-β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD.}, } @article {pmid41133841, year = {2025}, author = {Yao, L and Ni, J and Wei, M and Li, T and Li, F and Wang, T and Xiao, W and Shi, J and Tian, J}, title = {Recent Advances in the Application of Artificial Intelligence in Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050410489250930175402}, pmid = {41133841}, issn = {1875-5828}, abstract = {Artificial intelligence (AI) refers to a system that can simulate and execute the processes of human thinking and learning, and make informed decisions. Fueled by the development of AI, the quality and effectiveness of medical work have gained momentum. AI technology plays an increasingly important role in healthcare, exhibiting substantial potential in clinical practice and decision-making processes. In Alzheimer's disease (AD), where early diagnosis and treatment remain challenging due to clinical heterogeneity and insidious progression, AI could offer excellent solutions. AI models can integrate multi-modal data to identify pre-symptomatic biomarkers and stratify high-risk cohorts, improving diagnostic accuracy, assisting with personalizing treatment and care. Furthermore, AI can accelerate drug discovery and development through drug-target identification and predictive modeling of compound efficacy. However, data quality, supervision, transparency, privacy, and ethical concerns need to be addressed. By identifying and retrieving studies for the systematic review, this article provides a comprehensive overview of current progress and related AI applications in AD.}, } @article {pmid41133228, year = {2025}, author = {Wang, S and Shi, Y and Xin, R and Kang, H and Xiong, H and Ren, J}, title = {Exploring the role of insulin resistance in bridging the metabolic syndrome and Alzheimer's disease-a review of mechanistic studies.}, journal = {Frontiers in endocrinology}, volume = {16}, number = {}, pages = {1614006}, pmid = {41133228}, issn = {1664-2392}, mesh = {*Insulin Resistance/physiology ; Humans ; *Alzheimer Disease/metabolism/pathology/etiology ; *Metabolic Syndrome/metabolism/pathology ; Animals ; Oxidative Stress ; Renin-Angiotensin System ; }, abstract = {The association between metabolic syndrome (MetS) and Alzheimer's disease (AD) has attracted widespread attention; nevertheless, the precise mechanism of action between the two is not yet fully elucidated. This review systematically explores the complex mechanisms of insulin resistance (IR) in MetS and AD. We first detail the intrinsic mechanisms of insulin resistance and emphasize its central role in the pathophysiology of MetS. Further, we reveal the underlying mechanisms by which insulin resistance in turn triggers AD through a multidimensional pathway that promotes the accumulation of pathological products, induces blood-brain barrier dysfunction, impairs neuroplasticity, induces neuroinflammatory responses, aberrantly activates the renin-angiotensin-aldosterone system, and exacerbates oxidative stress. In addition, we summarize potential strategies for targeting IR in AD treatment and demonstrate the promising prospects for improving insulin resistance in promoting cognitive recovery. This study offers a novel theoretical framework for elucidating the intricate relationship between MetS and AD. Furthermore, it provides a scientific foundation for the formulation of preventive and therapeutic strategies for metabolic and neurodegenerative diseases.}, } @article {pmid41132583, year = {2025}, author = {Zou, Z and Lei, D and Wang, X and Yin, Y and Li, H and Di, X and Li, X}, title = {Crocin Ameliorates Cognitive Impairment and Pathological Changes in Alzheimer's Disease Model Mice by Regulating Gut Microbiota.}, journal = {Food science & nutrition}, volume = {13}, number = {10}, pages = {e71117}, pmid = {41132583}, issn = {2048-7177}, abstract = {Alzheimer's disease (AD), a primary cause of dementia, places a significant strain on both patients and society due to the absence of effective treatments. Recent research suggests that the gut microbiota may play a role in the development of AD. Crocin, a compound derived from traditional medicine, has demonstrated potential in alleviating neurological disorders and influencing gut microbiota, yet its specific mechanisms in AD remain unclear. In this study, we administered Crocin or saline to 5xFAD mice and wild-type controls. We discovered that Crocin treatment led to notable improvements in cognitive function, as measured by the Morris water maze test, reduced beta-amyloid (Aβ) accumulation, and decreased neuroinflammation, as indicated by reduced microglial and astrocyte activation. Metagenomic sequencing revealed a significant increase in the gut microbiota diversity, specifically the abundance of Firmicutes, Verrucomicrobiota, and Akkermansia. Additionally, Crocin enhanced intestinal barrier function by upregulating tight junction proteins and Secretory immunoglobulin A, while improving the structure of the jejunal mucosa. These results suggest that Crocin may alleviate cognitive deficits and neuropathological changes in 5xFAD mice, possibly through modulation of the gut microbiota and strengthening the gut barrier, presenting it as a promising therapeutic approach for AD.}, } @article {pmid41132573, year = {2025}, author = {Sriramcharan, P and Ahmed, SS and Natarajan, J and Kumar, RR and Antony, J and Kumar, AP and Anjali, PB and Ganganagappa, N and Shah, RM and Madar, IH}, title = {Cerium oxide nanoparticles synthesized via green route exhibit neuroprotective effects in Alzheimer's-induced Albino Wistar rats.}, journal = {3 Biotech}, volume = {15}, number = {11}, pages = {398}, pmid = {41132573}, issn = {2190-572X}, abstract = {UNLABELLED: Green synthesis of cerium oxide nanoparticles emerges as a feasible therapeutic strategy for disorders like Alzheimer's to determine its antioxidant and cytotoxicity in the in vitro environment, following in vivo studies, safety and effectiveness were confirmed. This approach has gained increased reliability compared to physical and chemical methods due to its non-toxic and environmentally friendly nature. The synthesized nanoparticles are then characterized using Fourier transform infrared spectrometry (FTIR), particle size, scanning electron microscopy (SEM), X-ray diffraction (XRD), and Raman spectroscopy. Design optimization was applied to the selected variables to get the best-fit values of the experiment. FTIR spectroscopy revealed amide, carboxyl, and ester groups in the cerium oxide particles produced by Candida albicans, indicating their significance in nanoparticle stabilization. The particle size and zeta potential of cerium oxide nanoparticles were found to be 152 nm and - 15 mV, respectively. Various antioxidant studies, such as 2, 2-Diphenyl-2-Picryl Hydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS), anti-lipid peroxidation, and catalase, were conducted, revealing that synthesized nanoparticles had high antioxidant activity. SEM images produced high-quality, evenly distributed images. Cerium oxide nanoparticles effectively inhibited SK-N-SH human neuroblastoma cells, with an IC50 value of 65 µg/ml. An in vivo study was performed using an amyloid-beta-induced intracerebroventricular rat model. The finding demonstrates the induction of AD in rats led to spatial memory impairments, whereas the treatment with cerium oxide nanoparticles suggests a significant improvement in neuroprotective effect. This outcome was validated through Morris water maze behavioral assessment and histopathological analysis. The results indicated that the synthesized cerium oxide nanoparticles, optimizing using the Box-Behnken design, resulted in strong antioxidant and cytotoxic activities (65%). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04563-4.}, } @article {pmid41131967, year = {2025}, author = {Javed, A and Mandal, P and Khan, I and Singh, A and Akhtar, J and Maheshwari, S and Prajapati, BG}, title = {Liposomal Drug Delivery for Neurological Disorders: Advances and Challenges.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {25}, number = {3}, pages = {245-260}, pmid = {41131967}, issn = {1875-6166}, mesh = {Humans ; *Liposomes/chemistry/administration & dosage/metabolism ; *Drug Delivery Systems/methods/trends ; *Nervous System Diseases/drug therapy/metabolism ; Animals ; Blood-Brain Barrier/drug effects/metabolism ; *Neuroprotective Agents/administration & dosage ; }, abstract = {Liposomal drug delivery methods are becoming increasingly viable options for improving treatment outcomes for neurological illnesses. These systems provide a flexible framework for the formulation of medications intended for delivery to the brain, protecting the medication from enzymatic breakdown and enhancing its bioavailability. To maximize liposome-drug interactions and improve brain-targeted delivery efficiency, a variety of formulation strategies are used, such as surface modification and remote loading. By utilizing various pathways to cross the blood- -brain barrier (BBB), such as passive diffusion and receptor-mediated transcytosis, liposomes facilitate the effective transport of therapeutic drugs to the brain parenchyma. Liposomal formulations show potential for targeted drug delivery, reducing off-target effects, and improving treatment efficacy in neurological conditions like Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis, and brain cancers. For instance, in Parkinson's disease, liposomal delivery of neuroprotective agents can help maintain dopamine levels and protect dopaminergic neurons. In Alzheimer's disease, liposomes can be engineered to deliver drugs that reduce amyloid-beta plaques or tau tangles. For brain cancer, liposomal chemotherapy can target tumor cells more precisely while minimizing damage to surrounding healthy tissue. In stroke, liposomal delivery of neuroprotective agents can reduce the extent of brain damage, while in multiple sclerosis, liposomes can be used to deliver drugs that modulate the immune response. However, the clinical translation of liposomal drug delivery systems for brain diseases faces challenges related to scalability, stability, and immunogenicity, in addition to regulatory barriers. Scalability issues arise from the complex manufacturing processes required to produce liposomes consistently on a large scale. Stability concerns involve maintaining the integrity of liposomes during storage and after administration. Immunogenicity can be a problem if the liposomes trigger an unwanted immune response, potentially reducing their effectiveness or causing adverse effects. To overcome these obstacles, multidisciplinary cooperation is essential. Collaboration among materials scientists, pharmacologists, neurologists, and regulatory experts can drive the development of more robust liposomal formulations. Continuous research is needed to refine liposome designs, such as by optimizing lipid composition, surface charge, and size to improve stability and targeting capabilities. Advanced techniques like PEGylation (coating liposomes with polyethylene glycol) can help reduce immunogenicity and extend circulation time in the bloodstream. Despite these challenges, liposomal methods present intriguing prospects for transforming medication administration to the brain and offering effective treatments for neurological illnesses. The development of more sophisticated liposomal technologies, combined with a deeper understanding of their mechanisms of action, could lead to significant breakthroughs in the treatment of neurological disorders. For example, research into ligand- targeted liposomes, which use specific molecules to bind to receptors on the BBB, holds promise for enhancing delivery specificity and efficiency. To fully realize the therapeutic promise of these novel drug delivery systems, further advancements in liposomal technologies and a deeper understanding of their mechanisms are necessary. This includes not only technical improvements but also comprehensive preclinical and clinical studies to evaluate safety, efficacy, and long-term effects. As our knowledge expands and technology progresses, liposomal drug delivery could become a cornerstone of neurological disease treatment, providing new hope for patients with previously intractable conditions.}, } @article {pmid41131557, year = {2025}, author = {Buchanan, RA and Kramer, AT and Calipari, ES and Bowman, AB and Nobis, WP and Harrison, FE}, title = {Differential impact of manganese on glutamate clearance, electroencephalography, and sleep in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70821}, pmid = {41131557}, issn = {1552-5279}, support = {DK135073/DK/NIDDK NIH HHS/United States ; DK020593/DK/NIDDK NIH HHS/United States ; //FEH and ABB/ ; T32 ES007028/ES/NIEHS NIH HHS/United States ; P50 HD103537/HD/NICHD NIH HHS/United States ; HD103537//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01 ES031401/ES/NIEHS NIH HHS/United States ; R01 ES035518/ES/NIEHS NIH HHS/United States ; ES007028/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Manganese/toxicity/metabolism/pharmacology ; Electroencephalography ; *Glutamic Acid/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Sleep/drug effects ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; *Brain/drug effects/metabolism ; Mice, Inbred C57BL ; }, abstract = {INTRODUCTION: Underlying glutamate dysregulation in Alzheimer's disease can be worsened by environmental factors like manganese (Mn) exposure. This study examined how excess Mn affects glutamatergic signaling and neurotransmission in a beta-amyloid mouse model. METHODS: APP/PSEN1 and control mice were exposed to systemic Mn subcutaneously. Gene expression, glutamate clearance dynamics, electroencephalography (EEG) activity, and sleep architecture were analyzed using quantitative polymerase chain reaction (qPCR), Western blot, ex vivo hippocampal slices, and EEG recordings. RESULTS: Mn exposure elevated brain Mn levels and altered glutamate dynamics in both WT and APP/PSEN1 mice. Wild-type (WT) mice showed faster glutamate clearance, increased spiking, disrupted sleep, and brain wave changes. APP/PSEN1 mice exhibited slower glutamate clearance, altered gene expression, increased glial fibrillary acidic protein (GFAP), and changes in non-rapid eye movement (NREM) delta and rapid eye movement (REM) alpha power. DISCUSSION: Mn exposure altered glutamate clearance and brain activity, particularly in WT mice. APP/PSEN1 mice showed impaired clearance, limited gene expression changes, and altered EEG patterns, suggesting distinct or pre-existing compensatory mechanisms. HIGHLIGHTS: Manganese exposure significantly alters glutamate clearance dynamics differentially in wild-type and APP/PSEN1 mouse models of Alzheimer's disease. Acute manganese treatment disrupts sleep architecture, evidenced by changes in electroencephalography (EEG) patterns and vigilance states. APP/PSEN1 mice exhibit slower glutamate clearance and altered gene expression compared to wild-type mice following manganese exposure. Distinct brain wave frequency shifts were observed in response to manganese treatment, particularly affecting delta, theta, and alpha rhythms. Findings suggest a potential exacerbation of excitatory/inhibitory imbalances due to environmental manganese exposure in Alzheimer's pathology.}, } @article {pmid41129981, year = {2026}, author = {Wang, B and Chang, Y and Shen, L and Ma, Y and Zhang, Z and Du, J and Wang, Y and Li, Y and Zhao, F and Wang, J and Pang, X and Fan, W and Du, L and Yan, L}, title = {Multifunctional near-infrared fluorescent probe for imaging of hydrogen peroxide and photodynamic therapy of amyloid-β aggregation in Alzheimer's disease.}, journal = {Talanta}, volume = {298}, number = {Pt B}, pages = {129009}, doi = {10.1016/j.talanta.2025.129009}, pmid = {41129981}, issn = {1873-3573}, mesh = {*Hydrogen Peroxide/analysis/metabolism ; *Alzheimer Disease/drug therapy/metabolism/diagnostic imaging ; *Amyloid beta-Peptides/metabolism/chemistry ; *Photochemotherapy ; *Fluorescent Dyes/chemistry/pharmacology/chemical synthesis ; Animals ; Humans ; *Photosensitizing Agents/chemistry/pharmacology/chemical synthesis/therapeutic use ; Mice ; Infrared Rays ; Protein Aggregates/drug effects ; Optical Imaging ; }, abstract = {Photodynamic therapy (PDT) has shown significant potential in eliminating amyloid-β (Aβ) aggregates, the characteristic pathological marker of Alzheimer's disease (AD). However, traditional photosensitizers have limitations such as off-target oxidation and single functionality, which severely hinder their specificity and therapeutic efficiency in clearing Aβ plaques. Given the complexity of AD's pathological mechanisms, the development of novel photosensitizers with both targeting ability and multifunctionality has become an urgent priority. In this study, a H2O2-responsive near-infrared (NIR) fluorescent probe ENBS-P was designed and synthesized. By integrating the dual functions of H2O2 visualization and precise photodynamic therapy, it has achieved efficient application in both in vitro and in vivo models. ENBS-P could be specifically activated by H2O2 to release ENBS, resulting in a significant enhancement of fluorescence signal at 720 nm (λex = 640 nm), thus realizing highly sensitive in situ detection of H2O2 (LOD = 0.2 μM). In addition, benefiting from a more efficient intersystem crossing (ISC) process from S1 to T1, the therapeutic molecule ENBS, generated after the specific activation of ENBS-P by H2O2, could produce superoxide radical anions (O2[-•], Type I photoreaction) under NIR light excitation. Importantly, through imaging-guided PDT, it could effectively inhibit the aberrant aggregation of Aβ42 and promote the dissociation of formed aggregates. This study overcomes the limitations of traditional photosensitizers by providing an innovative "diagnosis-treatment" integrated strategy for the early diagnosis and therapy of AD, holding significant promise for advancing precision medicine in AD.}, } @article {pmid41129661, year = {2025}, author = {Wu, CS and Huang, WL and Wang, SH and Wu, MS and Chen, KS and Cheng, SH and Chiu, YM}, title = {Association Between Autoimmune Diseases, Treatments, and Dementia Risk: A Population-Based Case-Control Study From Taiwan.}, journal = {The Journal of clinical psychiatry}, volume = {86}, number = {4}, pages = {}, doi = {10.4088/JCP.25m15774}, pmid = {41129661}, issn = {1555-2101}, mesh = {Humans ; Taiwan/epidemiology ; Female ; Male ; *Autoimmune Diseases/epidemiology/drug therapy/complications ; *Dementia/epidemiology/etiology ; Middle Aged ; Aged ; Case-Control Studies ; Comorbidity ; Prevalence ; Aged, 80 and over ; Risk Factors ; Immunosuppressive Agents/therapeutic use ; }, abstract = {Objectives: This study aimed to assess the risk of dementia associated with specific autoimmune diseases and the impact of related pharmacologic treatments. Methods: Patients 55 years or older diagnosed with dementia by neurologists or psychiatrists between 2010 and 2021 were identified using claims data from Taiwan's National Health Insurance program. We examined 22 autoimmune diseases for their associations with dementia, controlling for age, gender, urbanization level, and comorbidities. Results: Dementia prevalence was higher among individuals with autoimmune diseases (10.5% in cases vs. 8.7% in comparisons). Thirteen autoimmune diseases were linked with an elevated dementia risk, particularly Behçet disease, multiple sclerosis, and systemic lupus erythematosus. Associations with vascular dementia were stronger than with Alzheimer disease. Although overall dementia risk was higher in women, no significant sex differences were observed for specific autoimmune diseases. Nonsteroidal anti-inflammatory drugs and corticosteroids did not significantly alter dementia risk among individuals with autoimmune diseases; however, immunosuppressants were associated with a reduced risk when used for more than 180 days. Conclusions: Certain autoimmune diseases are significantly associated with an increased risk of dementia, particularly vascular dementia, highlighting the distinct role of inflammation. Effective prevention or treatment of autoimmune diseases may reduce dementia incidence by 0.8%. While immunosuppressants show potential for risk reduction, further prospective studies are needed to confirm this effect.}, } @article {pmid41128826, year = {2025}, author = {Hoveizi, E and Bijavi, G and Parsa, H}, title = {Advancing Cell Therapy to Enhance Passive Avoidance Memory: Integrative Approaches Combining Neural-Like Cells and Rosmarinic Acid Through Behavioral, Molecular, and Histological Analyses.}, journal = {Neurochemical research}, volume = {50}, number = {6}, pages = {334}, pmid = {41128826}, issn = {1573-6903}, mesh = {Animals ; Rosmarinic Acid ; *Depsides/pharmacology/therapeutic use ; *Cinnamates/pharmacology/therapeutic use ; Male ; *Alzheimer Disease/therapy/metabolism/pathology ; Rats ; *Avoidance Learning/physiology/drug effects ; *Cell- and Tissue-Based Therapy/methods ; *Memory/physiology/drug effects ; Mesenchymal Stem Cells/cytology ; Rats, Sprague-Dawley ; *Neurons/drug effects/metabolism ; Cell Differentiation/physiology/drug effects ; Dental Pulp/cytology ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration, synaptic dysfunction, and cognitive decline. Regenerative strategies aim to replace lost neurons and modulate the inflammatory milieu to restore neural networks. This study examined the effects of neural-like cells (NLCs) derived from dental pulp mesenchymal stem cells (DPSCs) on a chitosan scaffold using rosmarinic acid (RA) in AD rats. In this study, DPSCs were extracted from teeth, characterized and differentiated, induced an AD model by destroying the Meynert nucleus, conducted passive avoidance tests, analyzed histology and immunohistochemistry, and measured inflammatory and oxidative stress markers. The extraction and differentiation of DPSCs were successful. Differentiated DPSCs into neural progenitors showed increased expression of Tuj-1, Map2, Nestin, and NF (RT-PCR, p < 0.001). Behavioral tests confirmed the AD model after seven days, and histology showed neuronal loss and gliosis following Meynert destruction. Histomorphology revealed improved brain tissue and significantly increased choline acetyltransferase (ChAT) expression in the treatment groups. Notable behavioral improvements were observed in the Y‑maze and shuttle box for treated rats compared with the AD group. Biochemical analyses showed a significant decrease in inflammatory markers IL‑1β, IL‑6, and TNF‑α, along with increases in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) in the RA-treated groups. The results provide reliable evidence that DPSCs, in combination with RA, exert a promising therapeutic effect and represent a meaningful advance toward the clinical application of combination therapies for patients with AD.}, } @article {pmid41127243, year = {2025}, author = {Li, G and Li, S and Zhou, W}, title = {Kynurenine pathway: a possible new mechanism for exercise in the prevention and treatment of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1617690}, pmid = {41127243}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease in clinical practice. The kynurenine pathway (KP) is a potential intersection of factors associated with the development of AD (central nervous inflammation, glutamate excitotoxicity, and tau phosphorylation, among others). Pharmacological modulators targeting KP enzymes, such as inhibitors or agonists, and their major neuroprotective metabolites are beneficial in alleviating AD progression. Exercise significantly improves AD symptoms and also impacts KP pharmacokinetics. Promoting the production of neuroprotective active metabolites by KP may be one of the central mechanisms by which exercise improves AD symptoms. This article reviews the possible role of KP in AD neurodegeneration and AD exercise prevention and treatment.}, } @article {pmid41126950, year = {2025}, author = {Frost, B and Kolb, H and Algeciras-Schimnich, A and Betthauser, TJ and DeVos, S and Edelmayer, RM and Elwood, F and Fleisher, AS and Henley, D and Horie, K and Hyman, B and Kreisl, WC and Kulic, L and Leuzy, A and Palma, JA and Parmentier-Batteur, S and Patru, MM and Rabinovici, GD and Reyderman, L and Sperling, RA and Van Der Geyten, S and Wildsmith, KR and Mahinrad, S and Carrillo, MC and Weber, CJ}, title = {Tau biology, biomarkers, and therapeutics.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {4}, pages = {e70165}, pmid = {41126950}, issn = {2352-8737}, abstract = {UNLABELLED: As Alzheimer's disease (AD) research advances, tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. The Fall 2024 Alzheimer's Association Research Roundtable convened experts from academia, industry, National Institutes of Health (NIH), and the United States Food and Drug Administration (FDA) to explore current progress and future directions in tau-centered diagnostics and therapeutics. Discussions addressed the integration of tau biomarkers into the 2024 Revised Diagnostic Criteria for AD, updates to amyloid and tau positron emission tomography (PET) imaging, and modeling of biomarker trajectories. Presenters highlighted tau-targeting therapeutics including antisense oligonucleotides, monoclonal antibodies, and small molecules, alongside innovations in drug delivery. The interplay between anti-amyloid and anti-tau therapies and strategic design of combination trials were key themes. Regulatory insights facilitated discussions on drug approval pathways. The meeting highlighted the rapid evolution of tau research and emphasized opportunities to improve diagnostics, trial design, and treatment strategies in AD. HIGHLIGHTS: The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government, to explore current progress and future directions in tau-centered diagnostics and therapeutics.Tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development.Discussions addressed the integration of tau biomarkers into the 2024 revised diagnostic criteria for AD, updates to amyloid and tau PET imaging, modeling of biomarker trajectories, tau-targeting therapeutics, and interplay between anti-amyloid and anti-tau therapies and strategic design of combination trials.}, } @article {pmid41126823, year = {2025}, author = {Atkinson, J and Dokiburra, A and Groover, H and Godbout, JP and Segal, BM and Zhang, Y}, title = {Targeting senescent microglia in progressive multiple sclerosis: a geroscience-informed approach.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1681724}, pmid = {41126823}, issn = {1664-3224}, mesh = {Animals ; *Microglia/drug effects/pathology/metabolism/immunology ; Mice ; *Encephalomyelitis, Autoimmune, Experimental/drug therapy/immunology/pathology ; *Cellular Senescence/drug effects ; Humans ; *Multiple Sclerosis/drug therapy/pathology ; *Senotherapeutics/pharmacology/therapeutic use ; Female ; Disease Models, Animal ; Senescence-Associated Secretory Phenotype/drug effects ; *Multiple Sclerosis, Chronic Progressive/drug therapy/pathology ; Mice, Inbred C57BL ; }, abstract = {Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disorder of the central nervous system (CNS). Age is the strongest predictor of disease phenotype, with the majority of older adults transitioning to a progressive form marked by irreversible neurological decline. This clinical progression is associated with smoldering, CNS-compartmentalized inflammation and neurodegeneration, for which there are currently no effective disease-modifying therapies. Cellular senescence, characterized by the secretion of pro-inflammatory mediators collectively known as the senescence-associated secretory phenotype (SASP), increases with age and contributes to tissue injury. In MS, neuroinflammation can further promote cellular senescence, creating a self-reinforcing cycle of damage. Senescent microglia have been identified within MS lesions, where their SASP may impair remyelination and exacerbate neurodegeneration. Senolytic agents selectively target and eliminate senescent cells by disrupting anti-apoptotic pathways. In experimental autoimmune encephalomyelitis (EAE), a widely used model of MS, senolytic treatment reduces senescent microglia burden and attenuates disease severity in an age- and drug-dependent manner. Specifically, here we show that middle-aged mice (40-44 weeks) with EAE exhibit improved clinical outcomes and survival following treatment with either dasatinib plus quercetin (D+Q) or navitoclax. Early-phase clinical trials of senolytics in age-related diseases have demonstrated functional benefits, including improved gait speed in idiopathic pulmonary fibrosis and CNS penetrance in Alzheimer's disease. Translating senolytic therapy to MS will require careful selection of CNS-penetrant and well-tolerated agents, identification of appropriate patient populations, and deployment of responsive biomarkers. Senolytic therapy represents a promising geroscience-based strategy to meet the urgent therapeutic need in progressive MS.}, } @article {pmid41126448, year = {2025}, author = {Biel, D and Steward, A and Dewenter, A and Dehsarvi, A and Zhu, Z and Roemer-Cassiano, SN and Frontzkowski, L and Hirsch, F and Palleis, C and Höglinger, G and Brendel, M and Franzmeier, N and , }, title = {A systematic comparison of ATN biomarkers for monitoring longitudinal cognitive changes in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70783}, pmid = {41126448}, issn = {1552-5279}, support = {EXC2145SyNergy-ID390857198//Munich Cluster for Systems Neurology/ ; AARG-22-973496/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Biomarkers/blood ; *tau Proteins/blood ; Positron-Emission Tomography ; Male ; Female ; Longitudinal Studies ; Aged ; Magnetic Resonance Imaging ; Amyloid beta-Peptides ; Aged, 80 and over ; *Cognitive Dysfunction/diagnostic imaging ; Brain/diagnostic imaging/pathology ; Cognition ; }, abstract = {INTRODUCTION: With anti-amyloid beta (Aβ) therapies approved for Alzheimer's disease (AD), surrogate biomarkers are needed to monitor clinical treatment efficacy. Therefore, we systematically compared longitudinal changes in A/T/N biomarkers (amyloid-positron emission tomography [PET], tau-PET, plasma phosphorylated tau at threonine 217 [p-tau217], and magnetic resonance imaging) for tracking cognitive changes. METHODS: We analyzed longitudinal biomarker and cognitive change rates from the Alzheimer's Disease Neuroimaging Initiative (N = 141) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) (N = 151), estimated using linear mixed models. Using linear models, we tested biomarker changes as predictors of cognitive changes, comparing predictive strengths across biomarkers using bootstrapping. RESULTS: Tau-PET, plasma p-tau217, and cortical thickness changes accurately tracked change rates in Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive Subscale 13-item version, Clinical Dementia Rating-Sum of Boxes, and Preclinial Alzheimer Cognitive Composite scores. In contrast, amyloid-PET change rates were not linked to cognitive changes. DISCUSSION: Plasma p-tau217 offers a cost-effective AD-specific alternative to tau-PET and could potentially be implemented for monitoring cognitive changes in AD trials, while amyloid-PET lacks utility. Cortical thickness changes accurately track cognitive changes but may be confounded by pseudo-atrophy in anti-Aβ treatments. HIGHLIGHTS: Longitudinal changes in tau-PET, plasma p-tau217, cortical thickness - but not amyloid-PET - effectively track cognitive decline. Cortical thickness may be confounded by pseudo-atrophy in anti-Aβ trials. Plasma p-tau217 is a robust and cost-effective alternative to tau-PET as an AD-specific surrogate biomarker for monitoring cognitive changes.}, } @article {pmid41126430, year = {2025}, author = {Alhawarri, MB}, title = {Hypothesis-Driven Insights and Clinical Trial Updates in Alzheimer's Disease Pathogenesis.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273387383250924031644}, pmid = {41126430}, issn = {1996-3181}, abstract = {BACKGROUND: Alzheimer's disease (AD) is the primary cause of dementia and a significant threat to healthy aging. The prevalence of AD and other non-communicable diseases (NCDs) is significantly influenced by the progressive decline in physiological functions that is associated with aging. METHODS: This review summarizes the results of drug interventions for AD that have been conducted in the past five years, with a particular emphasis on Phase I, Phase III, and Phase IV clinical trials. Systematic investigations of clinical trial registries and databases were employed to identify clinical trials. A total of 106 Phase I, 52 Phase III, and 13 Phase IV trials were considered, excluding studies on devices, biologics, and diagnostic tests. RESULTS: This review summarizes a wide range of therapy approaches aimed at different facets of AD pathogenesis, including amyloid-beta aggregation, tau protein dysfunction, neuroinflammation, synapse loss, and metabolic dysregulation. AD's complex nature highlights the need for multi-target treatment strategies, which may encompass combination therapies and innovative targets that show potential in addressing the complex pathogenesis of AD. DISCUSSION: Current clinical studies demonstrate a variety of therapies aimed at various pathogenic processes of AD. Progress in therapeutic discovery, including synthetic molecules and bioactive natural materials, suggests potential strategies for successful AD treatment. The efficacy of natural products as therapeutic agents is especially significant because of their multi-target effects. CONCLUSION: Effective strategies to prevent the progression of AD require a thorough comprehension of its complex pathophysiology. Current clinical studies are essential for discovering viable chemicals and treatment strategies to combat this multifactorial neurodegenerative disorder, AD.}, } @article {pmid41125269, year = {2025}, author = {Lin, DE and Gunaga, S and Mowbray, FI and Isaacs, ED and Markwalter, D and George, N and Hay, AE and Manfredi, R and Westlake, E and Akhter, M and Bowman, JK and Rebollo-Lee, N and Gacioch, B and Ginsburg, AD and Brooten, JK and Pajka, S and Selman, K and Bain, P and Davis, JJ and Liu, S and Ouchi, K}, title = {Emergency department-initiated palliative care screening among older adults: a systematic review and meta-analysis protocol.}, journal = {BMJ open}, volume = {15}, number = {10}, pages = {e095894}, pmid = {41125269}, issn = {2044-6055}, mesh = {Humans ; *Palliative Care/methods ; Systematic Reviews as Topic ; *Emergency Service, Hospital ; Aged ; Meta-Analysis as Topic ; Quality of Life ; Research Design ; Length of Stay/statistics & numerical data ; *Mass Screening/methods ; Hospitalization/statistics & numerical data ; }, abstract = {INTRODUCTION: The rapidly growing population of older adults (individuals aged 65 years and older) presents a new set of challenges for healthcare providers in the emergency department (ED), given the prevalence of severe and life-threatening conditions among this group, such as chronic cancer, Alzheimer's disease/dementia and congestive heart failure. ED encounters often represent a critical point in an older patient's trajectory of care and can thus be an important opportunity for various interventions such as palliative care consultation. Therefore, identifying those who will benefit most from palliative care is of high importance, especially in determining the course of future treatment. Thus, we aim to conduct a systematic review assessing the efficacy of palliative care screening in the ED by assessing inpatient length of stay as the primary outcome and quality of life, percentage of hospitalisation and cost of care as secondary outcomes. METHODS: This study will use Ovid MEDLINE, Embase, EBSCO CINAHL, Web of Science and Cochrane as databases. The study population comprises adults aged 60 years and older, with no focus on any specific clinical specialty or disease. Patients who have not received palliative care screening will serve as the comparator. Only studies with an applicable comparator will be considered. Studies published from 1 January 2000 to 1 July 2025 will be included.All articles will be reviewed independently and in duplicate, and every author will participate in the review, data abstraction and conflict resolution process. ETHICS AND DISSEMINATION: Ethical approval is not required as it is a protocol for a systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42024562389.}, } @article {pmid41124320, year = {2025}, author = {Li, C and Feng, L and Li, M and Dai, C}, title = {Research progress on the regulation of Nrf2/HO-1 signaling pathway by traditional Chinese medicine in the treatment of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1475-1487}, doi = {10.1177/13872877251389011}, pmid = {41124320}, issn = {1875-8908}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *NF-E2-Related Factor 2/metabolism ; *Signal Transduction/drug effects/physiology ; *Medicine, Chinese Traditional/methods ; *Heme Oxygenase-1/metabolism ; Animals ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder with a complex pathogenesis. Oxidative stress, neuroinflammation and apoptosis play key roles in the occurrence and development of AD. The Nrf2/HO-1 signaling pathway, as an important endogenous antioxidant stress pathway in cells, is of great significance in combating oxidative damage and neurodegeneration. In recent years, an increasing number of studies have shown that traditional Chinese medicine can exert therapeutic effects on AD by regulating the Nrf2/HO-1 signaling pathway. This article aims to review the research progress of traditional Chinese medicine in regulating the Nrf2/HO-1 signaling pathway for the treatment of AD, providing new ideas and strategies for the treatment of AD.}, } @article {pmid41124311, year = {2025}, author = {Sosa Pérez, S and Urrutia Amable, N and Viada González, CE and Lorenzo-Luaces, P and Sánchez Valdés, L and Crombet Ramos, T and León Monzón, K and Rodríguez Obaya, TJ and Pérez Ruiz, L}, title = {NeuroEPO plus (NeuralCIM[®]) in Alzheimer's disease: Post-trial observational follow-up study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {3}, pages = {1422-1435}, doi = {10.1177/13872877251386885}, pmid = {41124311}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Male ; Female ; Follow-Up Studies ; Aged ; *Erythropoietin/therapeutic use/administration & dosage ; Treatment Outcome ; Aged, 80 and over ; Neuropsychological Tests ; Double-Blind Method ; Mental Status and Dementia Tests ; Activities of Daily Living ; Middle Aged ; }, abstract = {BackgroundNeuroEPO plus is a recombinant erythropoietin with a sialic acid content like that produced by astrocytes, lacking the hematopoietic activity of conventional erythropoietin.ObjectiveTo evaluate the efficacy and safety of treatment with neuroEPO plus.MethodsIt was a post-trial observational follow-up study with four groups, NE: subjects who continued treatment with neuroEPO plus after trial, PB-NE: subjects who received a placebo during the trial and then receive neuroEPO plus, NE-CTRL: subjects who received neuroEPO plus during the trial and then interrupted treatment and CTRL: subjects who were never treated. NeuroEPO plus was administrated three times a week nasally. The primary outcome was changed from baseline in the score on the11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog11) at 96 weeks. Secondary outcomes included Global Deterioration Scale, Montreal Cognitive Assessment, Neuropsychiatric Inventory, and Lawton Instrumental Activities of Daily Living Scale.ResultsThe adjusted median change from baseline in the ADAS-Cog11 score at 96 weeks was -6.0 in NE group and 11.0 in the CTRL group (difference, 21.0; 95% confidence interval [CI], 14.6-27.4; p = 0.000), -1.0 in the PB-NE (difference, 15.4; 95% CI, 9.0-21.8; p = 0.000) and 4.0 in the NE-CTRL (difference, 8.3; 95% CI, 1.4-15.2; p = 0.011). The results for secondary outcomes showed statistically significant differences.ConclusionsSubjects who continued or started treatment with neuroEPO plus stabilized or slowed down the progression of the disease. These results and the method of drug administration, make neuroEPO plus an attractive option to consider for Alzheimer's disease patients.}, } @article {pmid41124234, year = {2025}, author = {Sun, Y and Jiang, X and Yi, X and Wang, C and Zhang, X and Shen, R and Yang, A and Kou, X}, title = {Novel Biochanin A Carbamate Derivatives as Multifunctional Anti-Alzheimer's Disease Metal Chelators: Design, Synthesis, and Activity Evaluation.}, journal = {Chemistry & biodiversity}, volume = {22}, number = {12}, pages = {e01827}, doi = {10.1002/cbdv.202501827}, pmid = {41124234}, issn = {1612-1880}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Chelating Agents/chemistry/chemical synthesis/pharmacology ; *Genistein/chemistry/pharmacology/chemical synthesis ; *Drug Design ; Humans ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Structure-Activity Relationship ; Animals ; *Carbamates/chemistry/pharmacology/chemical synthesis ; Reactive Oxygen Species/metabolism ; Molecular Structure ; Rats ; Dose-Response Relationship, Drug ; Cell Survival/drug effects ; Acetylcholinesterase/metabolism ; Neuroprotective Agents/chemical synthesis/chemistry/pharmacology ; }, abstract = {Considerable evidence suggests that metal ions play crucial roles in Alzheimer's disease (AD) progression, spurring the development of metal-involved therapeutic strategies. In this study, biochanin A, a bioactive ingredient derived fromTrifolium pratense L. (a traditional Chinese medicine [TCM]), was identified as a lead compound for the rational design of multifunctional metal chelators. A series of biochanin A derivatives (compounds a-e) was synthesized through a one-step carbamate introduction reaction. Their drug-likeness and pharmacokinetic profiles were assessed using an online prediction server. The bioactivities, including metal ion chelation, β-amyloid aggregation regulation, reactive oxygen species elimination, cholinesterase inhibition, and neurocytotoxicity were evaluated. The results indicated that compounds (a-e) possessed favorable pharmacokinetic profiles and potential as multifunctional metal chelators with minimal neurocytotoxicity, with compound d emerging as a particularly promising candidate. These findings may provide meaningful information for developing novel multifunctional metal chelators for AD treatment and innovative drugs derived from TCM.}, } @article {pmid41123015, year = {2026}, author = {Ebbert, KA and Chen, R and Culibrk, RA and Yeisley, DJ and Hahn, MS}, title = {Rapamycin and Suramin Effects on TNF-⍺-Mediated Mast Cell and Brain Microvascular Endothelial Cell Dysfunction.}, journal = {Biotechnology and bioengineering}, volume = {123}, number = {1}, pages = {255-268}, doi = {10.1002/bit.70082}, pmid = {41123015}, issn = {1097-0290}, support = {//This study was supported, in part, by the National Institute of Health R03AG067140 and R03AG067970 to M.S.H./ ; }, mesh = {*Sirolimus/pharmacology ; *Mast Cells/drug effects/metabolism ; *Endothelial Cells/drug effects/metabolism ; Humans ; *Tumor Necrosis Factor-alpha/metabolism ; *Brain/blood supply ; Microvessels/drug effects ; Cell Line ; Blood-Brain Barrier/drug effects ; Cells, Cultured ; Signal Transduction/drug effects ; }, abstract = {Chronic blood-brain barrier (BBB) disruption due to impaired function of brain microvascular endothelial cells (BMECs) is commonly observed in neuroinflammatory and neurodegenerative conditions. Current treatment approaches are generally limited in their capacity to reduce this dysfunction, with the Akt/mTOR/GSK pathway modulator rapamycin showing recent promise in ameliorating neuroinflammatory BBB dysfunction. Understanding the role of early, cellular level BMEC dysfunction, particularly in the context of interplay with immune cells involved in neuroinflammation, such as mast cells (MCs), is important for identifying targets for therapeutic intervention related to BBB disruption. In the present work, we investigate primary human BMECs and human MC line HMC-1.2 dysfunction in response to inflammatory insult with TNF-α and paracrine interactions, with an emphasis on the Akt/mTOR/GSK pathway-an upstream regulator of angiogenesis and MC activation-and associated extracellular and intracellular cytokine production and oxidative stress. We further compare alterations in BMEC-MC paracrine inflammatory crosstalk in response to Akt/mTOR/GSK pathway modulator suramin (100 µM) relative to rapamycin (250 nM). In monoculture, TNF-α stimulation significantly increased oxidative stress-assessed through measuring PGE2-extracellularly in BMECs. Similarly, proangiogenic and pro-inflammatory cytokine and chemokine secretion was increased in both TNF-α stimulated BMEC and MC monocultures. Additionally, TNF-α stimulation increased BMEC levels of the Akt/mTOR/GSK pathway intermediates p-p70S6K and p-RPS6 and MC levels of p-GSK3α and p-GSK3β. Coculture of TNF-α stimulated BMECs and MCs resulted in a modest increase in extracellular PGE2, and effects on extracellular cytokine/chemokine levels were primarily limited to increases in pro-inflammatory CCL2, CCL3 and CCL5 relative to TNF-α-stimulated BMEC monoculture. In contrast, the levels of intracellular cytokines in MCs increased 2-100 fold with TNF-α-stimulated coculture, concomitant with a decrease in MC p-p70S6K levels. Rapamycin treatment of TNF-⍺-stimulated cocultures resulted a modest increase in extracellular PGE2 as well as decreases in extracellular chemokines CCL2 and CCL3. In contrast, suramin treatment significantly decreased extracellular PGE2, GM-CSF, CCL2, and CCL5 while markedly increasing the BBB-stabilizing PDGF-BB. However, suramin also increased intracellular BMEC levels of multiple pro-inflammatory cytokines. Neither rapamycin nor suramin improved the intracellular inflammatory profile of cocultured MCs, indicating that MC activation had not been resolved by either treatment.}, } @article {pmid41122827, year = {2025}, author = {Tang, S and Wu, Y and Wang, R and Li, Y and Li, J and Peng, Y and Liu, S and Men, L and Hou, Z and Liu, Z and Liu, Z}, title = {Revealing the Formula Pattern of Congming Decoction by Ultra-High-Performance Liquid Chromatography Coupled With Quadrupole-Orbitrap Mass Spectrometry From the Perspective of Chemical Constituents, In Vitro, and In Vivo Properties.}, journal = {Journal of separation science}, volume = {48}, number = {10}, pages = {e70306}, doi = {10.1002/jssc.70306}, pmid = {41122827}, issn = {1615-9314}, support = {82274062//National Natural Science Foundation of China/ ; 20240602085RC//Department of Science and Technology of Jilin Province/ ; 20220101289JC//Natural Science Foundation of Jilin Province/ ; }, mesh = {Chromatography, High Pressure Liquid ; Animals ; *Drugs, Chinese Herbal/chemistry/analysis/pharmacokinetics/metabolism ; Rats ; Mass Spectrometry ; Rats, Sprague-Dawley ; Male ; Medicine, Chinese Traditional ; }, abstract = {The Congming decoction (CMD) is a classic traditional Chinese medicine formula, composed of Poria cocos (Schw.) Wolf, Polygalae Radix, and Acori Tatarinowii Rhizoma. The material basis for the rationality of CMD's compatibility remains unclear in both in vitro and in vivo studies. The relationship between its components and therapeutic efficacy still presents a research gap. Therefore, this study aims to reveal the co-extraction dissolution patterns, metabolic regularity in vitro, and absorption and distribution characteristics in vivo of CMD, thereby exploring the scientific connotation of formulation. Utilizing ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry technology, a total of 183 constituents were identified in CMD, with 72 recognized as differential compounds before and after combination, suggesting that co-boiling enhances the solubility of active ingredients. In vitro intestinal microbiota results indicated that combination reduced metabolism rates, allowing for greater absorption as the prototype. In vivo analysis identified 62 constituents within rat plasma and tissues; comparing content differences among groups found that the combinations regulate hepatic metabolism and enhance distribution of effective components, potentially serving as a significant material basis for treating Alzheimer's disease (AD). Furthermore, a targeted network pharmacology strategy was established to explore the mechanism of CMD in treating AD. This study clarified the chemical composition, metabolic patterns in vitro, and distribution rules in vivo regarding CMD, and also compared variations before and after composition. It provided new insights into the rationality of CMD's compatibility in the treatment of AD from multiple dimensions and levels.}, } @article {pmid41122812, year = {2025}, author = {Dodge, HH and Chen, L and Wu, CY and Cutter, G and Bowman, GL and Feldman, HH and Arnold, SE}, title = {Seeking optimal repeated fluid biomarker assessments to enhance precision and statistical power in clinical trials: SLIM method.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70787}, pmid = {41122812}, issn = {1552-5279}, support = {//the Epstein Family Collaboration of Powder for Pennies/ ; P30AG062421/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; *Alzheimer Disease/blood/cerebrospinal fluid ; *Clinical Trials as Topic/methods ; *Research Design ; Computer Simulation ; }, abstract = {INTRODUCTION: Plasma biomarkers are increasingly used as surrogate outcomes in clinical trials for Alzheimer's disease and related dementias (ADRD) due to their non-invasive nature. In early-phase trials designed to evaluate mechanisms of action and biological efficacy, assessing pre-post changes in plasma biomarkers within the same individuals - using a single-arm placebo lead-in design - offers a potentially cost-effective alternative to parallel-group designs by minimizing between-subject variability. However, plasma biomarkers are also subject to within-individual variability, which can obscure true treatment effects. METHODS: One strategy to address this limitation is to collect repeated measures during each study period. This approach can improve measurement precision, enhance the signal-to-noise ratio, and increase statistical power, even with modest sample sizes. RESULTS: We propose an innovative early-phase trial design, Single-arm Lead-In with Multiple measures (SLIM), which incorporates repeated biomarker assessments over a short follow-up period. DISCUSSION: Using simulation studies, we demonstrate that the SLIM design can substantially reduce required sample sizes. HIGHLIGHTS: SLIM involves repeated biomarker assessments during both the lead-in and post-treatment periods. It minimizes between-subject variability and improves the precision of within-subject estimates. It is well suited for early-phase, short-duration trials. It is not suitable for cognitive tests or other outcomes prone to practice or placebo effects. SLIM design can be an alternative to the traditional parallel design by reducing required sample sizes, thereby lowering the recruitment burden.}, } @article {pmid41122803, year = {2025}, author = {Chaunsali, L and Li, J and Fleischel, E and Prim, CE and Kasprzak, I and Jiang, S and Hou, S and Escalante, M and Cope, EC and Olsen, ML and Tewari, BP and Sontheimer, H}, title = {Degradation of perineuronal nets in hippocampal CA2 explains the loss of social cognition memory in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70813}, pmid = {41122803}, issn = {1552-5279}, support = {R01NS123069/NH/NIH HHS/United States ; R01 NS123069/NS/NINDS NIH HHS/United States ; R01 NS036692/NS/NINDS NIH HHS/United States ; R01NS036692/NH/NIH HHS/United States ; R01 AG065836/AG/NIA NIH HHS/United States ; R01AG065836/NH/NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/psychology/genetics ; Mice ; Disease Models, Animal ; *CA2 Region, Hippocampal/metabolism/pathology ; *Extracellular Matrix/metabolism ; Mice, Transgenic ; Matrix Metalloproteinases/metabolism ; *Social Behavior ; *Memory Disorders ; }, abstract = {INTRODUCTION: Loss of social cognition memory impairs Alzheimer's disease (AD) patients to recognize family members, friends, and caregivers. We investigate the role of perineuronal nets (PNNs), specialized coats of extracellular matrix around hippocampal CA2 neurons in AD-associated social memory impairments. METHODS: We utilized 5XFAD mouse model of AD and employed immunohistochemistry, microscopy, bulk RNA-sequencing, animal behavior, gene-knockout, and drug-treatment approaches. RESULTS: AD mice showed profound disruption of CA2 PNNs with concomitant impairment of social cognition memory. Genetic or enzymatic CA2 PNN disruption in wild-type mice mimicked these impairments. Transcriptomic analysis shows upregulation of PNN-cleaving matrix metalloproteinases (MMP) in AD mice causing disequilibrium of PNN synthesis and remodeling. Chronic inhibition of MMPs retains CA2 PNN and delays social memory impairments in 5XFAD mice. DISCUSSION: AD-associated social memory impairments are caused by loss of CA2 PNNs. Inhibition of PNN proteolysis by MMPs preserves social memory, suggesting PNN as a promising therapeutic target. HIGHLIGHTS: Perineuronal nets (PNNs) are disrupted in the CA2 area of the hippocampus in 5XFAD Alzheimer's disease (AD) mice at 6 months of age and beyond. Social memory deficits in 5XFAD mice coincide with the disruption of CA2 PNNs and PNN loss alone is sufficient to cause loss of social memory. Bulk RNA sequencing of hippocampal CA2 tissue reveals alterations in PNN remodeling enzymes. Inhibition of matrix metalloproteinase (MMP) activity with GM6001 prevents PNN disruption and protects against social memory deficits in the 5XFAD AD mouse model.}, } @article {pmid41122453, year = {2025}, author = {Jangid, K and Devi, B and Dahiya, R and Mishra, J and Kumar, V and Bhatti, JS and Thareja, S and Kumar, V}, title = {Investigation of the multifunctional profile of dihydroquinazoline derivatives as potential therapeutics for Alzheimer's disease.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {41122453}, issn = {2632-8682}, abstract = {Multitarget directed ligands represent an innovative strategy in the management of Alzheimer's disease (AD) by addressing its multifactorial etiology. These agents are designed to simultaneously modulate multiple key targets involved in the disease progression, offering a holistic approach for the effective treatment of AD. The current work presents the synthesis and evaluation of novel dihydroquinazoline-based multitargeting agents for the management of Alzheimer's disease. Most of the compounds showed good selectivity for AChE and MAO-B, and two compounds, viz.K2V-9 and K2V-12, emerged as potent inhibitors against both the targets. Compound K2V-9 displayed IC50 values of 1.72 ± 0.01 μM and 0.950 ± 0.52 μM against AChE and MAO-B, respectively. Compound K2V-12 showed IC50 values of 1.10 ± 0.078 μM and 1.68 ± 0.25 μM against AChE and MAO-B, respectively. Moreover, amyloid β self-aggregation inhibition studies were performed, where K2V-9 and K2V-12 showed percentage inhibitions of 37.34% and 48.10%, respectively, after 48 h. Both compounds were found to be non-toxic and neuroprotective and showed the capability of reducing the ROS levels in SHSY-5Y cells. Reversibility and kinetic studies of these lead compounds showed that both molecules produced reversible and mixed-type of inhibition against the targeted enzymes. In the docking and molecular dynamics simulation studies, K2V-9 and K2V-12 were found to be well accommodated in the active cavity with good thermodynamic stability.}, } @article {pmid41122344, year = {2025}, author = {Casey, CS and Patel, N and Vasileva-Metodiev, SZ and Cotton, S and Walker, C and Nilforooshan, R}, title = {Real-world diagnosis and management of mild cognitive impairment and Alzheimer's disease dementia in the United Kingdom.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251370708}, pmid = {41122344}, issn = {2542-4823}, abstract = {BACKGROUND: Timely diagnosis of Alzheimer's disease (AD) remains challenging in the United Kingdom and improvements are needed with the introduction of new therapies. OBJECTIVE: To examine the United Kingdom diagnostic and current treatment journey for people with mild cognitive impairment (MCI) and AD dementia to identify future opportunities for new treatments. METHODS: Physician-reported data were drawn from the Adelphi Real World Dementia Disease Specific Programme™, a cross-sectional survey of physicians treating patients with MCI or AD dementia in the United Kingdom between 2022 and 2024. Analyses were descriptive. RESULTS: Physicians (n = 109) reported data for 717 patients with MCI or AD dementia (including 264 with MCI or mild dementia). Overall median (interquartile range) time from symptom onset to first consultation was 26.0 (9.1-52.9) weeks. Time from consultation to diagnosis, for patients not diagnosed at initial consultation, was 15.2 (5.1-21.0) weeks for patients who first consulted and were diagnosed by a general practitioner and 21.9 (12.6-39.0) weeks for those who consulted a general practitioner and were diagnosed by a specialist. Few patients (4.9%) had a biomarker-confirmed diagnosis. Delays due to waiting for specialist referrals and diagnostic tests were reported for 57.6% and 26.9% of patients, respectively. Acetylcholinesterase inhibitors were the most common first-line treatment (82.0%). CONCLUSIONS: Our data highlighted delays in AD diagnosis and potential areas for United Kingdom health system improvement. Expediting timely diagnosis through increased public awareness, expanded biomarker use and addressing disparities in services is crucial to maximize access to emerging new therapies.}, } @article {pmid41121478, year = {2025}, author = {Hsieh, CY and Chuang, CH and Gomez, MC and Tayo, LL and Huang, SM and Tsai, PW}, title = {Computational Analysis and in vitro Verification Insights into Quercetin's Suppression of Neuroinflammation in BV-2 Microglia through NF-κB Pathway Inhibition.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673395813250901012530}, pmid = {41121478}, issn = {1875-533X}, abstract = {INTRODUCTION: Neuroinflammation, primarily mediated by activated microglia, is a significant contributor to neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Quercetin (QCT), a dietary flavonoid, has demonstrated anti-inflammatory and neuroprotective properties; however, the detailed molecular mechanisms behind these effects remain unclear. This study aimed to investigate the anti-inflammatory actions of QCT, particularly focusing on its potential to suppress the activation of microglia and subsequent neuroinflammation. METHODS: BV-2 microglial cells were stimulated with lipopolysaccharide (LPS) to induce an inflammatory response and were subsequently treated with various concentrations of QCT. Cell viability was assessed using the MTT assay. Levels of pro-inflammatory cytokines (IL-6, TNF- α) and nitric oxide (NO) were quantified through ELISA and Griess reaction methods, respectively. Western blot analysis was conducted to examine inducible nitric oxide synthase (i- NOS), NF-κB, IκBα, and phosphorylated IκBα protein expressions. In silico approaches, including protein-protein interaction (PPI) network analysis and molecular docking, were employed to explore potential molecular mechanisms involving NF-κB signaling pathways. RESULTS: Treatment with QCT significantly reduced the secretion of IL-6 (96%) and TNF-α (87%), as well as NO production (42%), in a dose-dependent manner. Western blot results demonstrated a marked reduction in iNOS expression and inhibition of NF-κB activation through reduced phosphorylation of IκBα following QCT treatment. Molecular docking indicated a strong binding affinity between QCT and IKKβ, suggesting inhibition of the NF-κB pathway. DISCUSSION: The findings indicated QCT to exert potent anti-inflammatory effects in LPS-stimulated BV-2 cells by modulating key proteins involved in the NF-κB signaling pathway. Specifically, the docking results implied QCT's direct interaction with the catalytic subunit IKKβ, inhibiting IκBα phosphorylation and subsequent NF-κB activation. The results have been found to be consistent with previous literature, reinforcing QCT's role in reducing neuroinflammation through specific molecular targets and pathways. Further in vivo studies are necessary to validate the findings. CONCLUSION: Quercetin effectively suppressed neuroinflammation in microglial cells through inhibition of the NF-κB signaling pathway, reducing levels of critical pro-inflammatory mediators. The outcomes have highlighted the potential of quercetin as a preventive nutraceutical for neurodegenerative diseases, necessitating future in vivo investigations to confirm its therapeutic efficacy.}, } @article {pmid41121098, year = {2025}, author = {Afolayan, O and Nwaogu, V and Idowu, O and Dosumu, O}, title = {Differential oxido-reductive activities of aged garlic extract and S-allyl-cysteine in genetically modified Drosophila model of Alzheimer's disease.}, journal = {BMC complementary medicine and therapies}, volume = {25}, number = {1}, pages = {392}, pmid = {41121098}, issn = {2662-7671}, abstract = {Alzheimer’s disease (AD) is a progressive neurodegenerative disorder frequently associated with ageing. It is characterised by the loss of neurons in the hippocampus and cortex, leading to declines in cognitive function and memory. Recent research has spotlighted Aged Garlic Extract (AGE) and its bioactive component, S-allyl-cysteine (SAC), as promising candidates for the treatment of AD due to their potent antioxidant, anti-inflammatory, and neuroprotective properties. These features help mitigate oxidative stress and neuronal damage associated with the disease. The present study aimed to evaluate the neuroprotective effects of AGE and SAC using a Drosophila melanogaster (Drosophila) model of Alzheimer’s disease. The Drosophila (UAS-Aβ > Elav-GAL4) were reared on a diet supplemented with varying concentrations of AGE (10 µL, 20 µL, and 40 µL) and SAC (at doses of 25, 50, and 75 mg/kg). Key parameters measured included larval motility, negative geotaxis, and oxidative stress markers. The AD models exhibited reduced motor abilities, decreased antioxidant levels, increased oxidative stress, and elevated acetylcholinesterase (AChE) activity. However, treatment with different concentrations of AGE and SAC significantly improved locomotor function and modulated redox activities, along with a reduction in AChE activity. This study highlights the neuroprotective potential of AGE and its active component, SAC, in the Drosophila AD model, indicating that the beneficial effects of AGE are primarily attributed to SAC.}, } @article {pmid41120520, year = {2025}, author = {Rahman, MO and Ahmed, SS and Alqahtani, AS and Rehman, MT and Sultana, N and Bouhrim, M and Ali, MA and Lee, J}, title = {Identification of stigmasterol derived AChE inhibitors for Alzheimer's disease using high throughput virtual screening and molecular dynamics simulations.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {36676}, pmid = {41120520}, issn = {2045-2322}, support = {ORF-2025-132//King Saud University/ ; }, mesh = {*Stigmasterol/chemistry/analogs & derivatives/pharmacology ; *Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Molecular Dynamics Simulation ; *Alzheimer Disease/drug therapy ; Humans ; High-Throughput Screening Assays ; Molecular Docking Simulation ; *Acetylcholinesterase/metabolism/chemistry ; Neuroprotective Agents/chemistry ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, poses a significant global health burden due to its intricate pathology and the absence of curative treatments. Current therapies primarily offer symptomatic relief, often with limited efficacy and complications, thereby underscoring the urgent need for innovative, safer, and more effective interventions. Stigmasterol, a plant-derived phytosterol, has demonstrated neuroprotective properties, including anti-inflammatory and antioxidant effects, which positions this sterol as a compelling candidate for further investigation in AD treatment. In this investigation, high-throughput virtual screening of 972 stigmasterol analogs (SAs) was conducted to identify potential acetylcholinesterase (AChE) inhibitors, followed by ADMET filtering, molecular dynamics (MD) simulations, MM/GBSA free binding energy estimations, and DFT calculations. Three lead compounds, including SA4 (-10.9 kcal/mol), SA12 (-10.6 kcal/mol), and SA15 (-10.5 kcal/mol), demonstrated superior binding affinities compared to stigmasterol (-9.6 kcal/mol) and the control drug donepezil (-8.6 kcal/mol). Docking interaction analysis revealed strong binding by hydrogen bonds and hydrophobic interactions, whereas pharmacokinetic, pharmacodynamic, and toxicity assessments confirmed the favorable characteristics of these compounds. MD simulations (200 ns) demonstrated the structural compactness of the compounds, which was further supported by principal component analysis and Gibbs free energy landscape experiments. MM/GBSA identified SA4 as the most potent analog (-82.21 kcal/mol), followed by SA15 (-80.40 kcal/mol) and SA12 (-69.72 kcal/mol). A DFT-based molecular reactivity analysis revealed decreased reactivity and increased kinetic stability of the lead candidates in their transition from free to bound states. These findings provide insights into the therapeutic potential of stigmasterol analogs as AChE inhibitors, thus offering the groundwork for in vivo and in vitro validation for advancing AD treatment.}, } @article {pmid41120130, year = {2025}, author = {Marziliano, A and Babar, H and Patel, P and Gieniusz, M and Mongelli, J and Burns, E and Applebaum, AJ and Pessin, H and Breitbart, W and Sinvani, L and Perissinotto, C and Diefenbach, MA}, title = {The adaptation of meaning centered psychotherapy to develop RELOAD-C: a web-based tool to reduce loneliness in caregivers of persons with Alzheimer's disease and related dementias.}, journal = {Translational behavioral medicine}, volume = {15}, number = {1}, pages = {}, doi = {10.1093/tbm/ibaf059}, pmid = {41120130}, issn = {1613-9860}, support = {K01AG076888//National Institute on Aging (NIA) of the National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Caregivers/psychology ; *Alzheimer Disease/psychology/nursing ; *Psychotherapy/methods ; Male ; Female ; *Loneliness/psychology ; *Dementia/nursing/psychology ; Middle Aged ; Internet ; Aged ; Internet-Based Intervention ; }, abstract = {BACKGROUND: More than 60% of caregivers of persons with Alzheimer's disease and related dementias (AD/ADRD) are lonely. Meaning and purpose in life is associated with reduced feelings of loneliness, but has not yet been systematically fostered among caregivers of patients with AD/ADRD. Adapting meaning-centered psychotherapy (MCP), an evidence-based treatment for increasing meaning and purpose in life in cancer caregivers, might decrease loneliness in the dementia caregiver population. PURPOSE: The purpose of this manuscript is to report on the development, usability, and acceptability testing of REducing LOneliness in Alzeheimer's Disease-Care Partners (RELOAD-C), a web-based platform that features six brief videos and aims to reduce loneliness in caregivers of patients with dementia through introducing major concepts and principles adapted from meaning centered psychotherapy. METHOD: Within 12 months, RELOAD-C was developed through two rounds of one-on-one interviews with 15 dementia caregivers to obtain feedback on video scripts, recording of videos, and placement of videos and written content (e.g. thought exercises) on the website. Following this, RELOAD-C underwent rigorous usability and acceptability testing by another 16 dementia caregivers. RESULTS: Quantitative assessments show that RELOAD-C is deemed usable by caregivers (mean = 1.69 on system usability scale, where possible range is 1-5 and lower scores indicate more favorable views of the website; and more than 90% of the usability sample correctly engaged in ≥8 of 10 discreet tasks). Qualitative data indicate acceptability of the intervention with feedback such as "love that the videos are clear and load fast." CONCLUSIONS: RELOAD-C is a web-based intervention focused on reducing loneliness in dementia caregivers. It contains six therapist-narrated videos and written content, reinforcing MCP principles. It is currently undergoing pilot testing in preparation for a large-scale randomized controlled clinical trial evaluating its efficacy in reducing loneliness in dementia caregivers.}, } @article {pmid41118083, year = {2025}, author = {Kopi, TA and Shanehbandpour-Tabari, F and Arani, RM and Ataie, A and Pouramir, M and Khaleghzadeh-Ahangar, H}, title = {Piperine Prevents Scopolamine-Induced Cognitive Impairment via its Antioxidant and Anti-Inflammatory Roles; Suggesting Potential Modulation of Necroptosis-Related Genes Including MLKL and TNF-α.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {4}, pages = {142}, pmid = {41118083}, issn = {1559-1166}, support = {724133561//Babol University of Medical Science/ ; }, mesh = {Animals ; *Benzodioxoles/pharmacology/therapeutic use ; *Piperidines/pharmacology/therapeutic use ; Male ; *Alkaloids/pharmacology/therapeutic use ; *Polyunsaturated Alkamides/pharmacology/therapeutic use ; Rats, Wistar ; Rats ; Tumor Necrosis Factor-alpha/genetics/metabolism ; *Cognitive Dysfunction/prevention & control/drug therapy/metabolism/chemically induced ; Necroptosis ; Hippocampus/metabolism/drug effects ; *Antioxidants/pharmacology/therapeutic use ; Scopolamine/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; Protein Kinases/genetics/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Caspase 8/genetics/metabolism ; }, abstract = {Alzheimer's disease (AD) is the leading cause of dementia, characterized by cognitive decline and neurodegeneration. Given the limitations of current treatments, research has turned to natural substances such as piperine, which is known for its neuroprotective properties. This study investigates the effects of piperine on cognitive function and genes associated with oxidative stress, inflammation, and necroptosis-related genes in a rat model of cognitive impairment. Fifty adult male Wistar rats were used, divided into five groups: an intact group, a control group (vehicle solution followed by scopolamine), and three experimental groups receiving piperine (5, 10, and 20 mg/kg) followed by scopolamine during the training period. Behavioral assessment was conducted using the Morris Water Maze (MWM) test. Hippocampal tissue was collected after euthanasia for gene expression analysis of Nrf2, HO‑1, TNF‑α, Fas, TRAIL, MLKL, and Caspase‑8. Spatial learning and memory improved significantly in piperine-treated groups, with no impact on swimming velocity, indicating cognitive enhancement without affecting motor functions in the scopolamine-induced cognitive impairment model. Piperine pretreatment prevented oxidative stress and inflammation, as evidenced by the restoration of Nrf2, HO-1, and Caspase-8 and the reduction of TNF-α, Fas, TRAIL, and MLKL expression levels. These findings suggest that piperine has antioxidative, anti‑inflammatory, and cognitive‑enhancing effects, with particular effects possibly on necroptosis, and could be a valuable addition to the current AD treatment paradigm, warranting further investigation in clinical trials.}, } @article {pmid41118046, year = {2025}, author = {Aswinanand, B and Palani, KN and Santhanam, SD and Ramamurthy, K and Palaniappan, S and Arasu, MV and Guru, A and Muthuramamoorthy, M and Kumaradoss, KM and Arockiaraj, J}, title = {Pyrimidine Derivative, (E)-N-[4-(4-Chlorophenyl)-6-(4-Methylphenyl)Pyrimidin-2-yl]-1-(Furan-2-yl)Methanimine, Named BN5 Ameliorates Cognitive Dysfunction and Regulates esr1 and esr2b Expression in Female In Vivo Zebrafish Alzheimer Model.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {20}, number = {1}, pages = {94}, pmid = {41118046}, issn = {1557-1904}, mesh = {Animals ; Female ; Zebrafish ; *Pyrimidines/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Cognitive Dysfunction/drug therapy/metabolism ; *Estrogen Receptor alpha/biosynthesis/genetics ; *Estrogen Receptor beta/biosynthesis/genetics ; Disease Models, Animal ; *Furans/pharmacology/therapeutic use ; *Imines/pharmacology/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia, characterized by a progressive decline in cognitive functions. It is more prevalent in women, especially after menopause, likely due to factors like longer life expectancy and hormonal changes. Current therapies focus on cholinesterase inhibitors, but recent studies suggest that pyrimidine derivatives hold promise as multi-target agents targeting complex mechanisms of AD. This study evaluated the potential of a pyrimidine derivative, (E)-N-[4-(4-chlorophenyl)-6-(4-methylphenyl)pyrimidin-2-yl]-1-(furan-2-yl)methanimine (named BN5), in a scopolamine (SCO)-induced female zebrafish model. SCO induces cognitive dysfunction mimicking AD conditions. BN5, particularly at a 60 µM concentration, significantly improved AD-related parameters, including anxiety, memory, shoaling, and social behaviour in vivo. Biochemical analyses supported these findings, as BN5 reversed SCO-induced changes in acetylcholinesterase (AChE) activity and oxidative stress markers, such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), malondialdehyde (MDA), and γ-Aminobutyric acid (GABA) levels. Additionally, BN5 demonstrated positive regulation of neurotransmitter-related genes such as appb, bdnf, mbpa, and il-1β, essential for neural function and cognitive processes. It also upregulated estrogen receptor genes esr1 and esr2b, which have neuroprotective roles but are often downregulated in postmenopausal women due to hormonal changes. These results highlight the therapeutic potential of BN5, as it alleviates cognitive impairments through Aβ aggregation inhibition and addresses the decline in estrogen receptor activity, providing a targeted treatment option particularly beneficial for females, who are at greater risk of developing AD.}, } @article {pmid41117350, year = {2025}, author = {Khachaturian, Z}, title = {History of Alzheimer's Disease Research Centers: From inception in 1984 to evolution beyond 2025.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70778}, pmid = {41117350}, issn = {1552-5279}, support = {1975-1982/AG/NIA NIH HHS/United States ; 1983-1991/AG/NIA NIH HHS/United States ; 1978-1995/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/history/therapy ; Humans ; History, 20th Century ; United States ; *Biomedical Research/history ; History, 21st Century ; }, abstract = {This paper reviews the history of the so-called Alzheimer Movement in the United States, the origins of the Alzheimer's Disease Research Centers (ADRC) program, and their critical role in shaping the National Plan to Address Alzheimer's Disease by 2035. The long narration unfolds in three parts: (1) Beginnings, (2) Accomplishments, and (3) Charting the Next Step. HIGHLIGHTS: This paper reviews the history of the Alzheimer movement in the United States, the origins of the ADRC program, and the centers' critical role in shaping the National Plan to Address Alzheimer's Disease by 2035. The long narration unfolds in three parts: (1) Beginnings: Establishing a Foothold, (2) Accomplishments: Key Achievements and Future Lessons, and (3) Charting the Next Step: Rethinking the ADRC's role after 2035. This perspective offers a high-level view of the scientific landscape during the inception of programmatic research in aging and dementia. The story covers the significant challenges involved in starting such an undertaking. It recounts the rationale, intent, achievements, and structure of the ADRCs. The narrative focuses on the politics of science that shaped programs like the ADRC and NACC, particularly through earmarked funding. It explains why the program prioritized the creation of infrastructure and building capacity for longitudinal clinical studies. The discussion of future directions will (1) explain the reasoning for reformulating the mission and structure of the ADRC's concept to accommodate a comprehensive range of emerging needs and (2) explore the role of the re-engineered centers as a catalyst to promote and maintain brain health to prevent cognitive impairments. It will suggest some possible options to restructure some current centers into comprehensive regional centers as instruments to deal with new challenges.}, } @article {pmid41116989, year = {2025}, author = {Lei, L and Mei, SY and Lü, Y and Huang, GQ and Lü, PR and Liu, Q and Zhang, N}, title = {[Effect of moxibustion on synaptic plasticity in mice with Alzheimer's disease based on the CaMKⅡ/RyR3 pathway].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {50}, number = {10}, pages = {1161-1168}, doi = {10.13702/j.1000-0607.20240673}, pmid = {41116989}, issn = {1000-0607}, mesh = {Animals ; *Alzheimer Disease/therapy/genetics/metabolism/physiopathology/enzymology/psychology ; *Moxibustion ; Mice ; *Neuronal Plasticity ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism/genetics ; Male ; Mice, Inbred C57BL ; Humans ; *Ryanodine Receptor Calcium Release Channel/metabolism/genetics ; Acupuncture Points ; Hippocampus/metabolism ; Female ; }, abstract = {OBJECTIVES: To explore the mechanism by which moxibustion promotes synaptic plasticity of hippocampal neurons and improves learning and memory in mice with Alzheimer's disease (AD) based on the calmodulin-dependent protein kinase Ⅱ (CaMKⅡ)/ryanodine receptor (RyR)3 pathway. METHODS: Forty APP/PS1 mice were randomly divided into the model (n=15), moxibustion (n=25) groups, and 15 C57BL/6J mice served as the blank control group. The mice in the moxibustion group were given moxibustion at the "Baihui"(GV20) and "Yongquan"(KI1) acupoints, 30 minutes each time, once a day. A course of treatment lasted for 5 days, and there were a total of 4 courses of treatment. Ten mice from the moxibustion group were randomly selected as the moxibustion+inhibitor group, and were intraperitoneally injected with the CaMKⅡ protein inhibitor KN-93 (2 mg/100 g) one day before sample collection on the basis of moxibustion. After the treatment, the shuttle box test was used to evaluate the learning and memory ability of the mice. Transmission electron microscopy was used to detect the changes in the ultrastructure of synapses in the CA1 region of the hippocampus. Western blot was used to detect the expression levels of β-amyloid protein (Aβ) and CaMKⅡ protein in the hippocampus of the mice. Immunofluorescence staining was used to detect the positive expression of CaMKⅡ in the hippocampus and the co-expression of RyR3/PSD95. RESULTS: Compared with the blank control group, the number of active avoidance responses, the protein expression and positive expression of CaMKⅡ in the hippocampus, and the percentage of the co-expression area of RyR3/PSD95 of the mice in the model group were decreased (P<0.01, P<0.05), and the number of synaptic vesicles in the CA1 region of the hippocampus was decreased;while the expression of Aβ protein in the hippocampus was increased (P<0.01). Compared with the model group, the number of active avoidance responses, the protein expression and positive expression of CaMKⅡ in the hippocampus, and the co-expression area percentage of RyR3/PSD95 of the mice in the moxibustion group were increased significantly (P<0.01), and the number of synaptic vesicles in the CA1 region of the hippocampus was increased;while the expression of Aβ protein was decreased (P<0.05). Compared with the moxibustion group, the number of active avoidance, the positive expression of CaMKⅡ and the co-expression area percentage of RyR3/PSD95 in the moxibustion+inhibitor group were decreased (P<0.01), and the number of synaptic vesicles in the CA1 region of the hippocampus was decreased. CONCLUSIONS: Moxibustion can improve the learning and memory ability of AD model mice, and its mechanism may be related to up-regulating the expression of CaMKⅡ, activating the endoplasmic reticulum RyR3 channel, inducing the release of Ca[2+], and then promoting neuronal synaptic plasticity.}, } @article {pmid41114448, year = {2025}, author = {Sato, K and Niimi, Y and Ihara, R and Iwata, A and Nemoto, K and Arai, T and Higashi, S and Igarashi, A and Kasuga, K and Akiyama, H and Awata, S and Ikeda, M and Iwatsubo, T}, title = {Real-world lecanemab adoption in Japan 1 year after launch: Insights from 311 specialists on infrastructure and reimbursement barriers.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70652}, pmid = {41114448}, issn = {1552-5279}, support = {JPMH23CA2008//MHLW Health Labour Sciences Research Grant/ ; 24GB1001//MHLW Health Labour Sciences Research Grant/ ; JP24K10653//JSPS KAKENHI/ ; JP25K19014//JSPS KAKENHI/ ; JP23dk0207048//AMED Research and Development Grants for Dementia/ ; JP24dk0207054//AMED Research and Development Grants for Dementia/ ; JP24dk0207068//AMED Research and Development Grants for Dementia/ ; //Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; Japan ; *Alzheimer Disease/drug therapy ; Surveys and Questionnaires ; Male ; *Insurance, Health, Reimbursement ; Female ; }, abstract = {INTRODUCTION: Lecanemab was approved for early Alzheimer's disease in Japan, with ≈ 6000 patients treated in the first year post approval. This study explores real-world practices, challenges, and potential solutions. METHODS: We conducted an anonymized online survey of clinical specialists authorized to prescribe lecanemab, obtaining responses from 311 specialists who collectively treated 3259 patients with lecanemab. RESULTS: A majority of respondents (79%) reported wait times of ≤ 3 months from first consultation to initial infusion. One fourth reported tight outpatient space and staffing and significantly lower capacity of treatment than anticipated. Safety concerns were limited, with amyloid imaging-related abnormality-related interruptions in 3.5%. More than half highly supported additional reimbursement for infusion-related services and insurance coverage for apolipoprotein E (APOE) testing. DISCUSSION: Early access to lecanemab appears feasible, yet infrastructure and financial hurdles remain. Dedicated reimbursement and insurance coverage for APOE testing may be essential for ensuring safer, more accessible, and sustainable use of this therapy in Japan. HIGHLIGHTS: Results from an online survey of 311 Japanese specialists prescribing lecanemab in its first year are reported. Majority of wait times from first consultation to initial infusion were 1 to 3 months. Tight affordability of infusion space and staffing was reported by one quarter. Establishing additional medical fee for infusion management was highly expected. Reimbursement of apolipoprotein E test in Japanese health insurance system was also demanded.}, } @article {pmid41113923, year = {2025}, author = {Shine, S and Chandrapragasam, V}, title = {Acetylcholinesterase inhibitory potency of Lactobacillus plantarum fermentation extracts, and antioxidant scavenging effects against LPS-induced nitric oxide production in PC12 cell lines.}, journal = {3 Biotech}, volume = {15}, number = {11}, pages = {393}, pmid = {41113923}, issn = {2190-572X}, abstract = {Nutrient optimization of Lactobacillus plantarum MTCC 1325 with cinnamon (40 µg/mL) and pantothenic acid (4 µg/mL) resulted in a chloroform extract of Media D that exhibited a strong activity profile relevant to the therapeutic approach to Alzheimer's disease. Across 20-100 µg/mL extracts were non-cytotoxic to undifferentiated PC12 cells. Chloroform extract of Media D showed potent radical scavenging [IC50(superoxide) = 41.7 ± 2.1 µg/mL, IC50(NO) = 33.4 ± 1.1 µg/mL], high total phenolics (68.6 ± 1.1 mg GAE/g), and acetylcholinesterase inhibition [IC50 = 33.2 ± 4.2 µg/mL, galantamine (standard) = 22.5 ± 3.2 µg/mL]. Pre-treatment with chloroform extract of Media D reduced LPS-induced cytotoxicity [IC50 = 32.6 ± 3.6 µg/mL] and lowered nitrite accumulation up to 1.69-fold versus LPS. GC-MS of the active fraction resolved six constituents, consistent with lipid and aromatic metabolites. Together, these results support a nutrient-first media design strategy, demonstrating that selective modulation of media composition under fixed incubation parameters can enrich L. plantarum culture-derived metabolites with antioxidants, anti-inflammatory, and AChE inhibitory activities related to the medical management of AD. This is a preliminary in vitro study using one strain and a single-cell model, Extract were crude and tested with modest replication, and library matched GC-MS identification. Mechanistic markers were not quantified, and in vivo validation is warranted.}, } @article {pmid41111974, year = {2025}, author = {Woo, HG and Park, MS and Park, JY and Chun, H and Song, TJ}, title = {Association of hemorrhoidal disease with dementia risk: a nationwide cohort study.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1655944}, pmid = {41111974}, issn = {1664-2295}, abstract = {INTRODUCTION: Research on the association between hemorrhoidal diseases (HDs) and dementia is limited. We explored this relationship in a population-based longitudinal cohort and proposed that individuals with HD may experience a higher incidence of dementia. METHODS: Our study included 381,031 participants drawn from results from the South Korean health-screening cohort database, between 2005 and 2010. HD was identified based on at least two claims using the International Classification of Diseases, Tenth Revision (ICD-10) code I84. We used propensity score matching (PSM) to categorize the participants into two groups based on the presence or treatment of HD. The primary outcome was the incidence of all-cause dementia as determined by two or more claims with ICD-10 codes (F00-03, G30, and G31). Secondary outcomes included the occurrence of Alzheimer's (F00 or G30) and vascular dementia (F01). RESULTS: Over a median follow-up period of 15.49 years (interquartile range: 12.21-18.77 years), the cumulative incidence of all-cause dementia was 80,488 cases (22.47%). Multivariate analysis showed that the group with HD consistently had a higher incidence of all-cause dementia than the group without HD after PSM (hazard ratio [HR], 1.243; 95% confidence interval [CI], 1.199-1.288). Participants who underwent surgical procedures or treatment for HD revealed a significantly lower incidence of all-cause dementia after PSM (HR, 0.925; 95% CI, 0.872-0.981). DISCUSSION: This study revealed a significantly higher incidence of all-cause dementia among participants with hemorrhoidal disease, suggesting that while hemorrhoidal disease may not directly cause dementia, it may serve as a marker of an underlying systemic condition that increases dementia risk.}, } @article {pmid41111606, year = {2025}, author = {Wu, X and Zhang, R and Chen, W and Mei, Y and Hu, Q and Lan, W and Zhang, Y and Ye, Z and Huang, C and Zhu, B}, title = {Preoperative perivascular space burden predicts treatment response to deep cervical lymphovenous anastomosis in Alzheimer's disease: A pilot study.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251387366}, pmid = {41111606}, issn = {2542-4823}, abstract = {BACKGROUND: Deep cervical lymphovenous anastomosis (DLVA) shows promise for Alzheimer's disease (AD) treatment, but patient selection criteria remain undefined. Perivascular spaces (PVS) may predict glymphatic enhancement potential. OBJECTIVE: To investigate whether preoperative magnetic resonance imaging (MRI) measures of PVS burden can predict treatment response to DLVA in AD patients and explore potential mechanisms through longitudinal glymphatic function assessment. METHODS: Retrospective analysis of 10 AD patients undergoing DLVA. Preoperative T1-weighted MRI quantified PVS volumes using Frangi filtering. Treatment response was assessed at one month using Mini-Mental State Examination/Montreal Cognitive Assessment improvements ≥2 points. RESULTS: Total PVS volume demonstrated perfect predictive accuracy for treatment response (AUC = 1.000) with an optimal cut-off of 5150 mm³ (sensitivity 100%, specificity 100%). White matter PVS volume also showed strong predictive performance (AUC = 0.875, cut-off 3630 mm³, sensitivity 75%, specificity 100%). The improved group had significantly higher preoperative PVS volumes (total PVS: p = 0.012, Cohen's d = 2.631; white matter PVS: p = 0.050, Cohen's d = 1.689). Preliminary longitudinal analysis revealed divergent Analysis Along the Perivascular Space (ALPS) index changes: the improved group showed mean increase (+0.0276), while the non-improved group demonstrated decrease (-0.0252). CONCLUSIONS: Preoperative PVS burden serves as a powerful predictor of DLVA response, with higher volumes indicating sufficient anatomical reserve for therapeutic benefit. These findings establish PVS volume as clinically actionable biomarkers for precision patient selection in glymphatic-targeted AD interventions.}, } @article {pmid41110764, year = {2025}, author = {Tagad, A and Galatage, ST and Hankuntimath, N and Hugar, S and Raikar, SR and Patil, VP and Manjappa, AS}, title = {Neuroprotective potential of green-synthesized silver nanoparticles from Psidium guajava in a scopolamine-induced rat model of Alzheimer's disease.}, journal = {Annales pharmaceutiques francaises}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.pharma.2025.10.006}, pmid = {41110764}, issn = {2772-803X}, abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative condition marked by progressive memory decline and cognitive dysfunction, and oxidative stress, with no definitive cure currently available. The present study aimed to develop a plant-based nanotherapeutic approach for AD by synthesizing silver nanoparticles (AgNPs) using the ethanolic leaf extract of Psidium guajava (PG) via a green synthesis method. Formation of PG-AgNPs was confirmed by a characteristic surface plasmon resonance (SPR) peak observed in UV-Visible spectroscopy and a visible colour change to dark brown. The synthesized nanoparticles exhibited a mean particle size of 107±4nm, a polydispersity index (PDI) of 0.364±0.08, and a zeta potential of -30.7±2.3mV, indicating good colloidal stability. Energy-dispersive X-ray diffraction (E-XRD) confirmed the crystalline nature and elemental composition of silver. In a scopolamine-induced rat model of AD, treatment with PG-AgNPs significantly improved cognitive performance. Rats treated with PG-AgNPs showed a statistically significant increase (P<0.001) in spontaneous alternation behaviour, prolonged step-through latency in the passive avoidance test (P<0.001), and a significant reduction in escape latency time in the Morris Water Maze test (P<0.001) compared to the disease control group. Biochemical analyses revealed that PG-AgNPs significantly reduced lipid peroxidation (LPO) levels (P<0.001) and significantly increased catalase (CAT) activity (P<0.001), indicating strong antioxidant potential. In conclusion, P. guajava leaf extract and its green-synthesized silver nanoparticles demonstrated statistically significant neuroprotective, antioxidant, and cognitive-enhancing effects, supporting their potential as a novel therapeutic strategy for the treatment of Alzheimer's disease. Further research is needed to explore and conform their clinical applicability.}, } @article {pmid41110751, year = {2025}, author = {Wang, Y and Deng, L and Wang, L and Liu, W}, title = {Schisandrin B combined with vitamin D inhibits NLRP3 inflammasome to improve cognitive dysfunction and Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1007}, number = {}, pages = {178268}, doi = {10.1016/j.ejphar.2025.178268}, pmid = {41110751}, issn = {1879-0712}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; Male ; *Alzheimer Disease/drug therapy/metabolism/psychology ; *Cognitive Dysfunction/drug therapy/metabolism/psychology ; *Inflammasomes/metabolism/antagonists & inhibitors ; *Polycyclic Compounds/pharmacology/therapeutic use ; *Vitamin D/pharmacology/therapeutic use ; Rats ; Rats, Sprague-Dawley ; *Lignans/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism ; Cyclooctanes/pharmacology ; Cognition/drug effects ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Behavior, Animal/drug effects ; }, abstract = {PURPOSE: This study investigates the therapeutic effects of Schisandrin B (Sch B) combined with vitamin D (VD) on cognitive dysfunction and Alzheimer's disease (AD)-like pathology in aged rats induced by a high-fat and high-sugar (HFHS) diet, with a focus on the inhibition of NLRP3 inflammasome activation as a potential mechanism. METHODS: Eighteen-week-old male Sprague-Dawley rats were randomly assigned to five groups: Control, HFHS, HFHS + Sch B, HFHS + VD, and HFHS + Sch B + VD. After 20 weeks of treatment, metabolic parameters (body weight, fasting blood glucose, insulin resistance, lipid profiles), inflammatory markers, and hippocampal protein expression were assessed. Cognitive function was evaluated using the Morris water maze, novel object recognition, open field, and elevated plus maze tests. RESULTS: Combined Sch B and VD markedly attenuated body weight gain, fasting blood glucose, fasting serum insulin, and homeostatic model assessment of insulin resistance (HOMA-IR), while improving lipid profiles (TG, TC, LDL-C). Behavioral tests revealed significant improvements in spatial learning, memory, and object recognition (p < 0.01), with combined therapy outperforming monotherapy. Additionally, the combination downregulated hippocampal NLRP3 inflammasome components (ASC, cleaved caspase-1, IL-1β, IL-18) and reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). CONCLUSION: In this HFHS diet-induced aging rat model, Sch B combined with VD improved cognitive performance and reduced AD-like lesions, likely via inhibition of NLRP3 inflammasome-mediated neuroinflammation. These findings provide mechanistic insights and support further preclinical evaluation of this combination as a potential strategy for AD prevention and intervention.}, } @article {pmid41110688, year = {2025}, author = {Qin, RZ and Peng, SY and Huang, ZX and Zhang, BF and Tang, RN and Zhao, YC and Jiang, FS and Xu, XH and Pan, JL and Li, MY}, title = {Coelonin, an active component extract from Bletilla striata (Thunb.) Reichb.f., alleviates lipopolysaccharide-induced acute lung injury by increasing the expression of non-coding RNA Gm27505 and inhibiting the M1 polarization of macrophages caused by inflammatory responses.}, journal = {The international journal of biochemistry & cell biology}, volume = {189}, number = {}, pages = {106871}, doi = {10.1016/j.biocel.2025.106871}, pmid = {41110688}, issn = {1878-5875}, mesh = {Animals ; *Lipopolysaccharides/toxicity ; *Acute Lung Injury/chemically induced/drug therapy/pathology/genetics/immunology/metabolism ; Mice ; *Orchidaceae/chemistry ; RAW 264.7 Cells ; *Macrophages/drug effects/metabolism/pathology ; *Inflammation/drug therapy/pathology/chemically induced/genetics ; *RNA, Untranslated/genetics ; Male ; *Plant Extracts/pharmacology/chemistry ; *Phenanthrenes/pharmacology ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {Coelonin is a dihydrophenanthrene compound derived from the traditional Chinese medicine Bletilla striata (Thunb.) Reichb.f., which exhibits significant anti-inflammatory activity and effectively inhibits lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 cells. Although previous studies have demonstrated the protective effect of Bletilla striata against LPS-induced acute lung injury (ALI), the potential protective role and underlying molecular mechanisms of its major active component, Coelonin, in ALI remain unclear. In this study, an LPS-induced mouse ALI model was established to systematically evaluate the protective effects of Coelonin on ALI. Furthermore, transcriptomic analysis was utilized to investigate the anti-inflammatory mechanisms mediated by Coelonin through the regulation of non-coding RNA (ncRNA)-associated inflammatory pathways. The results indicated that Coelonin significantly ameliorated LPS-induced pathological damage in lung tissues and markedly reduced the levels of inflammatory markers in bronchoalveolar lavage fluid (BALF). In vitro experiments using the murine alveolar macrophages (MH-S) cell line further confirmed the anti-inflammatory activity of Coelonin. Transcriptome analysis revealed that Coelonin markedly upregulates the expression of the ncRNA Gm27505, which was previously found to be downregulated in a mouse model of Alzheimer's disease. To date, there have been no reports on the biological functions of Gm27505. Bioinformatics analysis and real-time quantitative fluorescence PCR (qPCR) confirmed that this ncRNA is primarily localized within the nucleus. Overexpression of Gm27505 in MH-S cells significantly downregulated the expression of inflammation-related genes such as Il6, Tnfα, Il27, and Ccl3 induced by LPS stimulation. Moreover, overexpression of Gm27505 promoted macrophage polarization toward the M2 phenotype while suppressing M1 polarization. These findings suggest that the ncRNA Gm27505 plays an important biological role and is critically involved in the regulation of inflammatory responses. Coelonin may alleviate LPS-induced ALI in mice by up-regulating Gm27505 expression and modulating macrophage polarization. Therefore, Gm27505 may represent a potential target for the prevention and treatment of ALI, providing new research directions for future therapeutic strategies against related diseases.}, } @article {pmid41110565, year = {2025}, author = {Lv, H and Liu, Y and Yang, X and Xu, X and Zhou, J and Yu, W}, title = {Research progress on the role of oxidative stress in the pathogenesis of vascular dementia and its treatment.}, journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association}, volume = {34}, number = {12}, pages = {108475}, doi = {10.1016/j.jstrokecerebrovasdis.2025.108475}, pmid = {41110565}, issn = {1532-8511}, mesh = {Humans ; *Oxidative Stress/drug effects ; *Dementia, Vascular/metabolism/physiopathology/drug therapy/pathology/therapy/psychology ; Animals ; *Antioxidants/therapeutic use/adverse effects ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; *Brain/metabolism/drug effects/pathology/physiopathology ; Cognition/drug effects ; *Neuroprotective Agents/therapeutic use/adverse effects ; Mitochondria/metabolism/drug effects/pathology ; }, abstract = {BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease, imposing a substantial burden on global health. Accumulating evidence indicates that oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defense, plays a pivotal role in the pathogenesis of VaD. OBJECTIVE: This review aims to summarize the latest research progress on the involvement of oxidative stress in the pathogenesis of VaD and explore emerging therapeutic strategies targeting oxidative stress. RESULTS: Oxidative stress is deeply involved in multiple pathological processes of VaD. Its root cause lies in chronic cerebral hypoperfusion (CCH), which leads to mitochondrial dysfunction and excessive ROS production. Such oxidative damage exacerbates blood-brain barrier (BBB) disruption, neuroinflammation, and neuronal apoptosis, ultimately resulting in cognitive decline. Key molecular mechanisms include the activation of NADPH oxidase, impairment of the Nrf2 antioxidant pathway, and dysregulation of SIRT1. Therapeutic strategies have evolved from traditional antioxidants (e.g., α-lipoic acid) to novel approaches, including targeting the Nrf2/HO-1 pathway (e.g., using saffron-rich GJ-4 extract), regulating mitochondrial function, utilizing natural compounds (e.g., resveratrol acting via SIRT1 activation), and non-pharmacological interventions such as acupuncture. These strategies alleviate oxidative stress through multi-target mechanisms and have demonstrated significant efficacy. CONCLUSION: The central role of oxidative stress in VaD provides new targets for treatment, but a shift from single-target antioxidant therapy to multi-level intervention is required. Future research should focus on developing targeted antioxidant therapies, exploring combination treatment regimens, and validating biomarkers applicable for early detection and therapeutic efficacy assessment.}, } @article {pmid41110363, year = {2026}, author = {Kuyrukcu Ozturk, O and Oyardi, O and Ilikci Sagkan, R and Dundar, Y}, title = {Synthesis and biological evaluation of some pyrimidine derivatives as multifunctional ligands for the treatment of Alzheimer's disease.}, journal = {Bioorganic & medicinal chemistry}, volume = {132}, number = {}, pages = {118445}, doi = {10.1016/j.bmc.2025.118445}, pmid = {41110363}, issn = {1464-3391}, mesh = {*Pyrimidines/pharmacology/chemical synthesis/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; Structure-Activity Relationship ; Horses ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Bacillus cereus/enzymology/drug effects ; Electrophorus ; Molecular Docking Simulation ; Ligands ; Humans ; Molecular Structure ; Dose-Response Relationship, Drug ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder and acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and sphingomyelinase (SMase) enzymes are among its therapeutic targets. In this study, a series of tetrahydropyrimidine and hexahydropyrimidine derivatives were synthesized and evaluated for their inhibition of Bacillus cereus SMase, electric eel AChE (EeAChE), and equine BuChE (eqBuChE) as potential agents against AD. Among the synthesized compounds, 4-oxo-6-(pyridin-2-yl)-2-thioxohexahydropyrimidine-5‑carbonitrile (compound 24) was found to be the most active compound against B. cereus SMase, with an IC50 value of 1.61 μM. In addition, 2-(benzylthio)-4-octyl-6-oxo-1,6-dihydropyrimidine-5‑carbonitrile (compound 14) and 4-octyl-6-oxo-2-(phenethylthio)-1,6-dihydropyrimidine-5‑carbonitrile (compound 16) exhibited selective eqBuChE inhibition with IC50 values of 3.68 and 1.65 μM, respectively. The mode of inhibition of the selected compounds was determined by enzyme kinetic study. These compounds were also examined for their metal-chelating properties with various biometals and effect of B. cereus-induced hemolysis on sheep erythrocytes. Additionally, compound 24 showed no cytotoxic effect on the HUVEC cell line at its IC50 concentration. The biological data were supported by the results of molecular docking studies, and in-silico physicochemical properties/ADME predictions of the selected compounds were determined.}, } @article {pmid41109840, year = {2026}, author = {Davidson, MH and Szarek, M and Scheltens, P and Vijverberg, E and Hsieh, A and Ditmarsch, M and Kling, D and Curcio, D and Nicholls, SJ and Ray, KK and Cummings, JL and Kastelein, JJ}, title = {Effect of obicetrapib, a potent cholesteryl ester transfer protein inhibitor, on p-tau217 levels in patients with cardiovascular disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {1}, pages = {100394}, doi = {10.1016/j.tjpad.2025.100394}, pmid = {41109840}, issn = {2426-0266}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Anticholesteremic Agents/therapeutic use/pharmacology ; Biomarkers/blood ; *Cardiovascular Diseases/drug therapy/blood ; *Cholesterol Ester Transfer Proteins/antagonists & inhibitors ; Cholesterol, LDL/blood ; Double-Blind Method ; *tau Proteins/blood ; }, abstract = {BACKGROUND: Cholesteryl ester transfer protein (CETP) inhibition reduces low density lipoprotein-cholesterol (LDL-C) while simultaneously increasing high density lipoprotein-cholesterol (HDL-C) levels and improving HDL-particle functionality. These lipoprotein modifications may provide a novel pathway for Alzheimer disease (AD) prevention through effects on lipid modulation, antioxidant activity, and neuro-inflammation. This approach could prove particularly beneficial for APOE4 carriers, who face elevated risks for both AD and atherosclerotic cardiovascular disease (ASCVD). OBJECTIVES: To examine the effects of obicetrapib, an oral CETP inhibitor, on biomarker changes indicative of AD pathology among patients with ASCVD DESIGN: This was a pre-specified substudy of the BROADWAY trial, a phase 3, double-blind, placebo-controlled pivotal registration trial to evaluate the LDL-C lowering efficacy of obicetrapib in adult patients with established ASCVD and/or heterozygous familial hypercholesterolemia (HeFH), whose LDL-C was not adequately controlled, despite being on maximally tolerated lipid-lowering therapy. SETTING: The trial was conducted across 188 sites in China, Europe, Japan, and the United States. Participants were recruited from cardiology clinics and lipid specialty centers from 2021 to 2024. PARTICIPANTS: Participants with ASCVD in BROADWAY who had known ApoE status and phosphorylated tau-217 (p-tau217) measured at baseline and 12 months. INTERVENTION: Participants in BROADWAY were randomized 2:1 to receive oral obicetrapib 10 mg daily or placebo for 12 months. MEASUREMENTS: AD plasma biomarkers were measured at baseline and 12 months using standardized SIMOA assays. The key outcome measure of interest was change in plasma p-tau217 from baseline to 12 months. Other outcome measures included changes in p-tau217/(Aβ42:40), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). RESULTS: The analysis population consisted of 1535 (61 %) of the 2530 BROADWAY participants. Median age was 67 years and 67.0 % were male. Baseline p-tau217 levels varied significantly by ApoE subgroups, with ApoE4 carriers generally having higher concentrations and ApoE4/E4 participants exhibiting the highest median concentration (0.56 pg/mL). Obicetrapib significantly attenuated p-tau217 increases compared to placebo (adjusted mean 2.09 % vs 4.94 %; P = 0.025). Treatment differences were most pronounced in ApoE4 carriers, where adjusted mean increases were 1.92 % and 6.91 %, for obicetrapib and placebo, respectively (P = 0.041). Furthermore, among ApoE4/E4 participants, there was a 7.81 % adjusted mean decrease in p-tau217 with obicetrapib compared to a 12.67 % increase with placebo, representing a 20.48 % treatment difference (P = 0.010). Positive trends were observed across secondary biomarkers, with obicetrapib also significantly limiting increases in the p-tau217/Aβ42:40 ratio compared to placebo (2.51 % vs 6.55 %; P = 0.004). In addition, among ApoE4/E4 participants, obicetrapib demonstrated significant effects on GFAP (-6.39 % vs +8.85 %; P = 0.006) and NfL (-10.49 % vs +6.82 %; P = 0.020). Strong correlations were observed between end-of-study obicetrapib plasma concentrations and biomarker improvements (r=-0.64), suggesting CETP inhibition as a potential mechanism, although other drug effects may also contribute to these changes. CONCLUSIONS: Obicetrapib significantly slowed AD biomarker progression over 12 months in participants with ASCVD, with the greatest effects in ApoE4 carriers. Among ApoE4/E4 participants, obicetrapib reduced p-tau217 levels by a placebo-adjusted 20.48 % and demonstrated consistent effects across multiple AD biomarkers. These findings represent the first demonstration of an oral intervention capable of reducing both beta-amyloid and tau pathology biomarkers in ApoE4 carriers, offering a potential preventive strategy for this high-risk population who currently have no effective prevention options. Future research will need to establish whether these biomarker changes translate to clinical benefits in dedicated AD prevention trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05142722.}, } @article {pmid41109234, year = {2025}, author = {Boon, BDC and Piura, YD and Moloney, CM and Chalk, JL and Lincoln, SJ and Rutledge, MH and Rothberg, DM and Kouri, N and Hinkle, KM and Roemer, SF and Johnson, DR and Burkett, BJ and Lowe, VJ and Petersen, RC and Dickson, DW and Reichard, RR and Nguyen, AT and Graff-Radford, J and Knopman, DS and Graff-Radford, NR and Murray, ME}, title = {Neuropathological changes and amyloid-related imaging abnormalities in Alzheimer's disease treated with aducanumab versus untreated: a retrospective case-control study.}, journal = {The Lancet. Neurology}, volume = {24}, number = {11}, pages = {931-944}, pmid = {41109234}, issn = {1474-4465}, support = {R01 AG069052/AG/NIA NIH HHS/United States ; RF1 AG069052/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; R01 AG075802/AG/NIA NIH HHS/United States ; P50 NS072187/NS/NINDS NIH HHS/United States ; R01 AG073282/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/pathology/metabolism/genetics ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Aged ; Retrospective Studies ; Case-Control Studies ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; *Brain/pathology/diagnostic imaging/drug effects ; Middle Aged ; Aged, 80 and over ; }, abstract = {BACKGROUND: Understanding the neuropathological effects of amyloid β (Aβ)-targeting therapies and amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease is critical for optimising treatment efficacy and patient outcomes. Comparing Aβ PET imaging with neuropathological assessments provides context for evaluating the extent of Aβ clearance and interpreting in-vivo biomarkers. We aimed to assess clinicopathological changes and ARIA-related effects in aducanumab-treated versus untreated Alzheimer's disease. METHODS: This retrospective case-control study included five aducanumab-treated participants from clinical trials conducted at the Mayo Clinic (2016-21) who underwent autopsy (2020-23). Treated participants were matched by autosomal dominant Alzheimer's disease mutation or APOE genotype, age at cognitive symptom onset, and sex to 12 untreated participants from the Mayo Clinic Alzheimer's Disease Research Center and Mayo Clinic Study of Aging cohorts in the Mayo Clinic brain bank (Jacksonville, FL, USA). Cognitive, imaging, and neuropathological outcomes were compared using descriptive analyses and Mann-Whitney U tests. FINDINGS: Aducanumab-treated participants comprised four males and one female, all carrying at least one APOE ∊4 allele, with two harbouring a PSEN1 mutation. Cumulative dosages of aducanumab ranged from 5 mg/kg to 241 mg/kg; all participants cognitively declined during treatment, and two exhibited ARIA. Reductions in [[18]F]florbetapir PET Centiloid values ranged from -6% to -81% compared with baseline. Treatment-to-death intervals ranged from 5 months to 41 months. Neuropathological analyses revealed clearance of Aβaa1-8 and Aβ42 localised to cortical layer I in treated participants, with no significant clearance in deeper cortical layers. Regions corresponding to ARIA on MRI showed microinfarcts with haemosiderin, complement activation, and CD68-positive vessel walls originating from Aβ-laden leptomeningeal and penetrating vessels. INTERPRETATION: Disproportionate Aβ clearance and ARIA-associated neuropathology localised to superficial cortical layers suggest a distinctive pattern of target engagement by aducanumab. These findings inform understanding and monitoring of similar Aβ-targeting therapies. FUNDING: Alzheimer Nederland, National Institute on Aging, and Alzheimer's Association.}, } @article {pmid41109226, year = {2025}, author = {Iwatsubo, T}, title = {Neuropathology of Alzheimer's disease after anti-amyloid β antibody treatment.}, journal = {The Lancet. Neurology}, volume = {24}, number = {11}, pages = {897-899}, doi = {10.1016/S1474-4422(25)00348-5}, pmid = {41109226}, issn = {1474-4465}, } @article {pmid41107348, year = {2025}, author = {Zeng, Z and Zhou, F and Zheng, Y and Shi, W and Hu, W and Wang, X and Ye, M and Zhou, J and Ye, P and Yuan, F and Zou, Y and Yan, Q and Dai, Y and Tang, D}, title = {Comprehensive analysis of LncRNA-miRNA-mRNA CeRNA network associated with umbilical cord blood PBMC in down syndrome.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {36352}, pmid = {41107348}, issn = {2045-2322}, support = {No. 2017B020209001//Science and Technology Planning Project of Guangdong Province/ ; }, mesh = {Humans ; *RNA, Messenger/genetics/metabolism ; *Down Syndrome/genetics/blood ; *MicroRNAs/genetics ; *RNA, Long Noncoding/genetics ; *Fetal Blood/metabolism/cytology ; *Gene Regulatory Networks ; *Leukocytes, Mononuclear/metabolism ; Female ; Computational Biology/methods ; Gene Expression Profiling ; Gene Expression Regulation ; RNA, Competitive Endogenous ; }, abstract = {Down syndrome (DS), a typical chromosomal disease caused by all or part of an extra genomic copy of chromosome 21. Few reports have investigated roles of competing endogenous RNA (ceRNA)-mediated regulatory mechanisms in DS pathogenesis. RNA from PBMCs of cord blood from DS and non-DS fetuses was used for RNA-Seq to profile lncRNAs, miRNAs, and mRNAs. Bioinformatics revealed DS-associated differential gene expression. Predicted miRNA-mRNA/lncRNA interactions were used to build and visualize ceRNA networks in Cytoscape. A total of 216 DEmiRNAs, 651 DElncRNA and 15,789 DEmRNA transcripts were identified in umbilical cord blood PBMC RNA preparations from DS and non-DS control subjects. KEGG pathway enrichment analysis showed that DEmRNAs were involved in pathways such as Huntington's disease, Alzheimer's disease, Parkinson's disease, etc., which are closely related to DS. The 11 mRNAs corresponding to the highest degree PPI network nodes (RPS27A, UBA52, UBC, RPL11, RPS27, MRPS7, RPL23, RPL9, NFKB1, RBX1, and RELA) may play important roles in expression of DS-associated phenotypic characteristics. Finally, we constructed upregulated and downregulated lncRNA-miRNA-mRNA ceRNA sub-networks and found several pairs of ceRNAs that might be involved in DS. MIAT might serve as a ceRNA to sponge hsa-miR-378c and ultimately regulate the expression of RBX1 to affect the cell cycle and lead to DS occurrence. In this study, we comprehensively analysed gene regulatory mechanisms associated with DS progression. The lncRNA-associated ceRNAs identified here may contribute to DS diagnosis and treatment.}, } @article {pmid41107250, year = {2025}, author = {Chang, JS and Huang, HZ and Yuan, M and Zhou, Y and Liu, D and Zhan, KB and Zhu, LQ}, title = {Alcohol addiction and Alzheimer's disease: a molecular collision course.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {410}, pmid = {41107250}, issn = {2158-3188}, mesh = {Humans ; *Alzheimer Disease/metabolism/etiology ; *Alcoholism/complications/metabolism/therapy ; Oxidative Stress ; *Brain/metabolism ; Cognitive Dysfunction ; Neuroprotective Agents/therapeutic use ; }, abstract = {Chronic alcohol consumption is increasingly recognized as a risk factor for Alzheimer's disease (AD), contributing to cognitive decline through multiple biological pathways. Excessive alcohol intake accelerates neurodegeneration by impairing the brain's ability to clear toxic proteins, disrupting neurotransmitter balance, and exacerbating inflammation and oxidative stress. These effects collectively weaken neuronal resilience, making the brain more vulnerable to AD-related damage. Emerging therapeutic strategies focus on mitigating alcohol-induced harm through neuroprotective drugs, inflammation-targeting treatments, and neurotransmitter modulators. Lifestyle-based interventions, including early abstinence, cognitive training, and precision nutrition, also show promise in reducing risk and slowing disease progression. Future research should prioritize personalized treatment approaches and novel drug delivery methods to improve outcomes for individuals affected by both conditions.}, } @article {pmid41106565, year = {2026}, author = {Sun, T and Li, Z and Xiao, B and Yang, J and Han, M and Zhang, J and Liu, S and Ma, H and Song, J and Su, Y and Cao, B and Zhang, X and Xie, Z and Zhu, H and Chen, Y and Ma, J and Wang, P and Zhang, Z}, title = {Multi-target neuroprotection of Atractylodes macrocephala ethyl acetate extract against Alzheimer's disease: from bioactivity-guided screening to mechanistic validation.}, journal = {Journal of ethnopharmacology}, volume = {355}, number = {Pt B}, pages = {120735}, doi = {10.1016/j.jep.2025.120735}, pmid = {41106565}, issn = {1872-7573}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/isolation & purification/therapeutic use ; *Plant Extracts/pharmacology/therapeutic use/isolation & purification ; Caenorhabditis elegans ; Amyloid beta-Peptides/metabolism ; *Atractylodes/chemistry ; Mice ; Acetates/chemistry ; Humans ; Disease Models, Animal ; Antioxidants/pharmacology/isolation & purification ; Cell Line ; Neurons/drug effects ; Anti-Inflammatory Agents/pharmacology/isolation & purification ; Microglia/drug effects ; Peptide Fragments ; }, abstract = {Atractylodes macrocephala (AM) has traditionally been used for treating inflammatory conditions, edema, and digestive issues. It is now being explored for its potential in treating Alzheimer's disease (AD), which is characterized by cognitive decline and impairments in learning and memory. While AM shows promise as a potential treatment for AD, further research is needed to identify its specific bioactive components and understand its mechanisms of action. AIM OF THE STUDY: This study aim to identify and evaluate bioactive fractions from AM for their potential to treat AD. The research focused on assessing the antioxidant, anti-inflammatory, and neuroprotective properties of these fractions to determine the most effective one. The ultimate goal was to find a basis for isolating active neuroprotective components from AM that could be used to develop new AD therapies. MATERIALS AND METHODS: To identify AM fractions with potential against AD, the study began with in vitro assessments of their ability to inhibit amyloid-β (Aβ) aggregation and their antioxidant capacity. The neuroprotective effects of these fractions were then evaluated against Aβ1-42 and D-galactose-induced toxicity in neuronal and microglial cell lines. A C. elegans AD model (CL4176 strain) was employed to assess the impact on Aβ-induced neurodegeneration (paralysis). Based on this comprehensive screening, the ethyl acetate extract (AMEA) emerged as the most promising fraction. Its mechanism of action was investigated using network pharmacology and validated in vivo using APP/PS1 transgenic mice. Finally, key compounds within AMEA were isolated and characterized. RESULTS: Compared to other extracts, AMEA showed stronger antioxidant, anti-inflammatory, and neuroprotective effects. In AD model mice, AMEA treatment protected the hippocampal neuronal structure, reduced damage to the pyramidal cell layer, and prevented dendritic spine loss. AMEA also significantly lowered the levels of key pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and reduced markers of microglial (IBA-1) and astrocyte (GFAP) activation, indicating reduced neuroinflammation. AMEA inhibited Aβ aggregation and improved cognitive function by reducing Aβ deposition in APP/PS1 transgenic mice. Network pharmacology analysis showed that AMEA is associated with neurodegenerative disease pathways and can regulate inflammatory mediators. UPLC-OE/MS analysis tentatively identified thirty-three phytochemicals in AMEA, including sesquiterpenoids, phenylpropanoids, coumarins, and flavonoids. Molecular docking revealed high binding affinity of compounds 3, 9, and 11 towards TNF-α, IL-6, and IL-1β, and ELISA results confirmed that compounds 3 and 11 markedly downregulated the expression of key neuroinflammatory factors. Structural isolation and bioactivity analysis of AMEA revealed that it contains bioactive components capable of protecting nerve cells from Aβ toxicity. CONCLUSIONS: This research concludes that the AMEA fraction of AM demonstrates significantly superior neuroprotective effects against the primary pathological features of AD compared to other solvent fractions. AMEA exhibited greater efficacy in inhibiting Aβ aggregation, neutralizing free radicals, protecting nerve cells, and reducing brain inflammation across various models, including C. elegans and AD mice. Furthermore, chemical component isolation and structural identification of the AMEA fraction yielded compounds such as atractylenolide and atractylenolactam, along with their dimers, many of which possess neuroprotective properties. In conclusion, this study establishes a basis for the future identification and development of neuroprotective compounds from AM.}, } @article {pmid41106076, year = {2025}, author = {Yang, G and Li, J and Guo, J and Liu, Y and Yan, J and Huang, H and Liu, J and Peng, C and Gan, M and Shu, J}, title = {Monoterpenoids from Verbena officinalis exert anti-neuroinflammatory effect through suppression of the NF-κB/MAPK signaling cascades.}, journal = {Bioorganic chemistry}, volume = {166}, number = {}, pages = {109098}, doi = {10.1016/j.bioorg.2025.109098}, pmid = {41106076}, issn = {1090-2120}, mesh = {Animals ; Mice ; *Anti-Inflammatory Agents/pharmacology/chemistry/isolation & purification ; Cell Line ; Cytokines/antagonists & inhibitors/biosynthesis/metabolism ; Dose-Response Relationship, Drug ; Lipopolysaccharides/pharmacology/antagonists & inhibitors ; *MAP Kinase Signaling System/drug effects ; Microglia/drug effects/metabolism ; Mitogen-Activated Protein Kinases/metabolism/antagonists & inhibitors ; Molecular Structure ; *Monoterpenes/pharmacology/chemistry/isolation & purification ; *NF-kappa B/metabolism/antagonists & inhibitors ; Nitric Oxide/antagonists & inhibitors/biosynthesis ; Signal Transduction/drug effects ; Structure-Activity Relationship ; Alzheimer Disease/drug therapy ; }, abstract = {Using bioactivity-guided isolation, we identified 11 monoterpenoids from V. officinalis, including 7 previously undescribed compounds (1-3, 5, and 8-10), two of which feature a rare C4-4'/C5-2' skeleton. At 12.5 μM, all isolated compounds significantly suppressed NO and pro-inflammatory cytokine production in LPS-stimulated BV2 microglial cells. Notably, compound 5 demonstrated the most potent anti-neuroinflammatory effects by modulating the NF-κB/MAPK signaling pathway, positioning it as a potential lead compound for AD treatment. These findings not only underscore the therapeutic value of V. officinalis but also broaden the pharmacological understanding of its monoterpenoid constituents.}, } @article {pmid41105718, year = {2025}, author = {Lara-Simon, E and Gispert, JD and Garcia-Ojalvo, J and Villoslada, P and , }, title = {Multiscale networks in Alzheimer's disease identify brain hypometabolism as central across biological scales.}, journal = {PLoS computational biology}, volume = {21}, number = {10}, pages = {e1013583}, pmid = {41105718}, issn = {1553-7358}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism/diagnostic imaging ; Humans ; *Brain/metabolism/diagnostic imaging ; Positron-Emission Tomography ; Biomarkers/metabolism/cerebrospinal fluid ; Systems Biology ; Aged ; Magnetic Resonance Imaging ; Male ; Amyloid beta-Peptides/metabolism ; Female ; tau Proteins/metabolism ; Computational Biology ; Aged, 80 and over ; }, abstract = {Alzheimer's disease encompasses multiple biological scales, spanning molecular factors, cells, tissues, and behavioral manifestations. The interplay among these scales in shaping the clinical phenotype is not yet fully comprehended. In particular, there is great interest in understanding the heterogeneity of the clinical aspects of AD in order to improve treatment and prevention, by targeting those aspects most susceptible to the disease. Here we employed a systems biology approach to address this issue, utilizing multilayer network analysis and deep phenotyping. This integrative analysis incorporated genomics, cerebrospinal fluid biomarkers, tau and amyloid beta (Aβ) PET imaging, brain MRI data, risk factors, and clinical information (cognitive tests scores, Clinical Dementia Rating and clinical diagnosis) obtained through the ADNI collaboration. Multilayer networks were built based on mutual information between the elements of each layer and between layers. Boolean simulations allowed us to identify paths that transmit dynamic information across layers. The most prominent path for predicting variables in the cognitive phenotype layer included the PET radiotracer fluorodeoxyglucose (FDG) in the posterior cingulate. Combinations of different symptomatic variables, mainly related to mental health (depression, mood swings, drowsiness) and vascular features (hypertension, cardiovascular history), were also part of the paths explaining the average phenotype. Our results show that integrating the flow of information across biological scales reveals relevant paths for AD, which can be subsequently explored as potential biomarkers or therapeutic targets. In particular, our results point for paths related with brain hypometabolism as a key feature in AD.}, } @article {pmid41105605, year = {2025}, author = {Bi, X and Xiao, X and Zhou, L and Liu, Q and Liu, Y and Tu, Q and Zhou, Y}, title = {Exploring multitarget molecular mechanisms of cannabidiol in Alzheimer's disease treatment using molecular simulations and modeling.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {3}, pages = {1287-1301}, doi = {10.1177/13872877251386440}, pmid = {41105605}, issn = {1875-8908}, mesh = {*Cannabidiol/pharmacology/therapeutic use/metabolism/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; tau Proteins/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; *Amyloid beta-Peptides/metabolism ; Phosphorylation/drug effects ; }, abstract = {BackgroundAlzheimer's disease is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaque deposition and neurofibrillary tangles composed of hyperphosphorylated tau. Dysregulation of glycogen synthase kinase-3β (GSK3β) promotes tau hyperphosphorylation and amplifies Aβ-induced neurotoxicity, driving pathogenesis. Despite extensive research, current therapies targeting these core mechanisms remain largely ineffective at halting disease progression.ObjectiveBased on prior clinical and preclinical evidence, we hypothesize that cannabidiol (CBD), a non-psychoactive phytocannabinoid, may exert multitarget therapeutic effects in AD by modulating Aβ aggregation, tau hyperphosphorylation, and GSK3β activity.MethodsWe investigated CBD's interactions with Aβ-42/40, tau, and GSK3β using molecular docking, molecular dynamics simulations and ADMET predictions.ResultsOur results show that CBD binds to Aβ with binding free energies of -7.81 kcal/mol, -7.46 kcal/mol, and -7.25 kcal/mol, disrupting aggregation by interacting with key residues (HIS6, HIS13, HIS14, GLU14, GLU22, ASP15, and ASP23). MD simulations confirm that CBD destabilizes Aβ's β-sheet structure, preventing fibril formation. CBD binds tau with binding free energies of -9.91 kcal/mol, -9.70 kcal/mol, and -9.66 kcal/mol, disrupting tau aggregation and preventing neurofibrillary tangle formation. MD simulations show that CBD induces structural changes in tau, reducing β-sheet packing and inhibiting tau-tau interactions. CBD also binds to GSK3β with binding energies of -8.94 kcal/mol, -8.51 kcal/mol, and -8.41 kcal/mol, competing with ATP to inhibit its kinase activity and reduce tau phosphorylation. ADMET analysis indicates CBD's favorable oral bioavailability and low toxicity.ConclusionsThese findings support CBD as a promising multitarget therapeutic for AD, warranting further preclinical and clinical investigations.}, } @article {pmid41105579, year = {2025}, author = {Zhu, X and Liu, S and Wang, L and Liu, J and Gu, D and Huang, C}, title = {Predicting the conversion time from normal cognition to mild cognitive impairment based on dual attention convolutional networks.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {3}, pages = {1115-1131}, doi = {10.1177/13872877251386078}, pmid = {41105579}, issn = {1875-8908}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis/psychology ; Disease Progression ; Aged ; *Neural Networks, Computer ; Male ; *Cognition/physiology ; Female ; *Attention/physiology ; Early Diagnosis ; Aged, 80 and over ; Neuropsychological Tests ; Time Factors ; }, abstract = {BackgroundDementia, a progressive neurological disorder, is a leading cause of disability and death globally, often underdiagnosed in its early stages. Early diagnosis, prevention, and treatment are crucial for mitigating its impact on individuals and society.ObjectiveThis study aimed to predict the exact conversion time from normal cognition (NC) to mild cognitive impairment (MCI), and to provide insights for early diagnosis and treatment of dementia.MethodsA novel dual attention convolutional network model was proposed to handle high-dimensional features and limited patients' records in short-sequence time series data. It integrated feature and temporal attention modules to capture dependencies and used a custom loss function to enhance clinical interpretability.ResultsThe model significantly reduced mean squared error (MSE) by 9.67% and mean absolute error (MAE) by 26.24%, while increasing the r-square (R2) by 16.71% compared to a basic convolutional model. It effectively predicted NC to MCI conversion, offering valuable guidance for early intervention.ConclusionsThe dual attention convolutional network model effectively predicted NC to MCI conversion, providing a valuable tool for early dementia diagnosis and treatment.}, } @article {pmid41104322, year = {2025}, author = {Hyung, H and Jang, S and Kim, SY and Bae, JE and Park, JY and Lim, SG and Ko, J and Jang, S and Kim, JB and Chae, HY and Park, S and Yi, J and Choi, DK and Kim, MO and Lee, HS and Cho, DH and Young Ryoo, Z}, title = {Down-regulation of HSPA9 reduces tyrosine hydroxylase-positive neurons in mouse substantia nigra and induces Parkinson's disease-like motor impairments.}, journal = {Animal cells and systems}, volume = {29}, number = {1}, pages = {615-627}, pmid = {41104322}, issn = {1976-8354}, abstract = {Parkinson's disease (PD) is a progressive neurological disorder characterized by the degeneration of midbrain dopaminergic neurons and disabling motor impairments. Heat shock protein family A member 9 (HSPA9) play a crucial role in neuronal homeostasis by regulating the import of various mitochondrial proteins. HSPA9 is down-regulated in neurodegenerative diseases such as Alzheimer's disease and PD, and its loss leads to excessive mitochondrial fragmentation with oxidative stress, which subsequently causes damage to dopaminergic neurons. Moreover, HSPA9 interacts with multiple PD-associated proteins, including Pink1, DJ-1, and α-synuclein, however precise roles of HSPA9 in PD pathophysiology remain unclear. To further explore the contributions of HSPA9 in PD pathogenesis, we developed an HSPA9 knockout mouse. Haploinsufficiency of Hspa9 (Hspa9 [+/-]) was associated with the loss of tyrosine hydroxylase-positive neurons in the striatum and substantia nigra. Furthermore, Hspa9 haploinsufficiency induced excessive mitochondrial fission, enhanced apoptotic signaling, and resulted in diminished motor performance during the rotarod test. Administration of the mitochondrial neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Hspa9 [+/-] mice further exacerbated the loss of dopaminergic neurons, aggravated motor impairments, and enhanced activation of apoptosis effector caspase-3. These results suggest that down-regulation of HSPA9 may contribute to the development and progression of PD, potentially offering a new therapeutic strategy for PD treatment.}, } @article {pmid41104248, year = {2025}, author = {Kasaei, A and Forouzanfar, M and Jafarinia, M}, title = {Neuroprotection by Resveratrol in Chronic Cerebral Hypoperfusion: A Study on Synaptogenesis Enhancement and Apoptosis Inhibition.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {24}, number = {1}, pages = {e162425}, pmid = {41104248}, issn = {1726-6890}, abstract = {BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a key contributor to vascular dementia (VaD) and Alzheimer's disease. Resveratrol (RSV), a polyphenol with potential neuroprotective properties, may mitigate CCH-induced neuronal damage, but its mechanisms remain unclear. OBJECTIVES: This study investigated RSV's effects on memory enhancement through synaptogenesis and apoptosis inhibition in the hippocampus in a rat CCH model. METHODS: Forty male rats were randomly divided into four groups: Sham, 2-VO (bilateral carotid artery occlusion), 2-VO+RSV (2.5 mg/kg), and 2-VO+RSV (5 mg/kg). Initial group sizes (n = 10 each) were maintained by replacing deceased animals (2-VO: 7, 2-VO+RSV2.5: 4, 2-VO+RSV5: 6 deaths). The RSV was administered via intraperitoneal injection (ip) for 35 days post-surgery. Cognitive function was assessed using Morris water maze (MWM) and shuttle box tests. Hippocampal mRNA/protein levels of B-cell lymphoma 2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase-3, Ras homolog family member A (RhoA), Rho-associated coiled-coil containing protein kinase 2 (ROCK2), calcium/calmodulin-dependent protein kinase II alpha (CaMKII-α), and N-methyl-D-aspartate receptor subunit 2B (NMDAR2B) were measured. RESULTS: The RSV (5 mg/kg) significantly improved spatial memory in the MWM. Also, RSV at doses of 2.5 and 5 mg/kg significantly increased the entrance latency to the dark compartment (P < 0.05 and P < 0.01 vs 2-VO, respectively). There was a downregulation of pro-apoptotic markers (Bax, Caspase-3) and Rho/ROCK gene expressions, and an upregulation of anti-apoptotic Bcl-2 gene expression and synaptic proteins (CaMKII-α, NMDAR2B) after RSV treatment. The RSV at 5 mg/kg significantly reduced the Bax/Bcl-2 ratio compared to the 2-VO group. CONCLUSIONS: The RSV protects against CCH-induced neuronal damage by inhibiting apoptosis and enhancing synaptic plasticity. These findings highlight RSV's therapeutic potential for vascular cognitive impairment.}, } @article {pmid41103911, year = {2025}, author = {Bhansali, PR and Sonkusare, SM and Savale, SS and Wijayasinghe, YS and Liao, Y and Sloan, DC and Chaturbhuj, GU and Muntean, BS}, title = {Comprehensive medicinal chemistry survey highlights a portfolio of lead molecules for Alzheimer's disease therapy.}, journal = {Frontiers in chemistry}, volume = {13}, number = {}, pages = {1642190}, pmid = {41103911}, issn = {2296-2646}, abstract = {The World Health Organization reports 10 million new patients with dementia each year. The most common form of dementia is Alzheimer's disease (AD), which constitutes up to 70% of cases. AD is mainly characterized by loss of memory, which, in addition to its debilitating individual effect, represents a burden of 1.3 trillion US dollars globally. The staggering scale of hardship has spurred intense investigations from the scientific community in search of therapeutic solutions. Recent advances to combat AD involve the identification of numerous neural targets and concomitant chemical interventions as nodes of therapy. Due to disparate biological and chemical facets of AD therapy, a comprehensive perspective covering both arenas is currently missing from the literature. This perspective aims to provide an extensive understanding of anti-AD mechanics alongside small-molecule drug design efforts from a medicinal chemist viewpoint. We are confident that this survey of the literature will provide a resourceful motivation to propel future research efforts towards successful Alzheimer's disease therapy.}, } @article {pmid41103096, year = {2025}, author = {Bulut, Z and Karaküçük-Iyidoğan, A and Bilge, M and Sicak, Y and Turgut-Solak, ZD and Oruç-Emre, EE}, title = {Structure-Based Design of Chiral Thioureas as Anticholinesterase Inhibitors Using Enantiopure α-Methylbenzylamines: Synthesis, Enzyme Inhibition, and In Silico Studies.}, journal = {Archiv der Pharmazie}, volume = {358}, number = {10}, pages = {e70124}, doi = {10.1002/ardp.70124}, pmid = {41103096}, issn = {1521-4184}, support = {//This study was funded by the Scientific and Technological Research Council of Türkiye (TUBITAK) with project number 222Z293./ ; }, mesh = {*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; *Thiourea/pharmacology/chemistry/chemical synthesis/analogs & derivatives ; Structure-Activity Relationship ; Butyrylcholinesterase/metabolism ; *Drug Design ; Acetylcholinesterase/metabolism ; Stereoisomerism ; Molecular Docking Simulation ; Molecular Structure ; Humans ; Dose-Response Relationship, Drug ; *Benzylamines/chemistry/pharmacology/chemical synthesis ; Animals ; Computer Simulation ; }, abstract = {A detailed analysis of the research on the treatment of Alzheimer's disease indicates that selective inhibition of butyrylcholinesterase (BChE) is the most promising strategy for identifying a drug target. According to this perspective, in this study, a new series of potential BChE inhibitors (1a-8a and 1b-8b) were designed using a structure-based design approach and synthesized as enantiomer pairs based on the benzyl thiourea attached to a chiral moiety. The in vitro anticholinesterase activity studies against acetylcholinesterase (AChE) and BChE consistently demonstrated that the majority of the designed compounds exhibited selective and potent BChE inhibition. Also, the present results of the study reveal that compound 6b, which has a methyl group at the para position of the phenyl ring and has an S configuration, was the most potent compound against BChE with an IC50 value of 1.46 ± 1.99 μM (SI = 8.47). In contrast, the chiral thioureas (8a and 8b) bearing a cyclohexyl group demonstrated higher selectivity toward AChE, with SI values of 2.10 and 2.32, respectively. Notably, compounds 2a and 2b showed dual inhibitory effects with similar potency for AChE and greater potency for BChE, compared to the standard drug galantamine. The molecular docking method, which showed a good correlation with our in vitro anticholinesterase activity results, was used to predict the interactions of all chiral thioureas within the binding pockets of AChE and BChE. Further structural improvement of these molecules in future studies may lead to the emergence of more potent AChE and BChE inhibitors.}, } @article {pmid41102960, year = {2025}, author = {Agarwal, U and Kapoor, G and Tonk, RK}, title = {A Review on the Pathophysiology of Alzheimer's Disease.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037416859250915091846}, pmid = {41102960}, issn = {1875-5550}, abstract = {INTRODUCTION: Alzheimer's disease is characterized by a complex and multifactorial pathogenesis, involving key features such as amyloid-beta plaques, tau tangles, and neuron loss. Understanding the disease requires investigating its underlying causes, as these hallmarks reflect the intricate physiological processes involved. Identifying the root factors driving AD is essential for developing effective treatments. METHOD: This literature review was conducted using PubMed and Scopus databases, covering studies published from October 1999 to April 2025. The review included 190 references focused on the pathophysiology of Alzheimer's disease (AD). The selected studies analysed the primary pathophysiology leading to AD, particularly the accumulation of amyloid-beta plaques, tau tangles, and neuronal loss. RESULT: The study highlights several key biological factors associated with Alzheimer's Disease (AD). These include genetic mutations, mitochondrial dysfunction, hormonal imbalances, inflammation, oxidative stress, cellular division abnormalities, and reduced levels of dopamine-related neurotransmitters. It also highlights issues with calcium regulation and the imbalance of metals, such as copper, iron, lead, and zinc, in the body. Lifestyle choices such as drinking alcohol and smoking, along with changes in blood vessels and problems with the blood-brain barrier, were also found to play a role in how the disease develops. Additionally, the presence of certain pathogens was suggested as a possible factor in the disease's underlying mechanisms. DISCUSSION: The results indicate that a complex combination of genetic, biochemical, and environmental factors shapes the development and progression of Alzheimer's disease. Genetic mutations seem to play a significant role in affecting enzyme functions, which can disrupt vital biological processes. Problems with mitochondria and hormonal imbalances contribute to the deterioration of nerve cells, while oxidative stress and neuroinflammation are key mechanisms that worsen cellular damage. Disruptions in calcium signalling and imbalances in bio-metals further disturb neuronal stability. Lifestyle choices, blood vessel issues, and blood-brain barrier problems highlight the multifaceted nature of the disease. The study also highlights the close relationship between oxidative stress and neuroinflammation, suggesting that they may form a feedback loop that accelerates disease progression. Additionally, the possible involvement of infectious agents adds another layer of complexity, indicating that infections might trigger or worsen neurodegeneration in vulnerable individuals. CONCLUSION: To better understand and address Alzheimer's disease, it is essential to examine the fundamental processes that trigger its development. The various and interconnected factors involved- such as genetic mutations, cellular problems, environmental factors, and exposure to pathogens- require a comprehensive and integrated approach to research and treatment. Recognizing that neuroinflammation and oxidative stress play key roles in the progression of the disease can help guide future efforts toward early detection and more precise interventions.}, } @article {pmid41102777, year = {2025}, author = {Lin, Y and Yoo, JM and Li, Y and Heo, Y and Okumura, M and Won, HS and Vendruscolo, M and Lim, MH and Lee, YH}, title = {Disease-disease interactions: molecular links of neurodegenerative diseases with cancer, viral infections, and type 2 diabetes.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {52}, pmid = {41102777}, issn = {2047-9158}, support = {A439200//Korea Basic Science Institute/ ; C539200//Korea Basic Science Institute/ ; C512120//Korea Basic Science Institute/ ; C523200//Korea Basic Science Institute/ ; A412580//Korea Basic Science Institute/ ; A423310//Korea Basic Science Institute/ ; CCL22061-100//National Research Council of Science & Technology/ ; RS-2022-NR069719//National Research Foundation of Korea/ ; RS-2022-NR070709//National Research Foundation of Korea/ ; RS-2021-NR057690//National Research Foundation of Korea/ ; RS-2023-00221332//National Research Foundation of Korea/ ; RS-2024-00356469//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; *Neoplasms/metabolism ; *Virus Diseases/metabolism ; }, abstract = {Neurodegenerative disorders, notably Alzheimer's and Parkinson's diseases, are unified by progressive neuronal loss and aberrant protein aggregation. Growing evidence indicates that these conditions are linked to cancer, infectious diseases, and type 2 diabetes through convergent molecular processes. In this review, we examine the mechanistic foundations of these links, focusing on shared features such as protein misfolding and aggregation, chronic inflammation, and dysregulated signalling pathways. We integrate cellular, animal, and human data to illustrate how pathogenic proteins may influence one another through cross-seeding and co-aggregation, and assess the implications of such interactions for disease susceptibility, progression, and treatment response. Understanding these underlying mechanisms may provide a conceptual framework for developing therapeutic approaches that target the molecular basis of multiple complex disorders.}, } @article {pmid41102562, year = {2025}, author = {, and Cao, H and Song, Z and Duggan, MR and Erus, G and Srinivasan, D and Tian, YE and Bai, W and Rafii, MS and Aisen, P and Belsky, DW and Walker, KA and Zalesky, A and Ferrucci, L and Davatzikos, C and Wen, J}, title = {MRI-based multi-organ clocks for healthy aging and disease assessment.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {41102562}, issn = {1546-170X}, support = {RF1AG092412//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; }, abstract = {Biological aging clocks across organ systems and tissues have advanced understanding of human aging and disease. In this study, we expand this framework to develop seven magnetic resonance imaging-based multi-organ biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney and pancreas. Using data from 313,645 individuals curated by the MULTI Consortium, we link the seven MRIBAGs to 2,923 plasma proteins, 327 metabolites and 6,477,810 common genetic variants. Genome-wide associations identify 53 MRIBAG-locus pairs (P < 5 × 10[-8]). Genetic correlation and Mendelian randomization analyses support organ-specific and cross-organ interconnection, including 24 non-MRI biological aging clocks and 525 disease endpoints. Through functional gene mapping and Bayesian co-localization multi-omics evidence, we prioritize nine druggable genes as targets for future anti-aging treatments. Furthermore, the seven MRIBAGs are linked to future risk of systemic disease endpoints (for example, diabetes mellitus) and all-cause mortality. Finally, participants with more youthful versus more aged brain profiles exhibited distinct cognitive decline trajectories over 240 weeks of treatment with the Alzheimer's disease drug solanezumab, although this heterogeneity cannot be fully attributed to the drug. In summary, we developed seven MRIBAGs that enhance the existing multi-organ biological aging framework, and we demonstrate their clinical potential to advance aging research.}, } @article {pmid41101301, year = {2025}, author = {Sasidharan, A and Somayaji, Y and Fernandes, R}, title = {Shifting Microglial Phenotypes: Targeting Disease-Associated Microglia in Neurodegeneration.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {21}, pages = {4147-4158}, doi = {10.1021/acschemneuro.5c00159}, pmid = {41101301}, issn = {1948-7193}, mesh = {Humans ; *Microglia/metabolism/pathology/immunology ; *Neurodegenerative Diseases/metabolism/pathology/immunology ; Animals ; Phenotype ; Neuroinflammatory Diseases/metabolism ; Phagocytosis/physiology ; }, abstract = {Neurodegenerative disorders are marked by the gradual degeneration of neurons and deterioration of cognitive function. One key underlying factor in these diseases is neuroinflammation. An essential component of this process is microglia, which are the innate immune cells that maintain homeostasis in the brain. A common outcome of microglial dysregulation in neurodegenerative diseases is chronic neuroinflammation, which exacerbates neuronal damage and impairs synaptic function. This review focuses on the dual roles that disease-associated microglia (DAMs) play in neural inflammation and neuroprotection as well as their distinct transcriptional profile in neurodegenerative diseases. DAMs engage in phagocytosis to remove debris, in addition to releasing cytokines that promote inflammation. To create an effective medicine, it is imperative to comprehend these dual functions. The roles of DAMs in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are discussed, along with the mechanisms (such as the TREM2-APOE pathway) causing their activation. This review attempts to highlight the important aspects that could direct future investigations and treatment development by clarifying the interactions between DAMs and neurodegenerative diseases.}, } @article {pmid41099783, year = {2025}, author = {Alavian, F and Hajimohammadi, A}, title = {Interplay between gut Microbiome and glymphatic system in cognitive function and memory regulation.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {1038}, pmid = {41099783}, issn = {1573-4978}, mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Cognition/physiology ; *Glymphatic System/metabolism/physiology ; *Memory/physiology ; Animals ; Brain/metabolism ; Neurodegenerative Diseases/metabolism ; Dysbiosis ; Aquaporin 4/metabolism ; }, abstract = {The glymphatic system, a network of perivascular channels in the brain, clears toxins and metabolic products such as amyloid-β (Aβ), supporting cognitive function and preventing neurodegenerative diseases. The gut microbiome also affects brain health and cognitive functions by producing anti-inflammatory metabolites and neurotransmitters. In this narrative review study, recently published articles from reputable scientific databases were collected and analyzed. Characteristics related to the gut microbiome, its metabolites, and their impact on the glymphatic system and ultimately cognitive function were examined. These findings indicate that microbial metabolites such as short-chain fatty acids (SCFAs) and neurotransmitters such as serotonin and melatonin reduce brain inflammation and improve sleep quality and synaptic plasticity, which are essential for memory stabilization. Disruption of the gut microbiome (dysbiosis) leads to increased inflammation and dysfunction of the glymphatic system, resulting in the accumulation of toxic proteins and decreased cognitive function. Proper polarization of aquaporin-4 (AQP4), a water channel protein critical for fluid homeostasis in the brain, in astrocytes is essential for the effective functioning of this system, and its disruption is associated with diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Understanding the interaction between the gut microbiome and the glymphatic system presents a new pathway for regulating memory and cognitive health, which could be an important target for the prevention and treatment of neurodegenerative diseases. Enhancing the gut microbiome through probiotics and a healthy diet may improve glymphatic system function and brain health, thereby preventing cognitive disorders.}, } @article {pmid41099201, year = {2025}, author = {Bolzetta, F and Durante, G and Tessari, A and Lazzarin, M and Busonera, F and Pontarin, A and Villanova, M and Vernuccio, L and Saccaro, C and Custodero, C and Portincasa, P and Barbagallo, M and Veronese, N}, title = {A simple nomogram to predict the onset of dementia in mild cognitive impairment: A retrospective study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {834-843}, pmid = {41099201}, issn = {1875-8908}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis/complications/psychology ; Male ; Female ; Aged ; *Dementia/diagnosis/etiology/psychology ; Retrospective Studies ; *Nomograms ; Neuropsychological Tests ; Aged, 80 and over ; Disease Progression ; Mental Status and Dementia Tests ; Follow-Up Studies ; Predictive Value of Tests ; }, abstract = {BackgroundCurrently there is no effective treatment to reverse Alzheimer's disease, thus prevention is crucial. Patients with mild cognitive impairment (MCI) have higher rate of progression to dementia. Two commonly used cognitive tests, Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT), have only modest accuracy at predicting conversion from MCI to dementia, whereas other potentially predicting factors are difficult to implement in clinical practice.ObjectiveThe aim of this study was to assess the performance of a combination of simple cognitive tests and routine clinical data to predict onset clinical dementia over 3-year follow-up in a cohort of outpatients with MCI.MethodsMedical history was collected, and an advanced neuropsychological assessment was performed at baseline and at follow-up.Results98 participants were included (mean age 76.6 ± 4.5 years), and 49 developed dementia. Participants who developed dementia had significantly lower MMSE and CDT scores, as well as higher presence of hypercholesterolemia at the baseline evaluation. In the multivariate binary logistic regression analysis, the OR were 0.71 (CI95% 0.58-0.87) for MMSE, 0.77 (CI95% 0.65-0.93) for CDT, and 3.9 (CI95% 1.4-10.9) for hypercholesterolemia. The ROC curve combining these three factors obtained a value of AUC of 0.825 (CI95% 0.74-0.91). A nomogram was then developed for the risk of evolution from MCI to dementia at 3 years.ConclusionsCombining history of hypercholesterolemia with CDT and MMSE tests, may result in a simple prediction model to predict the onset of dementia over 3 years.}, } @article {pmid41099145, year = {2025}, author = {García Ribas, G and Ferrer-Picón, E}, title = {Tolerability of rivastigmine transdermal patch in patients with Alzheimer's disease: a narrative review.}, journal = {Expert opinion on drug safety}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/14740338.2025.2576520}, pmid = {41099145}, issn = {1744-764X}, abstract = {INTRODUCTION: The rivastigmine transdermal patch was developed to provide similar efficacy to oral rivastigmine in the treatment of Alzheimer's disease (AD), but with improved tolerability. AREAS COVERED: Randomized clinical trials and observational studies reporting on the tolerability of the rivastigmine transdermal patch in patients with AD, identified through a systematic literature search. EXPERT OPINION: Rivastigmine was the first cholinesterase inhibitor for which a transdermal formulation was developed; consequently, there is a substantial body of evidence on its efficacy and tolerability. The incidence of gastrointestinal AEs is markedly reduced with the transdermal patch compared with oral rivastigmine, while the efficacy of the patch remains similar to that of the oral formulation. Application site reactions are generally mild and do not cause much discomfort for the patient, and the risk of can be reduced by simple measures such as site rotation and good skin care. Tolerability of the patch improves over time, including at the highest dose level. Overall, the available evidence supports transdermal rivastigmine being generally well tolerated at doses up to 13.3 mg/24 h in patients with AD.}, } @article {pmid41098825, year = {2025}, author = {Zhang, X and Huang, S and Xu, H and Hu, Y and Gao, L}, title = {Research progress on plant-derived natural compounds regulating the MAPK signaling pathway for the prevention and therapy of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1666082}, pmid = {41098825}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder. It is characterised by the following: amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation and oxidative stress. Unfortunately, there is no curative treatment available. Recently, natural products have attracted growing interest as potential therapeutic agents for AD, thanks to their multi-target actions and favourable safety profiles. This review highlights recent advances in the use of various natural compounds, including flavonoids, phenolic compounds, saponins, terpenoids, alkaloids and coumarins, with a particular focus on how they modulate the mitogen-activated protein kinase (MAPK) signaling pathway. Representative agents such as myricetin, nobiletin, resveratrol, gallic acid, paeoniflorin, ganoderic acid A, huperzine A, triptolide, berberine, crocin, and ginsenosides have been shown to regulate MAPK subpathways (ERK, JNK, p38), thereby attenuating oxidative stress, neuroinflammation, synaptic dysfunction, and neuronal apoptosis. Preclinical studies suggest that these compounds improve cognitive function and ameliorate AD-related pathology, thereby supporting the idea that MAPK signaling is a critical therapeutic target. Nevertheless, current evidence is limited by short-term animal experiments, insufficient toxicological evaluations, and challenges related to bioavailability and blood-brain barrier penetration. Future studies should emphasize long-term efficacy, safety assessments, optimized drug delivery systems, and high-quality clinical trials. Overall, natural products represent a valuable source for AD drug discovery, and targeting MAPK signaling offers promising opportunities for novel therapeutic development.}, } @article {pmid41097927, year = {2025}, author = {Kowa, H and Sato, S and Kamiki, E and Nishimoto, T}, title = {[Significance of Amyloid Plaque Removal in Alzheimer's Disease Treatment: Development of Amyloid β-Targeting Antibody Drugs Based on the Amyloid Cascade Hypothesis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {10}, pages = {1129-1136}, doi = {10.11477/mf.188160960770101129}, pmid = {41097927}, issn = {1881-6096}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Plaque, Amyloid/drug therapy/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies/therapeutic use ; }, abstract = {In a hyper-aging society, taking measures against dementia, especially against dementia due to Alzheimer's disease, which accounts for about two thirds of dementia cases, is an important task socially and economically. Forty years have passed since amyloid β was isolated from a patient, 30 years have passed since the amyloid cascade hypothesis was proposed and antibody drugs based on this hypothesis have emerged, which has led to the new era of Alzheimer's disease treatment. This article reviews the significance of amyloid plaque removal with amyloid β-targeting antibody treatment for Alzheimer's disease. (Recieved October 17, 2024; Accepted June 6, 2025; Published October 1, 2025).}, } @article {pmid41097350, year = {2025}, author = {Chakhari, S and Marco-Contelles, J and Iriepa, I and Carreiras, MDC and Chabchoub, F and Ismaili, L and Refouvelet, B}, title = {Multicomponent Synthesis of Multi-Target Quinazolines Modulating Cholinesterase, Oxidative Stress, and Amyloid Aggregation Activities for the Therapy of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {19}, pages = {}, pmid = {41097350}, issn = {1420-3049}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *Quinazolines/chemical synthesis/pharmacology/chemistry ; *Amyloid beta-Peptides/metabolism/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Humans ; Antioxidants/pharmacology/chemical synthesis/chemistry ; Protein Aggregates/drug effects ; Acetylcholinesterase/metabolism ; *Cholinesterases/metabolism ; Peptide Fragments/metabolism/chemistry ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta (Aβ) peptide, intracellular neurofibrillary tangles (NFTs), severe neuronal loss, and a marked decline in cholinergic function. Due to the limited efficacy of currently available therapies, the search for new chemical scaffolds able to target multiple pathological mechanisms remains an urgent priority. Among the most promising strategies are heterocyclic frameworks that can simultaneously interact with cholinesterase (ChE) enzymes and inhibit amyloid-β (Aβ) aggregation while also exhibiting antioxidant activity. In this context, we report a series of quinazoline derivatives synthesized via a sequential, one-pot multicomponent reaction, in good yields. Several of these compounds demonstrated notable antioxidant properties, as well as inhibitory effects on ChE activity and Aβ1-42 self-aggregation, highlighting their potential as multifunctional agents for the treatment of neurodegenerative disorders. Notably, 2-ethyl-4-(3,4-Dimethoxyphenyl)aminoquinazoline (3h) demonstrated the most balanced biological profile among the tested compounds, exhibiting an ORAC value of 5.73 TE, an acetylcholinesterase (AChE) inhibition IC50 = 6.67 μM, and 36.68% inhibition of Aβ1-42 aggregation, closely approaching the activity of curcumin. These findings highlight compound 3h as a promising quinazoline-based hit for the development of multifunctional agents targeting AD.}, } @article {pmid41097203, year = {2025}, author = {Mohib, O and Bomans, S and Jimenez Garcia, B and Leemans, L and Ligneel, C and De Waele, E and Beckwée, D and Janssens, P}, title = {Clinical Benefits of Exogenous Ketosis in Adults with Disease: A Systematic Review.}, journal = {Nutrients}, volume = {17}, number = {19}, pages = {}, pmid = {41097203}, issn = {2072-6643}, support = {G075423N//Research Foundation - Flanders/ ; }, mesh = {Humans ; *Ketosis ; *Ketone Bodies/therapeutic use/administration & dosage ; Adult ; Cardiovascular Diseases ; *Metabolic Diseases ; COVID-19 ; Mental Disorders/drug therapy ; Nervous System Diseases ; }, abstract = {BACKGROUND/OBJECTIVES: Ketone bodies are increasingly studied for their potential therapeutic effects, particularly through exogenous ketosis, in a variety of diseases. This systematic review aimed to rigorously assess the clinical efficacy of exogenous ketosis in adults with medical conditions. METHODS: Following PRISMA guidelines, we systematically searched MEDLINE and Scopus databases. Our inclusion criteria were defined according to the PICOS framework, focusing on studies involving exogenous ketosis in adult patients with specific diseases. The study is registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42023492846). RESULTS: After a stringent selection process, fifty-one studies were analyzed. Twenty-two studies focused on neurological disorders, one on psychiatric disorders, twenty-two on metabolic disorders, five on cardiovascular disorders, and one on an inflammatory disorder. Exogenous ketosis demonstrated potential benefits across multiple conditions, including Alzheimer's disease, mild cognitive impairment, McArdle's disease, various forms of heart failure, cardiogenic shock, pulmonary hypertension, and COVID-19-related acute respiratory distress syndrome, although evidence is mostly limited to surrogate endpoints with insufficient hard outcome data. Subtherapeutic ketone concentrations induced by medium-chain triglycerides and limited follow-up periods often precluded firm conclusions regarding clinically meaningful outcomes. CONCLUSIONS: Exogenous ketosis shows potential in neurological, metabolic, and cardiovascular disorders, while evidence in psychiatric and inflammatory conditions remains scarce and preliminary. Ketone esters appear preferable for effective and tolerable ketosis. Future research should focus on identifying responsive patient populations, optimizing treatment regimens, and conducting long-term clinical trials with hard endpoints to validate these findings.}, } @article {pmid41097011, year = {2025}, author = {Campagnoli, LIM and Varesi, A and Fahmideh, F and Hakimizad, R and Petkovic, P and Barbieri, A and Marchesi, N and Pascale, A}, title = {From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41097011}, issn = {1422-0067}, mesh = {Humans ; *Metformin/therapeutic use/pharmacology ; *Hypoglycemic Agents/therapeutic use/pharmacology ; *Diabetes Mellitus, Type 2/drug therapy/metabolism ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; AMP-Activated Protein Kinases/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; }, abstract = {Metformin, an oral antihyperglycemic drug, represents the cornerstone of pharmacological treatment for type 2 diabetes mellitus (T2DM). Its primary glucose-lowering effects are well established, predominantly mediated through the activation of AMP-activated protein kinase (AMPK). This activation leads to a reduction in hepatic glucose production (primarily by inhibiting gluconeogenesis and glycogenolysis) and an increase in peripheral glucose uptake and utilization. Beyond its direct impact on glucose metabolism, metformin also improves insulin sensitivity and has beneficial effects on lipid profiles. Increasingly, research shows that metformin has pleiotropic effects. In addition to its recognized antihyperglycemic action, metformin is emerging as a regulator of cellular processes implicated in aging. Indeed, emerging evidence suggests a potential role of metformin in modulating pathways associated with longevity and ameliorating the symptoms of age-related diseases, including neurodegenerative disorders (such as Alzheimer's and Parkinson's diseases), cardiovascular diseases, age-related macular degeneration, and osteoporosis. The proposed mechanisms for these broader effects involve AMPK activation, modulation of the mTOR pathway, reduction of oxidative stress, and promotion of autophagy. After exploring the established role of metformin in T2D, this review provides a comprehensive investigation of its promising applications in the context of age-related diseases, offering valuable insights into its multifaceted therapeutic potential beyond glycemic control.}, } @article {pmid41097004, year = {2025}, author = {Daponte, A and Koros, C and Skarlis, C and Siozios, D and Rentzos, M and Papageorgiou, SG and Anagnostouli, M}, title = {Neurofilament Biomarkers in Neurology: From Neuroinflammation to Neurodegeneration, Bridging Established and Novel Analytical Advances with Clinical Practice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41097004}, issn = {1422-0067}, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Neurofilament Proteins/metabolism/blood ; *Neurodegenerative Diseases/metabolism/diagnosis ; *Neuroinflammatory Diseases/metabolism/diagnosis ; Animals ; }, abstract = {Neuroaxonal damage underlies permanent disability in various neurological conditions, both neuroautoimmune and neurodegenerative. It is crucial to accurately quantify and monitor axonal injury using biomarkers to evaluate disease progression and treatment effectiveness and offer prognostic insights. Neurofilaments (NFs), and especially neurofilament light chain (NfL), show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. Recent advances in ultrasensitive immunoassays enable the reliable detection of NFs in blood, transforming them from research tools into clinically applicable measures. In multiple sclerosis (MS), serum NfL correlates with disease activity, treatment response, and long-term disability, and may complement MRI in monitoring subclinical progression. In MS, NfL is primarily emerging as a marker of disease activity and treatment response; in amyotrophic lateral sclerosis (ALS), it has progressed further, being integrated into clinical trials as a pharmacodynamic endpoint and considered by regulatory agencies as a drug development tool. Additionally, NFs are increasingly being investigated in Alzheimer's disease, frontotemporal dementia, and other neurodegenerative disorders, though their disease specificity is limited. Ongoing challenges include older and novel assay harmonization, normative range interpretation, biological and analytical variability, and integration with other molecular and imaging biomarkers. This critical narrative review synthesizes the existing literature on NFs as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers and discusses their role in therapeutic development and precision medicine in neuroautoimmune and neurodegenerative diseases.}, } @article {pmid41096835, year = {2025}, author = {Nairuz, T and Heo, JC and Park, HJ and Lee, JH}, title = {Photobiomodulation at 660 nm Alleviates Alzheimer's Disease Pathology Through Amyloid-β Reduction and SIRT1 Upregulation in the Hippocampus of 5xFAD Mice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096835}, issn = {1422-0067}, support = {DBSD1-06,NRF-2022R1I1A307278, RS-2023-00237791,HI21C0977, RS-2021-KH118978, RS-2024-00433896,RS-2022-00166898,2020R1A6C101B189//Korea government (MSIT and Daegu Metropolitan City), the Basic Research Program through the National Research Foundation of Korea,Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), the Korea government (th/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/radiotherapy/genetics/therapy ; *Sirtuin 1/metabolism/genetics ; *Hippocampus/metabolism/radiation effects/pathology ; *Low-Level Light Therapy/methods ; Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; Mice ; Disease Models, Animal ; Up-Regulation/radiation effects ; Male ; Humans ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, synaptic dysfunction, and cognitive decline. Current pharmacological treatments provide only symptomatic relief without altering disease progression. Photobiomodulation therapy (PBMT), a light-based intervention, has shown neuroprotective potential, although its exact neurobiological mechanisms in AD pathogenesis remain obscure. In this study, we investigated the effects of PBMT using a 660 nm wavelength light-emitting diode (LED) in 5xFAD transgenic mouse, a well-established model of early-onset AD. Mice were subjected to once daily PBMT sessions over a defined treatment period and outcomes were assessed through immunohistochemical analysis of hippocampal regions (CA1, CA2, CA3, and dentate gyrus) alongside behavioral testing using the Y-maze spontaneous alternation task. PBMT significantly reduced Aβ plaque load across hippocampal regions, accompanied by improved preservation of neuronal morphology. Furthermore, PBMT significantly upregulated SIRT1 expression, a critical regulator of synaptic plasticity and memory processes. Behaviorally, PBMT-treated mice displayed enhanced spatial working memory compared with controls, indicating a functional benefit linked to the observed molecular and structural changes. These findings suggest that 660 nm PBMT attenuates hallmark AD pathology, promotes neuroprotective pathways, and improves cognition, highlighting its potential as a disease-modifying therapy that warrants further preclinical and clinical investigation.}, } @article {pmid41096792, year = {2025}, author = {Athanasaki, A and Tsantzali, I and Theodorou, A and Michalopoulou, A and Constantinides, VC and Boufidou, F and Tzartos, JS and Tsalouchidou, PE and Zompola, C and Paraskevas, SG and Bonakis, A and Giannopoulos, S and Tsivgoulis, G and Kapaki, E and Paraskevas, GP}, title = {The Biomarker Profile of Alzheimer's Disease for Disease-Modifying Treatment Eligibility: Questions and Debates.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096792}, issn = {1422-0067}, mesh = {*Alzheimer Disease/metabolism/diagnosis/drug therapy/therapy/blood ; Humans ; *Biomarkers/blood/metabolism ; tau Proteins/metabolism/blood ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common cause of cognitive decline; currently, anti-amyloid monoclonal antibodies are available for clinical use as disease-modifying treatments, while many other substances are being tested in clinical trials. Molecular biomarkers for AD have been studied for more than two decades, and various guidelines and diagnostic recommendations have been published. However, there are still questions and controversies about the biomarker profile needed to confirm AD and the eligibility for such established treatments and clinical trials. Is amyloid positivity sufficient for eligibility, or is a biomarker for tau biochemistry/pathology also needed? What is the role of hybrid ratios combining amyloid and tau? Should we rely on plasma biomarkers alone? This review aimed to describe and discuss such questions and controversies.}, } @article {pmid41383699, year = {2024}, author = {Huang, S and Zhang, M}, title = {The role of angiotensin II type 1 receptor pathway in cerebral ischemia‒reperfusion injury: Implications for the neuroprotective effect of ARBs.}, journal = {Neuroprotection (Chichester, England)}, volume = {2}, number = {2}, pages = {100-119}, pmid = {41383699}, issn = {2770-730X}, abstract = {Cerebral ischemia-reperfusion (I/R) injury is a crucial factor that impacts the prognosis of recanalization therapy for acute ischemic stroke (AIS). It has been found that the brain renin-angiotensin system, especially the angiotensin II type 1 receptor (AT1R) pathway, plays a significant role in cerebral I/R injury. This pathway is involved in processes such as oxidative stress, neuroinflammation, apoptosis, and it affects cerebrovascular autoregulation and the maintenance of blood-brain barrier. AT1R blocker (ARB), widely used as an antihypertensive agent, has demonstrated stroke prevention capabilities in numerous prospective studies, independent of its antihypertensive characteristics. Studies focusing on neurological diseases like Alzheimer's disease, Parkinson's disease, and cognitive impairment have confirmed that ARBs exhibit neuroprotective effects and aid in improving neurological functions. Preclinical studies have shown that ARBs can reduce infarct volume and brain edema, inhibit multiple signaling pathways associated with I/R injury, restore energy levels in damaged brain regions, and rescue the penumbra by promoting neovascularization in cerebral I/R models. These findings suggest that ARBs have potential to become a novel category of neuroprotecting agents for clinical treatment of AIS. Therefore, this review primarily provides a theoretical foundation and practical evidence for the future clinical utilization of ARBs as neuroprotective agents following reperfusion therapy for AIS. It outlines the role of cerebral I/R injury through the AT1R pathway and highlights the research progress made on ARBs in I/R models.}, } @article {pmid41341247, year = {2024}, author = {Lefkovitz, I and Walsh, S and Blank, LJ and Jetté, N and Kummer, BR}, title = {Direct Clinical Applications of Natural Language Processing in Common Neurological Disorders: Scoping Review.}, journal = {JMIR neurotechnology}, volume = {3}, number = {}, pages = {e51822}, pmid = {41341247}, issn = {2817-092X}, abstract = {BACKGROUND: Natural language processing (NLP), a branch of artificial intelligence that analyzes unstructured language, is being increasingly used in health care. However, the extent to which NLP has been formally studied in neurological disorders remains unclear. OBJECTIVE: We sought to characterize studies that applied NLP to the diagnosis, prediction, or treatment of common neurological disorders. METHODS: This review followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) standards. The search was conducted using MEDLINE and Embase on May 11, 2022. Studies of NLP use in migraine, Parkinson disease, Alzheimer disease, stroke and transient ischemic attack, epilepsy, or multiple sclerosis were included. We excluded conference abstracts, review papers, as well as studies involving heterogeneous clinical populations or indirect clinical uses of NLP. Study characteristics were extracted and analyzed using descriptive statistics. We did not aggregate measurements of performance in our review due to the high variability in study outcomes, which is the main limitation of the study. RESULTS: In total, 916 studies were identified, of which 41 (4.5%) met all eligibility criteria and were included in the final review. Of the 41 included studies, the most frequently represented disorders were stroke and transient ischemic attack (n=20, 49%), followed by epilepsy (n=10, 24%), Alzheimer disease (n=6, 15%), and multiple sclerosis (n=5, 12%). We found no studies of NLP use in migraine or Parkinson disease that met our eligibility criteria. The main objective of NLP was diagnosis (n=20, 49%), followed by disease phenotyping (n=17, 41%), prognostication (n=9, 22%), and treatment (n=4, 10%). In total, 18 (44%) studies used only machine learning approaches, 6 (15%) used only rule-based methods, and 17 (41%) used both. CONCLUSIONS: We found that NLP was most commonly applied for diagnosis, implying a potential role for NLP in augmenting diagnostic accuracy in settings with limited access to neurological expertise. We also found several gaps in neurological NLP research, with few to no studies addressing certain disorders, which may suggest additional areas of inquiry. TRIAL REGISTRATION: Prospective Register of Systematic Reviews (PROSPERO) CRD42021228703; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=228703.}, } @article {pmid41383445, year = {2024}, author = {Zhu, Y and Liao, L and Gao, S and Tao, Y and Huang, H and Fang, X and Yuan, C and Gao, C}, title = {Neuroprotective effects of repetitive transcranial magnetic stimulation on Alzheimer's disease: Undetermined therapeutic protocols and mechanisms.}, journal = {Neuroprotection (Chichester, England)}, volume = {2}, number = {1}, pages = {16-32}, pmid = {41383445}, issn = {2770-730X}, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by gradual deterioration of cognitive functions, for which an effective treatment is currently unavailable. Repetitive transcranial magnetic stimulation (rTMS), a well-established noninvasive brain stimulation method, is utilized in clinical settings to address various neuropsychiatric conditions, such as depression, neuropathic pain, and poststroke dysfunction. Increasing evidence suggests that rTMS may enhance cognitive abilities in individuals with AD. However, its optimal therapeutic protocols and precise mechanisms are currently unknown, impeding its clinical implementation. In the present review, we aimed to summarize and discuss the efficacy-related parameters in rTMS treatment, encompassing stimulus frequency, stimulus pattern, stimulus intensity, and the configuration of the stimulus coil. Furthermore, we reviewed promising rTMS therapeutic protocols involving various combinations of these factors, that were examined in clinical studies. Based on our analysis, we propose that a multisite high-frequency rTMS (HF-rTMS) regimen has value in AD therapy, and that promising single-site protocols, such as HF-rTMS, applied over the left dorsolateral prefrontal cortex, precuneus, or cerebellum are required to be validated in larger clinical studies. Lastly, we provide a comprehensive review of the potential mechanisms underlying the neuroprotective effects of rTMS on cognition in AD in terms of brain network modulation as well as cellular and molecular reactions. In conclusion, the interaction of diverse mechanisms may be responsible for the total therapeutic effect of rTMS on AD. This review provides theoretical and practical evidence for the future clinical application and scientific research of rTMS in AD.}, } @article {pmid41141948, year = {2023}, author = {Sarko, L and Saha, K}, title = {Harnessing chimeric antigen receptor (CAR)-T cells as a potential treatment for Alzheimer's disease.}, journal = {Cell & gene therapy insights}, volume = {9}, number = {7}, pages = {1003-1010}, pmid = {41141948}, issn = {2059-7800}, support = {R35 GM119644/GM/NIGMS NIH HHS/United States ; T32 GM135119/GM/NIGMS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) significantly burdens global healthcare systems given limited treatment options to delay or stop disease progression. Chimeric antigen receptor (CAR) T cell therapy, an immunotherapeutic approach that has produced remarkably effective responses in cancer, offers a potential avenue for the treatment of AD. Here, we discuss three significant challenges of adapting CAR-T cell therapy for AD: (i) identifying a suitable antigen target; (ii) limited permeability of the blood-brain barrier; and (iii) long-term persistence and durability of manufactured CAR-T cell products. Potential strategies to overcome these hurdles provide an attractive opportunity to revolutionize the treatment for AD and potentially other neurodegenerative disorders.}, } @article {pmid41096715, year = {2025}, author = {Mima, Y and Yamamoto, M and Iozumi, K}, title = {Review of Promising Off-Label Use of Deucravacitinib.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096715}, issn = {1422-0067}, mesh = {Humans ; *Off-Label Use ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; Animals ; *TYK2 Kinase/antagonists & inhibitors/metabolism ; Signal Transduction/drug effects ; Clinical Trials as Topic ; Psoriasis/drug therapy ; Bridged-Ring Compounds ; Pyrimidines ; }, abstract = {Tyrosine kinase 2 (TYK2) mediates the signaling pathways of proinflammatory cytokines such as interleukin (IL)-12, IL-23, and type I interferons (IFNs) and plays a pivotal role in the pathogenesis of psoriasis and various other immune-mediated diseases. Deucravacitinib, a selective oral TYK2 inhibitor, has been approved for the treatment of psoriasis and demonstrated high efficacy and a favorable safety profile. This review summarizes the potential for expanding deucravacitinib indications based on case reports, clinical trials, and preclinical studies. Diseases in which TYK2 pathway has been demonstrated to be involved and for which clinical benefit of deucravacitinib has been reported include discoid lupus erythematosus, systemic lupus erythematosus, alopecia areata, lichen planus, palmoplantar pustulosis, psoriatic arthritis, systemic sclerosis, interstitial pneumonia, inflammatory bowel disease, and chronic recurrent multifocal osteomyelitis. Furthermore, emerging research suggests potential therapeutic applications in neurodegenerative diseases such as Alzheimer's disease, and malignancies such as type 1 diabetes, vascular calcification in chronic kidney disease, T-cell acute lymphoblastic leukemia, and multiple sclerosis. Deucravacitinib may exert therapeutic effects by broadly suppressing cytokine signaling in a diverse range of inflammatory disorders. Ongoing clinical trials and mechanistic studies are required to clarify the efficacy and support its future indications.}, } @article {pmid41096667, year = {2025}, author = {Skarlis, C and Angelopoulou, E and Rentzos, M and Papageorgiou, SG and Anagnostouli, M}, title = {Monoclonal Antibodies as Therapeutic Agents in Autoimmune and Neurodegenerative Diseases of the Central Nervous System: Current Evidence on Molecular Mechanisms and Future Directions.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096667}, issn = {1422-0067}, mesh = {Humans ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/immunology ; Animals ; *Central Nervous System Diseases/drug therapy/immunology ; Neuromyelitis Optica/drug therapy ; Central Nervous System/drug effects/immunology ; Multiple Sclerosis/drug therapy ; }, abstract = {Monoclonal antibodies (mAbs) have revolutionized the treatment landscape for neurological diseases, providing targeted, mechanism-based therapies for conditions ranging from autoimmune demyelinating disorders to neurodegenerative diseases. In multiple sclerosis (MS), mAbs against CD20, CD52, and α4-integrins offer disease-modifying efficacy by altering immune responses, depleting B cells, or blocking leukocyte migration into the central nervous system (CNS). Similarly, novel agents under investigation, such as frexalimab and foralumab, modulate T and B cell interactions and regulatory immunity. In neuromyelitis optica spectrum disorder (NMOSD), mAbs targeting IL-6, the complement cascade, and B cell lineage have demonstrated significant clinical benefit in preventing relapses and disability. In Alzheimer's disease (AD), several anti-amyloid mAbs have gained regulatory approval. Anti-tau and anti-α-synuclein antibodies, though promising, have shown limited efficacy to date in AD and parkinson's disease (PD), respectively. The evolving armamentarium of mAbs reflects a paradigm shift toward personalized neuroimmunology and neurodegeneration-targeted treatments, based on ongoing clarification of molecular and neuroinflammatory mechanisms. In this context, the present review summarizes current evidence on mAbs used in CNS disorders, with an emphasis on their pathophysiological targets, molecular mechanisms, clinical efficacy, and safety.}, } @article {pmid41096666, year = {2025}, author = {Świątek, G and Nowakowska-Gołacka, J and Słomińska-Wojewódzka, M and Glac, W and Harackiewicz, O and Kurowska-Rucińska, E and Wrona, D}, title = {Minocycline Treatment Improves Memory and Reduces Anxiety by Lowering Levels of Brain Amyloid Precursor Protein and Indoleamine 2,3-Dioxygenase in a Rat Model of Streptozotocin-Induced Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096666}, issn = {1422-0067}, mesh = {Animals ; *Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Male ; *Minocycline/pharmacology/therapeutic use ; Rats ; *Anxiety/drug therapy/metabolism ; Streptozocin ; Rats, Wistar ; Disease Models, Animal ; *Memory/drug effects ; *Amyloid beta-Protein Precursor/metabolism ; Brain/metabolism/drug effects ; Hippocampus/metabolism/drug effects ; Maze Learning/drug effects ; }, abstract = {Minocycline (MINO), a classic antibiotic, may have psychotropic activity related to the modulation of the tryptophan-kynurenine pathway. In this study, we investigated the effects of MINO on (1) memory and anxiety behaviors, (2) the modulation of brain levels of amyloid precursor protein (APP) and 2,3-indoleamine dioxygenase (IDO1) levels, and (3) peripheral inflammatory markers in a streptozotocin (STZ)-induced rat model of sporadic Alzheimer's disease (sAD). After repeated treatment with a dose of 35 mg/kg MINO for seven consecutive days, male Wistar rats with sAD showed (1) improvements in early (29 days after injection, probe test) reference memory (decreased latency to reach the platform, increased time in the critical quadrant of the Morris water maze) and anxiety disorders (increased time in the open arms of the elevated plus maze; increased exploration and entrances in the center of the white-light illuminated open field) 45-46 and 90-91 days after STZ injection; (2) reduced APP and IDO1 levels in the hippocampus and prefrontal cortex; and (3) induction of anti-inflammatory response in blood (increased TCD4[+] lymphocyte number and interleukin-10 production). This suggests that MINO, due to its anti-inflammatory action, improves memory and anxiety behavior related to sAD, indicating its neuroprotective and psychotropic properties.}, } @article {pmid41096642, year = {2025}, author = {Mochol, M and Jablonowski, L and Pawlik, A and Rasławska-Socha, J and Chamarczuk, A and Lipski, M and Mazurek-Mochol, M}, title = {The Role of Vitamin C in Selected Autoimmune and Immune-Mediated Diseases: Exploring Potential Therapeutic Benefits.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096642}, issn = {1422-0067}, mesh = {Humans ; *Autoimmune Diseases/drug therapy/metabolism/immunology ; *Ascorbic Acid/therapeutic use/pharmacology ; Antioxidants/therapeutic use ; Animals ; Dietary Supplements ; *Immune System Diseases/drug therapy ; Oxidative Stress/drug effects ; }, abstract = {Autoimmune diseases are characterized by immune response dysregulation against self-components, leading to chronic inflammation and tissue damage. Vitamin C (VitC), a water-soluble vitamin with established functions in antioxidant defence and collagen synthesis, has also been of interest based on its potential immunomodulatory effects. This review discusses the role of VitC in the course and progression of (A) autoimmune diseases (multiple sclerosis, rheumatoid arthritis, Sjögren's disease, type 1 diabetes, Hashimoto's thyroiditis, pernicious anaemia, antiphospholipid syndrome), (B) other immune-mediated diseases (Crohn's disease, periodontitis), and (C) Alzheimer's disease, a neurodegenerative disorder with autoimmune features. Results from clinical, observational, and experimental trials show that VitC deficiency is common in many of these diseases and may contribute to increased oxidative stress and immune disequilibrium. Supplementation has been associated with improved antioxidant levels, control of inflammatory mediators, and, in some cases, clinical outcomes like disease activity decrease or symptom load. Although findings vary across conditions and few large, randomized trials are available, the overall evidence indicates that maintaining good VitC status can be useful in maintaining immune homeostasis and reducing inflammation. VitC should be viewed as an adjunct to be employed safely, perhaps and ideally within larger treatment regimens, but not in place of effective therapies. Further research, including large-scale clinical trials, will be required to determine more clearly optimal dosing, timing of treatment, and patient population most likely to benefit. By integration of current knowledge, this review recognizes both promise in VitC for treatment of autoimmune/immune-mediated disease and promise in its potential use within future treatment regimens.}, } @article {pmid41096572, year = {2025}, author = {Zhang, X and Fu, Y and Li, X and Zhang, Y and Li, L and Yi, T and Jiang, H and Lu, Y}, title = {Phlorizin Ameliorates Amyloid-β Toxicity and Enhances Fatty Acid β-Oxidation in Caenorhabditis elegans via NHR-49-Dependent Pathway.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096572}, issn = {1422-0067}, support = {7252230//Beijing Municipal Science & Technology Commission/ ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/drug effects/genetics ; *Amyloid beta-Peptides/toxicity/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Fatty Acids/metabolism ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species/metabolism ; Alzheimer Disease/metabolism/drug therapy ; Lipid Metabolism/drug effects ; Longevity/drug effects ; Signal Transduction/drug effects ; Disease Models, Animal ; Receptors, Cytoplasmic and Nuclear ; }, abstract = {Phlorizin (PHZ) is a glucoside of phloretin, belonging to the dihydrochalcone class within flavonoids; It is one of the active ingredients of the plant Cynomorium, and it has been shown that PHZ can regulate lipid metabolism disorders as well as having anti-aging properties. However, no studies have investigated whether PHZ ameliorates Aβ-induced toxicity in Alzheimer's disease (AD) by regulating fatty acid β-oxidation. This study aims to investigate the effects of PHZ on the regulation of fatty acid β-oxidation and resistance to Aβ-associated toxicity on the AD Caenorhabditis elegans and the mechanisms of action. Wild-type N2 and AD model CL4176 C. elegans were used; lifespan, heat stress resistance, chronic paraquat stress, reactive oxygen species (ROS), behavioral performance, and lipofuscin accumulation assays were examined to evaluate the anti-aging effects; and non-esterified fatty acid (NEFA), triglyceride (TG) and lipidomic contents were quantified after PHZ treatment. The detection of genes related to fatty acid β-oxidation pathways was performed using qRT-PCR. nhr-49 knockout mutant RB1716; and GFP-binding mutants PMD150 WBM170 were used to observe the effect of PHZ on NHR-49 pathways, and molecular docking studies were performed by combining PHZ with NHR-49 proteins. Results showed that PHZ improved worms' survival and delayed senescence, as demonstrated by enhanced performance in lifespan, heat stress, ROS, and paraquat assays and chronic paraquat assays; PHZ also reduced lipid accumulation in worms, affected the unsaturated fatty acid pathway, and significantly increased the expression of fatty acid metabolism-related genes nhr-49, acs-2, and cpt-5, and can be tightly coupled to NHR-49 targets. PHZ may play an anti-Aβ toxicity role by regulating lipid metabolism disorders through the NHR-49-related pathway and anti-aging in AD worms.}, } @article {pmid41096196, year = {2025}, author = {Siwecka, N and Golberg, M and Świerczewska, D and Filipek, B and Pendrasik, K and Bączek-Grzegorzewska, A and Stasiołek, M and Świderek-Matysiak, M}, title = {Sleep Disorders in Neurodegenerative Diseases with Dementia: A Comprehensive Review.}, journal = {Journal of clinical medicine}, volume = {14}, number = {19}, pages = {}, pmid = {41096196}, issn = {2077-0383}, abstract = {Dementia is a growing problem of global relevance, currently affecting over 55 million people worldwide. The number of new dementia cases is still increasing, primarily due to the aging of society. Dementia is defined as a substantial decline in cognitive function, and it is inherently associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, and vascular dementia. Of note, most patients suffering from neurodegenerative conditions, in addition to cognitive impairment, often experience various types of sleep disorders, including insomnia, rapid eye movement sleep behavior disorder, sleep-disordered breathing, and circadian rhythm disturbances. There is increasing evidence of a bidirectional interaction between sleep disturbances and mental health. Disrupted sleep may directly aggravate neuropsychiatric symptoms, like depression, anxiety, agitation, and hallucinations, and conversely, such symptoms can make sleeping more difficult. This creates a feedback loop that inevitably leads to disease progression and deterioration in quality of life. In this review, we provide an up-to-date overview of the nature and mechanisms behind sleep disorders in major neurodegenerative diseases, summarize treatment strategies for handling sleep disturbances, and discuss the clinical relevance of sleep-mental health interactions in the context of neurodegeneration-associated dementia. Neurodegeneration is a complex problem on the border between neurology and psychiatry, and it poses a challenge to the healthcare system, as it requires multidisciplinary approaches for optimal management. Understanding the connection between sleep and neuropsychiatric symptoms offers further opportunities for better symptom control, improved quality of life, and slower cognitive decline.}, } @article {pmid41094207, year = {2025}, author = {Chen, Z and Ma, S and Wang, C and Liu, J and Yang, X}, title = {A ratio electrochemiluminescence sensor for monitoring amyloid-beta based on g-C3N4-heme with luminol as the internal standard.}, journal = {Mikrochimica acta}, volume = {192}, number = {11}, pages = {737}, pmid = {41094207}, issn = {1436-5073}, support = {ZR2023MB083//Natural Science Foundation of Shandong Province/ ; }, mesh = {*Luminol/chemistry ; *Amyloid beta-Peptides/analysis/blood ; *Electrochemical Techniques/methods ; *Biosensing Techniques/methods ; Aptamers, Nucleotide/chemistry ; *Luminescent Measurements/methods ; Humans ; Graphite/chemistry ; Limit of Detection ; *Nitriles/chemistry ; Metal Nanoparticles/chemistry ; Electrodes ; Gold/chemistry ; Aniline Compounds/chemistry ; Tin Compounds/chemistry ; }, abstract = {Monitoring of the amyloid-beta (Aβ) peptide is crucial for the diagnosis and treatment of Alzheimer's disease. Here, a label-free, signal-on ratiometric electrochemiluminescence (ECL) aptasensor was fabricated for the detection of Aβ peptide. Specifically, graphite-like carbon nitride (g-C3N4) nanosheets and luminol served as the cathodic and anodic ECL emitters, respectively. K2S2O8 and H2O2 were used as the coreactants for the two emitters. Luminol was first coated on the indium tin oxide (ITO) electrode and used as the internal standard in the ratiometric biosensor. Polyaniline was then electrodeposited on the surface of the luminol-modified electrode to improve the biocompatibility and conductivity of the sensing interfaces. Gold nanoparticles were subsequently modified on the surface of polyaniline to immobilize a DNA aptamer. g-C3N4-heme incubated with different concentrations of Aβ solution to form g-C3N4-heme-Aβ complex, in which Aβ could specifically bind to the DNA aptamer and thus introduce g-C3N4 into the system. As a result, it was observed that the ratio value of ECL intensity (I1/I2) significantly increased with the increase of Aβ concentration. Under the optimized conditions, the biosensor has a good linear response in the range 10 fM to 10 nM with a detection limit of 4.2 fM. Consequently, the ratiometric ECL sensor, characterized by high sensitivity and favorable stability, offers a reliable method for the determination of Aβ.}, } @article {pmid41094020, year = {2025}, author = {Makinde, IA and Hammed, SO and Kumar, N and Kuthi, NA and Umar, HI and Hassan, TA and Kehinde, IO and Bello, RO and Aborode, AT and Jimoh, TO and Mahamat, AO and Khalid, M and Almohammed, OA}, title = {Identification of novel DYRK1A inhibitors as treatment options for alzheimer's disease through comprehensive in silico approaches.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {36114}, pmid = {41094020}, issn = {2045-2322}, support = {ORF-2025-77//King Saud University/ ; }, mesh = {Dyrk Kinases ; *Protein-Tyrosine Kinases/antagonists & inhibitors/chemistry/metabolism ; *Protein Serine-Threonine Kinases/antagonists & inhibitors/chemistry/metabolism ; *Alzheimer Disease/drug therapy ; Quantitative Structure-Activity Relationship ; *Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; Humans ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Benzimidazoles/pharmacology/chemistry ; Computer Simulation ; Aminopyridines/pharmacology/chemistry ; }, abstract = {This study aims to identify potential DYRK1A inhibitors from a curated database and utilize a QSAR model to predict the bioactivity of drug compounds in inhibiting the enzyme involved in tau protein oligomerization, a key process in AD pathology. 192 compounds were sourced from the SuperNatural 3.0 database and docked against DYRK1A using Maestro 12.5. The top five lead compounds and the reference drug Abemaciclib underwent ADMET profiling via the AI Drug Lab Server and a 200 nanosecond molecular dynamics simulation using Desmond. A machine learning-based Quantitative Structure-Activity Relationship (QSAR) analysis was then performed to predict their biological activity based on pIC50 values. The top five compounds, identified as 45,934,388, CNP0344929, CNP0360040, CNP0309850, and CNP0426983, demonstrated binding affinities of -13.337, -12.746, -11.712, -11.656, and - 11.416 kcal/mol, respectively, outperforming Abemaciclib (-6.528 kcal/mol). None of the compounds violated Lipinski's Rule of Five, and all exhibited favorable ADMET profiles, including optimal blood-brain barrier penetration and structural stability. The QSAR model successfully predicted the pIC50 values of the hit compounds (6.16, 5.758, 5.752, 6.003, 5.982), comparable to Abemaciclib (6.32). These findings highlight five promising DYRK1A inhibitors with potential therapeutic applications for AD.}, } @article {pmid41093210, year = {2025}, author = {Manzoor, SI and Ahanger, IA and Kamli, MR and Malik, MA and Dar, TA}, title = {Nano-conjugation of small molecule modulators of protein aggregation: Enhancing the therapeutic precision.}, journal = {International journal of biological macromolecules}, volume = {331}, number = {Pt 2}, pages = {148293}, doi = {10.1016/j.ijbiomac.2025.148293}, pmid = {41093210}, issn = {1879-0003}, mesh = {Humans ; *Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; *Small Molecule Libraries/chemistry/pharmacology/therapeutic use ; Animals ; *Nanoparticles/chemistry ; Precision Medicine ; }, abstract = {Protein aggregation is a central hallmark of several neurodegenerative and systemic diseases, including Alzheimer's, Parkinson's, cataract and type 2 diabetes. Consequently, targeting protein aggregation is emerging as a promising therapeutic strategy for these diseases. Small molecule modulators have exhibited considerable potential in stabilizing native protein conformations and promoting the dissolution of toxic aggregates, leading to delayed disease progression. Some also target proteostatic pathways, promoting clearance of misfolded proteins to prevent further aggregation. Despite being promising, their clinical efficacy often faces challenges due to poor bioavailability, limited stability, and lack of specificity. Recent advances in nanotechnology have introduced nano-conjugation as a potential strategy for maximizing the therapeutic efficacy of these small molecule modulators. By ensuring targeted delivery, increased availability, improved stability and controlled tissue release, nano-conjugation has not only overcome the limitations but also acts as a future pathway to precision medicine in protein aggregation diseases. The present review article provides a comprehensive overview of small molecule modulators of protein aggregation and explores how nano-conjugation enhances their therapeutic efficacy. Moreover, it highlights emerging clinical trials and explores future directions in the application of nano-conjugated small molecule modulators as a potential treatment strategy for protein aggregation diseases.}, } @article {pmid41093142, year = {2026}, author = {Marizzoni, M and Mombelli, E and Alboni, S and Rosa, M and Moretti, DV and Mirabelli, P and Coppola, L and Luongo, D and Salamone, D and Saleri, S and Piazza, F and Begni, V and Salvatore, M and Frisoni, GB and Cattaneo, A}, title = {Microbiota-gut-brain axis dysregulation in Alzheimer's disease and its modulation through probiotic supplementation.}, journal = {Brain, behavior, and immunity}, volume = {131}, number = {}, pages = {106138}, doi = {10.1016/j.bbi.2025.106138}, pmid = {41093142}, issn = {1090-2139}, mesh = {Humans ; *Probiotics/administration & dosage/therapeutic use/pharmacology ; *Alzheimer Disease/microbiology/metabolism ; *Gastrointestinal Microbiome/physiology/drug effects ; Male ; Female ; Aged ; *Brain/metabolism ; *Brain-Gut Axis/physiology ; Middle Aged ; Dietary Supplements ; Inflammation/metabolism ; Feces/microbiology ; Aged, 80 and over ; }, abstract = {BACKGROUND: The microbiota-gut-brain axis (MGBA) has been implicated in the pathophysiology of Alzheimer's Disease (AD).Probiotics reduced the progression of ADin different mouse models, possibly through MGBA modulation, but human data are still limited. OBJECTIVE: Here, we evaluated whether differences in the gut microbiome (GM), pro-inflammatory markers and other MGBA mediators were associated with probable AD (pAD). We also assessed the impact of a 12-week probiotic treatment on MGBA. METHODS: Forty-five pAD patients and 47 healthy subjects (HC) were recruited at IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli of Brescia (Italy). An uncontrolled clinical investigation was performed to test the effects of 12-week probiotic supplementation in the pAD group. Fecal microbiota composition, intestinal and blood inflammatory markers, and microbiota-related metabolites were assessed before supplementation in all participants and after only in pAD. RESULTS: pAD patients showed intestinal inflammation, an altered GM profile, blood changes in the tryptophan metabolism, and reduced glutamate levels compared with HC (p-value < 0.049). Probiotic supplementation partially modulated these alterations, determining a reduction in several pro-inflammatory mediators, and an increase of GM-related protective factors, such as butyrate (p-value < 0.040) in pAD. CONCLUSIONS: These findings confirmed the presence of MGBA alterations in AD and suggested a potential beneficial effect of probiotic supplementation through modulation of GM functionality rather than composition. Further research is required to confirm these results and their clinical relevance.}, } @article {pmid41093115, year = {2026}, author = {Shen, Z and Wu, M and Sun, S and Ling, Y and Chen, X and Zhang, J and Zhou, X and Zhou, C}, title = {Lingguizhugan decoction improves cognitive impairment in APP/PS1 mice by promoting meningeal lymphatic drainage based on fatty acid degradation pathway.}, journal = {Journal of ethnopharmacology}, volume = {355}, number = {Pt B}, pages = {120748}, doi = {10.1016/j.jep.2025.120748}, pmid = {41093115}, issn = {1872-7573}, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Fatty Acids/metabolism ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Male ; *Alzheimer Disease/drug therapy/metabolism ; Disease Models, Animal ; Presenilin-1/genetics ; Mice, Inbred C57BL ; *Lymphatic Vessels/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/drug effects/metabolism ; Molecular Docking Simulation ; Cognition/drug effects ; }, abstract = {Lingguizhugan Decoction (LGZG), a classic traditional Chinese medicine formula, has been demonstrated in numerous studies to possess therapeutic potential for Alzheimer's disease (AD). However, it remains unclear whether its mechanism of action involves the meningeal lymphatic system. AIM OF THE STUDY: Investigate if LGZG improves cognition in APP/PS1 mice by restoring meningeal lymphatic vessels (mLVs) drainage. MATERIALS AND METHODS: Assessed cognitive behavior and pathology in LGZG-treated APP/PS1 mice. Used tracers and immunofluorescence (LYVE-1/TR-d3) to evaluate mLVs drainage and markers. Conducted untargeted brain metabolomics and dura mater micro-proteomics. Performed molecular docking and functional analysis focusing on fatty acid pathways. RESULTS: LGZG ameliorated cognitive impairment and Aβ deposition in mice. Improved Aβ clearance correlated with enhanced mLVs function (confirmed by tracing). Metabolomics and micro-proteomics identified impaired fatty acid degradation as a key pathological factor. LGZG, at clinically relevant doses, restored mLVs drainage and rescued cognition by activating the fatty acid degradation pathway. CONCLUSION: Lingguizhugan Decoction ameliorates AD-like pathologies and cognitive deficits in APP/PS1 mice by enhancing Aβ clearance via regulating the "fatty acid degradation-meningeal lymphatic axis." This finding reveals a novel multi-target mechanism of LGZG and offers a fresh perspective on metabolic intervention for AD treatment.}, } @article {pmid41093093, year = {2025}, author = {Tuo, C and Sui, X and Cui, C and Han, F and Jiao, J and Cai, H and Wu, M}, title = {Pramipexole improves cognitive deficits and synaptic plasticity impairments in 3xTg-AD mice through enhancing autophagy.}, journal = {Experimental neurology}, volume = {395}, number = {}, pages = {115503}, doi = {10.1016/j.expneurol.2025.115503}, pmid = {41093093}, issn = {1090-2430}, abstract = {Autophagy dysfunction plays important roles in the pathogenesis of Alzheimer's disease (AD), and activation of autophagy might be a potential strategy in AD treatment. Although some autophagy inducers play beneficial roles in AD, no autophagy inducer has been available in AD clinical treatment due to lack of efficacy or obvious side effects. A recent study demonstrated that pramipexole (PPX) can activate autophagy in the brain without interfering with protein synthesis, thereby avoiding the side effects associated with prolonged use of an autophagy inducer. However, whether PPX can exert neuroprotective effects on AD and whether its potential mechanism is related to autophagy remains unclear. In the present study, the effects of PPX on the cognitive function of 3xTg-AD mice were observed using multiple behavioral tests, then synaptic plasticity was evaluated through in vivo hippocampal electrophysiological recordings and by measuring synaptic proteins, while Aβ and tau pathologies were detected using immunofluorescence staining and western blot. Finally, autophagy was detected and the potential target was predicted using bioinformatics analysis, qRT-PCR and molecular docking. Results demonstrated that PPX significantly improved cognitive deficits and hippocampal long-term potentiation (LTP) depression, increased the expression of PSD95, reduced Aβ deposition and tau hyperphosphorylation, activated autophagy by increasing LC3-II/LC3-I ratios and decreasing p62 levels, and restored Beclin1 expression. Bioinformatics analysis identified MAPK1 as a key target in PPX-ameliorated AD by enhancing autophagy. These findings suggest that PPX alleviates AD-related cognitive deficits and neuropathologies through increased autophagy, emphasising its potential as a disease-modifying therapeutic strategy for AD.}, } @article {pmid41091591, year = {2025}, author = {Magham, SV and Shanavas, S and Pindiprolu, SSSKS and Nagappan, K and More, S and Chaudhury, D and Ramakkamma, AR and Singh, MT and Wadhwani, A and Bose, B and Thaggikuppe Krishnamurthy, P}, title = {Targeting GSK-3β to Modulate the Wnt Pathway: A Promising Neuroprotective Strategy for Alzheimer's Disease.}, journal = {Molecular pharmaceutics}, volume = {22}, number = {11}, pages = {6561-6574}, doi = {10.1021/acs.molpharmaceut.5c00329}, pmid = {41091591}, issn = {1543-8392}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; Nanoparticles/chemistry ; *Neuroprotective Agents/pharmacology/pharmacokinetics/administration & dosage ; *Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; Rats, Wistar ; *Indoles/pharmacology/chemistry/pharmacokinetics/administration & dosage ; *Wnt Signaling Pathway/drug effects ; Humans ; Male ; Tissue Distribution ; *Oximes/pharmacokinetics/chemistry/pharmacology/administration & dosage ; Brain/metabolism/drug effects ; Stearic Acids/chemistry ; Cell Line, Tumor ; Drug Delivery Systems/methods ; Particle Size ; Liposomes ; }, abstract = {Alzheimer's disease (AD) is marked by amyloid-β plaques and neurofibrillary tangles. Glycogen synthase kinase-3β (GSK-3β) is a promising therapeutic target for mitigating several AD-related pathologies via modulation of the Wnt pathway. However, nonspecific GSK-3β inhibition by indirubin-3'-oxime (IMX) may result in significant off-target effects, necessitating the development of brain-targeted delivery systems. Solid lipid nanoparticles (SLNs) are biocompatible nanocarriers for brain-targeted delivery of therapeutics. Polysorbate 80 (PS80) and stearic acid (SA)-modified SLNs encapsulating IMX (PS80-SA SLNs-IMX) were prepared using the solvent injection method. The formula was optimized using full factorial design (FFD). The optimized formulation was biophysically characterized. The neuroprotective efficacy of PS80-SA SLNs-IMX was then evaluated in vitro using cell lines (IMR-32 & N2a). Biodistribution study was carried out in Wistar rats to evaluate the site-specific distribution of IMX and SLNs. The optimized PS80-SA SLNs-IMX exhibited a particle size of 185.7 ± 2.7 nm, a polydispersity index of 0.22 ± 0.01, a ζ potential of -21.02 ± 1.53 mV, and an entrapment efficiency of 99.4 ± 0.12%. Surface morphology analysis revealed that they are spherical in shape, and in vitro release study revealed the sustained release of PS80-SA SLNs-IMX until 48 h. Accelerated stability study results revealed the formulation stability with negligible changes in the PS, PDI, and ZP up to 6 months. MTT assay results have shown that PS80-SA SLNs-IMX has a negligible cytotoxic effect. ROS and neuroprotective assays have demonstrated antioxidant and neuroprotective effects of PS80-SA SLNs-IMX against OKA-induced neurotoxicity. ELISA depicted a significant reduction in Aβ1-42 and p-tau upon treatment with PS80-SA SLNs-IMX. Western blot analysis confirmed the effect of PS80-SA SLNs-IMX on the inhibition of GSK-3β and the activation of the Wnt pathway. Biodistribution study results revealed that PS80-SA SLNs-IMX has a significant increase in brain concentration when compared to naïve IMX, indicating the brain-specific distribution of PS80-SA SLNs-IMX. In conclusion, PS80-SA SLNs-IMX demonstrated enhanced neuronal cell uptake and significant neuroprotective activity in vitro. To our knowledge, this is the first report of PS80-SA SLNs-IMX with high entrapment and robust neuroprotection in an okadaic acid (OKA)-induced tauopathy model, underscoring the translational potential for AD therapy.}, } @article {pmid41090735, year = {2025}, author = {Shen, X and Li, H and Zhang, B and Li, Y and Zhu, Z}, title = {Tau-Targeted Therapeutic Strategies: Mechanistic Targets, Clinical Pipelines, and Analysis of Failures.}, journal = {Cells}, volume = {14}, number = {19}, pages = {}, pmid = {41090735}, issn = {2073-4409}, support = {A126H5//University of Nottingham/ ; }, mesh = {Humans ; *tau Proteins/metabolism/antagonists & inhibitors ; *Molecular Targeted Therapy ; Animals ; *Alzheimer Disease/metabolism/drug therapy ; Protein Processing, Post-Translational ; *Tauopathies/drug therapy/metabolism ; Phosphorylation ; }, abstract = {Tau protein, a neuron-enriched microtubule-associated protein encoded by the MAPT gene, plays pivotal roles in microtubule stabilisation, axonal transport, and synaptic plasticity. Aberrant post-translational modifications (PTMs), hyperphosphorylation, acetylation, ubiquitination, oxidative stress and neuroinflammation disrupt tau's normal functions, drive its mislocalization, and promote aggregation into neurofibrillary tangles, a hallmark of Alzheimer's disease (AD) and related tauopathies. Over the past two decades, tau-targeted therapies have advanced into clinical development, yet most have failed to demonstrate efficacy in human trials. This review synthesises mechanistic insights into tau biology and pathology, highlighting phosphorylation and acetylation pathways, aggregation-prone motifs, and immune-mediated propagation. We analyse the current therapeutic landscape, including kinase and phosphatase modulators, O-GlcNAcase inhibitors, aggregation blockers, immunotherapies, and microtubule-stabilising agents, while examining representative clinical programs and the reasons underlying their limited success. By combining mechanistic understanding with clinical experience, this review outlines emerging opportunities for rational treatment development, aiming to inform future tau-targeted strategies for AD and other tauopathies.}, } @article {pmid41090155, year = {2025}, author = {Li, JM and Huang, J and Liao, Y and Hu, T and Wang, CL and Zhang, WZ and Huang, CW}, title = {Gene and RNA Editing: Revolutionary Approaches to Treating Diseases.}, journal = {MedComm}, volume = {6}, number = {10}, pages = {e70389}, pmid = {41090155}, issn = {2688-2663}, abstract = {Gene editing and RNA editing technologies are advancing modern medicine by enabling precise manipulation of genetic information at the DNA and RNA levels, respectively. The third-generation gene editing tools, particularly Clustered regularly interspaced shortpalindromic repeats (CRISPR)/CRISPR-associated (Cas) system, have transformed genetic disease treatment with high efficiency, precision, and cost effectiveness, while RNA editing, via adenosine deaminase acting on RNA (ADAR) enzymes and CRISPR-Cas13, offers reversible regulation to avoid genomic integration risks. Despite advancements, challenges persist in delivery efficiency, tissue specificity, and long-term safety, limiting their clinical translation. This review systematically discusses the molecular mechanisms and technological evolution of these tools, focusing on their promising applications in treating nervous system disorders (e.g., Alzheimer's, Parkinson's), immune diseases (e.g., severe combined immunodeficiency, lupus), and cancers. It compares their technical attributes, analyzes ethical and regulatory issues, and highlights synergies between the two technologies. By bridging basic research and clinical translation, this review provides critical insights for advancing precision medicine, reshaping disease diagnosis, prevention, and treatment paradigms.}, } @article {pmid41089659, year = {2025}, author = {Xu, B and Ding, S and Xu, W and Fredericks, C and Zhao, Y}, title = {GenCPM: a toolbox for generalized connectome-based predictive modeling.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1627497}, pmid = {41089659}, issn = {1662-4548}, abstract = {Understanding brain-behavior relationships and predicting cognitive and clinical outcomes from neuromarkers are central tasks in neuroscience. Connectome-based Predictive Modeling (CPM) has been widely adopted to predict behavioral traits from brain connectivity data; however, existing implementations are largely restricted to continuous outcomes, often overlook essential non-imaging covariates, and are difficult to apply in clinical or disease cohort settings. To address these limitations, we present GenCPM, a generalized CPM framework implemented in open-source R software. GenCPM extends traditional CPM by supporting binary, categorical, and time-to-event outcomes and allows the integration of covariates such as demographic and genetic information, thereby improving predictive accuracy and interpretability. To handle high-dimensional data, GenCPM incorporates marginal screening and regularized regression techniques, including LASSO, ridge, and elastic net, for efficient selection of informative brain connections. We demonstrate the utility of GenCPM through analyses of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study and the Alzheimer's Disease Neuroimaging Initiative (ADNI), showing enhanced predictive performance and improved signal attribution compared to standard methods. GenCPM offers a flexible, scalable, and interpretable solution for predictive modeling in brain connectivity research, supporting broader applications in cognitive and clinical neuroscience.}, } @article {pmid41089460, year = {2025}, author = {Gerasimov, E and Berg, M and Bolshakova, A and Bezprozvanny, I and Vlasova, O}, title = {Chemogenetic Modulation of Astrocytic Activity Rescues Hippocampus Associated Neurodegeneration in Alzheimer's Disease Mice Model 5xFAD.}, journal = {Neural plasticity}, volume = {2025}, number = {}, pages = {9880933}, pmid = {41089460}, issn = {1687-5443}, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy/genetics/physiopathology ; *Astrocytes/drug effects/metabolism ; Mice ; *Hippocampus/drug effects/pathology/metabolism/physiopathology ; *Clozapine/analogs & derivatives/pharmacology ; Mice, Transgenic ; Disease Models, Animal ; Male ; Long-Term Potentiation/drug effects ; Chemogenetics ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by Aβ-amyloid accumulation and cognitive decline. Despite extensive research, effective treatments remain elusive. Astrocytes, the most abundant glial cells, play a crucial role in synaptic transmission, neuronal excitability, and plasticity. In AD, astrocytes become reactive, exhibiting aberrant calcium signaling and altered neurotransmitter release, making them promising targets for disease-modifying therapies. To address this, we explored designer receptors exclusively activated by designer drugs (DREADDs), specifically the hM3D(Gq) receptor, which selectively modulates intracellular Ca[2+] levels in astrocytes upon activation by clozapine-N-oxide (CNO). Using daily CNO administration in 8-month-old 5xFAD mice, we observed a significant enhancement of impaired long-term potentiation formation, accompanied by cognitive improvements in the fear conditioning (FC) and Morris water maze (MWM) tests. Additionally, anxiety levels and social preference deficits in 5xFAD mice were fully restored following astrocytic activity modulation. Importantly, this approach reduced Aβ-amyloid plaque burden and demonstrated a trend toward mitigating astrocytic reactivity, further highlighting its therapeutic potential. Our findings suggest that targeting astrocytic activity via Gq-coupled receptors represents a novel and promising strategy for AD treatment, offering a noninvasive and effective approach to mitigating disease progression.}, } @article {pmid41088943, year = {2025}, author = {Haseeb, M and Hatiboglu, MA}, title = {Carbon Dot Nanoparticle-based Therapeutic Approaches in Major Neurological Disorders.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575398775250811070903}, pmid = {41088943}, issn = {1875-5607}, abstract = {Neurological disorders (NDs) are diseases that arise due to deformities mainly in the central nervous system (CNS) and also affect the nerves throughout the human body. NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple Sclerosis (MS), and a variety of brain malignancies, pose a major healthcare challenge and are the main cause of mortality on the global scale. There are very limited treatment options for the majority of the NDs, and the currently available drugs commonly fail to penetrate the BBB and deliver the drug to the target effectively. These challenges have necessitated the advent of new drug delivery methods that can cross the BBB with ease and deliver the drug by accurately targeting the diseased area in a safe and biocompatible manner. Nanoparticle-based drug delivery strategies offer significant advantages in BBB penetration and drug delivery due to their unique properties. Carbon dots, among nanoparticles with a size below 10 nm, are highly biocompatible, fluorescent molecules that offer ease of functionalization, drug conjugation, and effective detection within biological systems. The literature is rich in reviews on the synthesis, characterization, and application of CDs. However, a review specifically focused on the therapeutic potential of CDs in major NDs is missing. This review aims to fill that gap by presenting a detailed account of the carbon dot-based therapeutic approaches in the treatment of major NDs. It briefly discusses the properties of CDs, the main routes of synthesis, major raw materials, and key synthesis parameters that affect their properties, while placing a greater emphasis on their therapeutic potential. The review provides a detailed assessment of literature from the past 15 years on the development and current challenges in the application of CDs as therapeutic and drug delivery agents. Our analysis reveals that limited research has been conducted on CD-based therapeutics in NDs, particularly in MS and brain tumors, where original research is scarce. This review article highlights the major developments in the therapeutic uses of carbon dots in NDs, addresses a critical research gap, and provides a comprehensive overview of various studies related to carbon-dot-based therapeutic approaches for major NDs.}, } @article {pmid41088853, year = {2025}, author = {Collij, LE and Mattsson-Carlgren, N and Janelidze, S and Ossenkoppele, R and Hansson, O}, title = {Complementary utility of plasma biomarkers and Aβ-PET for diagnosis, risk-stratification, and treatment monitoring in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70763}, pmid = {41088853}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/blood/therapy/diagnosis ; *Positron-Emission Tomography ; *Biomarkers/blood ; *Amyloid beta-Peptides/blood/metabolism ; Risk Assessment ; }, abstract = {With the rapid development of blood biomarkers (BBMs) related to amyloid-β (Aβ) pathology in Alzheimer's disease (AD), the question arises whether these can replace the accepted reference standard, positron emission tomography (PET), for assessing Aβ burden. BBMs can differentiate Aβ status reliably in cognitively impaired patients, but two-threshold strategies to further improve their performance demonstrate the need for pathological confirmation by Aβ-PET in a non-negligible portion of individuals (∼10%-40%), especially in early-stage disease where BBM performance declines due to lower AD prevalence, reducing the test's positive predictive value (PPV) and increasing the risk for false-positives. This may be increasingly relevant in the future, considering the development of (very) early interventions against AD. Further, BBMs do not accurately reflect the actual Aβ load or change after immunotherapy. Consequently, there are clear remaining needs for Aβ-PET in several clinically important settings as (i) a confirmatory test and (ii) to determine treatment response. HIGHLIGHTS: When used as stand-alone tests, blood biomarkers (BBMs) demonstrate good sensitivity and specificity (84%-90%) relative to amyloid-β positron emission tomography (Aβ-PET). Two-threshold strategies improve BBM performance but require confirmatory testing by, for example, Aβ-PET in a non-negligible portion of patients that fall in an intermediate range or "gray-zone" (∼10%-40%). In early/preclinical populations, BBM performance declines due to lower AD prevalence, reducing the test's positive predictive value (PPV) and increases the gray-zone population. Currently available BBMs cannot reliably estimate Aβ-PET burden or track Aβ-plaque removal post-immunotherapy.}, } @article {pmid41088262, year = {2025}, author = {Ritchie, M and Hussen, K and Langford, O and Navarro, C and Kotadiya, Z and Donohue, MC and Aisen, P and Sperling, RA and Grill, JD and Raman, R}, title = {Recruitment and retention in a preclinical AD trial: comparisons between academic and non-academic sites.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {222}, pmid = {41088262}, issn = {1758-9193}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; *Patient Selection ; Female ; Aged ; Patient Dropouts/statistics & numerical data ; Academic Medical Centers ; Middle Aged ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) clinical trials enroll participants at various site types including research-focused academic institutions and independent non-academic sites. Limited research has examined the impact of site type on recruitment and retention outcomes. METHODS: To evaluate potential differences between site types, we used data from the Anti-Amyloid Treatment for Asymptomatic AD (A4) trial, the largest completed preclinical AD trial to date. We first compared the frequency of varying recruitment sources between site types. We then examined potential differences in participant- and site-level characteristics. To assess potential site type differences in retention, we fit a multivariable logistic regression model adjusting for variables associated with site type. For participants who prematurely discontinued, we examined potential differences by site type in reasons for dropout. RESULTS: One thousand and fifty-eight participants were randomized at 50 academic (N = 835) and 15 non-academic (N = 223) sites in North America. Academic sites had higher proportions of participants recruited through earned media and organizational referrals and lower proportions recruited through internal referrals and advertisements, compared to non-academic sites. Participant-level characteristics differed between site types. Compared to non-academic sites, academic sites had higher proportions of participants with a family history of dementia and a professional degree (highest education category), but lower proportions of individuals with a history of diabetes, a CDR-SB score above 0, and belonging to a racial and ethnic underrepresented group. Though the results were not statistically significant, non-academic sites had a higher screening rate (number of participants screened/site/month), but a lower randomization rate (randomized/screened) compared to academic sites. No site type differences in completion rates were observed. When examining reasons for discontinuation, we found that among the 72 participants who discontinued the trial at non-academic sites, 56 (77.8%) withdrew consent or were lost to follow up. In contrast, 140 out of 243 (57.6%) participants who discontinued the trial in academic sites withdrew consent or were lost to follow up. CONCLUSION: Our findings shed light on important site type differences that investigators should consider when making choices around site, design, and conduct in multisite preclinical AD trials.}, } @article {pmid41087559, year = {2025}, author = {Alghamdi, AM and Ashraf, MU and Bahaddad, AA and Almarhabi, KA and Al Shehri, WA and Daraz, A}, title = {A novel approach hybrid of ensemble learning and 3-D CNN mechanism: early-stage diagnosis of Alzheimer's disease using EEG signals.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {35893}, pmid = {41087559}, issn = {2045-2322}, support = {UJ-24-SUCH-1247//University of Jeddah/ ; }, mesh = {*Alzheimer Disease/diagnosis/physiopathology ; Humans ; *Electroencephalography/methods ; *Neural Networks, Computer ; *Deep Learning ; Early Diagnosis ; Male ; Aged ; Female ; *Diagnosis, Computer-Assisted/methods ; Ensemble Learning ; }, abstract = {Alzheimer's disease (AD) is a progressive neurological disorder that causes brain cell degeneration and leads to dementia. Early and accurate detection of AD is crucial, as it allows timely treatment before the brain suffers permanent damage. In recent years, computer-aided methods using Artificial Intelligence (AI) have shown promise in improving the diagnosis of AD, healthy cognition (HC), and other types of dementia. However, distinguishing between AD and HC using Electroencephalography (EEG) signals remains challenging, mainly due to difficulties in identifying meaningful features from the signals. To address this issue, we propose a novel method called EDL3DCNN, which combines Ensemble Deep Learning (EDL) with a 3D Convolutional Neural Network (3D-CNN). This model is designed to diagnose and classify AD and HC subjects accurately. We trained and evaluated the model using two publicly available EEG datasets related to AD. The EDL3DCNN model, leveraging multiple 3D-CNN classifiers, achieved a high classification accuracy of 99.02%. Our results demonstrate that integrating EDL with 3D-CNN offers a robust and scalable solution for computer-aided AD diagnosis.}, } @article {pmid41087268, year = {2026}, author = {Liang, T and Liu, S and Dang, B and Luan, X and Guo, Y and Steimbach, RR and Hu, J and Lu, L and Yue, P and Wang, R and Zheng, M and Gao, J and Yin, X and Chen, X}, title = {Corrigendum to 'Multimechanism biological profiling of tetrahydro-β-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease' [Eur. J. Med. Chem. 275 (2024) 116624].}, journal = {European journal of medicinal chemistry}, volume = {301}, number = {}, pages = {118254}, doi = {10.1016/j.ejmech.2025.118254}, pmid = {41087268}, issn = {1768-3254}, } @article {pmid41086934, year = {2025}, author = {Piekarczyk, N and Berezka, P and Majkutewicz, I and Myślińska, D and Kaczor, JJ}, title = {Combined vitamin D3 and dimethyl fumarate treatment alleviates cognitive dysfunction, oxidative stress, and inflammation in a rat model of sporadic Alzheimer's disease.}, journal = {Free radical biology & medicine}, volume = {241}, number = {}, pages = {748-759}, doi = {10.1016/j.freeradbiomed.2025.10.259}, pmid = {41086934}, issn = {1873-4596}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/pathology/metabolism ; Oxidative Stress/drug effects ; Rats ; *Cholecalciferol/pharmacology/administration & dosage ; *Dimethyl Fumarate/pharmacology/administration & dosage ; Male ; *Cognitive Dysfunction/drug therapy/pathology/metabolism/chemically induced ; Rats, Wistar ; Disease Models, Animal ; Streptozocin/toxicity ; Hippocampus/drug effects/metabolism/pathology ; *Inflammation/drug therapy/pathology ; tau Proteins/metabolism/genetics ; Glutathione/metabolism ; Antioxidants ; Neuroprotective Agents/pharmacology ; Drug Therapy, Combination ; }, abstract = {Alzheimer's disease (AD) concerns early oxidative and inflammatory disturbances that accelerate tau pathology and cognitive decline. We investigated whether combined treatment with vitamin D3 (VitD3) and dimethyl fumarate (DMF), two agents with complementary antioxidant and immunomodulatory actions, provides additive neuroprotection in the intracerebroventricular streptozotocin (ICV-STZ) rat model of sporadic AD. Male Wistar rats (n = 50) were divided into SHAM, STZ, VITD (STZ + VitD3 2000 IU/kg), DMF (STZ + DMF 50 mg/kg), or COMBO (STZ + VitD3+DMF) groups and treated orally for 90 days. Spatial learning and memory were assessed in the Morris Water Maze. Hippocampal oxidative stress indices (8-isoprostanes (8-Izo)), glutathione (GSH), glutathione disulfide (GSSG), and -SH groups and tau phosphorylation (pTau Ser396) were measured, and circulating vitamin D metabolites quantified by LC-MS/MS. STZ-induced cognitive impairment, elevated lipid peroxidation, increased the GSSG/GSH ratio, and raised pTau in CA1-CA3. VitD3 or DMF each improved acquisition and attenuated the 8-Izo increase; DMF normalized glutathione redox parameters, whereas VitD3 alone decreased GSH despite reducing lipid peroxidation. The COMBO provided the most consistent behavioral improvement and mitigated region-specific pTau elevations while maintaining redox balance. VitD3 treatment increased 25(OH)D3 and 3-epi-25(OH)D3 and reduced the 24,25(OH)2D3/25(OH)D3 ratio, indicating altered vitamin D metabolism. All treated groups showed a decrease in plasma TNF-α. These findings suggest that simultaneous modulation of vitamin D signaling and DMF may synergistically target oxidative, inflammatory, and tau-related mechanisms involved in sporadic AD. Future research should clarify brain-region vitamin D metabolite dynamics and the long-term impacts on protein thiol levels and cognitive function.}, } @article {pmid41085546, year = {2025}, author = {Chander, R and Sharma, R and Agnihotri, VK}, title = {Natural β-citronellol derivatives as potential dual enzyme inhibitors for the treatment of type 2 diabetes and Alzheimer's diseases.}, journal = {Natural product research}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/14786419.2025.2572038}, pmid = {41085546}, issn = {1478-6427}, abstract = {Effective strategies for treating type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) involve inhibition of α-amylase, α-glucosidase for T2DM and block acetylcholinesterase (AChE) enzymes for treating AD. To explore this potential natural β-citronellol, isolated from Dracocephalum heterophyllum Benth essential oil, was derivatized to yield three derivatives (Compounds 2-4), analysed using NMR and GC-MS techniques. The results showed that compounds 2 and 4 had the most significant α-glucosidase and AChE inhibition. Parent compound 1, along with 3 and 4, displayed the highest α-amylase inhibition. Network pharmacology identified CXCR4 (score: 14) and PIK3CA (score: 12) as top-ranked targets. These findings suggest that PIK3CA, which regulates glucose metabolism, insulin signalling, and cell survival, while CXCR4 suggests potential for neuroprotective and anti-inflammatory roles. Structure-activity relationship indicated that alkoxy group functionalization at β-carbon of β-citronellol is essential for activity. It highlights, a single β-citronellol derivative can manage dual T2DM and AD diseases.}, } @article {pmid41085520, year = {2025}, author = {Mathai, A and Kannoth, S and Nambiar, V and Gopinath, S and Thevarkalam, M and Anandakuttan, A and Kalingavarman, S and Mony, U and Raj, M and Bhaskaran, R}, title = {Immune system modifications in atypical parkinsonism related to autoimmunity - a case control study.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/17582024.2025.2573597}, pmid = {41085520}, issn = {1758-2032}, abstract = {BACKGROUND: Inflammation is known in atypical parkinsonism (AP), but the role of autoimmunity is unclear. This study evaluates immune system modifications suggesting autoimmunity in AP. METHODS: Included patients with AP diagnosed at Amrita Institute of Medical Sciences, Kochi (December 2018-May 2019), and age- and sex-matched controls. Fifteen immune parameters, including T regulatory cells, RORγt, and cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IL-21, IL-22, IL-23, TNF, IFN-γ, GM-CSF, NF-κB, TGF-β), were assessed in peripheral blood (flow cytometry and ELISA). RESULTS: Twenty-six cases (mean age 67.8 ± 7.5 years; 16 males) and 15 controls (mean age 68.1 ± 3.5 years; 10 males) studied. Diagnoses included progressive supranuclear palsy (n = 15), multiple system atrophy (n = 1), frontotemporal dementia with parkinsonism (n = 2), and unspecified AP (n = 8). AP cases had significantly higher RORγt (p = 0.041), IL-6 (p = 0.004), TNF (p = 0.020), IL-10 (p = 0.027), and IL-4 (p = 0.048). CONCLUSIONS: Elevated RORγt and cytokines suggest immune dysregulation and possible autoimmune mechanisms in AP, warranting further investigation.}, } @article {pmid41085169, year = {2025}, author = {Ismail, Z and Sivananthan, S and Main, S and Ménard, A and McLaren-Beato, J and Chambers, LW and Welch, V and Vedel, I and Smith, EE and Ewa, V and Feldman, S}, title = {Culturally sensitive CLEAR guidelines on disclosing and communicating a diagnosis of dementia.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70744}, pmid = {41085169}, issn = {1552-5279}, support = {P004637//Public Health Agency of Canada/ ; BMS-20-002//Academic Health Science Centre (AHSC)/ ; //University of Toronto Academic Health Science Centre (AHSC) Alternative Funding Plan (AFP) Innovation Fund./ ; }, mesh = {Humans ; *Dementia/diagnosis/psychology/ethnology ; Canada ; *Communication ; *Disclosure ; *Cultural Competency ; *Physician-Patient Relations ; *Truth Disclosure ; Primary Health Care ; *Practice Guidelines as Topic ; *Culturally Competent Care ; }, abstract = {Providing a dementia diagnosis is challenging, especially in primary care and considering diverse patient backgrounds. The Alzheimer Society of Canada (ASC), the College of Family Physicians of Canada, and the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD) guideline group partnered with patients, care partners, and clinicians to generate contemporaneous guidance for primary care practitioners. While relevant to all communities, Black and Chinese Canadians were formally represented in working groups. A literature review identified needs areas. Informed by Guidelines International Network (GIN) principles and through iterative group meetings with all partners, these needs were explored and incorporated into guidance. The Compassionate Language and Empathetic Approaches for Respectful Dementia Disclosure (CLEAR) offers recommendations on: holistic engagement, fostering hope, acknowledging care partners, identifying disclosing clinicians, appointment structure and environment, person-centered communication, specific discussion topics, and emotional supports, all through a cultural competence lens. These guidelines address communication challenges in disclosing a dementia diagnosis and enhancing care and support for persons living with dementia and their care partners. HIGHLIGHTS: Healthcare practitioners (HCPs) struggle with disclosing and communicating dementia diagnoses. Guidance is limited in primary care and different patient ethnocultural groups. We developed culturally sensitive guidelines with scripts and practical materials. Appropriate communication techniques and terminology are recommended in Compassionate Language and Empathetic Approaches for Respectful Dementia Disclosure (CLEAR). Patient-centered and holistic approaches for the patient and care partner are emphasized.}, } @article {pmid41085158, year = {2025}, author = {Fischer, DL and Grinberg, LT and Ahrendsen, JT and Beach, TG and Bieniek, KF and Castellani, RJ and Chkheidze, R and Cobos, I and Cohen, M and Crary, JF and Dickson, DW and Dugger, BN and Dunlop, SR and Farrell, K and Ghetti, B and Haeri, M and Harrison, W and Head, E and Hiniker, A and Huang, EJ and Huttner, A and Jamshidi, P and Kapasi, A and Keene, CD and Kofler, J and Latimer, CS and McKee, AC and Mente, K and Miller, MB and Montine, TJ and Morris, M and Murray, ME and Nelson, PT and Newell, KL and Perrin, RJ and Ramani, B and Reichard, RR and Roy, S and Schlachetzki, JCM and Seeley, WW and Serrano, GE and Spina, S and Teich, AF and Wang, SJ and Wisniewski, T and Lee, EB}, title = {Celebrating neuropathology's contributions to Alzheimer's Disease Research Centers.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70734}, pmid = {41085158}, issn = {1552-5279}, support = {UE5NS070680/GF/NIH HHS/United States ; R01AG075802/GF/NIH HHS/United States ; P30AG072976/GF/NIH HHS/United States ; P30AG019610/GF/NIH HHS/United States ; P30AG072980/GF/NIH HHS/United States ; P30AG072977/GF/NIH HHS/United States ; P30AG066515/GF/NIH HHS/United States ; P30AG066514/GF/NIH HHS/United States ; R01AG054008/GF/NIH HHS/United States ; R01NS095252/GF/NIH HHS/United States ; R01AG062348/GF/NIH HHS/United States ; P30AG062677/GF/NIH HHS/United States ; R01AG062517/GF/NIH HHS/United States ; U24NS133949/GF/NIH HHS/United States ; P30AG072972/GF/NIH HHS/United States ; K01AG070326/GF/NIH HHS/United States ; RF1NS128908/GF/NIH HHS/United States ; P30AG066508/GF/NIH HHS/United States ; P30AG072947/GF/NIH HHS/United States ; R24AG073199/GF/NIH HHS/United States ; P30AG066509/GF/NIH HHS/United States ; P30AG062715/GF/NIH HHS/United States ; U19AG066567/GF/NIH HHS/United States ; U19AG060909/GF/NIH HHS/United States ; UM1MH130981/GF/NIH HHS/United States ; UM1MH134812/GF/NIH HHS/United States ; U24AG072458/GF/NIH HHS/United States ; U24NS133945/GF/NIH HHS/United States ; U24NS135651/GF/NIH HHS/United States ; R24AG073137/GF/NIH HHS/United States ; U01NS137500/GF/NIH HHS/United States ; U01NS137484/GF/NIH HHS/United States ; U01AG082350/GF/NIH HHS/United States ; R01AG082730/GF/NIH HHS/United States ; R01AG087226/GF/NIH HHS/United States ; R01AG088656/GF/NIH HHS/United States ; R01AG060942/GF/NIH HHS/United States ; R01AG080585/GF/NIH HHS/United States ; R01NS129609/GF/NIH HHS/United States ; R01AG069912/GF/NIH HHS/United States ; P30AG066468/GF/NIH HHS/United States ; U19AG068054/GF/NIH HHS/United States ; R01MH116046/GF/NIH HHS/United States ; R01AG090551/GF/NIH HHS/United States ; P30AG072959/GF/NIH HHS/United States ; DP2AG086138/GF/NIH HHS/United States ; R01AG082346/GF/NIH HHS/United States ; P30AG066507/GF/NIH HHS/United States ; P01AG003991/GF/NIH HHS/United States ; P30AG066444/GF/NIH HHS/United States ; U19AG024904/GF/NIH HHS/United States ; U19AG032438/GF/NIH HHS/United States ; R01AG068319/GF/NIH HHS/United States ; R01AG053267/GF/NIH HHS/United States ; R01NS111978/GF/NIH HHS/United States ; UF1NS120463/GF/NIH HHS/United States ; P50AG023501/GF/NIH HHS/United States ; P01AG019724/GF/NIH HHS/United States ; U01AG057195/GF/NIH HHS/United States ; U19AG063911/GF/NIH HHS/United States ; P30AG072958/GF/NIH HHS/United States ; P30AG066512/GF/NIH HHS/United States ; R01AG077422/GF/NIH HHS/United States ; U01OH012486/GF/NIH HHS/United States ; U24NS135568/GF/NIH HHS/United States ; R01AG087280/GF/NIH HHS/United States ; R13AG059336/GF/NIH HHS/United States ; P30AG072979/GF/NIH HHS/United States ; P01AG066597/GF/NIH HHS/United States ; P01AG084497/GF/NIH HHS/United States ; RF1AG065341/GF/NIH HHS/United States ; P30AG062429/GF/NIH HHS/United States ; P30AG062421/GF/NIH HHS/United States ; P30AG066530/GF/NIH HHS/United States ; P30AG066518/GF/NIH HHS/United States ; P30AG066462/GF/NIH HHS/United States ; P30AG072975/GF/NIH HHS/United States ; P30AG072978/GF/NIH HHS/United States ; P30AG066519/GF/NIH HHS/United States ; P30AG079280/GF/NIH HHS/United States ; P30AG062422/GF/NIH HHS/United States ; P30AG066511/GF/NIH HHS/United States ; P30AG072946/GF/NIH HHS/United States ; P30AG072973/GF/NIH HHS/United States ; P30AG066506/GF/NIH HHS/United States ; P30AG072931/GF/NIH HHS/United States ; P30AG066546/GF/NIH HHS/United States ; P30AG086401/GF/NIH HHS/United States ; P30AG086404/GF/NIH HHS/United States ; P20AG068082/GF/NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //The Fred and Barbara Erb Family Foundation/ ; //Rainwater Charitable Trust/Tau Consortium/ ; //Karen Strauss Cook Research Scholar Award/ ; //Rainwater Charitable Trust/ ; SG-25-1416824//Alzheimer's Association Florida Gulf Coast/ ; 2024-351073//Chan Zuckerberg Initiative/ ; //Silicon Valley Community Foundation/ ; 685-2023-06//CurePSP/ ; //Allen Institute for Brain Science/ ; //Nancy and Buster Alvord Endowment/ ; //Shanahan Family Foundation/ ; //Barrist Family Foundation/ ; W81XWH-21-S-TBIPH2//U.S. Department of Defense/ ; //Stuart Katz and Dr. Jane Martin/ ; //10,000 Brains NeuroAI Inc/ ; //DeCrane Family Fund for PPA Research/ ; //Bluefield Project to Cure FTD/ ; }, mesh = {Humans ; *Alzheimer Disease/pathology ; *Biomedical Research/history ; History, 20th Century ; History, 21st Century ; National Institute on Aging (U.S.) ; *Neuropathology/history ; United States ; }, abstract = {Our understanding of Alzheimer's disease (AD) and related dementias (ADRD) has grown exponentially, thanks to significant investments by the National Institute on Aging (NIA). This article celebrates the 40th anniversary of the NIA's Alzheimer's Disease Research Centers, highlighting the pivotal role of neuropathology as the bedrock for neurodegeneration research. Neuropathology has championed the key principles of proteinopathy, selective vulnerability, and stereotypic spread. Furthermore, neuropathologic studies advanced our understanding of ADRD prevalence, heterogeneity, clinical-pathological correlations, and genetic underpinnings, spurring biomarker development for target engagement and disease monitoring. Disease-modifying therapies for AD were inspired and informed by neuropathology. The neuropathology community is poised to refine diagnostics, leveraging digital pathology and integrating genetics and pathomics to enhance subtyping for novel precision medicine approaches. Despite some common misconceptions and logistical challenges, neuropathology continues to be a critical component of the ADRD research infrastructure, serving as a key bridge between allied basic and clinical sciences. HIGHLIGHTS: We celebrate 40 years of NIA-funded ADRCs and their contributions through neuropathology studies that have significantly advanced our understanding and treatment of ADRD. Neuropathology uncovers principles of neurodegenerative disease: proteinopathy, selective vulnerability, and stereotypic spread, informing diagnostics and therapies. Development of AD biomarkers with reference to neuropathology enhances accuracy in diagnosis and monitoring, paving the way for targeted disease-modifying therapies. Integration of digital pathology, genetics, and novel tools in neurodegeneration research promises advanced precision medicine approaches and refined diagnostics. Misconceptions and logistical challenges to neuropathological research are addressed to improve understanding and collaboration.}, } @article {pmid41085151, year = {2025}, author = {Zhu, CW and Flournoy, C and Raman, R and Sano, M}, title = {Employment, volunteering, and health-related resource use in pre-symptomatic AD: Results from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70641}, pmid = {41085151}, issn = {1552-5279}, support = {P30 AG066514/AG/NIA NIH HHS/United States ; U19AG010483/AG/NIA NIH HHS/United States ; R01AG063689/AG/NIA NIH HHS/United States ; U24AG057437/AG/NIA NIH HHS/United States ; //Eli Lilly/ ; NIRG-12-243012/ALZ/Alzheimer's Association/United States ; //GHR Foundation/ ; //C.W.Z. and M.S. are also supported by the Department of Veterans Affairs, Veterans Health Administration/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Female ; *Employment/statistics & numerical data ; Aged ; Longitudinal Studies ; *Volunteers/statistics & numerical data ; Prodromal Symptoms ; }, abstract = {INTRODUCTION: Little is known about productive time use and health-related resource use during "pre-symptomatic" AD, defined by the presence of brain amyloid in the absence of cognitive symptoms. We compared changes in resource use and participation in paid employment and/or volunteering in cognitively unimpaired older adults with amyloid accumulation (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease [A4] study, N = 1165) to otherwise matched participants without amyloid accumulation (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN] study, N = 507). METHODS: Health-related resource use was self-reported using the Resource Use Inventory (RUI). Longitudinal analyses examined effect on RUI from study (A4 vs LEARN), time, and their interaction, controlling for Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (ADCS-PACC) and the Clinical Dementia Rating (CDR) scale, and their change scores from baseline. RESULTS: Over time, paid employment and volunteering decreased, and unpaid help and hospitalization increased. Results showed clear associations between ADCS-PACC and CDR with RUI. DISCUSSION: Little detectable impact of amyloid levels on RUI was found in pre-symptomatic AD that has been identified as an ideal stage to target for dementia prevention. HIGHLIGHTS: Using data from a cohort of cognitively unimpaired older adults with evidence of amyloid accumulation enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study and otherwise matched participants who did not meet subthreshold levels of amyloid accumulation enrolled in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study, this study showed clear associations between clinical variables and resource use and participation in paid employment and volunteering but suggested little detectable impact of amyloid levels on rate of change during the preclinical stage. Our results suggest that economic benefits from currently available treatment that effectively removes amyloid may not be immediately or concurrently observed during the short timeline of clinical trials. It is critical that our examination of economic consequence of treatment include broad ranges of items on resource use and productivity loss, longer time horizon, and that we balance between cost of detection, treatment, and burden and benefit.}, } @article {pmid41085131, year = {2025}, author = {Bauer, A and Rabe, C and Schiffman, C and Rose, F and Respondek, G and Gullotta, F and Schlieker, L and Jethwa, A and Schrurs, I and Manuilova, E and Ostrowitzki, S and Bittner, T}, title = {Blood-based pre-screening in the SKYLINE secondary prevention Ph3 gantenerumab study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70676}, pmid = {41085131}, issn = {1552-5279}, support = {//F. Hoffmann-La Roche Ltd/ ; //Roche Diagnostics International Ltd (Rotkreuz, Switzerland)/ ; }, mesh = {Humans ; *Alzheimer Disease/blood/drug therapy/diagnosis/prevention & control ; *tau Proteins/blood ; Female ; Biomarkers/blood/cerebrospinal fluid ; Male ; Retrospective Studies ; Aged ; *Secondary Prevention/methods ; Amyloid beta-Peptides/blood ; Apolipoprotein E4/blood ; Positron-Emission Tomography ; *Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {INTRODUCTION: SKYLINE was a secondary prevention study that used blood-based biomarker (BBBM) pre-screening to screen out participants with a low likelihood of amyloid positivity by positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. METHODS: This retrospective analysis used data from SKYLINE (ClinicalTrials.gov: NCT05256134; terminated prematurely) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to compare predicted and actual clinical performance characteristics of various biomarker combinations using prototype Elecsys[®] plasma immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). RESULTS: In >3500 participants screened in SKYLINE, tau phosphorylated at threonine 181 (pTau181) and apolipoprotein E4 protein (ApoE4p) was the highest-performing BBBM combination. Actual clinical performance of the BBBM pre-screening in SKYLINE was similar to predictions based on A4 in terms of screen-out rate, positive predictive value, and 1-negative predictive value. DISCUSSION: BBBM pre-screening in SKYLINE using prototype plasma pTau181 and ApoE4p immunoassays effectively alleviated participant burden by avoiding unnecessary PET or CSF testing. HIGHLIGHTS: We compared blood-based biomarker (BBBM) performance in SKYLINE and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4). Pre-screening improved amyloid positivity (defined by positron emission tomography/cerebrospinal fluid) screen failure rate. Tau phosphorylated at threonine 181 (pTau181) and apolipoprotein E4 protein was the highest-performing combination among BBBMs tested. Pre-screening eased participant burden by reducing subsequent screening procedures.}, } @article {pmid41084412, year = {2025}, author = {Lee, A and Al-Dahwi, S and Angell, T and Arulalagan, A and Bloxsom, R and Clarkson, H and Faure, R and Goodarzi, S and Gupta, M and Kale, A and Lam, K and Mahon-Daly, F and Parry, C and Pradhan, V and Ryan-Phillips, F and Shah, S and Sidhu, S and Smiddy, J and Sridhar, A and Tahmid, SF and Wight, R and Roberts, N and Topiwala, A}, title = {A systematic review of brain health in adults with chronic pain.}, journal = {Anaesthesia}, volume = {}, number = {}, pages = {}, doi = {10.1111/anae.70021}, pmid = {41084412}, issn = {1365-2044}, abstract = {INTRODUCTION: Recent research has linked chronic pain with an increased risk of clinical dementia diagnosis. Yet structural and functional brain changes associated with chronic pain and their potential role in accelerating brain ageing have not been characterised comprehensively. Understanding these effects is crucial to developing targeted prevention and management strategies. METHODS: We conducted a systematic review of all English language articles in MEDLINE and Embase. Studies were eligible if they compared neuroimaging, clinical, biological, cognitive or mental health outcomes in adults with chronic pain to healthy controls. Following screening, data were extracted and the risk of bias was assessed. RESULTS: Of 5805 identified studies, 365 met the inclusion criteria. Most were cross-sectional studies with small sample sizes; conducted in middle-aged populations in China or the USA; had moderate to high risk of bias; and represented > 30 distinct pain phenotypes. Magnetic resonance imaging was the most common method for assessing brain health. Key findings in patients with chronic pain included: lower grey matter volumes and reduced fractional anisotropy; evidence of accelerated brain ageing including older brain age and higher white matter hyperintensities; mixed results in resting state functional connectivity; increased power densities and connectivity on electroencephalography; and higher levels of serum brain-derived neurotrophic factor. The most consistently affected brain regions across magnetic resonance imaging studies were the insula; anterior and posterior cingulate; thalamus; hippocampus; primary motor cortex; and cerebellum. DISCUSSION: Adults with chronic pain exhibit widespread alterations in brain health compared with healthy controls. Several observed features overlap with biomarkers of Alzheimer's disease and other forms of neurodegeneration. These findings highlight the need for larger, well-designed studies incorporating clearly defined pain phenotypes, multimodal imaging and causal inference methods to clarify the role of chronic pain in brain ageing and dementia risk.}, } @article {pmid41084258, year = {2025}, author = {Raabe, AC and Correa, RAS and Rodrigues, CCPR and Vieira, RP}, title = {History, Challenges, and Perspectives of CNS-Targeted Transdermal Formulations.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128409331250915220233}, pmid = {41084258}, issn = {1873-4286}, abstract = {Central nervous system (CNS) disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Schizophrenia (Sch) present significant challenges for healthcare systems, both in terms of prevalence and the complexity of pharmacological treatment. While current therapies offer symptomatic relief, there is a high rate of failure in addressing the full spectrum of clinical symptoms and patient adherence issues, especially in long-term care. Since ancient times, various civilizations, including the Chinese, Egyptians, and indigenous South African cultures, have investigated and utilized the transdermal route for therapeutic and medicinal applications. Recent advances in transdermal drug delivery systems (TDS) offer a promising alternative to traditional routes of administration, enhancing drug absorption and minimizing side effects, such as gastrointestinal distress. This review explores the potential of TDS for improving the pharmacotherapy of AD, PD, and Sch. We also highlight the ongoing challenges in optimizing TDS formulations, such as drug absorption through the skin, skin irritation, and maintaining therapeutic efficacy. Furthermore, the review discusses the progress in prodrug design strategies aimed at enhancing skin permeation and bioavailability, particularly in the context of CNS-targeted drugs. The need for continued research into TDS technology is emphasized, as it holds promise for improving treatment adherence, patient quality of life, and caregiver burden, thereby advancing therapeutic options for CNS disorders.}, } @article {pmid41084249, year = {2025}, author = {Tamaddon-Abibigloo, Y and Dastmalchi, S and Mahdipanah, F and Asadi, E and Khezrpour, S and Valizadeh, P and Shahbazi-Mojarrad, J}, title = {Isatin Derivatives as Emerging Promising Anti-Alzheimer Agents: Focusing on Their Chemical Structure and Biological Targets.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266394265250828164308}, pmid = {41084249}, issn = {1873-4294}, abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder with a complex pathology. Until now, there is no generally effective treatment for AD. Isatin is a natural alkaloid whose derivatives have shown a wide spectrum of biological activities. This molecule is also the basic scaffold for several compounds with useful biological properties against AD. In this review, for the first time, we focus on the anti-AD properties of isatin derivatives. We tried to present comprehensive data about their structure and mechanism of action. Results showed that indirubins, isatin Schiff Bases, and spiro derivatives of isatin were the most studied molecules. The most studied targets were the glycogen synthase kinase-3, cholinesterases, and amyloid beta aggregation. It was concluded that isatin could be considered an important scaffold for the development of new anti-AD compounds.}, } @article {pmid41082949, year = {2025}, author = {Ye, Q and Gast, G and Holmes, TC and Xu, X}, title = {Hippocampal neural circuit mechanisms in Alzheimer's disease revealed by viral-genetic circuit mapping.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107139}, doi = {10.1016/j.nbd.2025.107139}, pmid = {41082949}, issn = {1095-953X}, mesh = {*Alzheimer Disease/genetics/pathology/physiopathology ; Animals ; *Hippocampus/pathology/physiopathology/virology ; Humans ; Disease Models, Animal ; *Nerve Net/pathology/physiopathology ; Mice ; Rabies virus/genetics ; Neural Pathways/pathology/physiopathology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts in countries with aging populations. Existing therapeutic approaches that have been based on neurochemical and neuropathological findings are largely ineffective. This lack of progress suggests we require a new framework for future AD therapies. The examination of neural circuit mechanisms in AD mouse models is an emerging focus for identifying new AD treatment strategies. We now know there are neural circuit-level maladaptive alterations in AD brains, some of which appear very early in the disease process before neuropathological features are detectable. Recent advancements in viral-genetic technologies allow us to quantitatively map the cell-type-specific neural circuit connections in AD mouse models. Monosynaptic rabies virus mapping reveals age-progressive changes in both long-range and local hippocampal neural circuit connectivity in AD mouse models - and provides explanations for human AD behavioral defects, such as sex differences and higher level visual deficits. These recent developments in neural circuits level concepts and technology present new opportunities for studying AD pathogenesis for early identification of the disease and for developing novel therapeutic interventions.}, } @article {pmid41082483, year = {2025}, author = {Hao, X and Ding, N and Zhang, Y and Wu, M and Ning, Y and Wang, Z and Li, Z}, title = {Acupuncture Strategies in a Mouse Model of Alzheimer's Disease.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {223}, pages = {}, doi = {10.3791/68809}, pmid = {41082483}, issn = {1940-087X}, mesh = {*Alzheimer Disease/therapy/microbiology ; Animals ; *Acupuncture Therapy/methods/instrumentation ; Mice ; Disease Models, Animal ; Brain ; Male ; Gastrointestinal Microbiome/physiology ; Mice, Inbred C57BL ; Intestines/microbiology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease. Numerous studies have demonstrated that alterations in intestinal flora can influence the central nervous system (CNS) through multiple pathways, ultimately contributing to the onset and progression of AD. Recent research suggests the limitations of pharmacological therapies, emphasizing the need for multi-targeted interventions in AD treatment. Traditional Chinese medicine (TCM) highlights the physiological and pathological relationship between the brain and the intestine. Therefore, therapeutic strategies targeting gastrointestinal regulation to enhance brain function are of great importance for delaying the pathological progression of AD. This protocol introduces a brain-intestine coordination acupuncture method. The experimental results showed that this acupuncture protocol could modulate intestinal flora, suppress intestinal inflammation and neuroinflammation in AD model mice, thereby achieving bidirectional therapeutic effects on brain-intestine regulation. Moreover, a mouse bag fixation device for acupuncture treatment was described in this study, which can reduce stress reaction and improve experimental efficiency.}, } @article {pmid41082320, year = {2025}, author = {Verrienti, G and Lombardozzi, G and Albergo, G and De Filippis, S}, title = {Trazodone in neurology, a new life for an old molecule - an updated, comprehensive, systematic review of clinical trials.}, journal = {International journal of psychiatry in clinical practice}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/13651501.2025.2572291}, pmid = {41082320}, issn = {1471-1788}, abstract = {INTRODUCTION: The triazolopyridine derivative trazodone is approved for the treatment of major depressive disorder (MDD) in adults; according to the available literature, this molecule, through a specific dose-dependent profile of action, was found to be a potential therapeutic option in some neurological conditions. This systematic review aimed to synthesise the available evidence on the use of trazodone in neurological patients. METHODS: PubMed was searched for articles published from inception until March 2025. Article reference lists were screened, and relevant articles were retrieved for consultation. Clinical trials specifically investigating trazodone in neurological populations were included, following PRISMA guidelines for systematic reviews. RESULTS: Out of 69 records initially retrieved, 14 studies met the inclusion criteria, comprising 13 randomised controlled trials and 1 retrospective study, with a total of 608 patients. Most of the included studies focused on individuals with dementia, while others explored its use in different neurological disorders. CONCLUSIONS: Despite being an older antidepressant, trazodone remains widely prescribed. Beyond treating depression in neurological patients, it may may be useful in the treatment of some neurological aspects. However, current evidence remains limited. Further high-quality research is necessary to better define the therapeutic potential of trazodone in the management of neurological conditions.}, } @article {pmid41082199, year = {2025}, author = {Lu, M and Kim, MJ and Collins, EC and Shcherbinin, S and Ellinwood, AK and Yokoi, Y and Brooks, DA and Hansson, O and Knopman, DS and Sims, JR and Mintun, MA}, title = {Posttreatment Amyloid Levels and Clinical Outcomes Following Donanemab for Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ 2 Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {82}, number = {12}, pages = {1251-1256}, pmid = {41082199}, issn = {2168-6157}, mesh = {Humans ; Aged ; Female ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; Male ; Aged, 80 and over ; Middle Aged ; tau Proteins/metabolism ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; Double-Blind Method ; Treatment Outcome ; Biomarkers/blood ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Plaque, Amyloid/drug therapy/metabolism ; }, abstract = {IMPORTANCE: Accumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit. OBJECTIVE: To assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD. This was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025. INTERVENTIONS: Participants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks. MAIN OUTCOMES AND MEASURES: Participants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker. RESULTS: Analyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (R2, 0.73 [95% CI, 0.37-0.97]) and CDR-SB score (R2, 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 (R2, 0.86 [95% CI, 0.73-0.97]), p-tau181 (R2, 0.88 [95% CI, 0.77-0.97]), and GFAP (R2, 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL (R2, 0.03 [95% CI, 0.00-0.54]). CONCLUSIONS AND RELEVANCE: The findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04437511.}, } @article {pmid41082159, year = {2025}, author = {Ntondini, TL and Naki, T and Alven, S}, title = {The therapeutic efficacy of nanoparticles in the treatment of alzheimer's disease.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {41082159}, issn = {2240-2993}, abstract = {The build-up of beta-amyloid plaques in the brain leads to Alzheimer's disease (AD), a neurodegenerative condition. AD affects more than 30 million individuals globally every year. No cure for AD has been discovered yet. The available therapeutic options are administered to slow down the progress of the disease. The currently available treatment plans are used to relieve symptoms and improve cognitive abilities, thus slowing progression. Nanotechnology is highly effective and has demonstrated significant benefits across various medical applications. Nanoparticles have been explored as promising drug delivery systems for the targeted delivery of anti-AD therapeutics and for the precise diagnosis of the condition. Nanoparticles, such as dendrimers, lipid-based nanoparticles, polymer-based nanoparticles, and metal-based nanoparticles, have been designed and reported to inhibit Aβ aggregation, fibril formation, and disaggregating mature fibrils, prevent neuroinflammation and Aβ1-42-induced cell damage, treat oxidative stress and lower hallmark of Aβ, and display excellent capability to bypass blood-brain barrier (BBB). This review is focused on the preclinical therapeutic outcomes of nanoparticles and the challenges encountered in the treatment of AD. This review highlights the significant advancements of nanoparticles that are currently undergoing clinical trials for management of AD.}, } @article {pmid41081549, year = {2025}, author = {Bellio, TA and Krunic, A and Campion, MS and Dupaguntla, R and Labadorf, A and Stein, TD and Lin, H and Mellott, TJ and Blusztajn, JK}, title = {Perinatal Choline Supplementation Promotes Resilience Against Progression of Alzheimer's Disease-Like Brain Transcriptomic Signatures in App[NL-G-F] Mice.}, journal = {Aging cell}, volume = {24}, number = {11}, pages = {e70148}, pmid = {41081549}, issn = {1474-9726}, support = {RF1 AG057768/AG/NIA NIH HHS/United States ; //NIH Office of Dietary Supplements/ ; R21 AG056901/NH/NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; R21 AG059195/AG/NIA NIH HHS/United States ; RF1 AG057768/NH/NIH HHS/United States ; RF1 AG078299/NH/NIH HHS/United States ; R01 AG045031/AG/NIA NIH HHS/United States ; R21 AG056901/AG/NIA NIH HHS/United States ; R01 AG045031/NH/NIH HHS/United States ; R21 AG 059195/NH/NIH HHS/United States ; RF1 AG078299/AG/NIA NIH HHS/United States ; P30 AG072978/NH/NIH HHS/United States ; }, mesh = {Animals ; *Choline/pharmacology/therapeutic use/administration & dosage ; *Alzheimer Disease/genetics/pathology/metabolism ; Mice ; *Dietary Supplements ; *Transcriptome/drug effects ; Female ; *Brain/metabolism/drug effects/pathology ; Disease Models, Animal ; Disease Progression ; Mice, Transgenic ; Humans ; Male ; }, abstract = {Alzheimer's disease (AD)-the leading cause of dementia-has no cure, inadequate treatment options, and a limited understanding of prevention measures. We have previously shown that perinatal dietary supplementation with the nutrient choline ameliorates cognitive deficits and reduces amyloidosis across the brain in App[NL-G-F] AD model mice. Here, we analyzed transcriptomic abnormalities in these mice and tested the hypothesis that they may be attenuated by perinatal choline supplementation (PCS). Wild-type (WT) and App[NL-G-F] dams consumed a diet containing 1.1 (control) or 5 g/kg (supplemented) of choline chloride from 2 weeks prior to mating until weaning. At 3, 6, 9, or 12 months of age, the offspring RNA was sequenced in the hippocampus and cerebral cortex. As compared to WT, the App[NL-G-F] mice reared on the control diet had age-dependent upregulation of expression of mRNAs and lncRNAs related to inflammation and reduced expression of mRNAs related to neuronal function. As compared to App[NL-G-F] mice on the control diet, PCS App[NL-G-F] mice increased expression of synaptic genes and downregulated inflammation-related genes starting at 6 months in the cortex; increased expression of GABAergic function and ATP metabolism genes, and decreased expression of inflammatory genes in the hippocampus at 12 months. These changes counteracted the effects of App[NL-G-F] genotype seen in mice on the control diet. The expression of many of these choline-protected genes correlated with clinical dementia rating, inflammation, and tauopathy in human postmortem dorsolateral prefrontal cortex AD samples, indicating their relevance to the disease process. The results suggest that adequate choline intake could be a preventive strategy for AD.}, } @article {pmid41080679, year = {2025}, author = {Mishra, K and Tripathi, S and Tiwari, AK and Rana, R and Yadav, P and Chourasia, MK}, title = {Cerium-based nanoparticles for neurodegeneration: emerging redox therapeutics beyond pharmaceuticals.}, journal = {RSC advances}, volume = {15}, number = {45}, pages = {37540-37569}, pmid = {41080679}, issn = {2046-2069}, abstract = {Delivering therapeutic agents across the blood-brain barrier (BBB) remains a formidable hurdle in the treatment of neurodegenerative diseases, which are primarily driven by mitochondrial dysfunction, oxidative stress, and neuroinflammation. Although our understanding of these disease mechanisms has advanced, effective treatments are still limited due to the restrictive nature of the BBB. In this context, nanotechnology has emerged as a promising approach, offering engineered nanocarriers capable of traversing the BBB and enabling targeted drug delivery to the brain. Amongst the various nanomaterials explored, cerium-based nanoparticles have gained particular attention as promising candidates for neurodegenerative disease therapy. Their multifunctionality stemming from reversible redox behaviour, enzyme-mimicking activity, sustained antioxidant effects, and anti-inflammatory properties, combined with their ability to penetrate the BBB and provide neuroprotection, positions them as a powerful platform for future therapeutic strategies. This review begins with a concise overview of the shared pathological mechanisms underlying neurodegenerative diseases, highlights BBB-related drug delivery challenges, and discusses nanocarrier strategies for brain targeting, focusing on cerium-based nanoparticles. We then delved into the structural features, synthesis techniques, and distinctive redox properties of cerium-based nanomaterials, with emphasis on cerium oxide and cerium vanadate. Their therapeutic potential is explored across Alzheimer's and Parkinson's diseases, as well as in stroke, multiple sclerosis, and glioblastoma. Key insights into their physicochemical properties, BBB permeability, and neuroprotective mechanisms are provided. We also address current limitations, including nanoparticle stability, toxicity, and translational barriers, and conclude with future directions for optimizing cerium-based nanozymes in neurotherapeutics.}, } @article {pmid41079916, year = {2025}, author = {Alba, LCO and Anlacan, VMM and Navarra, CJA and Jamora, RDG}, title = {YouTube as an educational resource: Evaluating the quality and reliability of videos for family caregivers of persons living with Alzheimer's disease dementia.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251368887}, pmid = {41079916}, issn = {2542-4823}, abstract = {BACKGROUND: YouTube is increasingly used by patients and caregivers as a source of health information. However, the quality and reliability of content on Alzheimer's disease dementia (ADD) remain uncertain. OBJECTIVE: This study aimed to determine whether YouTube videos on ADD provide reliable and high-quality information for caregivers and to assess whether the most popular videos are also the most trustworthy. METHODS: In December 2024, YouTube was systematically searched for ADD-related videos. Two independent physicians reviewed each video, scoring it using modified DISCERN (mDISCERN) for reliability and the Global Quality Scale (GQS) for content quality. Videos were categorized by goal and assessed for quality, accuracy, comprehensiveness, and specific content. RESULTS: There were 117 videos included in the study. Using the mDISCERN scale, 70 videos (59.8%) were deemed with good reliability, 33 videos (28.2%) have moderate reliability, and 14 videos (12%) have poor reliability. Using the GQS, 61 videos (51.1%) have high quality, 16 videos (28%) were assessed as excellent quality, 34 videos (29%) as moderate quality, and 7 videos (6%) as low quality. Videos from academic institutions, news agency and physicians exhibited higher mDISCERN and GQS scores compared to other groups and a significant correlation was seen between mDISCERN and GQS (p < 0.001). CONCLUSIONS: The videos on ADD produced by healthcare professionals and academic institutions have high quality and good reliability, covering disease properties, treatment choices, and patient experiences. However, video popularity does not significantly correlate with content reliability and quality.}, } @article {pmid41078387, year = {2025}, author = {Zapata-Restrepo, LM and Miller, BL and Rivas, J and Possin, K and Valcour, V and Piña-Escudero, SD and Ibañez, A and Kosik, KS}, title = {Case of early onset Alzheimer's disease associated with a novel PSEN1 variant identified in Colombia.}, journal = {NPJ dementia}, volume = {1}, number = {1}, pages = {31}, pmid = {41078387}, issn = {3005-1940}, abstract = {Early-onset Alzheimer's disease (EOAD) is a rare form of dementia that often progresses more quickly than late-onset cases, and is more commonly associated with autosomal dominant mutations. A 47-year-old male presented with progressive cognitive and behavioral decline, a family history of EOAD, and was later found to have a novel pathogenic PSEN1 variant (c.519 G > T, p.Leu173Phe). Initial evaluations, including neuroimaging and laboratory tests, were unremarkable. Neuropsychological testing later revealed memory impairment, executive dysfunction, and neuropsychiatric symptoms. These features, alongside the identified mutation, are consistent with phenotypic presentations of EOAD involving the third transmembrane domain of PSEN1. Pharmacological treatment with cholinesterase inhibitors and antipsychotics yielded limited benefit. Notably, the extended follow-up time, of more than 10 years from the early symptomatic stage, is a unique and valuable feature of this case study, providing rare longitudinal insight into the natural course of genetically confirmed EOAD.}, } @article {pmid41078145, year = {2025}, author = {Wang, F and Liu, J and Bai, D and Li, L and Fedgchin, M and Henley, D and Li, H and Zhang, F}, title = {A Phase 1 Study of the Pharmacokinetics, Safety, and Tolerability of Posdinemab (JNJ-63733657) in Healthy Chinese Adults.}, journal = {Journal of clinical pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1002/jcph.70116}, pmid = {41078145}, issn = {1552-4604}, support = {//Johnson & Johnson/ ; }, abstract = {Posdinemab, a humanized immunoglobulin G1/κ monoclonal antibody, binds with high affinity to phosphorylated tau protein which is associated with Alzheimer's disease (AD) pathophysiology. Posdinemab reduced tau seeding in murine models and was well tolerated in Phase-1 clinical studies. This open-label, single-arm, Phase-1 study examined the effects of posdinemab with single intravenous dose (60 mg/kg) in healthy adults from China. The main objectives were to assess posdinemab serum pharmacokinetics (PK, primary), safety and tolerability (secondary), and presence of anti-drug antibodies (ADAs; secondary). Results were compared with Phase-1 European first-in-human (NCT03375697) and Japanese (NCT03689153) studies. Healthy Chinese participants (N = 10), mean age 60.0 (SD 3.80) years and 60% female, received posdinemab. Mean posdinemab serum Cmax was 1401 µg/mL, median tmax was 0.08 days, mean AUCinf was 18162 µg·day/mL, mean CL was 3.36 mL/day/kg, and mean elimination t1/2 was 17.5 days. Most participants (n = 8; 80%) experienced ≥1 treatment-emergent adverse event (TEAEs), most common (20%) of which were arthralgia and back pain. Four participants (40.0%) were positive for posdinemab ADAs post-dose with peak titers of 1:22.5 (n = 3) and 1:360 (n = 1). Serum posdinemab concentrations in ADA-positive and ADA-negative participants were generally comparable. In conclusion, PK profile of posdinemab in healthy participants from China was in the expected range and comparable to previous Phase-1 studies in Europe and Japan. There were no new safety concerns. These results support further global development of posdinemab in AD.}, } @article {pmid41077117, year = {2025}, author = {Elamin, SA and Al Shibli, AN and Shaito, A and Al-Maadhadi, MJMB and Zolezzi, M and Pedersen, S}, title = {Anti-amyloid monoclonal antibody therapies in Alzheimer's disease - a scoping review.}, journal = {Neuroscience}, volume = {589}, number = {}, pages = {50-61}, doi = {10.1016/j.neuroscience.2025.10.011}, pmid = {41077117}, issn = {1873-7544}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide, and with advancements in the medical field, Anti-amyloid monoclonal antibodies (AA mAbs) targeting amyloid-β have emerged as potential disease-modifying agents altering AD pathology. This scoping review mapped the characteristics, patterns, and gaps in clinical trials investigating the efficacy and safety of AA mAbs in AD treatments, with focus on cognitive, functional, biochemical, imaging, and safety outcomes. It highlighted patterns, gaps, and limitations of the existing literature. A systematic search of PubMed/MEDLINE, Embase, Scopus, and Web of Science was conducted for studies published since inception to February 2022, and eligible studies that investigated efficacy and safety outcomes of AA mAbs in treatment of AD were included. A majority of the included trials reported a combination of cognitive, functional, biochemical, and imaging outcomes. Across the sample, reductions in amyloid burden were frequently reported (10 trials), with a smaller subset of studies reporting significant cognitive and functional improvements (4 trials), primarily lecanemab and aducanumab in addition to one pooled analysis of solanezumab. ARIA-E and ARIA-H were frequently reported among the safety concerns, particularly in high-dose and APOE ε4 carrier populations. Notable limitations were observed in the reviewed literature including a disconnect between biomarker changes and consistent clinical benefits and, importantly, limited population diversity and patient-reported outcomes. This review highlights the need for rigorous, diverse, and patient-centered research. Addressing these gaps is critical in ensuring safe, effective, and equitable treatment for all patients living with Alzheimer's disease.}, } @article {pmid41076749, year = {2025}, author = {Kunath, N and Ramfjord, HAB and Kvisvik, EV and Konyves-Kolonics, M and Rolfseng Grøntvedt, G and Serysheva, II and Komorowski, L and Wildemann, B and Jarius, S}, title = {ITPR1 autoantibody-associated autoimmunity as a cause of newly emerging cognitive decline mimicking Alzheimer's disease: Case report and brief review of the literature.}, journal = {Journal of neuroimmunology}, volume = {409}, number = {}, pages = {578774}, doi = {10.1016/j.jneuroim.2025.578774}, pmid = {41076749}, issn = {1872-8421}, mesh = {Humans ; Middle Aged ; *Alzheimer Disease/diagnosis/immunology/diagnostic imaging ; *Autoantibodies/blood/immunology ; *Autoimmunity/immunology ; *Cognitive Dysfunction/immunology/blood/diagnosis/etiology/diagnostic imaging ; Diagnosis, Differential ; *Inositol 1,4,5-Trisphosphate Receptors/immunology ; }, abstract = {BACKGROUND: Since its first description in 2014, anti-inositol 1,4,5-trisphosphate receptor type 1 (ITPR1, also termed IP3R1) autoimmunity has been recognized as causing a clinically heterogeneous spectrum of symptoms. While first described in patients with autoimmune cerebellar ataxia, this facultative paraneoplastic disease has been associated also with peripheral neuropathy, dysautonomia, sleep disorders, neuropsychiatric/psychotic symptoms, and cognitive decline. METHODS: Retrospective case study. RESULTS: We report the case of a 58-year-old patient who was admitted with acute confusion, rapidly progressive cognitive decline, and hallucinations. A history of mild cognitive impairment over several years and low cerebrospinal fluid (CSF) amyloid beta-42 and elevated CSF tau protein were suggestive of Alzheimer's disease (AD). However, pleocytosis, intrathecal IgG synthesis and blood-CSF barrier dysfunction prompted screening for antineuronal antibodies, which revealed ITPR1-IgG1/anti-Sj antibodies in both serum and CSF. Brain MRI showed limbic hyperintensities and hippocampal atrophy. No neoplastic disease was found. Immunosuppressive treatment stabilized the disease course but did not lead to symptom improvement. CONCLUSIONS: This case underscores the clinical importance of CSF analysis and testing for anti-neural autoantibodies, including less common reactivities, in case of rapid cognitive decline even in patients with known or suspected neurodegenerative disease, such as AD, with ITPR1 representing a novel autoimmune target antigen.}, } @article {pmid41076604, year = {2025}, author = {Ebadpour, N and Abavisani, M and Karav, S and Kesharwani, P and Sahebkar, A}, title = {Exosome/Extracellular Vesicles-Based Therapeutics in Alzheimer's Disease: Neuroprotective Roles and Future Perspectives.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {4}, pages = {137}, pmid = {41076604}, issn = {1559-1166}, mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; *Exosomes/metabolism/transplantation ; *Extracellular Vesicles/metabolism/transplantation ; Animals ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is marked by memory loss, cognitive decline, and characteristic pathological features including β-amyloid (Aβ) plaques, tau tangles, and neuroinflammation. Despite extensive research, effective therapies remain elusive. Exosome/EVs-based therapeutics have emerged as a promising avenue for AD treatment. Neuron-derived exosomes/extracellular vesicles (EVs) (NDEs) and stem cell-derived exosomes/EVs exhibit neuroprotective effects by promoting Aβ degradation, modulating tau pathology, and reducing inflammation. Notably, NDEs carry insulin-degrading enzyme (IDE) and cellular prion proteins (PrPC), aiding Aβ clearance. However, exosomes also present challenges, such as the potential propagation of pathogenic tau and complement-mediated neurotoxicity. Neural and mesenchymal stem cell-derived exosomes further demonstrate therapeutic efficacy by altering amyloid precursor protein processing and activating PI3K/Akt/mTOR signaling to reduce AD pathology. Despite these advancements, clinical translation requires a deeper understanding of exosome/EVs biology, improved isolation techniques, and personalized strategies. Continued research may establish exosomes as a transformative approach in AD therapy.}, } @article {pmid41076002, year = {2025}, author = {Pantiya, P and Chattipakorn, N and Chattipakorn, SC}, title = {Exploring the role of CD147 in cerebrovascular and Alzheimer's pathologies: Insights into mechanisms and interventions.}, journal = {Experimental neurology}, volume = {395}, number = {}, pages = {115498}, doi = {10.1016/j.expneurol.2025.115498}, pmid = {41076002}, issn = {1090-2430}, abstract = {Cluster of Differentiation 147 (CD147), a multifunctional transmembrane glycoprotein, has been identified as a key regulator in the pathophysiology of cerebrovascular diseases and Alzheimer's disease (AD). In cerebrovascular diseases, CD147 contributes to neurological dysfunction by modulating pathways related to extracellular matrix remodeling, angiogenesis, and neuroinflammation. In AD, CD147 exhibits a complex, context-dependent role. Upregulation of CD147 has been implicated in increased amyloid-beta (Aβ) production and impaired energy metabolism, both of which contribute to cognitive decline. Paradoxically, other studies suggest that CD147 may exert neuroprotective effects by promoting Aβ degradation and preserving blood-brain barrier (BBB) integrity. These contradictory findings highlight the dualistic nature of CD147's functions, suggesting it may act as both a pathogenic and protective factor in AD. As evidence regarding its roles continues to grow, a more integrated understanding is needed to determine whether CD147 should be pursued as a viable biomarker or therapeutic target in cerebrovascular and neurodegenerative diseases. Therefore, this review aims to comprehensively synthesize current findings from clinical data, animal models, and in vitro studies to elucidate CD147's functions in cerebrovascular disease and AD. Additionally, we explore emerging therapeutic strategies targeting CD147-related pathways, which may offer promising avenues for neuroprotection.}, } @article {pmid41075815, year = {2025}, author = {Wu, JY and Lin, YM and Hsu, WH and Liu, TH and Tsai, YW and Huang, PY and Chuang, MH and Yu, T and Lai, CC}, title = {Glucagon-Like Peptide-1 Receptor Agonists and Dementia Risk Reduction in Older Adults With Type 2 Diabetes: A Retrospective Cohort Study.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {12}, pages = {105901}, doi = {10.1016/j.jamda.2025.105901}, pmid = {41075815}, issn = {1538-9375}, mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy ; Aged ; Retrospective Studies ; Male ; Female ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Dementia/prevention & control/epidemiology ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Aged, 80 and over ; *Hypoglycemic Agents/therapeutic use ; Propensity Score ; *Risk Reduction Behavior ; }, abstract = {OBJECTIVE: To evaluate the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on dementia risk compared with dipeptidyl peptidase-4 inhibitors (DPP-4is) among older adults with type 2 diabetes (T2D). DESIGN: Retrospective cohort study using an active-comparator, new-user design with propensity score matching. SETTING AND PARTICIPANTS: Data were obtained from the TriNetX Global Collaborative Network, which includes electronic health records from 134 health care organizations worldwide. Participants were adults aged ≥65 years with T2D who initiated GLP-1RA or DPP-4i therapy between January 2017 and November 2024. METHODS: Eligible participants were matched 1:1 on baseline characteristics using propensity score matching (PSM). The primary outcome was incident dementia. Secondary outcomes included prescriptions for dementia-related drugs, Alzheimer's disease, and vascular dementia. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, and subgroup and sensitivity analyses were performed. RESULTS: After PSM, 82,689 patients were included in each treatment group. GLP-1RA use was associated with a lower risk of dementia compared with DPP-4i (HR, 0.58; 95% CI, 0.55-0.61; P < .0001). Stratified analyses revealed consistent risk reductions across age, sex, and GLP-1RA type. In addition, GLP-1RA was also associated with lower risks of dementia-related drug prescriptions (HR, 0.76; 95% CI, 0.70-0.81), Alzheimer's disease (HR, 0.62; 95% CI, 0.56-0.70), and vascular dementia (HR, 0.62; 95% CI, 0.55-0.70). Sensitivity analyses supported the robustness of these findings. CONCLUSIONS AND IMPLICATIONS: GLP-1RA use in older adults with T2D is associated with a significantly lower risk of dementia compared with DPP-4i. These findings suggest the potential neuroprotective benefits of GLP-1RAs and highlight their importance in managing T2D with a view toward reducing dementia risk. Further studies are warranted to explore the underlying mechanisms and validate these observations in randomized controlled trials.}, } @article {pmid41075024, year = {2025}, author = {Abedimanesh, N and Miri, SA and Mohammadi, A and Shahmohammadi, F and Danafar, H and Eskandari, MR and Hejazi, S and Andalib, S and Motlagh, B}, title = {Protective and therapeutic effects of betanin nanoparticles in an alzheimer's rat model: modulation of behavior and expression of AQP4, BDNF, SIRT6, and Seladin-1.}, journal = {Metabolic brain disease}, volume = {40}, number = {7}, pages = {286}, pmid = {41075024}, issn = {1573-7365}, support = {A-12-898-19//The Vice Chancellor for Research of Zanjan University of Medical Sciences, Zanjan, Iran/ ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/genetics/metabolism/biosynthesis ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; *Nanoparticles/administration & dosage ; *Sirtuins/genetics/biosynthesis/metabolism ; *Neuroprotective Agents/administration & dosage/pharmacology/therapeutic use ; Male ; *Aquaporin 4/genetics/biosynthesis/metabolism ; *Betacyanins/administration & dosage/therapeutic use/pharmacology ; *Nerve Tissue Proteins/biosynthesis/genetics/metabolism ; Disease Models, Animal ; Hippocampus/metabolism/drug effects ; Microfilament Proteins/biosynthesis/genetics/metabolism ; Antioxidants ; Behavior, Animal/drug effects ; Maze Learning/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, oxidative stress, and neuroinflammation. Betanin, a natural antioxidant, has shown neuroprotective potential, but its clinical use is limited by poor bioavailability. This study investigates the effects of betanin-loaded nanomicelles, designed to enhance brain delivery, in a scopolamine-induced rat model of AD. Nanomicelles were synthesized and characterized using TEM, DLS, and FT-IR. Rats received either pre- or post-treatment with betanin nanomicelles, free betanin, donepezil, or saline. Cognitive performance was assessed using the Morris Water Maze. Gene expression levels of AQP4, BDNF, SIRT6, and Seladin-1 were measured using real-time PCR, and antioxidant activity was evaluated by assessing glutathione (GSH) and glutathione reductase (GR) in hippocampal tissue. Betanin nanomicelles improved spatial memory, increased BDNF and SIRT6 expression, and reduced AQP4 levels, indicating potential neuroprotection. Seladin-1 expression was notably elevated in the pre-treatment group, suggesting support for neuronal survival. Antioxidant assays showed restoration of GSH and GR activity. These findings suggest that betanin nanomicelles may enhance cognitive function and modulate neuroprotective pathways more effectively than free betanin, supporting their potential as a novel therapeutic strategy for AD.}, } @article {pmid41074172, year = {2025}, author = {Chen, J and Zhang, X and Sun, J and Zhi, Y and Xie, Z and Guan, Y and Zhang, Z and Wu, C}, title = {Photothermal nano-agents: an innovative trident weapon for accurate and effective treatment of alzheimer's disease.}, journal = {Journal of nanobiotechnology}, volume = {23}, number = {1}, pages = {650}, pmid = {41074172}, issn = {1477-3155}, support = {82404876//National Natural Science Foundation of China/ ; 2024M760845//China Postdoctoral Science Foundation/ ; 2025T181064//China Postdoctoral Special Funding Project/ ; 232301420087//The Joint Fund of Science and Technology Development Program of Henan Province/ ; HN2025064//Postdoctoral funding in Henan Province/ ; }, mesh = {*Alzheimer Disease/therapy ; Humans ; *Photothermal Therapy/methods ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Infrared Rays ; *Nanoparticles/chemistry/therapeutic use ; Brain/metabolism ; Phototherapy/methods ; }, abstract = {Alzheimer's disease (AD) is a degenerative neurological illness for which effective therapy alternatives are currently lacking. Photothermal therapy (PTT) employs the localized thermal effects of nano-photothermal agents (NPTAs) under near-infrared (NIR) light for the treatment of diverse conditions. PTT presents numerous benefits for AD therapy, including operational flexibility, non-invasiveness, spatiotemporal modulation, and synergistic multimodal treatment approaches. The primary mechanisms of PTT for AD treatment encompass the following facets: Initially, localized heat impacts may transiently disrupt the blood-brain barrier (BBB), facilitating the trans-BBB transport of therapeutic medicines. Secondly, the photothermal action can efficiently dissociate Aβ aggregates and Tau protein while inhibiting Aβ aggregation, hence diminishing neurotoxicity and reinstating cognitive function. Third, during PTT, NPTAs can achieve imaging of biomarkers such as Aβ and Tau at the site of AD lesions and actively monitor the therapy process. Despite being in its nascent stages for AD treatment and encountering numerous challenges, such as poor biocompatibility, inadequate penetration of deep brain tissue by NIR light, and cumulative toxicity risks, PTT remains a promising therapeutic strategy to overcome the limitations of AD treatment. This study elucidates the pathophysiology of AD, the processes by which NPTAs enter the brain, and the mechanism of NPTAs in AD theranostics, with a particular focus on current developments in NIR-activated NPTAs for AD treatment. It further discusses the challenges in this emerging field and proposes future research directions, thereby facilitating the clinical translation of PTT-based strategies in AD treatment.}, } @article {pmid41073674, year = {2025}, author = {Woo, MS and Therriault, J and Hosseini, SA and Wang, YT and Macedo, AC and Rahmouni, N and Aumont, É and Servaes, S and Tissot, C and Fernandez-Arias, J and Trudel, L and Hall, B and Bezgin, G and Quispialaya-Socualaya, K and Goncalves, M and Chan, T and Stevenson, J and Zheng, Y and Mitchell, S and Hopewell, R and Pola, I and Tan, K and Di Molfetta, G and Lussier, FZ and Massarweh, G and Vitali, P and Soucy, JP and Gauthier, S and Ashton, NJ and Blennow, K and Pascoal, TA and Zetterberg, H and Benedet, AL and Rosa-Neto, P}, title = {Glia inflammation and cell death pathways drive disease progression in preclinical and early AD.}, journal = {EMBO molecular medicine}, volume = {17}, number = {11}, pages = {3064-3079}, pmid = {41073674}, issn = {1757-4684}, support = {MOP-11-51-31; RFN 152985, 159815, 162303//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; MOP-11-51-31 -team 1//Canadian Consortium of Neurodegeneration and Aging/ ; NIRG-12-92090, NIRP-12-259245//Alzheimer's Association (AA)/ ; #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C//Alzheimer's Association (AA)/ ; ZEN-21-848495, SG-23-1038904 QC//Alzheimer's Association (AA)/ ; CFI Project 34874; 33397//Brain Canada Foundation/ ; 2020-VICO-279314//FRQ | Fonds de Recherche du Québec - Santé (FRQS)/ ; IT27627//Mitacs Graduate Fellowship/ ; F225864C02//Max E Binz Fellowship-Medicine/ ; M159875C51//Grad Excellence Award in Neurology and Neurosurgery/ ; 2023_EKMS.03//Else Kröner Fresenius Foundation/ ; WO 2835/1-1//Deutsche Forschungsgemeinschaft (DFG)/ ; S0199/10110/2025//Corona-Stiftung (Corona Foundation)/ ; #2023-00356, #2022-01018 and #2019-02397//Swedish Research Council/ ; #2017-00915 and #2022-00732//Swedish Research Council/ ; 101053962//European Union Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//Alzheimer Drug Discovery Foundation, USA/ ; #22HLT07//European Partnership on Metrology (EPM)/ ; #FO2022-0270//Swedish State/ ; #ALZ2022-0006, #FO2024-0048-TK-130 and FO2024-0048-HK-24//Swedish State/ ; 860197//European Union's Horizon 2020 research and innovation programme Marie Sklodowska-Curie grant/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//UK Dementia Research Institute (UK DRI)/ ; #AF-930351, #AF-939721, #AF-968270, and #AF-994551//Swedish Alzheimer Foundation/ ; #ALFGBG-965240 and #ALFGBG-1006418//ALF agreement/ ; JPND2019-466-236//European Union Joint Programme for Neurodegenerative Disorders/ ; }, mesh = {Humans ; *Neuroglia/pathology/metabolism ; *Alzheimer Disease/pathology ; Disease Progression ; *Cell Death ; *Inflammation/pathology ; Amyloid beta-Peptides/metabolism ; Female ; Male ; Proteomics ; Brain/pathology/diagnostic imaging ; Aged ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; *Neuroinflammatory Diseases/pathology ; }, abstract = {Accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are followed by the activation of glia cells and infiltration of peripheral immune cells that collectively accelerate neurodegeneration in preclinical AD models. Yet, the role of neuroinflammation for neuronal injury and disease progression in preclinical and early symptomatic AD remains elusive. Here, we combined multiplexed immunoassays and SomaScan proteomics of the cerebrospinal fluid (CSF) with MRI and PET brain imaging of people across the AD continuum to identify pathways that are associated with AD progression. Unbiased clustering revealed that glia-mediated inflammation, activation of cell death pathways (CDPs) and synaptic pathologies were among the earliest Aβ-induced changes, and were associated with disease progression in preclinical AD. Mediation analysis revealed that activation of CDPs were decisive drivers of inflammation in early symptomatic AD. The cycle of glia-mediated neuroinflammation and neuronal injury characterizes preclinical AD and has implications for novel treatment approaches.}, } @article {pmid41073581, year = {2025}, author = {Lanskey, JH and Jafarian, A and Hughes, LE and Karadag, M and Kocagoncu, E and Rouse, MA and Adams, NE and Naessens, M and Raymont, V and Woolrich, M and Singh, KD and Henson, RN and Rowe, JB}, title = {Alzheimer's disease and memantine effects on NMDA-receptor blockade: non-invasive in vivo insights from magnetoencephalography.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {41073581}, issn = {1476-5578}, support = {ARUK-PG2017B-19//Alzheimer's Research UK (ARUK)/ ; 220258/WT_/Wellcome Trust/United Kingdom ; SUAG/092 G116788; SUAG/096 G116788//RCUK | MRC | Medical Research Foundation/ ; }, abstract = {To accelerate new treatments for Alzheimer's disease, there is the need for human pathophysiological biomarkers that are sensitive to treatment and disease mechanisms. In this proof-of-concept study, we assess new biophysical models of non-invasive human MEG imaging to test the pharmacological and disease modulation of NMDA-receptor inhibition. Magnetoencephalography was recorded during an auditory mismatch negativity paradigm from (1) neurologically-healthy people on memantine or placebo (n = 19, placebo-controlled crossover design); (2) people with Alzheimer's disease at baseline and 16-months (n = 42, amyloid-biomarker positive, longitudinal observational design). Optimised dynamic causal models inferred voltage-dependent NMDA-receptor blockade using Parametric Empirical Bayes to test group effects. The mismatch negativity amplitude was attenuated when Alzheimer's disease was more severe (lower baseline mini-mental state examination) and after follow-up (versus baseline). Memantine increased NMDA-receptor inhibition, compared to placebo. Alzheimer's disease reduced NMDA-receptor inhibition in proportion to severity and over time. In line with preclinical studies, we confirm in humans that memantine and Alzheimer's disease have opposing effects on NMDA-receptor inhibition. The ability to infer such receptor dynamics and pharmacology from non-invasive physiological recordings has wide applications, including the assessment of other neurological disorders and novel drugs intended for symptomatic or disease-modifying treatments.}, } @article {pmid41073019, year = {2025}, author = {Li, A and Yu, Y and Zhang, Z and Wufuer, R and Wang, D and Zhang, L}, title = {Pd-modified MXene enabled electrochemical sensing platform for ratiometric detection of acetylcholinesterase inhibitors via modulation effect of Prussian blue.}, journal = {Analytica chimica acta}, volume = {1376}, number = {}, pages = {344625}, doi = {10.1016/j.aca.2025.344625}, pmid = {41073019}, issn = {1873-4324}, mesh = {*Ferrocyanides/chemistry ; *Electrochemical Techniques/methods ; *Cholinesterase Inhibitors/analysis ; *Palladium/chemistry ; Acetylcholinesterase/metabolism ; Humans ; Limit of Detection ; *Nanocomposites/chemistry ; *Metal Nanoparticles/chemistry ; Electrodes ; Nitrites ; Transition Elements ; }, abstract = {BACKGROUND: Sensitive detection of acetylcholinesterase (AChE) inhibitors is crucial for pharmaceutical screening, managing neurodegenerative diseases, and drug development. However, their therapeutic use is often limited by toxicity and side effects. Current detection methods for AChE inhibitors suffer from issues like low sensitivity, high cost, and interference from complex biological matrices. Therefore, there is a growing and urgent demand for sensitive, reliable, and cost-effective sensors that enable early diagnosis, accurate monitoring of drug efficacy, and personalized treatment plans in various clinical settings. RESULTS: In this work, a novel ratiometric electrochemical sensor was developed using Pd-modified MXene integrated with Prussian blue (PB) nanocomposites for AChE inhibitor detection. The Pd-modified MXene provides high electrical conductivity and abundant surface sites for nanoparticle immobilization, enhancing electron transfer and signal strength. Pd nanoparticles improve the electrocatalytic activity of the electrode, boosting electron transfer. PB acted as a redox mediator that oxidized thiocholine (TCh), the enzymatic product of AChE-catalyzed hydrolysis of ATCh, and was reoxidized to generate a stable redox potential serving as an internal reference. This enabled dual-signal ratiometric detection, improving accuracy and resistance to background interference. Using berberine as a model inhibitor, the sensor exhibited a linear range of 0.13-41 μmol/L and a detection limit of 10.0 nmol/L. The sensor demonstrated excellent reproducibility, retaining 93.1 % of its initial response after 28 days, and detected berberine in tablet and serum samples with high recovery, showing broad applicability. SIGNIFICANCE: This work highlights the synergistic effects of Pd-MXene and PB, offering a portable, cost-effective strategy for highly sensitive AChE inhibitor detection. The dual-signal ratiometric detection system enhances both sensitivity and accuracy, making it ideal for biomedical and pharmaceutical applications, with significant potential for early diagnosis and monitoring of neurodegenerative diseases.}, } @article {pmid41072129, year = {2026}, author = {Guo, G and Wen, G and Liu, L and Song, R and Cao, P and Yang, J and Zaiane, OR}, title = {BrainOSM: Outlier screening for multi-view functional brain network analysis.}, journal = {Computer methods and programs in biomedicine}, volume = {273}, number = {}, pages = {109092}, doi = {10.1016/j.cmpb.2025.109092}, pmid = {41072129}, issn = {1872-7565}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology ; *Autism Spectrum Disorder/diagnostic imaging/physiopathology ; *Brain/diagnostic imaging/physiopathology ; Magnetic Resonance Imaging ; Algorithms ; Neuroimaging ; }, abstract = {PURPOSE: Identifying biomarkers for mental diseases is vital for understanding their underlying mechanisms, facilitating early diagnosis, and enabling more personalized treatment strategies. In this study, we focus on diagnosing autism spectrum disorder (ASD) and alzheimer's disease (AD) by analyzing functional brain networks (FBNs), which are represented as graphs capturing the functional connectivity patterns of the brain. The primary challenges in modeling FBNs for this disorder stem from two key issues: (i) the heterogeneity among graphs, and (ii) the disease-unrelated information within graphs. METHOD: We introduce a two-stage framework, BrainOSM, which combines outlier screening in datasets with a multi-view graph pooling module for enhanced graph classification. Specifically, the first stage employs progressive uncertainty-based outlier screening to reduce the interference of inter-graph heterogeneity. The second stage integrates multi-graph pooling, multi-view learning, and prior subnetwork regularization to refine graph structures, effectively tackling the challenge of disease-unrelated information within graphs. RESULTS: To validate the effectiveness of our method, we assess its performance on two public datasets: the Autism Brain Imaging Data Exchange (ABIDE) dataset and the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. On the ABIDE dataset, BrainOSM achieved an average accuracy of 70.23% and an AUC of 70.42%, corresponding to improvements of 8.55% and 7.74% over the traditional GCN method. On the ADNI dataset, it reached an average accuracy of 82.29% and an AUC of 83.23%, showing gains of 8.97% and 11.78%, respectively. Our code is publicly available at https://github.com/guoguiliang111/BrainOSM. CONCLUSION: Our extensive experiments confirm the generalizability and the effectiveness of BrainOSM for mental disease classification. Visual analyses further demonstrate that the model effectively identifies subnetworks associated with mental diseases, highlighting its potential for clinical interpretation. Moreover, our findings indicate that outlier screening plays a crucial role in improving classification accuracy when dealing with heterogeneous datasets.}, } @article {pmid41071446, year = {2025}, author = {Li, S and Gao, Y and Zhang, Y and Zhang, J and Zhao, Y and Chang, C and Gao, X and Zhang, J and Yang, G}, title = {Picroside II Alleviates the Progression of Alzheimer's Disease via the NLRP3/Caspase-1/GSDMD Pathway.}, journal = {Neuromolecular medicine}, volume = {27}, number = {1}, pages = {68}, pmid = {41071446}, issn = {1559-1174}, support = {Grant No. 20220997//the Medical Science Research Project of Hebei Provincial Health Commission/ ; Grant No. 21377745D//the Key Research and Development Plan of Hebei Province/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology ; *NLR Family, Pyrin Domain-Containing 3 Protein/physiology/genetics ; Mice ; *Cinnamates/therapeutic use/pharmacology ; *Caspase 1/physiology/genetics ; Signal Transduction/drug effects ; *Iridoid Glucosides/therapeutic use/pharmacology ; Male ; Disease Progression ; Mice, Transgenic ; *Neuroprotective Agents/therapeutic use/pharmacology ; Plaque, Amyloid ; Mice, Inbred C57BL ; Cytokines ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; Inflammasomes ; }, abstract = {Alzheimer's disease (AD), an irreversible, degenerative disorder, affects the central nervous system. However, its accurate pathology remains unclear, and studies on treatment modalities are ongoing. Picroside II (PII) is an active compound in the medicinal herb Rhizoma coptis. It has strong effects, including antioxidation, anti-inflammatory, antiapoptotic, and neuroprotective effects. In this study, we analyzed how PII affects cognitive impairment in mice with AD and its underlying mechanism. PII at doses of 20 or 40 mg/kg was given to APP/PS1 mice through intraperitoneal injection for 2 months. Moreover, we carried out the Morris water maze test to evaluate cognitive function. Immunofluorescence analysis was performed to observe cortical Aβ plaque deposition, neuronal loss, and inflammatory cell expression. An enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of the cortical inflammatory factors tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Western blotting and quantitative polymerase chain reaction (qPCR) were performed to measure NLRP3, ASC, GSDMD, and caspase-1 expression. PII improved cognitive function, reduced Aβ plaque deposition and glial activation, and alleviated cortical neuronal loss in APP/PS1 mice. Furthermore, PII decreased the levels of cortical inflammatory factors (TNF-α, IL-6, and IL-1β). In addition, it suppressed NLRP3, ASC, GSDMD, and caspase-1 expression at the mRNA and protein levels. PII enhances the cognitive function of APP/PS1 mice by reducing inflammation and pyroptosis via the suppression of the NLRP3/caspase-1/GSDMD pathway. Therefore, PII is a candidate anti-AD therapeutic agent.}, } @article {pmid41070709, year = {2025}, author = {Chen, S and Ou, R and Wei, Q and Li, C and Song, W and Zhao, B and Yang, J and Fu, J and Ma, Y and Liu, J and Wang, X and Fang, D and Hu, T and Xiao, L and Zhang, S and Huang, R and Guo, X and Feng, F and Chen, X and Shang, H}, title = {Lecanemab treatment for Alzheimer's Disease of varying severities and associated plasma biomarkers monitoring: A multi-center real-world study in China.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70750}, pmid = {41070709}, issn = {1552-5279}, support = {82271272//National Natural Science Foundation of China/ ; 2023YFQ0098//Science and Technology Bureau Fund of Sichuan Province of China/ ; YCXJ-JZ-2022-007//Beijing E town Coorperation & Development Foundation/ ; 2025-108//the Sichuan Provincial Cadre Healthcare Research Project/ ; No.2022ZD0211605//the Sci-Tech Innovation 2023 "Brain Science and Brain-like Research/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/blood ; Male ; Female ; Biomarkers/blood ; China ; Aged ; Prospective Studies ; tau Proteins/blood ; Middle Aged ; Treatment Outcome ; Amyloid beta-Peptides ; Neuropsychological Tests ; Aged, 80 and over ; Severity of Illness Index ; }, abstract = {INTRODUCTION: We investigated real-world efficacy, safety, and plasma biomarker dynamics of Lecanemab in Chinese patients with Alzheimer's disease (AD). METHODS: A multi-center prospective cohort study enrolled 68 AD patients. Cognitive scales and plasma biomarkers were assessed at baseline (V0), 2.5 months (V1), and 7 months (V2). RESULTS: Alzheimer's Disease Assessment Scale-Cognitive Subscale 14-item version (ADAS-cog14) scores improved significantly at both follow-ups, and plasma p-tau181 consistently declined. Both p-tau181 and p-tau217 correlated with cognition and partially predicted treatment response (area under the curve [AUC] = 0.734 and 0.713). Mixed-effects modeling confirmed their dynamic association with ADAS-cog14 scores. Subgroup analyses indicated benefits across sex and apolipoprotein E4 status, while moderate-to-severe cases showed limited response. Lecanemab was well tolerated, with asymptomatic amyloid-related imaging abnormalities in 17.65% and mild infusion reactions in 5.88%. DISCUSSION: These findings support the short-term efficacy and safety of Lecanemab in early AD and highlight plasma biomarkers as a treatment-responsive biomarker. HIGHLIGHTS: Lecanemab improved cognitive function in Chinese patients with mild cognitive impairment due to Alzheimer's disease (AD-MCI) and mild AD over a short period. Plasma p-tau181 and p-tau217 showed significant correlation with cognitive scores, and their baseline level could partially predict the efficacy of lecanemab. Lecanemab showed a favorable safety profile with low, manageable rates of amyloid-related imaging abnormalities (ARIA) and infusion reactions.}, } @article {pmid41070364, year = {2025}, author = {Igarashi, A and Kimura, N and Ataka, T and Ito, T and Sasaki, K and Kobayashi, C and Tani, M and Sakata, Y and Azuma, M and Chida, A and Takeshima, T and Iwasaki, K and Matsubara, E}, title = {Simulation of Alzheimer's diagnostic flows with blood biomarker test options in Japan.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {4}, pages = {e70157}, pmid = {41070364}, issn = {2352-8737}, abstract = {INTRODUCTION: This study projected the diagnostic testing landscape for lecanemab treatment in Japan under different workflows. METHODS: A dynamic simulation estimated wait times and treatment-eligible patient numbers under four scenarios: current diagnostic workflow, blood biomarker (BBM) tests as triage tools, BBM tests for confirmatory diagnostics, and both combined. Willingness-to-pay (WTP) and intangible costs were assessed via an online survey to estimate testing demand. RESULTS: The maximum mean wait time under the current workflow was projected at 6.4 months, decreasing with BBM integration. The number of treatment-eligible patients increased considerably with BBM-based confirmatory diagnostics. BBM triage testing reduced wait times but temporarily increased treatment-eligible patients. DISCUSSION: Replacing positron emission tomography (PET) or cerebrospinal fluid with BBM-based diagnostics may increase treatment eligibility because of lower costs, driving higher demand for testing. HIGHLIGHTS: A dynamic simulation models Alzheimer's diagnostic workflows in Japan.Blood biomarker (BBM) tests reduce diagnostic wait times for Alzheimer's in Japan.Implementing BBM tests improves access to Alzheimer's diagnostics.Study quantifies demand for diagnostic testing based on costs and accessibility.Testing costs impact the number of treatment-eligible Alzheimer's patients.}, } @article {pmid41070139, year = {2025}, author = {Weber, DM and Stroh, MA and Taylor, SW and Lagier, RJ and Louie, JZ and Clarke, NJ and Vaillancourt, DE and Rayaprolu, S and Duara, R and Racke, MK}, title = {Development and Clinical Validation of Blood-Based Multibiomarker Models for the Evaluation of Brain Amyloid Pathology.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {6}, pages = {e200546}, pmid = {41070139}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Plasma biomarkers provide new tools for evaluating patients with mild cognitive impairment (MCI) for Alzheimer disease (AD) pathology. Such tools are needed for anti-amyloid therapies that require efficient and accurate diagnostic evaluation to identify potential treatment candidates. This study sought to develop and evaluate the clinical performance of a multimarker combination of plasma beta-amyloid 42/40 (Aβ42/40), ptau-217, and APOE genotype to predict amyloid PET positivity in a diverse cohort of patients at a memory clinic and evaluate >4,000 results from "real-world" specimens submitted for high-throughput clinical testing. METHODS: Study participants were from the 1Florida AD Research Center. Demographics, clinical evaluations, and amyloid PET scan data were provided along with plasma specimens for model development in the intended-use cohort (MCI/AD: n = 215). Aβ42/40 and ApoE4 proteotype (reflecting high-risk APOE ɛ4 alleles) were measured by mass spectrometry and ptau-217 by immunoassay. A likelihood score model was determined for each biomarker separately and in combination. Model performance was optimized using 2 cutpoints, 1 for high and 1 for low likelihood of PET positivity, to attain ≥90% specificity and sensitivity. These cutpoints were applied to categorize 4,326 real-world specimens and an expanded cohort stratified by cognitive status (normal cognition [NC], MCI, AD). RESULTS: For the intended-use cohort (46.0% prevalence of PET positivity), a combination of Aβ42/40, ptau-217, and APOE4 allele count provided the best model with a receiver operating characteristic area under the curve of 0.942 and with 2 cutpoints fixed at 91% sensitivity and 91% specificity, yielding a high cutpoint with 88% positive predictive value and 87% accuracy and a low cutpoint with 91% negative predictive value and 85% accuracy. Incorporating the APOE4 allele count also reduced the percentage of patients with indeterminate risk from 15% to 10%. The cutpoints categorized the real-world clinical specimens as having 42% high, 51% low, and 7% indeterminate likelihood of PET positivity and differentiated between NC, MCI, and AD dementia cognitive status in the expanded cohort. DISCUSSION: Combining plasma biomarkers Aβ42/40, ptau-217, and APOE4 allele count is a scalable approach for evaluating patients with MCI for suspected AD pathology.}, } @article {pmid41069980, year = {2025}, author = {Ghaleb, J and Khouzami, KK and Nassif, N and Attieh, P and Ajlani, MFA and Sleiman, JB and Khalouf, A and Harb, F and Azar, S and Kannan, A and Ghadieh, HE}, title = {Unveiling Tirzepatide's Therapeutic Spectrum: A Dual GIP/GLP-1 Agonist Targeting Metabolic, Neurological, and Cardiovascular Health.}, journal = {International journal of endocrinology}, volume = {2025}, number = {}, pages = {2876156}, pmid = {41069980}, issn = {1687-8337}, abstract = {Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as a groundbreaking treatment for Type 2 diabetes mellitus (T2DM) and obesity. Initially developed for glycemic control, recent clinical and preclinical data reveal its broader therapeutic potential across a range of metabolic and systemic conditions. This review explores tirzepatide's mechanisms of action, clinical efficacy, and safety profile, with particular attention to its impact on T2DM, obesity, cardiovascular health, metabolic-associated fatty liver disease (MAFLD), chronic kidney disease (CKD), and neurological disorders such as Alzheimer's and Parkinson's diseases. By addressing multiple pathophysiological pathways, including insulin resistance, inflammation, and oxidative stress, Tirzepatide presents a unique opportunity to redefine treatment paradigms beyond glycemic management. Our review also synthesizes recent evidence on the efficacy and safety of tirzepatide for obesity management specifically in Asian populations; a group frequently underrepresented in global trials. This demographic focus introduces a valuable dimension to the existing body of knowledge. As ongoing trials continue to evaluate its long-term effects, tirzepatide stands at the forefront of a new era in integrated cardiometabolic and neuroprotective therapeutics.}, } @article {pmid41069798, year = {2025}, author = {Stites, SD and Lee, BN and Kuz, C and Adams, M and Harkins, K and Xie, SX and Walke, L and Sankar, P and Hamilton, R}, title = {An online vignette study of diagnostic testing: Racial and ethnic differences in Alzheimer's disease diagnosis confidence and stigma.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {4}, pages = {e70178}, pmid = {41069798}, issn = {2352-8729}, abstract = {INTRODUCTION: Understanding how biomarker testing affects Alzheimer's disease (AD) diagnosis confidence and AD stigma among race and ethnicity groups is essential for supporting early diagnosis and treatment. METHODS: Adults (N = 3548) rated confidence in an AD diagnosis based on four diagnostic evaluations and answered questions about AD stigma based on a clinical vignette. The sample reflects response and completion rates of 53% and 91.3%, respectively. Bivariate and multivariable regression analyses were conducted. RESULTS: Black participants showed the smallest increase (11.86 points) in diagnosis confidence of all race groups when a brain scan was included in the diagnostic evaluation. AD diagnosis confidence changed across diagnostic evaluation categories based on level and type of AD stigma domain and race group. DISCUSSION: Use of brain scans in evaluations can heighten diagnosis confidence in all race groups. Yet, no group had 100% confidence in an AD diagnosis with any evaluation. Recommendations are discussed. HIGHLIGHTS: Confidence in an Alzheimer's disease (AD) diagnosis varies across racial groups.Within racial groups, AD diagnosis confidence differs with diagnostics.Even with cutting-edge biomarker testing, no racial group had 100% confidence in an AD diagnosis.Patient-centered care and systemic changes are needed to widen distribution of diagnostic technologies and improve access to care.}, } @article {pmid41069328, year = {2025}, author = {Tettevi, EJ and Simpong, DL and Maina, M and Adjei, S and Asuming-Brempong, E and Osei-Atweneboana, MY and Ocloo, A}, title = {Antibiotic-Induced Gut Dysbiosis Modulates Alzheimer's Disease-Associated Gene Expression and Protein Aggregation in 3xTg-AD Mice via the Gut-Brain Axis.}, journal = {Brain and behavior}, volume = {15}, number = {10}, pages = {e70946}, pmid = {41069328}, issn = {2162-3279}, support = {//Council for Scientific and Industrial Research - Water Research Institute/ ; }, mesh = {Animals ; *Dysbiosis/chemically induced/metabolism ; *Alzheimer Disease/metabolism/genetics/microbiology ; Mice ; *Gastrointestinal Microbiome/drug effects/physiology ; *Anti-Bacterial Agents/pharmacology/adverse effects ; Female ; *Brain/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *Brain-Gut Axis/drug effects/physiology ; Amyloid beta-Peptides/metabolism ; Gene Expression/drug effects ; tau Proteins/metabolism ; Anxiety/metabolism ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that poses a major global health challenge due to its increasing prevalence and lack of effective treatments. Emerging evidence suggests the gut-brain axis may play a pivotal role in AD pathogenesis. However, causal links between dysbiosis and late-stage AD pathology remain unclear. METHODS: This study evaluated the effects of antibiotic-induced gut dysbiosis in aged 3xTg-AD mice (46-48 weeks). Female mice were randomly assigned to control or treatment groups and administered a broad-spectrum antibiotic cocktail (ampicillin, vancomycin, and neomycin) for 14 days. Behavioral tests (Y-maze, elevated plus maze) were performed to assess cognitive and anxiety-like behaviors. Gut microbiota composition was assessed via 16S rRNA qPCR. Gene expression of Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), and Tumor Necrosis Factor-Alpha (TNF-α) was analyzed via qRT-PCR, and cerebral amyloid-β1-42 and tau protein levels were quantified by ELISA. RESULTS: Antibiotic treatment induced significant dysbiosis, with > 90% reduction in Firmicutes and Bacteroidetes. Dysbiotic mice displayed impaired spatial working memory, heightened anxiety-like behavior, and reduced locomotor activity. Molecular analyses revealed region-specific dysregulation of cholinergic genes: AChE was upregulated in the hippocampus but downregulated in the cortex, while BChE showed the opposite trend. TNF-α was significantly elevated in both regions, indicating neuroinflammation. Dysbiosis also led to increased brain levels of amyloid-β1-42 and tau. CONCLUSION: Gut microbiome disruption exacerbates late-stage AD pathology, driving cognitive deficits, neuroinflammation, and hallmark protein aggregation. These findings support the gut-brain axis as a critical modulator of AD and highlight the microbiome as a potential therapeutic target.}, } @article {pmid41069042, year = {2025}, author = {Kennemer, AA and Gao, Z and Davis, PB and Kaelber, DC and Xu, R}, title = {Timing of neurorehabilitation and subsequent Alzheimer's disease risk in patients with moderate to severe traumatic brain injury: A nationwide retrospective cohort study in the United States.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {3}, pages = {1155-1165}, pmid = {41069042}, issn = {1875-8908}, support = {R01 AG057557/AG/NIA NIH HHS/United States ; R01 AG076649/AG/NIA NIH HHS/United States ; R01 AA029831/AA/NIAAA NIH HHS/United States ; R56 AG062272/AG/NIA NIH HHS/United States ; R01 AG061388/AG/NIA NIH HHS/United States ; RF1 AG076649/AG/NIA NIH HHS/United States ; UM1 TR004528/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/epidemiology/etiology ; Male ; Female ; Retrospective Studies ; Aged ; *Brain Injuries, Traumatic/rehabilitation/epidemiology/complications ; Middle Aged ; United States/epidemiology ; Aged, 80 and over ; *Neurological Rehabilitation/methods ; Cohort Studies ; Cognitive Dysfunction/epidemiology ; Time Factors ; *Time-to-Treatment ; }, abstract = {BackgroundTraumatic brain injury (TBI) is associated with an increased risk of Alzheimer's disease (AD). It is unknown if prompt neuro-rehabilitative treatment following moderate or severe TBI mitigates this risk compared with delayed treatment.ObjectiveTo determine whether immediate neuro-rehabilitative treatment following moderate or severe TBI reduces the risk of AD and related cognitive outcomes compared with delayed treatment.MethodsWe conducted a retrospective cohort using the TriNetX Analytics Platform, which includes health records from over 100 million US patients. Adults aged 50-90 years with moderate or severe TBI were included if they received immediate treatment (within 1 week) or delayed treatment (>1 week). Outcomes were AD risk at 3- and 5-year follow-up, with additional outcomes of mild cognitive impairment (MCI), dementia, and AD-related medication prescriptions. Cox proportional hazards models were applied to propensity score-matched cohorts, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated.ResultsOf 37,081 eligible patients, 17,636 remained after propensity score matching. Immediate treatment was associated with lower AD risk compared with delayed treatment (HR, 0.59; 95% CI, 0.41-0.86 at 3 years; HR, 0.70; 95% CI, 0.52-0.94 at 5 years). Similar risk reductions were observed for MCI, dementia, and AD-related medication use.ConclusionsImmediate treatment following moderate or severe TBI was associated with significantly reduced risk of AD and related cognitive decline. These findings suggest that prompt intervention may mitigate long-term neurodegenerative consequences of TBI.}, } @article {pmid41069006, year = {2025}, author = {Kang, W and Gao, C and Li, X and Wang, X and Zhong, H and Wei, Q and Tang, Y and Huang, P and Shen, R and Chen, L and Zhang, J and Fang, R and Wei, W and Zhang, F and Zhou, G and Yuan, W and Chen, X and Yang, Z and Wu, Y and Xu, W and Zhu, S and Zhang, L and He, N and Fang, W and Zhang, M and Zhang, Y and Ju, H and Bai, Y and Liu, J}, title = {Safety and effectiveness of lecanemab in Chinese patients with early Alzheimer's disease: Evidence from a multidimensional real-world study.}, journal = {Chinese medical journal}, volume = {138}, number = {22}, pages = {2907-2916}, pmid = {41069006}, issn = {2542-5641}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Cognitive Dysfunction/drug therapy ; Aged, 80 and over ; Amyloid beta-Peptides/blood/metabolism ; Biomarkers ; East Asian People ; }, abstract = {INTRODUCTION: Lecanemab has shown promise in treating early Alzheimer's disease (AD), but its safety and efficacy in Chinese populations remain unexplored. This study aimed to evaluate the safety and 6-month clinical outcomes of lecanemab in Chinese patients with mild cognitive impairment (MCI) or mild AD. METHODS: In this single-arm, real-world study, participants with MCI due to AD or mild AD received biweekly intravenous lecanemab (10 mg/kg). The study was conducted at Hainan Branch, Ruijin Hospital Shanghai Jiao Tong University School of Medicine. Patient enrollment and baseline assessments commenced in November 2023. Safety assessments included monitoring for amyloid-related imaging abnormalities (ARIA) and other adverse events. Clinical and biomarker changes from baseline to 6 months were evaluated using cognitive scales (mini-mental state examination [MMSE], montreal cognitive assessment [MoCA], clinical dementia rating-sum of boxes [CDR-SB]), plasma biomarker analysis, and advanced neuroimaging. RESULTS: A total of 64 patients were enrolled in this ongoing real-world study. Safety analysis revealed predominantly mild adverse events, with infusion-related reactions (20.3%, 13/64) being the most common. Of these, 69.2% (9/13) occurred during the initial infusion and 84.6% (11/13) did not recur. ARIA-H (microhemorrhages/superficial siderosis) and ARIA-E (edema/effusion) were observed in 9.4% (6/64) and 3.1% (2/64) of participants, respectively, with only two symptomatic cases (one ARIA-E presenting with headache and one ARIA-H with visual disturbances). After 6 months of treatment, cognitive scores remained stable compared to baseline (MMSE: 22.33 ± 5.58 vs . 21.27 ± 4.30, P = 0.733; MoCA: 16.38 ± 6.67 vs . 15.90 ± 4.78, P = 0.785; CDR-SB: 2.30 ± 1.65 vs . 3.16 ± 1.72, P = 0.357), while significantly increasing plasma amyloid-β 42 (Aβ42) (+21.42%) and Aβ40 (+23.53%) levels compared to baseline. CONCLUSIONS: Lecanemab demonstrated a favorable safety profile in Chinese patients with early AD. Cognitive stability and biomarker changes over 6 months suggest potential efficacy, though high dropout rates and absence of a control group warrant cautious interpretation. These findings provide preliminary real-world evidence for lecanemab's use in China, supporting further investigation in larger controlled studies. REGISTRATION: ClinicalTrials.gov , NCT07034222.}, } @article {pmid41068898, year = {2025}, author = {Climacosa, FMM and Ornos, EDB and Gapaz, NCLL and Guantia, MGR and Cruz, JMC and Manalo, RVM and Yu, ML and Qureshi, AP and Carampel, AC and Asis, JLB and Reyes, JCB and Dacasin, AB and Anlacan, VMM}, title = {The role of genetic polymorphisms on drug response in Alzheimer's disease: a systematic review.}, journal = {BMC medical genomics}, volume = {18}, number = {1}, pages = {154}, pmid = {41068898}, issn = {1755-8794}, abstract = {UNLABELLED: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting over 32 million people globally. The variability in treatment response to AD medications is influenced by genetic factors, sex, comorbidities, and medication history. Pharmacogenomics, the study of how an individual’s genetic makeup influences drug response, offers a promising approach to understanding these differences. This systematic review investigated the role of genetic polymorphisms in affecting treatment outcomes in AD. Following PRISMA guidelines, we systematically searched PubMed, Scopus, Cochrane, and PharmGKB databases for studies on AD, pharmacogenomics, and treatment response. Ten researchers independently screened the articles, with two independent reviewers resolving conflicts. A total of 1126 records were identified, and after removing duplicates and screening, 58 studies met inclusion criteria. APOE emerged as the most consistently studied gene, with ε2 and ε3 alleles generally associated with better responses to acetylcholinesterase inhibitors (AChEIs) and NMDA receptor antagonists, while ε4 carriage predicted poorer outcomes. The CYP2D610 allele, common in East Asian populations, was linked to enhanced donepezil response due to slower drug metabolism. Other genes, including ABCA1, A2M, CHRNA7, CHRFAM7A, and CHAT, showed potential associations with treatment response, particularly with AChEIs, though results varied across populations and study designs. Polymorphisms in inflammatory, metabolic, and vascular genes such as IL6, IDE, and ACE were also associated with cognitive outcomes, but findings were largely exploratory. In conclusion, APOE and CYP2D6 remain the most promising pharmacogenetic markers in AD, particularly for guiding donepezil therapy. However, evidence remains inconsistent due to varying study designs, populations, and clinical metrics. Additional genes show potential but require further validation. Larger, multiethnic studies with standardized treatment protocols and outcomes are needed to establish the clinical utility of pharmacogenomics in AD therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12920-025-02225-1.}, } @article {pmid41068796, year = {2025}, author = {Mu, Z and Chen, Y and Hu, Y and Wang, H and Li, J}, title = {Tailored brain metastatic tumor cells-derived apoptotic bodies ameliorate Alzheimer's disease by promoting microglia efferocytosis and neuroinflammation mitigation.}, journal = {Journal of nanobiotechnology}, volume = {23}, number = {1}, pages = {633}, pmid = {41068796}, issn = {1477-3155}, support = {No. KYCX25_3261//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; No. 81502997//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Microglia/metabolism/drug effects ; Mice ; *Brain Neoplasms/secondary/pathology/metabolism ; Liposomes/chemistry ; Humans ; Cell Line, Tumor ; Manganese Compounds/chemistry/pharmacology ; Sirolimus/pharmacology/chemistry ; Apoptosis ; *Neuroinflammatory Diseases ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Nanocomposites/chemistry ; Brain/pathology ; Male ; Phagocytosis/drug effects ; Efferocytosis ; Oxides ; }, abstract = {Neuroinflammation, characterized by microglial overactivation and oxidative stress, plays a critical role in the initiation and progression of Alzheimer's disease (AD). In this study, we focus on simulating the natural efferocytosis process to reprogram microglial and mitigate chronic neuroinflammation for combinational AD therapy. To achieve this goal, engineered apoptotic bodies derived from brain metastatic tumor cells (LAbs) are successfully developed. Specifically, LAbs-based nanocomposites were fabricated by hybridizing LAbs with liposomes co-loaded with manganese dioxide nanoenzyme (BMn) and autophagy-activating rapamycin (Rapa), referred to as LAbs@Lip@BMn/Rapa. LAbs@Lip@BMn/Rapa exhibits efficient BBB penetration via LAbs-associated brain metastasis propensity of apoptotic bodies. Within the AD microenvironment, oxygen produced through BMn catalyzation in response to H2O2 triggers the structural disintegration of LAbs-camouflaged liposomes and their reassembly into ultra-small vesicles, thereby significantly enhancing intracranial delivery efficiency. In vitro and in vivo experiments confirm that this multi-target strategy effectively normalizes microglia toward anti-inflammatory M2 phenotype, scavenges reactive oxide species (ROS) accumulation, promotes β-amyloid and phosphorylated tau clearance through synergistic intervention, restores the pathological microenvironment in the brain, and enhances cognitive functions in AD model mice. This study demonstrates a novel LAbs-based biomimetic construction strategy that effectively penetrates the BBB and regulates microglia functions, offering a promising approach for AD treatment.}, } @article {pmid41066687, year = {2025}, author = {Reichau, K and Scheiner, M and Poeta, E and Bringmann, G and Monti, B and Decker, M}, title = {Total Syntheses of the Amaryllidaceae Alkaloids Carltonines A-C and the Neuroprotective and Immunomodulatory Evaluation of Carltonine B.}, journal = {Journal of natural products}, volume = {88}, number = {10}, pages = {2460-2471}, doi = {10.1021/acs.jnatprod.5c00841}, pmid = {41066687}, issn = {1520-6025}, mesh = {*Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; *Amaryllidaceae Alkaloids/pharmacology/chemical synthesis/chemistry ; Animals ; Mice ; *Amaryllidaceae/chemistry ; Molecular Structure ; Alzheimer Disease/drug therapy ; Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Butyrylcholinesterase/metabolism ; *Immunomodulating Agents/pharmacology/chemical synthesis ; }, abstract = {The inhibition of butyrylcholinesterase (BChE) represents an emerging approach for the treatment of Alzheimer's disease (AD). In 2020, three previously undescribed Amaryllidaceae alkaloids, carltonines A-C (1-3), were isolated, and their inhibitory activity on BChE was reported. Herein, we describe the first, nonstereoselective total synthesis of carltonine A-C (1-3) and confirmed their inhibitory activity using Ellman's assay, with nanomolar BChE inhibition by carltonine B (2). Further kinetic studies revealed that carltonine B (2) acts as a reversible, competitive inhibitor of BChE. In addition, racemic carltonine B (2) was evaluated in a phenotypic screening using murine hippocampal nerve cells, where it demonstrated protective effects against glutamate-induced oxytosis and ferroptosis at concentrations ranging from 5 to 10 μM and against iodoacetic acid-induced ATP depletion. Finally, in studies using lipopolysaccharide-activated microglial N9 cells, carltonine B (2) exhibited immunomodulatory effects by downregulating pro-inflammatory markers such as NOS2 and IL-1β without affecting anti-inflammatory signaling pathways.}, } @article {pmid41066449, year = {2025}, author = {Hanson, M and Liu, Y and Ozawa, T and Yin, H and Mattke, S}, title = {Potential barriers to timely Alzheimer's disease diagnosis and treatment: Tracer delivery and patient travel to amyloid PET scanners in the United States.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {3}, pages = {1023-1028}, doi = {10.1177/13872877251385118}, pmid = {41066449}, issn = {1875-8908}, mesh = {*Alzheimer Disease/diagnostic imaging/therapy ; Humans ; United States/epidemiology ; *Positron-Emission Tomography/methods ; *Travel ; *Health Services Accessibility ; Aged ; *Amyloid/metabolism ; }, abstract = {Several disease-modifying Alzheimer's disease treatments are available or in clinical trials. Participation in these trials and access to approved treatments often require amyloid positron emission tomography (PET) scans. Amyloid PET requires a radioactive tracer with a short half-life so PET scanner must be near a cyclotron facility that produces and delivers viable tracers. We examined the size and composition of the US population that faces likely geographic obstacles due to travel time constraints. Our estimate that 1.5 million older Americans would drive more than one hour to a qualifying PET site raises concern for differences in access to memory care.}, } @article {pmid41066226, year = {2025}, author = {Weiss, S and Harris, K and Carney, OL and Maza, VI and Wickline, S and Henderson, A and Widjaja, T and Garrett, B and Hill, DL and Liskovec, L and Chen, P and LeRoy, AS}, title = {Initial development of the writing to heal app: A structured writing series for caregivers of spouses living with Alzheimer's disease and related dementias.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {552-570}, pmid = {41066226}, issn = {1875-8908}, support = {K01 AG073824/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Caregivers/psychology ; *Writing ; *Spouses/psychology ; Female ; Male ; *Mobile Applications ; *Alzheimer Disease/psychology/nursing ; Aged ; Middle Aged ; *Dementia/psychology/nursing ; *Stress, Psychological/psychology/therapy ; Focus Groups ; }, abstract = {BackgroundCaregiving for a spouse living with Alzheimer's disease and related dementias (ADRD) is incredibly stressful, which puts caregivers at risk for developing health problems themselves.ObjectiveTo develop an intervention that supports caregivers and helps mitigate the stress associated with caregiving.MethodsIn Part I, we used qualitative methods (e.g., data collected via focus groups with people caring for a spouse living with ADRD) to identify opportunities for targeted treatment and potential barriers to a cognitive-based online expressive writing (EW) intervention tailored to spousal caregivers. In Part IIa, we conducted a second wave of focus groups, throughout which we iteratively adapted a mobile app-based writing intervention for stress and grief among spousal caregivers, while continuously monitoring caregivers' perceived acceptability and feasibility of each proposed feature. Finally, to prepare for app development, we conducted preliminary usability testing (Part IIb), during which caregivers interacted with a prototype of the future app to complete a number of proposed task flows.ResultsCaregivers reported having dynamic needs and requested an intervention that was efficient, mobile, and readily accessible. Further, people caregiving for a spouse living with ADRD have specific motivations for writing (e.g., needing an outlet to release their emotions) as well as unique barriers to the intervention (e.g., lack of time, security concerns).ConclusionsA mobile-based writing intervention catering to the specific needs of these individuals may be a helpful coping resource for caregivers.}, } @article {pmid41066175, year = {2025}, author = {Toyoda, H and Kim, D and Koh, BG and Sano, T and Kanematsu, T and Oh, SB and Kang, Y}, title = {Chronic stress impairs autoinhibition in neurons of the locus coeruleus to increase asparagine endopeptidase activity.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {41066175}, issn = {2050-084X}, support = {20K06926//Japan Society for the Promotion of Science/ ; 23K06346//Japan Society for the Promotion of Science/ ; 26290006//Japan Society for the Promotion of Science/ ; 21K06441//Japan Society for the Promotion of Science/ ; Brain Pool Program//Ministry of Science and ICT/ ; Naito Grant//Naito Foundation/ ; RS-2023-00264409//Ministry of Science and ICT/ ; RS-2023-00302281//Ministry of Science and ICT/ ; }, mesh = {Animals ; *Locus Coeruleus ; *Neurons/physiology/enzymology/metabolism ; Mice ; *Cysteine Endopeptidases/metabolism ; Male ; Monoamine Oxidase/metabolism ; Norepinephrine/metabolism ; *Stress, Physiological ; Mice, Inbred C57BL ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism ; }, abstract = {Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer's disease (AD). Increases in cytosolic noradrenaline (NA) concentration and monoamine oxidase A (MAO-A) activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced exclusively in cytoplasmic vesicles from dopamine by dopamine-β-hydroxylase. Since reuptake of autocrine-released NA following spike activity is the major source of NA accumulation, we investigated whether and how chronic stress can increase the spike activity accompanied by NA autocrine. Overexcitation of LC neurons is normally prevented by the autoinhibition mediated by activation of α2A-adrenergic receptor (AR)-coupled inwardly rectifying potassium-current (GIRK-I) with autocrine-released NA. Patch-clamp study revealed that NA-induced GIRK-I in LC neurons was decreased in chronic restraint stress (RS) mice, while a similar decrease was gradually caused by repeated excitation. Chronic RS caused internalization of α2A-ARs expressed in cell membrane in LC neurons and decreased protein/mRNA levels of α2A-ARs/GIRKs in membrane fraction. Subsequently, chronic RS increased the protein levels of MAO-A, DOPEGAL-induced asparagine endopeptidase (AEP), and tau N368. These results suggest that chronic RS-induced overexcitation due to the internalization of α2A-ARs/GIRK is accompanied by [Ca[2+]]i increases, subsequently increasing Ca[2+]-dependent MAO-A activity and NA autocrine. Thus, it is likely that internalization of α2A-AR increased cytosolic NA, as reflected in AEP increases, by facilitating reuptake of autocrine-released NA. The suppression of α2A-AR internalization may have a translational potential for anxiety/AD treatment.}, } @article {pmid41066060, year = {2025}, author = {Jeevanandam, J and Tsenov, G and Danquah, MK and Ruiz-Molena, D and Boussios, S and Ovsepian, SV}, title = {Smart Nanomedicines for Neurodegenerative Diseases: Empowering New Therapies with Molecular Imaging and Artificial Intelligence.}, journal = {Molecular diagnosis & therapy}, volume = {}, number = {}, pages = {}, pmid = {41066060}, issn = {1179-2000}, abstract = {Neurodegenerative diseases (NDDs) remain among the most challenging disorders to treat, owing to their multifactorial pathology, limited drug delivery across the blood-brain barrier, and lack of effective disease-modifying therapies. Smart nanomedicines are emerging as powerful tools to overcome these challenges by enabling targeted delivery, controlled release, and enhanced bioavailability of therapeutics. In parallel, advances in molecular imaging, combined with machine learning (ML) and artificial intelligence (AI), are transforming the design, validation, and optimization of nanomedicines. This article integrates the rapidly evolving fields of nanomedicine and AI/ML-driven imaging to evaluate their synergistic potential toward NDD therapy. The capabilities of AI-aided imaging for mapping nanomedicine biodistribution, predicting therapeutic outcomes, guiding nanoparticle design, and ensuring quality control at preclinical and clinical stages in NDDs are discussed. This synergistic approach opens new avenues for precision medicine, enabling personalized and adaptive treatment strategies for Alzheimer's, Parkinson's, and other NDDs by linking smart nanocarriers with intelligent imaging analytics. Hence, this article presents a roadmap for translating AI-guided nanomedicine-integrated imaging platforms into clinically viable solutions, marking a paradigm shift in the diagnosis and treatment of NDDs.}, } @article {pmid41064738, year = {2025}, author = {Niu, L and Li, Y and Wu, H and Zhao, L and Zhang, J and Lu, F and Zhao, G and Jia, F and Zhu, J and Liu, M}, title = {Causal effect of serum lipopolysaccharide activity levels and inflammatory proteins on Alzheimer's disease: A Mendelian randomization study combined with meta-analysis in a large-scale cohort.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251385589}, pmid = {41064738}, issn = {2542-4823}, abstract = {BACKGROUND: Neuroinflammation represents a central pathological mechanism in Alzheimer's disease (AD). Lipopolysaccharide (LPS) is a potent inducer of neuroinflammation and demonstrates elevated circulating levels in AD patients. OBJECTIVE: This study aims to investigate the genetic association between serum LPS activity level, inflammatory proteins and AD. METHODS: A two-sample mendelian randomization (MR) analysis was performed to explore the causal effect of serum LPS activity level and 91 inflammatory proteins on AD, including 1, 260, 136 sporadic AD and 2, 838, 825 familial AD patients, respectively. Meta-analysis was conducted on multiple datasets to determine statistically significant results that was initially observed in one dataset. RESULTS: Serum LPS activity level is a risk factor for early onset sporadic AD with OR = 1.392, 95% CI: 1.038-1.869. In most other sporadic AD datasets, LPS shows a trend of increasing the risk of AD onset. After meta-analysis in 10 independent datasets, no association between LPS and sporadic AD was observed. In most familial AD datasets, LPS level demonstrated a trend of decreasing AD risk in MR analysis, however, meta-analysis of the combined 8 datasets showed no statistically significant difference. Two inflammatory proteins, AXIN1 and IL-1 alpha, were identified as significant risk factors for sporadic AD. CONCLUSIONS: This study suggested that serum LPS activity level may present a risk effect in early onset sporadic AD. Two inflammatory proteins AXIN1 and IL-1 alpha were associated with the risk of sporadic AD. These findings provide a new perspective for the early diagnosis and treatment of sporadic and familial AD.}, } @article {pmid41064556, year = {2025}, author = {Ota, M and Nakayama, K and Kitabatake, A and Takahashi, T and Nemoto, K and Arai, T}, title = {Spatial Patterns of Cerebral Blood Flow in Alzheimer's Disease Identified by the Subtype and Stage Inference Algorithm.}, journal = {Dementia and geriatric cognitive disorders extra}, volume = {15}, number = {1}, pages = {108-118}, pmid = {41064556}, issn = {1664-5464}, abstract = {INTRODUCTION: Much research has focused on the deposition of amyloid and tau proteins in the Alzheimer's disease (AD) brain, but many amyloid and tau models assumed a single spatial progression of amyloid and tau accumulation. We estimated the changing patterns of an indirect biomarker, i.e., the cerebral blood flow (CBF), in AD, and we discuss the pathological process of AD. METHODS: The participants were 341 patients who visited our hospital's outpatient department for memory loss (146 males, 195 females): 115 diagnosed with AD, 176 diagnosed with mild cognitive impairment, and 50 diagnosed with subjective cognitive decline. For the evaluation of disease-related changes in their CBF, the patients underwent 99mTc-ethyl cysteinate dimer single-photon emission computed tomography scans. We differentiated the subtypes of CBF in AD by using a machine-learning algorithm called the "Subtype and Stage Inference (SuStaIn)"algorithm. RESULTS: When we divided the data into two groups, the SuStaIn algorithm identified two different CBF subtypes: the typical AD pattern and a cortical pattern with hippocampal sparing. CONCLUSION: We observed two subtypes of the pattern of change in the CBF of individuals with AD, and these subtypes were highly similar to previous findings derived from SuStaIn algorithm applied differing neuroimaging modalities. Such subtyping derived from CBF imaging might have clinical utility in the treatment of AD.}, } @article {pmid41064234, year = {2025}, author = {Rodríguez-Romero, A and Belachew, S and Bartholomé, E and Mazzà, C and Reyes, Ó and Luque, C and Pless, S and Bernasconi, C}, title = {Biomarkers of Alzheimer's disease modification using adaptive cognitive assessments to improve responsiveness-a simulation study.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1653261}, pmid = {41064234}, issn = {1662-4548}, abstract = {INTRODUCTION: Clinical studies assessing cognition in Alzheimer's and other neurodegenerative diseases require endpoints that are sensitive to treatment response across a broad range of cognitive abilities. However, responsiveness of conventional cognitive assessments typically varies with the performance level, especially due to non-linearities such as floor or ceiling effects. Here, we evaluate 6 newly developed smartphone-based and gamified Adaptive Cognitive Assessments (ACAs) entailing a system of dynamic difficulty adaptation to individual performance, which is expected to improve adherence but also measurement properties. Deployment of such ACAs to maximize their discriminative ability in comparative studies requires exploration of many free parameters and complex dynamics. METHODS: In simulations of cohorts of patients with cognitive impairment, we compared two ACAs paradigms: after 14 daily tests allowing performance-based difficulty adaptation, the difficulty level was either (1) fixed or (2) kept adaptive for a period of 4 years with weekly testing. Sensitivity to between-group effects was assessed in cohorts characterized by cognitive decline observed in neurodegenerative diseases. RESULTS: The discriminative ability of the two paradigms depends on features of the study design and subjects. At study end, the adaptive difficulty paradigm clearly outperformed the fixed-difficulty paradigm in terms of responsiveness for cognitive decline rates >2.5% per year. DISCUSSION: ACA can increase biomarker responsiveness to treatment effects over fixed difficulty. ACA deployment should be guided by study and assessment features, including duration, expected cognitive decline rates and effect size. In the high-dimensional parameter space of ACA instruments, study simulations are indispensable to identify suitable deployment strategies.}, } @article {pmid41063670, year = {2025}, author = {Seyyedabadi, B and Babataheri, S and Naseri, M and Laher, I and Soraya, H}, title = {Ivermectin and non-parasitic disorders: An update.}, journal = {Current opinion in pharmacology}, volume = {85}, number = {}, pages = {102574}, doi = {10.1016/j.coph.2025.102574}, pmid = {41063670}, issn = {1471-4973}, mesh = {Humans ; *Ivermectin/therapeutic use/pharmacology/adverse effects ; Animals ; *Antiparasitic Agents/therapeutic use/pharmacology/adverse effects ; Neuroprotective Agents/therapeutic use/pharmacology/adverse effects ; }, abstract = {Ivermectin, a broad-spectrum anti-parasitic agent, demonstrates potential therapeutic benefits in treating non-parasitic ailments, particularly in neurological, respiratory, inflammatory, dermal, cardiovascular, and neoplastic disorders. For instance, ivermectin targets both DNA and RNA viruses, inhibits angiogenesis, and has anti-cancer properties, which result from inhibiting RNA helicase, inducing mitochondrial dysfunction, apoptosis, necrosis, and autophagy, as well as promoting oxidative stress. While the precise neurological impacts of ivermectin are not fully understood, it also has anticonvulsant properties in rats. Recent discoveries have revealed the neuroprotective effects of ivermectin in cerebral ischemia/reperfusion and Alzheimer's disease. Although there is limited research on the influence of ivermectin on the cardiovascular system, some studies have reported cardioprotective effects of ivermectin. However, a recent study suggested that ivermectin pre-treatment may have detrimental effects on myocardial ischemia. Consequently, numerous questions regarding the therapeutic/adverse effects of ivermectin remain unanswered and necessitate further investigation. We review the effects of ivermectin in non-parasitic diseases with an emphasis on current research in this field.}, } @article {pmid41062840, year = {2025}, author = {Youssef, B and Ibrahim, EA and Moselhy, SS and ElShebiney, S and Elabd, WK}, title = {Phytochemical based on nanoparticles for neurodegenerative alzheimer disease management: Update review.}, journal = {Discover nano}, volume = {20}, number = {1}, pages = {176}, pmid = {41062840}, issn = {2731-9229}, abstract = {Alzheimer's disease (AD) is one of the most common chronic neurodegenerative diseases and dementia, with about 46 million cases worldwide and going to become tripled by 2050. It is characterized by formation and aggregation of amyloid-β plaques, tau tangles, and inflammatory mediators. The treatment protocol poses challenging obstacles particularly, effectiveness drug delivery to the brain. However, the available therapies with low potency and blood-brain barrier (BBB) are most challenges for developing novel treatments. New delivery systems that interact with biological systems at the molecular level, such as nanotechnology can overcome these problems and open new therapeutic avenues. Nanoparticles showed different applications in medicine due to its bioavailability, transport and low toxicity. This review explored the therapeutic potential of natural phytochemical nanomedicine that important in AD treatment through improving drug delivery system across BBB, increasing bioavailability and minimizing neurotoxicity.}, } @article {pmid41061790, year = {2025}, author = {Li, S and Zheng, F and Liu, S and Wu, R and Zhang, L and He, X and Li, M and Li, L}, title = {Physical exercise protects neurons from energy deficit and improves cognitive function by upregulating astrocytic Slc2a1 in Alzheimer's disease.}, journal = {Experimental neurology}, volume = {395}, number = {}, pages = {115493}, doi = {10.1016/j.expneurol.2025.115493}, pmid = {41061790}, issn = {1090-2430}, abstract = {Alzheimer's disease (AD) has been associated with impaired energy metabolism and neuronal mitochondrial dysfunction, which contribute to the development of anxiety-like behaviors and spatial memory deficits. Astrocytes are recognized as a critical source of metabolites for neurons, supporting mitochondrial respiration. Although physical exercise (PE) has shown therapeutic potential in AD models, the molecular mechanisms linking PE to metabolic reprogramming remain elusive. In a 5xFAD mouse model, this study shows that PE increased the expression of solute carrier family 2 member 1 (Slc2a1) and decreased the expression of GFAP in astrocytes. We demonstrate that both PE and the overexpression of astrocytic Slc2a1 alleviated neuronal mitochondria damage and neuron death, shifts astrocytes to an anti-inflammatory phenotype and reduced Aβ accumulation. Conversely, knockdown of Slc2a1 abrogated the protective effects of PE. In vitro, we established an AD glucose-deficiency cell model by incubating cells with 5.5 mM glucose and oligomeric Aβ (oAβ). Our results showed that Slc2a1 overexpression increased lactate secretion in the supernatant of C8-D1A astrocytes. Furthermore, both Slc2a1 overexpression in C8-D1A cells and lactate treatment rescued oAβ-induced mitochondrial oxidative stress and membrane potential alterations in energy-deficient HT22 neurons, thereby enhancing lactate secretion from astrocytes and promoting the lactate shuttle to neuron for energy supply. Collectively, our findings indicate that PE ameliorates anxiety-like behavior and spatial memory deficits, mitigates mitochondrial damage in neurons, and reduces Aβ accumulation in 5xFAD mice through the upregulation of Slc2a1 in astrocytes. Our findings identify Slc2a1 as a pivotal mediator of metabolic support induced by PE and highlights astrocyte-neuron lactate shuttling as a promising therapeutic target for AD.}, } @article {pmid41061335, year = {2025}, author = {Shahsavari, F and Eidi, A and Sotoodehnejadnematalahi, F}, title = {Neuroprotective effects of sodium molybdate in a beta-amyloid-induced rat model of Alzheimer's disease: An In Vivo preclinical study.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {92}, number = {}, pages = {127774}, doi = {10.1016/j.jtemb.2025.127774}, pmid = {41061335}, issn = {1878-3252}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism ; *Molybdenum/pharmacology/therapeutic use/administration & dosage ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Rats, Wistar ; Disease Models, Animal ; Rats ; *Amyloid beta-Peptides/toxicity ; Hippocampus/drug effects/metabolism/pathology ; }, abstract = {BACKGROUND: Molybdenum, as a trace element, exhibits various pharmacological properties, including antioxidant, anti-inflammatory, and free radical-scavenging activities. This study aimed to evaluate the effects of sodium molybdate on neurotoxicity induced by beta-amyloid (Aβ) in adult male Wistar rats. METHODS: Forty-eight rats were randomly divided into eight groups: Healthy control group, Experimental groups receiving sodium molybdate (0.1, 0.2, and 0.4 mg/kg intragastrically daily), Alzheimer's control group (intrahippocampal injection of Aβ bilaterally), and Alzheimer's experimental groups receiving sodium molybdate (0.1, 0.2, and 0.4 mg/kg intragastrically daily) for 30 consecutive days following Aβ injection. Histopathological changes in the hippocampus were assessed using Hematoxylin and Eosin staining, and amyloid plaques were evaluated via Congo Red staining. The expression levels of GFAP and S100 proteins were investigated by immunohistochemistry, and changes in the expression level of Bax/Bcl2 ratio were evaluated by Real-time PCR in the hippocampus. FINDINGS: Our results revealed a dose-dependent attenuation of neuronal degeneration, and reduced amyloid plaque formation in the Alzheimer's experimental groups following sodium molybdate administration. Treatment with sodium molybdate at doses of 0.2 and 0.4 mg/kg significantly reduced the levels of both S100 and GFAP proteins (P < 0.05 and P < 0.001 respectively) compared to the Alzheimer's control group. Furthermore, sodium molybdate administration at a dose of 0.1 mg/kg significantly reduced the Bax/Bcl2 expression ratio (P < 0.05), with greater reductions observed at 0.2 and 0.4 mg/kg doses (P < 0.01). CONCLUSION: The results of this study suggest that sodium molybdate may exert protective effects against neurological disorders caused by Aβ in a rat model of Alzheimer's disease.}, } @article {pmid41061323, year = {2025}, author = {Zhang, J and Zhang, L and Sun, X and Yang, Y and Kong, L and Lu, C and Lv, G and Wang, T and Wang, H and Fu, F}, title = {Corrigendum to "Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation" [The Journal of Pharmacology and Experimental Therapeutics 359 (2016) 374-382].}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {392}, number = {10}, pages = {103699}, doi = {10.1016/j.jpet.2025.103699}, pmid = {41061323}, issn = {1521-0103}, } @article {pmid41058018, year = {2025}, author = {Pascual-Lucas, M and Lacosta, AM and Montañés, M and Canudas, J and Loscos, J and Monleón, I and Allué, JA and Sarasa, L and Fandos, N and Romero, J and Sarasa, M and Torres, M and Whyms, D and Terencio, J and Piñol-Ripoll, G and Boada, M}, title = {Safety, tolerability, immunogenicity, and efficacy of ABvac40 active immunotherapy against Aβ40 in patients with mild cognitive impairment or very mild Alzheimer's disease: A randomized, double-blind, placebo-controlled phase 2 study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70776}, pmid = {41058018}, issn = {1552-5279}, support = {//Araclon Biotech-Grifols/ ; }, mesh = {Humans ; Double-Blind Method ; *Alzheimer Disease/therapy/immunology/drug therapy ; Male ; *Amyloid beta-Peptides/immunology ; Female ; Aged ; *Cognitive Dysfunction/therapy/immunology/drug therapy ; *Immunotherapy, Active/methods ; Treatment Outcome ; *Peptide Fragments/immunology ; *Alzheimer Vaccines/therapeutic use/adverse effects ; Middle Aged ; Aged, 80 and over ; }, abstract = {INTRODUCTION: ABvac40 is an investigational active immunotherapy (vaccine) targeting Aβ40. This study assessed the safety and immunogenicity of ABvac40 in patients with amnestic mild cognitive impairment or very mild Alzheimer's disease. METHODS: AB1601 was a multicenter, randomized, double-blind, placebo-controlled phase 2 study. Patients (n = 124) received five monthly injections plus a 10-month booster of ABvac40 or placebo, with 18-24 months of follow-up. Primary endpoints included safety, tolerability, and immunogenicity. Secondary endpoints assessed immune response, neuropsychological changes, and disease biomarkers. RESULTS: Treatment-emergent adverse events (TEAEs) and serious TEAEs were comparable between ABvac40 (90.6% and 26.6%) and placebo (93.3% and 26.7%). Amyloid-related imaging abnormalities-hemorrhage (ARIA-H) were similar (12.5% ABvac40; 15.0% placebo), with no ARIA-edema (ARIA-E) or meningoencephalomyelitis. ABvac40 induced a specific, sustained immune response in plasma, with detectable antibodies in CSF. DISCUSSION: These findings support further investigation of ABvac40 as a potential disease-modifying therapy. NCT03461276 (ClinicalTrials.gov) HIGHLIGHTS: ABvac40 was safe and well-tolerated in early-stage Alzheimer's disease patients. No amyloid-related imaging abnormalities-edema (ARIA-E) or encephalitis observed; ARIA-hemorrhage (ARIA-H) rates were similar across groups. Specific, sustained immune response to ABvac40 in plasma, with cerebrospinal fluid (CSF) antibody penetration. Cognitive scales and magnetic resonance imaging (MRI) volumetric data favored ABvac40 over placebo. Results support further development of ABvac40 as a disease-modifying therapy.}, } @article {pmid41057918, year = {2025}, author = {Erichsen, JM and Register, TC and Sutphen, C and Ma, D and Gaussoin, SA and Rudolph, M and Rundle, M and Bateman, JT and Lockhart, SN and Sai, KKS and Whitlow, C and Craft, S}, title = {A phase 2A/B randomized trial of metabolic modulators intranasal insulin and empagliflozin for MCI and early AD.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70704}, pmid = {41057918}, issn = {1552-5279}, support = {//Aptar Pharma/ ; //National Institute of Aging/ ; T32 AG033534/AG/NIA NIH HHS/United States ; PTC-22-975243/ALZ/Alzheimer's Association/United States ; //Kulynych Cente for Memory and and Cognition/ ; //Kulynych Center for Memory and Cognition/ ; P30 AG072947/AG/NIA NIH HHS/United States ; T32 AG0333534/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Glucosides/administration & dosage/therapeutic use ; *Cognitive Dysfunction/drug therapy ; *Benzhydryl Compounds/administration & dosage/therapeutic use ; Male ; Administration, Intranasal ; Female ; *Alzheimer Disease/drug therapy ; *Insulin/administration & dosage/therapeutic use ; Aged ; Double-Blind Method ; *Sodium-Glucose Transporter 2 Inhibitors/administration & dosage/therapeutic use ; Biomarkers/cerebrospinal fluid ; Treatment Outcome ; }, abstract = {INTRODUCTION: Agents targeting metabolic/vascular disorders are promising candidates to treat Alzheimer's disease (AD) and enhance safety and efficacy of other therapies. METHODS: In a 2×2 factorial double-blinded randomized trial, participants with mild cognitive impairment (MCI), early AD, or who were amyloid positive received intranasal insulin (INI; 40 IU q.i.d.), the sodium-glucose cotransporter-2 inhibitor empagliflozin (10 mg q.d. oral tablet), both, or placebo for 4 weeks. The primary outcome was treatment-related adverse events (TRAEs). Secondary outcomes included the modified Preclinical Alzheimer's Cognitive Composite-5 (mPACC5), fluid biomarkers, cerebral blood flow (CBF), and fractional anisotropy (FA). RESULTS: TRAEs were mild and similar for all groups. INI increased mPACC5, modulated FA and CBF, and reduced plasma glial fibrillary acidic protein. Empagliflozin lowered cerebrospinal fluid tau and modulated CBF. Both agents moderated immune/inflammatory/neurovascular markers. DISCUSSION: INI and empagliflozin treatment was safe with promising effects on cognition, fluid, and imaging biomarkers. A longer and larger trial is needed to confirm these results. CLINICAL TRIAL REGISTRATION: NCT05081219 HIGHLIGHTS: Agents targeting metabolic or vascular disorders are promising candidates to prevent or treat Alzheimer's disease (AD). Intranasal insulin and empagliflozin were safe alone or in combination for mild cognitive impairment/AD. Insulin improved cognition and markers of inflammation and immune function. Empagliflozin reduced markers of vascular injury and neurodegeneration. A longer, larger trial is needed to validate these results.}, } @article {pmid41056473, year = {2025}, author = {Crump, C and Wei, J and Vickrey, BG and Edwards, AC and Schulz, PE and Sieh, W and Sundquist, J and Sundquist, K}, title = {Risk of major depression in partners of people with Alzheimer's disease: a national cohort study.}, journal = {Age and ageing}, volume = {54}, number = {10}, pages = {}, pmid = {41056473}, issn = {1468-2834}, support = {R03 AG083596/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/psychology/epidemiology/diagnosis ; Female ; *Depressive Disorder, Major/epidemiology/psychology/diagnosis ; Male ; Aged ; Sweden/epidemiology ; Risk Factors ; Incidence ; Aged, 80 and over ; Middle Aged ; Cohort Studies ; Risk Assessment ; *Spouses/psychology ; *Caregivers/psychology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) may cause significant psychosocial distress not only in the patient but also their partner. However, long-term risks of major depression in partners of AD patients are largely unknown. METHODS: A national cohort study was conducted of all 145 289 partners of people diagnosed with all-cause dementia, including 57 113 partners of people diagnosed with AD, in Sweden during 1998-2017, and 1 300 561 population-based controls. Cox regression was used to compute hazard ratios (HRs) for subsequent risk of major depression identified from nationwide outpatient and inpatient diagnoses through 2018, adjusting for sociodemographic factors and prior mental disorders. RESULTS: The 10-year cumulative incidence of major depression was 5.4% in partners of people with AD, 5.6% in partners of people with all-cause dementia, and 3.9% in controls. The adjusted relative rate of major depression was increased ~1.5-fold in partners of people with AD (HR, 1.53; 95% CI, 1.35-1.72) or all-cause dementia (1.45; 1.34-1.57), compared with controls. These risks were elevated among both women (AD: HR, 1.41; 95% CI, 1.22-1.64; all-cause dementia: 1.36; 1.24-1.50) and men (AD: 1.81; 1.46-2.25; all-cause dementia: 1.73; 1.48-2.01). Risks remained significantly elevated ≥3 years later in both women (1.3- to 1.5-fold) and men (1.5-fold). Risks were generally highest in partners aged ≥85 years. CONCLUSIONS: In this large national cohort, partners of people diagnosed with AD or all-cause dementia had ~1.5-fold risks of major depression, which remained elevated several years later. Partners of people with dementia need psychosocial support and long-term follow-up for timely detection and treatment of depression.}, } @article {pmid41056389, year = {2025}, author = {Sharma, M and Deshmukh, S and Thakre, T and Waskar, R and Pardhekar, A}, title = {Ayurvedic Management of Alzheimer's Disease: A Clinical Case Study.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {41056389}, issn = {1078-6791}, abstract = {ABSTRACT: Alzheimer's disease is a progressive neurodegenerative disorder that primarily affects memory, cognition, and behavior, often leading to severe functional decline. A 55-year-old male patient came with complaints of confusion in daily activities, forgetting names, misplacing objects, frequent episodes of crying, and loss of communication skills for the past 1 year. He was clinically diagnosed with Alzheimer's Disease. The patient was treated with an Ayurvedic treatment protocol, involving internal administration of Brahmi ghrit, Saraswatarishta with gold, Ashwagandha powder, and Rasona Ksheerpaka, along with Panchakarma therapies including Nasya with Panchendriya taila, Shirobasti, and Abhyanga with Balashwagandha taila. After the treatment, the patient showed marked improvements in memory retention, orientation, and mood stability. This case showed that Ayurvedic interventions aid in slowing cognitive decline and improving daily functioning in Alzheimer's patients, highlighting the need for integrative and individualized treatment approaches in neurodegenerative disorders. KEYWORDS: neurodegeneration, Alzheimer's disease, Dementia, Ayurvedic medicines, Brahmi ghrit, case report.}, } @article {pmid41055317, year = {2025}, author = {Li, J and Sun, W and Wang, X and Ding, F and Li, L and Lin, X and Zhao, Y}, title = {Astaxanthin Suppresses Amyloid-Beta-Induced Toxicity in AD Transgenic Caenorhabditis elegans via Promoting Skn-1-Dependent Proteasomal Activity.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {20}, pages = {3954-3963}, doi = {10.1021/acschemneuro.5c00130}, pmid = {41055317}, issn = {1948-7193}, mesh = {Animals ; Caenorhabditis elegans ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Amyloid beta-Peptides/toxicity/metabolism ; Xanthophylls/pharmacology ; Animals, Genetically Modified ; *Proteasome Endopeptidase Complex/metabolism/drug effects ; *Transcription Factors/metabolism/genetics ; *Alzheimer Disease/metabolism/drug therapy ; *DNA-Binding Proteins/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; }, abstract = {Astaxanthin is a ketocarotenoid that exhibits a variety of bioactivities, including neuroprotection, but the detailed mechanisms by which astaxanthin exerts neuroprotection remain unclear. In the present study, the effects of astaxanthin on amyloid-beta (Abeta)-induced toxicity were investigated in a Caenorhabditis elegans (C. elegans) model of Alzheimer's disease (AD). It is demonstrated that astaxanthin treatment significantly alleviated the Abeta-induced paralytic phenotype in AD C. elegans while reducing the production of reactive oxygen species and restoring the level of glutathione. Further analyses revealed that astaxanthin treatment resulted in a decrease in Abeta accumulation in AD C. elegans. Moreover, astaxanthin restored the proteasomal activity in AD C. elegans by elevating the expression of genes encoding the central subunits of the 20S proteasome. Therefore, astaxanthin might reduce Abeta accumulation via promoting proteasomal function. In addition, astaxanthin treatment increased the expression of skinhead-1 (skn-1), while knockdown of skn-1 expression by RNA interference diminished the inhibition of astaxanthin on Abeta-induced toxicity in AD C. elegans. The elevation of the expression of proteasome subunit genes and the enhancement of proteasomal activity by astaxanthin were also dependent on SKN-1. Overall, these findings indicated that astaxanthin exerted its protection against Abeta-induced toxicity in AD C. elegans via maintaining redox balance and promoting SKN-1-mediated proteasomal activity.}, } @article {pmid41054805, year = {2025}, author = {Teipel, S and Singh, D and Dubbelman, MA and Pan, G and Tang, Y and König, A}, title = {Early detection of Alzheimer's disease: From multiplex assays and imaging to point of care devices and AI-based functional monitoring.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1_suppl}, pages = {S5-S7}, doi = {10.1177/13872877251383339}, pmid = {41054805}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging ; Early Diagnosis ; *Artificial Intelligence ; *Point-of-Care Systems ; Biomarkers ; Neuroimaging/methods ; }, abstract = {The advent of disease-modifying treatments and risk-reduction strategies in the clinic have increased the demand for biomarkers for early disease detection, prediction of clinical course of disease, individual risk prediction and monitoring of treatment effects. The studies in this special issue span ultra-sensitive fluid assays and automated laboratory platforms, structural and molecular neuroimaging, electrophysiology, digital cognitive and behavioral monitoring, multi-omics, neuromodulation, and the computational frameworks necessary to integrate these diverse data.}, } @article {pmid41054216, year = {2025}, author = {Sánchez de Muniain, L and Escalada, P and Ramírez, MJ and Solas, M}, title = {Astrocytes as Metabolic Sensors Orchestrating Energy-Driven Brain Vulnerability in Alzheimer's Disease.}, journal = {Journal of neurochemistry}, volume = {169}, number = {10}, pages = {e70252}, pmid = {41054216}, issn = {1471-4159}, support = {PID2021-128737NB-I00//MCIN/AEI/10.13039/501100011033/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Astrocytes/metabolism/pathology ; *Energy Metabolism/physiology ; *Brain/metabolism/pathology ; Animals ; Oxidative Stress/physiology ; }, abstract = {Alzheimer's disease (AD), the leading neurodegenerative disorder linked to aging, emerges within a paradoxical metabolic landscape. Despite rising cellular energy demands due to accumulated damage and stress, overall energy expenditure remains stable or declines with age. The brain, acting as the central regulator, responds to hypermetabolic signals from aged tissues by activating energy-conserving mechanisms. In this scenario, astrocytes, strategically located between blood vessels and neurons, play a pivotal role as energy sensors, adapting to systemic stress and modulating brain metabolism. This review explores how astrocytes undergo metabolic reprogramming in the early stages, potentially becoming maladaptive over time, fueling neuroinflammation, oxidative stress, and accelerating AD. By understanding astrocyte energetics, we uncover new avenues for biomarkers and therapies that could transform AD treatment.}, } @article {pmid41053519, year = {2025}, author = {Amiri, M and Afshary, H and Bezaatpour, A and Hatamikia, S and Wei, J and Boukherroub, R and Szunerits, S}, title = {A critical review on neurodegenerative biomarker diagnostics: where is the field heading to?.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {24}, pages = {5435-5448}, pmid = {41053519}, issn = {1618-2650}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Biomarkers/analysis ; Nanotechnology/methods ; }, abstract = {Neurodegenerative diseases (NDD), a collection of disorders with different underlying causes and clinical presentations, are recognized as a major area of concern of our society today. The most common NDD are Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease, each one of them being characterized by the progressive degradation of nerve cells and accumulation of misfolded and aggregated proteins in the affected brain region. Diagnosing NDD is challenging, due to the heterogeneity of the disease and the overlap of symptoms. Yet, early detection and accurate diagnosis are crucial for effective NDD management. With the emergence of disease-modifying therapies for AD, monitoring disease progression and treatment success is becoming essential. The future of NND diagnostics is focusing on developing less invasive, cost-effective strategies that enable early NDD identification and detection with improved patient outcomes. The integration of biotechnology and nanotechnology is seen as crucial for advancing the analytical science aspect of NDD. The creation of these innovative tools and methodologies is on the verge of enabling new possibilities for clinical diagnostics, but is also faced with several hurdles that will be critically evaluated.}, } @article {pmid41053038, year = {2025}, author = {Ficchì, S and Cauzzi, E and La Barbera, L and De Paolis, ML and Loffredo, G and Spoleti, E and Ferrari, I and Saba, L and Biamonte, F and Nobili, A and Krashia, P and D'Amelio, M}, title = {Optogenetic stimulation of midbrain dopaminergic neurons rescues hippocampal synaptic plasticity deficits in a mouse model of Alzheimer's disease.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {371}, pmid = {41053038}, issn = {2158-3188}, support = {AARG-21-851219/ALZ/Alzheimer's Association/United States ; }, mesh = {Animals ; *Alzheimer Disease/physiopathology/therapy ; *Dopaminergic Neurons/physiology ; *Optogenetics ; Disease Models, Animal ; Mice ; *Mesencephalon/physiopathology ; *Neuronal Plasticity/physiology ; *Hippocampus/physiopathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Oxidopamine ; *Long-Term Potentiation/physiology ; Male ; Synaptic Transmission ; }, abstract = {We previously demonstrated that the Tg2576 mouse model of Alzheimer's Disease (AD) exhibits degeneration of midbrain dopaminergic neurons, resulting in reduced dopamine (DA) outflow in the hippocampus. These impairments temporally coincide with synaptic plasticity deficits at CA3-CA1 synapses. Notably, systemic administration of dopaminergic agents/drugs rescues the hippocampal deficits in Tg2576 mice. However, whether direct stimulation of the remaining midbrain dopaminergic neurons can restore glutamatergic transmission and rescue plasticity dysfunctions in the context of AD remains unexplored. Here, using both 6-hydroxydopamine (6-OHDA) neurotoxic lesion and optogenetic stimulation in C57BL/6N and DATCre/Tg2576 mice, respectively, we demonstrate that midbrain DA is essential for hippocampal High-Frequency Stimulation-induced Long-Term Potentiation (HFS-LTP) in CA3-CA1 synapses. Indeed, lesioning midbrain DA neurons with 6-OHDA abolishes HFS-LTP and impairs novel object recognition memory. Conversely, optogenetic activation of the midbrain-hippocampal dopaminergic pathway in DATCre/Tg2576 mice enhances glutamatergic transmission and rescues plasticity deficits. Our results highlight the phase-specific role of DA in HFS-LTP, since 6-OHDA lesion affects the late but not the early phase, aligning with prior studies on D1/D5 receptor involvement in protein synthesis-dependent plasticity. Furthermore, we provide novel insights into midbrain DA neuron regulation, demonstrating that phasic, but not prolonged, optogenetic stimulation effectively engages DA neuron activity, restoring hippocampal function in Tg2576 mice. Notably, phasic DA release induces "DA-LTP" via D1/D5 receptors, and restores HFS-LTP in CA3-CA1 synapses of AD mice, underscoring a potential compensatory mechanism counteracting plasticity deficits induced by DA neuron degeneration in Tg2576 mice. These findings support targeting the dopaminergic midbrain as a promising strategy for AD treatment, complementing pharmacological and non-invasive neuromodulatory approaches.}, } @article {pmid41052971, year = {2025}, author = {Chen, J and Xiang, P and Duro-Castano, A and Cai, H and Guo, B and Liu, X and Yu, Y and Lui, S and Luo, K and Ke, B and Ruiz-Pérez, L and Gong, Q and Tian, X and Battaglia, G}, title = {Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {331}, pmid = {41052971}, issn = {2059-3635}, support = {769798 CheSSTag//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; }, mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; *Amyloid beta-Peptides/genetics/metabolism ; Mice ; *Alzheimer Disease/genetics/drug therapy/pathology/metabolism ; Humans ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics ; *Cognition/drug effects ; Receptors, LDL/genetics ; Disease Models, Animal ; Transcytosis ; }, abstract = {The blood‒brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer's disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques. We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1 (LRP1) on the BBB. Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport, biasing LRP1 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβ removal. In AD model mice, this intervention significantly reduced brain Aβ levels by nearly 45% and increased plasma Aβ levels by 8-fold within 2 h, as measured by ELISA. Multiple imaging techniques confirmed the reduction in brain Aβ signals after treatment. Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory, with performance levels comparable to those of wild-type mice. These cognitive benefits persisted for up to 6 months post-treatment. This work pioneers a new paradigm in drug design, where function arises from the supramolecular nature of the nanomedicine, harnessing multivalency to elicit biological action at the membrane trafficking level. Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective. We establish a compelling case for BBB modulation and LRP1-mediated Aβ clearance as a transformative foundation for future AD therapies.}, } @article {pmid41052930, year = {2025}, author = {Emami Naeini, S and Bhandari, B and Hill, B and Perez-Morales, N and Rogers, HM and Khodadadi, H and Young, N and Maciel, LM and Yu, JC and Hess, DC and Morgan, JC and Lopes Salles, É and Wang, LP and Baban, B}, title = {Rethinking Alzheimer's: Harnessing Cannabidiol to Modulate IDO and cGAS Pathways for Neuroinflammation Control.}, journal = {eNeuro}, volume = {12}, number = {10}, pages = {}, pmid = {41052930}, issn = {2373-2822}, mesh = {*Cannabidiol/pharmacology/administration & dosage ; Animals ; *Alzheimer Disease/metabolism/drug therapy/immunology ; *Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism/drug effects ; Mice ; Male ; Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Nucleotidyltransferases/metabolism/drug effects ; Disease Models, Animal ; Signal Transduction/drug effects ; }, abstract = {Alzheimer's disease (AD) has traditionally been associated with amyloid-β plaques, but growing evidence underscores the role of neuroinflammation in disease progression. The autoinflammatory hypothesis of AD suggests chronic immune dysfunction contributes to neuronal damage, making immune modulation a promising therapeutic strategy. Cannabidiol (CBD), a phytocannabinoid with anti-inflammatory properties, may offer therapeutic potential. This study investigates how CBD independently influences two key neuroinflammatory regulators in AD: the indoleamine 2,3-dioxygenase (IDO) pathway and the cyclic GMP-AMP synthase (cGAS) pathway. Though mechanistically distinct, both shape CNS immune responses. Targeting these immune-metabolic axes provides a mechanistic alternative to amyloid- or tau-based approaches by addressing upstream drivers of neuroinflammation and immune dysregulation. Using the male 5XFAD transgenic AD mouse model, we administered CBD via inhalation and assessed IDO and cGAS expression using flow cytometry, immunofluorescence (IF), and gene expression analysis. We evaluated cytokine levels and used STRING-based bioinformatics to identify CBD-target interactions. CBD treatment significantly reduced IDO and cGAS expression, correlating with decreased proinflammatory cytokines, including TNF-α, IL-1β, and IFN-γ. Bioinformatics identified potential interactions between CBD and immune targets such as AKT1, TRPV1, and GPR55. These targets were prioritized based on their roles in neuroinflammatory signaling and high-confidence interactions with CBD. AKT1 regulates inflammatory signaling and cell survival, TRPV1 modulates nociception and neuroinflammation, and GPR55 influences immune cell activation. These findings support CBD as a potential monotherapy or adjunctive treatment for AD by targeting distinct neuroinflammatory pathways, including IDO and cGAS. Further studies are warranted to fully explore its therapeutic potential.}, } @article {pmid41052547, year = {2025}, author = {Ajoolabady, A and Kim, B and Abdulkhaliq, AA and Ren, J and Bahijri, S and Tuomilehto, J and Borai, A and Khan, J and Pratico, D}, title = {Dual role of microglia in neuroinflammation and neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107133}, doi = {10.1016/j.nbd.2025.107133}, pmid = {41052547}, issn = {1095-953X}, mesh = {*Microglia/metabolism/immunology ; Humans ; *Neurodegenerative Diseases/immunology/metabolism/pathology ; *Neuroinflammatory Diseases/immunology/metabolism/pathology ; Animals ; HMGB1 Protein/metabolism ; Brain/immunology/metabolism ; }, abstract = {Microglia are the principal innate immune cells of the central nervous system, playing cardinal roles in regulating immunity and mediating neuroinflammation - a chronic inflammatory response occurring in the brain and spinal cord. Microglia exhibit a dual role in this process: they can suppress neuroinflammation through anti-inflammatory polarization or inhibition of proinflammatory intracellular signaling, or conversely, they can exacerbate neuroinflammation via activation of proinflammatory pathways and phenotypes. This seemingly binary behavior is further complicated by a network of internal and external molecular effectors that influence microglial polarization and function, guiding them toward either neuroprotection or neurotoxicity. In this narrative review, we aimed to elucidate the dual role of microglia in neuroinflammation, particularly in the context of neurodegenerative diseases and other brain pathologies. Special emphasis is placed on the most recent findings related to key proteins such as TREM2 (triggering receptor expressed on myeloid cells 2) and HMGB1 (high mobility group box 1 protein). By examining the molecular mechanisms and pathways involving these proteins, we highlight promising therapeutic targets for modulating neuroinflammation and advancing developing novel treatment strategies for neurodegenerative and other brain-related disorders.}, } @article {pmid41052542, year = {2025}, author = {Hansen, N and Wiltfang, J}, title = {[Disease-modifying therapy with lecanemab for early Alzheimer's dementia].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {93}, number = {11}, pages = {453-460}, pmid = {41052542}, issn = {1439-3522}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a severe and progressive neurodegenerative disease of the brain that has so far been treated with symptomatic drug and non-drug therapies as standard treatment. Following the approval of the monoclonal anti-amyloid antibody by the FDA, AD therapy has changed, as this therapy has made it possible to attenuate the biological disease process of AD. Lecanemab has been recommended by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for approval in patients with early AD under two conditions. Firstly, homozygous ApoE4 carriers and secondly, patients receiving oral anticoagulants should not receive lecanemab. The following narrative review explains the mechanism of action, safety and side effects of lecanemab. Furthermore, risk factors for side effects are described. Finally, the first experiences with lecanemab are reported and the efficacy and financial aspects are discussed. Lecanemab leads to a temporary reduction in amyloid-ß deposits and to a benefit that can be reflected in everyday competence, cognition and quality of life and can be described as a breakthrough in AD's therapy due to its demonstrable biological and clinical efficacy.}, } @article {pmid41051912, year = {2025}, author = {Hickman, LB and Pandey, B and Fish, A and Bandla, M and Husein, A and Allas, C and Kottakota, H and Herzog, L and Vossel, K and Stern, JM}, title = {Late-onset epilepsy of unknown etiology is more treatment-responsive than acquired lesional late-onset epilepsy.}, journal = {Epilepsia open}, volume = {10}, number = {6}, pages = {1847-1859}, pmid = {41051912}, issn = {2470-9239}, support = {UE5 NS065723-16/NS/NINDS NIH HHS/United States ; R01 AG058820/AG/NIA NIH HHS/United States ; R01 AG075955/NS/NINDS NIH HHS/United States ; R01 AG058820/NS/NINDS NIH HHS/United States ; UH2 AG083254/AG/NIA NIH HHS/United States ; R56 AG074473/AG/NIA NIH HHS/United States ; UH2 AG083254/NS/NINDS NIH HHS/United States ; UE5 NS065723/NS/NINDS NIH HHS/United States ; R56 AG074473/NS/NINDS NIH HHS/United States ; R01 AG075955/AG/NIA NIH HHS/United States ; R01 NS033310/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; *Epilepsy/etiology/drug therapy/diagnostic imaging/physiopathology ; Electroencephalography ; Age of Onset ; Magnetic Resonance Imaging ; *Anticonvulsants/therapeutic use ; Aged, 80 and over ; }, abstract = {OBJECTIVE: Late-onset epilepsy of unknown etiology (LOEU) carries an elevated risk of dementia, suggesting that it may represent an early manifestation of neurodegenerative or cerebrovascular disease. Direct comparisons between LOEU and acquired lesional late-onset epilepsy (LOE) may elucidate clinical features specific to LOEU. METHODS: We performed a retrospective chart review of patients with LOE, with first documented seizure at age 55 or older, whose evaluation included an epilepsy-protocol brain MRI and/or inpatient video-EEG evaluation. Etiology was determined from neuroimaging lesions and medical history. Patients without an identified etiology were categorized as LOEU. Analyses were performed controlling for sex, age of onset, and epilepsy duration. RESULTS: We identified 75 LOEU (mean onset: 64.9 years, 38.7% female) and 57 acquired lesional LOE cases with etiologies including cortical stroke, hemorrhage, neoplasm, trauma, or infection (mean onset: 66.5 years, 36.8% female). LOEU was less likely to have a history of status epilepticus (6.7% vs. 21.1%, aOR: 0.28, p < 0.03) or to have undergone inpatient video-EEG monitoring (13.3% vs. 24.6%, aOR: 0.34, p < 0.04). LOEU was prescribed fewer ASMs compared to acquired lesional LOE (aOR: 0.43, p < 0.02), and LOEU patients prescribed multiple ASMs had lower average 12-month seizure frequency than acquired lesional LOE (median: 0.2 vs. 1.0, p < 0.01). LOEU had lower rates of vascular comorbidities than acquired lesional LOE, though rates of subsequent dementia were not significantly different (5-year risk: 16.6% vs. 17.7%). An exploratory cluster analysis demonstrated an LOEU subgroup with older onset, higher prevalence of white matter hyperintensities, cerebral atrophy, epileptiform discharges, and greater epilepsy severity. SIGNIFICANCE: LOEU was associated with fewer proxies for epilepsy severity, signifying that LOEU is more often treatment-responsive than acquired lesional LOE. LOEU has lower rates of comorbid vascular disease compared to acquired lesional LOE, suggesting that occult cerebrovascular disease is not overrepresented in LOEU relative to other forms of LOE. PLAIN LANGUAGE SUMMARY: People who develop epilepsy after age 55 without a known cause usually respond well to treatment and need fewer antiseizure medications than people with epilepsy from a known brain injury. In this study, they had fewer hospital stays for seizure monitoring and fewer vascular problems. Dementia risk was high in patients with late-onset epilepsy, both when the cause was known and when it was unknown. Late-onset epilepsy without a known cause is often less severe but still needs regular monitoring for memory and thinking problems.}, } @article {pmid41051689, year = {2025}, author = {Azam, HMH and Mumtaz, M and Rödiger, S and Schierack, P and Hussain, N and Aisha, A}, title = {MicroRNAs in neurodegenerative diseases: from molecular mechanisms to clinical biomarkers, detection methods and therapeutic strategies-advances and challenges.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {12}, pages = {6277-6319}, pmid = {41051689}, issn = {1590-3478}, mesh = {Humans ; *MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/diagnosis/therapy/genetics/metabolism ; Biomarkers/metabolism ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) pose significant challenges in early detection and treatment due to their complex pathophysiology and heterogeneous clinical presentations. MicroRNAs (miRNAs), small noncoding RNAs that regulate gene expression, have emerged as promising diagnostic biomarkers and therapeutic targets in NDDs. Pathological examination of affected tissues reveals early synaptic dysfunction, protein misfolding, and neuroinflammation occur prior to overt clinical symptoms, highlighting the importance of sensitive diagnostics approaches in prodromal stages. This review summarizes for researchers on the role of miRNAs in NDDs by examining their diagnostic potential in biofluids such as blood and cerebrospinal fluid, and their therapeutic applicability through inhibition or replacement strategies. Literature from peer-reviewed databases was assessed with a focus on recent advances in molecular detection platforms, computational modeling of miRNA-mRNA interactions, and preclinical/clinical investigations.More than 2600 human miRNAs have been identified, collectively regulating over half of mammalian protein-coding genes. Quantitative methodologies, particularly reverse transcription quantitative PCR (RT-qPCR), enable reliable miRNA profiling, facilitating early diagnosis and prognosis of NDDs. Therapeutic strategies, including antagomirs, mimics, sponges and viral or non-viral delivery systems, show promise in modulating disease pathways. However, significant challenges remain, including variability in miRNA extraction and quantification protocols, off-target effects, delivery barriers across the blood brain barrier and limited reproducibility across studies. MiRNAs represent a class of molecular tools with potential to transform diagnostics and therapeutics in NDDs. Future research should prioritize methodological standardization, validation in large multicenter cohorts, and improved computational approaches to elucidate miRNA-mediated regulatory networks in NDDs. Replication studies and translational research are essential harnessing the the full clinical utility of miRNAs in the management of Alzheimer disease, Parkinson disease and other NDDs. Graphical Abstract.}, } @article {pmid41051550, year = {2025}, author = {Yang, T}, title = {Molecular Mechanisms of EDC-Induced Alzheimer's Disease and of Traditional Chinese Medicine Active Substances in Treating AD and Antagonizing EDC-Induced Effects.}, journal = {Neurochemical research}, volume = {50}, number = {5}, pages = {319}, pmid = {41051550}, issn = {1573-6903}, mesh = {*Alzheimer Disease/chemically induced/drug therapy/metabolism ; Molecular Docking Simulation/methods ; *Medicine, Chinese Traditional/methods ; Humans ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Animals ; Network Pharmacology ; Ginsenosides/therapeutic use/pharmacology ; Protein Interaction Maps/drug effects ; }, abstract = {AD, a progressive neurodegenerative disorder, imposes an increasingly heavy burden on global public health, with its pathogenesis remaining incompletely understood. Meanwhile, EDCs-widely present in the environment, food, and consumer products-have emerged as a significant public health concern due to their diverse health risks, including potential contributions to neurodegenerative processes such as AD by disrupting neurohomeostasis. Furthermore, as natural compounds, ginsenosides and other AS have been the focus of numerous studies exploring their role in treating AD, thanks to their advantages of multi-target properties and low side effects. However, the specific molecular pathways through which EDCs induce AD, as well as the mechanisms by which AS may counteract EDC-induced toxicity and intervene in AD, remain unclear. Against this background, this study sought to: (1) explore the molecular pathways through which EDCs may induce AD by disrupting neurohomeostasis; (2) preliminarily investigate the potential of AS in treating AD and antagonizing EDC-induced AD at the molecular level. To achieve these goals, we integrated network toxicology, network pharmacology, and molecular docking to construct a multi-dimensional interaction network among EDCs, AD, and AS. By establishing intersecting target sets for EDCs-AD and AS-AD, core targets were identified via topology analysis of protein-protein interaction (PPI) networks. GO and KEGG enrichment analyses highlighted key pathways, including serotonergic synapse and neuroactive ligand-receptor interaction. Molecular docking further explored interactions between EDCs/AS and core target proteins. The results suggest that EDCs may drive neurodegeneration in AD by impairing synaptic function, while AS may counteract these effects by enhancing synaptic activity, stabilizing membrane microenvironments, inhibiting Aβ aggregation, alleviating neuroinflammation, and restoring metabolic homeostasis. Further analysis indicated that AS exhibit stronger binding ability to core targets compared to EDCs, implying a potential antagonistic effect of AS against EDCs. This study provides insights into the molecular mechanisms underlying EDC-induced AD and establishes a multi-target theoretical framework for AS-mediated antagonism of EDC toxicity, offering a reference for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid41051385, year = {2025}, author = {Xie, D and Zheng, Q and Lv, J and Zhang, Q and Cui, Z and Huang, S and Yu, W and Chen, B and Que, W and Fu, S and Xi, Y and Chen, J and Ye, X and Chen, S and Zhao, H and Yamamoto, T and Koyama, H and Wang, X and Cheng, J}, title = {Uric Acid Functions as an Endogenous Modulator of Microglial Function and Amyloid Clearance in Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {48}, pages = {e10270}, pmid = {41051385}, issn = {2198-3844}, support = {82370895//National Natural Science Foundation of China/ ; U01 AG024904/AG/NIA NIH HHS/United States ; W81XWH-12-2-0012//DOD ADNI/ ; 82271451//National Natural Science Foundation of China/ ; 82260163//National Natural Science Foundation of China/ ; 2020J01018//Natural Science Foundation of Fujian Province/ ; 2022Y4007//Fujian Provincial Industry-University-Research Collaborative Innovation Project Plan/ ; }, mesh = {*Alzheimer Disease/metabolism ; *Uric Acid/metabolism/pharmacology ; *Microglia/metabolism/drug effects ; Animals ; Mice ; *Amyloid beta-Peptides/metabolism ; Humans ; Phagocytosis/drug effects ; Disease Models, Animal ; Mice, Transgenic ; Male ; Plaque, Amyloid/metabolism ; }, abstract = {Epidemiological studies have linked uric acid (UA), the end product of purine metabolism in humans, with reduced Alzheimer's disease (AD) risk. Decreased serum UA levels are observed in AD patients versus age-matched controls, while upstream purine metabolites remained unchanged. In 5×FAD mice, two months of UA supplementation improved cognitive function and reduced amyloid plaque burden. Mechanistically, UA enhances microglial amyloid-β (Aβ) phagocytosis and induces transcriptional reprogramming in AD mouse microglia, characterized by upregulated phagocytic pathways and attenuated inflammatory responses. UA treatment restored the recycling of Aβ receptors CD36 and TREM2 in microglia, enhanced lysosomal biogenesis, and facilitated Aβ degradation. These findings identify UA as a critical endogenous modulator of microglial Aβ processing and suggest exploring UA supplementation as a therapeutic strategy for AD.}, } @article {pmid41051231, year = {2025}, author = {Paul, S and Guruprasad, L}, title = {Hexagonal Boron Nitride Nanoparticles for Inhibition of Small Fragment Tau Aggregation.}, journal = {The journal of physical chemistry. B}, volume = {129}, number = {41}, pages = {10752-10764}, doi = {10.1021/acs.jpcb.5c04935}, pmid = {41051231}, issn = {1520-5207}, mesh = {*Nanoparticles/chemistry ; *Boron Compounds/chemistry/pharmacology ; *tau Proteins/chemistry/metabolism/antagonists & inhibitors ; Protein Aggregates/drug effects ; Humans ; Molecular Dynamics Simulation ; }, abstract = {The aberrant folding of the Tau protein is correlated with several neurodegenerative diseases, such as Alzheimer's and other tauopathies. Recent studies on the neurotoxic species of Tau have identified some smaller nucleating domains of the full-length protein to initiate Tau aggregation and are shown as potential therapeutic targets in Tau pathology. Two hexapeptides, namely, PHF6 ([306]VQIVYK[311]) and PHF6* ([275]VQIINK[280]), have been recognized as the most important aggregation-prone Tau fragments among all. Currently, low-dimensional nanomaterials have shown a plethora of applications in bionanomedicine, including the treatment of amyloid diseases. Hexagonal boron nitride (h-BN) nanoparticles, analogous to carbon nanomaterials, have become potential candidates in this field due to their lower cytotoxicity compared to carbon nanoparticles and biocompatibility. In this study, we have explored the aggregation pattern of PHF6 and PHF6* and the effects of a two-dimensional (2D) h-BN nanosheet (BNNS) on these peptide oligomerizations. Atomistic simulations reveal that the PHF6-PHF6 homomer aggregation is highly favored due to the aromatic π-π interaction between the Tyr residues; furthermore, the heteromeric interaction between PHF6 and PHF6* is stronger than the self-association of PHF6* homomers. In the presence of BNNS, the peptides get absorbed on the nanosurface through weak hydrophobic interactions and aromatic π-π stacking and remain in their monomeric random coil structure. Also, the h-BN nanosheet can destabilize the preformed oligomers of the hexapeptides, hence providing a new direction toward the use of h-BN and other related nanomaterials as potential antiaggregating agents against amyloid deposition.}, } @article {pmid41051040, year = {2025}, author = {Agarwal, U and Paliwal, S and Yadav, V and Pannu, A and Tonk, RK and Verma, S}, title = {Pathological Insights into Neurodegenerative and Neurodevelopmental Disorders: Perspectives for the Development of Novel Treatment Approaches.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273402657250905055635}, pmid = {41051040}, issn = {1996-3181}, abstract = {Neurodegenerative and neurodevelopmental disorders represent a significant global health burden, characterized by progressive neuronal dysfunction and loss. Both diseases, despite their diverse etiologies and mechanisms, share a complex interplay of genetic, environmental, and biological factors. Neurodegenerative diseases are caused by multiple factors, including aging, mitochondrial dysfunction, oxidative stress, inflammation, genetic mutations, and protein misfolding. In contrast, neurodevelopmental disorders are primarily influenced by epigenetic alterations, neurotransmitter imbalances, early brain damage, environmental factors, and genetic variations. Despite extensive research, effective treatments remain unavailable due to the complexity of their pathologies and the biochemical pathways involved. A deep understanding of the complexities and individual differences associated with these disorders is crucial for developing effective treatments. In this background, this review provides a comprehensive overview of neurodegenerative and neurodevelopmental disorders, including their clinical symptoms, etiology, pathogenesis, underlying mechanisms, potential drug targets, reported drugs, advanced treatment options, and challenges in the drug discovery process. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to April 2025. By understanding the complexities of these disorders, researchers can develop novel therapeutic approaches, including potential drugs and advanced treatment methods, to mitigate their devastating impact.}, } @article {pmid41050964, year = {2025}, author = {Zhou, Z and Chen, X and Kou, W and Meng, F and Yu, L and Wen, J and Boey, J and Shah, V and Malagón, P}, title = {Modified Dynamic Lymphaticovenular Anastomosis for Surgical Management of Alzheimer Disease.}, journal = {Plastic and reconstructive surgery. Global open}, volume = {13}, number = {10}, pages = {e7082}, pmid = {41050964}, issn = {2169-7574}, abstract = {Alzheimer disease (AD) is a neurodegenerative disorder that frequently results in progressive cognitive decline. Despite the extensive research conducted on AD, there is presently no solution available due to its increasing prevalence. Recent research has suggested cervical lymphaticovenular anastomosis (LVA) as a therapeutic strategy to improve lymphatic outflow and potentially reduce AD symptoms. We established an amended LVA protocol to mitigate the risk of venous reflux, a prevalent issue associated with the original LVA methodology. A 64-year-old man of Chinese descent exhibited the typical signs and symptoms of AD. The absence of substantial progress with standard medical treatment led to the consideration of LVA. We used a lower limb vein graft for the LVA, anastomosing it to the cervical lymphatic vessels and external jugular vein. The cognitive function of the patient got better after LVA, as shown by higher Mini Mental State Examination and Montreal Cognitive Assessment scores. Fewer β-amyloid and tau protein deposits were observed on positron emission tomography/computed tomography scans. No adverse occurrences or issues were observed. The success in this case demonstrated the potential role of LVA in the management of AD. However, further thorough research is required to evaluate the efficacy of our technique.}, } @article {pmid41050469, year = {2025}, author = {Wang, Y and Liu, T and He, Y and Tang, Y and Tan, P and Huang, L and Huang, D and Wen, T and Shao, L and Wang, J and Wang, Y and Han, Z}, title = {Identifying Alzheimer's disease-related pathways based on whole-genome sequencing data.}, journal = {Computational and structural biotechnology journal}, volume = {27}, number = {}, pages = {4132-4144}, pmid = {41050469}, issn = {2001-0370}, abstract = {Alzheimer's disease (AD) is a highly inheritable neurodegenerative disorder for which pathway-specific genetic profiling provides insights into its key biological mechanisms and potential treatment targets. Traditional disease-pathway analyses for AD have certain limitations, such as environmental interference and arbitrary sample division. We present a comprehensive framework that starts with genome data, avoiding these drawbacks and offering intrinsic pathway-specific genetic profiling for AD. Whole genome sequencing data from 173 individuals were used to quantify transcriptomes in 14 brain regions, estimate individual-level pathway variant scores, and analyze AD risk for each patient. These results were combined to identify AD-related pathways and quantify their interactions. The predicted expression levels were consistent with previous findings, and the estimated AD risk showed a significant correlation with Braak/Thal scores. A total of 3798 pathways were identified as potentially associated with AD, with about 19.7 % previously reported. The pathways identified as AD risk related primarily address six core biological themes, including: Immunity and inflammation, Metabolism, Protein homeostasis, DNA/RNA and Epigenetics, Synapse and structure, Cell cycle. Specifically, key pathways, such as NF-κB signaling and GSK3β activation, were linked to AD pathogenesis. The interactions among pathways highlighted shared gene functions in AD. In summary, we provided an effective framework for disease-pathway analysis, revealing the interdependence or compensatory effects of pathways in AD.}, } @article {pmid41050397, year = {2025}, author = {Liu, W and Zhao, Y and Liu, T and Wang, Y and Yin, D and Zou, S and Zou, C and Zhang, Z and Zhi, H and Wang, Y}, title = {Kaixin San Jiawei granule improves cognitive function and alleviates neuronal damage in Alzheimer's disease via multi-component and multi-target mechanisms.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1650534}, pmid = {41050397}, issn = {1663-9812}, abstract = {BACKGROUND: Kaixin San Jiawei Granule (KSG) is a traditional Chinese medicine formulation derived from classical prescriptions. Although it has shown promise in treating Alzheimer's disease (AD), its precise mechanisms of action remain unclear. This study aimed to systematically investigate the molecular mechanisms underlying KSG's therapeutic effects on AD through an integrative approach combining network pharmacology with experimental validation. METHODS: An in vivo AD model was established in male KM mice via intraperitoneal injection of scopolamine. Cognitive function was assessed using the Morris water maze, and hippocampal levels of acetylcholine (ACh), acetylcholinesterase (AChE), glutathione peroxidase (GSH-Px), and reactive oxygen species (ROS) were measured using ELISA. In vitro, PC12 cells were exposed to Aβ25-35 to induce apoptosis. Immunofluorescence staining, Western blotting, and qPCR were used to assess the expression of amyloid-beta (Aβ), apoptosis-related protein caspase-3, and inflammatory cytokines (TNF-α, IL-1β). Active components of KSG and their potential targets and pathways were identified using mass spectrometry and network pharmacology, while partial validation was performed using molecular docking and Western blotting. RESULTS: In vivo, KSG significantly alleviated scopolamine-induced cognitive deficits in mice. Treatment increased hippocampal levels of ACh and GSH-Px while reducing AChE and ROS. In vitro, KSG mitigated Aβ25-35-induced cytotoxicity in PC12 cells, decreased Aβ accumulation, and downregulated the expression of TNF-α and IL-1β. However, KSG had no significant effect on telomerase activity, telomere length, or the expression of the telomere-associated protein POT1. Mass spectrometry and network pharmacology analyses identified genistein, quercetin, and apigenin as key active compounds with TP53, AKT1, PTGS2, and CNR2 identified as core targets. Molecular docking validation confirmed the favorable binding activity between them. The calcium signaling, PI3K-Akt, and MAPK pathways emerged as the primary enriched pathways. CONCLUSION: KSG improves cognitive function and attenuates Aβ-induced neuronal damage in AD through multi-component, multi-target synergistic mechanisms. These effects appear to be mediated by modulation of the cholinergic system, inhibition of oxidative stress and inflammation, and suppression of neuronal apoptosis. These findings provide a theoretical basis and experimental support for developing novel AD therapies based on traditional Chinese medicine.}, } @article {pmid41049759, year = {2025}, author = {Meden, A and Žnidaršič, N and Knez, D and Wang, Y and Xu, Z and Yang, H and Zhang, W and Pišlar, A and Perdih, A and Brezar, SK and Grgurevič, N and Pajk, S and Sun, H and Gobec, S}, title = {Pleiotropic prodrugs for both symptomatic and disease-modifying treatment of Alzheimer's disease.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {9}, pages = {4807-4828}, pmid = {41049759}, issn = {2211-3835}, abstract = {The inherent complexity of Alzheimer's disease (AD) and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology. Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action. Pseudo-irreversible inhibition of the first therapeutic target, human butyrylcholinesterase (hBChE), enhances cholinergic transmission, and thereby provides symptomatic treatment, same as the standard therapeutics in use for AD. Simultaneously, this step also functions as a metabolic activation that liberates a nanomolar selective α 2-adrenergic antagonist atipamezole, which blocks pathological amyloid β (Aβ)-induced and noradrenaline-dependent activation of GSK3β that ultimately leads to hyperphosphorylation of tau, thus achieving a disease-modifying effect. Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition, metabolic activation in human plasma, blood-brain barrier permeability, and p.o. bioavailability in mice. Multi-day in vivo treatment with 8 in an Aβ-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine, the current drug of choice for AD therapy. Furthermore, decreased GSK3β activation and lowered tau phosphorylation were observed in APP/PS1 mice. This surpasses the symptomatic-only treatment with cholinesterase inhibitors, as it directly blocks an essential pathological cascade in AD. Therefore, these multifunctional α 2-adrenergic antagonists-butyrylcholinesterase inhibitors, exemplified by lead compound 8, present an innovative, small molecule-based, disease-modifying approach to treatment of AD.}, } @article {pmid41049755, year = {2025}, author = {Yang, Y and Diao, Y and Jiang, L and Li, F and Chen, L and Ni, M and Wang, Z and Fang, H}, title = {A computational medicine framework integrating multi-omics, systems biology, and artificial neural networks for Alzheimer's disease therapeutic discovery.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {9}, pages = {4411-4426}, pmid = {41049755}, issn = {2211-3835}, abstract = {The translation of genetic findings from genome-wide association studies into actionable therapeutics persists as a critical challenge in Alzheimer's disease (AD) research. Here, we present PI4AD, a computational medicine framework that integrates multi-omics data, systems biology, and artificial neural networks for therapeutic discovery. This framework leverages multi-omic and network evidence to deliver three core functionalities: clinical target prioritisation; self-organising prioritisation map construction, distinguishing AD-specific targets from those linked to neuropsychiatric disorders; and pathway crosstalk-informed therapeutic discovery. PI4AD successfully recovers clinically validated targets like APP and ESR1, confirming its prioritisation efficacy. Its artificial neural network component identifies disease-specific molecular signatures, while pathway crosstalk analysis reveals critical nodal genes (e.g., HRAS and MAPK1), drug repurposing candidates, and clinically relevant network modules. By validating targets, elucidating disease-specific therapeutic potentials, and exploring crosstalk mechanisms, PI4AD bridges genetic insights with pathway-level biology, establishing a systems genetics foundation for rational therapeutic development. Importantly, its emphasis on Ras-centred pathways-implicated in synaptic dysfunction and neuroinflammation-provides a strategy to disrupt AD progression, complementing conventional amyloid/tau-focused paradigms, with the future potential to redefine treatment strategies in conjunction with mRNA therapeutics and thereby advance translational medicine in neurodegeneration.}, } @article {pmid41049729, year = {2025}, author = {Ren, F and Wei, J and Chen, Q and Hu, M and Yu, L and Mi, J and Zhou, X and Qin, D and Wu, J and Wu, A}, title = {Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {9}, pages = {4327-4385}, pmid = {41049729}, issn = {2211-3835}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, with few effective treatments currently available. The multifactorial nature of AD, shaped by genetic, environmental, and biological factors, complicates both research and clinical management. Recent advances in artificial intelligence (AI) and multi-omics technologies provide new opportunities to elucidate the molecular mechanisms of AD and identify early biomarkers for diagnosis and prognosis. AI-driven approaches such as machine learning, deep learning, and network-based models have enabled the integration of large-scale genomic, transcriptomic, proteomic, metabolomic, and microbiomic datasets. These efforts have facilitated the discovery of novel molecular signatures and therapeutic targets. Methods including deep belief networks and joint deep semi-non-negative matrix factorization have contributed to improvements in disease classification and patient stratification. However, ongoing challenges remain. These include data heterogeneity, limited interpretability of complex models, a lack of large and diverse datasets, and insufficient clinical validation. The absence of standardized multi-omics data processing methods further restricts progress. This review systematically summarizes recent advances in AI-driven multi-omics research in AD, highlighting achievements in early diagnosis and biomarker discovery while discussing limitations and future directions needed to advance these approaches toward clinical application.}, } @article {pmid41048559, year = {2025}, author = {Ma, X and Wang, F and Wang, G and Zhao, M and Zheng, Y and Guo, Y and Wu, J and Liu, Y and Liu, Y and He, G and Ren, L and Gong, Z and Wang, J and Chen, L and Hu, S and Chu, Q and Li, Z and Wu, J and Li, R and Zhang, X and Shi, Q and Lian, H and Ye, J}, title = {A surgical therapy for Alzheimer's disease with lymphaticovenular anastomosis.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251384244}, pmid = {41048559}, issn = {2542-4823}, abstract = {BACKGROUND: Deep cervical lymphaticovenular anastomosis (dcLVA) surgery is able to control aging-associated Alzheimer's disease in patients. However, the efficacy rate remains unknown. OBJECTIVE: This study is designed to test the surgery efficacy in the treatment of mild-to-moderate AD patients. METHODS: This is a single-center retrospective study of dcLVA treatment of mild-to-moderate AD for 3 months. A total of 41 patients received the surgery, in which lymph vessels and lymph nodes in the district III of cervical area were identified using indocyanine fluorescence dye. The afferent lymphatics of the obstructed lymph nodes were connected to the jugular vein to fix the lymphatic blockage under a fluorescent microscope. The efficacy rate was examined at 3-month post-surgery by clinical scores and biomarkers. RESULTS: Lymph flow obstruction was observed on both sides of cervical area in the AD patients. The obstruction was successfully resolved through the surgery, and AD progression was attenuated or even reversed in the patients according to improvement in the scales of MMSE, ADL, NPI, CDR-SB, and CGI-EI. The average effectiveness rate was 50% by the CDR-SB score improvement. The efficacy was higher with shorter disease duration but not influenced by age and APOE4 genotype. Aβ42/40 ratio and p-tau181 were improved in more than 67% patients. There were 2 cases of mild adverse reactions that were controlled immediately by regular treatments. CONCLUSIONS: The data demonstrate that dcLVA surgery is an effective and safe therapy for AD in mild-to-moderate patients with 50% efficacy rate as measured by improvement of the CDR-SB score.}, } @article {pmid41048557, year = {2025}, author = {Jeong, H and Kang, D and Kim, JE and Lim, J and Lee, HW}, title = {Preliminary study on the feasibility of virtual reality-based cognitive training on patients with mild to moderate Alzheimer's disease.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251385901}, pmid = {41048557}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that causes a decline in cognitive functions, considerably affecting a patient's life. Recently, virtual reality (VR) technology has emerged as a new tool used in the cognitive training of patients with AD. OBJECTIVE: This study aimed to investigate the safety, feasibility, and clinical efficacy of VR-based cognitive training for patients with mild to moderate AD. METHODS: Thirteen participants diagnosed with mild to moderate AD underwent VR training sessions by using the MentiTree software. Each session was conducted for 30 min twice a week for 9 weeks (total of 540 min). Cognitive functions were assessed before and after the intervention. RESULTS: Although 1 of the 13 participants experienced adverse effects, the 9-week cognitive training was well tolerated and had a high feasibility of 93%±24.65%. A tendency toward improvement was observed in the visual recognition memory of the participants (p = 0.034), but other domains did not significantly change. CONCLUSIONS: VR-based cognitive training is safely accepted by patients with mild to moderate AD. The potential of VR in AD treatment should be further explored using a randomized control group.}, } @article {pmid41048330, year = {2025}, author = {Puducheri, S and Zhou, OT and Kapadia, K and Romano, MF and Yalamanchili, S and Agrawal, A and Carlota Andreu-Arasa, V and Farris, CW and Mian, AZ and Paul, AB and Rohatgi, S and Setty, BN and Small, JE and Kolachalama, VB}, title = {Augmenting radiological assessment of imaging evident dementias with radiomic analysis.}, journal = {NPJ dementia}, volume = {1}, number = {1}, pages = {27}, pmid = {41048330}, issn = {3005-1940}, abstract = {Accurate differential diagnosis of dementia is essential for guiding timely treatment, particularly as anti-amyloid therapies become more widely available and require precise patient characterization. Here, we developed a radiomics-based machine learning (ML) approach to enhance neuroimaging assessments in distinguishing Alzheimer's disease (AD) from other imaging-evident dementias (OIED). We retrospectively analyzed 1041 individuals from the National Alzheimer's Coordinating Center with confirmed dementia diagnoses and at least one T1 or T2/FLAIR MRI scan. Using FastSurfer and a Lesion Prediction Algorithm, we extracted volumetric and lesion features, which were then used to train ML models. Model performance was compared to the independent evaluations of seven fellowship-trained neuroradiologists. The classifier achieved an AUROC of 0.79 ± 0.01 for AD and 0.66 ± 0.03 for OIED, performing comparably to expert assessments. Interpretation using SHAP values showed strong alignment with imaging features known to align with AD or OIED, respectively. These findings highlight the potential of radiomics to augment neuroimaging workflows.}, } @article {pmid41047765, year = {2025}, author = {Jayarathne, H and Manchanayake, DH and Sullivan, R and Chimienti, N and Kadri, O and Gurdziel, K and Kim, S and Jang, H and Ginsburg, BC and Miller, RA and Yakar, S and Sadagurski, M}, title = {Canagliflozin Reprograms the Aging Hippocampus in Genetically Diverse UM-HET3 Mice and Attenuates Alzheimer's-Like Pathology.}, journal = {Aging cell}, volume = {24}, number = {12}, pages = {e70255}, pmid = {41047765}, issn = {1474-9726}, support = {R01 ES033171/ES/NIEHS NIH HHS/United States ; P30 ES036084/ES/NIEHS NIH HHS/United States ; P30ES036084//CURES/ ; P30ES020957/ES/NIEHS NIH HHS/United States ; P30CA022453/GF/NIH HHS/United States ; P30 CA022453/CA/NCI NIH HHS/United States ; P30 ES020957/ES/NIEHS NIH HHS/United States ; R01ES033171/ES/NIEHS NIH HHS/United States ; S10 OD030484/OD/NIH HHS/United States ; //Impetus Grants for Longevity Research/ ; RF1AG078170/AG/NIA NIH HHS/United States ; RF1 AG078170/AG/NIA NIH HHS/United States ; S10OD030484/GF/NIH HHS/United States ; P30ES036084/GF/NIH HHS/United States ; }, mesh = {Animals ; *Hippocampus/drug effects/pathology/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; *Canagliflozin/pharmacology/therapeutic use ; Male ; Female ; *Aging/drug effects ; Disease Models, Animal ; Mice, Transgenic ; }, abstract = {Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana's potential to combat brain aging and AD through sex-specific mechanisms.}, } @article {pmid41047763, year = {2025}, author = {Pinto, A and Haytural, H and Loss, CM and Alvarez, C and Ertas, A and Curtis, O and Williams, AR and Murphy, G and Salleng, KJ and Gografe, S and Visavadiya, NP and Khamoui, AV and Altıntaş, A and Kafri, T and Barres, R and Deshmukh, AS and van Praag, H}, title = {Muscle Cathepsin B Treatment Improves Behavioral and Neurogenic Deficits in a Mouse Model of Alzheimer's Disease.}, journal = {Aging cell}, volume = {24}, number = {11}, pages = {e70242}, pmid = {41047763}, issn = {1474-9726}, support = {NNF18CC0034900//Novo Nordisk Fonden/ ; NNF23SA0084103//Novo Nordisk Fonden/ ; NNF19SA0059305//Novo Nordisk Fonden/ ; R01 HL155986/HL/NHLBI NIH HHS/United States ; 9AZ02//Florida Department of Health/ ; RO1HL155986/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Cathepsin B/pharmacology/therapeutic use/metabolism ; Mice ; Disease Models, Animal ; *Neurogenesis/drug effects ; *Muscle, Skeletal/metabolism/drug effects ; Hippocampus/metabolism ; *Behavior, Animal/drug effects ; Male ; Mice, Transgenic ; }, abstract = {Increasing evidence indicates skeletal muscle function is associated with cognition. Muscle-secreted protease Cathepsin B (Ctsb) is linked to memory in animals and humans, but has an unclear role in neurodegenerative diseases. To address this question, we utilized an AAV-vector-mediated approach to express Ctsb in skeletal muscle of APP/PS1 Alzheimer's disease (AD) model mice. Mice were treated with Ctsb at 4 months of age, followed by behavioral analyses 6 months thereafter. Here we show that muscle-targeted Ctsb treatment results in long-term improvements in motor coordination, memory function, and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment normalizes hippocampal, muscle, and plasma proteomic profiles to resemble that of wildtype (WT) controls. In AD mice, Ctsb increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes. In muscle, Ctsb treatment elevates protein translation in AD mice, whereas in WT mice mitochondrial proteins decrease. In WT mice, Ctsb treatment causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.}, } @article {pmid41047679, year = {2025}, author = {Wang, R and Yang, X}, title = {Research Progress on the Pathogenesis, Therapeutic Strategies, and Phthalocyanine Compounds for Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050406141250822082635}, pmid = {41047679}, issn = {1875-5828}, abstract = {Alzheimer's disease (AD) is a formidable and complex neurodegenerative disorder driven by multifactorial interactions, including amyloid-beta (Aβ) aggregation, neurofibrillary tangles, and neuroinflammation etc. Current therapies mainly consist of cholinesterase inhibitors and NMDA receptor antagonists, which can alleviate symptoms but fail to reverse disease progression. In recent years, emerging approaches such as immunotherapy and gene therapy have shown potential but remain in clinical exploration. Phthalocyanine (Pc) compounds, with their ability to inhibit Aβ fibril formation, favorable biocompatibility, and optical properties, have demonstrated potential in AD diagnosis and treatment. This review discusses the pathogenesis, therapeutic strategies, and research progress of Pc compounds in AD. Furthermore, the elucidation of their mechanisms of action, the optimization of blood-brain barrier penetration, and the promotion of clinical translation are needed to provide new directions for AD therapy.}, } @article {pmid41047654, year = {2025}, author = {Shichijo, F}, title = {[Precautions for Neurosurgeons in Administering Anti-Amyloid β Antibody Therapy].}, journal = {No shinkei geka. Neurological surgery}, volume = {53}, number = {5}, pages = {1000-1012}, doi = {10.11477/mf.030126030530051000}, pmid = {41047654}, issn = {0301-2603}, mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy ; *Amyloid beta-Peptides/immunology ; *Antibodies, Monoclonal/therapeutic use ; *Neurosurgeons ; }, abstract = {In Japan, anti-amyloid β (Aβ) monoclonal antibodies, including lecanemab and donanemab, have recently been approved as disease-modifying therapies for early-stage Alzheimer's disease (AD). These drugs, developed based on the amyloid cascade hypothesis, target toxic Aβ aggregates: lecanemab selectively binds to soluble protofibrils, while donanemab targets Aβ plaques. The Ministry of Health, Labour and Welfare (MHLW) has issued Optimal Use Guidelines that specify criteria for administration: informed consent from both patients and caregivers; cognitive assessments (MMSE and CDR); confirmation of Aβ pathology via amyloid PET or cerebrospinal fluid (CSF) testing; and MRI screening to assess the risk of amyloid-related imaging abnormalities (ARIA). ARIA is a significant adverse event and requires regular MRI monitoring. Initial administration is limited to certified facilities staffed by experienced specialists and equipped with the necessary diagnostic infrastructure. After six months, treatment may be continued at collaborating institutions. The APOEε4 genotype is a known risk factor for ARIA but is not covered by insurance. Caution is advised when co-administering anticoagulants or antiplatelet agents. The guidelines also require the use of official treatment cards to inform healthcare providers. This article summarizes the clinical precautions, diagnostic requirements, and facility standards necessary for implementing anti-Aβ antibody therapy in accordance with current MHLW Guidelines in Japan.}, } @article {pmid41047650, year = {2025}, author = {Miyajima, M and Kawai, Y and Bandai, H}, title = {[Hydrocephalus and Dementia].}, journal = {No shinkei geka. Neurological surgery}, volume = {53}, number = {5}, pages = {969-974}, doi = {10.11477/mf.030126030530050969}, pmid = {41047650}, issn = {0301-2603}, mesh = {Humans ; *Dementia/etiology/diagnosis/surgery ; *Hydrocephalus, Normal Pressure/complications/surgery/diagnosis ; Neuropsychological Tests ; }, abstract = {Idiopathic normal pressure hydrocephalus (iNPH), also known as Hakim's disease, is a major cause of reversible dementia in adults. iNPH primarily affects frontal lobe-related cognitive functions, including attention, executive function, and working memory, even in early stages. Although memory impairment is also present, recognition memory is often preserved, distinguishing iNPH from Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD), especially apathy, depression, and anxiety, are common in iNPH and are generally less active than those seen in AD. Neuropsychological assessments reveal significant impairments in frontal lobe tests such as the Frontal Assessment Battery and Trail Making Test-B. Shunt surgery leads to substantial improvement in attention and executive function, reflecting the reversible nature of iNPH. However, memory functions, particularly delayed recall, show limited recovery, indicating possible overlap with neurodegenerative mechanisms. Early surgical intervention is associated with better outcomes, while delayed treatment or advanced brain atrophy may reduce effectiveness. Comprehensive cognitive evaluation is essential for assessing treatment response, planning rehabilitation, and providing appropriate patient and family guidance.}, } @article {pmid41047647, year = {2025}, author = {Ota, M and Arai, T}, title = {[Pharmacological Interventions in Dementia].}, journal = {No shinkei geka. Neurological surgery}, volume = {53}, number = {5}, pages = {943-950}, doi = {10.11477/mf.030126030530050943}, pmid = {41047647}, issn = {0301-2603}, mesh = {Humans ; Cholinesterase Inhibitors/therapeutic use ; *Dementia/drug therapy ; }, abstract = {Pharmacological interventions for dementia include medications aimed at alleviating its core symptom: cognitive dysfunction. These medicines are known as anti-dementia drugs. As our understanding of Alzheimer's disease (AD) has advanced, the amyloid hypothesis stating that amyloid proteins are involved in the pathogenesis of AD has been proposed. To date, anti-dementia drugs such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists have focused on symptomatic treatment. In recent years, based on the amyloid hypothesis, the development of medicines that target either (1) the enzyme that produces amyloid beta (Aβ) or (2) Aβ itself, has been promoted as a treatment strategy for AD. In 2021, the first drug targeting Aβ, aducanumab, was launched in the USA. In Japan, lecanemab and donanemab are now available as monoclonal antibodies targeting Aβ. Additionally, medications have been used to manage the behavioral and psychological symptoms of dementia (BPSD), Parkinsonism, and rapid eye movement sleep behavior disorder. Furthermore, dementia is a major risk factor for delirium, which often occurs during the course of dementia. In this study, we introduce pharmacotherapy with anti-dementia drugs, BPSD treatment, and delirium.}, } @article {pmid41047645, year = {2025}, author = {Ishiguro, T and Kasuga, K}, title = {[Current Status and Future Perspectives of Biomarkers in Alzheimer's Disease Diagnosis].}, journal = {No shinkei geka. Neurological surgery}, volume = {53}, number = {5}, pages = {923-931}, doi = {10.11477/mf.030126030530050923}, pmid = {41047645}, issn = {0301-2603}, mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; *Biomarkers/cerebrospinal fluid/blood ; Amyloid beta-Peptides ; tau Proteins/blood ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia, characterized by the pathological accumulation of amyloid-β (Aβ) and phosphorylated tau in the brain. Recent advances in biomarker technology have significantly improved AD diagnosis and treatment. Cerebrospinal fluid biomarkers and amyloid positron emission tomography imaging are now available in clinical settings and serve as key tools in identifying early-stage AD, especially when considering anti-Aβ monoclonal antibody therapies. In 2024, the Alzheimer's Association proposed revised diagnostic criteria that integrate both biomarker-based and clinical staging systems. This framework introduces a classification of "core biomarkers" that reflect AD-specific pathology and defines biological and clinical symptom stages. Furthermore, blood-based biomarkers, such as plasma p-tau217 and MTBR-tau243, are gaining attention as minimally invasive tools for early diagnosis and disease staging. As these biomarkers become more accessible, proper interpretation within a clinical context remains essential. In Japan, biomarker testing is currently recommended only for symptomatic individuals, and its use requires careful judgment regarding indications and relevance to the clinical setting. This review outlines the evolution of diagnostic criteria, current and emerging biomarkers, and their implications for personalized AD care while emphasizing the need for expert clinical interpretation to ensure responsible and patient-centric use.}, } @article {pmid41047224, year = {2025}, author = {Graham, N and Zimmerman, K and Hain, J and Rooney, E and Lee, Y and Del Giovane, M and Parker, T and Wilson, M and Patel, M and Veleva, E and Swann, O and Heslegrave, AJ and Li, LM and Zetterberg, H and Friedland, D and Sylvester, R and Sharp, D}, title = {Midlife plasma proteomic profiles indicate altered amyloid and tau processing in former elite rugby players.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2025-336593}, pmid = {41047224}, issn = {1468-330X}, abstract = {BACKGROUND: Contact sports, including rugby union, are associated with higher rates of neurodegenerative dementia, due to various underlying pathologies such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). New ultrasensitive multiplexed immunoassays may clarify disease mechanisms after repetitive head impacts (RHI) and traumatic brain injury, potentially aiding risk-stratification, early diagnosis and dementia treatment. METHODS: Midlife participants in the ABHC cohort underwent plasma biomarker quantification (NULISA - NUcleic acid Linked Immuno-Sandwich Assay; n=124 markers), 3T MRI, trauma exposure ascertainment and phenotyping. Regressions quantified exposure-specific protein expression, relationship to trauma (including position) and brain atrophy, using cluster analysis to test correlates of traumatic encephalopathy syndrome (TES). RESULTS: 197 former elite rugby players and 33 controls were assessed. 24 (12.2%) met criteria for TES but none had dementia. Ex-players returned reduced plasma glial fibrillary acidic protein (GFAP), kallikrein-6 (KLK6) and synaptosomal-associated protein 25 (SNAP25). Ex-forwards specifically showed reduced plasma beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid beta-38 (Aβ38), and increased phospho-tau181 (p-tau181). KLK6 was lower in ex-backs than controls. No biomarkers related to career duration, concussion load or regional brain volume, nor did clustering relate to TES. CONCLUSIONS: Ex-players showed distinctive plasma biomarker changes, more prominently in ex-forwards, possibly reflecting greater RHI exposure. Plasma KLK6, an endothelial serine protease, was reduced across the ex-player group, with potential diagnostic or prognostic utility in future. Reduced GFAP and SNAP25 in ex-forwards has an uncertain basis, while elevated p-tau-181 more so than p-tau217 points towards non-AD tau pathology. Our findings motivate longitudinal characterisation, including comparison with other neurodegenerative diseases.}, } @article {pmid41047041, year = {2025}, author = {Fan, X and Wang, H and Ping, J and Li, M and Gu, J and Qian, W}, title = {Synaptic scaffold protein PSD-95: a therapeutic target for Alzheimer's disease.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 3}, pages = {117401}, doi = {10.1016/j.bcp.2025.117401}, pmid = {41047041}, issn = {1873-2968}, mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Disks Large Homolog 4 Protein/metabolism/antagonists & inhibitors/genetics ; Animals ; *Synapses/metabolism/drug effects ; *Drug Delivery Systems/methods ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder marked by gradual cognitive deterioration and distinct neuropathological characteristics. The abnormal accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are the hallmarks of AD. In fact, synaptic loss and damage occur earlier than amyloid plaques and NFTs in the progression of AD and are most closely associated with the cognitive deficits exhibited by AD patients. In this review, we discuss the expression level, localization, posttranslational modification and interaction proteins of PSD-95, as well as their roles in synaptic plastisity. We also review the mechanisms through which PSD-95 contributes to synaptic dysfunction in AD. Moreover, the potential of PSD-95 as an early biomarker for AD is also discussed, along with the therapeutic approaches that target PSD-95 for patients afflicted with the disease. The objective of this review is to offer comprehensive insights into the early pathogenesis of Alzheimer's disease and to aid in the development of novel diagnostic and treatment methodologies grounded in this understanding.}, } @article {pmid41046825, year = {2025}, author = {Manful, EE and Adu-Amankwaah, F and Madhvi, A and Bubb, K and Pietersen, RD and Baker, B}, title = {Therapeutic potential of IFIT2 in human diseases.}, journal = {Cytokine}, volume = {196}, number = {}, pages = {157049}, doi = {10.1016/j.cyto.2025.157049}, pmid = {41046825}, issn = {1096-0023}, mesh = {Humans ; Neoplasms/metabolism ; Animals ; Autoimmune Diseases/metabolism ; RNA-Binding Proteins/metabolism ; Adaptor Proteins, Signal Transducing ; *Intracellular Signaling Peptides and Proteins/metabolism ; Apoptosis Regulatory Proteins ; }, abstract = {The interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is a crucial member of the interferon-stimulated gene (ISG) family, widely acknowledged for its antiviral activity. IFIT2 functions primarily through AU-rich RNA binding, aiding in viral suppression by inhibiting protein translation and promoting apoptosis via mitochondrial pathways. While traditionally known for its role in antiviral defence, emerging research highlights its broader significance in cancer, bacterial and fungal infections, autoimmune diseases, neurological disorders, and metabolic and cardiovascular conditions. Notably, IFIT2 is the only IFIT family member with established tumour suppressor properties, demonstrating anti-proliferative effects in multiple cancers, including lung, renal, colorectal, breast, and gallbladder cancers. Beyond oncology, IFIT2 has been implicated in the host response to Mycobacterium tuberculosis, Plasmodium spp., Candida albicans, and Treponema pallidum, where it modulates immune responses and infection outcomes. It is upregulated in several autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, and multiple sclerosis, suggesting its potential as a diagnostic and therapeutic biomarker. Furthermore, transcriptomic analyses have linked IFIT2 to disease progression and treatment response in conditions like diabetic ulcers, gestational diabetes, ischaemic cardiomyopathy, schizophrenia, and Alzheimer's disease. This review thoroughly examines the molecular structure, regulatory mechanisms, and diverse roles of IFIT2 in human diseases. It addresses its interaction with key immune pathways, its ability to modulate apoptosis and inflammation, and its potential as a prognostic marker and therapeutic target. Although its mechanistic functions in numerous diseases remain only partly understood, IFIT2 emerges as a versatile immune effector with considerable translational promise. Further investigation into its biological roles will be crucial for utilising its therapeutic potential across infectious, inflammatory, metabolic, and neoplastic diseases.}, } @article {pmid41046632, year = {2026}, author = {Fuh, JL and Wang, SJ and Wang, PN and Wu, HM and Su, WS and Lin, HM and Yang, FY}, title = {Safety and efficacy of transcranial ultrasound stimulation for the treatment of Alzheimer's disease: A randomized, double-blind, placebo-controlled trial.}, journal = {Ultrasonics}, volume = {159}, number = {}, pages = {107844}, doi = {10.1016/j.ultras.2025.107844}, pmid = {41046632}, issn = {1874-9968}, mesh = {Humans ; *Alzheimer Disease/therapy ; Aged ; Double-Blind Method ; Male ; Female ; Aged, 80 and over ; Middle Aged ; *Ultrasonic Therapy/methods/adverse effects ; Pilot Projects ; Treatment Outcome ; Magnetic Resonance Imaging ; }, abstract = {Transcranial ultrasound stimulation (TUS) has emerged as a potential neuromodulatory intervention for Alzheimer's disease (AD). This pilot randomized, double-blind, placebo-controlled trial evaluated TUS's safety and preliminary efficacy in patients with mild AD. Patients aged 50-90 years were enrolled and randomly assigned at a 2:1 ratio to receive TUS treatment for 30 sessions (15 min/day, 5 days/week for 6 weeks) or a placebo procedure. Safety was monitored through magnetic resonance imaging, adverse event reporting, and laboratory assessments. Efficacy was assessed with the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Mini-Mental State Examination (MMSE). Nine of 30 patients screened were enrolled (six TUS, three placebo). All patients completed the study, and no serious clinical or radiographic adverse events related to TUS were observed. At 52 weeks, the change in ADAS-cog score from baseline remained relatively stable in the TUS group compared to worsening in the placebo group (0.5 ± 4.7 vs. 5.0 ± 4.0, p = 0.237), particularly in the memory domain. The change in MMSE score from baseline showed a significant benefit in the TUS group at 24 weeks compared to placebo (2.2 ± 2.2 vs. -3.0 ± 2.6, p < 0.05), and this improvement persisted to 52 weeks. This study demonstrates the safety and feasibility of repeated TUS sessions in AD and suggests potential benefits in preserving cognitive function. Larger, adequately powered trials are required to validate these preliminary findings and further define the therapeutic potential of TUS in AD.}, } @article {pmid41046322, year = {2025}, author = {Wu, KC and Lin, CY and Tran, T and Lin, JH and Yeh, HH and Ho, CJ and Chern, Y and Lin, CJ}, title = {Preclinical Evaluation of a Novel Molecule Targeting Nucleoside Homeostasis to Restore Energy Metabolism and Cognitive Function in Alzheimer's Disease.}, journal = {Pharmacology research & perspectives}, volume = {13}, number = {5}, pages = {e70176}, pmid = {41046322}, issn = {2052-1707}, support = {AS-BRPT-110-11//Academia Sinica, Taiwan/ ; AS-KPQ-111-KNT//Academia Sinica, Taiwan/ ; MOST 110-3111-Y-001-002//Ministry of Science and Technology, Taiwan/ ; MOST 110-3111-Y-001-003//Ministry of Science and Technology, Taiwan/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Energy Metabolism/drug effects ; Mice ; Disease Models, Animal ; *Nucleosides/metabolism ; Homeostasis/drug effects ; Brain/metabolism/drug effects ; Mice, Transgenic ; *Cognition/drug effects ; Male ; Equilibrative Nucleoside Transporter 1/metabolism ; Mice, Inbred C57BL ; Humans ; Cognitive Dysfunction/drug therapy ; Positron-Emission Tomography ; }, abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia, characterized by progressive cognitive decline and cerebral metabolic impairment. Yet, the therapeutic options for addressing the disease pathogenesis are limited. Here, we report an approach by targeting brain nucleoside homeostasis and energy metabolism to alleviate AD-associated cognitive deficits. A compound, J4, was designed to modulate nucleoside homeostasis by interacting with the equilibrative nucleoside transporter-1 (ENT1). The effects of J4 on brain nucleoside homeostasis and energy metabolism were examined in mice. Two AD animal models, THY-Tau22 and APP/PS1 mice, were used to evaluate the translational potential of J4 for the treatment of AD. Cognitive function and functional ability were assessed using the Morris water maze, Y-maze, and nesting behavior tests. The pharmacodynamic marker was explored, and the pharmacokinetic and safety properties of J4 were evaluated. As a result, being administered after disease onset, oral J4 administration rescued memory and cognitive dysfunction in both tau and amyloid AD mouse models. Metabolomic analysis showed that J4 increased brain nucleoside levels and facilitated brain primary metabolism, including glucose metabolism and the pentose phosphate pathway. The [[18]F]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging further demonstrated that glucose metabolism can be used as a pharmacodynamic biomarker for the target engagement of J4 on ENT1. The nonclinical studies also demonstrated the ideal pharmacokinetic and safety profiles of J4, supporting that targeting nucleoside homeostasis can improve brain energy metabolism and is a promising approach for AD treatment.}, } @article {pmid41046244, year = {2025}, author = {Chatterjee, S and Soria, M and Norville, ZC and Thompson, KR and Lillie, J and Kreitzer, AC and Wood, MW}, title = {Preclinical efficacy of the muscarinic agonist ML-007 in psychosis models depends on both M1 and M4 receptors.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {41046244}, issn = {1740-634X}, abstract = {Muscarinic agonists represent a new class of treatments for psychosis with a mechanism distinct from typical and atypical antipsychotics. The muscarinic subtype M4 has been proposed as the primary mediator of efficacy but results from recent clinical trials with M4-selective compounds have drawn this hypothesis into question. Instead, activation of both M1 and M4 receptor subtypes may be required for robust treatment effects. Here, we characterize the clinical-stage muscarinic agonist ML-007 in preclinical models and explore its therapeutic potential for treating psychosis in schizophrenia and Alzheimer's disease. ML-007 is a potent brain-penetrant agonist at both M1 and M4 muscarinic receptors that has demonstrated compelling efficacy across a range of preclinical models of psychosis in schizophrenia including amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, and conditioned avoidance response. Moreover, ML-007 is approximately ten-fold more potent than the comparator xanomeline in all animal models. Dose-response experiments in M1 and M4 knockout mice reveal that the efficacy of ML-007 is dependent on both M1 and M4 receptors. Taken together, our data suggest that both M1 and M4 receptors contribute to the potent efficacy of ML-007 in preclinical rodent models of psychosis.}, } @article {pmid41046022, year = {2025}, author = {Zhou, X and Lin, X and He, Y and Huang, N and Luo, Y}, title = {TDP-43 in Alzheimer's disease: Pathophysiology and therapeutic strategies.}, journal = {Pharmacological research}, volume = {221}, number = {}, pages = {107977}, doi = {10.1016/j.phrs.2025.107977}, pmid = {41046022}, issn = {1096-1186}, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/physiopathology ; *DNA-Binding Proteins/metabolism/genetics/antagonists & inhibitors ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Brain/metabolism/drug effects/pathology/physiopathology ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the dysregulation of multiple molecular mechanisms. In recent years, transactive response DNA-binding protein 43 kDa (TDP-43) has increasingly been recognized as a critical pathological protein and has become a prominent focus in AD research. TDP-43 is involved not only in physiological processes such as RNA metabolism, protein quality control, and mitochondrial regulation but also in AD pathology through abnormal aggregation, dysregulated nucleocytoplasmic transport, and aberrant posttranslational modifications, leading to neurotoxicity, mitochondrial dysfunction, and disrupted protein homeostasis. Studies have shown that TDP-43 closely interacts with two core pathological hallmarks of AD, β-amyloid (Aβ) and tau. By promoting Aβ oligomerization and tau hyperphosphorylation, TDP-43 accelerates the pathological progression of this disease. Given the multifaceted role of TDP-43 in AD, therapeutic strategies targeting TDP-43 have shown great potential. Approaches such as modulating its RNA splicing activity, inhibiting pathological aggregation, restoring the balance of nucleocytoplasmic transport, and preventing its mitochondrial localization offer new avenues for AD treatment. This review systematically summarizes the pathological mechanisms of TDP-43 in AD and its interactions with Aβ and tau and discusses the feasibility of targeting TDP-43 as a therapeutic strategy. Future studies should further elucidate the role of TDP-43 in the early stages of AD and develop specific therapeutic agents that target TDP-43, with the aim of providing new insights for precision treatment of AD.}, } @article {pmid41045719, year = {2025}, author = {Swerdlow, NR and Sprock, J and Gonzalez, CE and Din, JM and Minhas, J and Talledo, J and Molina, JL and Joshi, YB and Léger, GC and Powell, L and Rana, B and Delano-Wood, L and Light, GA}, title = {Do cognitive and neurophysiological effects of acute memantine "challenge" predict its clinical benefits in Alzheimer's Disease?.}, journal = {Psychiatry research}, volume = {353}, number = {}, pages = {116740}, doi = {10.1016/j.psychres.2025.116740}, pmid = {41045719}, issn = {1872-7123}, abstract = {"Personalized" interventions based on patients' "biomarkers" may be valuable for treatments that benefit only subsets of patients. The NMDA antagonist, memantine, slows clinical progression of Alzheimer's disease (AD); this effect is heterogeneous in magnitude and duration. This study tested whether acute cognitive or neurophysiological responses to memantine challenge predicted sensitivity to memantine's therapeutic effects. Thirty individuals with mild-to-moderate severity AD (M:F = 13:17) and 24 comparably aged healthy subjects (HCS) (M:F = 12:12) were enrolled. Participants with AD were characterized on 9 experimental measures and their changes after acute memantine "challenge" (20 mg). We then assessed whether acute memantine effects on these measures predicted clinical change over a 24-week open-label trial of memantine. Baseline cognitive (Repeatable Battery for the Assessment of Neuropsychological Status) and neurophysiological measures (prepulse inhibition, P3a latency and auditory steady state response power and coherence) were impaired in participants with AD (p's<0.05-0.0001); neurophysiological deficits were modestly reduced by acute memantine challenge. As a group, participants with AD showed no significant clinical changes across 24 weeks of memantine treatment; subgroups exhibited either small gains or deterioration. With one exception (mismatch negativity latency, p < 0.017), sensitivity of experimental measures to acute memantine challenge did not significantly predict clinical sensitivity to memantine. In summary, a challenge dose design identified neurophysiological measures sensitive to memantine in mild-to-moderate severity AD; acute memantine effects on one measure weakly predicted clinical outcomes over 24 weeks. Impairment in specific measures among participants with AD, and their opposition by memantine, might inform future efforts to identify treatment biomarkers in AD.}, } @article {pmid41045350, year = {2025}, author = {Alsaadi, T and Almadani, A and AlRukn, S and Hassan, A and Sarathchandran, P and Shatila, A and Szolics, M and Benito, D and Ince, S and Krieger, DW}, title = {Expert Guidance on Cognitive Impairment in Alzheimer's Disease: A Practical Seven-Step Approach from the United Arab Emirates.}, journal = {Neurology and therapy}, volume = {14}, number = {6}, pages = {2507-2535}, pmid = {41045350}, issn = {2193-8253}, abstract = {INTRODUCTION: Cognitive impairment (CI) spans a spectrum from mild CI to severe dementia, with Alzheimer's disease (AD) the most prevalent cause of CI and dementia. Although dementia burden and prevalence in Arab countries reflect general global trends, the United Arab Emirates (UAE) differs from Western countries both culturally and regarding management resources. Further guidance is therefore needed for the diagnosis and management of CI in the UAE. METHODS: A task force of eight neurologists and two non-voting collaborators with special dementia expertise was convened to develop evidence-based position statements/recommendations to guide the diagnosis and management of AD, including the use of amyloid-targeting therapies (ATTs), in the UAE clinical setting. A modified Delphi survey method was chosen to obtain a consensus, ensuring that drafted expert statements reflected diverse perspectives and experiences. Discordance was predefined as > 25% of panelists rating an expert statement as ≤ 3 on the Likert scale. Consensus was predefined as a median rating ≥ 7 without discordance. Expert statements achieving consensus were adopted. RESULTS: A seven-step framework for diagnosing and managing CI in the UAE was developed, with consensus achieved on all statements. Recommendations largely aligned with international guidelines on AD dementia management and treatment, combined with UAE-specific guidance. The framework spans the full patient journey from initial symptoms to diagnosis (including biomarker use), initial treatment (including ATTs where appropriate), and subsequent monitoring and management as the disease progresses. CONCLUSIONS: Management of CI and dementia in UAE requires consideration of international guidelines in the context of regional and local cultural sensitivities and healthcare resources. A holistic approach is recommended, combining appropriate pharmacological treatment with lifestyle interventions, education, and support for patients and care partners. Patients require ongoing monitoring to ensure the approach is tailored to the disease stage and provides optimal quality of life and reduced burden for patients and care partners.}, } @article {pmid41044993, year = {2025}, author = {Yan, Q and Qin, Q and Zhang, S and Chen, F and Ru, Y and Zhong, Y and Wu, G}, title = {Glial cell nutrient sensing: mechanisms of nutrients regulating Alzheimer's pathogenesis and precision intervention.}, journal = {Critical reviews in food science and nutrition}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/10408398.2025.2568606}, pmid = {41044993}, issn = {1549-7852}, abstract = {Modern nutrition is a core element of clinical treatment. Although some literature addresses neuro-nutrition's effects on Alzheimer's disease (AD), a systematic discussion of how the body's six essential nutrients impact AD is lacking. Moreover, neural glial cells directly participate in the pathological regulation of AD. A novel conceptual framework linking "essential nutrients - glial cells - AD" needs to be summarized. Therefore, this review examines the regulatory roles of glial cells (astrocytes, microglia, and their networks) in AD and explores how essential nutrients impact AD via glial cells. Specifically, vitamins (NR, NMN, etc.), minerals (copper, iron, selenium, etc.), proteins and amino acids (arginine, citrulline, methionine, etc.), lipids (fatty acids, phosphatidylinositol, etc.), and carbohydrates (trehalose, oligosaccharides, plant polysaccharides, etc.) can influence important functions such as brain energy metabolism remodeling, inflammatory factor secretion, and phagocytic clearance by regulating microglia and astrocytes. Moreover, a significant strength of this review is its clear exposition of nutrient alterations observed in AD patients, coupled with detailed recommendations for nutritional interventions targeting AD prevention and management. Furthermore, it also investigated beneficial dietary patterns for improving AD. In conclusion, this review explores the "essential nutrients -glial cell" molecular interactions, laying the foundation for precision nutrition-based AD strategies.}, } @article {pmid41042852, year = {2025}, author = {Bellaflor, S and Barfoot, MK and Boddy, J and Wallace, PJ and Baranowski, RW and Cheung, SS and Fajardo, VA and MacPherson, REK}, title = {Heat therapy increases brain HSP70 and BDNF content in male mice.}, journal = {Journal of neurophysiology}, volume = {134}, number = {5}, pages = {1445-1452}, doi = {10.1152/jn.00301.2025}, pmid = {41042852}, issn = {1522-1598}, support = {2017-03904//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; 2019-05833//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; 2018-04077//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; Male ; *HSP70 Heat-Shock Proteins/metabolism ; Mice ; *Hyperthermia, Induced ; *Hippocampus/metabolism ; *Prefrontal Cortex/metabolism ; Pilot Projects ; *Brain/metabolism ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Aspartic Acid Endopeptidases/metabolism ; }, abstract = {Heat shock proteins (HSPs) are molecular chaperones that play important roles in protein homeostasis, with HSP70 linked to a role in neuroprotection. HSP70 is upregulated in response to various stressors, such as heat therapy (HT), which has been shown to increase brain-derived neurotrophic factor (BDNF) content. BDNF reduces the activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the rate-limiting enzyme responsible for the generation of amyloid-β (Aβ) peptides that form the characteristic Aβ plaques observed in Alzheimer's disease brains. The current pilot study examined whether 4 wk of HT can increase HSP70 and BDNF content (pro and mature forms) in the brain, and alter markers of amyloid precursor protein (APP) processing. Male mice had their core temperature maintained between 37.0 and 38.0°C in Control (CON, n = 16) and 40.5 and 41.5°C in Heat Therapy (HT, n = 16) for 20 min every 72 h over 4 wk. Seventy-two hours after the last treatment, the prefrontal cortex (PFC) and hippocampus (HIP) were collected. HT significantly increased HSP70 levels in both the hippocampus and prefrontal cortex compared with controls (P = 0.0007, PFC CON = 1.001 [0.314], PFC HT = 1.546 [0.948], HIP CON = 1.000 [0.356], HIP HT = 2.207 [0.756]). In the HIP, proBDNF levels were also higher in the HT group relative to both the control group and the PFC (P < 0.05, PFC CON = 1.000 [0.156], PFC HT = 0.984 [0.607], HIP CON = 1.001 [0.242], HIP HT = 1.575 [0.482]. There were no differences in mature BDNF in either PFC or HIP regions (P > 0.05, PFC CON = 1.000 [0.273], PFC HT = 1.174 [0.266], HIP CON = 0.999 [0.130], HIP HT = 0.971 [0.207]), The findings from our pilot study suggest that HT enhances the expression of HSP70 and BDNF, indicating the potential to modulate key neuroprotective proteins. Future studies in dedicated preclinical mouse models of Alzheimer's disease using the heat therapy regimen are warranted.NEW & NOTEWORTHY Four weeks of heat therapy increases heat shock protein (HSP)70 and brain-derived neurotrophic factor (BDNF) levels in the hippocampus and prefrontal cortex of mice, regions crucial for memory and cognition. These findings highlight the promise of heat therapy as a nonpharmacological strategy to enhance brain resilience against neurodegenerative diseases.}, } @article {pmid41042837, year = {2025}, author = {Boongird, C and Anothaisintawee, T and Tearneukit, W and Wongpipathpong, W and Suthutvoravut, U and Thongpan, M and Pongsettakul, N and Attia, J and McKay, GJ and Rattanasiri, S and Thakkinstian, A}, title = {Bridging the gap: Efficacy of combined therapies for cognitive, behavioral, and functional outcomes in Alzheimer's disease - results from a systematic review and network meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {509-521}, pmid = {41042837}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology/drug therapy ; Cognition ; *Cognitive Behavioral Therapy/methods ; Combined Modality Therapy ; Donepezil/therapeutic use ; Randomized Controlled Trials as Topic ; Rivastigmine/therapeutic use ; Treatment Outcome ; }, abstract = {BackgroundEvidence regarding efficacy of combined pharmaco- and non-pharmacotherapies and their comparative effectiveness for Alzheimer's disease (AD) is limited.ObjectiveTo estimate the comparative efficacy of pharmacotherapies, non-pharmacotherapies, and combined therapies for improving cognitive, behavioral, and functional outcomes in patients with AD.MethodsRelevant studies were identified from Medline via PubMed and Scopus databases (March 2021-December 2022). Randomized-controlled trials were eligible if they assessed the efficacy of pharmacotherapies, non-pharmacotherapies, or combined therapies in patients aged 60 years or older, and measuring cognitive, behavioral, or functional outcomes. A network meta-analysis was conducted to estimate relative treatment effects, and interventions were ranked using surface under the cumulative ranking (SUCRA) curve. Confidence in the findings was evaluated using the Confidence in Network Meta-Analysis (CINeMA) framework.ResultsA total of 153 randomized-controlled trials were analyzed. Compared to placebo/usual care, donepezil plus cognitive therapy and rivastigmine plus cognitive rehabilitation significantly improved Mini-Mental State Examination scores. Behavioral outcomes were improved by rivastigmine plus cognitive stimulation, brain stimulation plus exercise, and occupational therapy. Functional status improved significantly with rivastigmine plus cognitive stimulation and exercise. Based on SUCRA ranking, rivastigmine plus cognitive rehabilitation ranked highest for cognitive improvement (92.8%), brain stimulation plus exercise ranked highest for the behavioral outcome (93.1%), and rivastigmine plus cognitive stimulation ranked highest for functional improvement (94.1%).ConclusionsDonepezil plus cognitive therapy and rivastigmine plus cognitive rehabilitation were the most effective treatments for improving cognitive outcomes. Rivastigmine plus cognitive stimulation ranked highest for both behavioral and functional outcomes, while exercise remains an important strategy for supporting daily functioning in patients with AD.}, } @article {pmid41042700, year = {2025}, author = {Xu, X and Tan, H and Yin, K and Xu, S and Wang, Z and Serrano, GE and Beach, TG and Wang, X and Peng, J and Wu, R}, title = {Comprehensive and Site-Specific Characterization of Protein N-Glycosylation in AD Samples Reveals Its Potential Roles in Protein Aggregation and Synaptic Dysfunction.}, journal = {Analytical chemistry}, volume = {97}, number = {40}, pages = {21873-21882}, pmid = {41042700}, issn = {1520-6882}, support = {P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; R35 GM156318/GM/NIGMS NIH HHS/United States ; RF1 AG064909/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Glycosylation ; *Alzheimer Disease/metabolism/pathology ; *Protein Aggregates ; *Glycoproteins/metabolism/chemistry/analysis ; Proteomics ; *Synapses/metabolism ; Male ; Female ; Brain/metabolism ; Aged ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Emerging evidence strongly suggests that protein glycosylation is strongly related to this disease. However, the extent and functional consequences of site-specific N-glycosylation alterations in AD remain to be further explored. Here, we employed a dendrimer boronic acid (DBA)-based enrichment strategy combined with multiplexed proteomics to systematically analyze protein N-glycosylation in post-mortem human brain tissues. We identified 3,105 N-glycosylation sites on 1,299 glycoproteins from nine AD cases and nine healthy controls, and performed a systematic and site-specific investigation of glycosylation alterations in AD. Glycoproteins involved in cholesterol efflux were upregulated, whereas those associated with chemical synaptic transmission and ion transport were significantly downregulated in AD compared to control brain samples. We observed widespread dysregulation of N-glycosylation across multiple protein domains, particularly in the ConA-like lectins/glucanases and Zn-dependent exopeptidases domains. Notably, we identified 161 N-glycosylation sites located within aggregation-prone regions (APRs), and reduced glycosylation at APRs on plaque-associated glycoproteins may be associated with protein aggregation and plaque formation. Additionally, downregulated N-glycosylation sites were enriched in synaptic membrane proteins, such as Ca[2+] ion channels, GABA-gated chloride channels, and glutamate receptors, implicating glycosylation loss in synaptic dysfunction. Our findings suggest that the loss of N-glycosylation may contribute to the pathogenesis of AD through impairing synaptic transmission and promoting protein aggregation. This study provides novel insights into glycosylation-dependent mechanisms of neurodegeneration, highlighting N-glycosylation as a potential therapeutic target for AD treatment.}, } @article {pmid41042497, year = {2025}, author = {Schreiber, CP and Kovacik, A and Bishop, J and Helman, J}, title = {Amyloid-related Imaging Abnormalities (ARIA) in the Context of Alzheimer's Disease and Amyloid-targeting Therapies: An Introduction for Advanced Practice Providers.}, journal = {Drugs & aging}, volume = {42}, number = {12}, pages = {1103-1111}, pmid = {41042497}, issn = {1179-1969}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; Brain/diagnostic imaging/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the accumulation of amyloid-beta (Aβ) and neurofibrillary tangles of hyperphosphorylated tau in the brain. Amyloid-targeting therapies (ATTs) are the first available disease-modifying treatments shown to slow cognitive and functional decline for patients with mild cognitive impairment owing to AD and early symptomatic AD. Currently two ATTs are commercially available, donanemab (Kisunla™) and lecanemab (Leqembi[®]). The main potential side effect and safety concern of ATT treatment is amyloid-related imaging abnormalities (ARIA). ARIA can be categorized into two types that can co-occur: ARIA-E (edema/sulcal effusion) and ARIA-H (hemorrhage/superficial siderosis). Although both are often asymptomatic and ARIA-E typically resolves radiographically over time, both forms can be radiologically and/or clinically serious. Treating clinicians should be equipped with a comprehensive understanding of ARIA. This review aims to provide advanced practice providers, who are pivotal to patient care in AD, with critical insights into ARIA to safely identify risk factors, understand treatment guidelines, and gain familiarity with appropriate management strategies. It emphasizes the importance of understanding APOE genotype and vascular factors in ARIA risk and recognizing the clinical and radiographic manifestations of ARIA. Practical recommendations are provided for monitoring and managing ARIA, including dose management strategies and education on symptom awareness. By fostering a comprehensive understanding of ARIA and its monitoring and management, this review aims to support the safe and effective implementation of ATTs, contributing to optimized patient care for those treated with ATTs.}, } @article {pmid41042431, year = {2025}, author = {Shah, N and Natesan, G and Gupta, R}, title = {Uncovering Necroptosis in Alzheimer's Disease: A Systematic Review of Evidence Across Experimental Models.}, journal = {Cellular and molecular neurobiology}, volume = {45}, number = {1}, pages = {83}, pmid = {41042431}, issn = {1573-6830}, mesh = {*Necroptosis/physiology ; *Alzheimer Disease/pathology/metabolism ; Humans ; Animals ; Disease Models, Animal ; Signal Transduction ; }, abstract = {Alzheimer's disease (AD), one of the most challenging neurodegenerative disorders, with high prevalence worldwide, is characterized by progressive cognitive decline and accumulation of amyloid-β plaques and neurofibrillary tau tangles. Despite significant research, the limited efficacy of current treatments underscores the critical need to identify novel pathogenic mechanisms and therapeutic targets. Necroptosis, a regulated and highly inflammatory form of programmed cell death, has emerged as one of the key contributors to AD pathogenesis. This systematic review comprises 25 high-quality in vivo, in vitro, and autopsy studies, published between 2015 and 2025, extracted from PubMed, Scopus, and Science Direct databases. The keywords include "necroptosis", "RIPK1", "RIPK3", "MLKL", "pMLKL", "necroptosis inhibitors", "Alzheimer's disease", and "neurodegeneration". The review summarizes the multiple molecular mechanisms, including TNF-α/TNFR1 signaling, TRIF-mediated RIPK3 activation, and RHIM-dependent MLKL phosphorylation, associated with necroptosis in the pathogenesis of AD. All the studies converge on necroptosis as a central pathogenic pathway linking key molecular and cellular abnormalities observed in AD. The accumulated evidence strongly supports prioritizing the development of brain-penetrant necroptosis inhibitors and clinical validation of associated biomarkers. These insights signal a significant shift in AD therapeutics, moving from symptomatic treatment to mechanistically targeted interventions that can alter disease progression.}, } @article {pmid41041548, year = {2025}, author = {Trigiani, L and Chernavsky, N and Kim, R and Hong, N and Hawkins, R and Le, E and Bahninameh, Z and Yamaguchi, K and Bernard, J and Huang, A and Rivera, D and Allan-Rahill, N and Lamont, M and Marongiu, R and Iadecola, C and Nishimura, N and Schaffer, C}, title = {Memory deficits in hypertensive ApoE4 mice reversed by P2Y12 inhibition via different mechanisms in males and perimenopausal females.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41041548}, issn = {2693-5015}, support = {R01 NS108472/NS/NINDS NIH HHS/United States ; R21 AG064455/AG/NIA NIH HHS/United States ; R01 NS095441/NS/NINDS NIH HHS/United States ; R01 NS127156/NS/NINDS NIH HHS/United States ; R01 NS126467/NS/NINDS NIH HHS/United States ; RF1 AG049952/AG/NIA NIH HHS/United States ; }, abstract = {Apolipoprotein E4 (ApoE4) genotype, hypertension, and biological sex are critical risk factors for Alzheimer's disease and related dementias. Yet, their combined impact on early cerebrovascular dysfunction, brain inflammation, and memory impairment remains poorly understood. We developed a translational mouse model incorporating human ApoE4, hypertension via angiotensin II infusion, and induced accelerated ovarian failure (AOF) to mimic perimenopause in females to investigate these interactions. Hypertensive ApoE4 mice of both sexes exhibited impaired spatial working memory, decreased cerebral blood flow, increased neuroinflammation, and decreased blood brain barrier integrity, recapitulating key early clinical features observed in human populations with these risk factors. Brain blood flow reduction was associated with an increased incidence of capillary stalling, with notable sex differences in the extent and cellular composition of stalls: in males, stalling was strongly elevated and mostly due to red blood cell arrest, while stalling was modestly elevated in peri-AOF females with most stalls including leukocytes. Treatment with prasugrel, a P2Y12 receptor inhibitor, improved memory performance in both sexes but was correlated with different physiological effects - restored cerebral blood flow in males and reduced microglia motility and inflammation in peri-AOF females. Platelet depletion mimicked prasugrel's blood flow and cognitive benefits in males, while microglia depletion selectively rescued memory in females. Our work emphasizes the necessity of including translationally relevant female mouse models in neurodegenerative disease studies, and our findings highlight the importance of risk profile-specific interventions and demonstrate that early vascular dysfunction may be a key, sex-dependent driver of cognitive decline.}, } @article {pmid41040848, year = {2025}, author = {Kumar, A and Pichet Binette, A and Bali, D and Janelidze, S and Stomrud, E and Palmqvist, S and Vogel, JW and Hansson, O and Mattsson-Carlgren, N}, title = {Cell-weighted polygenic risk scores are associated with β-amyloid and tau biomarkers in Alzheimer's disease.}, journal = {Brain communications}, volume = {7}, number = {5}, pages = {fcaf353}, pmid = {41040848}, issn = {2632-1297}, abstract = {The molecular pathways influencing the build-up of β-amyloid and tau pathology in Alzheimer's disease are unclear. To investigate how the involvement of different cell types influences β-amyloid and tau, we utilized single-cell RNA-seq data to derive cell-weighted polygenic risk scores. We included participants from the BioFINDER-1 study, including cognitively unimpaired (N = 734) individuals and patients with mild cognitive impairment (N = 235), Alzheimer's diseasedementia (N = 97) or non-Alzheimer's disease neurodegenerative diseases (N = 227). We developed seven polygenic risk scores, including six cell-weighted (for astrocytes, excitatory neurons, inhibitory neurons, microglia, oligodendrocyte precursor cells and oligodendrocytes) and one full polygenic risk score without cell specificity. For each of the polygenic risk score models, we calculated seven scores (polygenic risk score 1-7) based on different P-value thresholds (ranging from P-value < 0.05 to P-value < 5e-08) of variants from an independent large Alzheimer's disease genome-wide association study. We tested associations between the polygenic risk scores with β-amyloid [using cerebrospinal fluid (CSF) β-amyloid1-42/β-amyloid1-40], tau (using CSF pTau217) and cognitive measures (Mini-Mental State Examination score and Preclinical Alzheimer Cognitive Composite) using regression models adjusting for age, sex and the top genotype principal components. We also replicated the polygenic risk score association with β-amyloid (CSF β-amyloid1-42/β-amyloid1-40) and tau (CSF pTau217) in an independent cohort (BioFINDER-2), including cognitively unimpaired (N = 773) individuals and patients with mild cognitive impairment (N = 358), Alzheimer's disease dementia (N = 286) or non-Alzheimer's disease neurodegenerative diseases (N = 319). We observed differential cellular effects on β-amyloid, pTau217 and cognitive measures. There are substantial effects of neuronal-specific polygenic risk scores on β-amyloid, pTau217 and cognitive measures. The microglial-polygenic risk scores showed more significant effects on pTau217 than on β-amyloid. β-Amyloid positivity partly mediated the associations between polygenic risk scores and pTau217, with the lowest mediation effect observed for the microglial-polygenic risk scores (on average 33%). Cell-weighted gene expression has differential effects on pathological β-amyloid and tau metabolism, as well as cognitive decline. Cell-weighted gene expression related to microglia is preferentially relevant for the metabolism of soluble phosphorylated tau through partly β-amyloid-independent mechanisms. Cell-weighted gene expression related to neurons shows the strongest associations with cognition. These findings inform further studies that address specific cell types for various aspects of Alzheimer's disease, including the development of novel treatment strategies.}, } @article {pmid41040192, year = {2025}, author = {Scheidemantel, LP and Lopes, KP and Gaiteri, C and Menon, V and De Jager, PL and Schneider, JA and Buchman, AS and Wang, Y and Tasaki, S and Raittz, RT and Bennett, DA and Vialle, RA}, title = {Integration of aged brain multi-omics reveals cross-system mechanisms underlying Alzheimer's disease heterogeneity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41040192}, issn = {2692-8205}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; U01 AG079847/AG/NIA NIH HHS/United States ; }, abstract = {The molecular correlates of Alzheimer's disease (AD) are increasingly being defined by omics. Yet, the findings from different data types or cohorts are often difficult to reconcile. Collecting multiple omics from the same individuals allows a comprehensive view of disease-related molecular mechanisms, while addressing conflicting findings derived from single omics. Such same-sample multi-omics can reveal, for instance, when changes observed in the transcriptome share distinct but coordinated signals in epigenetics and proteomics, relationships otherwise unclear. Here, we apply a data-driven multi-omic framework to integrate epigenomic, transcriptomic, proteomic, metabolomic, and cell-type-specific population data from up to 1,358 aged human brain samples from the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). We demonstrate the existence of sprawling cross-omics cross-system biological factors that also relate to AD phenotypes. The strongest AD-associated factor (factor 8) involved elevated immune activity at the epigenetic level, decreased expression of heat shock genes in the transcriptome, and disrupted energy metabolism and cytoskeletal dynamics in the proteome. We also showed immune-related factors (factors 2 and 3) with discordant enrichments, reflecting reactive-like glial subpopulations and protective contributions from surveillance microglia. Both were negatively associated with AD pathology, suggesting potential immune resilience mechanisms. Finally, unsupervised clustering of participants revealed eleven molecular subtypes of the aging brain, including three clusters strongly associated with AD but displaying distinct molecular signatures and phenotypic characteristics. Our findings provide a comprehensive map of molecular mechanisms underlying AD heterogeneity, highlighting the complex role of neuroinflammatory processes, and yielding potential novel biomarkers and therapeutic targets for precision medicine approaches to AD treatment.}, } @article {pmid41039568, year = {2025}, author = {Wu, H and Qiu, Z and Mu, J and Wang, Y and Wang, J and Han, Y and Yang, R and Yuan, S and Yuan, M and Yang, R and Chen, X and Sun, Q and Li, F and Xiao, L and Zhang, M and Xu, J}, title = {Salt-sensitive hypertension promotes neuronal mitochondrial stress and neurodegenerative alterations via neuro-vascular metabolic reprogramming and local RAS signaling.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {220}, pmid = {41039568}, issn = {1742-2094}, support = {XJTU1AF-CRF-2023-021//The First Affiliated Hospital of Xi'an Jiaotong University/ ; 32271016//National Natural Science Foundation of China/ ; 81803026//National Natural Science Foundation of China/ ; 82071879//National Natural Science Foundation of China/ ; 82100454//National Natural Science Foundation of China/ ; 2023PT-09//the Health Research and Innovation Capacity Strengthening Platform Program of Shaanxi Province/ ; }, abstract = {UNLABELLED: Hypertension increases risks for cognitive impairment and Alzheimer’s disease (AD). In renal patients with both hypertension and cognitive decline, via rest-state fMRI, their cerebral cortical region showed maintained cerebral blood flow (CBF), but reduced signals of blood-oxygen-level-dependent (BOLD). In mice, although CBF was unchanged, deoxycorticosterone acetate (DOCA)-salt treatment markedly reduced cerebrovascular reactivity, with altered transcriptomic pattern in cortical endothelial cells (ECs) and astrocytes, showing downregulated expression of glucose transport 1 (GluT1) but upregulated metabolic reprogramming. Lipidomic analysis using prefrontal cortex (PFC) further revealed enhanced catabolism of glycerophospholipids and accumulation of free fatty acids. In the PFC of hypertensive mice, neurodegenerative alterations were observed, including reduced number of neuronal dendritic spines and more expression of phosphorylated Tau (p-Tau). Via both morphological and molecular tests, we identified that DOCA-salt hypertension was associated with significant mitochondrial injury and upregulated lysine succinylation in the PFC neurons. Upregulated lysine succinylation was largely mitochondria-located, and they were functionally enriched in gluconeogenesis-related energy metabolic pathways, the tricarboxylic acid (TCA) cycle, oxidative stress, and neurodegenerative diseases. In hypertensive mice, angiotensinogen (Agt) expression was markedly upregulated in most astrocytes, together with neuronal expression of Agtr1a. In cultured neuronal cells, angiotensin II (ang II) elevated mitochondrial membrane potential and ATP biosynthesis. In mice with neuronal AT1aR knockout (AT1N), DOCA-salt failed to induce cognitive impairment. Additionally, DOCA-salt-associated reduction of acetylcholine, accumulation of p-Tau, and upregulation of lysine succinylation were not observed in AT1N mice. Direct anti-hypertensive treatment did not abolish DOCA-salt-related pathological phenotypes, and enhanced lysine succinylation was not detected in hypertension models induced by norepinephrine or L-NAME. Our data provide evidence that hypertension induced metabolic rearrangement (enhanced energy metabolism from non-glucose source and upregulated mitochondrial oxidative phosphorylation) in the neuro-vascular unit, due to downregulated glucose uptake in ECs. Increased neuronal energy consumption, via local ang II/AT1R signaling, further exacerbated mitochondrial stress and neurodegenerative alterations. Together, by multi-omics analysis, this study provided novel insights regarding how hypertension increases the risk for age-related cognitive impairment. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03533-0.}, } @article {pmid41039514, year = {2025}, author = {El-Nagah, SMA and Abdel-Halim, M and Heikal, OA and AbdelKader, RM}, title = {Neuroprotective role of rice bran extract and its constituents in a neuroinflammatory mouse model.}, journal = {BMC complementary medicine and therapies}, volume = {25}, number = {1}, pages = {351}, pmid = {41039514}, issn = {2662-7671}, mesh = {Animals ; Mice ; *Neuroprotective Agents/pharmacology ; *Oryza/chemistry ; *Plant Extracts/pharmacology/chemistry ; Disease Models, Animal ; PPAR gamma/metabolism ; Male ; *Neuroinflammatory Diseases/drug therapy ; Brain/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; Alzheimer Disease/drug therapy ; }, abstract = {BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor known to play a critical role in regulating neuroinflammation and neurodegenerative processes, including Alzheimer's disease. Prior studies from our group demonstrated that rice bran extract (RBE) enhances cognitive function and increases PPARγ DNA-binding activity in the brain, effects that were abolished by PPARγ antagonism. These findings suggest that bioactive constituents within RBE may modulate PPARγ signaling. The current study aimed to provide additional evidence for the involvement of PPARγ activation in the neuroprotective effects of RBE and to identify key RBE-derived components that may contribute to these effects. METHODS: A neuroinflammatory mouse model was treated orally for 21 consecutive days with RBE. The brain CD36 and amyloid-beta (Aβ) protein levels were measured. HPLC and GC were used to assess the levels of RBE components. To measure alterations in fatty acid content after treatment with RBE, brain levels of DHA, EPA and AA were assessed using UHPLC/MS-MS. RESULTS: RBE treatment increased the brain levels of CD36, the direct PPARγ target, and decreased Aβ levels. A strong correlation was detected between the Aβ and CD36 protein levels. As RBE was found to be rich in linolenic acid (ALA), linoleic acid (LA) and oleic acid, their metabolites concentrations in mice brain were measured, and results indicated higher concentration of EPA and DHA after RBE treatment. CONCLUSIONS: RBE exerts neuroprotective effects potentially through activation of the PPARγ pathway, as evidenced by CD36 upregulation and Aβ reduction. The enrichment of RBE in polyunsaturated fatty acids (PUFAs), along with the observed increase in their brain-penetrant metabolites (EPA and DHA), suggests these lipids may contribute to the cognitive benefits of RBE.}, } @article {pmid41038644, year = {2025}, author = {Rohatgi, S and Zhu, S and Calle Cadavid, E and Ford, JN and Kozak, BM and Ganem Chagui, O and Vejdani-Jahromi, M and Griffin, HR and Farzaneh, H and Huang, RY and Seah, JC and Omid-Fard, N and Gomez-Isla, T and Dickson, JR and Ramírez Gómez, L and Romero, JM}, title = {Are Deep White Matter Hyperintensities Associated with Amyloid-Related Imaging Abnormalities in Patients with Alzheimer Disease Treated with Lecanemab?.}, journal = {AJNR. American journal of neuroradiology}, volume = {46}, number = {11}, pages = {2324-2329}, pmid = {41038644}, issn = {1936-959X}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/pathology ; Male ; Female ; Aged ; Retrospective Studies ; *White Matter/diagnostic imaging/pathology/drug effects ; *Magnetic Resonance Imaging/methods ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; Aged, 80 and over ; Glymphatic System/diagnostic imaging ; }, abstract = {BACKGROUND AND PURPOSE: Amyloid-related imaging abnormalities (ARIA) are common complications of antiamyloid immunotherapy for Alzheimer disease (AD). Identifying imaging biomarkers that predict ARIA risk may help guide treatment decisions. This study investigates the relationship between deep white matter hyperintensities (DWMH), perivascular spaces (PVS), and ARIA incidence in patients with AD treated with lecanemab. MATERIALS AND METHODS: This retrospective cohort study included 27 ARIA-positive patients identified between November 2023 and November 2024, and 27 age- and sex-matched ARIA-negative controls. Baseline MRI was assessed for DWMH burden (Fazekas score) and PVS grades in the basal ganglia and centrum semiovale. Simple logistic regression was performed to evaluate associations between imaging markers and ARIA risk. RESULTS: ARIA-positive patients had significantly higher Fazekas scores compared with ARIA-negative patients (1.37 versus 1.0; P = .0262), indicating a greater DWMH burden. PVS grades in the basal ganglia were numerically higher in ARIA-positive patients (1.81 versus 1.56, P = .0733) but did not reach statistical significance. Simple logistic regression identified the Fazekas score as a significant predictor of ARIA (OR: 2.812; 95% CI, 1.076-8.438; P = .0343). The area under the receiver operating characteristic curve for the model was 0.640 (95% CI, 0.492-0.788; P = .078). CONCLUSIONS: Higher DWMH burden, as quantified by the Fazekas score, is significantly associated with ARIA risk in patients with AD treated with lecanemab. These findings suggest that DWMH may serve as a potential imaging biomarker for ARIA risk stratification. Larger studies incorporating additional vascular biomarkers, including cerebral amyloid angiopathy markers, are warranted to refine risk prediction models.}, } @article {pmid41038490, year = {2025}, author = {Naghib, SM and Khorasani, MA and Sharifianjazi, F and Tavamaishvili, K}, title = {Bifunctional chitosan-based nanocarriers as promising therapeutic approach for brain disease therapy: A critical review focusing on multiple sclerosis over emerging strategies, technologies and applications.}, journal = {International journal of biological macromolecules}, volume = {330}, number = {Pt 3}, pages = {148003}, doi = {10.1016/j.ijbiomac.2025.148003}, pmid = {41038490}, issn = {1879-0003}, mesh = {Humans ; *Chitosan/chemistry/therapeutic use ; *Multiple Sclerosis/drug therapy ; Animals ; *Drug Carriers/chemistry ; Blood-Brain Barrier/drug effects/metabolism ; *Nanoparticles/chemistry ; *Brain Diseases/drug therapy ; Drug Delivery Systems ; Neuroprotective Agents/chemistry/therapeutic use/pharmacology ; }, abstract = {Chitosan (CS) has appeared as a promising candidate in brain disease (BD) (such as Alzheimer's, Parkinson's, and Multiple sclerosis (MS)) therapy due to its anti-inflammatory, antioxidative, and neuroprotective properties. CS's capacity to interact with the blood-brain barrier (BBB) enhances the central nervous system (CNS) drug permeability, offering new avenues for effective treatment strategies aimed at overcoming the limitations of conventional therapies. Furthermore, CS's role in regenerative medicine extends beyond drug delivery, as it fosters neural repair by providing a supportive microenvironment for oligodendrocyte proliferation and neuronal regeneration. Studies have shown that CS-based scaffolds, when combined with neurotrophic factors and stem cells, can enhance remyelination and neuroprotection in BD models. The immunomodulatory effects of CS further contribute to reducing neuroinflammation by shifting immune responses toward an anti-inflammatory phenotype, thereby mitigating the progression of BD-associated damage. This review provides a comprehensive analysis of the latest advancements in CS-based BD therapies, exploring its multifunctional applications in drug delivery, immune modulation, and tissue engineering. The discussion also addresses the current challenges in clinical translation, including variability in CS formulations, regulatory considerations, and potential safety concerns. Future research directions should focus on optimizing CS derivatives, improving its bioavailability, and integrating it with emerging therapeutic approaches such as gene therapy and biomimetic nanocarriers.}, } @article {pmid41038475, year = {2025}, author = {Zhou, J and Guo, X and Yu, W and Bu, H and Du, Y and Li, S and Kuang, H and Wu, L}, title = {Pharmacological action, mechanism and structure-activity relationship of traditional Chinese medicine polysaccharide in the treatment of Alzheimer's disease: A review.}, journal = {International journal of biological macromolecules}, volume = {330}, number = {Pt 2}, pages = {148017}, doi = {10.1016/j.ijbiomac.2025.148017}, pmid = {41038475}, issn = {1879-0003}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Polysaccharides/chemistry/therapeutic use/pharmacology ; Structure-Activity Relationship ; *Medicine, Chinese Traditional ; *Drugs, Chinese Herbal/chemistry/therapeutic use/pharmacology ; Animals ; }, abstract = {Alzheimer's disease (AD) is a significant neurodegenerative disorder characterized by a progressive decline in cognitive functions. The pathogenesis of AD remains largely elusive, resulting in Western medications that often exhibit limited efficacy and frequent side effects. In contrast, traditional Chinese medicine (TCM) has been utilized for managing AD, recognized for its favorable safety profile and multi-target therapeutic potential. Polysaccharides, which are essential bioactive components found in TCM extracts, have attracted considerable interest due to their safety and ability to target multiple biological pathways. This article examines the pharmacological effects and mechanisms of TCM polysaccharides in the treatment of AD, focusing on research conducted over the past decade. Additionally, it explores the structure-activity relationships of these polysaccharides, providing a foundation for further investigation into polysaccharide-based interventions for AD and suggesting potential avenues for future studies aimed at structural enhancements.}, } @article {pmid41037798, year = {2025}, author = {Park, HJ and Kim, J and Choi, J and Ryou, C and Shin, E and Lee, JY}, title = {Targeted genome editing of ZKSCAN3 mitigates the neurotoxicity caused by mutant HTT (huntingtin) in a Huntington disease animal model and three-dimensional cell culture of Huntington disease.}, journal = {Autophagy}, volume = {21}, number = {12}, pages = {3398-3412}, pmid = {41037798}, issn = {1554-8635}, mesh = {Animals ; *Huntington Disease/genetics/pathology ; Humans ; Disease Models, Animal ; Induced Pluripotent Stem Cells/metabolism ; Autophagy/genetics ; *Huntingtin Protein/genetics/metabolism/toxicity ; *Gene Editing/methods ; CRISPR-Cas Systems/genetics ; *Transcription Factors/genetics/metabolism ; Spheroids, Cellular/metabolism ; Mice ; *Mutation/genetics ; Lysosomes/metabolism ; Neurons/metabolism/pathology ; }, abstract = {Huntington disease (HD) is a neurodegenerative disease caused by the expression of a mutant form of HTT (huntingtin; mHTT), caused by an abnormal expansion of polyglutamine in HTT. In HD, macroautophagy/autophagy dysfunction can cause mHTT accumulation. Moreover, the promotion of autophagy is considered a therapeutic strategy for the treatment of HD. ZKSCAN3 (zinc finger with KRAB And SCAN domains 3) has been identified as a transcriptional repressor of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal functions. In this study, we conducted CRISPR-Cas9-based gene ablation to disrupt ZKSCAN3 in HD animal models and HD patient-induced pluripotent stem cell (iPSC) -derived three-dimensional (3D) spheroids. In animal models of HD, targeted in vivo zkscan3 ablation via a single adeno-associated virus (AAV) mediated CRISPR-Cas9 approach resulted in reduced mHTT levels, leading to improvements in both behavioral symptoms and the brain environment. Furthermore, CRISPR-Cas9 mediated ablation of ZKSCAN3 in 3D spheroids from HD patient-derived iPSC resulted in increased autophagy and lysosomal function, along with reduced mHTT accumulation. Specifically, in iPSC-derived neurons from HD patients, ZKSCAN3-depleted neurons demonstrated increased lysosomal function and reduced oxidative stress compared to controls. Additionally, transcriptional analysis of ZKSCAN3-edited neurons revealed an increased expression of genes involved in synaptic function and transporter activity. Taken together, these results suggest that in HD treatment strategies for improving neuronal function and the brain environment, ZKSCAN3 downregulation in neurons by autophagy activation may improve the brain environment through neuronal self-repair.Abbreviations: 2D: two-dimensional; 3D: three-dimensional; 4-HNE: 4-hydroxynonenal; AAV: adeno-associated virus; AD: Alzheimer disease; Aβ: beta-amyloid; DAPI: 4,6-diamidino-2-phenylindole; GFP: green fluorescent protein; HD: Huntington disease; HTT: huntingtin; IXMC: ImageXpress microconfocal high-content imaging system; Indel: insertion or deletion; iPSC: induced pluripotent stem cell; LAMP1: lysosomal-associated membrane protein 1; mHTT: mutant huntingtin; NPCs: neural precursor cells; RBFOX3/NeuN: RNA binding fox-1 homolog 3; PD: Parkinson disease; RNP: ribonucleoprotein; sgRNAs: single guide RNAs; ST: striatum; TFEB: transcription factor EB; TUBB3/Tuj-1: tubulin beta 3 class III; ZKSCAN3: zinc finger with KRAB and SCAN domains 3.}, } @article {pmid41036749, year = {2025}, author = {Bartolomeu, PF and Fortes, IS and Zimmer, AR and Lopes, MS and de Andrade, SF}, title = {8-Hydroxyquinoline Derivatives as Drug Candidates for the Treatment of Alzheimer's Disease.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673409645250823055140}, pmid = {41036749}, issn = {1875-533X}, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia among older adults worldwide. Amidst several hypotheses to explain the pathobiology of the disease are biochemical indicators such as β-amyloid (Aβ) plaques; neurofibrillary tangles, caused by hyperphosphorylated tau protein; oxidative stress; metal dyshomeostasis; low levels of acetylcholine, and neuroinflammation. Considering the multifactorial nature of AD, there has been an increase in research for novel multitarget compounds, mainly utilizing molecular hybridization for drug design. In this review, we focus on the 8-hydroxyquinoline moiety, a privileged metal-binding agent with Aβ antiaggregating properties, and its derivatives, aiming to have an effect on multiple molecular targets. Furthermore, the most prominent structure-activity relationships found on the analyzed compounds, along with the most promising strategies explored by researchers, are discussed. That way, we hope to provide a comprehensive perspective on the development of anti- Alzheimer agents based on the 8-hydroxyquinoline moiety in the last decade.}, } @article {pmid41035985, year = {2025}, author = {Ghaliby, FAKA and Alhasan, L}, title = {Histopathological study of the neuroprotective effects of Gum Arabic and Fenchol on neuronal cells in an Alzheimer's disease rat model.}, journal = {Open veterinary journal}, volume = {15}, number = {8}, pages = {3871-3877}, pmid = {41035985}, issn = {2218-6050}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/chemically induced ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Rats ; *Gum Arabic/pharmacology/therapeutic use ; Disease Models, Animal ; *Neurons/drug effects ; Interleukin-6/blood ; Brain/drug effects/pathology ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder influenced by environmental and genetic factors. It is primarily characterized by beta-amyloid plaque deposition, neurofibrillary tangles, and impaired neuronal signaling. Given the lack of a definitive cure, research has increasingly focused on identifying natural compounds with neuroprotective and therapeutic potential. AIM: This study evaluates the effects of natural compounds (Fenchol and Gum Arabic) on immune modulation and neuroinflammatory markers, specifically interleukin-6 (IL-6), in a rat model of AD. By examining the effects of these natural products on the immune response and brain tissue pathology, this research aims to provide new insights into their potential therapeutic benefits for slowing AD progression. METHODS: In this study, 36 adult male rats were randomly assigned to five groups: (1) a negative control group received standard feed and water, (2) a positive control group treated with aluminum chloride (17 mg/kg/day orally), (3) a Gum Arabic-treated group (2 ml, 10 g/100 ml orally) post-induction, (4) a Fenchol-treated group (2 ml, 5 mg/80 ml orally), and (5) a memantine-treated group (2 ml, 1.57 g/25 ml orally). After 1 month, histopathological assessments were performed to evaluate neuronal integrity, granule cell density, and beta-amyloid accumulation in the hippocampus. Additionally, serum IL-6 concentrations were measured via ELISA to assess systemic neuroinflammatory responses. Data were statistically analyzed using analysis of variance followed by least significant difference (LSD) post hoc tests. RESULTS: Histopathological analysis revealed significant neurodegeneration in the positive control group, characterized by cytoplasmic vacuolation, reduced granule cell density, and elevated beta-amyloid levels. The Gum Arabic-treated group exhibited a partial neuroprotective effect, with a notable reduction in neurodegeneration, increased granule cell density, and a 50% decrease in amyloid plaques. The Fenchol-treated group demonstrated improved neuronal integrity and a marked reduction in beta-amyloid aggregates. The memantine-treated group exhibited the most substantial neuroprotective effect, significantly preserving granule cells and minimizing beta-amyloid deposition. Biochemical analysis revealed that IL-6 levels were markedly elevated in the positive control group (85.00 ± 3.00 ng/l) compared to the negative control (60.00 ± 2.00 ng/l). All treatment groups showed significant reductions in IL-6 levels. Memantine and combined treatments restored IL-6 levels close to normal. Fenchol and Gum Arabic alone reduced IL-6 levels, though to a lesser extent, indicating partial inflammatory effects. CONCLUSION: The findings suggested that Gum Arabic and Fenchol possess neuroprotective properties, suggesting their potential as therapeutic agents for AD, with efficacy comparable to that of memantine. Their ability to downregulate IL-6 further highlights their potential in mitigating neuroinflammation associated with Alzheimer's pathology. Further investigations are warranted to elucidate their underlying mechanisms and evaluate their potential clinical applications.}, } @article {pmid41035827, year = {2025}, author = {Cai, M and Cai, K and Wei, Z and Zhou, J and Shu, J and Wang, W and Sun, W and Hu, J}, title = {Exercise-mediated cerebrovascular repair in Alzheimer's disease: from pathophysiology to therapeutic precision.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1632365}, pmid = {41035827}, issn = {1663-4365}, abstract = {Cerebrovascular dysfunctions, encompassing changes in cerebrovascular microstructure, blood-brain barrier (BBB) integrity, cerebrovascular reactivity, and cerebral blood flow (CBF), accelerate the pathological progression of Alzheimer's disease (AD). Exercise emerges as a promising non-pharmacological intervention that enhances cerebrovascular repair for the treatment of AD. This review summarizes the pathological vascular changes in AD pathology, such as pericyte loss, endothelial dysfunction, and capillary fibrosis, which exacerbate hypoperfusion, hypoxia, and amyloidogenesis. We further discuss the contributing vascular factors and underlying signaling mechanisms to explore potential targets for AD diagnosis and therapy. Finally, we present evidence concerning the impact of exercise on cerebral vascular signaling and the cells involved in vascular plasticity. We also address the impact of various exercise patterns on cerebrovascular health. This work aims to uncover the potential and intervention effects of exercise on cerebrovascular non-malignant alterations and will provide exercise strategies for treating AD.}, } @article {pmid41035821, year = {2025}, author = {Noto, NM and Speth, RC and Robison, LS}, title = {Cerebral amyloid angiopathy: a narrative review.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1632252}, pmid = {41035821}, issn = {1663-4365}, abstract = {Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the accumulation of amyloid-beta (Aβ) in the walls of cerebral vessels. It is commonly associated with cognitive decline, cerebral hemorrhage, and other neurological pathologies. Despite its prevalence and impact, there are currently no approved treatments for CAA. CAA frequently co-occurs with Alzheimer's disease (AD), but affected patients are often excluded from anti-amyloid therapies due to increased risks of cerebral edema and hemorrhage, underscoring the urgent need for alternative and safe approaches for treating individuals with CAA. Over the years, various animal models have been developed to investigate the pathophysiology of CAA and evaluate potential treatments. Recent studies have demonstrated that certain repurposed drugs, originally approved for other conditions, show promise for treating CAA. Additionally, it has been shown that positive lifestyle changes may benefit vascular health, reduce amyloid burden and neuroinflammation, and improve cognitive resilience in individuals with CAA. In this review, we summarize the current knowledge on CAA, its relationship with AD, insights from preclinical and clinical studies, and emerging evidence supporting the potential of drug repurposing and lifestyle modification in managing CAA.}, } @article {pmid41035200, year = {2025}, author = {Gaffour, A and Bakker, M and Bera, K and Pavlíková Přecechtělová, J}, title = {Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops.}, journal = {Biophysical journal}, volume = {124}, number = {21}, pages = {3800-3810}, pmid = {41035200}, issn = {1542-0086}, mesh = {*tau Proteins/metabolism/chemistry ; Molecular Dynamics Simulation ; Protein Binding ; *Adaptor Proteins, Signal Transducing/metabolism/chemistry ; *Tumor Suppressor Proteins/metabolism/chemistry ; *Phosphates/metabolism ; *Nuclear Proteins/metabolism/chemistry ; Humans ; *src-Family Kinases/metabolism/chemistry ; Static Electricity ; src Homology Domains ; Phosphorylation ; }, abstract = {Within the disordered tangles of Tau is a proline-rich region, which is selectively targeted by the SH3 domain of BIN1, a known genetic factor for Alzheimer disease, and may hold the key to understanding the disorder and treatment strategies. Hyperphosphorylation of Tau is known to disrupt complex formation, providing researchers with excellent preventative or remediative targets. This work compiles an extensive (>60 μs) collection of all-atomistic molecular dynamics simulations of the Tau(210-240) fragment, representing the majority of the P2 subdomain of the proline-rich region, benchmarking various force fields, phosphorylations, and modifications against experimental NMR chemical shifts and spin-spin coupling for comparison. Additionally, several simulations of the binding complex were analyzed for their binding energies by MMGBSA calculations and computational alanine scanning to pinpoint the exact residues involved and the disruptions caused by the phosphate group. We noted that the additional charges decrease salt bridges formed by positive residues in Tau, particularly on R221, and negative residues in BIN1 by up to 32%, and a strong preference in Tau, particularly in the latter half, for contact toward the distal and n-Src loops instead of residues in the RT-Src loop.}, } @article {pmid41034564, year = {2025}, author = {Makarov, N and Bordukova, M and Quengdaeng, P and Garger, D and Rodriguez-Esteban, R and Schmich, F and Menden, MP}, title = {Large language models forecast patient health trajectories enabling digital twins.}, journal = {NPJ digital medicine}, volume = {8}, number = {1}, pages = {588}, pmid = {41034564}, issn = {2398-6352}, support = {U19 AG024904/AG/NIA NIH HHS/United States ; 950293 - COMBAT-RES//European Union's Horizon 2020 Research and Innovation Programme/ ; }, abstract = {Generative artificial intelligence is revolutionizing digital twin development, enabling virtual patient representations that predict health trajectories, with large language models (LLMs) showcasing untapped clinical forecasting potential. We developed the Digital Twin-Generative Pretrained Transformer (DT-GPT), extending LLM-based forecasting solutions to clinical trajectory prediction. DT-GPT leverages electronic health records without requiring data imputation or normalization and overcomes real-world data challenges such as missingness, noise, and limited sample sizes. Benchmarking on non-small cell lung cancer, intensive care unit, and Alzheimer's disease datasets, DT-GPT outperformed state-of-the-art machine learning models, reducing the scaled mean absolute error by 3.4%, 1.3% and 1.8%, respectively. It maintained distributions and cross-correlations of clinical variables, and demonstrated explainability through a human-interpretable interface. Additionally, DT-GPT's ability to perform zero-shot forecasting highlights potential advantages of LLMs as clinical forecasting platforms, proposing a path towards digital twin applications in clinical trials, treatment selection, and adverse event mitigation.}, } @article {pmid41034513, year = {2025}, author = {Zhuo, Y and Lu, Y and Zhu, Y and Wen, N and Zou, G and Lu, H and Pei, X and Zhang, Y and Zhang, Q and Wang, X and Zhang, W and Zhang, Q and Wang, Z and Xie, S and Li, CQ and Tan, W and Qiu, L}, title = {Targeted clearance of extracellular Tau using aptamer-armed monocytes alleviates neuroinflammation in mice with Alzheimer's disease.}, journal = {Nature biomedical engineering}, volume = {}, number = {}, pages = {}, pmid = {41034513}, issn = {2157-846X}, support = {21991080//National Natural Science Foundation of China (National Science Foundation of China)/ ; 92253304//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {Extracellular Tau determines the progression of Alzheimer's disease, yet therapeutic strategies targeting it are hindered by poor brain delivery and limited clearance. Here we developed a Tau-clearing cell therapy based on monocytes functionalized with a high-affinity Tau-specific aptamer. The aptamer was covalently conjugated to the surface of monocytes (derived from bone marrow leucocytes and cultured under monocyte-inducing conditions) via bioorthogonal chemistry without affecting their viability or function. Upon intravenous administration in mice expressing mutant and disease-relevant human Tau, the engineered monocytes actively crossed the blood-brain barrier and accumulated in Tau-rich brain regions such as the hippocampus and striatum. They efficiently phagocytosed extracellular Tau, leading to a significant reduction in Tau burden. As a result, glial activation was suppressed, neuroinflammation was alleviated, and neuronal and mitochondrial integrity was preserved. Long-term treatment improved memory and spatial learning, without inducing toxicity or behavioural side effects. These results demonstrate that aptamer-guided monocytes can achieve targeted delivery, effective clearance and sustained neuroprotection, offering a promising strategy for therapeutic intervention in Alzheimer's disease.}, } @article {pmid41032155, year = {2025}, author = {Gao, X and Yang, K and Yuan, X and Song, M and Wang, T and Shen, C}, title = {Research progress of exosomes used in the Alzheimer's disease treatment.}, journal = {Discover nano}, volume = {20}, number = {1}, pages = {173}, pmid = {41032155}, issn = {2731-9229}, support = {82402735//National Natural Science Foundation of China/ ; 2023NSFSC1481//Natural Science Foundation of Sichuan Province/ ; 2023HXBH122//Postdoctoral Research Foundation of West China Hospital of Sichuan University/ ; }, abstract = {Alzheimer's disease (AD) is a common form of dementia characterized by memory loss, cognitive and linguistic abilities declining and self-care capabilities diminishment. With the aging population globally, AD poses a significant threat to public health. Current treatments for AD aim to alleviate symptoms and slow down disease progression, but due to the limited understanding of underlying disease mechanisms, AD is still impossible to be cured yet. In recent years, there has been an exponential growth in exosome-related research because of their excellent biocompatibility ability, loading capacity and cellular internalization, making exosome to be one of the hotspots and a promising strategy in AD therapy research. This comprehensive review systematically explores the potential roles of various exosome-based nanotherapeutic strategy in AD treatment, with a particular focus on their specific biological mechanisms of action. Firstly, we elaborated on the pathological mechanisms of AD formation as well as the mechanisms related to the formation, secretion and function of exosome. Additionally, we highlighted the research progress in the development of exosome-based nanotherapeutic strategies for AD treatment and their corresponding biological mechanisms. Furthermore, we delved into the challenges and opportunities these strategies facing in clinical application. Looking forward to future research directions and trends, our review aims to provide a more comprehensive understanding and guidance with the application of exosome in AD treatment. Exosome-based nanotherapeutic strategies, as a new therapeutic approach, have opened up new possibilities for the treatment of AD and brought new light to patients.}, } @article {pmid41032080, year = {2025}, author = {Khatun, P and Li, X and Xiaoxi, Z and Zhai, J and Ullah, A and Bo, Y and Lyu, Q}, title = {Effect of Omega-3 Polyunsaturated Fatty Acid Supplements on Cognitive Performance in Patients with Mild Cognitive Impairment or Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Nutrition reviews}, volume = {}, number = {}, pages = {}, doi = {10.1093/nutrit/nuaf167}, pmid = {41032080}, issn = {1753-4887}, support = {YJ20220181//2022 International Postdoctoral Exchange Fellowship Program/ ; 232102310069//Henan Medical Science and Technology Research Program/ ; //Preferential support for scientific research of overseas persons in Henan Province/ ; }, abstract = {CONTEXT: A positive effect of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on brain activity has been observed within subjects who have Alzheimer's disease (AD) or mild cognitive impairment (MCI). However, inconsistent findings have been reported regarding the efficacy or ineffectiveness of an n-3 PUFA dietary intervention for cognitive improvement. OBJECTIVE: To address this problem, our thorough investigation and statistical analysis sought to assess the impact of n-3 PUFA dietary intake on cognitive function among persons diagnosed with AD or MCI. DATA SOURCES: The databases consulted included PubMed, PubMed Central Library, and the Cochrane Library. DATA EXTRACTION: Nine articles reporting on the findings of randomized controlled trials that looked at the link between n-3 PUFA intake and cognitive performance-related outcomes were included in the comprehensive evaluation, with the meta-analysis utilizing 7 of these. Key details such as author, publication year, study area, research type, pathology (MCI or AD), were incorporated into the data extraction procedure. DATA ANALYSIS: Evaluation of the included studies used Cochrane risk-of-bias instruments, a random-effects model, standardized mean differences (SMDs) and 95% CIs. RESULTS: Our findings have provided evidence of the effectiveness of an n-3 PUFA treatment in improving Full-Scale IQ (FSIQ) (SMD -0.82; 95% CI: -1.57, -0.08; P = .000), information processing (SMD -2.90; 95% CI: -5.25, -0.56; P = .000), and digit span/working memory/attention aspects of cognitive functioning (SMD -1.89; 95% CI: -3.27, -0.51; P = .000). No evidence was found for the effectiveness of an n-3 PUFA treatment in improving image completion (SMD -0.07; 95% CI: -0.50, 0.35; P = .000), picture layout (SMD -0.08; 95% CI: -0.32, 0.16; P = .075), block design SMD -0.15; 95% CI: -0.37, 0.03; P = .123), or arithmetic aspects of cognitive functioning (SMD -0.33; 95% CI: -0.61, 0.04; P = .007). CONCLUSION: In summary, n-3 PUFAs have been found to significantly affect some domains of cognitive function, such as FSIQ, information processing, and digit span/working memory/attention in subjects with MCI. However, no significant effect was observed for some domains, such as picture completion, picture arrangement, or block design.}, } @article {pmid41031197, year = {2025}, author = {Wang, Q and Wang, DL and Zhang, XC and Jiang, XY and Jiang, HN and Yang, XY and Zhang, T and Lv, YY and Li, Q}, title = {Efficacy and safety of traditional Chinese medicine and Western medicine in Alzheimer's disease: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1607945}, pmid = {41031197}, issn = {1664-2295}, abstract = {OBJECTIVE: This study aimed to compare the efficacy and safety of traditional Chinese medicine (TCM) compounds with single Western medicines in treating Alzheimer's disease (AD) through a systematic review and meta-analysis. METHODS: In this study, we searched for randomized controlled trials on the treatment of AD with TCM compounds published before March 2025 in Chinese and English databases (PubMed, Embase, Cochrane, China National Knowledge Infrastructure, VIP, and Wanfang) and conducted a meta-analysis using Stata15.0 software. RESULTS: A total of 23 studies were included, involving 2,035 participants (1,173 in the experimental group and 862 in the control group). Traditional Chinese herbal compounds showed good clinical efficacy and maintenance effects in the treatment of AD. The effective rate of TCM compounds in treating AD was higher than that of Western medicine (relative risk ratio = 1.19, 95% CI: 1.04-1.37, p = 0.009). In terms of the Alzheimer's Disease Assessment Scale-Cognitive and Hierarchic Dementia Scale-Revised scores, TCM compounds were superior to Western medicine (standardized mean difference = -0.22, 95% CI: -0.40--0.05). There were no significant differences between the two groups in the Mini-Mental State Examination or Activities of Daily Living scores. Additionally, there were no significant differences in adverse reactions between the TCM compounds and Western medicine groups. CONCLUSION: The present research indicates that TCM compounds could be a promising therapeutic option for AD, demonstrating encouraging results in terms of efficacy and safety, particularly regarding certain cognitive functions.}, } @article {pmid41030887, year = {2025}, author = {Pan, Q and Lu, J and Xiao, Z and Zhang, H and Liu, G and Li, Y}, title = {Construction of a Rat Model of Hemilateral Parkinson's Disease Induced by Human Wild-Type α-Synuclein Overexpression.}, journal = {Neuropsychiatric disease and treatment}, volume = {21}, number = {}, pages = {2183-2194}, pmid = {41030887}, issn = {1176-6328}, abstract = {OBJECTIVE: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease. The precise etiology and pathogenesis of PD remain unclear. Human wild-type α-synuclein has been implicated in PD pathogenesis. The objective of this study is to examine the role of α-synuclein in PD by establishing a rat model of substantia nigra degeneration and Motor behavioral changes through the induced overexpression of human α-synuclein. METHODS: Rats were randomly assigned to either the Negative control group or the adeno-associated virus serotype 9 (AAV9) treatment group. Animals in the AAV9 group received 2.5 μL of AAV9 expressing human wild-type α-synuclein, while those in the Negative control group received an equal volume of AAV9 expressing green fluorescent protein via stereotactic unilateral injection into the substantia nigra pars compacta. Behavioral assessments were conducted at 1-, 3-, and 8-weeks following virus administration. Tyrosine hydroxylase and human α-synuclein expression in the substantia nigra pars compacta were analyzed. Additionally, dopamine, dihydroxyphenylacetic acid, and homovanillic acid levels in the striatum were quantified. RESULTS: After 3 weeks of virus induction, neurodegeneration of the right substantia nigra was observed, with a reduction in the number of tyrosine hydroxylase-immunopositive neurons in the AAV9 group. By 8 weeks, substantia nigra neurodegeneration had further progressed, and animals in the AAV9 group exhibited apomorphine-induced asymmetrical rotation and altered forelimb use. CONCLUSION: Overexpression of human wild-type α-synuclein led to substantia nigra degeneration and Motor behavioral changes in rats, providing a viable model for exploring the pathogenesis of Parkinson's disease. Limitations include the 8-week observation window and the absence of neuroinflammation markers.}, } @article {pmid41030378, year = {2025}, author = {Gazes, Y and Suzuki, H and Morris, LA and Lee, S and Jin, Z and Huey, ED and Chen, BB and Le Heron, C and Heibronner, SR and Vanegas-Arroyave, N}, title = {A transdiagnostic, multi-modal approach to understanding apathy: Methodological and analytical framework.}, journal = {Neuroimage. Reports}, volume = {5}, number = {4}, pages = {100289}, pmid = {41030378}, issn = {2666-9560}, abstract = {Apathy is characterized by loss of motivation and manifests as a reduction of goal-directed behavior. Apathy is highly prevalent across neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD), and is an important contributor to the disability and reduce quality of life in these conditions. The treatment of apathy remains challenging due to a lack of specific therapies, largely attributed to an incomplete understanding of its cognitive and neuroanatomical underpinnings, crucial for developing targeted interventions. Apathy can be mechanistically studied through effort-based decision-making (EBDM) paradigms, where individuals choose between low- and high-effort tasks for varying reward magnitudes. Anatomically, apathy has been associated with alterations in brain regions previously implicated in EBDM. Using a novel transdiagnostic study design in individuals with AD and PD, we aim to: (1) evaluate the independent effects of reward and effort sensitivity as a mechanistic link between apathy and neurodegeneration of basal ganglia-frontal networks and, (2) in a subset of PD patients receiving deep brain stimulation (DBS) surgery, determine whether electrical manipulation of subthalamic nucleus and/or DBS connectivity, directly alter reward and effort information processing and, consequently, goal-directed behavior. Understanding how neurodegeneration-alone or in combination with neuromodulatory interventions-drives apathy, is essential for guiding clinical decision-making and therapeutic development. Given its prevalence across neurodegenerative disorders, apathy provides a unique framework for investigating shared and disease-specific neuroanatomical, functional, and behavioral mechanisms. In this protocol paper, we describe the rationale and methodology of our proposed multimodal approach, to investigate apathy in a transdiagnostic cohort of individuals with AD and PD.}, } @article {pmid41029918, year = {2025}, author = {Agarwal, M and Singhal, M and Basist, P and Tamta, N and Kumar, S and Saha, S}, title = {Evaluation of Hordenine's Therapeutic Potential in Alzheimer's Disease-Induced Cognitive and Oxidative Impairments.}, journal = {Recent advances in food, nutrition & agriculture}, volume = {}, number = {}, pages = {}, doi = {10.2174/012772574X389943250908070348}, pmid = {41029918}, issn = {2772-5758}, abstract = {INTRODUCTION: This research aimed to investigate the potential of Hordenine (HR) against Alzheimer's Disease (AD) induced by Streptozotocin (STZ) in Wistar rats by evaluating its impact on cognitive function, oxidative stress, inflammatory cytokines, and neuroprotective biomarkers in comparison to donepezil. METHODS: The study involved five groups of Wistar rats: a control group, a group with STZinduced AD, and three treatment groups receiving varying doses of HR (50 mg/kg and 75 mg/kg) and donepezil (5 mg/kg). Over 28 days, the animals underwent various behavioural tests to assess cognitive function, along with biochemical analyses to measure A+cetylcholinesterase (AChE) activity, oxidative stress markers, inflammatory cytokines (IL-1β, TNF-α), and nuclear factor kappa B (NF-κB) levels, and histological examination. Additionally, molecular docking studies were performed to assess the interaction of HR with AChE. RESULTS: STZ administration caused significant cognitive decline, oxidative stress, and elevated inflammatory markers. HR supplementation, particularly at 75 mg/kg, significantly improved cognition, reduced oxidative stress, and decreased pro-inflammatory cytokines (IL-1β, TNF-α), as well as NF-κB levels, while increasing Brain-Derived Neurotrophic Factor (BDNF) expression. Molecular docking studies revealed strong binding of HR to AChE, suggesting potential inhibitory effects. DISCUSSION: Hordenine demonstrated promising neuroprotective effects against STZ-induced neurotoxicity by improving cognition and reducing oxidative stress and inflammation, suggesting HR's potential as an adjunct therapy for Alzheimer's disease, offering a protective mechanism that may complement existing treatments like donepezil. CONCLUSION: The research shows that the medicinal plant HR exhibits neuroprotective potential against AD induced by STZ. Further research involving clinical trials is warranted to fully establish the efficacy and safety of HR in the treatment of AD.}, } @article {pmid41029885, year = {2025}, author = {Zhou, J and Zhong, Y and Jin, C and Dong, L and Zhou, R and Wang, Y and Fan, Z and Zheng, X and Xing, X and Wang, J and Tian, M and Zhang, H}, title = {A novel electric field approach for improving cognitive function through ameliorating cell-specific pathology in P301S tauopathy mice.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {210}, pmid = {41029885}, issn = {1758-9193}, support = {82394433//National Natural Science Foundation of China/ ; 82030049//National Natural Science Foundation of China/ ; 2022YFE0118000//National Key Research and Development Program of China/ ; 226-2024-00059//Fundamental Research Funds for the Central Universities/ ; }, mesh = {Animals ; *Tauopathies/pathology/therapy/genetics ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Microglia/pathology/metabolism ; *Cognition/physiology ; Brain/pathology/metabolism ; Neurons/pathology/metabolism ; tau Proteins/genetics/metabolism ; *Cognitive Dysfunction/therapy/pathology ; Male ; Mice, Inbred C57BL ; Oxidative Stress/physiology ; *Electric Stimulation Therapy/methods ; }, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder, with no effective treatment currently available. Recently, non-pharmacological therapy, especially gamma frequency stimulation has shown promising therapeutic effects in Alzheimer's disease (AD) mouse models. Electric field (EF) is a non-invasive biophysical approach for neuronal protection. However, whether EF is beneficial in AD neuropathology remains unknown. In this study, we exposed the P301S tauopathy mouse model to EF at gamma frequency on the head. We demonstrated that EF treatment significantly improved the cognitive impairments in the P301S mice. This was accompanied by reduced tau pathologies, suppressed microglial activation, neuroinflammation and oxidative stress in the tauopathy mouse brain. Moreover, EF treatment induced cell-specific responses in neural cells, with neurons being more susceptible, followed by microglia and oligodendrocytes. EF also had favorable effects on synaptic protein in neurons, inflammatory response and complement signaling in microglia, and myelination in oligodendrocytes. This study provides strong evidence that EF at gamma frequency may have great potential to be a novel therapeutic intervention for P301S by attenuating neuropathology and offering neuroprotection.}, } @article {pmid41028047, year = {2025}, author = {Khan, MI and Jeong, ES and Tasreen, G and Khan, MZ and Shin, JH and Kim, JD}, title = {The therapeutic potential of beta-carotene against neuroinflammation and amyloid beta in SH-SY5Y cells.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {33803}, pmid = {41028047}, issn = {2045-2322}, support = {NRF-2018R1D1A1B07047021//National Research Foundation of Korea/ ; }, mesh = {Humans ; *beta Carotene/pharmacology ; *Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; Apoptosis/drug effects ; *Neuroprotective Agents/pharmacology ; Antioxidants/pharmacology ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Alzheimer Disease/drug therapy/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; }, abstract = {Neurodegenerative diseases, particularly Alzheimer's disease (AD), represent a significant public health challenge due to their increasing prevalence and the lack of effective treatments. In this study, we explored the neuroprotective effects of beta-carotene, a naturally occurring carotenoid, by investigating its ability to inhibit or reduce apoptosis and inflammation while enhancing antioxidant potential in SH-SY5Y neuroblastoma cells. Beta-carotene was extracted from Chlorella vulgaris using high-performance liquid chromatography (HPLC). We utilized SH-SY5Y cells, a widely employed in vitro model for studying neurodegenerative processes, to evaluate these therapeutic effects. A combination of colorimetric assays, enzyme-linked immunosorbent assays (ELISA), and quantitative real-time PCR (qRT-PCR) was used to assess the impact of beta-carotene on enzyme activity, cytokine production, and gene expression. The caspase assay results demonstrated that beta-carotene effectively reduced the activity of pro-apoptotic caspases and downregulated the expression of pro-apoptotic genes such as Bax, Bak and caspases, thereby inhibiting apoptosis in SH-SY5Y cells. Additionally, beta-carotene exhibited potent antioxidant properties by upregulating NRF2 and superoxide dismutase (SOD), along with enhancing ABTS and DPPH radical scavenging activities.showed antiinflamatory effects reduce the concentrations of proinflamatory cytokines TNFα, IL-1 β and IFN-γ, and supress the inflamtion patway by supressing the expression of Akt, PIK3, STAT1 and NF-kB, Akt etc. Importantly, beta-carotene treatment led to the suppression of β-secretase (BACE1), γ-secretase and acetylcholinesterase (AChE) activities, and the downregulation of genes involved in amyloid-beta production, including BACE1, and PECN1 eventualy resulted in dcerase concentration o Aβ peptides. These findings suggest that β-carotene could be a promising therapeutic candidate for the prevention and treatment of neurodegenerative diseases, particularly Alzheimer's disease, however further investigations are recomended in animal models and clinical trials before incorporating beta-cerotene into pharmaceutical formulations for AD treatment.}, } @article {pmid41027951, year = {2025}, author = {Sriram, S and Nivethitha, V and Arun Kaarthic, TP and Archita, S and Murugan, T}, title = {Advanced MRI based Alzheimer's diagnosis through ensemble learning techniques.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {33840}, pmid = {41027951}, issn = {2045-2322}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Magnetic Resonance Imaging/methods ; Deep Learning ; Neural Networks, Computer ; *Brain/diagnostic imaging ; *Machine Learning ; Aged ; Male ; Female ; Ensemble Learning ; }, abstract = {Alzheimer's Disease is a condition that affects the brain and causes changes in behavior and memory loss while making it hard to carry out tasks properly. It's vital to spot the illness early, for effective treatment. MRI technology has advanced in detecting Alzheimer's by using machine learning and deep learning models. These models use neural networks to analyze brain MRI results automatically and identify key indicators of Alzheimer's disease. In this study, we used MRI data to train a CNN for diagnosing and categorizing the four stages of Alzheimer's disease with deep learning techniques, offering significant advantages in identifying patterns in medical imaging for this neurodegenerative condition compared to using a CNN exclusively trained for this purpose. They evaluated ResNet50, InceptionResNetv2 as well as a CNN specifically trained for their study and found that combining the models led to highly accurate results. The accuracy rates for the trained CNN model stood at 90.76%, InceptionResNetv2 at 86.84%, and ResNet50 at 90.27%. In this trial run of the experiment conducted by combining all three models collaboratively resulted in an accuracy rate of 94.27% compared to the accuracy rates of each model working individually.}, } @article {pmid41027737, year = {2025}, author = {Dimitrov, D and Raja, S and Noor, H and Takahashi, T}, title = {Common Mechanism Underlying Synaptic Dysfunction Caused by Preformed Fibril-Induced Accumulation of α-Synuclein or Tau in a Culture Propagation Model.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {45}, number = {45}, pages = {}, pmid = {41027737}, issn = {1529-2401}, mesh = {*alpha-Synuclein/metabolism ; Animals ; *tau Proteins/metabolism ; Mice ; Humans ; *Synapses/metabolism/pathology ; Male ; Cells, Cultured ; Female ; Mice, Inbred C57BL ; *Neurons/metabolism ; }, abstract = {In sporadic neurodegenerative diseases, the endogenous proteins α-synuclein in Parkinson's disease and tau in Alzheimer's disease undergo pathogenic prion-like propagation over many years, accumulating in both soluble and insoluble forms in neurons including synapses, where they impair synaptic transmission and potentially cause various neuronal symptoms. To investigate the functional outcome of such synaptic accumulation, we induced accumulation of endogenous proteins in murine and human synapses by incubating mouse (of either sex) neuronal cultures with pathogenic preformed fibrils (pffs). Two weeks after treatment with human α-synuclein or tau pff, the respective endogenous proteins accumulated in neurons including presynaptic terminals, where we also observed tubulin accumulation, suggesting microtubule over-assembly. These were not associated with mRNA upregulation and were prevented by pharmacological stimulation of autophagy. Both pffs caused accumulation of p62 in cell bodies, suggesting compromised protein degradation. pHluorin imaging in synapses indicated a marked prolongation of vesicular endocytic time, which was rescued by pharmacological depolymerization of microtubules or by the overexpression of full-length dynamin 1. Since dynamin is a high-affinity binding partner of microtubules as well as an endocytic key molecule, over-assembled microtubules can sequester dynamin, thereby inhibiting endocytosis. We conclude that pff-induced accumulation of α-synuclein or tau in presynaptic terminals can disrupt vesicle endocytosis through a common mechanism. Since endocytosis-dependent vesicle recycling is critical for maintaining neurotransmitter release, its disruption can affect the neurocircuitry operations involved, thereby causing diverse symptoms associated with neurodegenerative diseases. Thus, our data suggest a common molecular mechanism underlying synaptic dysfunctions associated with Parkinson's and Alzheimer's diseases.}, } @article {pmid41025909, year = {2025}, author = {Sajimon, M and Wheeler, CJ and Foley, AR and Chan, K and Griffin, MN and Dinakarapandian, DM and Holberton, A and Joy, J and Paravastu, AK and Wood, LB and Raskatov, JA}, title = {Asparagine Deamidation Attenuates Toxicity, Aggregation, and Microglial Responses of Alzheimer's Amyloid-β.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {20}, pages = {4076-4085}, doi = {10.1021/acschemneuro.5c00544}, pmid = {41025909}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; *Microglia/metabolism/drug effects ; *Asparagine/metabolism ; *Alzheimer Disease/metabolism ; Animals ; *Peptide Fragments/metabolism/toxicity ; Humans ; Mice ; }, abstract = {Alzheimer's disease (AD) is a growing global challenge that imposes a tremendous burden on society and economies. Though recently approved anti-amyloid β (Aβ) immunotherapies show effectiveness in clearing amyloid and slowing cognitive decline, the removal of cerebral Aβ can also cause serious adverse events (SAEs). Therefore, decreasing the detrimental effects of Aβ in the brain without promoting SAEs is an unmet need in AD treatment. Here, we show that deamidation of Asparagine 27(N27) in Aβ1-42 can significantly reduce Aβ's neurotoxicity and decrease selective microglial pro-inflammatory cytokine production. We also show that deamidation of N27 produces a pronounced decrease in Aβ's aggregation propensity and decreases soluble oligomer formation, suggesting a potential mechanism for its mitigation of Aβ's detrimental cellular effects. Modulation of these Aβ properties by N27 deamidation represents a proof of concept for a potential strategy to alter the detrimental effects of Aβ that may not require its removal from the brain. Our findings on reducing Aβ's toxic properties by N27 deamidation may provide a basis for future therapeutic interventions.}, } @article {pmid41024939, year = {2024}, author = {Saleh, AY and Valentina, R and Susanto, TD and Saputra, DAY}, title = {Beyond stroke therapy, neuroaid (a chinese herbal) has an effect on cognition and neurogenesis, a bibliometric study.}, journal = {F1000Research}, volume = {13}, number = {}, pages = {799}, pmid = {41024939}, issn = {2046-1402}, mesh = {Humans ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Cognition/drug effects ; *Stroke/drug therapy ; Bibliometrics ; *Neurogenesis/drug effects ; Animals ; }, abstract = {INTRODUCTION: NeuroAiD, also known as MLC601 or MLC901, is a Chinese herbal combination used worldwide for stroke treatment. It contains herbal components and five hewan components. MLC601 contains herbal components and hewan components, while MLC901 has a similar herbal composition. NeuroAiD is used to support neurologic recovery after stroke and to aid cognitive function in Alzheimer's disease. Studies show that NeuroAiD has potential in treating Alzheimer's disease and is beneficial in both local and global stroke models and in the Kortikal culture. However, there is limited bibliometric research on NeuroAiD, which is a method of collecting data from published articles to analyze developments and trends in the field of research. This research contributes significantly to the literature and helps develop more effective stroke treatment strategies. METHODS: In this work, a literature review methodology is employed to gather data from the Scopus database using the keywords neuroaid. Data were analyzed using Biblioshiny and VOSviewer software to produce visualizations and bibliometric maps. We conducted quantitative and qualitative analysis. RESULTS: The research trend found are documents by year, most relevant sources, factorial map of the most cited documents, factorial map of The documents with the highest contributes, documents by author, documents by country or territory, documents by subject area, documents by affiliation, network visualization, overlay visualization of scopus database using vosviewer, density visualization, thematic map, thematic evolution, topic dendogram, and world cloud. CONCLUSIONS: The study investigates the potential of Neuroaid, a neuroprotective drug, for stroke prevention and cognitive function enhancement. It uses terms like "cognition" and "neurogenesis" to highlight its potential. While the study's focus may be limited, it provides valuable insights into research direction and potential areas of neuroaid for stroke treatment.}, } @article {pmid41024926, year = {2025}, author = {Bitar, I and Alabdalrazzak, M and Zamzam, M and Desai, Y and Abushaban, K}, title = {Clinically Silent Amyloid-Related Imaging Abnormality With Edema Following Lecanemab Therapy: A Case Report.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e91230}, pmid = {41024926}, issn = {2168-8184}, abstract = {Amyloid-related imaging abnormalities with edema (ARIA-E) are a known complication of anti-amyloid monoclonal antibody therapies such as lecanemab. ARIA-E represents vasogenic cerebral edema resulting from treatment-related disruption of vascular amyloid and appears on MRI as cortical or gyriform T2 fluid-attenuated inversion recovery (FLAIR) hyperintensities. Clinically, ARIA-E ranges from asymptomatic radiologic findings to symptomatic events such as headache, confusion, or seizures, making routine surveillance important during therapy. We present the case of a 60-year-old woman with biomarker-confirmed AD who developed radiographically evident ARIA-E following six biweekly infusions of lecanemab. Surveillance MRI revealed new cortically based and gyriform T2 FLAIR hyperintensities in the posterior occipital and bilateral temporal lobes, consistent with parenchymal and sulcal edema. Notably, the patient remained neurologically asymptomatic throughout the episode. Lecanemab therapy was discontinued, and she was managed conservatively with close outpatient follow-up. This case highlights the importance of routine imaging during anti-amyloid therapy and demonstrates that conservative management may be appropriate in select asymptomatic cases of ARIA-E.}, } @article {pmid41023855, year = {2025}, author = {Zou, M and Xu, SS and Zhu, SG and Yuan, CX and Huang, JF and Zhu, JH and Zhang, X and Wang, JY}, title = {Elevated D-dimer levels after lecanemab infusions: a case report.}, journal = {BMC geriatrics}, volume = {25}, number = {1}, pages = {742}, pmid = {41023855}, issn = {1471-2318}, support = {2023RC215//Zhejiang Provincial Medical Technology Program/ ; }, mesh = {Humans ; *Fibrin Fibrinogen Degradation Products/metabolism ; Aged, 80 and over ; Male ; *Alzheimer Disease/drug therapy/blood ; Infusions, Intravenous ; Biomarkers/blood ; }, abstract = {BACKGROUND: Lecanemab is a disease-modifying immunotherapy for Alzheimer's disease (AD) and has been increasingly prescribed to the patients in the world. It has a definite therapeutic effect in slowing cognitive decline in AD patients, but its adverse drug reactions should not be ignored. CASE PRESENTATION: We reported an 82-year-old Chinese AD patient who developed recurrent D-dimer elevation after lecanemab infusions. His D-dimer levels were positively correlated with activated partial thromboplastin time, C-reactive protein, and neutrophil percentage, but negatively correlated with platelet count. CONCLUSIONS: Elevated D-dimer levels may be associated with the enhanced phagocytic response to vascular amyloid β upon lecanemab treatment. Our report expands knowledge on lecanemab's adverse drug reactions, suggesting that D-dimer levels and potential thromboembolic events should be monitored during treatment. CLINICAL TRIAL NUMBER: not applicable.}, } @article {pmid41023476, year = {2025}, author = {Bhatt, K and Jayanthi, N and Kumar, M}, title = {FHESA: fourier decomposition and hilbert transform based EEG signal analysis for Alzheimer's disease detection.}, journal = {Physical and engineering sciences in medicine}, volume = {48}, number = {4}, pages = {2043-2058}, pmid = {41023476}, issn = {2662-4737}, mesh = {*Alzheimer Disease/diagnosis/physiopathology ; Humans ; *Electroencephalography ; *Fourier Analysis ; *Signal Processing, Computer-Assisted ; Algorithms ; Machine Learning ; Aged ; Male ; }, abstract = {Alzheimer's Disease (AD) is a chronic neurological disorder that impairs the cognitive and behavioral abilities of older people. Early detection and treatment are crucial for minimizing the progression of the disease. Electroencephalogram (EEG) makes it possible to investigate the brain activities linked to various forms of disabilities experienced by individuals with AD. Nevertheless, the EEG signals are non-linear and non-stationary in nature making it difficult to retrieve the concealed information from the EEG signals. Therefore, a Fourier Decomposition Method (FDM) and Hilbert Transform (HT) based EEG signals analysis (FHESA) method is developed in this paper for the automated detection of AD. The FHESA method aims to efficiently analyze the EEG data to identify the important brain regions vulnerable to AD, and to assess the impact of various EEG channels for the timely and early detection of AD. The proposed FHESA method is divided into three primary stages. The first stage deals with the decomposition of the EEG signals into a finite number of Fourier Intrinsic Band Functions (FIBFs). In the second stage, HT is applied to all FIBFs to obtain instantaneous amplitude, frequency, and phase, that are then used to construct feature vectors. In the last stage, various Machine Learning (ML) algorithms are used to classify these feature vectors for efficient AD detection. Two distinct data sets are employed to assess the effectiveness of the proposed FHESA method. The outcome demonstrates that with dataset-I and dataset-II, the proposed methodology can detect AD with 98% and 99% accuracy, respectively. The performance of the proposed FHESA method is compared to other state-of-the-art methods used for AD detection. The promising results show that the proposed FHESA method can assist neurological experts in identifying and utilizing EEG signals for AD detection.}, } @article {pmid41023471, year = {2025}, author = {Wang, Y and Yang, J and Jiang, X and Yuan, R and Cheng, R and Lu, N and Gao, A and Liu, S}, title = {Potential new drug sources for the treatment of Parkinson's disease: flavonoid O-glycosides.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {966}, pmid = {41023471}, issn = {1573-4978}, support = {82274125//National Natural Science Foundation of China/ ; }, mesh = {*Parkinson Disease/drug therapy ; *Flavonoids/therapeutic use/pharmacology/chemistry ; Humans ; *Glycosides/therapeutic use/pharmacology/chemistry ; Animals ; Biological Products/therapeutic use/pharmacology ; }, abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. With the increase in the global aging population, the global prevalence of PD has soared, and the burden of global medical resources is increasingly heavy. Although modern medicine has progressed in treating PD, existing drugs still have drawbacks regarding Mechanism and efficacy, intensifying the urgency of developing new drugs. Researchers have favored natural treatments for their safety in recent years and have increasingly become an essential source for developing new drugs. Flavonoid O-glycoside compounds are one of the main active ingredients of natural products and have shown satisfactory efficacy in treating PD, thus becoming potential drugs for treating neurodegenerative diseases. In this study, we systematically evaluated the Mechanism of several specific flavonoid O-glycoside compounds in the treatment of PD, conducted a relatively in-depth summary and discussion of their biological activities, and compared them with other flavonoid O-glycoside compounds. This provides a theoretical basis for further future mechanism research on flavonoid O-glycoside compounds. And lay the foundation and set an example for the development and application of natural products. This review indicates that flavonoid O-glycoside compounds are up-and-coming new therapeutic drugs for Parkinson's disease (PD) and can be used in PD prevention and treatment strategies.}, } @article {pmid41021789, year = {2025}, author = {Huang, M and Su, X and Bian, L and Xu, L and Pang, H and Song, Z and Sun, L and Zhang, H and Ma, Y}, title = {Preliminary efficacy analysis of middle meningeal artery embolization using Glubran 2 for chronic subdural hematoma.}, journal = {Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences}, volume = {}, number = {}, pages = {15910199251380388}, pmid = {41021789}, issn = {2385-2011}, abstract = {ObjectiveTo preliminarily conclude the safety and efficacy of middle meningeal artery embolization (MMAE) with Glubran 2 in treating chronic subdural hematoma (CSDH).MethodsThis retrospective analysis was performed on 40 consecutive CSDH patients who received MMAE with Glubran 2 between 2021 and 2023. The patients were followed up for 3 years post-operationally. Surgical procedures included burr hole drainage (BHD) and MMAE, both of which were performed under local anesthesia. MMAE with Glubran 2 was performed through transfemoral access. Postoperative recurrence was defined as an increase in hematoma volume based on computed tomography (CT) and/or magnetic resonance imaging (MRI) accompanied by clinical symptoms, which require further treatment within 3 years postoperatively.ResultsIn this study, 40 CSDH patients (34 male and six female) with a mean age of 68.2 ± 13.2 years were included. Of these, 38 patients underwent MMAE-assisted BHD. Two patients received MMAE alone. A single-branch embolization was performed on 20 hematomas in 18 patients, and a double-branch on 27 hematomas in 22 patients. At the three-year follow-up, 33 patients were successfully contacted, and 24 patients showed significant improvement or were asymptomatic after treatment. Three patients passed away owing to non-CSDH-related reasons. One patient developed decompensated liver cirrhosis, one experienced Alzheimer's disease, and four patients experiencing deteriorated functions were unclear but non-CSDH related as demonstrated by absorbed hematomas on head CT or MRI during return visits. The median follow-up time was 35 (IQR 27-40) months, and the median mRS score was 0 (IQR 0-0).ConclusionMMAE-assisted BHD with Glubran 2 is feasible, safe, and effective in treating CSDH, with no associated complications.}, } @article {pmid41020462, year = {2025}, author = {Lee, YC and Tai, YC}, title = {Seronegative but Cerebrospinal Fluid-positive NMDA Receptor Encephalitis in an Alzheimer's Dementia Patient with Good Treatment Outcome: A Case Report.}, journal = {Acta neurologica Taiwanica}, volume = {34}, number = {3}, pages = {161-164}, doi = {10.4103/ANT.ANT_113_0041}, pmid = {41020462}, issn = {1028-768X}, mesh = {Humans ; Female ; Aged ; *Alzheimer Disease/complications ; *Anti-N-Methyl-D-Aspartate Receptor Encephalitis/cerebrospinal fluid/complications/therapy ; Immunoglobulins, Intravenous/therapeutic use ; Treatment Outcome ; Electroencephalography ; Autoantibodies/cerebrospinal fluid ; }, abstract = {We present a rare case of elderly-onset anti-N-methyl-D-aspartate (NMDA) receptor encephalitis combined with underlying Alzheimer dementia, characterized by seronegativity but cerebrospinal fluid (CSF) antibody positivity, which showed a significant improvement following intravenous immunoglobulin (IVIG) treatment. The case highlights serial electroencephalogram (EEG) changes. We focus the discussion on factors contributing to favorable recovery. A 78-year-old woman with Alzheimer's dementia and hypertension experienced rapid onset of further cognitive decline over 1 week, presenting with disorientation, irrelevant speech, and disorganized behaviors. Myoclonus of both upper limbs and focal seizures 10 days later which lead her into intensive care unit (ICU) admission. Test results revealed positive anti-NMDA antibodies in CSF but negative in serum. Serial electroencephalograms (EEG) exhibited extreme delta brush activity transitioning to excess beta activity. Initial treatment with a 5-day course of steroid pulse therapy showed limited efficacy. Subsequently, 5 days of IVIG therapy provided marked improvement in consciousness and cognitive function and also normalized the EEG. This patient presented with severe neurological dysfunction, the need for ICU management, and presence of extreme delta brush EEG pattern. Generally, the prognosis was unfavorable. However, advanced age onset and anti-NMDA antibody positivity in CSF with seronegativity in serum may imply better prognosis. Thus, testing anti-NMDA receptor antibody in both serum and CSF is mandatory and under this complicated situation, timely immunotherapy may be the influencing factors of good prognosis.}, } @article {pmid41020412, year = {2025}, author = {Villeneuve, S and Poirier, J and Breitner, JCS and Tremblay-Mercier, J and Remz, J and Raoult, JM and Yakoub, Y and Gallego-Rudolf, J and Qiu, T and Fajardo Valdez, A and Mohammediyan, B and Javanray, M and Metz, A and Sanami, S and Ourry, V and Wearn, A and Pastor-Bernier, A and Edde, M and Gonneaud, J and Strikwerda-Brown, C and Tardif, CL and Gauthier, CJ and Descoteaux, M and Dadar, M and Vachon-Presseau, É and Baril, AA and Ducharme, S and Montembeault, M and Geddes, MR and Soucy, JP and Rajah, N and Laforce, R and Bocti, C and Davatzikos, C and Bellec, L and Rosa-Neto, P and Baillet, S and Evans, AC and Collins, DL and Chakravarty, MM and Blennow, K and Zetterberg, H and Spreng, RN and Pichet Binette, A and , }, title = {The PREVENT-AD cohort: Accelerating Alzheimer's disease research and treatment in Canada and beyond.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70653}, pmid = {41020412}, issn = {1552-5279}, support = {R01AG068563/AG/NIA NIH HHS/United States ; //Canada Foundation for Innovation/ ; PJT-367122/CAPMC/CIHR/Canada ; SG-23-1038904QC/ALZ/Alzheimer's Association/United States ; PJT-463677/CAPMC/CIHR/Canada ; P30 AG048785/AG/NIA NIH HHS/United States ; JPND2019-466-236//EU Joint Programme Neurodegenerative Disease Research/ ; PJT-410106/CAPMC/CIHR/Canada ; PJT-165921/CAPMC/CIHR/Canada ; AARG-22-927100/ALZ/Alzheimer's Association/United States ; R01 AG068563/AG/NIA NIH HHS/United States ; //Fonds de recherche du Québec - Santé/ ; PJT-178210/CAPMC/CIHR/Canada ; PJT-438655/CAPMC/CIHR/Canada ; //Fondation de la Famille Lemaire/ ; R01 EB026299/EB/NIBIB NIH HHS/United States ; 3R01AG068563-04S1/AG/NIA NIH HHS/United States ; PJT-451830/CAPMC/CIHR/Canada ; 2022-00732//Vetenskapsrådet/ ; //Fondation Brain Canada/ ; PJT-153287/CAPMC/CIHR/Canada ; //Fondation Jean-Louis Lévesque/ ; NIG-17-08//Alzheimer Society of Canada/ ; 2017-00915//Vetenskapsrådet/ ; //Canada First Research Excellence Fund/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/therapy ; Canada ; Aged ; Female ; Magnetic Resonance Imaging ; Male ; Disease Progression ; Longitudinal Studies ; Biomarkers/blood/cerebrospinal fluid ; Positron-Emission Tomography ; Cohort Studies ; Amyloid beta-Peptides ; Neuroimaging ; }, abstract = {The PResymptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) is an investigator-driven study that was created in 2011 and enrolled cognitively normal older adults with a family history of sporadic AD. Participants are deeply phenotyped and have now been followed annually for more than 12 years (median follow-up 8.0 years, SD 3.1). Multimodal magnetic resonance imaging (MRI), genetic, neurosensory, clinical, cerebrospinal fluid, and cognitive data collected until 2017 on 348 participants who agreed to open sharing with the neuroscience community were already available. We now share a new release including 6 years of additional follow-up cognitive data, and additional MRI follow-ups, clinical progression, new longitudinal behavioral and lifestyle measures (questionnaires, actigraphy), longitudinal AD plasma biomarkers, amyloid-beta and tau positron emission tomography (PET), magnetoencephalography, as well as neuroimaging analytic measures from all MRI modalities. We describe the PREVENT-AD study, the data shared with the global research community, as well as the model we created to sustain longitudinal follow-ups while also allowing new innovative data collection. HIGHLIGHTS: The PResymptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) is a single-site longitudinal study that started in 2011 with annual follow-up data collection on individuals at risk of Alzheimer's disease who were all cognitively normal at enrolment. All 387 participants were enrolled between 2011 and 2017 and 306 (79%) of these participants were still in the study as of December 2023. While the PREVENT-AD dataset was not originally planned to be shared with the global research community, 348 participants retrospectively consented for their data to be shared with researchers worldwide. The first release of data was in 2019. We now share a second release that includes 6 years of additional follow-up visits, information on clinical progression and novel cognitive, behavioral, genetic, plasma and neuroimaging (amyloid and tau positron emission tomography [PET], magnetoencephalography [MEG], and new magnetic resonance imaging [MRI] sequences) data. It also includes analytic outputs for neuroimaging modalities.}, } @article {pmid41019419, year = {2025}, author = {Punsawad, C and Kaewman, P and Techarang, T and Sketriene, D and Lalert, L}, title = {Low-Dose Paracetamol Treatment Protects Neuronal Oxidative Stress and Neuroinflammation in D-Galactose-Induced Accelerated Aging Model.}, journal = {Scientifica}, volume = {2025}, number = {}, pages = {5559483}, pmid = {41019419}, issn = {2090-908X}, abstract = {Aging increases the risk of neurodegenerative diseases such as Parkinson's and Alzheimer's (PD and AD) which are potentially linked to increased oxidative stress and inflammation. Paracetamol (APAP) is known for its antioxidant and anti-inflammatory properties; however, its potential neuroprotective effects against age-related oxidative stress and neuroinflammation remain inadequately investigated. Therefore, we aimed to examine whether low-dose APAP could mitigate oxidative stress and neuroinflammation in a D-galactose (D-gal)-induced aging model. In our study, fifty adult male ICR mice were divided into five groups (n = 10). Except for the normal control group, all mice received D-gal subcutaneous injections (200 mg/kg) and were fed vehicle, 15 or 50 mg/kg APAP, or 100 mg/kg vitamin E daily for six weeks. After treatment, liver function was assessed by serum liver enzyme analysis. The liver and brain pathologies were examined using hematoxylin and eosin staining. Brain oxidative stress was evaluated through malondialdehyde (MDA) measurement. Additionally, immunohistochemistry was used to determine levels of inflammatory cytokines (TNF-α, IL-1β, TGF-β, and IL-10) and the oxidative stress marker, NADPH Oxidase 4 (NOX4). The study found no significant changes in serum liver enzymes or liver morphology among the experimental groups. However, the D-gal group exhibited increased neuronal cell loss, along with elevated levels of MDA and NOX4 in the frontal cortex and hippocampus. Moreover, D-gal mice showed elevated levels of TNF-α, IL-1β, and TGF-β, accompanied by decreased IL-10 levels. Notably, treatment with low-dose APAP and vitamin E mitigated neuronal cell loss, decreased MDA levels, and attenuated NOX4 expression induced by D-gal injection. Furthermore, low-dose APAP, particularly at 50 mg/kg, and vitamin E reversed the alterations in TNF-α, IL-1β, and IL-10 induced by D-gal, while TGF-β was unaffected. We suggest that low-dose APAP exerts antioxidant and anti-inflammatory activities to protect against neurodegeneration in a mouse model of brain aging induced by chronic D-gal injection.}, } @article {pmid41019272, year = {2025}, author = {Fernandes, JVA and Ramos, JVO and Vilar, LADS and Holanda, MMA}, title = {Brexpiprazole for agitation in alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials.}, journal = {Indian journal of psychiatry}, volume = {67}, number = {9}, pages = {852-861}, pmid = {41019272}, issn = {0019-5545}, abstract = {BACKGROUND: Agitation in Alzheimer's disease (AD) severely affects patients and caregivers. Brexpiprazole, a serotonin-dopamine modulator, is the potential treatment; however, recent trials and variations in dosing have raised questions about its optimal efficacy and safety. AIM: To evaluate the efficacy and safety of brexpiprazole in the treatment of agitation associated with AD, with a focus on dose-specific outcomes. METHODS: A systematic search was conducted in PubMed, Embase, and the Cochrane Library for Randomized Controlled Trials (RCT) comparing brexpiprazole with placebo in AD-related agitation. Primary efficacy outcomes included changes in the Cohen-Mansfield Agitation Inventory (CMAI) and Clinical Global Impression-Severity (CGI-S) scores. Safety outcomes encompassed treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and mortality. Meta-analyses were performed using a random-effects model, with mean differences (MD) and odds ratios (OR) reported with 95% confidence intervals (CI). RESULTS: Four RCTs with 1,710 participants were included. Brexpiprazole 2 mg significantly reduced CMAI scores (MD: -5.618; 95% CI: -7.884, -3.351; P < 0.001) and CGI-S scores (MD: -0.513; 95% CI: -0.890, -0.135; P = 0.008) compared to placebo. Lower doses (0.5-1 mg) demonstrated limited efficacy. TEAEs were more frequent with brexpiprazole 2 mg (OR: 1.554; 95% CI: 1.045, 2.312; P = 0.030), while SAEs (OR: 1.389; P = 0.384) and mortality (OR: 2.189; P = 0.301) did not significantly differ from placebo. CONCLUSION: Brexpiprazole 2 mg is effective in reducing agitation symptoms in AD with an acceptable safety profile.}, } @article {pmid41018231, year = {2025}, author = {Tziveleka, LA and Cascione, M and Pellegrino, P and Bianco, A and Leporatti, S and De Matteis, V}, title = {Immunomodulatory natural polysaccharide-based nanoparticles for the treatment of neurodegenerative diseases.}, journal = {Ibrain}, volume = {11}, number = {3}, pages = {277-296}, pmid = {41018231}, issn = {2769-2795}, abstract = {Polysaccharide-based nanoparticles offer significant potential for the treatment of neurodegenerative diseases and the modulation of inflammatory responses in the central nervous system. These biopolymers, when derived from natural sources, possess inherent immunomodulatory properties, which can be leveraged to regulate immune activity, positioning them as promising candidates for both prophylactic and therapeutic strategies. Furthermore, when integrated with other materials, polysaccharides form nanocomposites with enhanced structural, physicochemical, and biological properties, making them highly versatile platforms for drug delivery in the central nervous system. This review provides a comprehensive analysis of polysaccharide-based nanoparticles, focusing on their application in the treatment of three major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Emphasis is placed on optimizing these nanomaterials for targeted drug delivery and immune modulation, underscoring their potential to improve therapeutic outcomes in neurodegenerative disorders. The review also examines the structural, chemical, and biological characteristics of key polysaccharides, and explores their innovative roles in combating neuroinflammation and neurodegeneration.}, } @article {pmid41017736, year = {2025}, author = {Laouini, SE and Bouafia, A and Azzi, M and Laib, I and Fellah, M and Abdullah, MMS and Al-Lohedan, HA and Abdullah, JAA}, title = {Synthesis and Characterization of Amoxicillin-Functionalized Ag/AgCl Nanoparticles: A Promising Multifunctional Platform for Next-Generation Nanomedicine.}, journal = {Journal of biomedical materials research. Part B, Applied biomaterials}, volume = {113}, number = {10}, pages = {e35661}, doi = {10.1002/jbm.b.35661}, pmid = {41017736}, issn = {1552-4981}, support = {ORF-2025-54//Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia, Ongoing Research Funding program/ ; }, mesh = {*Amoxicillin/chemistry/pharmacology ; *Silver/chemistry/pharmacology ; *Silver Compounds/chemistry/pharmacology ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Metal Nanoparticles/chemistry ; Escherichia coli/growth & development ; Animals ; *Nanomedicine ; Antioxidants/chemistry/pharmacology ; *Biofilms/drug effects/growth & development ; Cholinesterase Inhibitors/chemistry/pharmacology ; }, abstract = {This study synthesized and characterized amoxicillin-functionalized Ag/AgCl nanoparticles (Amoxicillin@Ag/AgCl NPs) for biomedical applications. The nanoparticles were prepared via a coprecipitation method and functionalized with amoxicillin to enhance therapeutic potential. Characterization techniques (X-ray diffraction [XRD], Fourier-transform infrared (FTIR), scanning electron microscopy [SEM], and UV-Vis) confirmed successful functionalization and improved physicochemical properties. The crystallite size increased from 17.29 ± 3.44 to 20.47 ± 4.17 nm, while the bandgap widened from 2.33 to 2.40 eV, indicating enhanced electronic interactions. Antioxidant activity was significantly improved, with 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging reaching 97.87% and β-carotene bleaching inhibition at 95.47% (175 μg/mL). The antibiofilm efficacy was notable, with inhibition rates of 90.24% for E. coli (250 μg/mL), 81.47% for S. typhimurium (175 μg/mL), and 87.68% for B. subtilis (250 μg/mL). In enzymatic inhibition studies, Amoxicillin@Ag/AgCl NPs showed neuroprotective potential, inhibiting acetylcholinesterase (AChE) (93.74% at 160 μg/mL) and butyrylcholinesterase (BChE) (97.41% at 80 μg/mL), highlighting their potential in Alzheimer's treatment. Additionally, they exhibited anti-inflammatory effects, inhibiting lipoxygenase (LOX) by 90.47% (120 μg/mL). To the best of our knowledge, this is the first report on the synthesis of Amoxicillin@Ag/AgCl NPs that simultaneously demonstrate strong antioxidant, antibiofilm, neuroprotective, and anti-inflammatory properties, underscoring their novelty as next-generation nanomedicines.}, } @article {pmid41017725, year = {2025}, author = {Zhang, J and He, S and Xiao, Q and Jiang, W and Wang, B and Lu, J and Gu, H and Liao, Y and Wang, Z and Xu, Y and Wang, D and Tang, X and Qi, L}, title = {Engineered mesenchymal stem cell-derived extracellular vesicles overexpressing miR-146a alleviate neuroinflammation in Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00404}, pmid = {41017725}, issn = {1673-5374}, abstract = {Alzheimer's disease is an inflammatory neurodegenerative disease for which no effective clinical treatment currently exists. We have previously reported that mesenchymal stem cell.derived extracellular vesicles delay retinal degeneration by exerting anti-inflammatory effects though the miR-146a.nuclear receptor subfamily 4 group A member 3 axis; however, it remains unclear how NR4A3 drives inflammation. Herein, we engineered mesenchymal stem cell. derived extracellular vesicles overexpressing miR-146a to explore their possible neuroprotective effects and the underlying mechanisms in both cell and animal models of Alzheimer's disease. In HT22 cells co-cultured with lipopolysaccharide-induced RAW264.7/BV2 cells, extracellular vesicles overexpressing miR- 146a significantly reduced the number of apoptotic cells and inhibited proinflammatory cytokine expression, nuclear factor (NF)-κB activation, and caspase-3/ apoptosis regulator BAX signaling. These effects of extracellular vesicles overexpressing miR-146a were replicated in 5×FAD mice. In addition, extracellular vesicles overexpressing miR-146a inhibited the activation of microglia and astrocytes, reduced amyloid-β and phosphorylated tau expression, lowered the number of apoptotic cells in the hippocampus, and improved the cognitive function of these Alzheimer's disease model mice. Mechanistically, miR-146a negatively regulated the expression of nuclear receptor subfamily 4 group A member 3 and suppressed the expression of proinflammatory cytokines and nuclear factor-κB signaling. Furthermore, NR4A3 overexpression promoted nuclear factor-κB and proinflammatory cytokine expression as well as nuclear factor-κB signaling. The upregulation of NR4A3 and the inflammatory response was reversed by miR-146a overexpression. Finally, NR4A3 was identified as a transcriptional activator of nuclear factor-κB using chromatin immunoprecipitation polymerase chain reaction. Collectively, these findings indicate that extracellular vesicles overexpressing miR-146a may alleviate the progression of Alzheimer's disease by exerting anti-inflammatory effects via the NR4A3. nuclear factor-κB axis. They are thus a potential therapeutic candidate for the clinical treatment of neurodegenerative diseases.}, } @article {pmid41017722, year = {2025}, author = {Xu, X and Li, J and Wang, F and Xue, K and He, J and Meng, X and Shen, Y}, title = {Genetic and pathway complexity in Alzheimer's disease: Insights from multi-omic data about the immune response and mitochondrial function.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00184}, pmid = {41017722}, issn = {1673-5374}, abstract = {Despite recent developments, the genetics and biology of Alzheimer's disease remain insufficiently characterized. As an important first step toward developing effective treatment strategies to slow or prevent Alzheimer's disease onset, the identification of relevant genetic markers is crucial. In the present study, we analyzed transcriptomic and multi-omic datasets across multiple cohorts (the Alzheimer's Disease Neuroimaging Initiative, Religious Orders Study and Rush Memory and Aging Project, Mount Sinai Brain Bank, and Mayo Clinic Alzheimer's Disease Genetics Studies) using gene set enrichment analysis, machine learning algorithms, and polygenic risk scoring to identify gene sets relevant to Alzheimer's disease risk and pathological features. For prioritized gene sets, we performed epigenome-wide association studies to assess DNA methylation patterns, and used multi-omic mediation analysis to characterize the causal gene regulatory networks. Overall, we identified several key gene sets relevant to Alzheimer's disease pathology-particularly, those related to immune system function and mitochondrial dysfunction. Upregulated pathways, including neutrophil degranulation and tumor necrosis factor-α signaling pathways, correlated strongly with aspects of neuroinflammation in Alzheimer's disease. By contrast, downregulated oxidative phosphorylation pathways further suggested mitochondrial dysfunction. Gene sets that contained mitochondrially located genes (e.g., SGK1 and LRRK1) were identified as significantly contributing to neurodegeneration. Moreover, genes such as CXCL1, TGFB2, and DUSP1 were consistently implicated in all datasets, thus emphasizing their involvement in immune modulation and mitochondrial function. The multimodal investigation outlined in the current study represents useful steps toward comprehending the genetic architecture of Alzheimer's disease, including an expanded understanding of the spatial interactions of genes associated with disease susceptibility. Mitochondrial dysfunction and immune modulation were pathological pathways that converged on Alzheimer's disease and future treatment novel options. Using the frameworks provided in the current comprehensive study, we present opportunities to explore targeted treatment strategies that may alter immune systems and mitochondrial function to optimize treatment outcomes for individuals at increased risk of or living with Alzheimer's disease.}, } @article {pmid41017717, year = {2025}, author = {Yuan, H and Shi, J and Gu, C and Yuan, J and Huang, C and Li, X and Zhou, K and Qi, J}, title = {Akkermansia muciniphila: A next-generation gut probiotic supporting neurorepair and functional recovery.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00701}, pmid = {41017717}, issn = {1673-5374}, abstract = {The brain-gut axis is a bidirectional signal transduction system between the gastrointestinal tract and the central nervous system that integrates neural, endocrine, and immune functions. In recent years, the role of the intestinal flora in regulating neural function and affecting the progression of different neurological diseases has received increasing attention. Akkermansia muciniphila is a mucindegrading bacterium of the intestinal flora present in the intestinal mucus layer that can regulate host immunity, the intestinal barrier and neuroimmune homeostasis. In recent years, a growing body of literature has suggested that Akkermansia muciniphila may play beneficial roles in nerve injury and regeneration by regulating brain-gut axis signalling. This review comprehensively summarizes the latest research results on the role of Akkermansia muciniphila in neurological diseases such as spinal cord injury, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The mechanisms by which Akkermansia muciniphila regulates inflammatory cytokines, neurotransmitters, and shortchain fatty acids are also highlighted. Various Akkermansia muciniphila-based interventions, such as those involving outer membrane proteins, extracellular vesicles, and pasteurized Akkermansia muciniphila, are discussed, and their therapeutic potential in restoring intestinal homeostasis, alleviating neuroinflammation, and supporting neuronal repair is explored. Although promising results from animal models have been reported, significant challenges remain in translating these findings into clinical practice and therapeutic applications. The differences in Akkermansia muciniphila colonization efficiency, host responses, and intervention strategies in different disease states limit the results of these studies. In addition, Akkermansia muciniphila may exhibit different mechanisms of action in acute and chronic neurodegenerative diseases, and thus more targeted mechanistic studies are needed. Despite these limitations, Akkermansia muciniphila represents a novel and potent pathway for the modulation of the brain-gut axis to support neural repair and functional recovery. By enhancing intestinal barrier integrity and regulating neuroimmunity, Akkermansia muciniphila has broad prospects as a microbial candidate for the treatment of central nervous system diseases. Future research should focus on optimizing the administration method and clinical trials to verify its efficacy, ultimately providing new treatment options in the field of neural regeneration and microbial therapy.}, } @article {pmid41017705, year = {2025}, author = {Wang, H and Wei, Y and Wang, J and Liu, J and Ou, S and Wang, J}, title = {Structure and function of voltage-gated sodium channel Nav1.6: Involvement in the pathological process of neural injury.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00354}, pmid = {41017705}, issn = {1673-5374}, abstract = {The voltage-gated sodium channel Nav1.6, encoded by the sodium voltage-gated channel alpha subunit 8 gene, is a crucial regulator of neuronal excitability, with widespread expression throughout the central and peripheral nervous systems. Recent breakthroughs in structural biology, particularly the elucidation of the cryo-EM architecture of Nav1.6 at a resolution of 0.31 nm, have provided unprecedented insights into its molecular organization and functional modulation. As a key mediator of action potential initiation and propagation, Nav1.6 possesses unique biophysical properties, including persistent and resurgent sodium currents that critically influence neuronal firing patterns. This comprehensive review synthesizes current knowledge on the physiological functions and pathological roles of Nav1.6 in multiple neurological conditions. Key findings include the following: (1) Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype-phenotype correlations, where gain-of-function variants lead to severe epileptic encephalopathies, while loss-of-function variants are associated with generalized epilepsy, highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967. (2) In Alzheimer's disease, Nav1.6 mediates amyloid-β oligomer-induced neuronal hyperexcitability through amyloid precursor protein-dependent membrane trafficking and regulates beta-secretase 1 expression via nuclear factor of activated T cells 1 signaling, suggesting novel disease-modifying strategies. (3) Parkinson's disease research has demonstrated that Nav1.6 upregulation in reactive astrocytes in the globus pallidus contributes to motor deficits through calcium-mediated abnormalities in neuronal synchronization. (4) Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration, with riluzole showing partial efficacy through sodium current modulation. (5) Multiple sclerosis pathophysiology features Nav1.6 redistribution in demyelinated axons, which drives calcium-dependent axonal injury via reverse Na+/Ca2+ exchange. (6) Chronic pain mechanisms involve Nav1.6 overexpression in dorsal root ganglia neurons, regulated by the p38 mitogen-activated protein kinase and tumor necrosis factor-α signaling pathways. (7) Traumatic brain injury models show that exercise-induced cognitive improvement is correlated with the normalization of Nav1.6-mediated excitability. Therapeutic development has progressed from nonselective sodium channel blockers to precision approaches, including state-dependent pore blockers designed using structural insights; allosteric modulators targeting specific conformations; gene therapy strategies using clustered regularly interspaced short palindromic repeats and antisense oligonucleotides; and miRNA-based regulation of channel expression. Current challenges include achieving sufficient subtype selectivity, optimizing blood-brain barrier penetration, and developing clinically relevant biomarkers for patient stratification. Future directions emphasize the integration of advanced technologies-such as singlecell multiomics to map neuronal subtype-specific expression patterns, patient-derived organoids for personalized drug testing, and machine learning-assisted drug design-to accelerate translation. Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.}, } @article {pmid41017698, year = {2025}, author = {Li, Y and Zhang, Y and Wang, Y and Ye, K and Liu, L and Tian, M and Han, X and Chen, X and Zheng, T and Li, F and Gao, X and Xia, Q and Wang, D}, title = {N6-methyladenosine modification regulates cell death in cognitive impairment.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00813}, pmid = {41017698}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are characterized by a decline in brain structure and function. Their pathology involves multiple cell death pathways, including ferroptosis, cuproptosis, and pyroptosis. These pathways are intricately linked to genes associated with metabolism, antioxidant defense, lipid metabolism, chronic inflammation, and nerve regeneration processes. Key regulators of atypical cell death pathways show aberrant N6-methyladenosine modification levels under pathological conditions. As the most abundant and dynamic RNA modification in brain tissue, N6-methyladenosine plays crucial functional roles. Notably, there exists an intricate interplay between N6-methyladenosine modifications and these cell death pathways, both of which are robustly associated with the pathogenesis of neurodegenerative diseases. However, the molecular mechanisms underlying this association remain unclear. This paper reviews the correlation between N6-methyladenosine and various cell death patterns in neurodegenerative diseases, with emphasis on the molecular mechanisms underlying the interaction between N6-methyladenosine epigenetic regulation and ferroptosis, cuproptosis, and pyroptosis in cognitive impairment. N6- methyladenosine-modified ferroptosis plays an important role in neurodegenerative diseases. There is also a close association between N6-methyladenosine modification and key molecules related to cuproptosis, which may promote the deposition of copper in the brain. Chronic inflammation, a hallmark of neurodegenerative diseases, is related to pyroptosis and N6-methyladenosine modification. It is widely thought that ferroptosis, cuproptosis, and pyroptosis are interconnected processes that may share a common pathway affecting the pathogenesis of neurodegenerative diseases, and are related to key molecules involved in N6-methyladenosine epigenetic modification. This suggests a great potential for future neurodegenerative diseases treatment strategies regulated by N6-methyladenosine modification. N6-methyladenosine modification plays a dual role in nerve injury and regeneration by dynamically regulating processes such as ferroptosis, cuproptosis, and pyroptosis and their key molecules. It maintains the "death-regeneration" balance in oxidative stress and inflammation while selectively promoting axon regeneration through the modulation of methylases. This mechanism indicates a considerable therapeutic target for neurological disorders.}, } @article {pmid41017390, year = {2025}, author = {Chen, JD and Chen, SY and Liao, CC and Fang, CY and Yen, GC}, title = {Enhancing cognitive memory function using Phyllanthus emblica polysaccharides via modulating autophagy and reshaping the gut microbiota.}, journal = {Food & function}, volume = {16}, number = {20}, pages = {8140-8159}, doi = {10.1039/d5fo03048j}, pmid = {41017390}, issn = {2042-650X}, mesh = {Animals ; *Gastrointestinal Microbiome/drug effects ; *Autophagy/drug effects ; Rats ; *Polysaccharides/pharmacology/administration & dosage/chemistry ; *Phyllanthus emblica/chemistry ; Male ; *Memory/drug effects ; Rats, Sprague-Dawley ; Alzheimer Disease/prevention & control ; Cognitive Dysfunction ; Plant Extracts/pharmacology ; *Cognition/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by neuroinflammation, oxidative stress, amyloid-beta (Aβ) plaque buildup, Tau hyperphosphorylation, and gut microbiota imbalance. Natural polysaccharides have been shown to mitigate cognitive decline by regulating the microbiota-gut-brain axis and autophagy, inhibiting neuroinflammation, enhancing Aβ efflux, and facilitating the clearance of Tau protein. Phyllanthus emblica polysaccharides (PEP) exhibit anti-inflammatory, antioxidant, and gut microbiota-modulating properties in colitis and obese mice. However, the potential of PEP in AD prevention remains unclear, prompting the need to investigate the underlying mechanisms of PEP in AD prevention. Physicochemical analysis characterized PEP (MW: 1.182 × 10[3] kDa) as a non-crystalline, heat-stable α-acidic pyran heteropolysaccharide composed of galactose and arabinose monosaccharides. In vivo results showed that PEP administration significantly alleviated cognitive decline by reducing neuroinflammatory cytokines (TNF-α, IL-6, and IL-1β) and MDA levels while increasing anti-inflammatory factors (IL-4 and IL-10) and antioxidants (SOD, catalase, and GPx) in AlCl3-treated rats. Mechanistically, PEP upregulated autophagy-related proteins (Atg5, Beclin1, and LC3B) and LRP1 expression while downregulating AD-related proteins (BACE1, APP, Aβ, and phospho-Tau[Ser404]). Additionally, PEP treatment elevated short-chain fatty acids (SCFAs) and SCFA-producing bacteria, particularly the Christensenellaceae_R-7_group. In summary, PEP demonstrated preventive effects by exerting antioxidant, anti-inflammatory, autophagy-inducing, AD-related protein-suppressing, and microbiota-modulating properties, alleviating cognitive impairment in rats subjected to AlCl3 treatment.}, } @article {pmid41017285, year = {2026}, author = {Guo, S and Wei, F and Sun, H and Jin, H and Cheng, W and Fu, C and Wang, H and Yin, Y}, title = {Astrocyte-Specific Nrf2 Expression Transforms Neurotoxic Reactive Astrocytes to Neuroprotective Phenotype in 3xTg-AD Mice.}, journal = {Glia}, volume = {74}, number = {1}, pages = {e70087}, doi = {10.1002/glia.70087}, pmid = {41017285}, issn = {1098-1136}, support = {82472014//National Natural Science Foundation of China/ ; 81974270//National Natural Science Foundation of China/ ; 24ZR1450000//Natural Science Foundation of Shanghai Municipality/ ; 23ZR1441200//Natural Science Foundation of Shanghai Municipality/ ; }, mesh = {Animals ; *NF-E2-Related Factor 2/genetics/metabolism/biosynthesis ; *Astrocytes/metabolism/pathology/drug effects ; Mice, Transgenic ; Mice ; *Alzheimer Disease/pathology/metabolism/genetics ; Hippocampus/metabolism/pathology ; Phenotype ; tau Proteins/metabolism/genetics ; *Neuroprotection/physiology ; Male ; Disease Models, Animal ; Cells, Cultured ; Mice, Inbred C57BL ; Amyloid beta-Peptides/metabolism ; }, abstract = {Astrocyte reactivity is a common feature of Alzheimer's disease (AD), with reactive astrocytes traditionally subdivided into neurotoxic or neuroprotective phenotypes. It's crucial to transform neurotoxic reactive astrocytes to neuroprotective phenotypes for the treatment of AD, particularly during the progression of the disease. In this study, we evaluated the role of nuclear factor E2-related factor 2 (Nrf2) in facilitating the phenotype transformation of reactive astrocytes in vivo and in vitro by overexpressing Nrf2 in hippocampal astrocytes of 3xTg-AD mice using adeno-associated virus (AAV) vectors, as well as treating neurotoxic reactive astrocytes with dimethyl fumarate (a Nrf2 activator). We also evaluated the therapeutic effect of astrocyte-specific Nrf2 in 3xTg-AD mice with coexpression of Aβ and tau pathologies. Our findings indicate that Nrf2 could facilitate the conversion of neurotoxic reactive astrocytes to neuroprotective phenotypes in vivo and in vitro. AAV-mediated astrocyte-specific Nrf2 expression improved cognitive function, reduced Aβ and tau pathologies, rescued the loss of neurons and synapses, and ameliorated neuroinflammation in 3xTg-AD mice. These findings highlighted the role of Nrf2 in modulating reactive astrocyte phenotypes and suggested the potential for utilizing AAV to target astrocyte-specific Nrf2 as a promising therapeutic strategy for AD.}, } @article {pmid41016794, year = {2025}, author = {Huang, Y and Wei, F and Cheng, X and Shi, Y and Liu, Z and Ye, L}, title = {Neurotropin alleviates Alzheimer's disease pathology by inhibiting FUS-mediated Calhm2 transcription, blocking the Calhm2/EFhd2 interaction, to improve mitochondrial dysfunction-associated microglia polarization.}, journal = {Bioscience trends}, volume = {19}, number = {5}, pages = {566-580}, doi = {10.5582/bst.2025.01220}, pmid = {41016794}, issn = {1881-7823}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Microglia/drug effects/metabolism ; *Mitochondria/drug effects/metabolism ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Calcium-Binding Proteins/metabolism ; Humans ; *Membrane Glycoproteins/metabolism/genetics ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Transcription Factors/metabolism ; *Polysaccharides/pharmacology/therapeutic use ; Transcription, Genetic/drug effects ; Male ; }, abstract = {Neurotropin, a non-protein extract widely used for the treatment of neuropathic pain, has recently been reported to protect against ischemic brain injury, enhance remyelination in demyelinating diseases, and ameliorate neuroinflammation and memory deficits. However, its role in microglial polarization and mitochondrial dysfunction in Alzheimer's disease (AD) remains poorly understood. In this study, we investigated the therapeutic potential of Neurotropin in the 5xFAD mouse model of AD. Neurotropin administration alleviated cognitive decline, reduced amyloid-β (Aβ) deposition, suppressed neuroinflammation, and preserved neuronal density. Mechanistically, Neurotropin improved mitochondrial morphology, restored ATP production, increased mitochondrial DNA copy number, and reduced oxidative stress while promoting a shift in microglial polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype. Transcriptomic and molecular analyses revealed that calcium homeostasis modulator family member 2 (Calhm2) was markedly upregulated in 5xFAD mice, colocalized with microglia, and transcriptionally regulated by fused in sarcoma (FUS), while Calhm2 interacted with EF-hand domain containing protein D2 (EFhd2). Neurotropin suppressed FUS-mediated Calhm2 transcription and attenuated Calhm2-EFhd2 interaction. Importantly, overexpression of Calhm2 in both microglial cells and 5xFAD mice abolished the beneficial effects of Neurotropin, leading to exacerbated mitochondrial dysfunction, oxidative stress, and inflammatory cytokine release. Together, these findings identify Calhm2 as a critical mediator of Neurotropin's neuroprotective effects and demonstrate that Neurotropin alleviates AD pathology by suppressing FUS-dependent Calhm2 transcription and blocking the Calhm2/EFhd2 interaction. This study provides new insights into the mechanism of Neurotropin action and highlights its therapeutic potential for AD.}, } @article {pmid41016150, year = {2025}, author = {Bautista-Aguilera, ÓM and Manik, A and Diez-Iriepa, D and Szałaj, N and Zaręba, P and Więckowska, A and Żmudzki, P and Honkisz-Orzechowska, E and Knez, D and Gobec, S and Sałat, K and Martínez-Alonso, B and Guarnizo-Herrero, V and Durán, GT and Torrado-Salmerón, C and Bellver-Sanchis, A and Nsiona-Defise, I and Ribalta-Vilella, M and Pallàs, M and López-Muñoz, F and Griñán-Ferré, C and Marco-Contelles, J and Iriepa, I}, title = {N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {192}, number = {}, pages = {118603}, doi = {10.1016/j.biopha.2025.118603}, pmid = {41016150}, issn = {1950-6007}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; Mice ; Disease Models, Animal ; Male ; *Benzimidazoles/pharmacology/pharmacokinetics/chemistry/therapeutic use ; Amnesia/drug therapy/chemically induced ; Scopolamine ; Humans ; Neuronal Plasticity/drug effects ; *Piperidines/pharmacology/chemistry/pharmacokinetics ; }, abstract = {As part of a project aimed at the pharmacological optimization of Contilisant, herein we describe molecular modelling studies that led to the identification of MBA-159 as a new polyfunctionalized, multitarget-directed ligand and a promising drug candidate for the treatment of Alzheimer's disease. We synthesized MBA-159 and conducted comprehensive in vitro and in vivo evaluations. In in vivo studies MBA-159 demonstrated favourable pharmacokinetics, anti-amnesic properties and significantly improved non-spatial memory (contextual and recognition memory) in a mouse model of scopolamine-induced amnesia. Additionally, MBA-159 showed a tendency to increase synaptic plasticity biomarkers and reduce neuroinflammatory trends (assessed by qPCR), as well as cognitive enhancement in a senescence-accelerated prone mouse 8 model.}, } @article {pmid41015981, year = {2025}, author = {Abushakra, S and Power, A and Watson, D and Porsteinsson, A and Sabbagh, M and MacSweeney, E and Cohen, S and Boada Rovira, M and Doraiswamy, PM and Liang, E and Flint, S and Kesslak, JP and McLaine, R and Albayrak, A and Schaefer, J and Yu, J and Tolar, L and Dickson, S and Hey, JA and Tolar, M}, title = {Clinical Efficacy, Safety and Imaging Effects of Oral Valiltramiprosate in APOEε4/ε4 Homozygotes with Early Alzheimer's Disease: Results of the Phase III, Randomized, Double-Blind, Placebo-Controlled, 78-Week APOLLOE4 Trial.}, journal = {Drugs}, volume = {85}, number = {11}, pages = {1455-1472}, pmid = {41015981}, issn = {1179-1950}, support = {R01 AG065253/AG/NIA NIH HHS/United States ; R01-AG065253/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Double-Blind Method ; Female ; *Alzheimer Disease/drug therapy/genetics/diagnostic imaging ; Aged ; Male ; *Apolipoprotein E4/genetics ; Aged, 80 and over ; Middle Aged ; Magnetic Resonance Imaging ; Administration, Oral ; Homozygote ; Treatment Outcome ; Cognitive Dysfunction/drug therapy ; Brain/drug effects/diagnostic imaging ; }, abstract = {BACKGROUND: The apolipoprotein E ε4 (APOE ε4) allele is the strongest genetic risk factor for Alzheimer's disease (AD), with homozygotes accumulating a high burden of cerebral beta-amyloid (Aβ) pathology. Valiltramiprosate/ALZ-801 is a small-molecule potent inhibitor of Aβ-oligomer formation. The efficacy, safety/tolerability, and brain volume effects of oral valiltramiprosate were evaluated in this phase III, randomized, double-blind, placebo-controlled, multi-center, 78-week trial in homozygotes with early symptomatic AD. METHODS: The study enrolled eligible APOE4/4 subjects aged 50-80 years with Early AD (Mini-Mental State Examination [MMSE] 22-30), which included mild cognitive impairment (MCI) and mild dementia, Clinical Dementia Rating-Global Score (CDR-G) of 0.5 or 1, who were randomized 1:1 to valiltramiprosate (265 mg twice/day) or placebo. The primary outcome was AD Assessment Scale-Cognitive Subscale (ADAS-Cog13); the key secondary outcomes were CDR-Sum of Boxes (CDR-SB) and Amsterdam-Instrumental Activities of Daily Living (IADL), and a secondary outcome was Disability Assessment for Dementia (DAD). The main imaging outcome was hippocampal volume on MRI; diffusion tensor imaging (MRI-DTI) assessed microstructural tissue integrity. Amyloid-related imaging abnormalities (ARIA) were monitored with MRIs every 26 weeks. RESULTS: A total of 325 participants enrolled and received study drug. At 78 weeks, the overall efficacy population did not show significant effects on ADAS-Cog13 or other clinical outcomes compared with placebo (ADAS-Cog13: 11% slowing; p = 0.607, N = 320), but showed significant slowing of hippocampal atrophy (18%, p = 0.017, N = 290). Prespecified analyses by disease severity (stratification variable) showed no significant clinical effects in mild AD (MMSE ≤26, N = 195). The prespecified MCI group (MMSE >26, N = 125) showed nominally significant positive effects on ADAS-Cog13 (52%, nominal p = 0.041) and DAD (96%, nominal p = 0.016), positive trend on CDR-SB (102%, nominal p = 0.053), with significant hippocampal atrophy slowing (26%, p = 0.004), and positive grey/white matter effects on MRI-DTI. In the MCI group, positive ADAS-Cog13 drug effects showed significant subject-level correlations with positive effects on imaging outcomes. The most common adverse events were nausea, vomiting, and decreased appetite (more than double placebo rate), with no increased risk of brain edema or microhemorrhages. CONCLUSIONS: The APOE4/4 Early AD population did not show significant clinical efficacy at 78 weeks but showed significant brain atrophy slowing. Prespecified analyses at the MCI stage showed nominally significant slowing of clinical decline with significant hippocampal atrophy slowing. Oral valiltramiprosate may provide a favorable benefit-risk profile and simple treatment paradigm for homozygotes with MCI. These results will inform the design of future MCI trials. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04770220; EudraCT Number: 2020-005755-20.}, } @article {pmid41015797, year = {2025}, author = {Shuang, NI and Xiaofei, L and Xiaoyan, G and Zuxi, GU and Panqing, WU and Chao, C and Shengnan, LI and Xianwei, G and Lianwei, XU}, title = {Mechanism of Tiaogeng decoction in a cognitive dysfunction mouse model.}, journal = {Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan}, volume = {45}, number = {5}, pages = {987-997}, pmid = {41015797}, issn = {2589-451X}, support = {81874482//Natural Science Foundation-funded Project: Mechanism of Tiaogeng Decoction improving Cognitive Function via Regulating Nuclear Factor-erythroid 2-related Factor 2/c-Jun N-terminal kinase/Aβ Oxidative Stress Network in Hippocampus Neurons/ ; }, mesh = {Animals ; *Drugs, Chinese Herbal/administration & dosage ; Mice ; *Cognitive Dysfunction/drug therapy/genetics/metabolism/psychology ; Female ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Oxidative Stress/drug effects ; Mice, Inbred C57BL ; Mice, Transgenic ; Humans ; Amyloid beta-Peptides/metabolism/genetics ; Apoptosis/drug effects ; NF-E2-Related Factor 2/metabolism/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; }, abstract = {OBJECTIVE: To explore the mechanism of action of Tiaogeng decoction (, TG) in alleviating oxidative stress damage in the hippocampus of a mouse model of cognitive impairment. METHODS: Amyloid precursor protein/presenilin-1 (APP/PS1) transgenic female mice were randomly divided into model, estradiol valerate, low-, medium-, and high-dose TG groups, female C57 mice were used as the control group (n = 12/group). After 12 weeks of treatment, the behavior of mice was tested with the Morris water maze, and brain tissue samples were collected, and changes in hippocampal neurons were observed using electron microscopy. The deposition of beta-amyloid protein (Aβ) amyloid plaques in the hippocampus was determined by light microscopy. Aβ1-42 protein levels were detected through immunofluorescence. Oxidative stress indicators in the hippocampus were detected by enzyme linked immunosorbent assay. The expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2), c-Jun N-terminal kinase (JNK), phospho-JNK (p-JNK), B-cell lymphoma-2 (Bcl-2), caspase-9, and cleaved caspase-9 were detected by Western blot. Hippocampal cell apoptosis was detected using the terminal deoxynucleotidyl transferase-mediated nick end Labeling. RESULTS: TG improved the cognitive function of APP/PS1 mice, as judged by improvements in several indices from the Morris water maze test. TG increased Nrf2, superoxide dismutase, and heme oxygenase-1 protein expression and reduced malondialdelyde and reactive oxygen species expression. TG also inhibited the expression of JNK proteins, upregulated the expression of Bcl-2, and downregulated the expression of caspase-9, reducing cell apoptosis. TG decreased the percentage of the hippocampal cornu ammonis 1 area positive for Aβ1-42, reducing mitochondrial damage caused by oxidative stress and Aβ protein deposition. CONCLUSIONS: TG may improve memory ability while reducing oxidative stress and apoptosis. It also reduces Aβ protein deposition in the hippocampus, protecting the central nervous system and improving memory function. TG may reduce the risk of AD.}, } @article {pmid41015375, year = {2025}, author = {Afridi, MB and Ali Shah, SW and Hussain, H and Elhenawy, AA and Mujtaba, M and Al-Otaibi, JS and Khan, H}, title = {Exploring Anticholinergic and anti-amnesic potential of methyl substituted monocarbonyl curcumin derivatives.}, journal = {European journal of pharmacology}, volume = {1007}, number = {}, pages = {178193}, doi = {10.1016/j.ejphar.2025.178193}, pmid = {41015375}, issn = {1879-0712}, mesh = {Animals ; *Curcumin/pharmacology/analogs & derivatives/therapeutic use/chemistry/metabolism ; Acetylcholinesterase/metabolism/chemistry ; Mice ; Butyrylcholinesterase/metabolism/chemistry ; Molecular Docking Simulation ; *Amnesia/drug therapy/chemically induced/metabolism ; *Cholinergic Antagonists/pharmacology/chemistry/therapeutic use/metabolism ; Male ; *Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/metabolism ; Scopolamine ; Maze Learning/drug effects ; Behavior, Animal/drug effects ; Structure-Activity Relationship ; }, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia or amnesia, characterized primarily by loss of acetylcholine (ACh), due to increased activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), both of which accelerate ACh degradation, and exacerbate cholinergic dysfunction. In this regard, the synthetic methyl-substituted monocarbonyl curcumin derivatives (BL1-BL3) were analyzed for AChE and BChE inhibition, followed by molecular docking studies. Scopolamine (1 mg/kg) was used to induce amnesia in mice. The results of BL1-BL3 demonstrated a significant inhibitory effect especially against AChE compared to BChE enzymes, with IC50 of 128.4, 118.4, 170.9 μg/mL against AChE and 334.3, 1168, 288.2 μg/mL against BChE, respectively. These compounds exhibited strong binding affinities to both target proteins in docking studies. Scopolamine administration induced significant memory deficits in mice, that was significantly (P < 0.001) mitigated by pretreatment with BL1-BL3 in the Y-maze test at both 7.5 and 15 mg/kg doses by restoring spontaneous alternation performance (SAP). In the novel object recognition test (NORT), a prominent (P < 0.001) improvement in memory retention was seen during the test phase, and enhanced the discrimination index (DI) at both tested doses. Biochemical analyses of hippocampal tissue further supported the behavioral data. Treatment with BL1-BL3 effectively decreases AChE and malondialdehyde (MDA) levels while increasing catalase (CAT) and superoxide dismutase (SOD) levels. Overall, BL2 was found to be most significant. In short, BL1-BL3 emerged as potential therapeutic agents for AD due to significant effects in vitro and in vivo experimental models, and are also equally supported by in silico studies.}, } @article {pmid41014665, year = {2025}, author = {Wei, H and Zhang, G and Yan, X and Zhao, A and Zheng, Y and Shao, Y and Yang, L and Wang, J and Jiang, X}, title = {Plant-derived natural products modulate astrocyte function: Therapeutic strategies for Alzheimer's disease.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {148}, number = {}, pages = {157238}, doi = {10.1016/j.phymed.2025.157238}, pmid = {41014665}, issn = {1618-095X}, mesh = {*Alzheimer Disease/drug therapy ; *Astrocytes/drug effects ; Humans ; *Biological Products/pharmacology ; Animals ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Alkaloids/pharmacology ; tau Proteins/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a gradually worsening neurodegenerative condition with limited treatment options, highlighting the need for novel therapies. Astrocytes play key roles in AD pathogenesis. Natural products show promise for treating AD through modulating amyloid-beta (Aβ) and tau pathology, inhibiting neuroinflammation and oxidative stress, and protecting cellular organelles. Preclinical evidence supports their efficacy in targeting astrocyte-related mechanisms, enhancing cognition, and reducing neuronal damage. PURPOSE: Systematically summarize and evaluate the medicinal benefits of plant-derived natural products in modulating astrocyte-mediated processes to attenuate AD progression. METHODS: A comprehensive literature review was performed in PubMed and Web of Science, utilizing targeted keywords such as "natural products", "active compounds", "Alzheimer's disease", and "astrocytes". The review primarily focused on studies published between 2013 and 2024, with the selected literature systematically categorized and analyzed. RESULTS: This review highlights the medicinal benefits of plant-derived natural products, such as flavonoids, alkaloids, polyphenols, and terpenes in targeting astrocyte morphology and function to combat AD. These bioactive compounds modulate key pathological processes, including neuroinflammation, oxidative stress, Aβ metabolism, tau hyperphosphorylation, mitochondrial dysfunction, and ER stress, outlining pathways to alleviate AD through astrocytic effects. The review also summarizes clinical progress and major challenges in translating these compounds, such as variability, low bioavailability, and delivery limitations. CONCLUSION: This study addresses a critical gap by systematically elucidating the relationship between astrocytes and AD, and therapeutic potential of plant-derived natural products. It aims to expand treatment options for patients and advance the development of therapeutic strategies in the field of AD management.}, } @article {pmid41013881, year = {2025}, author = {Jastrzębski, MK and Wójcik, P and Mudgal, A and Woźniak, S and Targowska-Duda, KM and Wronikowska-Denysiuk, O and Michalak, A and Jeleniewicz, W and Karcz, T and Raczek, J and Stepulak, A and Kaczor, AA}, title = {Unveiling the Therapeutic Potential of D2AAK1 and Its Derivatives: Mechanistic Insights and Applications in Neurodegenerative Disease Treatment.}, journal = {Journal of neurochemistry}, volume = {169}, number = {10}, pages = {e70232}, doi = {10.1111/jnc.70232}, pmid = {41013881}, issn = {1471-4159}, support = {2017/27/B/NZ7/01767//Narodowe Centrum Nauki/ ; 2021/43/B/NZ7/01732//Narodowe Centrum Nauki/ ; }, mesh = {Animals ; Mice ; Male ; *Neurodegenerative Diseases/drug therapy/metabolism ; Cell Survival/drug effects/physiology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Oxidative Stress/drug effects ; }, abstract = {The global rise in life expectancy has been accompanied by a growing prevalence of neurodegenerative diseases, such as Alzheimer's disease (AD). These complex disorders arise from multiple pathogenic factors and biological pathways, necessitating the development of multi-target therapeutic strategies. D2AAK1, discovered by our group, has emerged as a promising candidate due to its cytoprotective, antioxidant, and procognitive properties. This study aimed to further elucidate the mechanisms underlying the action of D2AAK1 and its derivatives, with a focus on their potential for neuroprotection and cognitive enhancement. The effect of D2AAK1 on cell viability was evaluated under normal conditions and during H2O2-induced oxidative stress using the resazurin assay. p38 MAPK activity was measured through cell-based ELISA. mRNA expression was analyzed using a two-step quantitative PCR method, and enzymatic effects were assessed via photometric, fluorescence, and luminescence techniques. Behavioral studies in murine models were performed to investigate the influence of the compounds on memory processes. It was found that D2AAK1 and its derivatives significantly enhanced cell viability, with some derivatives exhibiting greater potency than D2AAK1. In vivo, one derivative notably improved memory performance and reversed scopolamine-induced memory impairment in the novel object recognition test in male Swiss mice. Mechanistic studies revealed that D2AAK1 increased the expression of cytoprotective proteins such as Bcl-2 and HO-1, while concurrently reducing the expression and activity of pro-apoptotic factors, including caspase-3, p38 MAPK, and MAO-B. These dual actions culminated in enhanced cellular resilience and viability, translating into improved cognitive outcomes. The findings suggest that D2AAK1 and its derivatives, through their multi-factor mechanism of action, hold promise as therapeutic agents for the treatment of neurodegenerative diseases.}, } @article {pmid41013670, year = {2025}, author = {Sharma, N and Kim, D and Sharma, H and Kim, MI and Lee, H and Kim, M and Ryoo, N and Kang, MJ and Pyun, JM and Park, YH and Ryu, J and Oh, HJ and Yang, HS and Kim, HR and Kim, GH and Han, S and Yang, Y and Youn, YC and Teunissen, C and Zetterberg, H and Scheltens, P and An, SSA and Kim, YB and Kim, S and , }, title = {Bridging the barrier: insights into blood biomarkers and therapeutic strategies targeting choroid plexus and BBB dysfunction in alzheimer's disease.}, journal = {Biomarker research}, volume = {13}, number = {1}, pages = {116}, pmid = {41013670}, issn = {2050-7771}, support = {RS-2023-00251396//National Research Foundation of Korea (NRF)/ ; RS-2025-02292973//Korea Institute of Marine Science and Technology promotion/ ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia and accounts for approximately 60-80% of total dementia patients. Currently, accurate diagnosis for AD relies on cerebrospinal fluid (CSF) sampling or a positron emission tomography (PET) scan, methods that cannot be done in primary care centers where most people go with cognitive complaints. This Limitation calls for the urgent need to develop blood-related diagnostic tests that could facilitate early detection and enable timely treatment. Recent CSF proteomic research categorized AD into five molecular subtypes with discrete Genetic risk profiles. Subtypes 1-3, namely neuronal hyperplasticity, innate immune activation, and RNA dysregulation, were characterized by more classical AD-related changes, like accumulation of amyloid/tau and synaptic and immune dysfunction, respectively. On the contrary, non-traditional AD mechanisms in subtypes 4-5 were choroid plexus (CP) dysfunction and blood-brain barrier (BBB) dysfunction, emphasizing clearance deficits in association with brain barrier dysfunction. The unchanged tau levels later may be explained by an alternate disease mechanism (clearance dysfunction). These subtypes included BBB and CP dysfunction. Biomarker identification based on the mechanism of disease progression would increase the precision of diagnoses, allowing for tailored interventions and aiding in the creation of novel therapies for subtypes that might not react favorably to conventional amyloid/tau-targeting strategies. Finding biomarkers specific to each subtype would aid in patient classification, resulting in more individualized therapy as opposed to a "one-size-fits-all" strategy. The present review emphasized the importance of identifying blood-based biomarkers (BBMs) related to brain barrier dysfunction from CSF studies and personalized treatment strategies to streamline the diagnostic workup, and may be utilized in standard clinical practice for the early detection of AD.}, } @article {pmid41012536, year = {2025}, author = {Chen, BH and Jen, CT and Wang, CC and Pan, MH}, title = {Improving Alzheimer's Disease and Parkinson's Disease in Rats with Nanoemulsion and Byproducts Prepared from Cinnamon Leaves.}, journal = {Pharmaceutics}, volume = {17}, number = {9}, pages = {}, pmid = {41012536}, issn = {1999-4923}, support = {Grant no. 7100474//Tou-Fu Investment Co, Taipei, Taiwan/ ; }, abstract = {Background/Objectives: Cinnamon leaves, an important source of the functional compound cinnamaldehyde (CA), have been shown to be effective in improving type II diabetes and Parkinson's disease (PD) in rats following the incorporation of cinnamon leaf extract into a nanoemulsion. However, the effect of a cinnamon leaf extract nanoemulsion (CLEN) on improving Alzheimer's disease (AD), the most prevalent type of dementia, remains unexplored. The objectives of this study were to determine functional compounds in cinnamon leaves by UPLC-MS/MS, followed by the preparation of a nanoemulsion and its byproducts to study their effects on AD and PD in rats. Methods: Oven-dried (60 °C for 2 h) cinnamon leaf powder and hydrosol, obtained by steam distillation of cinnamon leaf powder, were stored at 4 °C. After determination of basic composition (crude protein, crude fat, carbohydrate, moisture and ash) of cinnamon leaf powder, it was extracted with 80% ethanol with sonication at 60 °C for 2 h and analyzed for bioactive compounds by UPLC-MS/MS. Then, the CLEN was prepared by mixing cinnamon leaf extract rich in CA with lecithin, soybean oil, tween 80 and ethanol in an optimal ratio, followed by evaporation to form thin-film and redissolving in deionized water. For characterization, mean particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency, and surface morphology were determined. Animal experiments were done by dividing 90 male rats into 10 groups (n = 9), with groups 2-8 being subjected to mini-osmotic pump implantation surgery in brain to infuse Amyloid-beta 40 (Aβ40) solution in groups 2-8 for induction of AD, while groups 9 and 10 were pre-fed respectively with cinnamon powder in water (0.5 g/10 mL) and in hydrosol for 4 weeks, followed by induction of AD as shown above. Different treatments for a period of 4 weeks included groups 1-9, with group 1 (control) and group 2 feeding with sterilized water, while groups 3, 4 and 5 were fed respectively with high (90 mg/kg), medium (60 mg/kg) and low (30 mg/kg) doses of cinnamon leaf extracts, groups 6, 7 and 8 fed respectively with high (90 mg/kg), medium (60 mg/kg) and low (30 mg/kg) doses of nanoemulsions, groups 9 and 10 fed respectively with 10 mL/kg of cinnamon powder in water and hydrosol (0.5 g/10 mL). Morris water maze test was conducted to determine short-term memory, long-term memory and space probing of rats. After sacrificing of rats, brain and liver tissues were collected for determination of Aβ40, BACE1 and 8-oxodG in hippocampi, and AchE and malondialdehyde (MDA) in cortices, antioxidant enzymes (SOD, CAT, GSH-Px) and MDA in both cortices and livers, and dopamine in brain striata by using commercial kits. Results: The results showed that the highest level of CA (18,250.7 μg/g) was in the cinnamon leaf powder. The CLEN was prepared successfully, with an average particle size of 17.1 nm, a polydispersity index of 0.236, a zeta potential of -42.68 mV, and high stability over a 90-day storage period at 4 °C. The Morris water maze test revealed that the CLEN treatment was the most effective in improving short-term memory, long-term memory, and spatial probe test results in AD rats, followed by the cinnamon leaf extract (CLE), powder in hydrosol (PH), and powder in water (PW). Additionally, both CLEN and CLE treatments indicated a dose-dependent improvement in AD rats, while PH and PW were effective in preventing AD occurrence. Furthermore, AD occurrence accompanied by PD development was demonstrated in this study. With the exception of the induction group, declines in Aβ40, BACE1, and 8-oxodG in the hippocampi and AchE and MDA in the cortices of rats were observed for all the treatments, with the high-dose CLEN (90 mg/kg bw) exhibiting the highest efficiency. The antioxidant enzyme activity, including that of SOD, CAT, and GSH-Px, in the cortices of rats increased. In addition, dopamine content, a vital index of PD, was increased in the striata of rats, accompanied by elevations in SOD, CAT, and GSH-Px and decreased MDA in rat livers. Conclusions: These outcomes suggest that the CLEN possesses significant potential for formulation into a functional food or botanical drug for the prevention and treatment of AD and/or PD in the future.}, } @article {pmid41012495, year = {2025}, author = {Sivamaruthi, BS and Kesika, P and Sisubalan, N and Chaiyasut, C}, title = {Advances in Gold Nanoparticles for the Diagnosis and Management of Alzheimer's Disease.}, journal = {Pharmaceutics}, volume = {17}, number = {9}, pages = {}, pmid = {41012495}, issn = {1999-4923}, abstract = {Alzheimer's disease (AD) presents a significant challenge in modern healthcare, prompting exploration into novel therapeutic strategies. This review clearly classifies different types of gold (Au) nanoparticles (NPs) (AuNPs), links them to the gut-brain axis, highlights recent advances, and points out future research needs, offering a more updated perspective than earlier reviews. Diverse approaches have emerged from single to hybrid and functionalized AuNPs, including innovative nanotherapeutic agents like Au nanorods-polyethylene glycol-angiopep-2 peptide/D1 peptide and noninvasive dynamic magnetic field-stimulated NPs. AuNPs have been reported for the neuroprotective properties. Clinical applications of AuNPs highlight their promise in diagnosis and therapeutic monitoring. However, challenges persist, notably in overcoming blood-brain barrier limitations and refining drug delivery systems. Furthermore, the incomplete understanding of AD's physiological and pathological mechanisms hinders therapeutic development. Future research directions should prioritize elucidating these mechanisms and optimizing AuNPs physicochemical properties for therapeutic efficacy. Despite limitations, nanomaterial-based therapies hold promise for revolutionizing AD treatment and addressing other central nervous system disorders. It also emphasizes the importance of further investigation into the potential of AuNPs, envisioning a future where they serve as a cornerstone in advancing neurological healthcare.}, } @article {pmid41011288, year = {2025}, author = {Łomankiewicz, D and Pilawa, B and Chodurek, E and Zdybel, M}, title = {Interactions of Extracts from Selected Plant Materials Supporting the Treatment of Alzheimer's Disease with Free Radicals-EPR and UV-Vis Studies.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {9}, pages = {}, pmid = {41011288}, issn = {1424-8247}, support = {BNW-1-073/K/3/F, PCN-2-015/N/1/F//Medical University of Silesia/ ; }, abstract = {Background/objectives: Interactions of infusions of Ginkgo biloba, ginseng, Yerba Mate, and green tea, with free radicals, were examined. The aim of these studies was to determine quenching of free radicals by the extracts from the selected plant raw materials that are useful in the treatment of Alzheimer's disease. Methods: The interactions were tested by an X-band (9.3 GHz) EPR spectroscopy and UV-Vis spectrophotometry. The model DPPH free radicals were used. The magnitude and changes with time of EPR and UV-Vis spectra of DPPH by the tested extracts were measured. Results: EPR and UV-Vis lines of DPPH free radicals decrease with increasing time of interactions of the extracts with DPPH, and after reaching the minimum value, it does not change with time. Ginseng infusion quenched free radicals the least. Ginkgo biloba extract quenches free radicals a little stronger than ginseng extract. Taking into account the tested extracts, Ginkgo biloba and ginseng extracts interact with free radicals less effectively compared to extracts of Yerba mate and green tea. Ginkgo biloba and ginseng extracts quench free radicals weaker than Yerba Mate and green tea extracts. Conclusions: Yerba Mate extract definitely had the strongest antioxidant properties. This extract quenches free radicals most effectively, what can be useful in the case of Alzheimer's disease. Given its strong antioxidant properties, green tea extract can also be particularly recommended in the case of Alzheimer's disease.}, } @article {pmid41010812, year = {2025}, author = {Yang, HM}, title = {Vascular Dementia: From Pathophysiology to Therapeutic Frontiers.}, journal = {Journal of clinical medicine}, volume = {14}, number = {18}, pages = {}, pmid = {41010812}, issn = {2077-0383}, support = {03-2025-0200//Seoul National University Hospital/ ; }, abstract = {Vascular dementia (VaD) represents the second-most common dementia type after Alzheimer's disease since it results from complications of cerebrovascular disease. Mixed pathologies combining vascular and neurodegenerative processes are the rule rather than exception in elderly dementia patients. The condition known as VaD includes various types of vascular damage that affect both large and small blood vessels in the brain which results in cerebral hypoperfusion, blood-brain barrier disruption, glymphatic dysfunction, and molecular cascades causing neuronal damage. The mechanisms of VaD include endothelial dysfunction, oxidative stress, chronic neuroinflammation, impaired glymphatic clearance, white matter demyelination, and synaptic failure. The disease susceptibility of individuals depends on genetic factors which include NOTCH3 mutations and vascular risk polymorphisms. The diagnostic field uses neuroimaging tools and fluid biomarkers such as neurofilament light chain, inflammatory markers, and Aβ/tau ratios for mixed pathology. The current practice of vascular risk management combines with new therapeutic approaches that use phosphodiesterase inhibitors for cerebral perfusion and NLRP3 inflammasome inhibitors for neuroinflammation, senolytics for cellular senescence, and remyelination agents for white matter repair. However, the majority of new treatment methods remain investigational with limited Phase III data. Future medical treatment development will depend on precision medicine approaches which use biomarker-guided treatment selection and combination strategies targeting multiple pathological mechanisms.}, } @article {pmid41010553, year = {2025}, author = {Matuszewski, W and Tomaszek, L and Szklarz, M and Górny, JM and Kordas, B and Rutkowska, J and Juranek, J}, title = {Beyond the Cardio-Renal-Metabolic Axis: Emerging Therapeutic Targets and Novel Mechanisms of Action of Flozins.}, journal = {Journal of clinical medicine}, volume = {14}, number = {18}, pages = {}, pmid = {41010553}, issn = {2077-0383}, abstract = {Contemporary diabetes management is progressively moving away from a glucocentric approach, with growing expectations that novel antidiabetic agents offer benefits beyond glycaemic control. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a cornerstone in the treatment of type 2 diabetes mellitus (T2DM). In addition to reducing blood glucose levels by promoting renal glucose excretion, these agents contribute significantly to cardio-renal-metabolic protection and are associated with improved cardiovascular outcomes and prolonged survival. Although SGLT2 inhibitors do not exhibit a class effect in all clinical aspects, growing evidence suggests their potential in a variety of additional therapeutic areas. We conducted an in-depth review of current scientific literature and clinical studies regarding this class of drugs. SGLT2 inhibitors demonstrate neuroprotective properties and may provide benefits in neurodegenerative disorders such as Alzheimer's and Parkinson's disease, potentially through the improvement of mitochondrial function and attenuation of inflammatory responses. Their anti-inflammatory and antioxidative effects are closely linked to reductions in cardiac and renal fibrosis. Other observed benefits include weight loss, improved insulin sensitivity, normalization of serum uric acid, and a reduction in hepatic steatosis-each with important metabolic implications. Furthermore, SGLT2 inhibitors have been shown to positively influence iron metabolism and improve erythrocyte indices. Emerging data also indicate beneficial effects in women with polycystic ovary syndrome. Another promising area of investigation involves the modulation of Klotho protein expression and support of vascular homeostasis. In oncology, SGLT2 inhibitors are gaining attention, with encouraging preclinical results observed in malignancies such as pancreatic, thyroid, breast, and lung cancers. Based on a comprehensive evaluation of the existing body of evidence, it is anticipated that the clinical indications for SGLT2 inhibitors will expand beyond the cardio-renal-metabolic axis in the near future.}, } @article {pmid41010550, year = {2025}, author = {Pacheco-Sánchez, B and Verheul-Campos, J and Vargas, A and Tovar, R and Rodríguez-Pozo, M and Navarro, JA and López-Gambero, AJ and Baixeras, E and Serrano-Castro, PJ and Suárez, J and Sanjuan, C and Rivera, P and Rodríguez de Fonseca, F}, title = {Early Oral Administration of D-Chiro-Inositol Reverses Hippocampal Insulin and Glutamate Signaling Deficits in the 3×Tg Humanized Mouse Model of Alzheimer's Disease.}, journal = {Nutrients}, volume = {17}, number = {18}, pages = {}, pmid = {41010550}, issn = {2072-6643}, support = {DTS22/00021//Instituto de Salud Carlos III. Proyectos de desarrollo tecnológico/ ; PI22/00427//Instituto de Salud Carlos III. Proyectos de Investigación en Salud/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Hippocampus/metabolism/drug effects ; *Insulin/metabolism ; Disease Models, Animal ; *Signal Transduction/drug effects ; Male ; Female ; Mice, Transgenic ; Mice ; Administration, Oral ; *Glutamic Acid/metabolism ; Humans ; }, abstract = {Background and Objective: Humanized models of Alzheimer's disease (AD) provide valuable tools for investigating the mechanisms of this neurodegenerative disorder, the leading cause of dementia. These models enable the study of AD progression and the potential disease-modifying properties of drugs or dietary nutrients delivered through nutrition. Here, we examine molecular markers of metabolic and synaptic dysfunction in the hippocampus of 6-month-old 3×Tg-AD mice and assess whether a dietary insulin sensitizer can delay synaptic decline. Methods: First we characterized the molecular phenotype of 3×Tg-AD at 12 months using shotgun proteomics and phosphoproteomics to assess metabolic and synaptic changes in the hippocampus. Then, we characterized the effects of early daily oral D-chiro-inositol (DCI, Gyneos[®]) for three months, starting at 3 months of age, to test restoration of insulin signaling and glutamatergic synaptic markers. To this end we evaluated a) insulin signaling pathway components (insulin receptor, IRS1, PI3K, AKT, GSK3β) at mRNA, protein, and phosphorylation levels, and b) the expression of glutamate receptors (mGluR5, GluR1, GluR2, NMDAR1, NMDAR2A, NMDAR2B). Sex effects were explored. Results: 12-month 3×Tg-AD mice exhibit metabolic and synaptic dysfunction in the hippocampus, with phosphoproteomic changes suggesting altered glutamatergic synapses. At 6 months, disruptions in insulin signaling were evident, including altered expression and phosphorylation of insulin pathway components, and changes in glutamate receptor subunits. Early DCI treatment largely reversed these alterations. Several effects showed sex dependency. Conclusions: Early insulin-sensitizing intervention via DCI can restore insulin signaling and counteract hippocampal synaptic impairments in this AD model, supporting the potential for nutrient-based strategies to delay synaptic decline. Sex differences underscore the need to tailor therapeutic approaches in modifying AD progression.}, } @article {pmid41010527, year = {2025}, author = {Barros, MI and Brandão, T and Irving, SC and Alves, P and Gomes, F and Correia, M}, title = {Omega-3 Polyunsaturated Fatty Acids and Cognitive Decline in Adults with Non-Dementia or Mild Cognitive Impairment: An Overview of Systematic Reviews.}, journal = {Nutrients}, volume = {17}, number = {18}, pages = {}, pmid = {41010527}, issn = {2072-6643}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Cognition/drug effects ; *Cognitive Dysfunction/prevention & control/drug therapy ; *Dietary Supplements ; *Fatty Acids, Omega-3/administration & dosage/therapeutic use/pharmacology ; Quality of Life ; Systematic Reviews as Topic ; }, abstract = {BACKGROUND/OBJECTIVES: As global aging accelerates, prevalence of mild cognitive impairment (MCI) continues to rise, challenging healthcare systems and diminishing older adults' quality of life. There is great interest in better understanding the neuroprotective/anti-inflammatory properties of omega-3 polyunsaturated fatty acids but the results from many published studies in humans come to different conclusions. This review aims to clarify the efficacy of n-3 fatty acids as a preventive or therapeutic strategy for cognitive health and to inform future clinical recommendations within aging populations. METHODS: Following PRISMA guidelines and a registered PROSPERO protocol, we reviewed systematic reviews (SRs) from 2014 to 2024 assessing exclusive n-3 fatty acid supplementation and cognitive outcomes via MMSE. Data were extracted on intervention details and cognitive scores. Meta-analyses used fixed and random-effects models, with Hedges' estimating overall impact. Quality was assessed using AMSTAR-2, and statistical analyses were performed (SPSS 28). RESULTS: A total of nine SRs incorporating 14 RCTs were included, representing 26,881 participants aged 40 years or older. The pooled random-effects meta-analysis showed a statistically significant but modest improvement in MMSE scores (effect size: 0.16; 95% CI: 0.01-0.32). Heterogeneity was moderate (I[2] = 42.8%), and no publication bias was detected. Further analyses revealed no significant associations between treatment duration or dosage and cognitive outcomes, suggesting a threshold effect rather than a dose-response relationship. CONCLUSIONS: These findings support n3-PUFA supplementation as a complementary approach to lifestyle-based strategies for cognitive health, including diet, physical activity, sleep optimization, and cognitive training. While benefits appear modest, consistent effects across studies warrant further high-quality research and well-designed studies to strengthen clinical recommendations.}, } @article {pmid41010145, year = {2025}, author = {Zahariev, N and Boyuklieva, R and Penkov, D and Lukova, P and Katsarov, P}, title = {Functionalized Magnetic Nanoparticles: Can They Revolutionize the Treatment of Neurodegenerative Disorders?.}, journal = {Materials (Basel, Switzerland)}, volume = {18}, number = {18}, pages = {}, pmid = {41010145}, issn = {1996-1944}, support = {BG-RRP-2.004-0007-C01//European Union-NextGenerationEU/ ; }, abstract = {Neurodegenerative disorders (NDs), including Alzheimer's disease and Parkinson's disease, pose a significant global health challenge characterized by progressive neuronal loss and limited therapeutic options. Early diagnosis remains a considerable hurdle due to the absence of reliable biomarkers and the restrictive nature of the blood-brain barrier (BBB), which complicates effective drug delivery. Magnetic nanoparticles (MNPs), particularly those based on iron oxide, have emerged as promising tools for both diagnostic and therapeutic applications in NDs, thanks to their superparamagnetism, biocompatibility, and customizable surfaces. This review examines various synthesis strategies for MNPs, encompassing physical methods (such as lithography, ball milling, and laser ablation) and chemical approaches (co-precipitation, thermal decomposition, hydrothermal synthesis, sol-gel processes, and polyacrylamide gel techniques), while highlighting how these techniques influence particle properties. This review also explores recent advancements in surface functionalization using polymers and coatings to enhance circulation time in the bloodstream and improve BBB penetration for targeted delivery. Furthermore, it emphasizes both in vitro and in vivo applications, showcasing MNPs' effectiveness in enhancing imaging sensitivity and enabling targeted drug and gene delivery. By linking synthesis methods, functionalization techniques, and biomedical outcomes, this review illustrates the transformative potential of MNPs as next-generation theranostic agents in precision medicine for neurodegenerative diseases.}, } @article {pmid41009662, year = {2025}, author = {Mironenko, IV and Kryukova, OV and Buianova, AA and Churov, AV and Arbatsky, MS and Kubrikova, AA and Petrusenko, YS and Repinskaia, ZA and Shmitko, AO and Ilyina, GA and Kost, OA and Dudek, SM and Strazhesko, ID and Isaev, RI and Mkhitaryan, EA and Tkacheva, ON and Rebrikov, DV and Danilov, SM}, title = {ACE-Dependent Alzheimer's Disease: Circulating ACE Phenotypes in Heterozygous Carriers of Rare ACE Variants.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009662}, issn = {1422-0067}, support = {075-15-2019-1789//Ministry of Science and Higher Education of the Russian Federation/ ; 125022602916-4//Ministry of Healthcare of Russian Federation/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/blood/enzymology ; Male ; Female ; Heterozygote ; Aged ; *Peptidyl-Dipeptidase A/genetics/blood ; Mutation ; Phenotype ; Aged, 80 and over ; Middle Aged ; Adult ; Genetic Predisposition to Disease ; }, abstract = {Damaging mutations of the Angiotensin I-converting enzyme (ACE) that result in low ACE levels may increase the risk of developing late-onset Alzheimer's disease (AD). We quantified blood ACE levels in EDTA-plasma from 147 subjects with 23 different heterozygous ACE mutations (and 70 controls) and estimated the effect of these mutations on ACE phenotype, using a set of monoclonal antibodies (mAbs) to ACE and two ACE substrates. We identified several mutations in both ACE domains (including the most frequent ACE mutation, Y215C), which led to decreased ACE levels in the blood, and thus could be considered as putative risk factors for late-onset AD. The precipitation of several ACE mutants (Q259R, A725P, C734Y) by specific mAbs changed significantly, and therefore, these mAbs could be markers of these mutations. Analysis of 50 of the most frequent ACE mutations demonstrates that more than 1.5% of the adult population may have mutations which lead to decreased ACE levels, and thus, the role of low ACE levels in the development of AD may be underappreciated. Intriguingly, statistical and cluster analyses of longevity patients revealed trends towards higher frequency of cognitive impairment among affected individuals with damaging ACE mutations. Systematic analysis of blood ACE levels in patients with various ACE mutations identifies individuals with low blood ACE levels who may be at increased risk for late-onset AD. Patients with transport-deficient ACE mutations theoretically could benefit from therapeutic treatment with a combination of chemical and pharmacological chaperones and proteasome inhibitors, as was demonstrated previously on a cell model of the transport-deficient ACE mutation Q1069R. Moreover, clinical association analysis suggests a trend linking damaging ACE mutations with increased risk of cognitive impairment.}, } @article {pmid41009529, year = {2025}, author = {Krasauskas, L and Veiveris, D and Žiaunys, M and Šulskis, D and Sakalauskas, A and Smirnovas, V}, title = {Tau Enhances Aggregation of S100A9 Protein and Further Association of Its Fibrils.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009529}, issn = {1422-0067}, support = {S-MIP-22-34//This research was funded by the Research Council of Lithuania/ ; }, mesh = {*tau Proteins/metabolism/genetics/chemistry ; *Calgranulin B/metabolism/chemistry/genetics ; Humans ; *Amyloid/metabolism/chemistry ; Protein Aggregates ; *Protein Aggregation, Pathological/metabolism ; Alzheimer Disease/metabolism/pathology ; Protein Binding ; }, abstract = {The formation and accumulation of amyloid fibrils is implicated as one of the main reasons for the onset and progression of several widespread neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Decades of effort to unravel the intricate mechanisms of amyloid aggregation have only led to limited success in developing potent treatment modalities. Generally, this failure is considered to be the result of our incomplete understanding of the processes governing protein transitions into these insoluble fibrillar structures. Recently, a growing number of studies have reported that multiple amyloidogenic proteins, including ones related to the most debilitating disorders, can cross-interact during aggregation. This process leads to different nucleation and fibril elongation rates, aggregate structures, and even their cytotoxicity. Despite this revelation, the entire amyloid interactome remains largely unexplored. In this work, we investigate the cross-interaction between the Alzheimer's disease-related Tau protein and a pro-inflammatory S100A9 protein, which has recently been implicated as a possible modulator of amyloid aggregation. We show that Tau 2N4R enhances the amyloid aggregation propensity of S100A9 and mediates the self-association of the resulting fibrils, demonstrating this pairing's potential role in the onset of neurodegenerative disorders.}, } @article {pmid41009493, year = {2025}, author = {Dwamena, A and Beragama-Arachchi, R and Wang, H}, title = {Boosting Neurogenesis as a Strategy in Treating Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009493}, issn = {1422-0067}, support = {RF1 AG072510/AG/NIA NIH HHS/United States ; AG072510//NIH/NIA/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/pathology ; *Neurogenesis ; Animals ; Neural Stem Cells/metabolism/cytology ; Epigenesis, Genetic ; Genetic Therapy ; }, abstract = {Alzheimer's disease (AD) causes progressive cognitive decline and neuronal loss, partly due to the buildup of amyloid-β (Aβ) plaques and tau tangles. Despite years of research, treatments targeting these hallmark pathologies have yielded only modest clinical success, prompting interest in regenerative approaches to restore the brain's ability to repair itself. One such approach focuses on adult hippocampal neurogenesis, the process by which neural stem cells (NSCs) produce new neurons throughout life. In AD, this process is impaired, worsening cognitive deficits. In this review, we examine the molecular pathways that control adult neurogenesis, including transcriptional, epigenetic, inflammatory, and metabolic mechanisms, and how they become dysregulated in AD. We also highlight various therapeutic strategies aimed at boosting neurogenesis, such as pharmacological treatments, stem cell therapy, gene therapy, and epigenetic modulation. Preclinical studies indicate that enhancing neurogenesis can improve cognition and reduce brain pathology in AD models. Several of these treatments are now being tested in clinical trials. Ultimately, promoting neurogenesis may offer a promising avenue to complement current AD therapies and help restore lost neural function.}, } @article {pmid41009371, year = {2025}, author = {Tyng, V and Kellman, ME}, title = {Kinetic Model with Feedback Cycle for Age-Dependent Amyloid Beta Accumulation in Mice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009371}, issn = {1422-0067}, mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; Mice ; *Alzheimer Disease/metabolism/pathology ; Kinetics ; *Aging/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *Models, Biological ; Feedback, Physiological ; Humans ; }, abstract = {Amyloid beta (Aβ) is believed to play a key role in Alzheimer's disease (AD), whose causes, progression, diagnosis, and treatment nonetheless remain poorly understood despite decades of research. Recent studies suggest that Aβ in its various forms participates in multiple mutual feedback loops ("vicious cycles") including tauopathy, oxidative stress, inflammation, calcium dysregulation, excitotoxicity, and probably many others, eventually leading to neurodegeneration and cognitive decline. Here, as an initial quantitative step toward modeling this vast complexity, we explore a simple kinetic model of a coupled feedback vicious cycle for Aβ buildup based on literature data for Tg2576 mice. The model is used to examine the efficacy of various hypothetical therapeutic approaches, either singly or in combination, to mitigate Aβ buildup. While our computational results support the possible efficacy of combination interventions, they also suggest caution, inasmuch as clear synergy is not found. This kinetic approach highlights the essential importance of the vicious cycle of positive feedback in a quantitative model.}, } @article {pmid41008652, year = {2025}, author = {Bilski, R and Dąbkowski, S and Kozieł, I and Kozicki, M and Małachowska, A and Przygocki, M and Tyska, O}, title = {Perspectives on Alzheimer's Disease Treatment Based on Counteracting Oxidative Stress.}, journal = {Biomolecules}, volume = {15}, number = {9}, pages = {}, pmid = {41008652}, issn = {2218-273X}, mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; *Oxidative Stress/drug effects ; *Antioxidants/therapeutic use/pharmacology ; Reactive Oxygen Species/metabolism ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism ; Monoamine Oxidase Inhibitors/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and one of the most pressing global health challenges. Increasing evidence highlights oxidative stress as a key factor in its pathogenesis, contributing to amyloid-β accumulation, tau hyperphosphorylation, neuroinflammation, and mitochondrial dysfunction. Oxidative stress markers, detected in the bodily fluids of AD patients, are considered promising diagnostic and prognostic tools. Despite extensive research, currently available therapies remain largely symptomatic, which emphasizes the need to develop novel, disease-modifying strategies. The aim of this review is to summarize current knowledge on the role of oxidative stress in the pathogenesis of AD and to evaluate therapeutic approaches aimed at its reduction. We discuss molecular mechanisms linking reactive oxygen species to neurodegeneration and present pharmacological strategies such as monoamine oxidase inhibitors and multifunctional agents, as well as natural antioxidants, dietary interventions, and novel therapeutic technologies. We pay particular attention to their efficacy, limitations, and translational challenges. A more profound understanding of oxidative stress-related mechanisms may facilitate the development of combined antioxidant, anti-inflammatory, and neuroprotective approaches, offering new perspectives for delaying disease progression and improving patient outcomes.}, } @article {pmid41008347, year = {2025}, author = {Scuderi, G and Fagone, P and Petralia, MC and Nicoletti, F and Basile, MS}, title = {Multifaceted Role of Nef in HIV-Associated Neurocognitive Disorder: Histopathological Alterations and Underlying Mechanisms.}, journal = {Brain sciences}, volume = {15}, number = {9}, pages = {}, pmid = {41008347}, issn = {2076-3425}, abstract = {Although antiretroviral regimens achieve durable suppression of human immunodeficiency virus (HIV) replication, individuals living with HIV remain at an increased risk of developing chronic comorbidities, such as HIV-associated neurocognitive disorder (HAND). In the absence of definitive biomarkers or curative treatments, HAND impacts the survival and quality of life in up to 50% of individuals with HIV. Therefore, novel strategies are highly warranted to improve the diagnosis, monitoring, and treatment of individuals with HAND and a deeper characterization of the still poorly understood pathogenesis of HAND is fundamental to this aim. The pathogenesis, progression, and clinical outcomes of HAND are influenced by different factors, including viral proteins like negative factor (Nef). Among HIV proteins, Nef emerges as a potential key contributor to HAND pathogenesis. Nef could drive specific histopathological alterations in the brain and could be involved in HAND through different interconnected pathogenetic mechanisms. These include: immune dysregulation, oxidative stress, mitochondrial dysfunction, disruption of autophagy, myelin damage and oligodendrocytes dysfunction, blood-brain barrier disruption, alterations of cholesterol homeostasis, and certain potential converging mechanisms with Alzheimer's disease. Both extracellular and intracellular Nef can contribute to the development of HAND. Interestingly, it has been proposed that Nef may participate in HAND through its incorporation into extracellular vesicles. This review explores the multifaceted role of Nef in HAND, highlighting the histopathological alterations and the pathogenetic mechanisms potentially involved and the potential emerging relevance of Nef as a diagnostic and therapeutic target in HAND.}, } @article {pmid41008294, year = {2025}, author = {Zeppieri, M and Visalli, F and Musa, M and Avitabile, A and Giglio, R and Tognetto, D and Gagliano, C and D'Esposito, F and Cappellani, F}, title = {Beyond the Eye: Glaucoma and the Brain.}, journal = {Brain sciences}, volume = {15}, number = {9}, pages = {}, pmid = {41008294}, issn = {2076-3425}, abstract = {Glaucoma is traditionally classified as an ocular disease characterized by progressive retinal ganglion cell (RGC) loss and optic nerve damage. However, emerging evidence suggests that its pathophysiology may extend beyond the eye, involving trans-synaptic neurodegeneration along the visual pathway and structural changes within central brain regions, including the lateral geniculate nucleus and visual cortex. In this narrative review, we have used the phrase 'brain involvement' to underscore central changes that accompany or follow retinal ganglion cell loss; we have not intended to redefine glaucoma as a primary cerebral disorder. Neuroimaging studies and neurocognitive assessments in adult glaucoma patients, primarily older individuals with primary open-angle glaucoma reveal that glaucoma patients may exhibit alterations in brain connectivity and cortical thinning, aligning it more closely with neurodegenerative disorders such as Alzheimer's and Parkinson's disease. This evolving neurocentric perspective raises important questions regarding shared mechanisms-such as mitochondrial dysfunction, chronic inflammation, and impaired axonal transport-that may link glaucomatous optic neuropathy to central nervous system (CNS) pathology. These insights open promising therapeutic avenues, including the repurposing of neuroprotective and neuroregenerative agents, targeting not only intraocular pressure (IOP) but also broader CNS pathways. Furthermore, neuroimaging biomarkers and brain-targeted interventions may play a future role in diagnosis, prognosis, and individualized treatment. This review synthesizes current evidence supporting glaucoma as a CNS disease, explores the mechanistic overlap with neurodegeneration, and discusses the potential clinical implications of glaucoma within a neuro-ophthalmologic paradigm.}, } @article {pmid41007711, year = {2025}, author = {Aljadaan, AM and AlSaadi, AM and Shaikh, IA and Whitby, A and Ray, A and Kim, DH and Carter, WG}, title = {Characterization of the Anticholinesterase and Antioxidant Properties of Phytochemicals from Moringa oleifera as a Potential Treatment for Alzheimer's Disease.}, journal = {Biomedicines}, volume = {13}, number = {9}, pages = {}, pmid = {41007711}, issn = {2227-9059}, support = {PhD scholarship to Adel Aljadaan//Cultural Bureau and Najran University PhD scholarship/ ; }, abstract = {Background/Objectives: Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by a decline in cognition that may be due, in part, to deficient cholinergic signalling. Cholinesterase inhibitors (ChEIs) are the first-line pharmacotherapies for treating the diminished cholinergic function in AD patients. Plant phytochemicals may provide useful ChEIs and mitigate other elements of AD pathology, including oxidative stress. Methods: Herein, the phytochemicals present in Moringa oleifera aqueous and methanolic extracts were identified by LC-MS/MS and the potential of several phytochemicals (4-O-caffeoylquinic acid (4-CQA), quercetin 3-β-D-glucoside (Q3-β-D), chlorogenic acid (CGA), and rutin) to act as ChEIs and antioxidants was assessed. Results: The phytochemicals inhibited human acetylcholinesterase (AChE) in the following order of potency: 4-CQA > Q3-β-D > CGA > rutin; for AChE from Electrophorus electricus, the order of potency was Q3-β-D > 4-CQA > CGA > rutin. For human butyrylcholinesterase (hBuChE), the order of potency was rutin > 4-CQA > Q3-β-D > CGA and for equine serum BuChE, it was 4-CQA > Q3-β-D > rutin > CGA. Molecular docking validated the binding of the phytochemicals to cholinesterases, with binding affinities comparable to or higher than those of ChEI drugs. All the phytochemicals displayed potent radical-scavenging and antioxidant activities across six assays. 4-CQA was the most effective antioxidant in three of the assays. Conclusions: M. oleifera contains phytochemicals with weak ChEI activity and potent antioxidant capacity, with potential use as nutraceuticals to treat the cholinergic signalling deficit and oxidative stress that typifies AD pathology.}, } @article {pmid41007671, year = {2025}, author = {Okła, E and Hołota, M and Michlewska, S and Zawadzki, S and Miłowska, K and Sánchez-Nieves, J and Gómez, R and De la Mata, FJ and Bryszewska, M and Ionov, M}, title = {Crossing Barriers: PEGylated Gold Nanoparticles as Promising Delivery Vehicles for siRNA Delivery in Alzheimer's Disease.}, journal = {Biomedicines}, volume = {13}, number = {9}, pages = {}, pmid = {41007671}, issn = {2227-9059}, support = {2018/30/Z/NZ1/00911//Polish National Science Centre/ ; 2024/00300/001-GP2024-02//Universidad de Alcalá/ ; CIBER-BBN, CB06/01/1021//Centro de Investigación Biomédica en Red/ ; }, abstract = {Background: The proportion of people suffering from neurodegenerative conditions, such as Alzheimer's disease (AD), is increasing in the population year on year. Despite the constant effort of researchers, these conditions remain incurable and can only be managed by alleviation or delaying of symptoms. The lack of suitable treatment is caused by constricted access to the brain, limited by the brain-blood barrier. The aim of this work was to investigate two pegylated gold nanoparticles as potential carriers of therapeutic siRNA and their impact on the cellular functions of Human Brain Endothelial Cells. Methods and Results: Nanoparticles AuNP14a and AuNP14b complexed with siRNA were internalized by HBEC-5i cells and located in the cytoplasm. The genotoxicity assay proved that the nucleus was not affected and complexed nanoparticles did not cause DNA damage. The reactive oxygen species formation and mitochondrial membrane potential changes were measured and showed an adaptive response of cells after compound administration. Results obtained in a cytotoxicity assay conducted on astrocytes and pericytes, which are components of the blood-brain barrier, confirmed the biosafety of tested nanoparticles. Conclusions: In summary, it was shown that AuNP14a and AuNP14b are promising candidates as nanocarriers for therapeutic nucleic acids through biological barriers.}, } @article {pmid41007667, year = {2025}, author = {Dziedziak, M and Mytych, A and Szyller, HP and Lasocka, M and Augustynowicz, G and Szydziak, J and Hrapkowicz, A and Dyda, M and Braksator, J and Pytrus, T}, title = {Gut Microbiota in Psychiatric and Neurological Disorders: Current Insights and Therapeutic Implications.}, journal = {Biomedicines}, volume = {13}, number = {9}, pages = {}, pmid = {41007667}, issn = {2227-9059}, abstract = {Recent studies increasingly highlight the complex interaction between gut microbiota and mental health, drawing attention to the role of the microbiota-gut-brain axis (MGBA) in the pathophysiology of mental and neurodevelopmental disorders. Changes in the composition of the gut microbiota-dysbiosis-are associated with conditions such as depression, schizophrenia, bipolar disorder (BD), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and neurodegenerative diseases such as Parkinson's and Alzheimer's. These microbial imbalances can affect brain function through a variety of mechanisms, including activation of the immune system, alteration of intestinal permeability, modulation of the digestive and central nervous systems, and changes in the production of neuroactive metabolites such as short-chain fatty acids, serotonin, and tryptophan derivatives. The aim of this paper is to review the current state of knowledge on therapeutic strategies targeting the gut microbiome-including probiotics, prebiotics, synbiotics, personalized dietary interventions, and fecal microbiota transplantation (FMT)-which are becoming promising adjuncts or alternatives to conventional psychopharmacology, offering a forward-looking and individualized approach to mental health treatment. Understanding the bidirectional and multifactorial nature of MGBA may pave the way for new, integrative treatment paradigms in psychiatry and neurology, requiring further research and exploration of their scope of application.}, } @article {pmid41007636, year = {2025}, author = {Abdalla, M and Ibrahim, M and Alkorbi, N and Alkuwari, S and Pedersen, S and Rathore, HA}, title = {Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease and Other Neurological Disorders: A Comprehensive Review.}, journal = {Biomedicines}, volume = {13}, number = {9}, pages = {}, pmid = {41007636}, issn = {2227-9059}, abstract = {Alzheimer's disease is the most common form of dementia, yet current treatments only offer symptomatic relief, with little preventative, therapeutic, or disease-modifying properties. As a result, there has been growing interest in targeting various disease mechanisms. One promising target is soluble epoxide hydrolase (sEH), an enzyme found in many organs, playing an important role in metabolism and detoxification. In the brain, sEH is mainly present in astrocytes, oligodendrocytes, and neuronal cell bodies, with higher concentrations in the cerebral cortex and striatum. The main function of sEH is the hydrolysis of epoxyeicosatrienoic acids (EETs), which are important anti-inflammatory molecules derived from arachidonic acid. Deletion of EPHX2, the encoding gene of sEH, maintains EET levels in the brain and helps mitigate inflammation. Multiple studies have found links between sEH function, inflammation, and neurodegeneration in Alzheimer's disease. Several compounds, including TPPU, benzohomoadamantane derivatives, and natural products, have shown significant beneficial effects, including reduction of amyloid-beta plaques, tau fibrils, and inflammation, while improving cognition and neuronal structure and function. sEH inhibitors have also been explored for their potential in the management of Parkinson's disease, vascular dementia, stroke, and other neurodegenerative conditions. Although these preclinical findings are promising, efficacy and safety concerns still need to be addressed, and further clinical trials are needed to translate these therapeutic agents into clinical practice.}, } @article {pmid41007258, year = {2025}, author = {Guan, Q and Cao, Y and Zou, J and Zhang, L}, title = {Bone-Derived Factors: Regulating Brain and Treating Alzheimer's Disease.}, journal = {Biology}, volume = {14}, number = {9}, pages = {}, pmid = {41007258}, issn = {2079-7737}, support = {82272608//National Natural Science Foundation of China/ ; No//Shanghai Oriental Talent Program Youth/ ; 11DZ2261100//Shanghai Key Laboratory of Human Performance/ ; }, abstract = {In recent years, the bidirectional regulatory mechanism of the bone-brain axis has become a hotspot for interdisciplinary research. In this paper, we systematically review the anatomical and functional links between bone and the central nervous system, focusing on the regulation of brain function by bone-derived signals and their clinical translational potential. At the anatomical level, the blood-brain barrier permeability mechanism and the unique structure of the periventricular organs establish the anatomical basis for bone-brain information transmission. Innovative discoveries indicate that the bone cell network (bone marrow mesenchymal stem cells, osteoblasts, osteoclasts, and bone marrow monocytes) directly regulates neuroplasticity and the inflammatory microenvironment through the secretion of factors such as osteocalcin, lipid transporter protein 2, nuclear factor κB receptor-activating factor ligand, and fibroblast growth factor 23, as well as exosome-mediated remote signaling. Clinical studies have revealed a bidirectional vicious cycle between osteoporosis and Alzheimer's disease: reduced bone density exacerbates Alzheimer's disease pathology through pathways such as PDGF-BB, while AD-related neurodegeneration further accelerates bone loss. The breakthrough lies in the discovery that anti-osteoporotic drugs, such as bisphosphonates, improve cognitive function. In contrast, neuroactive drugs modulate bone metabolism, providing new strategies for the treatment of comorbid conditions. Additionally, whole-body vibration therapy shows potential for non-pharmacological interventions by modulating bone-brain interactions through the mechano-osteoclast signaling axis. In the future, it will be essential to integrate multiple groups of biomarkers to develop early diagnostic tools that promote precise prevention and treatment of bone-brain comorbidities. This article provides a new perspective on the mechanisms and therapeutic strategies of neuroskeletal comorbidities.}, } @article {pmid41006538, year = {2025}, author = {Falvey, A and Palandira, SP and Chaudhry, S and Tynan, A and Consolim-Colombo, FM and Metz, CN and Brines, M and Chang, EH and Chavan, SS and Tracey, KJ and Pavlov, VA}, title = {The cholinergic drug galantamine ameliorates acute and subacute peripheral and brain manifestations of acute respiratory distress syndrome in mice.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {33217}, pmid = {41006538}, issn = {2045-2322}, support = {R01 GM121102/GM/NIGMS NIH HHS/United States ; R35 GM118182/GM/NIGMS NIH HHS/United States ; RO1GM128008/NH/NIH HHS/United States ; R35GM118182/NH/NIH HHS/United States ; R01 GM128008/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Galantamine/pharmacology/therapeutic use ; *Respiratory Distress Syndrome/drug therapy/pathology/metabolism/chemically induced ; Mice ; Disease Models, Animal ; Male ; *Cholinergic Agents/pharmacology/therapeutic use ; Bronchoalveolar Lavage Fluid/chemistry ; Acute Lung Injury/drug therapy/pathology ; Lipopolysaccharides ; Cytokines/metabolism/blood ; *Brain/drug effects/pathology ; Lung/pathology/drug effects ; Inflammation/drug therapy ; }, abstract = {Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute lung injury (ALI), which is a common cause of respiratory failure and high mortality in critically ill patients. Long-term mortality and cognitive impairment have been documented in ARDS patients after hospital discharge. Inflammation plays a key role in ALI/ARDS pathogenesis. Neural cholinergic signaling regulates cytokine responses and inflammation. Here, we studied the effects of galantamine, an approved cholinergic drug (for Alzheimer's disease) on ALI/ARDS severity and inflammation in mice, using a clinically relevant mouse model induced by intratracheal administration of hydrochloric acid and lipopolysaccharide. Mice were treated 30 min prior to each insult with vehicle or galantamine (4 mg/kg, i.p.). Galantamine treatment significantly decreased bronchoalveolar lavage (BAL) and serum TNF, IL-1b, and IL-6 levels, as well as BAL total protein and myeloperoxidase (MPO) and lung histopathology in ALI/ARDS mice. In addition, galantamine improved the functional state of mice with ALI/ARDS during a 10-day monitoring and attenuated lung injury and indices of brain inflammation at 10 days. These findings support further studies utilizing this approved cholinergic drug in therapeutic strategies for ALI/ARDS and its subacute sequelae.}, } @article {pmid41005603, year = {2025}, author = {Ramachandran, AK and Govindula, A and Ranadive, N and Birangal, SR and Bhat, V and Fayaz, SM and Shenoy, GG and Mudgal, J}, title = {Design, synthesis, and preclinical evaluation of novel 1-benzylpiperidine derivatives as multitarget agents against Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1006}, number = {}, pages = {178192}, doi = {10.1016/j.ejphar.2025.178192}, pmid = {41005603}, issn = {1879-0712}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology/physiopathology ; Animals ; *Piperidines/pharmacology/chemical synthesis/therapeutic use/chemistry/metabolism ; *Drug Design ; Mice ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/therapeutic use/chemistry/metabolism ; Acetylcholinesterase/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Drug Evaluation, Preclinical ; *Neuroprotective Agents/pharmacology/chemical synthesis/therapeutic use ; Microglia/drug effects/metabolism ; Maze Learning/drug effects ; Humans ; Structure-Activity Relationship ; Disease Models, Animal ; }, abstract = {Small molecules targeting pathologies of Alzheimer's disease (AD) is a promising approach. Identification of potential molecules using computational techniques and their synthesis provides potential applications in the treatment of AD. 2D fingerprint similarity screening, using the Tanimoto coefficient, identified structurally similar molecules to donepezil for lead identification. A molecule with a Tanimoto coefficient of 0.7 was chosen, and derivatives were synthesized. In silico screening of the synthesized compounds indicated strong binding to acetylcholinesterase (AChE). All molecules met drug-likeness criteria and showed 100 % oral absorption. Key interactions with AChE were observed, crucial for inhibitory activity. Molecular dynamics simulations over 100 ns showed stable binding conformations. In vitro assays for AChE and amyloid β (Aβ) inhibition were conducted after the cytotoxicity testing in microglial cells for all four synthesized compounds. Among the tested compounds at 5 μM, (E)-2-(((1-benzylpiperidin-4-yl)imino)methyl)-4-methylphenol (5MeSA4ABP) with AChE (57.46 ± 2.140 %) and Aβ inhibition (57.83 ± 0.08 %), was selected for lipopolysaccharide-induced AD-like mouse model. Behavioural analysis using Morris water maze and open field tests revealed memory impairment in mice. Brain estimations were performed to study the effect of treatments on AD markers such as interleukin-6 (IL-6), Aβ and AChE. In mice with AD pathology, oral administration of 5MeSA4ABP resulted in improved cognitive function without any impact on locomotor activity. Except brain AChE activity, treatment with 5MeSA4ABP significantly reversed the elevated brain IL-6 and Aβ levels. Thus, synthesized hybrid pharmacophores, 5MeSA4ABP, exert its activity via reducing neuroinflammation and plaque deposition. Future investigation are warranted for safety and efficacy mechanisms of 5MeSA4ABP against AD.}, } @article {pmid41005404, year = {2025}, author = {Wang, G and Duan, J and Sun, L and Pan, S and Liu, Q and Fu, K and Zhang, D and Yuan, X and Fan, B and Hu, B and Huang, B}, title = {Multi-omics integration reveals key miRNAs, immune inflammation, and signaling pathways in Alzheimer's disease: Implications for targeted therapy.}, journal = {International journal of biological macromolecules}, volume = {329}, number = {Pt 2}, pages = {147874}, doi = {10.1016/j.ijbiomac.2025.147874}, pmid = {41005404}, issn = {1879-0003}, mesh = {*Alzheimer Disease/genetics/immunology/metabolism/therapy/pathology ; *MicroRNAs/genetics ; Humans ; *Signal Transduction/genetics ; *Inflammation/genetics/immunology ; Gene Expression Profiling ; Gene Regulatory Networks ; Transcriptome ; Gene Expression Regulation ; Male ; Female ; Molecular Targeted Therapy ; Multiomics ; }, abstract = {Alzheimer's disease (AD), a common neurodegenerative disorder, has unclear molecular mechanisms and therapeutic targets. In this study, multi-omics analysis and experimental validation were performed. By integrating three miRNA-seq, four differentially expressed miRNAs (miR-339-3p, miR-28-3p, miR-423-3p, miR-144-5p) were identified, closely related to synaptic function and immune-inflammatory responses. By integrating blood RNA-seq data, we found 725 mRNAs linked to AD, immune, and apoptosis pathways. Peripheral blood single-cell transcriptomics showed altered immune cell proportions in AD patients, indicating systemic immunodysregulation. Integrating the three omics datasets identified 388 key genes involved in JAK-STAT, PI3K-Akt, and MAPK pathways. Experimental validation showed that combining candidate miRNAs significantly reduced AD marker expression and promoted neuronal progenitor cell marker expression, but had limited effect on mature neuronal markers (MAP2, NeuN). However, providing a suitable neuronal environment could induce neuronal differentiation, showing neuronal induction potential. These findings reveal the dual role of synaptic dysfunction and neuroinflammation in AD progression, offering new insights into AD's molecular network and proposing a treatment framework combining immunomodulation and neuroregeneration.}, } @article {pmid41004623, year = {2025}, author = {Mukesha, D and Sarter, M and Dubray, M and Durand, F and Boutillier, S and Pham-Van, LD and Halter, D and Kul, S and Blanc, F and Gürvit, H and Demiralp, T and Dubois, B and Gabelle, A and Marizzoni, M and Frisoni, GB and Pasquier, F and Sellal, F and Ivanoiu, A and Bier, JC and David, R and Démonet, JF and Magnin, E and Sacco, G and Firat, H}, title = {Targeted serum metabolomic profiling and machine learning approach in Alzheimer's disease using the Alzheimer's disease diagnostics clinical study (ADDIA) cohort.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {824-833}, pmid = {41004623}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/genetics ; *Machine Learning ; Male ; Female ; *Metabolomics/methods ; Aged ; Biomarkers/blood ; Cohort Studies ; Middle Aged ; Aged, 80 and over ; Apolipoproteins E/genetics ; }, abstract = {BackgroundMetabolic biomarkers can potentially be used for early diagnosis, prognostic risk stratification and/or early treatment and prevention of individuals at risk to develop Alzheimer's disease (AD).ObjectiveOur goal was to evaluate changes in metabolite concentration levels associated with AD to identify biomarkers that could support early and accurate diagnosis and therapeutic interventions by using targeted mass spectrometry and machine learning approaches.MethodsSerum samples collected from a total of 107 individuals, including 55 individuals diagnosed with AD and 52 healthy controls (HC) enrolled previously to ADDIA cohort were analyzed using the biocrates AbsoluteIDQ[®] p400 HR kit metabolite and lipid panel. Several machine learning models including Least Absolute Shrinkage and Selection Operator (LASSO), Partial Least Squares (PLS), Random Forest, and XGBoost were trained to classify AD and HC. Repeated cross-validation was used to ensure performance evaluation.ResultsThe LASSO and PLS models showed the strongest classification performance on the test set, achieving area under the ROC curve (AUC) values of 0.84 and 0.90, respectively. A refined model based on only the top 5 metabolites maintained strong performance, and the inclusion of Apolipoprotein E (APOE) genotype information notably improved classification accuracy, particularly by reducing false negatives in AD cases.ConclusionsThese results highlight important metabolic signatures that could help to reduce misdiagnosis and support the development of metabolomic panels to detect AD. The combination of multiple serum metabolic biomarkers and APOE genotyping can significantly improve classification accuracy and potentially assist in making non-invasive, cost-effective diagnostic approach.}, } @article {pmid41004106, year = {2025}, author = {Hwang, DJ and Cho, JY}, title = {Exercise as a Therapeutic Intervention for Alzheimer's Disease.}, journal = {Advances in neurobiology}, volume = {44}, number = {}, pages = {297-316}, pmid = {41004106}, issn = {2190-5215}, mesh = {Humans ; *Alzheimer Disease/therapy/prevention & control/physiopathology ; *Exercise Therapy/methods ; *Exercise/physiology ; Animals ; }, abstract = {Alzheimer's disease (AD) is a common form of dementia characterized by cognitive decline and abnormal accumulation of proximate neurotoxins in older adults. It accounts for up to 80% of all dementia cases. AD is not exclusively attributed to aging; rather, it involves complex and multifactorial brain changes that can lead to severe functional dependence and ultimately death. Although there has been progress in the development of novel treatments for AD, they are yet to yield disease-modifying effects. Early detection and therapeutic interventions are critical for preventing or delaying the onset of AD. We aimed to provide an overview of emerging evidence on physical exercise as a therapeutic strategy for the prevention and treatment of AD. Studies have demonstrated the potential of exercise in improving cognitive function, reducing the risk of AD, and slowing disease progression by promoting various neuroplastic changes. Therefore, regular exercise should be considered as a disease-modifying intervention for AD and included in comprehensive treatment protocols. Further studies are warranted to establish the optimal exercise regimen for individuals with AD; nonetheless, incorporating exercise into daily routines may contribute toward the prevention and management of AD.}, } @article {pmid41003796, year = {2025}, author = {Raza, A and Saleem, S and Imran, S and Rahman, S and Haroon, M and Razzaq, A and Hussain, A and Iqbal, J and Sathian, B}, title = {From metabolic dysregulation to neurodegenerative pathology: the role of hyperglycemia, oxidative stress, and blood-brain barrier breakdown in T2D-driven Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {7}, pages = {276}, pmid = {41003796}, issn = {1573-7365}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Oxidative Stress/physiology ; *Blood-Brain Barrier/metabolism/pathology ; *Diabetes Mellitus, Type 2/metabolism/pathology/complications ; Animals ; *Hyperglycemia/metabolism/pathology ; Insulin Resistance/physiology ; Brain/metabolism/pathology ; }, abstract = {Type 2 Diabetes (T2D) and Alzheimer's Disease (AD) share common risk factors that can be seen through T2D nearly doubling an individual's likelihood of developing AD. Some AD patients show signs of metabolic dysfunction as well. This review focuses on the potential mechanisms associated with these two diseases, like insulin resistance, inflammation, oxidative damage, mitochondrial injury, and cell death. One of the notable elements in this connection is the "brain insulin resistance," most frequently named as "type 3 diabetes," which impairs glucose metabolism and facilitates amyloid beta (Aβ) plaque synthesis while reducing the action of insulin-degrading enzyme (IDE). Moreover, the overactivity of glycogen synthase kinase-3 beta (GSK-3β) also triggers taurine protein pathology. Raised concentrations of glucose in blood can produce advanced glycation end products (AGEs), which further exacerbate neuroinflammation in tandem with the mitigation of neurotoxic Aβ oligomers. Inflammation and subsequent damage to mitochondria lead to the dissolution of synapses. Current vascular insults include the breakdown of the blood-brain barrier (BBB) and decreased brain perfusion, along with other contributory factors to conditions conducive to neurotoxicity. Recently, novel therapies are emerging, including GLP-1 agonists, intranasal insulin, and mitochondrial antioxidants, that show surprising results for treating both conditions, but on the contrary, bioavailability and the timing of interventions remain a big challenge in the management of these diseases. Eventually, further research should center on understanding the mechanisms of integration along with the development of molecular biology, neuroimaging, and outcome-driven treatment strategies. Comprehensive strategies that exist between T2D-AD for integration and preservation of brain and metabolic health are addressed in this review.}, } @article {pmid41003702, year = {2025}, author = {Salarinasab, S and Asgari Taei, A and Kaveh, N and Karima, S and Nikzamir, A and Dargahi, L}, title = {Regorafenib modulates glucose metabolism, insulin/GLP-1 signaling, and tau pathology in an STZ-induced model of Alzheimer's disease.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {41003702}, issn = {1432-1912}, support = {43006607//The authors declare that this study was funded by the Research Affairs of Shahid Beheshti University of Medical Sciences./ ; }, abstract = {PURPOSE: Alzheimer's disease (AD), often described as "type 3 diabetes" due to its metabolic and neuroendocrine features, is marked by impaired glucose metabolism and insulin signaling. This study aimed to investigate whether regorafenib, a multi-kinase inhibitor, could modulate glucose metabolism, insulin/glucagon-like peptide-1 (GLP-1) pathways, and tau pathology in a streptozotocin (STZ)-induced rat model of AD. METHODS: Male rats (n = 5-8/group) received intracerebroventricular STZ to induce AD-like pathology and were subsequently treated with regorafenib for two weeks. Cognitive function was assessed using the Y-maze and novel object recognition (NOR) tests. Glucose metabolism was evaluated via 18F-FDG micro-PET imaging and glucose tolerance tests. Serum and hippocampal markers of insulin, GLP-1, and tau phosphorylation were measured. RESULTS: Regorafenib-treated rats exhibited significant improvement in recognition memory in the NOR test, while enhancement in spatial working memory in the Y-maze did not reach statistical significance. Regorafenib improved glucose metabolism in both the brain and periphery, as demonstrated by imaging and tolerance testing. Treatment significantly increased serum insulin and GLP-1 levels, and reduced hippocampal hyperphosphorylated tau, although hippocampal gene expression of insulin and GLP-1 signaling pathways remained unchanged. CONCLUSION: Regorafenib may provide neuroprotective benefits in AD by improving glucose metabolism and reducing tau pathology. These findings suggest regorafenib as a potential novel therapeutic strategy for AD, though further research is needed to confirm its efficacy, assess long-term outcomes, and elucidate underlying mechanisms.}, } @article {pmid41003140, year = {2025}, author = {Alkhalifa, AE and Al Mokhlf, A and Ali, H and Al-Ghraiybah, NF and Syropoulou, V}, title = {Anti-Amyloid Monoclonal Antibodies for Alzheimer's Disease: Evidence, ARIA Risk, and Precision Patient Selection.}, journal = {Journal of personalized medicine}, volume = {15}, number = {9}, pages = {}, pmid = {41003140}, issn = {2075-4426}, abstract = {Alzheimer's disease (AD) is the most common cause of dementia, pathologically defined by extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Recent U.S. Food and Drug Administration (FDA) approvals of anti-amyloid monoclonal antibodies (mAbs) aducanumab, lecanemab, and donanemab represent the first disease-modifying therapies for early AD. These therapies have generated both optimism and controversy due to modest efficacy and safety concerns, particularly amyloid-related imaging abnormalities (ARIAs). This review synthesizes current evidence on the efficacy, safety, and biomarker-guided use of anti-Aβ mAbs in AD. Methods: We searched PubMed, Scopus, Web of Science, and Google Scholar to 31 July 2025 for studies on anti-amyloid mAbs in AD. Sources included peer-reviewed articles and regulatory reports. The extracted data covered study design, population, amyloid confirmation, dosing, outcomes, biomarkers, ARIA incidence, and management. Results: Anti-amyloid mAbs consistently demonstrated robust amyloid clearance and modest slowing of clinical decline in early symptomatic AD. Differences emerged across agents in efficacy signals, safety profiles, and regulatory outcomes. Lecanemab and donanemab showed more consistent cognitive benefits, while aducanumab yielded mixed findings, leading to its withdrawal. ARIAs were the most frequent adverse events, occurring more often in APOE ε4 carriers and typically during early treatment. Biomarker analyses also revealed favorable downstream effects, including reductions in phosphorylated tau and markers of astroglial injury, supporting engagement of disease biology. Conclusions: Anti-amyloid mAbs provide proof of concept for AD modification, with the greatest benefit in early disease stages and moderate tau burden. Optimal use requires biomarker confirmation of the amyloid, careful tau staging, and genetic risk assessment. While limitations remain, these therapies represent a pivotal step toward precision neurology and may serve as a foundation for multimodal strategies targeting tau, neuroinflammation, and vascular pathology.}, } @article {pmid41003116, year = {2025}, author = {Kalyvas, AC and Smyrni, N and Ioannidis, P and Grigoriadis, N and Afrantou, T}, title = {Bridging Epilepsy and Cognitive Impairment: Insights from EEG and Clinical Observations in a Retrospective Case Series.}, journal = {Journal of personalized medicine}, volume = {15}, number = {9}, pages = {}, pmid = {41003116}, issn = {2075-4426}, abstract = {Background: Epilepsy and cognitive impairment frequently coexist, yet their relationship remains complex and insufficiently understood. This study aims to explore the clinical and electrophysiological features of patients presenting with both conditions in order to identify patterns that may inform more accurate diagnosis and effective management within a personalized medicine framework. Methods: We retrospectively analyzed 14 patients with late-onset epilepsy and coexisting cognitive impairment, including mild cognitive impairment and Alzheimer's disease. Clinical history, cognitive assessments, neuroimaging, and electroencephalographic recordings were reviewed. EEG abnormalities, seizure types, and treatment responses were systematically documented. Results: Patients were categorized into two groups: (1) those with established Alzheimer's disease who later developed epilepsy and (2) those in whom epilepsy preceded cognitive impairment. Temporal lobe involvement was a key feature, with EEG abnormalities frequently localizing to the frontal-temporal electrodes and manifesting as background slowing, focal multiform slow waves, and epileptiform discharges. Levetiracetam was the most commonly used antiseizure medication, and it was effective across both groups. Conclusions: This case series highlights the value of EEG in characterizing patients with subclinical and overt epileptic activity and cognitive impairment comorbidity. The inclusion of a substantial number of cases with documented EEG abnormalities provides valuable insight into the interplay between epilepsy and neurodegenerative diseases. By integrating neurophysiological data with clinical and cognitive trajectories, this work aligns with the principles of precision medicine, facilitating a more comprehensive evaluation and tailored management approach. Further longitudinal studies are required to validate prognostic markers and guide optimal therapeutic strategies.}, } @article {pmid41002746, year = {2025}, author = {Iliuta, FP and Manea, M and Mares, AM and Varlam, CI and Ciobanu, CA and Ciobanu, AM and Lacau, RM and Manea, MC}, title = {Unraveling Dual Cognitive Disorders: A Case Report and Literature Review on Marchiafava-Bignami Disease and Possible Alzheimer's Disease.}, journal = {Diseases (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {41002746}, issn = {2079-9721}, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, particularly in those aged 65 and older. Dementia can also occur under age 45, known as young-onset dementia (YOD), although this is rarer. Marchiafava-Bignami disease (MBD) is a rare disorder characterized by demyelination and necrosis of the corpus callosum, primarily affecting individuals with chronic alcohol use. We present the case of a 49-year-old woman admitted for psychiatric and neurological evaluation due to a multidomain cognitive disorder with a sudden onset approximately four years prior, which progressed rapidly, resulting in complete dependence on others for daily activities. Her medical history included moderate depression, chronic alcohol consumption, and professional exhaustion. Psychological assessments revealed severe neurocognitive impairment. MRI scans highlighted significant bilateral parietal atrophy, hippocampal atrophy, and demyelinating lesions in the corpus callosum, consistent with MBD. Despite initial inconsistencies in biomarkers, later tests showed elevated tau protein, phosphorylated tau, and amyloid-beta, supporting an AD diagnosis. Clinical presentation, combined with neuroimaging findings and chronic alcohol consumption history, led to a diagnosis of AD with young onset and chronic MBD. This case illustrates the complexities involved in diagnosing overlapping neurodegenerative disorders. The coexistence of MBD and AD complicates the treatment plan, requiring a multifaceted approach addressing both neurodegenerative and nutritional aspects.}, } @article {pmid41002740, year = {2025}, author = {Bardhan, M and Anand, A and Javed, A and Chilo, MA and Khan, N and Garg, T and Surana, A and Huang, H and Samim, MM and Suresh, V and Khare, A and Menon, B and Kundu, T}, title = {Polymorphism of Melanocortin Receptor Genes-Association with Inflammatory Traits and Diseases.}, journal = {Diseases (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {41002740}, issn = {2079-9721}, abstract = {Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases.}, } @article {pmid41002439, year = {2025}, author = {Lanza, M and Basilotta, R and Caccamo, A and Casili, G and Repici, A and Oddo, S and Esposito, E}, title = {PF-04691502, a PI3K/mTOR Dual Inhibitor, Ameliorates AD-like Pathology in a Mouse Model of AD.}, journal = {Cells}, volume = {14}, number = {18}, pages = {}, pmid = {41002439}, issn = {2073-4409}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; Disease Models, Animal ; Mice ; Female ; Male ; Mice, Transgenic ; *Phosphoinositide-3 Kinase Inhibitors/pharmacology/therapeutic use ; Phosphatidylinositol 3-Kinases/metabolism ; Amyloid beta-Peptides/metabolism ; *MTOR Inhibitors/pharmacology/therapeutic use ; *Pyrimidines/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Mice, Inbred C57BL ; Brain/pathology/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impacts the lives of patients and their families. The pathological features of AD include the accumulation of amyloid-β (Aβ) and Tau, which disrupt neuronal function and communication, ultimately leading to neuronal loss and brain atrophy. Efforts to understand the molecular mechanisms underlying these pathological changes have led to advancements in diagnostic techniques and potential therapeutic interventions. However, the complexity of AD necessitates further research to develop more effective treatments and, ideally, preventive measures. Extensive research suggests that diminishing mTOR signaling increases lifespan and health span across various species. Increased PI3K/mTOR signaling has been linked to the progression of AD pathology, leading to neuronal degeneration and impairments in cognitive function. In this study, we explored the therapeutic potential of PF-04691502, a dual PI3K/mTOR inhibitor, in Alzheimer's disease (AD)-like pathology using male and female B6.Cg-Tg(APPswe, PSEN1dE9)85Dbo/Mmjax mice (APP/PS1), a well-established transgenic model of AD. Eighteen-month-old APP/PS1 and wild-type mice received oral administration of PF-04691502 at a dose of 1 mg/kg for 12 weeks. Following the treatment period, spatial learning and memory were evaluated using the Morris water maze. Subsequently, the mice brains were collected for neuropathological and biochemical assessments. Our findings showed that PF-04691502 enhanced cognitive performance in APP/PS1 mice and significantly reduced insoluble Aβ accumulation in the brain. Mechanistically, these effects were associated with enhanced autophagy induction. Treatment with PF-04691502 increased the LC3-II/LC3-I ratio, upregulated Beclin-1, and elevated LAMP-2 levels, indicative of stimulated autophagosome formation and lysosomal activity. Overall, these preclinical results suggest that PF-04691502 holds promise as a potential therapeutic agent for AD and other aging-related neurodegenerative diseases involving mTOR pathway dysregulation.}, } @article {pmid41002390, year = {2025}, author = {Katsipis, G and Tzekaki, EE and Iasonidou, S and Pantazaki, AA}, title = {The Diagnostic and Therapeutic Potential of Oligonucleotide Aptamers in Alzheimer's Disease.}, journal = {Cells}, volume = {14}, number = {18}, pages = {}, pmid = {41002390}, issn = {2073-4409}, mesh = {*Alzheimer Disease/diagnosis/drug therapy/therapy ; Humans ; *Aptamers, Nucleotide/therapeutic use ; Biomarkers/metabolism ; MicroRNAs/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Biosensing Techniques ; }, abstract = {Alzheimer's disease (AD) is the neurodegenerative condition with the outmost future challenges, with timely diagnosis and treatment being the most urgent. Discovery of more and more biomarkers is widely attempted; however, current diagnostic methods often lack sensitivity, specificity, and accessibility. Nucleotide aptamers-short, highly specific oligonucleotide or ligands-are now recognized as highly promising molecular agents for both measuring and targeting key AD biomarkers, with the most notorious being amyloid-beta (Aβ), tau protein, and disease-associated microRNAs (miRNAs). This review provides a comprehensive analysis of nucleotide aptamers related to AD, detailing their mechanisms of selection, recent advances in biosensing applications, and therapeutic potential. Aptamers, targeting the most significant biomarkers of AD, are mainly discussed, as well as ones interacting with novel, promising biomarkers, with a special aim on miRNAs. Additionally, aptamers are compared with conventional antibody-based approaches, highlighting their advantages in terms of stability, cost-effectiveness, and ease of modification. By elucidating the role of aptamers in AD diagnosis and treatment, this review underscores their promise as next-generation tools for precision medicine and neurodegenerative disease management.}, } @article {pmid41001643, year = {2025}, author = {Zhang, Z and Lv, M and Xu, J and Liu, Y and Qin, J and Fan, Z and Du, J}, title = {A Metal-Peptide Framework as a Nanozyme for the Attenuation of Amyloid‑β Aggregation and Reactive Oxygen Species.}, journal = {JACS Au}, volume = {5}, number = {9}, pages = {4346-4360}, pmid = {41001643}, issn = {2691-3704}, abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by abnormal performance in memory, cognition, and language, and it imposes a heavy economic burden worldwide. Amyloidosis and oxidative stress are highly associated with AD progression, yet limited clinical drugs are available at present. Nanozymes exhibit diverse enzyme-mimetic activities and have attracted widespread attention as a promising alternative candidate for scavenging reactive oxygen species to maintain the oxidation-antioxidation balance in cells. Neurotoxic amyloid-β (Aβ) aggregation is also a critical event in AD pathology. The development of dual-targeting nanomaterials with antiamyloidosis ability and enzyme-mimicking activity is expected to be a promising strategy for the treatment of amyloidosis and reactive oxygen species-mediated AD progression. Here, bimetallic-peptide framework nanozymes (CuZn-PEP NZs) with amyloid-β (Aβ) attenuating ability, multiple enzyme-mimicking properties, and broad-spectrum reactive oxygen species scavenging capacity were endowed to inhibit Aβ fibrillization, disaggregate Aβ fibrils, and scavenge Aβ fibril-induced reactive oxygen species. An obvious inhibitory effect on Aβ fibrillization and a disaggregation effect on Aβ fibrils were observed after treatment with CuZn-PEP NZs. Meanwhile, the cytotoxicity of Aβ fibrils toward PC12 cells was significantly reduced by CuZn-PEP NZs. Meanwhile, CuZn-PEP NZs with multiple redox pairs exhibit superoxide dismutase, catalase, and glutathione peroxidase-mimicking enzyme properties simultaneously, which further display cytoprotective effects against Aβ fibril-induced reactive oxygen species and mitochondrial damage. Besides, cellular studies verified that CuZn-PEP NZs possess excellent biocompatibility and blood-brain barrier penetration capacity. Overall, these bimetallic-peptide framework nanozymes represent a promising perspective for attenuation of amyloid-β aggregation and reactive oxygen species simultaneously, which highlights the potential of nanozymes for the treatment of amyloidosis and reactive oxygen species-mediated AD progression.}, } @article {pmid41001460, year = {2025}, author = {Qi, YS and Miller, LR and D'Ascenzo, MD and Berndt, JD and Whitney, GA and Duffy, F and Danziger, SA and Peskind, E and Li, G and Masters, CL and Fowler, C and , and Lipshutz, R and Aitchison, JD and Smith, JJ}, title = {An Indicator Cell Assay-based Multivariate Blood Test for Early Detection of Alzheimer's Disease.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41001460}, support = {R44 CA203455/CA/NCI NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R43 CA203455/CA/NCI NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P50 NS062684/NS/NINDS NIH HHS/United States ; R43 AG056215/AG/NIA NIH HHS/United States ; R44 AG051282/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; }, abstract = {The indicator cell assay platform (iCAP) is a novel next-generation approach for blood-based diagnostics that uses standardized cells as biosensors to amplify weak disease signals in blood. We developed an Alzheimer's disease iCAP (AD-iCAP) for early detection at the mild cognitive impairment/mild dementia stages. To develop the assay, patient plasma is incubated with standardized neurons, which transduce complex circulating signals into gene-expression readouts used to train multivariate disease classifiers via machine learning. We applied systems biology analyses (e.g., GSEA, PCA, correlation/network analyses) to optimize analytical and computational parameters, and then evaluated a locked model in a study with retrospectively collected samples. Performance was AUC 0.64 (95% CI 0.51-0.78, n=82) on an independent external-validation set and AUC 0.77 (95% CI 0.57-0.96, n=23) on a blind set, supporting prospective confirmation in a larger cohort. To overcome pre-analytical noise and reduce bias in feature-selection, modeling was done using a fixed panel of 84 candidate genes chosen a priori from an external AD-iCAP dataset generated with 5XFAD mouse plasma. Despite using no AD-specific prior knowledge in this approach, the assay readout was enriched for Alzheimer's-relevant pathways, including cholesterol biosynthesis, synaptic structure/neurotransmission and PIK3/AKT activation. Because the assay senses a multivalent cellular response, which is orthogonal to circulating amyloid or tau measurements, AD-iCAP may complement existing blood tests, and its multivariate readout offers a path to precision-medicine applications such as patient stratification for treatment response.}, } @article {pmid41001450, year = {2025}, author = {Digma, LA and Young, CB and Winer, JR and Cody, KA and Younes, K and Sheng, J and Insel, PS and Rissman, RA and Sperling, R and Mormino, EC}, title = {Continuum of Core 1 Biomarkers in Preclinical Alzheimer's Disease.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41001450}, support = {K01 AG078443/AG/NIA NIH HHS/United States ; K99 AG071837/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Biological Staging for Alzheimer's disease (AD) in clinically unimpaired (CU) individuals is critical for early detection efforts. In this study, we evaluated whether Core 1 biomarkers (plasma ptau-217 and amyloid-PET) within Biological Stage A, the earliest biological stage of AD, predicts progression of downstream biomarkers and cognition. METHODS: We used baseline plasma ptau-217 and amyloid-PET, and longitudinal tau-PET, atrophy, and cognition data from the recently completed Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study. PET data were used to identify participants within AD Biological Stage A (amyloid-PET positive and medial temporal tau-PET negative). Within these Stage A participants, linear mixed effects models were used to examine associations between continuous baseline levels of plasma p-tau217 and amyloid-PET burden with longitudinal regional tau-PET, atrophy, and cognition. We additionally evaluated whether continuous p-tau217 and amyloid-PET burden within this group was associated with higher risk of progression to Biological Stage B+ (tau-PET positive in the medial temporal lobe). In our statistical models, we included covariates for age, sex, and APOE4 carriage. RESULTS: Of 335 A4 participants with complete biomarker data, 222 were identified as being in Biological Stage A. Among Biological Stage A CU, continuous baseline plasma p-tau217 and amyloid-PET burden were independently associated with faster tau-PET accumulation and atrophy in AD-relevant regions (mean follow-up time for both tau-PET and MRI: 4.2 years), as well as faster cognitive decline (mean follow-up time for PACC: 5.7 years) (all p<0.05). Plasma p-tau217 and amyloid-PET burden were independently associated with higher risk of progression to Biological Stage B+. DISCUSSION: In CU individuals, early changing AD biomarkers during the initial stage of AD (Biological Stage A) provide prognostic information of downstream markers of disease. Evaluation of the utility of these continuous measures in a real-world setting is warranted. CLINICAL TRIAL INFORMATION: The A4 study was submitted for registration to clinicaltrials.gov on December 6th, 2023. The study is registered with ID NCT02008357. Screening and data collection for the study began in April 2014.}, } @article {pmid41001445, year = {2025}, author = {Orlichenko, A and Ding, S and Johns, E and Gu, Z and Tian, X and Li, X and Zhao, Y}, title = {Intervention on Modifiable Lifestyle and Physiological Factors via Variational Autoencoder Reveals Changes in Functional Connectivity-Mediated Risk for Alzheimer's Disease.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41001445}, support = {R01 AG068191/AG/NIA NIH HHS/United States ; R01 EB034720/EB/NIBIB NIH HHS/United States ; RF1 AG081413/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) remains without effective treatment, largely due to the fact that clinical symptoms emerge only after decades of silent pathological progression. It is urgently needed to identify modifiable risk factors in earlier life stages, when preventive interventions may still be effective. Functional connectivity (FC) has emerged as a promising neuromarker for both neurodegenerative processes and behavioral traits, making it a potential bridge between early-life health profiles and late-life AD risk. In this work, we introduce a novel integrative framework that models how early-life lifestyle and physiological factors influence AD risk through their impact on brain FC. Our approach combines a modified variational autoencoder (VAE) that simulates FC changes under interventions with a predictive model that estimates AD risk based on FC patterns. This design enables training of the generative and predictive components under different datasets and populations, with FC acting as the bridge between early-life modifiable factors and late-life disease risk. Applying our framework to data from the Human Connectome Project (HCP), UK Biobank (UKB), and Alzheimer's Disease Neuroimaging Initiative (ADNI), we validate its ability to capture known risk factors, such as age and polygenic risk score, on FC-mediated AD risk. We also identify earlier-life modifiable factors including tobacco use, sleep quality, physical activity and weight/BMI that significantly influence AD risk. Notably, we observe a U-shaped relationship between blood pressure and AD risk, and highlight the brain visual and somatomotor networks as key mediators of risk through FC. Our approach provides a powerful tool for investigating the effect pathways linking early-life interventions to neurodegenerative outcomes, with broad applicability to other brain-related disorders.}, } @article {pmid41001289, year = {2025}, author = {Uchida, K and Maruta, J and Kurozumi, H and Inoue, K}, title = {Motivation Through Treatment: How Lecanemab Initiation Facilitated Alcohol Cessation and Cognitive Stability in a Patient With Early Alzheimer's Disease.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e90907}, pmid = {41001289}, issn = {2168-8184}, abstract = {Excessive alcohol use can complicate the management of individuals in the early stages of cognitive decline, as memory impairment may limit the awareness of harmful habits and reduce motivation for behavioral change. Anti-amyloid therapies such as lecanemab have recently become available for early Alzheimer's disease (AD), but their use in individuals with a history of heavy alcohol consumption remains uncommon. Furthermore, the combined impact of abstinence and disease-modifying therapy on clinical outcomes is not well understood. We report the case of a woman in her early 80s initially diagnosed with mild cognitive impairment (MCI), who later progressed to mild AD. Despite repeated counseling, she had persistent difficulties reducing alcohol intake. As her cognitive symptoms worsened, psychiatric intervention and inpatient care were needed to achieve alcohol cessation. With structured support and lifestyle changes, including the involvement of her daughter, her daily routine stabilized. Following the initiation of lecanemab therapy, she maintained abstinence, experienced no significant treatment-related adverse effects, and showed no imaging abnormalities on follow-up MRI. Her Mini-Mental State Examination (MMSE) scores improved after the combined lifestyle and pharmacologic interventions. This case suggests that lifestyle stabilization and lecanemab therapy can work synergistically in individuals with early AD and prior excessive alcohol use. The initiation of regular infusions may have provided both therapeutic and motivational support for maintaining abstinence and daily structure.}, } @article {pmid41001105, year = {2025}, author = {Ali-Jerman, H and Somani, S and Al-Quraishi, Z and Maeyouf, K and Merkler, M and Gerasimou, S and Tate, RJ and Sakata, S and Mullin, M and Irving, C and Anderson, GJ and Bame, JR and MacKenzie, G and McNeill, G and Dufès, C}, title = {Intravenous Delivery of Angiopep-Functionalized Polypropylenimine Dendriplex Enhances Gene Expression in the Brain.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {11569-11591}, pmid = {41001105}, issn = {1178-2013}, mesh = {Animals ; *Dendrimers/chemistry/administration & dosage ; *Brain/metabolism ; Blood-Brain Barrier/metabolism ; Mice, Inbred BALB C ; Mice ; *Gene Transfer Techniques ; Genetic Therapy/methods ; DNA/administration & dosage/chemistry/genetics ; Administration, Intravenous ; Endothelial Cells/metabolism ; Cell Line ; Particle Size ; Gene Expression ; Endocytosis ; Peptides ; Polypropylenes ; }, abstract = {BACKGROUND: The application of gene therapy for treating neurological disorders, including brain cancer, Parkinson's, and Alzheimer's disease, is significantly limited by the current shortage of gene vectors that can effectively cross the blood-brain barrier (BBB) following intravenous administration. Recent studies demonstrated that angiopep-2 can enhance the delivery of therapeutic agents across the BBB through receptor-mediated endocytosis. This study therefore explores the potential of angiopep-2-conjugated generation-3 diaminobutyric polypropylenimine (DAB) dendrimer (DAB-Ang) as nanocarrier for brain-targeted gene delivery. METHODS: Angiopep-2 was conjugated to DAB dendrimer and evaluated in terms of DNA condensation ability, particle size, surface charge, and structural morphology. The cellular uptake was studied in vitro using bEnd.3 brain endothelial cells, and the in vivo efficacy of DAB-Ang dendriplexes for brain gene expression was evaluated in BALB/c mice following intravenous administration. RESULTS: DAB-Ang dendrimer successfully condensed up to 90% of DNA, forming stable spherical dendriplexes with sizes under 240 nm and positive zeta potentials. In vitro, DAB-Ang dendriplex achieved a 9-fold higher cellular uptake in brain endothelial cells in comparison to the unmodified complex, predominantly through clathrin-mediated endocytosis and macropinocytosis. In vivo studies showed significantly increased gene expression in the brain following DAB-Ang dendriplex treatment, achieving 1.8-fold and 3.2-fold higher expression in comparison to DAB dendriplex and naked DNA, respectively, with minimal off-target effects. CONCLUSION: Angiopep-2-conjugated DAB dendrimer demonstrated high specificity and efficacy in facilitating gene delivery to the brain, offering a promising platform for therapeutic applications in neurological disorders.}, } @article {pmid41000798, year = {2025}, author = {Stanton, AE and Pinals, RL and Choi, A and Truong, N and Kang, E and Jiang, A and Lozano Cruz, CF and Hawkins, S and Sarcar, R and Volkova, A and King, O and Agbas, E and Nakano, M and Chiu, CC and Bubnys, A and Wright, S and Staab, C and Bikdash, R and Forden, E and Langer, R and Tsai, LH}, title = {Vascular-Perfusable Human 3D Brain-on-Chip.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.09.18.676925}, pmid = {41000798}, issn = {2692-8205}, abstract = {UNLABELLED: Development and delivery of treatments for neurological diseases are limited by the tight and selective human blood-brain barrier (BBB). Although animal models have been important research and preclinical tools, the rodent BBB exhibits species differences and fails to capture the complexity of human genetics. Microphysiological systems incorporating human-derived cells hold great potential for modeling disease and therapeutic development, with advantages in screening throughput, real-time monitoring, and tunable genetic backgrounds when combined with induced pluripotent stem cell (iPSC) technology. Existing 3D BBB-on-chip systems have incorporated iPSC-derived endothelial cells but not the other major brain cell types from iPSCs, each of which contributes to brain physiology and disease. Here we developed a 3D Brain-Chip system incorporating endothelial cells, pericytes, astrocytes, neurons, microglia, and oligodendroglia from iPSCs. To enable this multicellular 3D co-culture in-chip, we designed a GelChip microfluidic platform using a 3D printing-based approach and dextran-based engineered hydrogel. Leveraging this platform, we co-cultured and characterized iPSC-derived brain-on-chips and modeled the brain microvasculature of APOE4 , the strongest known genetic risk factor for sporadic Alzheimer's disease. These 3D brain-on-chips provide a versatile system to assess BBB vascular morphology and function, investigate downstream neurological effects in disease, and screen therapeutics to optimize delivery to the brain. SIGNIFICANCE STATEMENT: The blood-brain barrier (BBB) is both a contributing factor to neurological disease and a major obstacle to its treatment, yet human-relevant models remain limited. Most existing brain-on-chip systems incorporate only subsets of BBB cell types and cannot capture the full cellular complexity of the human neurovascular unit. Here, we establish a vascular-perfusable 3D Brain-Chip using human induced pluripotent stem cell-derived brain cells including endothelial cells, pericytes, astrocytes, neurons, microglia, and oligodendroglia. This system enables systematic analysis of human genetic risk factors, such as APOE4 in Alzheimer's disease, and provides a powerful platform to investigate BBB function and dysfunction and accelerate the development of more effective neurological therapies.}, } @article {pmid41000621, year = {2025}, author = {Shaaban, D and Seerley, A and Crew, L and Kaylor, C and McElroy, S and Guter, E and Pounder, J and Panter, AG}, title = {The Impact of Formic Acid Treatment on Brain Tissues for Prion Inactivation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41000621}, issn = {2692-8205}, support = {P20 GM152335/GM/NIGMS NIH HHS/United States ; }, abstract = {There are significant risks in clinical, diagnostic, and research settings to those who investigate prion diseases, due to the difficult nature of inactivating prion proteins with standard decontamination methods. Formic acid treatment has been shown to be effective for decontaminating infectious prions and commonly used in biosafety practice to prevent occupational exposure. However, the impact of formic acid protocols on the morphology of tissue samples has not been adequately documented. The goal of this study is to examine morphologic effects of formic acid treatment on central nervous system tissue, using mouse model brain hemisphere tissues that exhibit varying degrees of neurodegeneration as a model. This study included normal, non-diseased wild-type tissues and a 5xFAD model, which recapitulates aspects of Alzheimer's Disease (AD). A model exhibiting Chronic Wasting Disease (CWD), a prion disease of deer and elk, was also used to analyze the effects of formic acid on tissues with spongiform changes. Tissues from both formic acid and untreated control treatment groups were embedded in paraffin, sectioned, stained, and imaged microscopically. Anatomical regions were analyzed and evaluated quantitatively to determine the width, area, and structural integrity of the tissue between treatment groups. Our findings demonstrated that while formic acid has been previously reported to effectively inactivate prions, it compromised the morphology of mouse brain tissues. Furthermore, the effects of formic acid were not distributed equally between regions of the brain. Age did not play a role in the morphologic changes seen in the formic acid treatment group. Interestingly, the presence of neurodegeneration in the tissues did not appear to exacerbate the effects of morphological changes post-formic acid treatment. These results emphasize the need to explore alternative prion inactivation methods that ensure the safety and reliability of handling prion-infected tissues without compromising the integrity of tissues.}, } @article {pmid41000001, year = {2025}, author = {Abdel-Aal, RA and Hareedy, MS and Badary, DM and Abdelnabi, S and Hussein, AMR}, title = {Neuroprotective Effects of Liraglutide and/or Rivastigmine Combination on the Rat Hippocampus.}, journal = {Drug development research}, volume = {86}, number = {7}, pages = {e70160}, doi = {10.1002/ddr.70160}, pmid = {41000001}, issn = {1098-2299}, support = {//The authors gratefully thank the Assiut Medical School Grants Office for the financial support, grant code 2022-12-20-001./ ; }, mesh = {Animals ; *Rivastigmine/pharmacology/administration & dosage ; *Neuroprotective Agents/pharmacology/administration & dosage/therapeutic use ; Male ; *Liraglutide/pharmacology/administration & dosage/therapeutic use ; *Hippocampus/drug effects/metabolism/pathology ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Rats ; Drug Therapy, Combination ; Aluminum Chloride ; tau Proteins/metabolism ; Acetylcholinesterase/metabolism ; Aspartic Acid Endopeptidases/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Disease Models, Animal ; Sequestosome-1 Protein/metabolism ; Rats, Wistar ; Aluminum Compounds ; }, abstract = {This study evaluated the neuroprotective potential of a combination therapy using liraglutide (LIRA), an antidiabetic agent, and rivastigmine (RIVA), a standard treatment for Alzheimer's disease (AD), in a rat model of aluminum chloride (AlCl3)-induced AD. Male rats were divided into five groups: control, AD (AlCl3,75 mg/kg for 60 days), RIVA-treated (1 mg/kg daily for 6 weeks), LIRA-treated (300 µg/kg daily for 6 weeks), and combination-treated (LIRA + RIVA). Cognitive function was assessed behaviorally, and hippocampal biomarkers related to AD-such as microtubule-associated protein Tau (MAPt), Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1), Sequestosome 1 (SQSTM1/p62), and acetylcholinesterase (AChE) activity-were evaluated. Histopathological changes, immunohistochemistry, and transmission electron microscopy were also assessed. The levels of MAPt, BACE1, SQSTM1/p62, and AChE in the LIRA + RIVA group were 11.32 ± 0.467 ng/mL, 1069 ± 80.1 pg/mL, 408.7 ± 19.41 pg/mL, and 0.805 ± 0.342 µmol of acetylthiocholine iodide hydrolyzed/min/g of tissue, respectively. These levels were significant (p < 0.01) when compared with the AlCl3 group. Histological findings supported these biochemical data, indicating enhanced neuroprotection. LIRA may have a potential neuroprotective effect due to the rise in AChE, BACE1, (SQSTM1/p62) amyloid beta (Aβ), and caspase-3 levels induced by AlCl3. Co-administration of LIRA and RIVA provided superior neuroprotective effects compared with RIVA alone, suggesting a promising therapeutic strategy for preserving cognitive function in AD.}, } @article {pmid40999308, year = {2025}, author = {Van Doeselaer, L and Colman, K and Crosiers, D and Dijkstra, F}, title = {Effect of patient education interventions on non-motor symptoms and disease outcomes in parkinson's disease: a systematic review.}, journal = {Acta neurologica Belgica}, volume = {125}, number = {5}, pages = {1195-1208}, pmid = {40999308}, issn = {2240-2993}, mesh = {Humans ; *Parkinson Disease/psychology/therapy/complications ; *Patient Education as Topic/methods ; Quality of Life/psychology ; Treatment Outcome ; }, abstract = {Parkinson's disease is the second most common neurodegenerative disease, characterized by both motor symptoms (MS) and non-motor symptoms (NMS). While MS have traditionally been the primary focus of treatment and research, NMS significantly contribute to disease burden. However, knowledge regarding NMS in Parkinson's patients seems particularly lacking. Educational interventions have previously shown a positive effect on health outcomes in chronic illnesses such as Alzheimer's disease and diabetes, warranting investigation into their impact on NMS in Parkinson's disease. We conducted a systematic review to evaluate whether education interventions on non-motor symptoms (NMS) in Parkinson's disease (PD) patients contribute to better disease outcomes. Education interventions showed significant effects on various patient-reported and physician-reported outcomes, including quality of life, motor symptoms, depression, fatigue, adherence to treatment, acceptance of diagnosis, satisfaction with care, psychosocial adjustment, and independence in activities of daily living. Some effects were temporary, implying the need for booster sessions in future education interventions. There was limited focus on the direct impact of education interventions on NMS other than depression and anxiety. No studies directly compared different education interventions, preventing conclusions on which type of intervention leads to the best outcome. In conclusion, education interventions on NMS in PD have significant effects on disease outcomes. Future research should determine the optimal timing for booster sessions and further investigate their impact on NMS beyond depression and anxiety. Direct comparisons between different education interventions are needed to identify the most effective approach.}, } @article {pmid40998043, year = {2025}, author = {Cheng, W and Ma, Y and Gao, F and Shi, Z and Zuo, D and Di, C and Jin, X and Chen, W and Ye, F and Li, Q}, title = {Effects of cranial X-ray irradiation in Presymptomatic 3 × Tg-AD mice.}, journal = {Experimental neurology}, volume = {395}, number = {}, pages = {115482}, doi = {10.1016/j.expneurol.2025.115482}, pmid = {40998043}, issn = {1090-2430}, abstract = {BACKGROUND: Recently, several animal studies have demonstrated the therapeutic potential of low-dose radiation therapy (LDRT) for Alzheimer's disease (AD), especially in decreasing amyloid-beta (Aβ) plaques. However, clinical concerns regarding the duration of efficacy and long-term safety of this treatment remain understudied. Additionally, LDRT has been shown to alleviate various neurological disorders. We hypothesize that the therapeutic mechanisms of LDRT in AD may extend beyond targeting Aβ and tau alone. In this study, we administered whole-brain X-ray irradiation (10 Gy in 5 fractions) to presymptomatic AD mice to re-examine its mechanism of action, duration of efficacy, and long-term safety profile. RESULTS: Two months after irradiation, the autonomous activity of 3 × Tg-AD mice was significantly enhanced, with specific improvements in the spatial learning and memory in females. Western blotting revealed reduced tau phosphorylation at Ser262 site in the hippocampus of females. SnRNA-seq demonstrated restored neuronal network in females. However, these therapeutic effects appeared exhibited transient characteristics. By ten months post-irradiation, no significant behavioral and AD-related pathological changes were detected across groups, except for the elevated Aβ1-42 in the hippocampus of females. CONCLUSIONS: In conclusion, the effects of early X-ray intervention on 3 × Tg-AD mice were sex-specific and time-dependent. The short-term improvement observed in female mice may be attributed to attenuated tau hyperphosphorylation and restored neuronal networks. Longitudinal observation over ten consecutive months post-irradiation showed no evidence of severe adverse effects.}, } @article {pmid40997839, year = {2025}, author = {Fox, NC and Belder, C and Ballard, C and Kales, HC and Mummery, C and Caramelli, P and Ciccarelli, O and Frederiksen, KS and Gomez-Isla, T and Ismail, Z and Paquet, C and Petersen, RC and Perneczky, R and Robinson, L and Sayin, O and Frisoni, GB}, title = {Treatment for Alzheimer's disease.}, journal = {Lancet (London, England)}, volume = {406}, number = {10510}, pages = {1408-1423}, doi = {10.1016/S0140-6736(25)01329-7}, pmid = {40997839}, issn = {1474-547X}, mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy ; *Antibodies, Monoclonal/therapeutic use ; Quality of Life ; Amyloid beta-Peptides/antagonists & inhibitors/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {Over the last three decades, the evidence on how to best treat the cognitive and non-cognitive symptoms of patients with Alzheimer's disease has increased. Although these pharmacological and non-pharmacological strategies have significantly improved health outcomes for patients with Alzheimer's disease, many lack stringent evidence of efficacy. In this second paper of the Series, we provide practical and realistic advice on how to prioritise pharmacological and non-pharmacological strategies to ameliorate cognitive impairment and behavioural and psychological symptoms of dementia. In this clinical environment, dementia specialists are faced with the challenge of holistically integrating the much anticipated and, in some respects, controversial anti-β amyloid monoclonal antibodies. Here, we present the current approval scenario of monoclonal antibodies, our view on how they might further contribute to improve patients' quality of life, and how they could be seamlessly integrated with existing best care options.}, } @article {pmid40997226, year = {2025}, author = {Teipel, S and Akmatov, M and Michalowsky, B and Riedel-Heller, S and Junghanss, C and Holstiege, J and Bohlken, J}, title = {Inverse association of cancer with diagnoses of dementia in a large health claims case-control study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {98-106}, doi = {10.1177/13872877251374675}, pmid = {40997226}, issn = {1875-8908}, mesh = {Humans ; *Dementia/epidemiology/diagnosis ; Male ; Female ; Case-Control Studies ; Aged ; *Neoplasms/epidemiology/diagnosis ; Aged, 80 and over ; Prevalence ; Middle Aged ; Risk Factors ; }, abstract = {BackgroundPrevious studies reported an inverse association of cancer with dementia risk.ObjectiveTo study associations of cancer diagnoses with risk of a dementia diagnosis in a large case-control study.MethodsWe included patients with a dementia diagnosis and controls matched 1:2 for age, sex, region, and earliest year of outpatient treatment in a case-control study from health insurance claims of outpatient consultations. Exposure included seventeen cancer categories. We compared the annual prevalence trajectories of cancer categories between dementia cases and controls over a period of 10 years before the index date. We report unadjusted odds ratios (ORs) and ORs adjusted for established dementia risk factors.ResultsWe included 1,686,759 patients with incident dementia and 3,373,518 matched controls. We identified four types of associations: Cancers with equal or lower prevalence in controls at year -10 and higher prevalence in controls after year 6 to 4 before the index date; with higher prevalence in controls at all time points; with a lower prevalence in controls up to three years before the index date and higher prevalence after that; and with equal prevalence in cases and controls until year -9 and a steep increase in controls after that. When using adjusted ORs the overall pattern of an inverse association of cancer with dementia was maintained.ConclusionsOur data suggest that a mixture of causes contributes to the inverse association of cancer and dementia diagnoses, including selective survival, underdiagnosis of dementia after cancer and of cancer in dementia, but also shared biological factors.}, } @article {pmid40997028, year = {2025}, author = {Ahmad, S and Siddiqua, A and Abbas, E and Wasim, M and Zia, SR and Khan, A and Siddiqi, HS and Arain, FM and Tabassum, S and Khaliq, S and Samad, N}, title = {Gender-Specific Neuroprotective Effects of Carum copticum and Thymol: Restoring Cholinergic Function and Cognition in an Aluminum-Induced Rat Model of Alzheimer's Disease.}, journal = {Chemistry & biodiversity}, volume = {22}, number = {12}, pages = {e01374}, doi = {10.1002/cbdv.202501374}, pmid = {40997028}, issn = {1612-1880}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; Male ; *Neuroprotective Agents/pharmacology/chemistry/isolation & purification/therapeutic use ; *Thymol/pharmacology/chemistry/isolation & purification/therapeutic use ; Rats ; Disease Models, Animal ; Female ; Acetylcholinesterase/metabolism ; Aluminum Chloride ; *Cognition/drug effects ; Molecular Docking Simulation ; Acetylcholine/metabolism ; Rats, Wistar ; Aluminum ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing memory loss. While treatments like donepezil and memantine offer limited symptom relief, natural compounds like Carum copticum Benth (Ajwain) and its active ingredient thymol show promising neuroprotective effects. This study examines the effects of C. copticum Benth and thymol, alone/combination, or with standard drugs, in an AD-like rat model induced by aluminum chloride and d-galactose. A total of 72 rats were divided into two groups of 36 each based on sex (male and female) and were then randomly assigned to six subgroups (n = 6 per group); healthy control, AD model, donepezil, memantine, C. copticum Benth, and C. copticum Benth + thymol. Behavioral tests assessed anxiety and memory. Biochemical analyses of the prefrontal cortex and hippocampus evaluated acetylcholine (ACh), acetylcholinesterase (AChE), and M1 receptor expression. Thymol's interaction with targets was studied via molecular docking. AD rats showed cognitive impairment, increased anxiety, reduced ACh, and elevated AchE. Treatment with C. copticum Benth and thymol significantly improved behavior and cholinergic function, comparable to standard drugs, and modulated M1 receptor expression. C. copticum Benth and thymol demonstrate therapeutic potential in AD, warranting further investigation as adjunct or alternative treatments.}, } @article {pmid40995095, year = {2025}, author = {J, A and Khan, S and H, AB and Albarrak, AM and Ali, A}, title = {An MRI based histogram oriented gradient and deep learning approach for accurate classification of mild cognitive impairment and Alzheimer's disease.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1529761}, pmid = {40995095}, issn = {2296-858X}, abstract = {Alzheimer's disease (AD) is a common form of dementia that affects the central nervous system, causing progressive cognitive decline, particularly in memory. Early, non-invasive diagnosis is critical for improving patient care and treatment outcomes. This study proposes a robust feature extraction approach combined with three classifiers to achieve optimal classification of AD stages. T1-weighted brain MRI scans were used as input data. Features were extracted using Harris Corner interest points and the Histogram of Oriented Gradients (HOG) method. Classification was performed using Support Vector Machine (SVM), K-Nearest Neighbor (KNN), and a Deep Neural Network (DNN)-based pipeline. The proposed system classified three AD stages-Control Normal (CN), Mild Cognitive Impairment (MCI), and AD-with high accuracy: KNN (88%), SVM (91.5%), and DNN (95.6%). The DNN approach outperformed other classifiers and was further compared with state-of-the-art deep learning models, demonstrating competitive performance. These results highlight the potential of the proposed framework for early, accurate AD diagnosis using non-invasive imaging.}, } @article {pmid40994826, year = {2025}, author = {Gong, L and Li, H and Li, M and He, Y and Liu, D and Zhou, W and Zhang, B and Xi, C}, title = {APOE genotype modulates the impact of sleep duration on locus coeruleus functional connectivity in pre-clinical Alzheimer's disease.}, journal = {Brain communications}, volume = {7}, number = {5}, pages = {fcaf341}, pmid = {40994826}, issn = {2632-1297}, abstract = {Sleep duration and Apolipoprotein E genotype are critical factors influencing Alzheimer's disease progression. This study investigates the interaction between sleep duration and Apolipoprotein E genotype on the functional connectivity of the locus coeruleus in clinically unimpaired older adults with elevated amyloid beta, a population at risk for pre-clinical Alzheimer's disease. The study included 692 clinically unimpaired older adults with elevated amyloid beta participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Study (A4). Resting-state functional MRI data were analysed to construct locus coeruleus-based functional connectivity networks, and a 2 × 2 analysis of covariance was conducted to examine the main and interactive effects of sleep duration (normal versus short sleep) and Apolipoprotein E genotype (ɛ4- versus ɛ4+) on locus coeruleus-functional connectivity. Structural equation modelling was used to explore whether locus coeruleus-functional connectivity mediated the relationship between age and cognitive performance. Significant main effects of sleep duration and Apolipoprotein E genotype on locus coeruleus-functional connectivity were observed in the right temporal pole, middle cingulate cortex, and superior temporal gyrus. An interactive effect of sleep and Apolipoprotein E genotype was noted, influencing left locus coeruleus-functional connectivity in regions in the precentral gyrus, and right locus coeruleus-functional connectivity network in the middle temporal gyrus and lateral orbitofrontal cortex. Mediation analysis revealed that locus coeruleus-functional connectivity in the middle cingulate cortex and lateral orbitofrontal cortex partially mediated age associated cognitive decline. These findings suggest that locus coeruleus-functional connectivity networks, influenced by sleep duration and Apolipoprotein E genotype, play a crucial role in cognitive aging, particularly in memory function. Understanding these interactions may inform early intervention strategies to preserve cognitive health in older adults at risk for Alzheimer's disease.}, } @article {pmid40993924, year = {2025}, author = {Gavade, S and Dubey, S and Tiwari, P}, title = {Benzimidazole Derivatives in Alzheimer's Therapy: Exploring Multi-Target Pathways.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037387954250901202157}, pmid = {40993924}, issn = {1875-5550}, abstract = {Alzheimer's disease (AD) is a leading cause of dementia worldwide and continues to be one of the most frequently diagnosed neurodegenerative disorders in adults aged 65 and older. While much progress has been made in exploring AD pathophysiology, there remains no current cure, and symptomatic treatment is the current standard at best. As life expectancy continues to rise, the global prevalence of AD is increasing, making it evident that new therapeutic strategies are sorely needed. The etiology of AD is complex and heterogeneous, with cholinergic dysfunction, taurelated dysfunction, amyloid cascade dysfunction, oxidative dysfunction, and neuroinflammation all contributing to the unique pathology. As a result, researchers are focused on safe and effective drug candidates capable of addressing all of these interrelated mechanisms. One group of such multidrug candidates is benzimidazole derivatives, which target numerous molecular targets, such as, but not limited to, cyclin-dependent kinase 5 (CDK5), tau protein, acetylcholinesterase (AChE), betasecretase 1 (BACE1), serotonin receptor 5-HT4, cannabinoid receptor CB2R, and the gammaaminobutyric acid receptor A (GABA-A). This study reveals the multitargeting promise of benzimidazole- based compounds that regulate not just symptomatic pathways but also pathways that are responsible for modifying AD disease activity. Ongoing studies in this area may lead to the discovery of new drugs that can not only manage the symptoms but also change the trajectory of this serious disease and provide hope to millions of AD patients.}, } @article {pmid40993834, year = {2025}, author = {Zhang, J and Song, A and Xiang, Y and Liu, J and Li, B and Li, X}, title = {Association Between Different Types of Lipids and Alzheimer's Disease, Parkinson's Disease, and Epilepsy: A Mendelian Randomization and Bioinformatics Analysis.}, journal = {Annals of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1111/ahg.70025}, pmid = {40993834}, issn = {1469-1809}, support = {82204079//National Nature Science Foundation of China/ ; }, abstract = {BACKGROUND: With the increasing prevalence of neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy (EP) worldwide, there is a growing burden on medical and healthcare resources. Therefore, it is crucial to identify the etiology of these diseases and implement targeted preventive, diagnostic, and treatment measures to address the existing shortage of medical resources. Lipids are integral components of biological membranes. They not only function in energy storage and maintaining cell structure but also play a pivotal role in intercellular communication and signal transmission. Hence, lipids may hold significant implications in the pathogenesis and progression of the aforementioned disorders. METHODS: Utilizing two-sample Mendelian randomization (MR) in this investigation, the IEU OpenGWAS database was analyzed to explore the potential causal association between 159 lipids and the mentioned conditions, with sensitivity analysis being performed. Differentially expressed genes (DEGs) were obtained through data analysis of these three diseases in the GEO database, followed by enrichment analysis and protein-protein interaction (PPI) network analysis. RESULTS: The findings indicated a potential causal association between the onset and progression of these disorders and 20 lipids categorized into six groups, which include sterol esters (SEs), ceramides (Cer), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and triacylglycerol (TAG). Furthermore, these lipids were found to regulate biological processes and pathways associated with endocytosis, synaptic vesicular circulation, signal release, MAPK signaling pathway, PI3 kinase (PI3K)-AKT signaling pathway, dopaminergic synapses, and malaria infection. It is worth noting that based on the comprehensive scores of protein interactions in the STRING database, as well as their connectivity and association strength with other proteins in the network, heat shock factor binding protein 1 (HSPB1), which is closely related to lipids and has a relatively close relationship with diseases, was identified as a key protein for AD. Similarly, RAB3A was identified as a key protein for PD. CD160 serves as the key protein of EP. CONCLUSION: This study, by combining MR with bioinformatics analysis, discovered the potential lipid-based biological processes, pathways, and biomarkers of AD, PD, and EP, respectively, suggesting new therapeutic targets for us, deepening our understanding of the mechanisms of neurological diseases, and providing support for future clinical interventions.}, } @article {pmid40993787, year = {2025}, author = {Lin, Y and Weng, R and Pan, H and Hou, Y and Sun, Y and Wen, J}, title = {Synbiotics in Alzheimer's disease: mechanisms, clinical evidence, and therapeutic prospects.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {1009}, pmid = {40993787}, issn = {1479-5876}, support = {82405349//National Natural Science Foundation of China (Youth) Program/ ; }, mesh = {*Synbiotics ; Humans ; *Alzheimer Disease/microbiology/therapy ; *Cognition ; *Brain-Gut Axis ; *Gastrointestinal Microbiome ; Animals ; Clinical Studies as Topic ; }, abstract = {BACKGROUND: Growing evidence implicates gut microbiota (GM) dysbiosis in Alzheimer's disease (AD) pathogenesis via the gut-brain axis. Dysbiosis contributes to neuroinflammation, amyloid-β deposition, tau hyperphosphorylation, blood-brain barrier disruption, and cognitive decline. Synbiotics (combinations of probiotics and prebiotics) offer a promising strategy to modulate GM, potentially ameliorating these AD hallmarks through multiple mechanisms including enhanced production of neuroprotective short-chain fatty acids (SCFAs), reduced inflammation, improved gut barrier integrity, and immunomodulation. OBJECTIVE: This review critically evaluates the current evidence on the therapeutic potential of synbiotics for AD. It aims to synthesize findings from preclinical and clinical studies regarding the efficacy of synbiotics in improving cognitive function and AD pathology, elucidate the underlying biological mechanisms including GM modulation, SCFA production, immune regulation, and gut-brain signaling, and identify key challenges and future research directions for translating GM-targeted interventions into effective AD therapies. CONCLUSION: Synbiotics demonstrate significant potential, particularly in early AD, by improving cognitive domains, reducing neuroinflammation and AD biomarkers, and modulating beneficial microbial metabolites. However, challenges include confounding factors, unresolved questions about causality, inconsistent results in advanced disease, and insufficient large-scale human trials. Future success hinges on rigorous longitudinal randomized controlled trials integrating multi-omics approaches, advanced in vitro models, and personalized strategies considering baseline microbiota and host genetics. While not a standalone cure, synbiotics represent a valuable component within multi-target therapeutic approaches aimed at modulating the gut-brain axis to slow AD progression.}, } @article {pmid40993746, year = {2025}, author = {Zhao, D and Wang, J and Zhu, Y and Zhang, H and Ni, C and Zhao, Z and Dai, J and He, R and Liu, G and Gan, C and Zhang, S and Tong, Z}, title = {Targeting the glymphatic system: Aβ accumulation and phototherapy strategies across different stages of Alzheimer's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {49}, pmid = {40993746}, issn = {2047-9158}, support = {62394314//Major Program of the National Natural Science Foundation of China/ ; 82071214//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; *Glymphatic System/metabolism/radiation effects ; *Amyloid beta-Peptides/metabolism ; Animals ; *Phototherapy/methods ; Brain/metabolism ; }, abstract = {The glymphatic system serves as the brain's clearance system. It deteriorates with age and is a significant contributor to the onset and progression of Alzheimer's disease (AD). Modulating cerebrospinal fluid (CSF)-based clearance and targeting key components of the glymphatic system, such as aquaporin-4, can enhance amyloid-beta (Aβ) clearance. Light therapy is emerging as a potential AD treatment approach, which involves the use of visible and near-infrared light at specific wavelengths (630/680/808/850/1070 nm), photosensitive proteins, and sensory stimulation at particular frequencies (e.g., 40 Hz). This phototherapy strategy can broadly influence the intracerebral fluid dynamics, including cerebral blood flow, CSF, and interstitial fluid (ISF), as well as structures related to the glymphatic system, such as vascular endothelial cells, glial cells, and neurons. Additionally, it may directly or indirectly inhibit Aβ accumulation by modulating endogenous small molecules, thereby improving cognitive function. Our previous research demonstrated that 630-nm red light can inhibit Aβ cross-linking by clearing endogenous formaldehyde and promoting ISF drainage. Notably, Aβ accumulation exhibits distinct characteristics at different phases of AD, accompanied by varying features of glymphatic system impairment. In the early stages, deep brain regions are significantly affected, whereas in the late stages, accumulation primarily occurs in the paracentral, precentral, and postcentral cortices. Owing to the limited penetration depth of light, this may pose a challenge to the clinical efficacy of phototherapy. Therefore, different stages of AD may require tailored phototherapeutic strategies. Meanwhile, it is important to acknowledge the ongoing controversies associated with lymphovenous anastomosis, a procedure that targets the glymphatic system. Therefore, this article reviews the characteristics of glymphatic system impairment across various AD stages and the mechanisms by which effective phototherapies modulate the glymphatic system. Potential phototherapeutic strategies corresponding to different stages of Aβ accumulation are also proposed.}, } @article {pmid40992617, year = {2025}, author = {Dahlén, AD and Roshanbin, S and Bucher, NM and Sehlin, D and Syvänen, S}, title = {Evaluating the impact of age and treatment on neuroinflammation-related proteins in mouse models of proteinopathies.}, journal = {Experimental neurology}, volume = {395}, number = {}, pages = {115475}, doi = {10.1016/j.expneurol.2025.115475}, pmid = {40992617}, issn = {1090-2430}, abstract = {Neuroinflammation plays a key role in Alzheimer's disease (AD), but the actions of microglial mediators may vary across stages of amyloid-beta (Aβ) pathology. While drugs targeting brain immune responses are advancing to clinical trials, biomarkers to monitor their effects are lacking. This study investigated proteins expressed by activated microglia in three mouse models of Aβ pathology and α-synuclein, both during disease progression and after treatment, to evaluate their potential as in vivo biomarkers. Immunofluorescent staining was performed on cortical sections from App[NL-G-F], tg-ArcSwe, and wild-type (WT) mice. TREM2, Axl, galectin-3, Aβ, and cytokines were measured by immunoassays in brain homogenates from WT, App[NL-G-F], tg-ArcSwe, and tg-UppSwe mice across four age groups and from mice subjected to three treatment strategies targeting Aβ (beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor NB-360 and antibody RmAb158) or α-synuclein (antibody RmAb38E2). TREM2 and Axl colocalized with Iba1 and Aβ in App[NL-G-F] and tg-ArcSwe mice, with age-dependent increases observed in both models but not in tg-UppSwe. The lectin galectin-3 increased with age across all genotypes, including WT. Aβ correlated with elevated TREM2, Axl, and Galectin-3. Two months of BACE1-inhibition reduced TREM2, Axl, and galectin-3 in tg-ArcSwe mice and TREM2 and Axl in App[NL-G-F] mice. In summary, microglial TREM2, Axl, and galectin-3 are promising biomarkers for tracking AD-related neuroinflammation. Microglial interactions with Aβ likely influence the outcomes of Aβ-targeting therapies, and characterizing their dynamic states will inform the development of diagnostic tools and treatments relying on microglial activation to alleviate pathologies associated with neurodegenerative diseases.}, } @article {pmid40992534, year = {2025}, author = {Bello, ST and Rafe, MR and Huang, F}, title = {New frontier for epilepsy treatment through targeting cellular senescence.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {142}, number = {}, pages = {111506}, doi = {10.1016/j.pnpbp.2025.111506}, pmid = {40992534}, issn = {1878-4216}, mesh = {Humans ; *Epilepsy/drug therapy/metabolism/pathology ; *Cellular Senescence/physiology/drug effects ; Animals ; *Senescence-Associated Secretory Phenotype/physiology/drug effects ; *Anticonvulsants/therapeutic use/pharmacology ; *Senotherapeutics/pharmacology/therapeutic use ; }, abstract = {Epilepsy is a life-threatening brain disorder that affects about 1-2 % of the world's population. Various mechanisms facilitating epilepsy development and seizure propagation have been identified. Nevertheless, an improved understanding of the cellular mechanisms that underlie epilepsy development is necessary for designing better therapeutic strategies for epilepsy treatment. Cellular senescence, a cellular mechanism wherein cell growth is permanently halted and causes cells to exit the proliferative pool, has been associated with neurological disorders such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, and epilepsy. How the various mechanisms that drive a cell towards senescence and the phenotypes that characterize senescent cells are associated with the development and progression of epilepsy might be necessary in improving our understanding of epilepsy. Therefore, this review discusses the mechanisms and pathways associated with cellular senescence and how senescence-associated secretory phenotype (SASP) promotes inflammation and tissue dysfunction. We then explained how different types of cells, including brain cells, become senescent, the inter-relationship between cellular senescence and epilepsy, and potential biomarkers common to epilepsy and cellular senescence. Finally, we reviewed the use of senolytics and senomorphics for epilepsy treatment. Further research can, therefore, be directed towards a thorough understanding of cellular senescence in epilepsy development, and this can open new frontiers for epilepsy treatment.}, } @article {pmid40991989, year = {2025}, author = {Kim, Y and Cho, M and Jeon, CJ and Goh, G and Kim, M}, title = {Neuroinflammatory suppression with protocatechuic acid attenuates Alzheimer's disease phenotypes in 5 ×FAD transgenic mice.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {192}, number = {}, pages = {118598}, doi = {10.1016/j.biopha.2025.118598}, pmid = {40991989}, issn = {1950-6007}, mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/metabolism/pathology ; *Hydroxybenzoates/pharmacology/therapeutic use ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Presenilin-1/genetics/metabolism ; Hippocampus/drug effects/metabolism/pathology ; Humans ; Amyloid beta-Protein Precursor/genetics/metabolism ; Microglia/drug effects/metabolism/pathology ; Phenotype ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Anti-Inflammatory Agents/pharmacology ; Male ; Amyloid beta-Peptides/metabolism ; Gastrointestinal Microbiome/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a complex pathobiology that includes neuroinflammation, the accumulation of extracellular amyloid-beta (Aβ) plaque, and intracellular neurofibrillary tangles comprising tau. Increasing evidence suggests that the aberrant activation of glial cells, including microglia and astrocytes, is a significant early characteristic that accelerates neuroinflammatory processes in the development of AD. Protocatechuic acid (PCA), a natural phenolic compound, has been investigated for its anti-inflammatory properties in various pathological conditions. Here, we demonstrated that administration of PCA significantly ameliorated neuroinflammation as well as cognitive deficits in the 5 ×FAD mouse model of AD, which overexpresses human amyloid precursor protein (APP) and presenilin-1 (PSEN1) genes carrying five familial Alzheimer's disease (FAD) mutations, leading to accelerated Aβ deposition. We further confirmed that PCA treatment significantly reduced microglial activation and downregulated the production of pro-inflammatory cytokines, astrogliosis, and tau hyperphosphorylation, thereby preserved the integrity of hippocampal neurons. Our RNA sequencing analysis revealed that PCA treatment restored the transcriptomic profile of hippocampal tissues in 5 ×FAD mice, particularly by downregulating genes associated with innate immune and inflammatory responses. Moreover, PCA alleviated gut dysbiosis and enhanced the integrity of the intestinal barrier. The findings suggest that PCA may serve as a promising therapeutic agent for early intervention in AD to mitigate its progression.}, } @article {pmid40991081, year = {2025}, author = {Belyaev, GP and Petrov, KA and Semenov, VE and Zueva, IV}, title = {Changes in Dendritic Spine Density and Morphology during Therapy with Acetylcholinesterase Inhibitors in a Mouse Model of Alzheimer's Disease.}, journal = {Bulletin of experimental biology and medicine}, volume = {179}, number = {3}, pages = {378-382}, pmid = {40991081}, issn = {1573-8221}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/genetics ; *Dendritic Spines/drug effects/pathology ; Mice, Transgenic ; *Cholinesterase Inhibitors/pharmacology/therapeutic use ; Mice ; Donepezil ; Disease Models, Animal ; *Uracil/analogs & derivatives/pharmacology/therapeutic use ; Entorhinal Cortex/drug effects/pathology/metabolism ; Presenilin-1/genetics/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Piperidines/pharmacology ; Male ; Humans ; Acetylcholinesterase/metabolism ; }, abstract = {We performed a comparative study of the effect of a new acetylcholinesterase inhibitor 1,3-bis[5-(o-nitrobenzylethylamino)pentyl]-6-methyluracil (C-35) and a commercial drug donepezil on the density and morphology of dendritic spines in the entorhinal cortex of transgenic APP/PS1 mice with a model of Alzheimer's disease. Administration of donepezil to transgenic mice did not significantly change spine density or morphology. In contrast, treatment with C-35 increased dendritic spine density by 56 and 34% in comparison with donepezil and the control group (untreated transgenic mice), respectively. This effect of C-35 was associated with an increase in the number of thin spines and a decrease number of stubby spines.}, } @article {pmid40990612, year = {2025}, author = {Naserramezani, Z and Palizvan, MR and Ganji, A and Ghazavi, A and Mosayebi, G}, title = {Synergistic neuroprotection of chitosan-cannabidiol nanoparticles in a rat model of Alzheimer's disease: Amelioration of cognitive deficits and neuroinflammation.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {790-804}, doi = {10.1177/13872877251379420}, pmid = {40990612}, issn = {1875-8908}, mesh = {Animals ; *Cannabidiol/administration & dosage/pharmacology ; *Alzheimer Disease/drug therapy/chemically induced/pathology ; Rats, Wistar ; Male ; Rats ; *Nanoparticles/administration & dosage ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Neuroinflammatory Diseases/drug therapy ; *Cognitive Dysfunction/drug therapy ; *Chitosan/administration & dosage/pharmacology ; Oxidative Stress/drug effects ; Streptozocin/toxicity ; Hippocampus/drug effects/pathology ; Maze Learning/drug effects ; }, abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, and oxidative stress. Current treatments are largely symptomatic, necessitating novel neuroprotective strategies.ObjectiveThis study aimed to investigate the anti-inflammatory and antioxidant effects of chitosan-cannabidiol (CS-CBD) nanoparticles in a streptozotocin (STZ)-induced rat model of AD.MethodsSixty male Wistar rats were randomly divided into five groups: control, AD model (STZ-induced), chitosan-treated, cannabidiol-treated, and CS-CBD-treated. AD was induced by intracerebroventricular injection of STZ (3 mg/kg). Treatments were administered intranasally for 21 days. Cognitive performance was assessed using the Morris water maze. After treatment, oxidative stress markers (NO, FRAP), liver enzymes (ALT, AST), and the expression of inflammatory and neuroprotective genes (IL1β, IL6, IL10, iNOS, PPARγ, BDNF) were evaluated by real-time PCR. Histological analysis of the hippocampus was also performed. Data were analyzed using one-way ANOVA and Tukey's post hoc test (p < 0.05).ResultsThe AD group showed significant impairments in memory and learning (p < 0.0001), increased oxidative stress, and upregulation of pro-inflammatory genes (IL1β, iNOS), with decreased neuroprotective markers (BDNF, PPARγ). CS-CBD treatment significantly improved cognitive function (p < 0.001), restored oxidative balance, reduced IL1β and iNOS expression, and elevated BDNF and PPARγ expression (p < 0.05). Histological analysis confirmed reduced neuronal degeneration and increased neuronal density in the CS-CBD group.ConclusionsCS-CBD nanoparticles exerted potent neuroprotective, antioxidant, and anti-inflammatory effects in an STZ-induced rat model of AD. These findings support the potential of CS-CBD nanoparticles as a promising adjunctive therapy for AD, warranting further investigation.}, } @article {pmid40990282, year = {2025}, author = {Barnwal, N and Dubey, S and Tiwari, P}, title = {Targeting Metabolic Dysregulation in Alzheimer's Disease: A Potential Therapeutic Strategy.}, journal = {Current drug metabolism}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892002408089250912080734}, pmid = {40990282}, issn = {1875-5453}, abstract = {Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-beta plaques and tau tangles. Emerging evidence implicates metabolic dysfunction as a critical contributor to the pathogenesis and pro-gression of AD. Impaired glucose metabolism, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are frequently observed in AD brains, suggesting that metabolic dysfunction may exacerbate neurodegeneration and cognitive deficits. This review explores the therapeutic potential of targeting met-abolic pathways to mitigate AD pathology. Key metabolic disruptions, including insulin resistance, re-duced cerebral glucose utilization, and mitochondrial inefficiency, are closely linked to neuronal energy deficits and synaptic dysfunction. Therapeutic approaches, such as insulin sensitizers, ketogenic diets, and mitochondrial-targeted antioxidants, have shown promise in preclinical and early clinical studies. Addi-tionally, strategies to modulate lipid metabolism, such as enhancing cholesterol efflux via APOE or re-ducing neurotoxic ceramides, offer potential avenues for intervention. The review also highlights the roles of neuroinflammation and oxidative stress as mediators of metabolic dysfunction in AD, underscoring the need for multifaceted approaches that target both metabolic and inflammatory pathways. The emerging field of precision medicine offers opportunities to tailor interventions based on individual metabolic pro-files, potentially enhancing treatment efficacy. Despite the growing recognition of metabolic dysfunction in AD, translating these insights into effective therapies remains challenging due to the disease's com-plexity and heterogeneity. Future research must focus on elucidating the interplay between metabolic pathways and AD pathology, identifying reliable biomarkers, and designing targeted interventions. By addressing the metabolic underpinnings of AD, this review underscores the potential of metabolic repro-gramming as a novel and integrative therapeutic strategy to slow or prevent disease progression and im-prove patient outcomes.}, } @article {pmid40990274, year = {2025}, author = {Maiese, K}, title = {Cannabis and Cannabidiol: Pioneering Treatment for the Nervous System with Alzheimer's Disease and Peripheral Organ Involvement with Nonalcoholic Fatty Liver Disease (NAFLD).}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026446790250918074353}, pmid = {40990274}, issn = {1875-5739}, } @article {pmid40990233, year = {2025}, author = {Shami, R and El Majzoub, R and Ismail, A and Kotaich, J and Kassem, M and Safadieh, G and Fayyad-Kazan, M and Chahine, B}, title = {Effects of triptolide herb on the progression of Alzheimer's disease preclinical models: a systematic review.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/17582024.2025.2562776}, pmid = {40990233}, issn = {1758-2032}, abstract = {AIM: This study aims to systematically evaluate and synthesize preclinical evidence on the neuroprotective effects of Triptolide (Tri) in Alzheimer's disease (AD) models, focusing on its impact on amyloid-beta accumulation, synaptic dysfunction, neuroinflammation, oxidative stress, autophagy, and apoptosis. INTRODUCTION: AD is the most common cause of dementia, yet current treatments largely target symptoms rather than underlying pathology. Tri, a bioactive compound from Tripterygium wilfordii, has shown promise due to its anti-inflammatory, antioxidant, and neuroprotective properties. METHODS: A systematic search of PubMed, Embase, and Web of Science was conducted up to 16 March 2024. English-language in vivo and in vitro studies on Tri's effects in AD models were included. Methodological quality was assessed using SYRCLE and SciRAP tools. The review is registered in PROSPERO (CRD42024521822). RESULTS: Out of 403 studies, 15 met the inclusion criteria (6 in vivo, 8 in vitro, 1 both). Tri reduced Aβ burden, enhanced memory and synaptic integrity, suppressed neuroinflammation and oxidative stress, and modulated autophagy and apoptosis. CONCLUSION: Tri demonstrates significant multi-target neuroprotective effects in AD preclinical models. Further high-quality studies are warranted to optimize dosing, delivery, and safety for clinical translation.}, } @article {pmid40990131, year = {2025}, author = {Devanarayan, V and Donohue, MC and Sperling, RA and Johnson, KA and Ye, Y and Charil, A and Doherty, T and Tian, L and Raman, R and Aisen, PS and Kramer, LD and Irizarry, MC and Dhadda, S}, title = {Multimodal prognostic modeling of individual cognitive trajectories to enhance trial efficiency in preclinical Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70702}, pmid = {40990131}, issn = {1552-5279}, support = {/AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; //Eli Lilly and Company/ ; /ALZ/Alzheimer's Association/United States ; //Accelerating Medicines Partnership/ ; //GHR Foundation/ ; //Eisai Inc./ ; }, mesh = {Aged ; Female ; Humans ; Male ; *Alzheimer Disease/drug therapy/diagnostic imaging/diagnosis/genetics ; Antibodies, Monoclonal, Humanized/therapeutic use ; Brain/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging/diagnosis ; Longitudinal Studies ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Prognosis ; tau Proteins/blood ; }, abstract = {INTRODUCTION: Cognitive decline in asymptomatic preclinical Alzheimer's disease (AD) is slow and variable, limiting detection of treatment effects. This study developed models to forecast trajectories and improve trial efficiency. METHODS: Models were trained on longitudinal Preclinical Alzheimer's Cognitive Composite (PACC) data up to 240 weeks from the Phase III A4 study of solanezumab. Baseline inputs included demographics, apolipoprotein E (APOE) ε4, clinical scores, amyloid positron emission tomography (PET), plasma pTau217, magnetic resonance imaging (MRI), and tau PET (sub-study). Stochastic gradient boosting was used, with evaluation via cross-validation and trial simulations. RESULTS: The best model without tau PET used pTau217, clinical, and MRI data (R[2] = 0.32; area under the receiver operating characteristic curve (AUROC) for classifying a 0.5-point PACC decline = 78.6%). Replacing MRI with tau PET improved performance (R[2] = 0.42; AUROC = 83.1%). Predicted trajectories as a prognostic covariate reduced sample sizes by 35% and increased power from 80% to 94.7%. DISCUSSION: Prognostic models can predict decline in preclinical AD and improve trial efficiency. GOV IDENTIFIERS: NCT02008357 (Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss (A4)) HIGHLIGHTS: Models forecast 4.5-year cognitive decline in amyloid-positive preclinical Alzheimer's disease (AD). Plasma pTau217 and tau positron emission tomography (PET) standardized uptake value ratios (SUVRs) in early-accumulating regions are key predictors. Tau PET improves prediction beyond plasma, magnetic resonance imaging (MRI), and clinical measures. Forecasted decline as a prognostic covariate improves power and cuts sample size in trial simulations. Alternative models underperform yet retain practical utility when tau PET or pTau217 is unavailable.}, } @article {pmid40989580, year = {2025}, author = {Jiang, H and He, D and Hu, Y}, title = {Cognitive deterioration in patients undergoing hemodialysis: how variations in age influence the development of new mechanisms and treatment approaches?.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1645702}, pmid = {40989580}, issn = {1663-4365}, abstract = {The mechanisms of age-related differences and innovative intervention strategies for cognitive dysfunction in hemodialysis patients are crucial for enhancing patient outcomes. This research thoroughly examined the varying pathological aspects of cognitive decline across different age groups. Children and adolescents experience heightened permeability of the blood-brain barrier during critical developmental phases, along with the disruptive effects of uremic toxins on neurotransmitters and synaptic plasticity, which result in diminished white matter integrity and abnormal functioning of the default mode network. Additionally, genomic variations, such as harmful CNVs, coexist with the central nervous system's high plasticity and susceptibility. In contrast, elderly patients face cognitive impairment due to the combined effects of vascular diseases (like small vessel disease and impaired cerebral blood flow regulation) and Alzheimer's-like pathology, exacerbated by dialysis-related hypotension, oxidative stress, and inflammation, which further contribute to reduced cerebral blood flow and neurodegeneration. Consequently, a life cycle-based layered intervention strategy is suggested: children should focus on safeguarding their neural development through collaborative gene-environment interventions and neural stem cell transplants, while elderly patients require standardized treatment for vascular diseases and comorbidities, including Alzheimer's disease. Evidence indicates that incremental dialysis, low temperature dialysis, and high-dose hemodiafiltration can significantly reduce inflammation and oxidative stress markers, slow cognitive decline across all ages, and offer new insights for targeted nephrology management due to their universal effects. Future multi-center cohort studies are necessary to confirm the long-term advantages of age-specific interventions and to support the development of personalized precision treatment systems.}, } @article {pmid40988261, year = {2025}, author = {Gao, Y and Wang, X and Su, X and Liu, W and Zhang, Q}, title = {Acupuncture for hiccups: Case reports and literature review.}, journal = {Medicine}, volume = {104}, number = {38}, pages = {e44036}, pmid = {40988261}, issn = {1536-5964}, support = {ZKYB2410//the Hospital-level Project of Zhejiang Rehabilitation Medical Center/ ; (2022)NO:239//The National Program For Talents In Traditional Chinese Medicine/ ; }, mesh = {Aged ; Aged, 80 and over ; Humans ; Male ; *Acupuncture Therapy/methods ; *Hiccup/therapy ; }, abstract = {RATIONALE: Persistent hiccups following a stroke are a common complication that can adversely affect the patient's condition and rehabilitation. Certain refractory cases fail to respond adequately to pharmacological treatment. We report 2 cases of successful treatment of persistent hiccups with acupuncture and a medical electromagnetic device (trade name, TDP, an abbreviation of the Chinese phrase "Te-ding Dian-ci-bo Pu"). PATIENT CONCERNS: The first patient was a 94-year-old male who had experienced continuous hiccups for 7 days. His comorbidities included Alzheimer disease, cardiac arrhythmia following pacemaker implantation, chronic kidney disease, glaucoma, and recent COVID-19 infection complicated by pneumonia. The second patient was a 70-year-old male who had experienced hiccups for 10 days. He had a history of cerebellar and brainstem infarction, hypertension, and hypopharyngeal carcinoma. DIAGNOSES: Both patients were diagnosed with persistent hiccups. INTERVENTIONS: Both patients received combined treatment with acupuncture and TDP. OUTCOMES: Following treatment, hiccups were alleviated to different degrees, and no recurrence was observed at follow-up. LESSONS: Neuroexcitatory imbalance and thoracoabdominal pressure asymmetry are considered underlying causes of persistent hiccups. Acupuncture combined with TDP may modulate periumbilical arteriovenous networks and abdominal pressure, thereby relieving hiccups. This case series suggests a novel, easily implemented, well-tolerated therapeutic option for the management of persistent hiccups.}, } @article {pmid40987722, year = {2025}, author = {Sauerteig-Rolston, MR and Fowler, NR and Sachs, GA and Boustani, M and Slaven, J and Monahan, PO and Burke, ES and Higbie, A and Torke, AM}, title = {Pragmatic trial of a virtual dementia collaborative care management program: protocol for the Aging Brain Care Virtual (ABCV) program.}, journal = {BMJ open}, volume = {15}, number = {9}, pages = {e108800}, pmid = {40987722}, issn = {2044-6055}, support = {U54 AG063546/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Dementia/therapy ; Pragmatic Clinical Trials as Topic ; Aged ; Telemedicine ; Female ; }, abstract = {INTRODUCTION: Providing care management, treatment and support to patients with Alzheimer's Disease and Related Dementias (ADRD) is a difficult task for health systems. Over the past 20 years, interventions designed to improve outcomes for patients living in the community with dementia and their care partners have moved progressively, but separately, from large scale trials and pragmatic models of collaborative care. Given the projected increase in the number of people living with dementia coupled with the realignment of payment for services to be value-based and provided in the community, system-level approaches are needed to address the complex needs of patients with a dementia diagnosis and their care partners. We designed a statewide, pragmatic trial to evaluate virtual delivery of an evidence-based dementia collaborative care program on patient healthcare utilization and medication use. METHODS AND ANALYSIS: The Aging Brain Care Virtual (ABCV) program is a 12-month embedded, cluster randomized, usual care controlled trial designed to test the effectiveness of a virtual dementia collaborative care program in 24 Indiana University Health primary care clinics (12 intervention, 12 control) across the state of Indiana, enrolling 860 persons living with dementia (430 intervention, 430 control) and their care partners. ABCV relies on a tailored approach in which dyad needs are identified during virtual visits and addressed with standardized protocols previously tested in a randomized controlled trial delivered in person. The ABCV trial will measure emergency department utilization (primary outcome) and appropriate medication use (secondary outcome) at 12 months using electronic medical record data. Additionally, this study will use semi-structured interviews with care partners and clinicians to explore the implementation context, process and outcomes of the ABCV program. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Indiana University Institutional Review Board (20249). Research findings will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT06245499.}, } @article {pmid40987707, year = {2025}, author = {Yuan, J and Dong, X and Gao, Y and Nao, J}, title = {Pleiotropic regulatory mechanisms and targeted therapeutic prospects of Galectin-3 in aging-related diseases.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {22}, number = {6}, pages = {e00744}, pmid = {40987707}, issn = {1878-7479}, mesh = {Humans ; *Aging/metabolism/drug effects ; *Galectin 3/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Diabetes Mellitus, Type 2/metabolism/drug therapy ; Alzheimer Disease/metabolism/drug therapy ; }, abstract = {Aging is a major risk factor for numerous chronic diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), atherosclerosis (AS), type 2 diabetes mellitus (T2DM), osteoarthritis (OA) and age-related macular degeneration (AMD). Galectin-3 (Gal-3), a unique β-galactoside-binding lectin, has emerged as a critical mediator in the pathogenesis of AD and other age-related disorders by modulating key mechanisms such as inflammation, oxidative stress, and apoptosis. While emphasizing neurological disorders (AD, PD), this review also examines Gal-3's role in systemic age-related conditions (T2DM, AS, OA, AMD) that frequently co-occur with or influence neurodegeneration. This review summarizes current knowledge on the expression patterns, molecular mechanisms, and therapeutic potential of Gal-3 in aging-related diseases. Elevated Gal-3 levels have been detected in the brain tissue and cerebrospinal fluid of AD patients, where it contributes to multiple pathological processes, including microglia-driven neuroinflammation, Aβ plaque deposition, tau hyperphosphorylation, oxidative damage, and neuronal apoptosis. Furthermore, Gal-3 upregulation is observed across various age-related diseases and correlates with disease progression, underscoring its potential as a diagnostic biomarker and therapeutic target. Preclinical studies demonstrate that Gal-3-targeted interventions-including small-molecule inhibitors (e.g., TD-139), natural compounds (e.g., modified citrus pectin), and other pharmacological agents-exert neuroprotective, anti-inflammatory, antioxidant, and anti-apoptotic effects by binding to Gal-3 and modulating its activity in animal models, offering promising avenues for multi-disease treatment. However, the dual roles and complex regulatory networks of Gal-3 present challenges for clinical translation, requiring context-specific therapeutic approaches tailored to distinct disease mechanisms. Future research should focus on elucidating tissue-specific mechanisms and optimizing combination therapies to enable precise targeting of aging-related pathologies.}, } @article {pmid40987594, year = {2025}, author = {Mandal, S and Shaw, S and Pandit, SK and Garai, P and Jana, NR}, title = {Ampholytic Carbon Dots Enable Imaging and Modulation of Amyloid Fibrillation with Reduced Neurotoxicity.}, journal = {Nano letters}, volume = {25}, number = {40}, pages = {14573-14581}, doi = {10.1021/acs.nanolett.5c03426}, pmid = {40987594}, issn = {1530-6992}, mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; *Carbon/chemistry ; Humans ; Reactive Oxygen Species/metabolism ; *Alzheimer Disease/metabolism/diagnostic imaging ; *Quantum Dots/chemistry ; *Amyloid/chemistry ; Lysosomes/metabolism ; Animals ; Optical Imaging ; }, abstract = {Neurodegenerative diseases like Alzheimer's are driven by protein aggregation, notably amyloid-β (Aβ) fibrillation and associated cytotoxicity. Here, we report the design of ampholytic carbon dots (ACDs) with red/green emission that bind/control amyloid fibrillation. These ACDs bind with amyloid structures via electrostatic and van der Waals interactions and effectively inhibit fibril formation as well as promote disintegration of mature fibrils. The fluorescence property of ACDs enable high-resolution fluorescence imaging of amyloid structures at intra/extracellular space. ACD-amyloid conjugates showed lysosomal entrapment with lower amyloid-induced cytotoxicity via the lowering of reactive oxygen species generation. Together, these results highlight the dual functionality of ACDs as imaging and antiamyloidogenic agents, offering a promising nanoplatform for the diagnosis and treatment of amyloid-associated neurodegenerative disorders.}, } @article {pmid40987553, year = {2025}, author = {Huang, X and Fang, Y and Song, J and Hao, Y and Cai, Y and Wei, P and Zhang, N}, title = {Rescuing lysosomal/autophagic defects via nanoapproach: implications for lysosomal/autophagic defect-related diseases.}, journal = {Journal of Zhejiang University. Science. B}, volume = {26}, number = {9}, pages = {813-842}, pmid = {40987553}, issn = {1862-1783}, support = {tsqn202103112//the Taishan Scholars Program of Shandong Province/ ; ZR2021QB202//the Shandong Provincial Natural Science Foundation/ ; 2021KJ052//the Development Plan of Youth Innovation Team in Colleges and Universities of Shandong Province/ ; CSTB2023TIAD-LDX0015//the Shandong-Chongqing Science and Technology Cooperation Project for Technological Innovation and Application Development/ ; }, mesh = {Humans ; *Lysosomes/physiology ; *Autophagy/physiology ; *Nanomedicine/methods ; Neurodegenerative Diseases/therapy ; Animals ; Nanostructures ; *Lysosomal Storage Diseases/therapy ; }, abstract = {The dysfunction of the lysosome and autophagy-lysosome system serves as a driving force for neurodegenerative diseases, metabolic disorders, inflammatory conditions, and other related diseases, closely influencing their onset and progression. Therefore, restoring the function of the lysosome or autophagy-lysosome system has become an increasingly crucial therapeutic strategy in disease management. In this review, we will introduce the lysosomal biogenesis, structure, and function, as well as the biological process of the autophagy-lysosome system. Various diseases closely associated with lysosomal/autophagic dysfunction are also reviewed, emphasizing the significance of targeting the function of the lysosome or autophagy-lysosome system in disease treatment. Finally, we focus on engineered nanomaterials that have the capabilities to restore the function of the lysosome or autophagy-lysosome system, and summarize different strategies and methods for achieving this goal. This review aims to elucidate the latest progress in the field of nanomedicine for lysosomal/autophagic defect-related diseases and inspire the development of innovative and clinically valuable nanomedicines.}, } @article {pmid40987204, year = {2025}, author = {Shahlaei, M and Afkhami, H and Ahmadieh-Yazdi, A and Mirmazloumi, SH and Sahraei, SS and Akbari, M and Yang, P and Manoochehri, H and Tanzadehpanah, H and Mahaki, H and Sundararaman, A and Mohan, S and Sheykhhasan, M and Al-Musawi, S and Dama, P}, title = {Exosomes in Alzheimer's disease: From pathogenesis to therapeutics-A comprehensive review of diagnostic and drug delivery applications.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {192}, number = {}, pages = {118548}, doi = {10.1016/j.biopha.2025.118548}, pmid = {40987204}, issn = {1950-6007}, mesh = {*Alzheimer Disease/drug therapy/diagnosis/metabolism/pathology ; *Exosomes/metabolism ; Humans ; *Drug Delivery Systems/methods ; Animals ; Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/metabolism ; Neuroprotective Agents/administration & dosage ; }, abstract = {Alzheimer's disease (AD) is still a major unmet medical challenge, with limited treatment options and a critical need for early diagnostics. Exosomes, nanoscale extracellular vesicles with a lipid bilayer, are pivotal players in intercellular communication and promising tools for AD management. Their unique ability to cross the bloodbrain barrier, low immunogenicity, and ability for cargo delivery make them ideal candidates for targeted drug delivery. This review comprehensively examines the biology of exosomes-including their structure, biogenesis, release, and uptake-and evaluates advanced methods for their isolation, purification, and characterization. We highlight their dual role in AD pathogenesis, where they can propagate pathological proteins such as amyloid-β and tau, and in therapeutic applications, where engineered exosomes deliver neuroprotective agents. Furthermore, exosomal biomarkers in biofluids show significant potential for noninvasive early diagnosis. Recent advances in loading strategies and surface engineering have been discussed, alongside challenges in scalability and safety. This synthesis bridges current knowledge with future directions, emphasizing the translational potential of exosomes in AD therapeutics and diagnostics.}, } @article {pmid40987016, year = {2025}, author = {Schuh, KM and Conrad, LM and Tronson, NC}, title = {Hormonal contraceptives modulate resilience to psychiatric and neurodegenerative disease.}, journal = {Hormones and behavior}, volume = {176}, number = {}, pages = {105823}, doi = {10.1016/j.yhbeh.2025.105823}, pmid = {40987016}, issn = {1095-6867}, mesh = {Humans ; Female ; *Resilience, Psychological/drug effects ; *Neurodegenerative Diseases/prevention & control/psychology ; Animals ; Depression ; Alzheimer Disease/prevention & control ; Stress, Psychological ; *Mental Disorders/prevention & control ; *Contraceptives, Oral, Hormonal/pharmacology ; }, abstract = {Hormonal contraceptives (HCs) are one of the most widely used classes of drug worldwide and are a critical part of women's health. Beyond their primary use for birth control, HCs exert many health benefits, including treatment of menstrual-related symptoms and reduced risk of certain types of cancers. Here, we focus on the role of HCs in promoting resilience to depression and Alzheimer's disease. Although risks for depression with HC use have been widely stated, HCs only increase risk for up to 10 % of users, and conversely improve mood and protect against depression for many others. Emerging evidence also suggests that HC use protects against age-related cognitive decline and Alzheimer's disease, even decades after HC use. We propose that these effects are due to modulatory effects of HCs on stress-related signaling and neuroimmune function. In this paper, we discuss how HCs interact with stress responsivity, neuroimmune signaling, and other individual differences to promote resilience or susceptibility to psychiatric and neurological disorders.}, } @article {pmid40986221, year = {2025}, author = {Yılmaz, ŞG and Almallohy, AM and Deveci, HA and Korkmaz, M and Balcı, SO}, title = {Thymoquinone regulates RSL3-induced ferroptosis in the alzheimer mouse hippocampus.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {942}, pmid = {40986221}, issn = {1573-4978}, support = {SBF.YLT.22.01//Gaziantep University/ ; }, mesh = {Animals ; *Ferroptosis/drug effects ; *Hippocampus/drug effects/metabolism/pathology ; Mice ; *Alzheimer Disease/metabolism/drug therapy ; Female ; *Benzoquinones/pharmacology ; Mice, Inbred C57BL ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Lipid Peroxidation/drug effects ; Maze Learning/drug effects ; Iron/metabolism ; Glutathione/metabolism ; }, abstract = {INTRODUCTION: Ferroptosis, a type of iron-dependent regulated cell death driven by lipid peroxidation, has emerged as a critical contributing factor to hippocampal neurodegeneration in Alzheimer's disease (AD). Dysregulated iron homeostasis exacerbates oxidative injury, impairing cognitive function. This study provides experimental evidence that thymoquinone (TQ) exerts neuroprotective effects in an AD-related ferroptosis model by modulating iron, lipid, and glutathione metabolism. METHODS: Thirty female C57BL/6 mice (8-10 weeks, 18-22 g) were randomly allocated into five groups: 1- Control, 2- artificial cerebrospinal fluid (aCSF; 20 ng/L), 3- RAS-selective lethal 3 (RSL3) (100 ng/10 µL in aCSF), 4- RSL3 + TQ (50 mg/kg in 1.0% w/v acacia gum), and 5- TQ alone (50 mg/kg in 1.0% w/v acacia gum). A bilateral hole was drilled according to the Bregma coordinates (0.5 mm back, 1 mm left-right, 2,5 mm deep) and a 10 µl Hamilton syringe was inserted perpendicularly from the skull to the brain. RSL3 (100 ng/10 µl) was infused with 4 µl (Intracerebral-IC). Cognitive and anxiety-like behaviors were assessed using the Morris Water Maze (MWM) and the Open Field Test (OFT). Hippocampal oxidative markers, total antioxidant status (TAS), and total oxidant status (TOS), were determined by spectrophotometric quantification. GPx4, XCT, and Fpn mRNA levels were measured by qRT-PCR. Protein expression and distribution were assessed by Western blotting and immunohistochemistry. Iron accumulation was visualized using Perl's Prussian blue staining method. RESULTS: RSL3-induced ferroptosis impaired spatial learning and increased anxiety-like behavior, accompanied by elevated hippocampal iron accumulation, oxidative stress, and downregulation of GPx4, XCT, and Fpn. TQ treatment significantly restored TAS levels, reduced TOS, suppressed iron deposition, and reversed ferroptosis-associated molecular changes, upregulating GPx4 and Fpn while attenuating XCT downregulation (P < 0.05). Ferroptosis-induced behavioral deficits were significantly improved by TQ. CONCLUSION: These findings identify TQ as a potent modulator of ferroptosis, acting through coordinated regulation of iron export, lipid peroxidation, and glutathione-dependent antioxidant defenses. TQ targeting convergent ferroptosis pathways is a promising therapeutic candidate to alleviate hippocampal neurodegeneration and cognitive decline in AD.}, } @article {pmid40986212, year = {2025}, author = {Syed, A and Elgorban, AM and Bahkali, AH and Wang, S and Wong, LS and Dhara, B and Uti, DE and Alum, EU and Atangwho, IJ}, title = {Therapeutic Potential of products derived from Pluchea lanceolata for Alzheimer's Disease Treatment.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {4}, pages = {122}, pmid = {40986212}, issn = {1559-1166}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Kelch-Like ECH-Associated Protein 1/metabolism/chemistry ; Molecular Docking Simulation ; NF-E2-Related Factor 2/metabolism/chemistry ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Molecular Dynamics Simulation ; *Triterpenes/chemistry/pharmacology/therapeutic use ; }, abstract = {AD is a neurodegenerative disorder and is associated with the presence of amyloid-β plaques and neurofibrillary tangles leading to net loss of neurons, which demonstrates an urgent unmet need to develop new human health therapies based on the fundamental mechanisms of oxidative stress and neuroinflammation. This work is a computational assessment of the potential use of neolupenol, a triterpenoid produced in Pluchea lanceolata, as a pharmacologically active compound that exerted its beneficial effect through the modulation of the Keap1-Nrf2 axis, one of the central regulators of the antioxidant response. Using an integrated approach that combined network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we identified neolupenol as a high-affinity Keap1-binding molecule capable of activating the Nrf2-mediated neuroprotective pathway. Virtual screening of 25 phytochemicals from Pluchea lanceolata (retrieved from the PubChem database) with customized filters revealed neolupenol as the top candidate, showing strong binding affinity (- 8.22 kcal/mol; Ki = 1.45 µM) toward the Keap1 Kelch domain (PDB ID: 2FLU). The docked complex demonstrated hydrogen bonds with VAL463 (2.17 Å), THR560, and ILE559, along with hydrophobic interactions involving CYS513, ALA366, and VAL514, which collectively stabilized the ligand at the Neh2-binding interface. Network pharmacology yielded 30 of such common targets of AD-neolupenol (e.g., GSK3B, CASP3, TNF, and BACE1), enriched in pathways such as amyloid processing, tau phosphorylation, oxidative stress response, and lipid metabolism (FDR-adjusted p < 0.0001). Complex stability was verified by MD simulations (100 ns): RMSD of the backbone 2.34-3.84 = 2.34 Å, unchanged radius of gyration (17.8-18.0 Å), and stable inter-hydrogen bonding. Residues VAL561, PHE577, and SER602 were found to have an interaction occupancy of > 70%, providing a basis of dynamic stability. The triterpenoid cavity appeared in neolupenol contributing to pleasant PK, the ability to herald the blood-brain barrier, and suboptimal toxicity. These results position neolupenol as a potent, multi-target neuroprotective agent that disrupts Keap1-Nrf2 interaction, promoting Nrf2 nuclear translocation and antioxidant gene activation. Future work warrants in vivo validation of its efficacy in mitigating AD pathology and clinical translation.}, } @article {pmid40986147, year = {2025}, author = {Sun, J and Zheng, Z}, title = {The active ingredient of Ginkgo biloba extract (quercetin) improved H2O2-induced microglia injury by activating NQO1-PI3K/Akt/mTOR signaling.}, journal = {In vitro cellular & developmental biology. Animal}, volume = {61}, number = {9}, pages = {1171-1184}, pmid = {40986147}, issn = {1543-706X}, mesh = {*Quercetin/pharmacology/chemistry ; TOR Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; *Plant Extracts/pharmacology/chemistry ; *Microglia/drug effects/pathology/metabolism ; *Signal Transduction/drug effects ; Animals ; *NAD(P)H Dehydrogenase (Quinone)/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Ginkgo biloba/chemistry ; Hydrogen Peroxide/toxicity ; Mice ; Cell Line ; Cellular Senescence/drug effects ; Oxidative Stress/drug effects ; Molecular Docking Simulation ; Humans ; Ginkgo Extract ; }, abstract = {Activated microglia are considered to be closely related to brain senescence and the pathogenesis of neurodegenerative diseases. Ginkgo biloba extract (GBE) is widely used to treat cognitive impairment and Alzheimer's disease (AD). This study aims to investigate the active ingredients of GBE and the underlying molecular mechanisms. The active ingredients of GBE in AD treatment were first analyzed by network pharmacology, culminating in the identification of the key ingredient, quercetin, and its targeted protein, NQO1. GO function enriched the oxidative stress pathway, while KEGG enriched the PI3K/Akt/mTOR pathway. Quercetin binding to NQO1 was verified by molecular docking and DARTS analysis. Cytotoxicity assay revealed no significant toxicity of GBE (0-1 mg/mL) and quercetin (0-0.4 μM) over 48 h. Subsequently, we constructed the microglial injury model by H2O2-induced HMC3 and BV2 cell lines. GBE and quercetin suppressed the senescence characteristics in H2O2-induced microglia. Further investigation revealed that the expression of NQO1 was downregulated in the injury model, and treatment with GBE and quercetin facilitated the protein expression of NQO1. In addition, silencing NQO1 reduced the promoting effect of quercetin on microglia viability and phosphorylation levels of PI3K, Akt, and mTOR. At the same time, it significantly increased the levels of p53, p21, p16 and β-galactosidase (SA-β-gal). Collectively, GBE mitigated H2O2-induced microglial injury, which activated the PI3K/Akt/mTOR pathway through the quercetin/NQO1 axis. These findings highlight quercetin/NQO1 signaling as a possible therapeutic target for senescence-related neurodegeneration.}, } @article {pmid40985039, year = {2025}, author = {Cahan, JG and Bonakdarpour, B}, title = {Primary Progressive Aphasia Treatment: Current Treatment Options in Neurology Article Topic: Management of Primary Progressive Aphasia.}, journal = {Current treatment options in neurology}, volume = {27}, number = {1}, pages = {39}, pmid = {40985039}, issn = {1092-8480}, abstract = {Primary progressive aphasia(PPA) is a rare neurodegenerative condition and variant presentation of Alzheimer's disease or Frontotemporal Dementia. It is characterized by progressive decline isolated to language functions. PPA provides a model for understanding the anatomy of language, where each cortical language center corresponds to distinct PPA subtypes. Understanding this anatomy and its corresponding PPA subtypes helps clinicians choose testing, interpret imaging, and tailor treatment. These subtypes are termed agrammatic/nonfluent, semantic, and logopenic PPA. Each subtype is probabilistically associated with three proteinopathies: the amyloid and tau of Alzheimer's disease and frontotemporal lobar degeneration due to Tau or TDP-43. We will discuss when biomarker testing is indicated and the nuances of choosing among the increasing array of biomarker tests to improve diagnostic certainty. While medical treatment is limited, there are increasing pharmacologic options for treating Alzheimer's disease. Non-pharmacologic strategies can also be tailored to the patient's specific subtype and caregivers' needs.}, } @article {pmid40984910, year = {2025}, author = {Bains, J and Ogunjobi, O}, title = {A Case Report Exploring Early-Onset Alzheimer's Disease With No Known Family History.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e90576}, pmid = {40984910}, issn = {2168-8184}, abstract = {This case report conveys a rare presentation of early-onset Alzheimer's disease (EOAD) in a 58-year-old female with no family history of dementia. The patient demonstrates progressive cognitive decline with features of memory loss and associated severe language impairment, subsequently leading to a delay in the definite diagnosis. A systematic literature review using PubMed and Google Scholar was undertaken to explore the features of EOAD and how it differs from late-onset Alzheimer's disease (AD), focusing on risk factors, clinical presentation, investigation, and management. Although this patient was not known to have a family history of AD, evidence suggestive of EOAD could be observed within a series of neuroimaging and diagnostic tests such as magnetic resonance imaging scans, cerebrospinal fluid analysis, and blood tests. Management of EOAD involves a combination of pharmacological and non-pharmacological interventions using a biopsychosocial approach. Overall, the case highlights challenges in recognition of EOAD in its early stages of presentation for patients with no family predisposition, whilst emphasizing the importance of early detection and management to help improve patient outcomes. It also focuses attention on the significant impact a condition such as EOAD can have on the family members involved. Further research would be required to potentially redefine diagnostic criteria and treatment strategies for conditions of such rarity.}, } @article {pmid40984655, year = {2025}, author = {Bloemer, J and Pinky, PD and Suppiramaniam, V and Reed, MN}, title = {Adiponectin Receptor Agonist Ameliorates Synaptic Dysfunction in 3xTg Alzheimer's Disease Mouse Model by Activation of AMPK.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {9}, pages = {e70616}, pmid = {40984655}, issn = {1755-5949}, support = {//American Foundation of Pharmaceutical Education/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/pathology/physiopathology ; *Receptors, Adiponectin/agonists/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *AMP-Activated Protein Kinases/metabolism ; Hippocampus/drug effects/physiopathology ; Mice ; Long-Term Potentiation/drug effects ; *Synapses/drug effects ; Male ; Amyloid beta-Protein Precursor/genetics ; Synaptic Transmission/drug effects ; tau Proteins/genetics ; Mice, Inbred C57BL ; Presenilin-1/genetics ; Piperidines ; }, abstract = {AIM: The hormone adiponectin impacts various facets of brain function, including neurogenesis, energy homeostasis, and synaptic processes. The use of adiponectin or adiponectin receptor agonists may protect against Alzheimer's disease (AD) and reduce AD pathology. Here, we investigated the ability of the adiponectin receptor agonist, AdipoRon, to restore synaptic function in an AD mouse model and the underlying mechanism. METHODS: Acute hippocampal slices from 3xTg-AD mice and age-matched controls were used to evaluate the ability of AdipoRon to rescue synaptic deficits in an AD model. Slices were incubated in AdipoRon or other pharmacological agents, followed by electrophysiological field recordings to evaluate synaptic function and plasticity. Signaling pathway alterations were evaluated by Western blot, with a focus on AMP-activated protein kinase (AMPK) signaling. RESULTS: Incubation of hippocampal slices with AdipoRon ameliorated long-term potentiation (LTP) and basal synaptic transmission deficits in 3xTg-AD mice. AdipoRon was unable to restore these parameters in the presence of the AMPK inhibitor, Compound C. AdipoRon altered presynaptic parameters by a mechanism that did not appear to be solely dependent on AMPK. AdipoRon slice incubation was associated with activation of AMPK, inhibition of GSK3β, and altered glutamatergic receptor subunit phosphorylation based on Western blot analysis. CONCLUSION: Activation of adiponectin receptors restores synaptic function in an AD model in part through AMPK signaling. These results warrant further investigation into adiponectin receptor agonists as a novel approach for AD prevention or treatment.}, } @article {pmid40983196, year = {2025}, author = {Yan, F and Niu, J and Zhang, Y and Sun, Y and Wang, J and Liang, G and Cui, J and Ge, Y and Yang, F and Feng, L}, title = {Rational design of MAO-B-activated fluorescent probe for activity evaluation and its biomedical applications.}, journal = {Free radical biology & medicine}, volume = {241}, number = {}, pages = {236-242}, doi = {10.1016/j.freeradbiomed.2025.09.034}, pmid = {40983196}, issn = {1873-4596}, mesh = {*Monoamine Oxidase/metabolism/chemistry ; *Fluorescent Dyes/chemistry/chemical synthesis ; *Monoamine Oxidase Inhibitors/pharmacology/chemistry ; Humans ; Hydrogen Peroxide ; Animals ; Oxidative Stress/drug effects ; *Oxazines/chemistry/chemical synthesis/pharmacology ; }, abstract = {Monoamine oxidase mainly includes two isoforms, monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), of which MAO-B is a crucial metabolic enzyme, acts on dopamine and β-phenylethylamine and can be selectively inhibited by pargyline. MAO-B has emerged as a significant drug target for a variety of nervous system diseases. In the present work, a highly selective and sensitive fluorescent probe named 3-aminopropyl (3-oxo-3H-phenoxazin-7-yl) carbamate (AHPC) was designed and developed. AHPC showed good stability and cell membrane permeability in biological systems, and could detect endogenous MAO-B activity in real time, and accurately evaluate the changes of MAO-B under H2O2-induced oxidative stress. In addition, AHPC was able to detect the distribution of MAO-B in different organs. As MAO-B is an important drug target, we developed a high-throughput, visual screening system for MAO-B inhibitors based on AHPC. Glycyrrhizae radix et rhizome was screened from 272 kinds of Chinese medicine and displayed strong inhibitory effect toward MAO-B. After further separation of Glycyrrhizae radix et rhizome, it was found that Licoisoflavone B was the main active ingredient to inhibit MAO-B activity in different enzyme sources, and was expected to be a lead compound for the treatment of MAO-B-related diseases. In conclusion, with the advantages of fluorescent probe technology, we not only developed a handy molecular tool for real-time detection of MAO-B distribution and function in complex biosystems, but also established a high-throughput visualization method for screening MAO-B inhibitors from traditional Chinese medicine, which are promising for the treatment of many MAO-B-related diseases.}, } @article {pmid40982764, year = {2026}, author = {Cao, Q and Liu, Z and Kang, H and Wang, L}, title = {Mechanisms and parameters of photobiomodulation for neurological and neuropsychiatric disorders: whether and how to apply?.}, journal = {Reviews in the neurosciences}, volume = {37}, number = {1}, pages = {77-91}, pmid = {40982764}, issn = {2191-0200}, mesh = {Humans ; *Low-Level Light Therapy/methods ; *Mental Disorders/therapy ; *Nervous System Diseases/therapy/radiotherapy ; Animals ; *Brain/radiation effects ; Brain Injuries, Traumatic ; }, abstract = {Neurological and neuropsychiatric disorders are among the leading causes of mortality and disability worldwide, with current treatment modalities including traditional therapies, psychological and supportive interventions, and emerging therapeutic approaches. Photobiomodulation (PBM), a neuromodulatory technique using lasers and light-emitting diodes (LEDs), has emerged as a promising intervention for enhancing brain function by stimulating neural activity, thereby protecting brain tissue and restoring function. Despite its widespread application, the precise mechanisms underlying the selection of critical parameters and their associated therapeutic effects remain incompletely understood. This systematic review synthesizes data from multiples studies over the past decade, investigating the effects of PBM on neurological and neuropsychiatric disorders, including traumatic brain injury (TBI), spinal cord injury (SCI), Alzheimer's disease (AD), Parkinson's disease (PD), generalized anxiety disorder (GAD), major depressive disorder (MDD), and healthy subjects. Emerging evidence suggests that the therapeutic mechanisms of PBM may involve enhanced energy metabolism, increased cerebral blood flow (CBF), modulation of oxidative stress, anti-inflammatory effects, neuroprotection and regeneration, enhanced synaptic plasticity, and regulation of resting-state brain networks. Regarding parameter selection, wavelength has emerged as a critical factor influencing penetration depth and the specific chromophore responsible for photon absorption and therapeutic efficacy. This review focuses on the characteristics of diverse wavelengths, as well as the roles of multiple chromophores and associated signaling pathways. Different irradiation modalities, including both non-invasive and invasive approaches, are examined, alongside optimal treatment windows for power and fluence. Additionally, less frequently addressed aspects, such as spot area and power density patterns, are considered.}, } @article {pmid40982213, year = {2025}, author = {Onuh, VC}, title = {Advancing Alzheimer's disease treatment: A literature review on senolytic intervention.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {42-52}, doi = {10.1177/13872877251376540}, pmid = {40982213}, issn = {1875-8908}, mesh = {*Alzheimer Disease/drug therapy/pathology ; Humans ; *Senotherapeutics/therapeutic use/pharmacology ; Animals ; *Cellular Senescence/drug effects/physiology ; Aging/drug effects ; Quercetin/therapeutic use/pharmacology ; Dasatinib/therapeutic use/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a leading cause of dementia, currently affecting over 50 million people globally. Despite decades of research, therapeutic development has continued to face high failure rates due to an incomplete understanding of the underlying disease mechanisms. Current drugs like rivastigmine focus on managing cognitive symptoms since there is no known cure to halt the disease's progression. However, recent research has suggested that advanced biological age, particularly the accumulation of senescent cells, is the most significant risk factor for AD pathology, and targeting these aging mechanisms may prove more effective in altering the disease progression. Senescent cells accumulate with age, contributing to inflammatory states and neurodegenerative diseases such as AD. Senolytic drugs, such as dasatinib and quercetin (D + Q), have shown promise in animal models by clearing senescent cells, delaying aging-related decline, and improving AD-related outcomes. This literature review aims to provide a comprehensive overview of the therapeutic potential of senolytic interventions for AD by examining the mechanisms of cellular senescence based on evidence of its accumulation in the human brain, critically analyzing the preclinical and clinical trials involving senolytic compounds, and discussing the implications and limitations of this approach. The findings from recent studies indicate that senolytics may pave the way for effective AD treatments, though further clinical validation is needed.}, } @article {pmid40981102, year = {2025}, author = {Juranek, JK and Kordas, B and Podlasz, P and Bossowska, A and Banach, M}, title = {Current Evidence on the Involvement of RAGE-Diaph1 Signaling in the Pathology and Treatment of Neurodegenerative Diseases-An Overview.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {32}, number = {3}, pages = {}, pmid = {40981102}, issn = {1873-149X}, abstract = {Neurodegenerative diseases are a group of disorders characterized by the progressive deterioration of the structure and function of central nervous system neurons and include, among others, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's (PD), Alzheimer's (AD), and Huntington's (HD) diseases. And while all these diseases seem to have different genetic and environmental components, growing evidence shows that they share common underlying pathological features such as increased neuroinflammation and excessive oxidative stress. RAGE, the receptor for advanced glycation end-products, is a signal transduction receptor, and its activation triggers an increase in proinflammatory molecules, oxidative stressors, and cytokines. Diaph1, protein diaphanous homolog 1, is an actin modulator and an intracellular ligand of RAGE. Studies demonstrated that RAGE and Diaph1 act together, and their downstream signaling pathways play a role in neurodegeneration. Here, based on current evidence and our own research, we provide an overview of the RAGE-Diaph1 signaling and discuss the therapeutic potential of targeted therapy aimed at RAGE-Diaph1 signaling inhibition in the prevention and treatment of neurodegenerative diseases.}, } @article {pmid40980544, year = {2025}, author = {Goodson, MM and Gwizdala, KL and Manrique, IR and Rao, A and Beyl, R and Martin, CK and Firmin, S and Salceanu, V and Newton, RL and Carmichael, OT}, title = {Acute Effect of Intranasal Insulin on Food Intake Among Middle-Aged African American Adults: The FIINAAL Study.}, journal = {Journal of the Endocrine Society}, volume = {9}, number = {10}, pages = {bvaf138}, pmid = {40980544}, issn = {2472-1972}, support = {P30 DK072476/DK/NIDDK NIH HHS/United States ; U54 GM104940/GM/NIGMS NIH HHS/United States ; }, abstract = {CONTEXT: Intranasal insulin has emerged as a promising potential treatment for cognitive decline. However, African American adults are under-represented in this research area, and unintentional weight loss is a possible detrimental side effect. OBJECTIVE: We assessed effects of acute intranasal insulin exposure on food intake and appetite-related constructs among middle-aged, obese, cognitively normal African American adults. We hypothesized that intranasal insulin would result in fewer calories consumed, greater feelings of fullness, and less hunger compared to placebo. METHOD: A total of 39 participants received intranasal doses of Novolin-R (40 IU) and a saline placebo on separate days in a double-blind, counterbalanced, crossover design, with 3-day, eucaloric, nutritionally balanced diets preceding each dose. Doses were preceded by a 4-hour fast and followed by a test lunch. Visual analog scales (VAS) were used to assess appetite immediately before and after each dose, and after each lunch. Mixed effects linear model t tests were used to compare questionnaires and lunch intake between insulin and placebo. RESULTS: There were no significant differences in food intake between conditions. However, feelings of fullness were significantly greater immediately after insulin compared to placebo. In addition, the desire to consume sweet foods decreased significantly more after insulin than after placebo. CONCLUSION: Acute intranasal insulin was associated with a reduced desire for sweet foods and with increased feelings of fullness, but not reduced food intake, among middle-aged African American adults. Eating behavior and appetite changes should be explored further as possible side effects of intranasal insulin treatment for cognitive decline in diverse populations.}, } @article {pmid40979532, year = {2025}, author = {Bishara, MA and Chum, PP and Miot, FEL and Hooda, A and Hartman, RE and Behringer, EJ}, title = {Molecular pathogenesis of Alzheimer's disease onset in a mouse model: effects of cannabidiol treatment.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1667585}, pmid = {40979532}, issn = {1662-4548}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a common neurodegenerative condition involving a complex blend of disturbances in synaptic development and maintenance, neurovascular cross-talk, ionic and nutrient transport, and mitochondrial metabolism. The precise molecular profile of AD onset with insight for major pathological contributors remains unclear with corresponding impedances in therapeutic development. The current study sought two objectives, as (i) to resolve the molecular pathogenesis from cognitive impairment to the onset of AD-like neuropathology and (ii) whether the novel agent cannabidiol (CBD), noted for its neuroprotective effects, influences the molecular transition associated with AD onset. METHODS: Dietary CBD was administered daily (80-100 mg/kg/day) in male 3xTg-AD mice and wild-type B6129SF2/J animals from 4.5 to 6.5 mo of age with inclusion of vehicle controls. RNA sequencing encompassed longitudinal and cross-sectional blood and brain samples, respectively. Metabolomics and behavioral analyses examined brain regions (cortex, hippocampus) and associated integrated neurocircuitry. RESULTS AND DISCUSSION: There were >1,000 differentially expressed markers of AD onset, whereby >75% were either eliminated or reversed in the direction of expression in response to CBD. Signaling pathways encompassed synaptic development and plasticity (e.g., Foxp2), neurovascular interactions (Smad9, Angptl6), receptors and ion channels (Gria4, Chrna2, Rgs7/Rgs7bp), mitochondrial genes (Ndufa7, Cox7a2), immunity (Ncr1), oxidation-reduction (Esr1), lipid synthesis (Fasn, ApoE), and carbohydrate metabolism (Mafa, Mlxipl). As potentially addressable with CBD treatment, AD onset represents molecular integration of neurovascular interactions, channelopathies, metabolic disturbances, and aberrations in developmental genes with involvement of major pathological contributors such as inflammation, oxidative signaling, dyslipidemia, and insulin resistance.}, } @article {pmid40979047, year = {2025}, author = {Yashaeva, L and Montoya, M and Joshi, J and Stephens, A and McNulty, O and Kaur, G}, title = {Advancing Care in Alzheimer's Disease: Current Treatments and Their Impact on Quality of Life.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e90527}, pmid = {40979047}, issn = {2168-8184}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. It is currently the most common cause of dementia globally and carries a significant disease burden, given the rising aging population worldwide. Although AD is debilitating for the patient, the complex nature of the disease is also a source of tremendous mental distress for caregivers. Finding, understanding, and evaluating the best treatments can be challenging and overwhelming when coping with a life-changing diagnosis of AD. Although there is currently no definite cure for AD, all the discussed treatments aim to improve a patient's quality of life and attenuate the time spent in disability. This study compiles and discusses the risks, benefits, and efficacy of all currently available treatments for AD, including treatments that target the control of cognitive and non-cognitive symptoms. Additionally, the manuscript discusses investigational therapeutics, including small molecules and immunotherapies in phase 2 or 3 clinical trials, and assesses non-pharmacological interventions that may alleviate disease burden.}, } @article {pmid40978711, year = {2025}, author = {Liu, C and Meng, Y and Liu, R and Wang, Z and Zhao, H}, title = {Pathological Mechanisms and Molecular Imaging Advances in Alzheimer's Disease.}, journal = {Clinical interventions in aging}, volume = {20}, number = {}, pages = {1583-1603}, pmid = {40978711}, issn = {1178-1998}, mesh = {*Alzheimer Disease/diagnostic imaging/pathology ; Humans ; *Molecular Imaging/methods ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Gastrointestinal Microbiome ; Early Diagnosis ; Extracellular Vesicles ; Multimodal Imaging ; }, abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders globally, where early diagnosis plays a pivotal role in delaying disease progression and improving patient outcomes. In recent years, the rapid, multidisciplinary advances in molecular imaging and emerging technologies have significantly advanced our understanding of AD pathogenesis, early diagnosis, and intervention strategies. Imaging tools such as positron emission tomography (PET) and magnetic resonance imaging (MRI), alongside emerging technologies like retinal imaging, nanosensors, and quantum dots (QDs), are continuously enhancing AD diagnostic pathways. Studies on the gut microbiome and extracellular vesicles (EVs) offer novel insights into AD pathogenesis. Furthermore, AI-driven multimodal data fusion techniques hold great promise for improving diagnostic accuracy. Future research will increasingly focus on multi-target synergistic intervention strategies, standardization of multimodal imaging, and the integration of AI with molecular diagnostics and treatment to enable early detection and personalized precision therapy for AD.}, } @article {pmid40978281, year = {2025}, author = {Porayette, P and Kaltcheva, MM and Perry, G and Butler, T and Vadakkadath Meethal, S and Atwood, CS}, title = {Progesterone induction of tau phosphorylation during the differentiation of human embryonic stem cells into neuroectodermal rosettes.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251370643}, pmid = {40978281}, issn = {2542-4823}, abstract = {BACKGROUND: Tau phosphorylation is associated with neuronal division and differentiation in the fetal brain, in neuroblastoma cells, in the hibernating brains of ground squirrels and black bears, and in post-mitotic neurons in the Alzheimer's disease (AD) brain. The disassembly of the rigid microtubule structure of neurons for neuronal division and neurite remodeling requires the removal of the microtubule stabilizing protein tau via its phosphorylation. OBJECTIVE: To determine if tau phosphorylation is required during neural embryogenesis. METHODS: Using an in vitro human model of early embryonic development, human embryonic stem cells (hESC) were differentiated into embryoid bodies (EBs; akin to an early blastocyst) and then into neuroectodermal rosettes (akin to a rudimentary neural tube containing neuroectodermal precursor cells) upon treatment with progesterone. The neuroectodermal rosettes were then treated with and without LiCl (Cdk5 inhibitor) or roscovitine (GSK-3β inhibitor) and assayed for the expression of tau, P-tau, nestin (an early marker of neurogenesis), Cdk5 and GSK-3β. RESULTS: Tau was not expressed in hESC, but tau expression and its phosphorylation increase upon progesterone-induced differentiation of hESC into neuroectodermal rosettes. Both Cdk5 and GSK-3β, enzymes associated with tau phosphorylation, were expressed in hESCs, EBs, and neuroectodermal rosettes. The GSK-3β inhibitor LiCl, but not the Cdk-5 inhibitor roscovitine, prevented tau phosphorylation and nestin expression and the formation of neuroectodermal precursor cells. CONCLUSIONS: These preliminary results suggest that progesterone induces tau expression and its phosphorylation during the differentiation of neuroectodermal rosettes from hESC and suggest that tau and its phosphorylation is obligatory for neuronal precursor cell mitosis. The parallels between neural embryogenesis and neurodegeneration are discussed in the context of tau phosphorylation and the aberrant re-entry of neurons into the cell cycle in AD.}, } @article {pmid40977903, year = {2025}, author = {Verlaan, T and Bouland, GA and Mahfouz, A and Reinders, MJT}, title = {scAGG: Sample-level embedding and classification of Alzheimer's disease from single-nucleus data.}, journal = {Computational and structural biotechnology journal}, volume = {27}, number = {}, pages = {3753-3761}, pmid = {40977903}, issn = {2001-0370}, abstract = {Identifying key cell types and genes in Alzheimer's Disease (AD) is crucial for understanding its pathogenesis and discovering therapeutic targets. Single-cell RNA sequencing technology (scRNAseq) has provided unprecedented opportunities to study the molecular mechanisms that underlie AD at the cellular level. In this study, we address the problem of sample-level classification of AD using scRNAseq data, where we predict the disease status of entire samples from the gene expression profiles of their cells, which are not necessarily all affected by the disease. We introduce scAGG (single-cell AGGregation), a sample-level classification model that uses a sample-level pooling mechanism to aggregate single-cell embeddings, and show that it can accurately classify AD individuals and healthy controls. We then investigate the latent space learnt by the model and find that the model learns an ordering of the cells corresponding to disease severity. Genes associated with this ordering are enriched in AD-linked pathways, including cytokine signalling, apoptosis, and metal ion response. We also evaluate two attention-based models that perform on par with scAGG, but entropy analysis of their attention scores reveals limited interpretability value. As scRNAseq is increasingly applied to large cohorts and cell-level disease association annotations do not exist, our approach provides a way to classify phenotypes from single-cell measurements. The yielded cell- and sample-level severity scores may enable identification of AD-associated cell subtypes, paving the way for targeted drug development and personalized treatment strategies in AD. Code is available at: https://github.com/timoverlaan/scAGG.}, } @article {pmid40976462, year = {2025}, author = {Shi, M and Chu, F and Zhu, J}, title = {Stem cells therapy in neurodegenerative and neuroimmune diseases: Current status of treatments and future prospects.}, journal = {Pharmacological research}, volume = {221}, number = {}, pages = {107960}, doi = {10.1016/j.phrs.2025.107960}, pmid = {40976462}, issn = {1096-1186}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegenerative and neuroimmune diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) share a common pathologic hallmark i.e. loss of neurons in the central nervous system (CNS), despite diverse pathological manifestations. These diseases present major challenges to global health due to incurable or extremely difficult to treat, imposing a heavy burden on society and families. Stem cell therapy, as a novel promising approach for treating various neurological diseases, harnesses the regenerative potential of stem cells to repair damaged neural tissues and circuits, and has become the only hope for patients to recover their health or delay the deterioration of disease symptoms. In recent years, researchers have successfully generated neurons from multiple types of stem cells, and good curative effects have been achieved in their animal models and in clinical trials. This comprehensive review elaborates on the relevant content of stem cell biology, focuses on conducting an in-depth analysis of the current application status of various stem cells in major neurodegenerative and neuroimmune diseases including MS, AD, PD and ALS, kindling the hope for the development of stem cell-based cell therapies in neurological diseases.}, } @article {pmid40976434, year = {2025}, author = {Melcop, J and Ong, JY and Ciaghi, S and Keramopoulou, M and Schatz, A and Winter, Y and Szele, FG and Stumpenhorst, K}, title = {Correlation of adult neurogenesis and cognitive performance in touchscreen tasks - assessing the novel small molecule OXS-N1 in mice.}, journal = {Neuroscience}, volume = {589}, number = {}, pages = {322-334}, doi = {10.1016/j.neuroscience.2025.09.024}, pmid = {40976434}, issn = {1873-7544}, mesh = {Animals ; *Neurogenesis/drug effects/physiology ; Mice, Inbred C57BL ; *Cognition/drug effects/physiology ; Mice, Transgenic ; Male ; *Alzheimer Disease/physiopathology/drug therapy/pathology ; Mice ; Hippocampus/drug effects ; Dentate Gyrus/drug effects ; Disease Models, Animal ; Reversal Learning/drug effects ; Neurons/drug effects/physiology ; }, abstract = {Adult hippocampal neurogenesis in the dentate gyrus is well-defined in rodents, and its role in cognitive functions as well as its potential as a therapeutic target for neurodegenerative diseases such as Alzheimer's disease remain a topic of great scientific interest. In this study, we evaluated the effects of a novel small molecule, OXS-N1, on neurogenesis and behavior in C57Bl/6 wild-type and 5xFAD Alzheimer's disease model mice, which were tested independently at different ages. Modern, home-cage based set-ups were implemented for automated, voluntary animal behavioral testing. OXS-N1 failed to enhance hippocampal cognitive functions in either cohort as assessed by two hippocampus-dependent touchscreen tasks. Contrary to previous short-term assessments, OXS-N1 also had no significant treatment effect on adult hippocampal neurogenesis in both wild-type and 5xFAD mice. We further analyzed correlations between individual mouse neurogenesis levels and behavioral performance independent of treatment. The density of adult-born neurons in the dentate gyrus showed no significant correlation with spatial pattern separation or reversal learning ability in the Location Discrimination task and did not affect associative memory acquisition in the Paired-Associates Learning task in either wild-type or 5xFAD mice. Our results provide further critical evidence on the complex role of adult neurogenesis for hippocampal cognition in health and disease.}, } @article {pmid40976394, year = {2025}, author = {Aumer, B and Rosa Porto, R and Coles, M and Ulmer, N and Watt, G and Kielstein, H and Karl, T}, title = {Combination treatment with medium dose THC and CBD had no therapeutic effect in a transgenic mouse model for Alzheimer's disease but affected other domains including anxiety-related behaviours and object recognition memory.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {257}, number = {}, pages = {174101}, doi = {10.1016/j.pbb.2025.174101}, pmid = {40976394}, issn = {1873-5177}, mesh = {Animals ; *Dronabinol/administration & dosage/pharmacology/therapeutic use ; *Cannabidiol/administration & dosage/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/psychology ; Mice, Transgenic ; Female ; Mice ; *Anxiety/drug therapy ; Disease Models, Animal ; *Recognition, Psychology/drug effects ; Behavior, Animal/drug effects ; Maze Learning/drug effects ; Drug Therapy, Combination ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that effects memory and behaviour. The phytocannabinoid cannabidiol (CBD) has been found to reverse impairments of recognition as well as spatial memory deficits of AD transgenic mice but had only limited effects on disease-relevant brain pathologies. Recent evidence suggests that combining CBD with other cannabinoids including delta-9-tetrahydrocannabinol (THC) may lead to improved therapeutic outcomes. Thus, this study evaluated the chronic effects of combined treatment with 3 mg/kg THC and 20 mg/kg CBD on 14.5-month-old APPSwe/PS1ΔE9 (APP/PS1) transgenic females and control littermates. Mice were treated with THCxCBD or vehicle (VEH) daily via intraperitoneal injections for 3 weeks before behavioural testing commenced. AD-relevant behavioural domains were analysed utilising Elevated Plus Maze (EPM), open field (OF), novel object recognition test (NORT), social interaction (SI), Y-maze (YM), and prepulse inhibition test (PPI). APP/PS1 females showed an anxiety-like phenotype and object recognition deficits that remained unchanged by cannabinoid treatment. Interestingly, some effects of THCxCBD appeared genotype-dependent with cannabinoid treatment causing an anxiogenic EPM response in APP/PS1 mice but having an anxiolytic-like effect in WT females. Moreover, THCxCBD administration disrupted the novel object preference of control females. Noteworthy, THCxCBD significantly decreased different fat depots and bodyweight of all mice across genotype. No other differences between genotypes or treatment groups were detected. In conclusion, the particular cannabinoid combination strategy utilised had no prominent therapeutic-like effect in 14.5-month-old APP/PS1 females.}, } @article {pmid40975511, year = {2025}, author = {Alshehri, ZS}, title = {Integrating artificial intelligence with small molecule therapeutics and precision medicine for neurochemical understanding of Alzheimer's diseases.}, journal = {Neuroscience}, volume = {586}, number = {}, pages = {44-57}, doi = {10.1016/j.neuroscience.2025.08.055}, pmid = {40975511}, issn = {1873-7544}, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/therapy/diagnostic imaging ; *Artificial Intelligence ; *Precision Medicine/methods ; Animals ; Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative condition and continues to pose significant clinical and research challenges due to its complex causes and limited treatment success. Conventional therapies have primarily focused on amyloid-beta (Aβ) and tau proteins, but these efforts have yet to produce optimal results. This review explores emerging interdisciplinary strategies that integrate artificial intelligence (AI), small molecule drugs, and precision treatments to tackle AD's intricacies. AI has significantly enhanced early detection, neuroimaging, and biomarker discovery using machine learning and deep learning. These state-of-art methods helps to analyze biomarker profiles and imaging data, thereby enabling tailored diagnostic and therapeutic strategies for individual patients. At the same time, computational methods have expedited the development of small molecules targeting Aβ buildup, tau pathology, and inflammation. Emerging treatments, including monoclonal antibodies, RNA-based therapies, and nanotechnology, provide promising alternatives to conventional approaches. The integration of AI with multi-omics and structure-guided drug design supports the creation of precise, individualized treatments. However, challenges in ethics, regulation, and clinical application persist. This review emphasizes the collaborative potential of AI, pharmacology, and biomedical engineering in revolutionizing AD treatment, highlighting the need for cross-disciplinary efforts to confront this urgent neurological condition.}, } @article {pmid40975319, year = {2026}, author = {Sukumaran, ES and S, AN}, title = {Why 7-ketocholesterol matters now: A rapid review of its pathogenic and therapeutic relevance.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {255}, number = {}, pages = {106865}, doi = {10.1016/j.jsbmb.2025.106865}, pmid = {40975319}, issn = {1879-1220}, mesh = {*Ketocholesterols/metabolism ; Humans ; Animals ; Oxidative Stress ; Inflammation/metabolism ; Antioxidants/therapeutic use ; Neurodegenerative Diseases/metabolism ; Biomarkers/metabolism ; Aging/metabolism ; }, abstract = {7-Ketocholesterol (7-KC), a major oxysterol formed through cholesterol autoxidation, is increasingly recognized as a pathogenic mediator in ageing and chronic disease. Detected in atherosclerotic plaques, Alzheimer's cortex, aged retina, and lysosomal storage disorders, 7-KC actively drives oxidative stress, chronic inflammation, organelle dysfunction, and oxiapoptophagy. These mechanisms underpin its role in cardiovascular, neurodegenerative, and metabolic pathologies. Recent advances highlight nutritional antioxidants, pharmacological agents, microbial bioremediation, and nanotechnology as promising therapeutic avenues. Recognizing 7-KC as both a biomarker and therapeutic target offers opportunities for innovation in diagnostics and treatment of age-related and inflammatory disorders.}, } @article {pmid40974909, year = {2025}, author = {Fazeli, B and Botzenhardt, S and Bachhuber, F and Klassen, P and Klose, V and Dorst, J and Wiesenfarth, M and Uzelac, Z and Jesse, S and Brenner, D and Anderl-Straub, S and Ludolph, AC and Otto, M and Weishaupt, J and Tumani, H and Halbgebauer, S}, title = {Comparative analysis of cerebrospinal fluid neurofilament medium, light and heavy chain in neurodegenerative diseases using an in-house assay for the detection of neurofilament medium chain.}, journal = {EBioMedicine}, volume = {120}, number = {}, pages = {105930}, pmid = {40974909}, issn = {2352-3964}, mesh = {Humans ; *Neurofilament Proteins/cerebrospinal fluid ; Male ; Female ; Biomarkers/cerebrospinal fluid ; *Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; Aged ; Middle Aged ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; ROC Curve ; Aged, 80 and over ; Frontotemporal Dementia/cerebrospinal fluid/diagnosis ; }, abstract = {BACKGROUND: Neurofilaments are key axonal proteins, with neurofilament light (NfL) and heavy (NfH) chain recognised as promising biomarkers for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, neurofilament medium chain (NfM) remained previously underexplored due to a lack of quantitative assays. In this study, we developed a sensitive immunoassay to measure NfM in cerebrospinal fluid (CSF) and analysed its levels in ALS, Alzheimer's disease (AD), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Correlations among neurofilaments and their diagnostic performance were also evaluated. METHODS: In this study CSF levels of three neurofilament proteins were measured in 305 participants, including patients with ALS (n = 91), AD (n = 59), FTD (n = 38), LBD (n = 18), non-neurodegenerative controls (CTRL, n = 51), and 48 individuals initially evaluated for ALS but ultimately diagnosed with other conditions (CTRL.DD). NfM levels were quantified using a homemade sandwich ELISA, while NfL and NfH were measured using commercialised Ella cartridges. FINDINGS: All three neurofilaments were significantly elevated in ALS compared to CTRL and CTRL.DD groups (p < 0.0001 for both), with NfM and NfL also increased in FTD (p < 0.0001 for both) and AD (NfM, p < 0.0001; NfL, p = 0.0001) compared to CTRL. NfH demonstrated the greatest distinction between ALS and FTD (p < 0.0001). Strong correlations were observed among neurofilament subunits, particularly between NfM and NfL (r = 0.93, 95% CI: 0.91-0.94, p < 0.0001). All neurofilaments effectively distinguished ALS from CTRL and CTRL.DD, with AUC values ranging from 0.92 to 0.99. NfM and NfL showed high accuracy in differentiating AD (NfM, AUC: 0.91; NfL, AUC: 0.89) and FTD (NfM, AUC: 0.91; NfL, AUC: 0.92) from CTRL, while NfH best separated ALS from FTD (AUC: 0.96). INTERPRETATION: This study provides a quantitative comparison of NfM with NfL and NfH in a neurodegenerative cohort, highlighting its potential diagnostic value. Further research with larger cohorts, longitudinal studies, and investigations into neurofilament distribution in different compartments is needed to clarify the distinct roles of NfM, NfL, and NfH in the diagnosis and treatment of neurological diseases. FUNDING: The present study was supported by the Else Kroener-Fresenius Foundation (2024-EKEA.126) and Chemische Fabrik Karl Bucher GmbH.}, } @article {pmid40974820, year = {2026}, author = {Zhu, XD and Huang, LP and Zhu, N and Yang, XY and Yan, FX and Liu, M and Zhang, P and Wu, QY and Zhou, J and Wu, Y}, title = {A UPLC-Q/TOF-MS-based plasma and hippocampal metabolomics analysis was conducted to investigate the impact of Erjing Pills on Alzheimer's Disease rats.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {267}, number = {}, pages = {117147}, doi = {10.1016/j.jpba.2025.117147}, pmid = {40974820}, issn = {1873-264X}, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Hippocampus/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism/blood ; Rats ; Metabolomics/methods ; Male ; Rats, Sprague-Dawley ; Chromatography, High Pressure Liquid/methods ; Maze Learning/drug effects ; Disease Models, Animal ; Mass Spectrometry/methods ; }, abstract = {Alzheimer's Disease (AD), the most common form of dementia, places a significant burden on individuals and society. In line with the doctrines of Chinese medical practice, kidney deficiency and insufficient marrow cannot nourish the brain, leading to insufficient blood, cerebral dysfunction, and ultimately dementia. Erjing Pills contain wolfberry and Polygonati Rhizoma, which tonify the kidneys and improve the essence. Although pharmacological studies have demonstrated that Erjing Pills can be used to prevent and treat AD, the detailed action mechanism is yet to be determined. To comprehensively reveal the mechanism of action of Erjing Pills in the prevention and treatment of AD, three pharmacodynamic evaluations, the water maze test, both hematoxylin-eosin and immunohistochemical techniques were utilized to assess the effects of Erjing Pills on AD rats. Furthermore, plasma and hippocampus metabolomics were conducted by various statistical analyses combined with UPLC-Q/TOF-MS were employed for a comprehensive and accurate analysis of the in vivo anti-AD effects of Erjing Pills. Erjing Pills enhanced learning and memory capacity decreased hippocampal Aβ deposition expression, and enhanced hippocampal morphology in AD rats. After Erjing Pills treatment, 38 plasma metabolites and 15 hippocampal metabolites of AD rats were regressed to levels similar to those of controls. Moreover, pathways impacted by Erjing Pills on AD included arachidonic acid metabolism, retinol metabolism, glycerophospholipid metabolism, and caffeine metabolism. Additionally, adrenaline, leukotriene B4, retinol, and paraxanthine clearly distinguished the Erjing Pills group from the AD group. These findings significantly enhance our comprehension of the metabolic pathways implicated in AD and shed light on the therapeutic mechanisms of Erjing Pills in alleviating symptoms in rats with AD.}, } @article {pmid40974595, year = {2025}, author = {Li, RX and Shang, X and Shen, PQ and Zhu, YF and Gao, EQ and Yue, Q}, title = {Ultrasensitive Electrochemical Detection of Amyloid-β Peptide Using a Homochiral Metal-Organic Framework Binding to the l-Diphenylalanine Targeting Site.}, journal = {ACS sensors}, volume = {10}, number = {10}, pages = {7260-7269}, doi = {10.1021/acssensors.4c03425}, pmid = {40974595}, issn = {2379-3694}, mesh = {*Amyloid beta-Peptides/analysis/cerebrospinal fluid/chemistry ; *Metal-Organic Frameworks/chemistry ; *Electrochemical Techniques/methods ; *Phenylalanine/analogs & derivatives/chemistry ; Limit of Detection ; *Peptide Fragments/analysis ; Humans ; Animals ; Binding Sites ; Zinc/chemistry ; Dipeptides ; }, abstract = {The high sensitivity and accuracy of amyloid-β peptide (Aβ) detection could provide strong support for early diagnosis, monitoring of disease progression, and effective treatment of Alzheimer's disease (AD). Improving the specificity and affinity of sensing materials for Aβ is key to detecting Aβ. Herein, an electrochemical sensor based on an unmodified homochiral MOF, Zn-BPIleBp, was developed for the first time for the detection of Aβ1-40, with an ultralow detection limit of 1.7 pM (7.36 pg/mL). The Zn-BPIleBp sensor also displays high-efficiency enantioselectivity and ultrasensitivity in identifying diphenylalanine (PhePhe) corresponding to the core recognition motif of Aβ1-40, with a high peak current ratio (IL/ID) of 2.78, large potential difference (EL - ED) of 140 mV, and ultralow detection limit of 34 fM for l-PhePhe. The sensor has been successfully applied for the ultrasensitive quantification of l-PhePhe and Aβ1-40 in racemic mixtures, artificial cerebrospinal fluid (aCSF) and fetal bovine serum (FBS). According to structural and spectral analysis, the high sensitivity and affinity of homochiral MOF toward Aβ1-40, without the involvement of any biomolecular modifications such as antibodies or aptamers, stem from the structural, hydrophobic, and chiral matching between the framework and Aβ1-40. This sensor proffers a fast, highly stable, reproducible, ultrasensitive, and accurate detection method for Aβ1-40, demonstrating great potential in the clinical application of AD. This work also opens up new perspectives for designing sensing platforms using MOFs as sensing materials and expanding their functionality and applications to the fields of biological and medical analysis.}, } @article {pmid40974571, year = {2025}, author = {Naveed, M and Kim, MH}, title = {Nanoparticle-mediated magnetic hyperthermia in the treatment of neurological disorders.}, journal = {Nanomedicine (London, England)}, volume = {20}, number = {22}, pages = {2791-2803}, pmid = {40974571}, issn = {1748-6963}, support = {R01 AG076699/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Hyperthermia, Induced/methods ; *Magnetite Nanoparticles/chemistry/therapeutic use ; Animals ; *Nervous System Diseases/therapy ; Alzheimer Disease/therapy ; Glioblastoma/therapy ; Magnetic Fields ; }, abstract = {Neurological disorders including gliomas and neurodegenerative diseases are characterized by dysregulation of the central nerve system (CNS). Despite recent advances in disease-modifying treatments, pharmacological approaches for neurological disorders still face limitations due to the complexity of these diseases and the challenges in targeting the underlying mechanisms. Magnetic hyperthermia, an approach that utilizes magnetic nanoparticles (MNPs) to generate localized heat in target cells and tissues by responding to an alternating magnetic field (AMF), has been developed as a non-pharmacological treatment approach for targeting tumor cells or pathogens, primarily through thermal inactivation. Recently, beyond its traditional application in thermal therapies, magnetic hyperthermia has been increasingly explored for neurological diseases. Importantly, recent studies demonstrate the ability of magnetic hyperthermia in eliciting various biological effects by means of triggering heat shock protein (HSP) signaling, enhancing immune responses, and activating heat-sensitive ion channels in neurons. This review highlights the current understanding of magnetic hyperthermia in stimulating molecular and cellular effects on brain tissue and further discusses its potential in the treatment of neurological disorders including Glioblastoma Multiforme (GBM), Alzheimer's Disease (AD), Parkinson's Disease (PD). The studies discussed in this review were selected by using the search tool on PubMed with the suggested key words.}, } @article {pmid40974521, year = {2025}, author = {Jiang, HN and Zhang, B and Zhang, J and Zhou, YY}, title = {Dihuang Yinzi Regulates cAMP/PKA/CREB-BDNF to Improve Synaptic Plasticity in APP/PS1 Mice: A Study Based on Brain Metabolomics.}, journal = {Chinese journal of integrative medicine}, volume = {31}, number = {11}, pages = {991-1000}, pmid = {40974521}, issn = {1993-0402}, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; Male ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Brain/metabolism/drug effects ; *Metabolomics ; Mice, Inbred C57BL ; *Neuronal Plasticity/drug effects ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Cyclic AMP-Dependent Protein Kinases/metabolism ; *Cyclic AMP/metabolism ; Reactive Oxygen Species/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; Mice, Transgenic ; Mice ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects ; Alzheimer Disease/drug therapy ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVE: To explore the mechanism of Dihuang Yinzi (DHYZ) in the treatment of Alzheimer's disease (AD) by integrating metabolomics and experimental verification. METHODS: Forty-eight male APP/PS1 mice were divided into model, high- (DHYZ-H), medium- (DHYZ-M), and low-dose DHYZ (DHYZ-L) groups (12 mice per group) according to a random number table. Mice in DHYZ groups were gavaged with DHYZ 6.34, 12.68, and 25.35 g/(kg·d), respectively. Twelve C57BL/6 mice were gavaged with distilled water as the blank group. Metabolomics was used to analyze differential metabolites in the brains of mice. Morris water maze test was used to detect the memory abilities of mice. The hematoxylin-eosin staining and transmission electron microscopy were used to observe the general morphology and ultrastructure of neurons. The enzyme-linked immunosorbent assay was used to detect the levels of superoxide dismutase (SOD), reactive oxygen species (ROS), and amyloid β -protein 1-42 (A β1-42). The real-time quantitative polymerase chain reaction was used to detect the mRNA expressions of density-regulated protein 1 (DRP1), fission 1 (FIS1), mitofusin-1 (MFN1), and optic atrophy protein 1 (OPA1). Western blot was used to detect the protein expressions of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response binding protein (CREB), brain-derived neurotrophic factor (BDNF), synapsin 1 (SYN1), synaptophysin (SYP), and postsynaptic density protein 95 (PSD95). RESULTS: A total of 82 differential metabolites were identified in the brains of APP/PS1 mice, among which 7 differential metabolites could be regulated by DHYZ. After DHYZ intervention, the memory abilities of mice significantly increased (P<0.05 or P<0.01), the number of synapses and neurons in the hippocampus increased, and the mitochondrial morphology and structure were relatively intact. The DHYZ groups exhibited a significant reduction in hippocampal ROS and A β1-42 levels, along with a significant elevation in SOD level (P<0.05 or P<0.01). The mRNA expressions of DRP1 and FIS1 were reduced, while the mRNA expressions of MFN1 and OPA1 were increased after DHYZ treatment (P<0.05 or P<0.01). The cAMP/PKA/CREB-BDNF pathway was activated, and the expressions of SYN1, SYP and PSD95 proteins were significantly increased in the DHYZ-H group (P<0.05 or P<0.01). CONCLUSIONS: DHYZ could improve mitochondrial dynamics and synaptic plasticity in APP/PS1 mice, inhibit oxidative stress, and thereby enhancing learning and memory abilities in APP/PS1 mice. Its mechanism might be related to activation of the cAMP/PKA/CREB-BDNF signaling pathway.}, } @article {pmid40973891, year = {2025}, author = {Xie, R and Liu, Z and Zheng, J and Tan, Q and Wu, H and Liang, Y}, title = {Bioavailability enhancement and neuropharmacological effects of Dauricine under intranasal administration to improve cognitive impairment via PI3K/AKT/mTOR pathway.}, journal = {Drug delivery and translational research}, volume = {}, number = {}, pages = {}, pmid = {40973891}, issn = {2190-3948}, support = {2025A1515010474//Basic and Applied Basic Research Foundation of Guangdong Province/ ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder strongly associated with aging, and Dauricine (DAU) has demonstrated significant neuropharmacological properties for AD treatment. However, its bioavailability is significantly limited when administered orally, leaving the mechanisms underlying its effects on AD largely unexplored. In this study, a DAU-loaded thermosensitive gel was formulated for delivery via the nasal-nerve route, and its potential to enhance the bioavailability of DAU in rat plasma and cerebrospinal fluid (CSF) was assessed through a pharmacokinetic study. The anti-Alzheimer's disease (AD) mechanism of DAU was investigated using network pharmacology approaches, molecular docking, and dynamics simulations, complemented by in vivo experimental validation. DAU can be effectively incorporated into a thermosensitive gel and administered to the brain within 30 min via intranasal delivery. Following nasal administration, the pharmacokinetic parameters of DAU in cerebrospinal fluid and plasma were significantly elevated compared to oral administration ([**]P < 0.01), indicating a substantial improvement in bioavailability at equivalent doses. Behavioral studies demonstrated that DAU (dose of 1 mg/kg and 2 mg/kg in gel) enhanced cognitive function in intracerebroventricular-streptozotocin (ICV-STZ) rats and decelerated aging processes by reversing oxidative stress and mitigating neuronal apoptosis. Additionally, DAU contributed to lowering blood glucose levels, increasing insulin-like growth factor 1 (IGF-1) content, and reducing insulin resistance. Network pharmacological analysis, molecular docking, molecular dynamics simulations, and in vivo experiments collectively suggested that DAU exerted significant therapeutic effects on Alzheimer's disease by inhibiting the PI3K/AKT/mTOR pathway. Our study demonstrates a significant enhancement in the bioavailability of DAU in the brain via nasal-nerve delivery route and also this research is the first to report that DAU ameliorates cognitive impairment in ICV-STZ rats through the PI3K/AKT/mTOR pathway. Our findings contribute to the scientific understanding of DAU's potential in Alzheimer's disease treatment and offer a novel experimental foundation for the development of anti-Alzheimer's drugs.}, } @article {pmid40972689, year = {2025}, author = {Zhang, H and Huang, Y and Wang, W}, title = {Aβ oligomers promote lipid droplet accumulation and inflammatory responses in astrocytes but not neurons.}, journal = {Brain research bulletin}, volume = {231}, number = {}, pages = {111556}, doi = {10.1016/j.brainresbull.2025.111556}, pmid = {40972689}, issn = {1873-2747}, mesh = {*Astrocytes/metabolism/drug effects ; Animals ; *Neurons/metabolism/drug effects ; *Lipid Droplets/metabolism ; *Amyloid beta-Peptides/metabolism/pharmacology ; Oxidative Stress/physiology/drug effects ; Cells, Cultured ; Inflammation/metabolism ; Lipid Metabolism/physiology/drug effects ; Mice ; Alzheimer Disease/metabolism ; }, abstract = {Lipid droplets (LDs) are dynamic organelles central to cellular lipid homeostasis. Emerging evidence implicates LDs in Alzheimer's disease (AD) pathogenesis, though their cell-type-specific roles remain poorly defined. Here, we investigated the effects of amyloid-beta oligomers (AβOs) on LDs accumulation, oxidative stress, and inflammatory activation in primary astrocytes and neurons. We found that AβOs selectively triggered robust LDs formation in astrocytes, accompanied by significant increases in triglyceride (TG) and cholesterol (TC) content, and upregulation of the LD-associated protein perilipin 2 (PLIN2). Furthermore, AβOs induced pronounced oxidative stress, evidenced by elevated Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and promoted inflammatory activation via increased secretion of tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) in astrocytes. By contrast, neurons showed no significant changes in lipid metabolism, oxidative stress, or inflammatory responses under identical treatment conditions. Our results underscore the central role of astrocytes in AβO-induced metabolic and inflammatory dysregulation, revealing a cell-type-specific vulnerability with potential implications for AD pathogenesis. These in vitro findings provide a mechanistic basis for lipid-focused therapeutic strategies, pending further in vivo validation.}, } @article {pmid40972402, year = {2025}, author = {Chavoshinezhad, S and Beirami, E and Izadpanah, E}, title = {Neutrophils and NETosis in Alzheimer's disease: Unraveling pathogenic mechanisms and novel therapeutic targets.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {192}, number = {}, pages = {118568}, doi = {10.1016/j.biopha.2025.118568}, pmid = {40972402}, issn = {1950-6007}, mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology/metabolism/immunology ; *Neutrophils/metabolism/drug effects/pathology ; Animals ; *Extracellular Traps/metabolism/drug effects ; Blood-Brain Barrier/metabolism/pathology ; Brain/metabolism/pathology/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system that causes cognitive decline, memory loss, and neuropsychiatric symptoms. The condition is characterized by the buildup of β-amyloid plaques (Aβ), neurofibrillary tangles (NFTs), and persistent neuroinflammation. Despite ongoing research, current therapeutic strategies remain palliative and fail to halt or reverse disease progression, underscoring the need for novel treatment approaches. Recent evidence highlights neutrophils, the most abundant blood cells, as key contributors to AD pathology. These cells cross the blood-brain barrier (BBB) via specific molecular pathways and accumulate in brain regions such as the cortex and hippocampus, particularly near Aβ plaques and NFTs. Once in the brain, neutrophils release reactive oxygen species (ROS), generate neutrophil extracellular traps (NETs) via NETosis, and secrete proinflammatory cytokines and granule components. This cascade contributes to BBB disruption, increased Aβ deposition, glial activation, chronic inflammation, neurodegeneration, and cognitive impairment in AD. This review highlights the molecular mechanisms underlying both lytic and non-lytic NET formation (NETosis), explores peripheral neutrophil alterations and their migration pathways across the BBB, and discusses the role of intracerebral neutrophils, NETs, and NETosis in AD pathophysiology. Finally, we explore emerging therapeutic strategies targeting NETs, neutrophils, and NETosis as potential disease-modifying approaches in AD.}, } @article {pmid40972159, year = {2025}, author = {Laabs, M and Mulac, D and Langer, K}, title = {Targeting the blood-brain barrier with lipoprotein-mimicking nanoparticles loaded with flurbiprofenaxetil and coated with apolipoprotein E3.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {214}, number = {}, pages = {107272}, doi = {10.1016/j.ejps.2025.107272}, pmid = {40972159}, issn = {1879-0720}, mesh = {*Flurbiprofen/administration & dosage/chemistry/analogs & derivatives ; *Blood-Brain Barrier/metabolism/drug effects ; Animals ; *Nanoparticles/chemistry/administration & dosage ; Swine ; *Apolipoprotein E3/chemistry/administration & dosage ; Endothelial Cells/metabolism ; Drug Carriers/chemistry ; Drug Liberation ; *Lipoproteins/chemistry ; Drug Delivery Systems ; }, abstract = {In previous studies, it has been demonstrated that lipoprotein-mimicking nanoparticles with a solid lipid core of cholesteryl oleate, a lecithin coating and adsorptively bound apolipoprotein E3 (ApoE) may serve as a potential vehicle for drug delivery to the central nervous system. In this study, the impact of drug characteristics, particularly lipophilicity, was evaluated to achieve a stable incorporation of model drugs into these lipid-based nanoparticles (LNPs). This study explored the lipophilicity of flurbiprofen, a potential drug in the treatment of Alzheimer's disease (AD), and its prodrug flurbiprofenaxetil across varying pH levels. Our findings highlight how flurbiprofen's lipophilicity was influenced by its protonation state, affecting its incorporation into LNPs and consequently its release behaviour under physiological conditions, while flurbiprofenaxetil showed minimal variations due to its chemical structure. We also investigated the interaction between lipoprotein mimicking nanoparticles and primary porcine brain capillary endothelial cells to improve drug delivery across the blood-brain barrier (BBB). Permeation studies indicated that modification with ApoE enhanced the bidirectional permeability of LNPs across the BBB through receptor-mediated transcytosis. Furthermore, we demonstrated and identified the uptake mechanism involving the low density lipoprotein receptor-related protein 1 (LRP1), allowing these LNPs to be recognized by the same receptors as endogenous lipoproteins. Overall, these findings highlight the potential of ApoE modified LNPs as a promising strategy for targeted drug delivery to the brain.}, } @article {pmid40971327, year = {2025}, author = {Gitlin-Leigh, G and Wilson, J and Howard, R and Howard, R and Costello, H}, title = {Effects of monoclonal antibody therapies on depression in Parkinson's disease and Alzheimer's disease: Systematic review and meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {500-508}, doi = {10.1177/13872877251378156}, pmid = {40971327}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology/complications ; *Parkinson Disease/psychology/drug therapy/complications ; *Antibodies, Monoclonal/therapeutic use ; *Depression/drug therapy/etiology ; Randomized Controlled Trials as Topic ; }, abstract = {BackgroundDepression in Alzheimer's disease (AD) and Parkinson's disease (PD) is common, disabling and difficult to treat. Pathological protein deposition in PD and AD has been associated with late-life depression, and inflammatory and vascular changes have been proposed as key mechanisms underlying depression in neurodegenerative disorders. Monoclonal antibody therapies (mAbs) effectively clear pathological protein aggregates in PD and AD but are associated with cerebral inflammation and microvascular damage.ObjectiveWe conducted a systematic review and meta-analysis to determine whether mAb treatment influences the risk or severity of depression in AD and PD.MethodsCochrane, Ovid MEDLINE/PubMed, PsycINFO and Embase databases were searched for articles published from inception to 8 April 2025. Randomized controlled trials of mAbs for PD or AD reporting a validated measure of depressive symptoms, or depression incidence were included and meta-analyzed.ResultsWe identified 13 studies including 8603 participants (treatment arm: n = 4690, placebo arm: n = 3913). All studies reported depression incidence as an adverse event, but none assessed changes in depressive symptom severity using standardized mood scales. Meta-analysis revealed no significant difference in the incidence of depression with mAb therapy (log risk ratio: -0.24, 95% CI (-0.52, 0.04), p = 0.09).ConclusionsWe observed no significant association between mAb therapy and risk of depression in PD or AD. However, the absence of validated symptom assessments in these trials represents a critical gap in outcome reporting. Future trials should incorporate standardized depressive symptom measures as outcomes to evaluate the potential neuropsychiatric risks of these therapies.}, } @article {pmid40971324, year = {2025}, author = {Su, X and Chen, H and Cao, J and Zhang, Y and Kang, Y and Wang, L and Yin, J and Jing, Y}, title = {The effect of deprivation of whisker stimulation on cognition and synaptic plasticity in male and female Alzheimer's disease mice.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {719-732}, doi = {10.1177/13872877251379079}, pmid = {40971324}, issn = {1875-8908}, mesh = {Animals ; *Vibrissae/physiology ; *Alzheimer Disease/psychology/pathology/physiopathology ; *Neuronal Plasticity/physiology ; Male ; Female ; Mice ; *Sensory Deprivation/physiology ; Disease Models, Animal ; Mice, Transgenic ; *Cognition/physiology ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; }, abstract = {BackgroundAmyloid-β (Aβ) and Aβ plaques can disrupt synaptic plasticity, leading to abnormalities in sensory function and cognition in Alzheimer's disease (AD). The whisker sensorimotor system is crucial for tactile perception, providing rodents with spatial and textural features information about their surroundings. Sensory inputs from whiskers have a clear topological localization in the barrel cortex.ObjectivePrevious studies have suggested that sensory stimulation can effectively ameliorate the pathology of AD mice and improve cognitive performance. However, it remains unknown whether tactile stimulation via whiskers can activate cortical sensory areas, protect synaptic structure and function.MethodsHere, we established a whisker deprivation (WD) model in the 5×FAD mouse.ResultsWe found that WD aggravated the deposition of Aβ1-42, 6E10 and fibrotic Aβ in the cortex, hippocampus and thalamus. Simultaneously, changes in dendritic morphology were consistent with the decreased pCreb levels in the hippocampal dentate gyrus region. WD also reduced axonal projections from layer L4/L5a to L2/3 in the barrel cortex, as well as projections from the entorhinal cortex to the DG, which may disrupt the integration of information in cortical functional columns and weaken the efficiency of information transmission. Additionally, we observed sex differences in effects of WD on AD pathology in 5×FAD mice, with female mice being more sensitive to WD treatment. Ultimately, WD impaired working memory, spatial memory and social behavior in 5×FAD mice.ConclusionsOur study suggested that WD exacerbated the progression of AD pathology in 5×FAD mice, which implicated with Aβ aggravation and synaptic dysfunction.}, } @article {pmid40971120, year = {2025}, author = {Kumar, RMR and Rajan, L and Chidambaram, SB}, title = {Exosomes as Emerging Therapeutic Platforms in Neurological and Psychiatric Disorders.}, journal = {Pharmaceutical medicine}, volume = {39}, number = {6}, pages = {427-443}, pmid = {40971120}, issn = {1179-1993}, support = {D.O. NO.BT/HRD/35/02/2006//Department of Biotechnology, Ministry of Science and Technology, India/ ; }, mesh = {Humans ; *Exosomes/metabolism ; *Mental Disorders/therapy/metabolism/diagnosis/drug therapy ; *Nervous System Diseases/therapy/metabolism/diagnosis/drug therapy ; Animals ; Biomarkers/metabolism ; }, abstract = {Exosomes, small extracellular vesicles (sEVs) that range in Size from 30 to 150 nm in diameter, have emerged as crucial mediators of intercellular communication within the central nervous system (CNS). They play significant roles in the pathogenesis and progression of various neurological and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, ischemic stroke, depression, bipolar disorder, and autism spectrum disorder. Exosomes carry a diverse cargo of proteins, nucleic acids, lipids, and other bioactive molecules that can influence neuronal function and synaptic plasticity. In disease states, exosomes derived from stressed neurons or glial cells can propagate neuroinflammation, synaptic dysfunction, and cognitive decline. They may also mediate the spread of abnormal proteins or microRNAs, disrupting neuronal connectivity and neurotransmitter signaling and contributing to the development of proteinopathies and neurotoxicity. Owing to their presence in bodily fluids such as blood plasma, cerebrospinal fluid, and saliva, exosomes hold promise as biomarkers for these disorders. Moreover, their regulatory roles present new opportunities for developing novel diagnostic biomarkers and therapeutic interventions. This review provides an overview of the multifaceted roles of exosomes in neurological and psychiatric disorders. We delve into their contributions to disease pathogenesis, their potential as diagnostic biomarkers, and the innovative therapeutic strategies leveraging exosome-based delivery systems. By exploring the current state of research, we aim to highlight the translational potential of exosomes in revolutionizing the diagnosis and treatment of these disorders.}, } @article {pmid40969901, year = {2025}, author = {Zhang, J and Du, X and Li, X and Lv, X and Wang, X}, title = {Hypoxia, Psychedelics, and Terminal Lucidity: A Perspective on Neuroplasticity and Neuropsychiatric Disorders.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {9}, pages = {2848-2854}, pmid = {40969901}, issn = {2575-9108}, abstract = {Hypoxia and psychedelics, despite their distinct origins, both induce altered states of consciousness and promote neuroplasticity, suggesting a shared underlying mechanism relevant to neuropsychiatric treatment and neurological recovery. Terminal lucidity, the transient resurgence of cognitive function in late-stage dementia, highlights the brain's latent capacity for rapid reorganization, a phenomenon that may be driven by transient hypoxia. Similarly, acute intermittent hypoxia and pharmacological agents like HypoxyStat, which modulate oxygen availability, have emerged as potential strategies for enhancing neural adaptability. This perspective explores the hypothesis that controlled reductions in oxygen availability(?)whether through psychedelics, near-death experiences, meditation, holotropic breathwork, or hypoxia therapies(?)trigger calcium signaling pathways that promote synaptogenesis and the formation of new neural circuits. Rather than restoring damaged connections, this process may enable functional rerouting, thereby supporting cognitive resilience and behavioral compensation in conditions such as stroke, Alzheimer's disease, and psychiatric disorders. By integrating insights from psychedelic research, hypoxia-based therapies, and neuroplasticity studies, we propose a unifying framework that leverages altered oxygen homeostasis as a novel therapeutic strategy for neuropsychiatric and neurodegenerative diseases.}, } @article {pmid40969869, year = {2025}, author = {Tanguturi, P and Mitchell, S and Moukha-Chafiq, O and Zhang, S and Tillotson, J and Ananthan, S and Augelli-Szafran, CE and Streicher, JM}, title = {Development of Delta Opioid Receptor Antagonists Which Prevent Alzheimer's Disease-Like Pathology in the 5X-Familial Alzheimer's Disease [5XFAD] Mouse Model.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {9}, pages = {3346-3370}, pmid = {40969869}, issn = {2575-9108}, abstract = {Alzheimer's Disease is a growing health concern, with no available disease-modifying treatments. A previous report suggested that a Delta Opioid Receptor (DOR) antagonist could prevent Alzheimer's-like pathology; however, no DOR antagonists are clinically approved. We thus expanded on our previous structure-activity relationship work on morphinan scaffold DOR antagonists to generate and evaluate new DOR antagonist ligands. We identified a lead compound 12 (SRI-22136) with sub-nM DOR potency, high selectivity, and high inhibition of β-secretase activity. We further evaluated 12 in CD-1 mice, finding full antagonist efficacy at 1 mg/kg by the intraperitoneal route. We then tested the ability of 12 to prevent Alzheimer's-like pathology in a 5XFAD transgenic mouse model, with daily treatment from 2 to 5 months of age. This treatment completely prevented Alzheimer's-like pathology, including memory deficits, β-secretase activity, Aβ1-42 accumulation, and brain inflammatory markers. Together these results suggest 12 as a potential new lead compound to prevent Alzheimer's Disease.}, } @article {pmid40969222, year = {2025}, author = {Liu, Y and Zhu, L and Pei, Z and Zhou, Z and Su, X and Ren, H and Fan, S and Lan, X and Lian, C and Shi, X and Guo, Y}, title = {Integrating repetitive transcranial magnetic stimulation and Mediterranean diet for cognitive and anxiety improvement in early Alzheimer's disease: A case report and literature review.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251377988}, pmid = {40969222}, issn = {2542-4823}, abstract = {A 52-year-old male with early-stage Alzheimer's disease and long-standing anxiety received 30 repetitive transcranial magnetic stimulation sessions over 8 months and 20-month Mediterranean diet intervention. Neuropsychological assessments [Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Clinical Dementia Rating, Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), Pittsburgh Sleep Quality Index) and resting-state electroencephalogram (rsEEG) were conducted at baseline, during treatment, and at 6-month follow-up. After treatment, MoCA and MMSE scores improved by 6 and 5 points; HAMA and HAMD scores declined by 7 and 3 points. rsEEG showed progressive increases in individual alpha peak frequency (8.69 to 10.22 Hz), enhancement of alpha power, and reduction in theta power. Cerebrospinal fluid amyloid-β42 levels also normalized. The patient reported marked mental well-being.}, } @article {pmid40969221, year = {2025}, author = {Shaukat, A and Riaz, R and Khaliq, N and Shams, Z and Akilimali, A}, title = {Brexpiprazole: Pioneering medication for managing agitation in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251379881}, pmid = {40969221}, issn = {2542-4823}, abstract = {Alzheimer's disease poses intricate challenges, affecting cognition and behavior, notably marked by agitation. The FDA's approval of brexpiprazole, an atypical antipsychotic, stands as a milestone, representing the first treatment for Alzheimer's-related agitation. brexpiprazole's modulation of serotonin-dopamine activity has proven effective in clinical trials, reducing agitation as measured by CMAI scores. Gradual dosage escalation is recommended, with potential side effects including nasopharyngitis, urinary tract infections, dizziness, somnolence, headache, and insomnia. Also useful for schizophrenia and treatment-resistant depression, providing ongoing treatment and potential well-being enhancement by managing agitation and other symptoms.}, } @article {pmid40968664, year = {2025}, author = {Shao, X and Sun, J and Wang, X and Yin, XS and Chen, Z and Xu, Y and Wang, T and Yuan, B and Qiu, W and Liu, F and Chen, Y and Ma, C}, title = {Intraventricular Creatine Treatment Attenuates Alzheimer's Disease-Related Neuropathological Changes and Memory Impairment via Inhibiting STAT1 Phosphorylation.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {19}, pages = {3790-3800}, pmid = {40968664}, issn = {1948-7193}, mesh = {Animals ; *STAT1 Transcription Factor/metabolism/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Phosphorylation/drug effects ; *Creatine/administration & dosage/pharmacology ; *Memory Disorders/drug therapy/metabolism/pathology ; Mice ; Male ; Humans ; Female ; Aged ; Mice, Transgenic ; Hippocampus/metabolism/drug effects ; Injections, Intraventricular ; Disease Models, Animal ; Mice, Inbred C57BL ; Brain/drug effects/metabolism/pathology ; Microglia/drug effects/metabolism ; }, abstract = {The importance of neuroinflammation in Alzheimer's disease (AD) has attracted increasing attention, and the functions of the STAT1 signaling pathway have also generated widespread interest. However, the role of STAT1 in AD-related neuroinflammation and memory impairment is unclear. Therefore, this study was undertaken to elucidate the roles of the STAT1 signaling pathway in the brain tissue of AD patients and mouse of an AD model. Our results revealed that STAT1 phosphorylation was largely colocalized with the neuronal marker NeuN. Compared with that in control (non-AD) brain tissues, STAT1 phosphorylation was significantly upregulated in the brain cortex and hippocampus of both AD patients and FAD mice. Intraventricular injection of creatine (STAT1 signaling inhibitor) significantly reduced the level of neuronal STAT1 phosphorylation in the brain cortex and markedly alleviated cognitive impairment in FAD mice. Furthermore, intraventricular creatine treatment also reduced the number of Aβ plaques and the level of IBA1 expression in IBA1-positive microglia in FAD mice. These findings indicate that STAT1 phosphorylation may play an important role in AD-related neuroinflammation and memory impairment. The alleviation effects of intraventricular creatine in FAD mice may suggest that STAT1 is a potential therapeutic target for the treatment of AD in humans.}, } @article {pmid40968433, year = {2025}, author = {Goyal, A and Kumari, A and Verma, A and Bhatiya, S and Yadav, HN}, title = {Cannabinoid Receptor 1: The Neural Gatekeeper of Health and Disease.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026403497250910124233}, pmid = {40968433}, issn = {1875-5739}, abstract = {INTRODUCTION: An essential component of the endocannabinoid system, cannabinoid receptor type 1 (CB1) is primarily expressed in the central nervous system, where it regulates several neurophysiological activities. Neurotransmitter release, synaptic plasticity, mood modulation, and cognitive processes are all influenced by CB1 receptors. The CB1 receptor is closely linked to a wide range of brain-related disorders, and regulating its activity may be a way to treat several brain-related diseases. METHODS: Literature search across Google Scholar, Scopus, PubMed, and Web of Science, covering publications from 1985 to 2025, aimed to gather extensive information on the pharmacological role of the CB1 receptor in various brain illnesses. Using keywords such as "CB1," "Brain," "Epilepsy," "Alzheimer's," "Parkinson's disease," "Neuroprotection," and "Neurodegeneration," this review consolidates existing knowledge and identifies potential avenues for future research. RESULTS: This study incorporates pre-clinical evidence and highlights the involvement of the CB1 receptor in etiologies, symptoms, and treatments related to distinct brain-related disorders. DISCUSSIONS: Potential treatment strategies that target the endocannabinoid system and the intricate relationship between CB1 receptor activity and its consequences in several brain disorders, including Parkinson's disease, Huntington's disease, Alzheimer's disease, depression, anxiety, etc., have been discussed. Additionally, the difficulties and disputes related to CB1 receptor modulation, including the contradictory actions of CB1 receptor agonists and antagonists, are also addressed. CONCLUSION: The CB1 receptor is a promising therapeutic target for brain disorders due to its key role in regulating various physiological functions in the CNS, suggesting potential for the treatment of several brain disorders.}, } @article {pmid40968081, year = {2025}, author = {Karki, A and Nawani, A and Sharma, S and Poddar, D and Singh, A}, title = {Early Alzheimer Biomarker Recognition Transition Metal Dichalcogenides as Electrochemical Biosensors for Detecting Alzheimer's Biomarkers.}, journal = {Critical reviews in analytical chemistry}, volume = {}, number = {}, pages = {1-24}, doi = {10.1080/10408347.2025.2558051}, pmid = {40968081}, issn = {1547-6510}, abstract = {Alzheimer's disease (AD) is a neurological ailment characterized by the degeneration of neurons in specific areas of the brain, resulting in memory loss, cognitive decline, and eventually dementia. AD is both lethal and currently incurable since the demise of brain cells cannot be reversed or stopped; however, ongoing advancements and research offer hope, aiming to uncover effective clinical and therapeutic strategies that could slow down the progression and improve patient outcomes. Surveys indicate that the treatment of AD is significantly expensive, with the global annual cost of treating AD amounting to US$1 trillion. Therefore, the early identification of this condition is of the utmost importance, as it can assist in slowing down the advancement of Alzheimer's and enable proper diagnosis. Biosensors are analytical instruments utilized for the early identification of AD and are in great demand due to their exceptional selectivity, sensitivity, and affordability. Biosensors integrated with transition-metal dichalcogenides (TMDCs) enhance the efficiency of a biosensor by significantly amplifying biosensing signals. This study examines AD and its underlying biochemical mechanisms, explicitly focusing on several hypotheses linked to AD, the biomarkers involved, and the use of TMDC-based biosensors for early detection of the illness with greater precision.}, } @article {pmid40968015, year = {2025}, author = {Vijayashankar, A and Keir, G and Sagnelli, M and Petrover, D and Djekidel, M and Glaser, J and Caravella, C and Clouston, SAP and Rini, J and Franceschi, AM}, title = {Added Value of Amyloid PET Quantification with the Centiloid Scale in Clinical Practice.}, journal = {AJNR. American journal of neuroradiology}, volume = {46}, number = {10}, pages = {2144-2153}, pmid = {40968015}, issn = {1936-959X}, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; Reproducibility of Results ; *Positron Emission Tomography Computed Tomography/methods ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Amyloid/metabolism ; Aged, 80 and over ; Sensitivity and Specificity ; *Positron-Emission Tomography/methods ; Observer Variation ; *Image Interpretation, Computer-Assisted/methods ; }, abstract = {BACKGROUND AND PURPOSE: The objectives for amyloid brain PET/CT and PET/MRI fusion images are to determine the agreement between visual interpretations of amyloid PET and to compare the results of visual interpretation with quantitative analysis as measured by the Centiloid (CL) scale. MATERIALS AND METHODS: One hundred sixty-seven clinical amyloid brain PET/CT scans were reviewed by 3 readers blinded to the original reports. Readers interpreted the amyloid PET scans as negative (0), positive (1), or indeterminate (2) for amyloid deposition. For quantitative analysis, 2 additional readers analyzed amyloid PET images using MIMNeuro to generate CL scores and regional standardized uptake ratios. Reader agreement was determined for visual and quantitative assessment. Using positive scan cutoffs of CL ≥ 40, we determined visual assessment-versus-quantitative assessment for scans consistently interpreted as positive by all 3 readers and for each reader. RESULTS: Fifty-three scans (31.74%) were rated amyloid-positive by all readers, while 62 scans (37.13%) were rated as amyloid-negative by all readers. The remaining 52 scans had inconsistent ratings with an agreement rate of 69.46%. Most (99/167; 59.28%) scans had CL scores above the CL-positive cutoff (CL ≥ 40), and 47/167 (28.14%) were CL-negative scans (CL <10). The lowest CL score to achieve visual positivity among all 3 readers was 57, while the lowest CL score to receive at least 1 indeterminate score was 11. The readers had a high degree of interreader reliability when rating scans as either positive (κ = 0.62) or negative (κ = 0.66) but were inconsistent when rating scans as indeterminate (κ = 0.17). Optimal cut-points were CL <3.6 for consistent negative and CL ≥28.8 for consistent visual positivity. CONCLUSIONS: Given the emergence of antiamyloid monoclonal therapies for early-stage Alzheimer disease, reliable detection of amyloidosis is critical for patient care. This study suggests that visual reads of amyloid PET may be insensitive when amyloidosis is milder but are spread across multiple regions (CL ranging from 40 to 59). Quantification of amyloid PET using the CL scale may help guide treatment of patients with mild amyloidosis who are under consideration for antiamyloid disease-modifying therapeutics.}, } @article {pmid40967916, year = {2025}, author = {Oh, KN and Bae, D and Oh, DR and Hong, JA and Kim, Y and Kim, E and Son, SA and Lee, KY and Kim, S}, title = {TLR4/NF-κB-Mediated Anti-Inflammatory and Cognitive Protective Actions of Curcuma longa and Ar-turmerone in Alzheimer's Disease Models.}, journal = {Journal of microbiology and biotechnology}, volume = {35}, number = {}, pages = {e2506044}, pmid = {40967916}, issn = {1738-8872}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Curcuma/chemistry ; *Toll-Like Receptor 4/metabolism/genetics ; *NF-kappa B/metabolism ; Amyloid beta-Peptides/toxicity ; *Anti-Inflammatory Agents/pharmacology ; Disease Models, Animal ; Rats ; *Neuroprotective Agents/pharmacology ; *Plant Extracts/pharmacology ; Hippocampus/drug effects/cytology ; Mice ; Signal Transduction/drug effects ; Male ; Neurons/drug effects ; *Sesquiterpenes/pharmacology ; Monocyclic Sesquiterpenes ; Cells, Cultured ; Rats, Sprague-Dawley ; Cognition/drug effects ; Curcumin/pharmacology ; Peptide Fragments ; Ketones ; }, abstract = {In our previous study, we systematically compared various extraction methods and identified the 80% ethanolic extract of Curcuma longa L. (CL-80) as the most effective in protecting neurons from stress-induced damage in both in vitro and in vivo models. Although curcumin, a major constituent of C. longa, has demonstrated neuroprotective effects, the role of ar-turmerone, a bioactive sesquiterpenoid also derived from C. longa, remains underexplored in Alzheimer's disease (AD) models. In this study, we evaluated the anti-inflammatory and cognitive-protective effects of CL-80 and ar-turmerone in both in vitro and in vivo models of amyloid-β (Aβ)-induced neurotoxicity. Primary cultured rat hippocampal neurons exposed to Aβ25-35 showed significantly increased expression of TNF-α, IFN-β, and iNOS, all of which were dose-dependently attenuated by CL-80 or ar-turmerone. Furthermore, both compounds suppressed Aβ-induced activation of the TLR4/NF-κB signaling axis at mRNA and protein levels. In an Aβ1-42-injected mouse model, oral administration of CL-80 or ar-turmerone significantly improved learning and memory performance in the Morris water maze and passive avoidance tests. Biochemical analyses of hippocampal tissues revealed reduced TLR4 expression and NF-κB activation, decreased acetylcholinesterase (AChE) activity, and restoration of acetylcholine (ACh) levels following treatment. Collectively, these findings suggest that both CL-80 and ar-turmerone exert neuroprotective effects by inhibiting TLR4/NF-κB-mediated neuroinflammation and preserving cholinergic function in an AD animal model. This study offers novel insight into the therapeutic potential of C. longa constituents for the treatment of AD.}, } @article {pmid40967471, year = {2025}, author = {Iqbal, A and Iqbal, K and Shah, YA and Ullah, F and Khan, J and Yaqoob, S}, title = {Multi-filter stacking in inception V3 for enhanced Alzheimer's severity classification.}, journal = {Neuroscience}, volume = {586}, number = {}, pages = {21-31}, doi = {10.1016/j.neuroscience.2025.08.049}, pmid = {40967471}, issn = {1873-7544}, mesh = {*Alzheimer Disease/classification/diagnostic imaging/pathology ; Humans ; Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/pathology ; Aged ; *Deep Learning ; Neural Networks, Computer ; Male ; Severity of Illness Index ; Female ; Support Vector Machine ; Aged, 80 and over ; }, abstract = {Alzheimer's disease, a progressive neurodegenerative disorder, is characterized by a decline in brain volume and neuronal loss, with early symptoms often presenting as short-term memory impairment. Automated classification of Alzheimer's disease remains a significant challenge due to inter-patient variability in brain morphology, aging effects, and overlapping anatomical features across different stages. While traditional machine learning techniques, such as Support Vector Machines (SVMs) and various Deep Neural Network (DNN) models, have been explored, the need for more accurate and efficient classification techniques persists. In this study, we propose a novel approach that integrates Multi-Filter Stacking with the Inception V3 architecture, referred to as CASFI (Classifying Alzheimer's Severity using Filter Integration). This method leverages diverse convolutional filter sizes to capture multiscale spatial features, enhancing the model's ability to detect subtle structural variations associated with different Alzheimer's disease stages. Applied to MRI data, CASFI achieved an accuracy of 97.27%, outperforming baseline deep learning models and traditional classifiers in both accuracy and robustness. This approach supports early diagnosis and informed clinical decision-making, providing a valuable tool to assist healthcare professionals in managing and planning treatment for Alzheimer's patients.}, } @article {pmid40967324, year = {2025}, author = {de Andrade, PRA and Motta, RC and Fonseca-Santos, B}, title = {Unlocking ferulic acid for neurological diseases and tailoring of nanoformulations to advance its brain delivery.}, journal = {International journal of pharmaceutics}, volume = {684}, number = {}, pages = {126173}, doi = {10.1016/j.ijpharm.2025.126173}, pmid = {40967324}, issn = {1873-3476}, mesh = {Humans ; *Coumaric Acids/administration & dosage/chemistry/pharmacokinetics ; Animals ; Brain/metabolism/drug effects ; Drug Delivery Systems ; *Nervous System Diseases/drug therapy ; *Nanoparticle Drug Delivery System ; Neurodegenerative Diseases/drug therapy ; Drug Compounding ; }, abstract = {Mental disorders represent a significant global health challenge, with a high prevalence and substantial impact on individual well-being. Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and various mood disorders, contribute significantly to the burden of neurological conditions worldwide. Identifying novel drug targets and exploring natural product-based molecules have become essential priorities in advancing treatment strategies for these complex diseases. Nanoencapsulation technology has emerged as a valuable tool to increase the stability, solubility, and bioavailability of natural products, thus improving their efficacy in treating neurological disorders. By encapsulating natural compounds such as ferulic acid (FA) in nanoscale delivery systems, researchers have aimed to overcome challenges related to poor solubility and bioavailability, ultimately enhancing therapeutic outcomes. In this review, we examine recent advancements focused on the therapeutic potential of FA in AD, PD, MS, brain cancer, depression (DP), anxiety (AX), and epilepsy (EP). Furthermore, we explored the use of nanoscale delivery systems to optimise the delivery of FA for improved treatment efficacy. We aim to inspire discoveries and innovative approaches to address neurological diseases by highlighting current progress and future directions in this field with FA.}, } @article {pmid40967100, year = {2025}, author = {Alsiraey, N and Dewald, HD}, title = {Restoring nitric oxide/Peroxynitrite equilibrium in impaired human neural progenitor cells: Nanomedical approaches and their potential impact on neurodegenerative disease treatment.}, journal = {Journal of inorganic biochemistry}, volume = {274}, number = {}, pages = {113073}, doi = {10.1016/j.jinorgbio.2025.113073}, pmid = {40967100}, issn = {1873-3344}, abstract = {Nitric oxide (NO), an essential inorganic signaling molecule, involved in many physiological processes and has promising therapeutic potential Its oxidation product, peroxynitrite (ONOO[¯]), is cytotoxic, and elevated ONOO[¯] levels induce nitroxidative stress, a factor implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Through pharmacological modulation of NO and ONOO[¯] levels in human neural progenitor cell (hNPCs), this study explores the potential pharmaceutical interventions targeting the NO and the neuronal nitric oxide synthase (nNOS) pathway, (NO/nNOS), to prevent or reduce AD progression by restoring the [NO]/[ONOO[¯]] balance. To achieve this, metalloporphyrin nanosensors have been effectively employed for real-time, in-situ measurement of NO and ONOO[¯] concentrations (200-300 nm diameter) were applied and precisely positioned 4-5 ± 1 μm from hNPCs membranes, enabling precise investigation of the [NO]/[ONOO[¯]] ratio. The [NO]/[ONOO[¯]] ratio emerged as a critical biomarker for the evaluation of nNOS coupling/uncoupling to the hNPC functioning/dysfunction. In healthy cells, this ratio was around 0.25 ± 0.005, While dysfunctional hNPCs treated to amyloid beta 42 (Aβ42)-a hallmark of AD-caused a dramatic 94 % drop, signaling severe cellular dysfunction. Based on these findings, potential pharmacological interventions have been proposed to prevent or reduce AD progression by restoring the [NO]/[ONOO[¯]] balance. Notably, a co-treatment of sepiapterin (SEP), a cofactor precursor for NO synthesis, with VAS 2870 (an NADPH oxidase inhibitor) partially restored the ratio to 0.1, indicating improved nNOS function.}, } @article {pmid40966774, year = {2025}, author = {Mahajan, G and Pandya, K and Tripathi, A and Kumar, D}, title = {Integrating molecular imaging with near-infrared theranostics to improve early detection and therapy of Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {165}, number = {}, pages = {108949}, doi = {10.1016/j.bioorg.2025.108949}, pmid = {40966774}, issn = {1090-2120}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy/diagnosis/therapy ; *Molecular Imaging/methods ; *Theranostic Nanomedicine ; *Fluorescent Dyes/chemistry/therapeutic use ; Early Diagnosis ; Animals ; Molecular Structure ; Infrared Rays ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) remains a significant unmet clinical need due to its asymptomatic prodromal phase and multifaceted pathophysiology, which comprises amyloid-β (Aβ) plaques characterized by neurofibrillary tangles (NFTs) of hyperphosphorylated tau. Conventional diagnostic methods, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), detect AD only after extensive neuronal loss. Recent progress in chemical biology has enabled the creation of multifunctional small-molecule theranostic probes that integrate diagnostic imaging with therapeutic intervention. This review emphasizes the design and molecular engineering of new probes in particular, near-infrared (NIR) dyes, aryl quinolines, cyanine-based fluorophores, and curcumin derivatives, which are highly specific for Aβ and tau aggregates, penetrate the blood-brain barrier (BBB) effectively, and are amenable to multimodal imaging including near-infrared imaging (NIR) fluorescence, MRI, PET. These probes commonly contain donor-acceptor motifs and exhibit environment-sensitive fluorescence, allowing for the real-time imaging of pathological protein aggregation. Furthermore, we consider dual-mode probes, such as PiB-C and BTTA, which combine metal chelation therapy with imaging, providing a targeted approach to disaggregate Aβ plaques concurrently visualizing therapeutic effectiveness. Through the combination of synthetic chemistry, molecular imaging, and neurotherapeutics, this transdisciplinary approach outlines a promising new paradigm for early AD detection and treatment. The development of these small-molecule theranostics presents new opportunities for personalized medicine in treating neurodegenerative diseases.}, } @article {pmid40966159, year = {2025}, author = {Ehrhardt, AC and Rogatzki, MJ}, title = {Yoga, Meditation, and Mindfulness for Treatment of Traumatic Brain Injury: A Scoping Review.}, journal = {Journal of integrative and complementary medicine}, volume = {}, number = {}, pages = {}, doi = {10.1177/27683605251379812}, pmid = {40966159}, issn = {2768-3613}, abstract = {Objective: The objective of this scoping review was to analyze research using yoga, meditation, and mindfulness (YMM) as a treatment for traumatic brain injury (TBI). Introduction: The rationale for this review was to provide an understanding of the methodology and outcome measures used in studies that include YMM as TBI treatment. There are currently no reviews that investigate how all three of these modalities are used in TBI treatment. This review is meant to draw attention to how this research is done and potentially improve future research study design. Inclusion Criteria: Criteria for studies included in this review were developed according to the participants, concept, and context framework. Specifically, participants must have experienced a TBI, the TBI had to be treated with yoga, mindfulness, meditation, or some combination of the three, subjects could not exclusively have had acquired brain injury such as stroke or Alzheimer's disease, and the study must have been published in the English language. Methods: PubMed, Google Scholar, Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature, PsyArXiv, ProQuest, and LoveYourBrain were searched for articles that met our criteria. A total of 72 articles were extracted to address 15 variables. Results: The majority of studies used either a pre-post or exploratory study design with no more than 29 female Caucasian subjects in the age range of 45-54 years. Most subjects participated in the study one month since their mild to severe TBI. In order to treat TBI symptoms, most studies used mindfulness, with the treatment done in person. Sessions of treatment typically occurred on a weekly basis for 10-30 min over 7-8 weeks. Outcome measures used to determine efficacy of treatment were primarily quality of life, followed by cognitive function and depression. Most studies were conducted in the United States after 2010 in the journal Brain Injury with no type of funding. Conclusions: Studies using YMM for treatment of TBI are typically done on a single type of population with a wide range of outcome variables and no control group. Future research may aim to include a control group and a variety of outcome measures consistent with those used in previous studies for result comparisons.}, } @article {pmid40964464, year = {2025}, author = {Ibrahim, R and Kambal, A and Abdelmajeed, MA}, title = {Glucagon-Like Peptide-1 Receptor Agonists in Neurodegenerative Diseases: A Comprehensive Review.}, journal = {Cureus}, volume = {17}, number = {9}, pages = {e92441}, pmid = {40964464}, issn = {2168-8184}, abstract = {There is a steadily increasing global burden of neurodegenerative diseases (NDs) such as dementia, including Alzheimer's disease (AD), and movement disorders like Parkinson's disease (PD), which emphasizes the importance of disease-modifying therapy (as opposed to symptomatic therapy). This review considers a new disease-modifying strategy through the so-called glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in these NDs, and the mechanistic rationale and evidence base. The review considers a multi-targeting strategy, translational issues, and a future research agenda. Translational challenges for these agents are also discussed, particularly the need to understand how the timing of treatment may influence outcomes. The review also considers unwanted side effects like unintended weight loss, which may compromise "at-risk" patient groups. In conclusion, GLP-1 RAs are an intriguing multitarget treatment option for people with NDs, and future research should focus on optimizing treatment for clinical trials, evolved agonists that can penetrate the central nervous system (CNS), and combination therapies.}, } @article {pmid40964378, year = {2025}, author = {Robinson-Cooper, L and Davidson, S and Koutoubi, R and Zhang, K and Park, H and Barker-Haliski, M}, title = {Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964378}, issn = {2692-8205}, support = {R01 AG067788/AG/NIA NIH HHS/United States ; }, abstract = {Presenilin 2 (PSEN2) gene variants increase the risk of early-onset Alzheimer's disease (AD). AD patients with PSEN2 variants have increased risk of unprovoked seizures versus age-matched healthy controls, yet few studies have interrogated PSEN2 contributions to seizures, and fewer have done so with aging. PSEN2 variant mice also do not exhibit amyloid-β (Aβ) accumulation, allowing for the assessment of Aβ-independent contributions to seizure risk in AD. Critically, PSEN proteolytic capacity may regulate hippocampal kainate-type glutamate receptors (KARs), with PSEN deletion reducing KAR availability and synaptic transmission in vitro (Barthet et al 2022). Kainic acid (KA) is a naturally occurring KAR agonist that acutely evokes severe seizures in mice. We thus hypothesized that PSEN2 knockout (KO) mice would have reduced latency to acutely evoked seizures and status epilepticus (SE), increased convulsive SE burden, worsened 7-day survival, and altered hippocampal KAR expression vs age-matched wild-type (WT) mice. Using a repeated low-dose systemic KA administration paradigm, we quantified the latency to acute seizures and convulsive SE, then quantified neuropathology in 3-4-month-old and 12-15-month-old male and female PSEN2 KO versus WT mice. GluK2 and GluK5 KAR subunit expression was colocalized in astrocytes and neurons by immunohistochemistry 7 days after KA-SE or sham-SE to define the interaction between PSEN2 loss and acute seizures on hippocampal KARs. Regardless of sex, young PSEN2 KO mice were more susceptible to KA-induced acute seizures than WTs. Young PSEN2 KO mice of both sexes also entered SE sooner than age-matched WT mice. In aged mice, there was no significant difference in latency to first seizure or SE onset between genotypes in either sex. However, regardless of genotype, aged females entered SE sooner than young females and experienced greater mortality. This was not observed in males. Among young animals, there was no difference in KAR expression between genotypes and regardless of treatment group. In both genotypes, hippocampal CA3 astrocytes expressed GluK5 following KA-SE, however, astrocytic GluK2 expression only occurred in WT mice. GluK5 expression was significantly reduced in untreated aged PSEN2 KO mice versus untreated WT mice, while total GluK2 expression did not differ between genotypes or seizure groups. Following KA-SE, astrocytic GluK5 expression was only present in WT animals in CA3, while both genotypes presented with astrocytic GluK5 expression. This study highlights that KARs are an understudied contributor to seizures in aging and AD that warrant further investigation.}, } @article {pmid40964168, year = {2025}, author = {Chai, Y and Shokri-Kojori, E and Saykin, AJ and Yu, M}, title = {Anxious-depressive symptoms and sleep disturbances across the Alzheimer disease spectrum.}, journal = {Nature. Mental health}, volume = {3}, number = {6}, pages = {594-612}, pmid = {40964168}, issn = {2731-6076}, support = {R01 AG019771/AG/NIA NIH HHS/United States ; U01 AG072177/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; }, abstract = {Patients with Alzheimer disease (AD) often experience neuropsychiatric symptoms, particularly anxious-depressive symptoms and sleep disturbances. These symptoms are associated with various factors related to AD, including amyloid-β and tau pathology, neurodegeneration, and cognitive decline, at different stages of the disease. However, it remains unclear whether anxious-depressive symptoms and sleep disturbances are merely symptoms or contribute as risk factors in the development and progression of AD. Consequently, there is a pressing need for a timely and informed discussion regarding these disturbances in AD. Here we discuss the most recent developments in understanding the etiology of anxious-depressive symptoms and sleep disturbances in AD, with a focus on how these symptoms interact with AD biomarkers to influence cognitive decline. Furthermore, we propose models of connections between anxious-depressive symptoms and/or sleep disturbances, AD biomarkers and cognition, aiming to inspire potential treatment plans for addressing these symptoms and exploring their impact on AD pathology and cognitive decline.}, } @article {pmid40964139, year = {2025}, author = {Kovacik, A and Vandergriff, K and Jarrett, B and Clevenger, C}, title = {An Update of the Treatment Landscape for Alzheimer's Disease: From Symptomatic Treatments to the Emergence of Amyloid-Targeting Therapies.}, journal = {Sage open aging}, volume = {11}, number = {}, pages = {30495334251376614}, pmid = {40964139}, issn = {3049-5334}, abstract = {Several approved Alzheimer's disease (AD) treatments help manage its associated cognitive symptoms (e.g., donepezil and memantine) or non-cognitive symptoms. However, disease-modifying AD therapies have recently emerged. These treatments aim to slow disease progression by targeting the pathology associated with progressive neurodegeneration. Specifically, two amyloid-targeting therapies (ATTs) are currently approved and available for use in the United States: the monoclonal antibodies donanemab (Kisunla™) and lecanemab (Leqembi[®]). Both treatments can slow disease progression and cognitive and functional decline in patients with mild cognitive impairment/mild dementia due to AD, but they are associated with class-based safety concerns, notably amyloid-related imaging abnormalities (ARIA). Because advanced practice providers (APPs) such as physician assistants and advanced practice nurses are key to AD patient care, they should be familiar with the biological continuum of AD and with ATTs and understand how to monitor and manage patients receiving these treatments. Therefore, this review aims to educate APPs about these new therapies. Specifically, it summarizes the approved indications and dosing for donanemab and lecanemab, as well as key clinical evidence of efficacy and safety. It also outlines practical considerations around the monitoring and management of patients treated with ATTs, including recommendations about treatment duration, adverse reaction management, and patient counseling.}, } @article {pmid40964091, year = {2025}, author = {Adhikary, K and Ganguly, K and Sarkar, R and Abubakar, M and Banerjee, P and Karak, P}, title = {Phytonutrients and their neuroprotective role in brain disorders.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1607330}, pmid = {40964091}, issn = {2296-889X}, abstract = {In the twenty-first century, cognitive impairment is a significant health problem. Function is substantially impaired by a number of neuropsychiatric and neurodegenerative diseases, such as Parkinsonism, schizophrenia, major depressive disorder, Alzheimer's disease and other types of cognitive impairment, cerebrovascular disabilities, seizure-related disorders, and brain traumas. Over time, a number of chemical messengers and signaling molecules have been identified as potential targets for treatment, and tests have been performed against these targets using both conventional and novel chemicals. Phytochemicals derived from medicinal plants are essential for preserving the chemical balance of the central nervous system because they change the activity of major inhibitory receptors that receive neurotransmitters. Many herbs have been used in conventional medicine to treat cognitive problems. Although the presence of receptors that are responsible or transporters for compounds called polyphenols and other phytochemicals in brain regions remains to be determined, multiple target substances seem to be a promising class of treatment options for treating disorders with multifactorial origins. Additional studies suggest that flavonoids possess significant anti-inflammatory properties in the brain, making them a promising therapeutic option for conditions such as ischemic or hemorrhagic stroke, as well as chronic neuroinflammatory disorders like Parkinson's and Alzheimer's disease. This review highlights how phytochemicals contribute to the protection against brain disorders and explores the underlying mechanisms involved in their action. It also emphasizes the core biological processes, providing deeper insight into the therapeutic potential of phytochemicals in the treatment of neurological conditions.}, } @article {pmid40963977, year = {2025}, author = {Wang, S and Luo, G and Zhao, Q and Zhang, S and Li, Z and Lu, J and Wang, F and Sun, D and Xu, H}, title = {Exploration of the potential role of plasma lipoprotein molecules in late-onset Alzheimer's disease among the Chinese population.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251378973}, pmid = {40963977}, issn = {2542-4823}, abstract = {BACKGROUND: Evidence suggests that lipoprotein metabolism play a crucial role in Alzheimer's disease (AD). However, their involvement in late-onset AD (LOAD) remains unclear. OBJECTIVE: This study aimed to uncover potential associations between lipoprotein metabolism and clinical LOAD diagnosis, cognitive function, and treatment. METHODS: We performed a lipidomic analysis of plasma samples from 46 individuals with LOAD and 16 healthy controls to investigate the potential association between lipoprotein profiles, LOAD diagnosis and cognitive function. Then, we conducted a protein-protein interaction analysis to explore the potential therapeutic role of lipoprotein molecules in LOAD. RESULTS: Our findings revealed that ApoA2 and HDL ApoA2 may be negatively associated with LOAD risk (odds ratio [OR] = 0.798, 95% confidence interval [CI] = 0.654-0.973, p = 0.026; OR = 0.785, 95% CI = 0.634-0.972, p = 0.026, respectively), while LDL-3 triglycerides showed a potential positive association (OR = 6.051, 95% CI = 1.789-20.470, p = 0.004). Additionally, HDL-4 ApoA1 may be positively correlated with cognitive function in LOAD (p = 0.047, r² = 0.087). Moreover, our findings suggest that ApoA2 may interact with targets of approved AD drugs. CONCLUSIONS: This study identifies potential key lipoprotein alterations associated with LOAD diagnosis and cognitive function, emphasizing the role of lipidomic insights in understanding and treating LOAD.}, } @article {pmid40963907, year = {2025}, author = {Yoon, BH and Kim, J and Sengupta, S and Park, CJ and Ko, M and Kang, JH and Ko, YT and Kim, Y and Lim, SM and Bae, Y and Choi, M and Jang, Y and Kwon, HJ and Son, HJ and Kim, HJ and Sim, T and Chang, KA and Lee, MS}, title = {Targeted autophagic clearance of Tau protects against Alzheimer's disease through amelioration of Tau-mediated lysosomal stress.}, journal = {Theranostics}, volume = {15}, number = {17}, pages = {9240-9260}, pmid = {40963907}, issn = {1838-7640}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Lysosomes/metabolism/drug effects ; *tau Proteins/metabolism/genetics ; *Autophagy/drug effects ; Mice ; Humans ; Disease Models, Animal ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism/drug effects ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; }, abstract = {Background: Lysosomal dysfunction could be an underlying cause of Alzheimer's disease, with Tau oligomer being an important inducer or amplifier of lysosomal stress associated with the disease. Tau oligomer is a well-known substrate of autophagy, and selective degradation of Tau with Tau-specific autophagy degrader might be feasible. Methods: Tau-specific autophagic degraders were synthesized by combining leucomethylene blue, linkers and a lysosomal degradation tag (Autac). Tau clearance and changes of Tau-mediated lysosomal stress by these degraders were studied in vitro. In vivo effects of a Tau-specific degrader were investigated employing a combined Tau/Aβ mutant mouse model characterized by an accelerated onset of neurological deficits. Human relevance was investigated using induced pluripotent stem cell (iPSC)-derived neuronal cells from an Alzheimer's disease patient. Results: Among Tau-specific Autac degraders, TauAutac-3 (TA-3) efficiently degraded Tau oligomer and monomer, an effect inhibited by bafilomycin A1, suggesting lysosomal Tau degradation. TA-3 treatment induced LC3, K63, OPTN or NDP52 puncta, which was partially colocalized with Tau oligomer. Signs of lysosomal stress, such as galectin-3 puncta, pHluorin fluorescence, altered lysosomal pH and CHMP2B recruitment, induced by Tau expression were reversed by TA-3. Autophagy impairment by Tau expression in vitro, likely due to lysosomal stress, was also reversed by TA-3. In vivo, TA-3 administration markedly reduced the accumulation of both Tau and Aβ in 6xTg mice, which was associated with amelioration of Tau-mediated lysosomal stress and autophagy impairment. Neuroinflammation characterized by increased numbers of GFAP[+] glial cells and Iba1[+] microglial cells, was also reduced following TA-3 administration. TA-3 remarkably improved neurologic deficits in 6xTg mice, such as impaired memory and reduced exploratory behavior. TA-3 reduced Tau and phospho-Tau accumulation in iPSC-derived neuronal cells from an Alzheimer's disease patient. Conclusion: These results suggest that Tau-specific autophagic (Autac) degraders could serve as novel therapeutic agents for Alzheimer's disease through reduction of Tau-mediated lysosomal stress.}, } @article {pmid40963573, year = {2025}, author = {Kaur, A and Alshammari, FS and Rehman, AU and Bharany, S}, title = {Intelligent Alzheimer's diagnosis and disability assessment: robust medical imaging analysis using ensemble learning with ResNet-50 and EfficientNet-B3.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1619228}, pmid = {40963573}, issn = {2296-858X}, abstract = {Neurodegenerative disorder Alzheimer's disease (AD) has progressive characteristics and leads to severe cognitive impairment that reduces life quality. Disease management along with effective intervention depends on the detailed diagnosis conducted early. The proposed framework builds an ensemble system from ResNet-50 and EfficientNet-B3 to conduct automated AD diagnostics by processing high-resolution Magnetic Resonance Imaging (MRI) images. The proposed model uses ResNet-50 to extract features coupled with EfficientNet-B3 as its robust classifier which achieves high accuracy alongside generalization performance. A large, high-quality dataset comprising 33,984 MRI images was used, ensuring diverse representation of different disease stages: the study included participants with four dementia stages organized as Mild, Moderate, Non-demented, and Very Mild Demented. The research applied several comprehensive data preprocessing methods combining normalization steps with rescaling algorithms alongside noise elimination techniques to achieve enhanced performance. Performance tests on the model required examination of accuracy along with precision and recall metrics and F1-score and ROC curve area measurements. The ensemble model delivered remarkable overall accuracy reaching 99.32% while surpassing separate deep learning architectures. The confusion matrix evaluation results showed superb classification results for Mild and Moderate stages along with non-dementia cases while maintaining minimal Wrong choices in Very Mild Demented cases. Experimental findings demonstrate the strength of deep learning algorithms to detect AD disease stages accurately. The robust and accurate performance of the proposed model indicates it has potential for use in medical environments to support radiologists in their work of early-stage AD screening and treatment development. Additional research in diverse clinical environments will strive to optimize and validate the model so it can meet real-world diagnostic requirements for medical use.}, } @article {pmid40963032, year = {2025}, author = {Hammonds, SK and Eftestøl, T and Kurz, KD and Fernandez-Quilez, A and , }, title = {Decision Strategies in AI-Based Ensemble Models in Opportunistic Alzheimer's Detection from Structural MRI.}, journal = {Journal of imaging informatics in medicine}, volume = {}, number = {}, pages = {}, pmid = {40963032}, issn = {2948-2933}, support = {F-12514//Helse Vest/ ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition and the most common form of dementia. Recent developments in AD treatment call for robust diagnostic tools to facilitate medical decision-making. Despite progress for early diagnostic tests, there remains uncertainty about clinical use. Structural magnetic resonance imaging (MRI), as a readily available imaging tool in the current AD diagnostic pathway, in combination with artificial intelligence, offers opportunities of added value beyond symptomatic evaluation. However, MRI studies in AD tend to suffer from small datasets and consequently limited generalizability. Although ensemble models take advantage of the strengths of several models to improve performance and generalizability, there is little knowledge of how the different ensemble models compare performance-wise and the relationship between detection performance and model calibration. The latter is especially relevant for clinical translatability. In our study, we applied three ensemble decision strategies with three different deep learning architectures for multi-class AD detection with structural MRI. For two of the three architectures, the weighted average was the best decision strategy in terms of balanced accuracy and calibration error. In contrast to the base models, the results of the ensemble models showed that the best detection performance corresponded to the lowest calibration error, independent of the architecture. For each architecture, the best ensemble model reduced the estimated calibration error compared to the base model average from (1) 0.174±0.01 to 0.164±0.04, (2) 0.182±0.02 to 0.141±0.04, and (3) 0.269±0.08 to 0.240±0.04 and increased the balanced accuracy from (1) 0.527±0.05 to 0.608±0.06, (2) 0.417±0.03 to 0.456±0.04, and (3) 0.348±0.02 to 0.371±0.03.}, } @article {pmid40962722, year = {2025}, author = {Wu, M and Hao, X and Li, T and Tian, JJ and Gao, XM and Li, ZG}, title = {[Effect of "Tongdu Qishen" acupuncture on pyroptosis in hippocampus and cortex of SAMP8 mice].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {50}, number = {9}, pages = {995-1004}, doi = {10.13702/j.1000-0607.20240754}, pmid = {40962722}, issn = {1000-0607}, mesh = {Animals ; *Pyroptosis ; Male ; Mice ; *Hippocampus/metabolism/cytology ; *Acupuncture Therapy ; Humans ; Acupuncture Points ; *Cerebral Cortex/metabolism/cytology ; Interleukin-1beta/genetics/metabolism ; Caspase 1/genetics/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; *Alzheimer Disease/therapy/genetics/physiopathology ; }, abstract = {OBJECTIVES: To explore the underlying mechanism of "Tongdu Qishen" acupuncture (dredging the Govern Vessel and normalizing mental activities) in treating SAMP8 mice from the perspective of pyroptosis. METHODS: Six-month-old male SAMP8 mice were randomly divided into model and "Tongdu Qishen" acupuncture (EA) groups, with 12 mice in each group. SAMR1 mice of the same age (n=12) were used as the normal group. In the EA group, EA (2 Hz/50 Hz, 20 min) was applied to "Baihui" (GV20) and "Yintang" (GV24[+]), and pricking bleeding was applied to "Shuigou" (GV26). The treatment was performed once a day, for a total of 28 days. Morris water maze test was used to evaluate the learning and memory ability of mice, and HE staining was used to observe the morphology of cells in the hippocampus and cortex. Nissl staining was used to observe the number of neurons in the hippocampus and cortex. Immunohistochemistry was used to observe the expressions of Aβ1-40, interleukin (IL)-1β and IL-18 in the hippocampus and cortex. The co-staining of TUNEL and Caspase-1 was detected by immunofluorescence. Western blot and real-time quantitative PCR were used to observe the protein and mRNA expression levels of Nod-like receptor 3 (NLRP3), Caspase-1 and Gasdermin D (GSDMD) in the hippocampus and cortex, respectively. RESULTS: Behavioral results showed that compared with the normal group, the escape latency was prolonged (P<0.001), the dwell time in the original platform quadrant and the times of crossing the original platform were considerably decreased (P<0.001) in the model group. In comparison with the model group, the escape latency was shortened (P<0.05, P<0.001, P<0.01), and the dwell time in the original platform quadrant was significantly increased (P<0.01) in the EA group. Following modeling, the number of neurons was decreased (P<0.001), the positive expression of Aβ1-40, IL-1β and IL-18 in the hippocampus and cortex, the co-expression of TUNEL and Caspase-1, and the protein and mRNA expression levels of NLRP3, Caspase-1, GSDMD were all increased (P<0.001) in the model group relevant to the normal group. After EA intervention, modeling induced increase and decrease of indexes mentioned above were completely reversed (P<0.01, P<0.05, P<0.001). CONCLUSIONS: "Tongdu Qishen" acupuncture may improve the cognitive function of SAMP8 mice by regulating the NLRP3/Caspase-1/GSDMD pathway, relieving the release of inflammatory factors and reducing the content of Aβ1-40.}, } @article {pmid40962125, year = {2026}, author = {Lian, W and Yuan, X and Zhou, F and Tong, Z and Cheng, Y and Zhang, W and He, J and Xu, J}, title = {Cornuside ameliorates LPS induced cognitive dysfunction and microglial NLRP3 inflammasome activation by enhancing Sirt1-mediated autophagy.}, journal = {Journal of ethnopharmacology}, volume = {355}, number = {Pt A}, pages = {120615}, doi = {10.1016/j.jep.2025.120615}, pmid = {40962125}, issn = {1872-7573}, mesh = {Animals ; *Sirtuin 1/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Autophagy/drug effects ; Mice ; *Microglia/drug effects/metabolism ; Inflammasomes/metabolism/drug effects ; Lipopolysaccharides/toxicity ; *Cognitive Dysfunction/drug therapy/chemically induced ; *Cornus/chemistry ; Male ; Mice, Inbred C57BL ; Cell Line ; Disease Models, Animal ; *Anti-Inflammatory Agents/pharmacology ; }, abstract = {Corni fructus are the fruits of Cornus officinalis Sieb. et Zucc. and is widely used in traditional Chinese Medicine for the treatment of dementia. Cornuside, derived from Corni fructus, has been shown to be effective in improving cognition of AD mouse. AIM: In the present study, we investigated the effect of cornuside on cognitive dysfunction and microglial NLRP3 inflammasome activation, as well as explored the underlying mechanism with respect to Sirt1 and autophagy. METHODS: AD mice were established and then treated with cornuside (3, 10, and 30 mg/kg) for 2 weeks. A series of behavioral tests were performed to assess cognition, including the Morris water maze, Y maze, nest building, step-down and step-through tests. Nissl staining was used to evaluate neuronal structural damage. LPS-stimulated BV2 cells were used for in vitro experiments. The anti-inflammatory effects of cornuside on cytokines and NLRP3 inflammasome activation were assessed using ELISA, RT-PCR, immunohistochemistry, western blotting, and immunofluorescence assays. To further elucidate the relationship between Sirt1, autophagy, and NLRP3 inflammasome activation, EX527 and 3-MA were used to inhibit Sirt1 and block autophagy flux in vitro, respectively. RESULTS: Cornuside significantly improved various behavioral performance and inhibited NLRP3 inflammasome activation in LPS-induced mice, as evidenced by decreased levels of NLRP3, ASC, pro-caspase1, caspase1, pro-IL-1β, IL-1β, GSDMD, GSDMD-NT and IL-18. Similar inhibitory effects of cornuside on NLRP3 inflammasome activation was also detected in LPS stimulated BV2 cells. The involvement of Sirt1 and autophagy were further explored in-vivo and in-vitro, revealing that cornuside increased the expression of Sirt1 and enhanced autophagy, with decreased SQSTM1/p62 and increased LC3BII. However, the inhibitory effect of cornuside on NLRP3 inflammasome activation was abrogated by 3-MA, and the effects of cornuside on promoting autophagy and inhibiting NLRP3 inflammasome activation was abolished by EX527. CONCLUSION: Cornuside exerts therapeutic effects on LPS induced AD mice by inhibiting microglial activation and NLRP3 inflammasome overactivation. And Sirt1 mediated autophagy activation is a vital mechanism by which cornuside degrades NLRP3 inflammasome, thereby alleviating neuroinflammation and improving cognitive function.}, } @article {pmid40959937, year = {2025}, author = {Navakkode, S and Kennedy, BK}, title = {Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer's Disease.}, journal = {Aging cell}, volume = {24}, number = {11}, pages = {e70235}, pmid = {40959937}, issn = {1474-9726}, support = {//NUS Medicine/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/physiopathology/genetics ; Disease Models, Animal ; Mice ; *Neuronal Plasticity/drug effects ; *Ketoglutaric Acids/pharmacology/therapeutic use ; Male ; Female ; Mice, Transgenic ; *Amyloid beta-Protein Precursor/metabolism/genetics ; Long-Term Potentiation/drug effects ; Synapses/drug effects/metabolism ; *Presenilin-1/metabolism/genetics ; Humans ; }, abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders, characterized by a progressive decline in cognitive function. Increasing evidence indicates that alpha-ketoglutarate (AKG), a key metabolite in the tricarboxylic acid (TCA) cycle, can extend lifespan and healthspan across various animal models, raising interest in its potential neuroprotective effects in age-related disorders such as AD. Our previous research found that dietary supplementation with calcium alpha-ketoglutarate (CaAKG), a calcium derivative of AKG, enhances both lifespan and healthspan in mice. However, little is known about the neuroprotective role of AKG/CaAKG in AD. Here, we show that CaAKG could rescue synaptic deficits that are associated with AD. Treatment with AKG or CaAKG ameliorates long-term potentiation (LTP) at hippocampal CA1 synapses in APP/PS1 mice, with a more profound effect in female AD mice than in males. The effects of CaAKG were mediated through an NMDA receptor-independent mechanism involving L-type calcium channels (LTCC) and calcium-permeable AMPA receptors (CP-AMPARs). Analysis of protein expression showed that AD hippocampal slices treated with CaAKG exhibited increased LC3-II levels, indicating enhanced autophagy. Similarly, rapamycin, an mTOR inhibitor, also rescued LTP deficits in AD mice, suggesting that the observed increase in autophagy may contribute to neuroprotection. Interestingly, rapamycin showed differential effects, as it rescued LTP in AD mice but blocked LTP in WT mice. We also observed that CaAKG facilitated synaptic tagging and capture (STC), a widely studied cellular model for associative memory, indicating its potential to facilitate associative memory. Overall, our findings suggest that CaAKG has neuroprotective effects in APP/PS1 mice. We propose CaAKG as a promising therapeutic target not only for aging but also for AD and potentially other age-associated neurodegenerative diseases, highlighting geroprotective strategies as viable alternatives for the prevention and treatment of AD.}, } @article {pmid40959879, year = {2025}, author = {Miller, ZA and Ossenkoppele, R and Graff-Radford, NR and Allen, IE and Shwe, W and Rosenberg, L and Olguin, DJ and Erkkinen, MG and Butler, PM and Spina, S and Yokoyama, JS and Desikan, RS and Scheltens, P and van der Flier, W and Pijnenburg, Y and Wolters, E and Rademakers, R and Geschwind, DH and Kramer, JH and Rosen, HJ and Rankin, KP and Grinberg, LT and Seeley, WW and Sturm, V and Perry, DC and Miller, BL and Rabinovici, GD and Gorno-Tempini, ML}, title = {Neurodevelopment and neural environment inform Alzheimer's disease age at onset and phenotype.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70668}, pmid = {40959879}, issn = {1552-5279}, support = {AG019724/NH/NIH HHS/United States ; AG062422/NH/NIH HHS/United States ; //Hellman Research Scientist Award/ ; AG062588/NH/NIH HHS/United States ; AG045611/NH/NIH HHS/United States ; DC015544/NH/NIH HHS/United States ; //Jon and Gale Love fund/ ; AG053435/NH/NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; AG048291/NH/NIH HHS/United States ; //Arking Foundation for Frontotemporal Dementia/ ; NS050915/NH/NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/epidemiology ; Age of Onset ; Female ; Phenotype ; Male ; Aged ; Risk Factors ; Middle Aged ; Cohort Studies ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Risk factors associated with sporadic non-amnestic and early-onset Alzheimer's disease (AD) remain underexamined. METHODS: We investigated a large, clinically heterogeneous, AD cohort for frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus) alongside novel factors (non-right-handedness, learning disability, seizures, autoimmune disease). RESULTS: Early-onset AD possessed lower frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus, all p < 0.001) and higher frequencies of novel factors (non-right-handedness, learning disability, active seizure, all p < 0.001; remote seizure, p = 0.002; and autoimmune disease, p = 0.007). An age at onset < 70 maximally distinguished novel from typical factors. Principal component analysis loaded novel factors into two components, non-right-handedness and learning disability versus seizure and autoimmune disease, which combined, resulted in an exponential decrease in age at onset from one factor alone. DISCUSSION: Identifying novel factors enriched in early-onset and non-amnestic AD introduces new theories of AD susceptibility and phenotypic heterogeneity, with significant implications for disease prediction and treatment. HIGHLIGHTS: We identified a suite of novel factors overrepresented in early-onset and non-amnestic AD. These factors can be broadly conceptualized as neurodevelopmental (non-right-handedness and learning disability) and neural environmental (seizure and autoimmunity). The combination of these factors produced exponential decreases in AD age at onset, compared to each alone, supporting a new theoretical framework for understanding AD risk with implications for disease prediction, prevention, and therapeutic intervention.}, } @article {pmid40959450, year = {2025}, author = {Shi, G and Ni, L and Kong, X and Ren, R and Shi, X and Xu, Y and Qu, Z and Zhou, H and Zhang, X}, title = {Unveiling the therapeutic potential of caudatin: Structural optimization, pharmacological mechanisms, and therapeutic implications.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1640365}, pmid = {40959450}, issn = {1663-9812}, abstract = {Caudatin is a C21 steroidal glycoside isolated from many species of the genus Cynanchum, has been utilized by traditional medicine to treat cancer and inflammation which is increasingly being considered a drug candidate because of the pharmacological activity it displays. This review provides a discussion of caudatin's structure-activity relationship (SAR), pharmacology, and therapeutic uses along with a synthesis of future challenges. Caudatin is a potent anti-cancer therapeutic that has been shown to modulate several important signaling pathways, which include but are not limited to: Wnt/β-catenin, NF-κB, and PI3K/AKT pathway, induce apoptosis through ROS mediated mitochondrial dysfunction, reduce metastatic spread through inhibition of epithelial-mesenchymal transition (EMT), and have an anti-inflammatory effect through inhibition of JNK/AP-1/NF-κB signaling. Caudatin has also displayed neuroprotection in models of Alzheimer's disease by activating TFEB and the autophagosome-lysosomal pathway mechanism of action, while also modulating PPARα. Furthermore, pharmacokinetic studies indicate that caudatin is rapidly absorbed and is able to selectively tail hepatic tissue while having little to no toxicity or significant adverse events in pre- clinical animal studies. Structure-activity studies suggest that modifications on the C-3 hydroxyl position, primarily with nitrogen heterocycles and/or sugars greatly enhance the bioactivity and solubility. With caudatin being such a great scaffold for medicinal chemistry, there is great opportunity to take advantage of caudatin as a building block to generate novel therapies which bridge traditional medicine with modern drug discovery. The future is aimed primarily at a combination strategy of synthetic derivatives, translational studies, and formulations. In further exploring caudatin as a treatment for cancer and neurodegenerative diseases, and inflammation.}, } @article {pmid40959086, year = {2025}, author = {Chen, R and Tang, X and Wang, Y and Wang, B and Mao, F}, title = {Protein palmitoylation: an emerging regulator of inflammatory signaling and diseases.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1652741}, pmid = {40959086}, issn = {1664-3224}, mesh = {Humans ; *Lipoylation ; *Signal Transduction ; *Inflammation/metabolism/immunology ; Animals ; *Protein Processing, Post-Translational ; Thiolester Hydrolases ; }, abstract = {Protein palmitoylation is a reversible lipid modification in which palmitoyl esters are covalently attached to cysteine residues of proteins. It controls various cellular physiological processes and alters protein stability, conformation, localization, membrane binding, and interaction with other effector proteins. Palmitoylation is catalyzed by a group of zinc finger DHHC-containing proteins (ZDHHCs), while the acyl-protein thioesterase family mediates depalmitoylation. Emerging evidence suggests that palmitoylation is critical for inflammatory signaling pathways, where palmitoylation is particularly important in the membrane localization of inflammation-associated proteins. Notably, dysregulation of palmitoylation has been associated with a variety of inflammatory diseases. Here, we provide an overview of the regulatory mechanisms of palmitoylation, explore the emerging role of palmitoylation in inflammatory signaling pathways, and examine the link between dysregulated palmitoylation and the pathogenesis of inflammatory diseases, including inflammatory bowel disease, autoimmune diseases, metabolic dysfunction-associated steatohepatitis, sepsis, Alzheimer's disease, Parkinson's disease, and diabetes. Finally, we discuss some of the challenges and opportunities facing the field. Targeting palmitoylation or its associated enzymes serves as a novel therapeutic approach for the treatment of inflammatory diseases.}, } @article {pmid40958782, year = {2025}, author = {Sun, LC and Li, WS and Chen, W and Zhao, DQ and Zhang, X and Li, CX and Ren, Z}, title = {Frontiers and Emerging Trends in Edaravone Research: A Bibliometric Analysis of Molecular Basis and Clinical Studies Using CiteSpace and VOSviewer.}, journal = {Journal of multidisciplinary healthcare}, volume = {18}, number = {}, pages = {5743-5758}, pmid = {40958782}, issn = {1178-2390}, abstract = {PURPOSE: Edaravone is a potent free-radical scavenger and antioxidant that has been widely investigated for its therapeutic potential in neurodegenerative diseases and oxidative stress-related conditions. Although previous studies have explored its molecular structure, pharmacological effects, and clinical applications, a comprehensive bibliometric analysis of its research trends and future directions remains lacking. METHODS: This study employed bibliometric methods to analyze edaravone-related publications from 2000 to 2024, using the Web of Science Core Collection database. The analysis examined publication trends; contributions by countries, institutions, and authors; and keyword clustering. Data visualization tools, such as CiteSpace and VOSviewer, were utilized to identify research clusters and emerging trends in edaravone research. RESULTS: The findings revealed a significant increase in edaravone-related publications, with China, Japan, and the United States as the leading contributors. Notable researchers, including Abe K and Yoshino H, have made substantial contributions to this field. Four major research clusters were identified: free radical scavenging, cerebral infarction, amyotrophic lateral sclerosis, and oxidative stress. Emerging trends suggest a growing interest in edaravone dexbornel for acute ischemic stroke treatment, as well as its potential applications in blood-brain barrier interactions and Alzheimer's disease. CONCLUSION: This bibliometric analysis highlights the growing interest in edaravone and its potential clinical application, particularly in neuroprotection. While this study provides valuable insights into current research trends, future studies should incorporate a broader range of sources and languages to obtain a more comprehensive understanding of the impact and scope of edaravone.}, } @article {pmid40957902, year = {2025}, author = {Ekins, TG and Rybicki-Kler, C and Deng, T and Brooks, IAW and Jedrasiak-Cape, I and Donoho, E and Ahmed, OJ}, title = {Psychedelic neuroplasticity of cortical neurons lacking 5-HT2A receptors.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {40957902}, issn = {1476-5578}, support = {R34 NS127101/NS/NINDS NIH HHS/United States ; R34NS127101//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; T32DC000011//U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)/ ; P50NS123067//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 MH129282/MH/NIMH NIH HHS/United States ; R01MH129282//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; T32 DC000011/DC/NIDCD NIH HHS/United States ; P50 NS123067/NS/NINDS NIH HHS/United States ; T32 NS076401/NS/NINDS NIH HHS/United States ; T32 DA007268/DA/NIDA NIH HHS/United States ; AARG-NTF-21-846572//Alzheimer's Association/ ; T32DA007268//U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/ ; }, abstract = {Classical psychedelic drugs show promise as a treatment for major depressive disorder and related psychiatric disorders. This therapeutic efficacy stems from long-lasting psychedelic-induced neuroplasticity onto prefrontal cortical neurons and is thought to require the postsynaptic expression of serotonin 2A receptors (5-HT2AR). However, other cortical regions such as the granular retrosplenial cortex (RSG) - important for memory, spatial orientation, fear extinction, and imagining oneself in the future, but impaired in Alzheimer's disease - lack 5-HT2AR and are thus considered unlikely to benefit from psychedelic therapy. Here, we show that RSG pyramidal cells lacking postsynaptic 5-HT2A receptors still undergo long-lasting psychedelic-induced synaptic enhancement. A newly engineered CRISPR-Cas-based conditional knockout mouse line reveals that this form of psychedelic-induced retrosplenial plasticity requires presynaptic 5-HT2A receptors expressed on anterior thalamic axonal inputs to RSG. These results highlight a broader psychedelic therapeutic utility than currently appreciated, suggesting potential for augmenting RSG circuit function in Alzheimer's disease, post-traumatic stress disorder, and other neuropsychiatric conditions, despite the lack of postsynaptic 5-HT2A receptors.}, } @article {pmid40956653, year = {2025}, author = {Shaker, A and Ljunggren, G and Vossen, LE and Religa, D and Raaschou, P}, title = {Impact of socio-economic and patient-centered characteristics on access to Alzheimer's disease medication in primary care: A population-based study in the Stockholm county, Sweden.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {180-192}, doi = {10.1177/13872877251375900}, pmid = {40956653}, issn = {1875-8908}, mesh = {Humans ; Sweden/epidemiology ; Male ; Female ; *Alzheimer Disease/drug therapy/epidemiology ; *Primary Health Care ; Aged ; Retrospective Studies ; Aged, 80 and over ; *Memantine/therapeutic use ; *Health Services Accessibility/statistics & numerical data ; Socioeconomic Factors ; *Cholinesterase Inhibitors/therapeutic use ; Cohort Studies ; Middle Aged ; Patient-Centered Care ; }, abstract = {BackgroundDespite treatment guidelines for Alzheimer's disease (AD), access to AD medications varies significantly within the same health care setting.ObjectivePredictors influencing access to AD medication were assessed in a retrospective cohort study comprising most individuals diagnosed with AD in Stockholm 2013-2021.Methods14,884 individuals were included, with an incident AD diagnosis between 2013-2021 in Stockholm, Sweden. The primary outcome was the dispensation of AD-specific drugs (cholinesterase inhibitors or memantine) within 90 days before to 180 days after AD diagnosis. We used a generalized linear mixed-effects model (GLMM). Variables included patient-centered characteristics such as age and comorbidities, and characteristics of the primary care centers (PCC) where the individuals were listed, including Care Need Index (CNI).ResultsOverall, 77% of diagnosed patients were dispensed AD medications. Individuals listed at PCCs with high CNI score, indicative of lower socio-economic resources of the area, were less likely to receive a dispensation of any AD medication compared with low CNI score (76.2% versus 84.8%; OR 0.65, 95% CI 0.50-0.86). The association between CNI score and likelihood of receiving AD medication was attenuated in subgroup analysis of individuals living in nursing homes. Also associated with lower likelihood of receiving AD medications were age ≥85 years (OR 0.25, 95% CI 0.21-0.28), nursing home residency (OR 0.37, 95% CI 0.34-0.41), and comorbidity (OR 0.63, 95% CI 0.57-0.70).ConclusionsSocio-economic factors strongly influenced the likelihood of receiving AD medication, in addition to more established factors such as age and comorbidities. Interventions are needed to eliminate barriers to equal drug treatment in AD, particularly those related to socio-economic disadvantages.}, } @article {pmid40956407, year = {2025}, author = {Guo, S and Wei, F and Chang, Y and Wu, S and Lou, Z and Ma, Y and Huang, Q and He, K and Fu, C and Cao, X and Liang, S and Cheng, W and Yin, Y}, title = {Early astrocyte-targeted intervention guided by [18]F-SMBT-1 imaging attenuates disease progression in 3xTg-AD mice.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {}, number = {}, pages = {}, pmid = {40956407}, issn = {1619-7089}, support = {82472014//National Natural Science Foundation of China/ ; 81974270//National Natural Science Foundation of China/ ; 24ZR1450000//Natural Science Foundation of Shanghai Municipality/ ; 23ZR1441200//Natural Science Foundation of Shanghai Municipality/ ; }, abstract = {PURPOSE: Astrocyte reactivity is a key pathological feature and potential therapeutic target of Alzheimer's disease (AD), however, the optimal timing of its modulation remains unexplored. This study aims to combine [18]F-SMBT-1 based molecular imaging with astrocyte-targeted intervention in 3xTg-AD mice to address this challenge. METHODS: PET imaging with [18]F-SMBT-1 was conducted in 3xTg-AD mice at 4, 6, 10, and 12 months of age, with age-matched wild-type (WT) mice as controls. The standardized uptake value ratio was calculated using cerebellum as the reference region by PMOD software. Immunofluorescence (IF) analysis was used to assess astrocyte reactivity ex vivo. Astrocyte-targeted intervention via Nrf2 overexpression was performed in 4-month-old 3xTg-AD mice using adeno-associated virus vectors. Following intervention, PET imaging with [18]F-SMBT-1 was performed to assess astrocyte reactivity, open field test and Morris water maze test were performed to evaluate cognitive function, and IF analysis was used to assess pathological feature of AD. RESULTS: In 3xTg-AD mice of different ages, higher uptake of [18]F-SMBT-1 was observed in the cortex and hippocampus compared to age-matched WT controls. IF analysis further confirmed the presence of reactive astrocytes activation in 3xTg-AD mice. Both in vivo [18]F-SMBT-1 imaging and ex vivo IF analysis identified early-onset astrocyte activation in 3xTg-AD mice. Based on these observations, we implemented early astrocyte-targeted intervention via Nrf2 overexpression at 4 months of age in 3xTg-AD mice. Subsequent in vivo [18]F-SMBT-1 PET imaging demonstrated a significant reduction in astrocyte reactivity following this intervention. Our findings also demonstrated that early astrocyte-targeted intervention might delay AD pathological progression in 3xTg-AD mice, as supported by attenuated anxiety-like behavior and ameliorated neuropathological features. CONCLUSION: [18]F-SMBT-1 PET imaging served as a diagnostic biomarker for monitoring astrocyte reactivity to guide therapeutic timing decisions, and as a therapeutic response indicator for evaluating treatment efficacy. Early astrocyte-targeted intervention demonstrated significant therapeutic potential. These findings highlighted the translational potential of molecular imaging-guided strategies and astrocyte-targeted therapies in AD.}, } @article {pmid40956219, year = {2025}, author = {Landhuis, E and Christiansen, J and Studios, NM}, title = {A Multipronged Assault: A new understanding of Alzheimer's is leading to a variety of new treatment approaches.}, journal = {Scientific American}, volume = {333}, number = {3}, pages = {89}, doi = {10.1038/scientificamerican102025-5T8bP0cW0x69LnvyUGc4td}, pmid = {40956219}, issn = {0036-8733}, } @article {pmid40955908, year = {2025}, author = {Atewogboye, O and Taylor, JP and Harrison, JR}, title = {Pharmacological strategies for managing dementia with Lewy bodies: an expert review of symptom-targeted care.}, journal = {Expert review of clinical pharmacology}, volume = {18}, number = {9}, pages = {645-653}, doi = {10.1080/17512433.2025.2562151}, pmid = {40955908}, issn = {1751-2441}, mesh = {Humans ; *Lewy Body Disease/drug therapy/physiopathology ; Antipsychotic Agents/adverse effects/administration & dosage/pharmacology ; Polypharmacy ; Cognitive Dysfunction/etiology/drug therapy ; Sleep Wake Disorders/etiology/drug therapy ; Animals ; }, abstract = {INTRODUCTION: Dementia with Lewy Bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease, characterized by a complex combination of cognitive, neuropsychiatric, motor, autonomic, and sleep-related symptoms. Symptom fluctuation, polypharmacy risks, and high sensitivity to commonly used drugs present unique challenges for management. AREAS COVERED: This review provides a comprehensive overview of the symptomatic management of DLB, organized by clinical domains. It critically evaluates current pharmacological and non-pharmacological treatment strategies for cognitive impairment, hallucinations, parkinsonism, autonomic dysfunction, and sleep disturbances. Evidence is drawn from clinical trials, meta-analyses, and extrapolated findings from related disorders such as Alzheimer's disease and Parkinson's disease. EXPERT OPINION: Effective DLB management requires an individualized, symptom-prioritized approach that carefully balances therapeutic benefit with potential adverse effects, particularly given the high risk of antipsychotic sensitivity and treatment-induced worsening of symptoms. Despite recent progress, evidence remains sparse for many symptom domains. Greater investment in DLB-specific clinical trials and development of targeted therapies is urgently needed to improve patient outcomes.}, } @article {pmid40955711, year = {2025}, author = {Tan, A and Wang, Z and Aumont, E and Li, A and Qin, X and Yang, X and Feng, W and Yang, J and Li, X and Xiao, J and Zhou, B and Xing, Y and Yi, Y and Li, J}, title = {Determinants of Treatment Willingness and Willingness-to-Pay for Lecanemab in China: A Network Analysis.}, journal = {Alzheimer disease and associated disorders}, volume = {39}, number = {4}, pages = {223-230}, doi = {10.1097/WAD.0000000000000689}, pmid = {40955711}, issn = {1546-4156}, mesh = {Humans ; China ; Male ; Female ; Surveys and Questionnaires ; Aged ; *Alzheimer Disease/drug therapy/economics/psychology ; *Caregivers/psychology ; Middle Aged ; *Patient Acceptance of Health Care ; }, abstract = {BACKGROUND: Lecanemab is the first disease-modifying therapy for Alzheimer disease (AD) approved in China. However, the factors affecting patient and caregiver willingness to adopt this novel treatment have not been assessed yet. OBJECTIVE: To investigate the factors influencing both treatment willingness and willingness-to-pay for lecanemab among Chinese AD patients and their caregivers. METHODS: We surveyed 195 AD patients and their caregivers using structured questionnaires assessing key factors influencing treatment willingness, including efficacy (W efficacy), adverse effects (W adverse), inconvenience (W inconvenience), cost (W cost), overall willingness to treat (W treat), and amount willing to pay (W amount). Additional variables included income, cognitive and functional assessments, caregiver burden (ZBI), health status (HS), education levels (patient/caregiver: edu, edu.c), psychiatric symptoms (PSY), and satisfaction with conventional treatments (effect). Network analysis mapped variable inter-relationships. RESULTS: W treat showed a strong direct association with W cost (0.99). W efficacy and W inconvenience indirectly influenced W treat through W cost (W efficacy -W inconvenience : 1.5, W inconvenience -W cost : 1.12, W cost -W treat : 0.99). Income (0.48) and effect (0.51) directly impacted W treat . Edu, edu.c, CDR, PSY, ZBI, and HS were indirectly correlated with W treat . W amount was directly associated with W treat (0.31), W cost (0.68), and W adverse (0.16). W efficacy and W inconvenience indirectly influenced W amount through W cost (W efficacy - W inconvenience : 1.5, W inconvenience -W cost : 1.12, W cost -W amount : 0.68). Network stability tests (CS >0.50) confirmed robustness. CONCLUSION: This study demonstrates that reducing payment barriers has a greater impact on real-world adoption of innovative therapies than clinical efficacy alone. Addressing financial constraints also enhances patients' willingness to pay. These findings provide evidence-based insights for developing patient-centered clinical decision pathways.}, } @article {pmid40955309, year = {2025}, author = {Wang, L and Feng, L and Ning, B and Wang, Z and Dai, C and Li, M}, title = {Natural Products from Chinese Medicine Targeting NF-κB Signaling: Emerging Therapeutic Avenues for Neurodegenerative Diseases.}, journal = {Drug design, development and therapy}, volume = {19}, number = {}, pages = {8135-8159}, pmid = {40955309}, issn = {1177-8881}, mesh = {Humans ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Biological Products/pharmacology/chemistry ; *Medicine, Chinese Traditional ; Signal Transduction/drug effects ; Animals ; *Drugs, Chinese Herbal/pharmacology/chemistry ; }, abstract = {This review summarizes recent advances in leveraging natural products from Chinese medicine to modulate the nuclear factor kappa B (NF-κB) signaling pathway for the prevention and treatment of neurodegenerative diseases (NDDs), focusing specifically on Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). NF-κB proteins regulate cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. Emerging evidence indicates that NF-κB plays a pivotal role in driving key hallmarks of NDD progression, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and dysregulation of the cell cycle. Natural products from Chinese medicine exert modulatory effects on NF-κB signaling through diverse pharmacological mechanisms, ultimately improving cognitive and motor impairments in preclinical NDDs models. The pleiotropic nature of natural products derived from traditional Chinese medicine (TCM)-which operate through subunit-specific modulation of NF-κB-underscores their potential as next-generation therapeutics. Investigating the intricate regulation of NF-κB by natural products from Chinese medicine will not only enrich our understanding of the pathogenesis of NDDs but also establish a theoretical foundation for the development of new therapeutic drugs for NDDs, providing innovative strategies for prevention and treatment.}, } @article {pmid40954136, year = {2025}, author = {Martínez-García, J and Fernández, B and Artime, E and Álvarez, L and González-Iglesias, H and Clases, D and Pereiro, R}, title = {ICP-MS for Multiplexed Protein Determination in Extracellular Vesicles from APP/PS1 Mice Blood Serum-Application to a Zn Supplementation Pilot Study.}, journal = {Analytical chemistry}, volume = {97}, number = {38}, pages = {20928-20936}, pmid = {40954136}, issn = {1520-6882}, mesh = {Animals ; *Extracellular Vesicles/metabolism/chemistry ; Pilot Projects ; Mice, Transgenic ; Mice ; *Zinc/administration & dosage/pharmacology ; Mass Spectrometry/methods ; Male ; *Alzheimer Disease/blood ; Female ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Biomarkers/blood ; Dietary Supplements ; }, abstract = {Neurodegenerative diseases represent a significant challenge due to their complex etiology, late diagnosis, and lack of effective treatments. Extracellular vesicles (EVs) have emerged as promising carriers of disease biomarkers, especially proteins, but their low abundance in biological fluids complicates their detection. Here, we present a novel strategy for the multiplexed quantitative determination of EV-associated proteins in blood serum from APP/PS1 transgenic mice, a model of Alzheimer's disease. The method combines inductively coupled plasma-time-of-flight mass spectrometry (ICP-ToFMS) with competitive immunoassays using metal nanocluster-labeled (AuNCs, PtNCs, IrNCs) antibodies targeting Alpha-Actinin 1 (ACTN), Galectin-3-binding protein (LG3BP), and Moesin (MSN). EVs were isolated using an optimized ultracentrifugation protocol to reduce the level of serum protein contamination. Proteomic screening identified target proteins with a known relevance to neurodegeneration, and the developed assay achieved detection limits in the low femtomolar range. The approach was applied to a pilot study on Zn supplementation in 16-month-old APP/PS1 mice, revealing sex-dependent and genotype-specific differences in protein expression but sex-independent patterns in regulatory mechanisms (especially for MSN and LG3BP). Among the studied markers, MSN levels showed statistically significant differences with Zn treatment in male homozygous mice. This work demonstrates the potential of ICP-MS for sensitive and multiplexed biomarker quantification in EVs, supporting its use in neurodegenerative research and supplementation studies.}, } @article {pmid40953123, year = {2025}, author = {Haaland, B and Dickson, SP and Santana, AF and Tanzi, RE and Dubois, B and Peters, O and Grimmer, T and Christensen, J and Mallinckrodt, C and Schneeberger, A and Hendrix, SB}, title = {Efficacy of AD04, an aluminum-based vaccine adjuvant, in patients with early Alzheimer's disease: Post hoc analysis of AFF006 (NCT01117818), a proof-of-concept, phase 2 randomized controlled trial.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {234-242}, doi = {10.1177/13872877251375985}, pmid = {40953123}, issn = {1875-8908}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Adjuvants, Immunologic/therapeutic use ; *Adjuvants, Vaccine/therapeutic use ; *Aluminum Hydroxide/therapeutic use ; *Alzheimer Disease/drug therapy ; *Alzheimer Vaccines/therapeutic use ; Amyloid beta-Peptides/immunology ; Double-Blind Method ; Proof of Concept Study ; Treatment Outcome ; }, abstract = {BackgroundThe AFF006 trial (NCT01117818) provided unexpected evidence of benefits of the vaccine adjuvant AD04 (aluminum oxyhydroxide) in patients with early Alzheimer's disease (AD), compared with AD02, a vaccine consisting of a peptide that mimics the N-terminal region of human amyloid-β (Aβ) conjugated with keyhole limpet hemocyanin.ObjectiveThe objective of this post hoc analysis was to assess whether this unexpected benefit of AD04 was an artifact of multiple testing (i.e., type I error inflation) or a robust result.MethodsIn this post hoc assessment, we used permutation testing to estimate type I error inflation due to the evaluation of multiple outcomes in AFF006. Efficacy was assessed using a patient-level global statistical test combining composite endpoints of cognition, function, and global AD. In addition, we examined the observed treatment benefits of AD04 in the context of effects observed in trials of aducanumab, donanemab, and lecanemab, monoclonal anti-Aβ antibodies that received regulatory approval for AD.ResultsThe global statistical test suggested a treatment benefit of AD04 versus ineffective AD02 arms, even after accounting for multiplicity (primary methodology p-value, 0.03; permutation test p-value, 0.02). The observed effect estimates for AD04 compared favorably with approved monoclonal antibodies.ConclusionsPost-hoc analyses are hypothesis generating rather than confirmatory. Adjusting for multiplicity using permutation testing can determine whether post-hoc effects are worth pursuing, or unlikely to be confirmed. These analyses have motivated a follow-up prospective randomized controlled trial, ADVANCE (EudraCT 2022-003532-73), in which optimized AD04 dosing will be compared to placebo in early AD.}, } @article {pmid40953121, year = {2025}, author = {Gao, M and Chen, J and Zhang, B and Li, J and Lang, J and Zhao, X and Zhang, Q}, title = {Melatonin alleviates cognitive impairment via modulating NLRP3/Caspase 1 pathway in db/db mice.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {157-169}, doi = {10.1177/13872877251375479}, pmid = {40953121}, issn = {1875-8908}, mesh = {Animals ; *Melatonin/pharmacology/therapeutic use ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism/etiology ; Mice ; Signal Transduction/drug effects ; *Caspase 1/metabolism ; Hippocampus/drug effects/metabolism ; Male ; Apoptosis/drug effects ; Diabetes Mellitus, Experimental/metabolism ; Neurons/drug effects/metabolism ; Mice, Inbred C57BL ; }, abstract = {BackgroundActivation of NLRP3 inflammasome has been implicated in cognitive impairment. Melatonin, known for its anti-inflammatory properties and traditional use in regulating circadian rhythms, is the focus of this study. This study intended to investigate the role of melatonin in diabetic cognitive impairment model.ObjectiveThe present study aimed to investigate the underlying mechanism of melatonin in alleviating diabetic cognitive impairment by suppressing NLRP3/Caspase 1 signaling pathway.MethodsCognitive function was assessed using Morris water maze test and Novel Object Recognition test. Apoptosis rate of hippocampal neurons was evaluated by TUNEL staining. Western blot was used to evaluate NLRP3/Caspase 1 pathway expression. Double immunofluorescence labelling of GFAP, Iba-1 or NeuN with NLRP3 respectively showed the localization of NLRP3 in hippocampus of db/db mice. In vitro, HT-22 cells treated with high glucose as cellular model were transfected with pc-DNA3.1-mNLRP3 or co-cultured with NLRP3 inhibitor MCC950 to elucidate NLRP3/Caspase 1 pathway in neuronal apoptosis regulation.ResultsMelatonin treatment improved cognitive function and morphologic abnormalities of hippocampal neurons. The double immunofluorescence labelling revealed melatonin inhibited NLRP3 inflammasome activation in hippocampal neurons rather than microglia or astrocytes. TUNEL staining and western blot showed melatonin markedly reversed the upregulation of NLRP3/Caspase 1 signaling pathway against neuronal apoptosis.ConclusionsMelatonin attenuates diabetic cognitive impairment in db/db mice with down-regulation of NLRP3/Caspase 1 signaling pathway. In vivo and vitro studies supported that NLRP3 activation in hippocampal neurons was associated with diabetic cognitive impairment progression.}, } @article {pmid40953107, year = {2025}, author = {Li, H and Wu, Y and Huang, T and Sun, Y and Lu, Z and Li, M and Wo, H and Shao, F and Tang, S and Zhao, Y and Dai, J and Yi, H and The Alzheimer's Disease Neuroimaging Initiative, }, title = {Development of a risk prediction model for Alzheimer's disease based on the UK Biobank prospective study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {142-156}, doi = {10.1177/13872877251375473}, pmid = {40953107}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/genetics/epidemiology/diagnosis ; United Kingdom/epidemiology ; Male ; Female ; *Biological Specimen Banks ; Risk Factors ; Prospective Studies ; Aged ; Proportional Hazards Models ; Middle Aged ; Risk Assessment ; Polymorphism, Single Nucleotide ; Multifactorial Inheritance ; Genetic Predisposition to Disease ; UK Biobank ; }, abstract = {BackgroundEarly prevention and intervention for Alzheimer's disease (AD) are critical due to the absence of effective therapeutic treatment. However, a widely accepted risk prediction model for AD has yet to be established.ObjectiveTo develop a novel risk prediction model for AD by leveraging recent advances in identifying risk factors, focusing on multi-omics data.MethodsGenetic data from the UK Biobank were employed to calculate the polygenic risk score (PRS) using the clumping and thresholding (C + T) method. Univariate Cox regression and Elastic Net Cox models were utilized to identify significant predictors in the training cohort. Subsequently, a multivariate Cox regression model was developed to construct the prediction model, which was visualized using a nomogram. The performance of the model was evaluated through calibration curves, receiver operating characteristic (ROC) curves, and the Hosmer-Lemeshow test.ResultsTen risk factors, including age, education, family history of dementia, diabetes, depression, hypertension, anemia, coronary heart disease (CAD), falls and PRS, were identified as significant predictors through Cox regression and Elastic Net Cox model. The model demonstrated strong predictive performance, with area under the curves (AUCs) of 0.864 [95% CI: (0.814, 0.911)], 0.860 [95% CI: (0.842, 0.876)], and 0.842 [95% CI: (0.819, 0.863)] at 5, 10, and 14 years, respectively, in the validation cohort.ConclusionsIncorporating colocalized single nucleotide polymorphisms (SNPs) into the PRS derived using the C + T method significantly enhances predictive accuracy. This study highlights the importance of integrating multimodal patient data, including colocalized genetic information, to refine AD risk prediction.}, } @article {pmid40952625, year = {2025}, author = {Kocanci, FG and Sarban, HE and Yildiz, F}, title = {Evaluating the Neuroprotective and Acetylcholinesterase Inhibitory Properties of Four Calcineurin Inhibitor Drugs: Tacrolimus, Pimecrolimus, Cyclosporin A, and Voclosporin.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {16592-16616}, pmid = {40952625}, issn = {1559-1182}, support = {32126//President of the Turkish Health Institutes (TUSEB)/ ; }, mesh = {*Tacrolimus/pharmacology/analogs & derivatives ; *Neuroprotective Agents/pharmacology ; *Calcineurin Inhibitors/pharmacology ; Humans ; *Cholinesterase Inhibitors/pharmacology ; *Acetylcholinesterase/metabolism ; Molecular Docking Simulation ; *Cyclosporine/pharmacology ; Cell Line, Tumor ; Hydrogen Peroxide ; Cell Survival/drug effects ; Molecular Dynamics Simulation ; }, abstract = {Neurodegenerative diseases (ND), marked by progressive neuronal degeneration, often involve dysregulation of acetylcholinesterase (AChE), a key enzyme in cholinergic neurotransmission. AChE inhibition is a well-established therapeutic strategy for Alzheimer's disease (AD), the most prevalent ND, as it aims to restore impaired cholinergic function. However, the effects of calcineurin inhibitors (CNIs), primarily used as immunosuppressants, on AChE activity remain largely unexplored. Recent evidence suggests CNIs possess neuroprotective properties, highlighting their potential for ND treatment. This study evaluated the binding affinities of FDA-approved CNIs-Tacrolimus (Tac), Pimecrolimus (Pim), Cyclosporine A (Csa), and Voclosporin (Voc)-to AChE via molecular docking and molecular dynamic simulation. AChE inhibition was assessed in vitro using the Ellman method and in H2O2-induced degenerative neuron-like SH-SY5Y cells via ELISA and qRT-PCR. Neuroprotection was examined through MTT assays and neurite analysis. Additionally, the antiapoptotic effect was examined by ELISA analysis measuring caspase-3. Docking studies confirmed strong AChE binding for all CNIs, with Voc exhibiting the highest affinity. Voc demonstrated superior in vitro AChE inhibition, surpassing galantamine at low concentrations. Cellular assays showed that CNIs, particularly Voc, significantly inhibited AChE expression at the gene level. Moreover, Voc markedly restored cell viability and reduced neuronal degeneration in H2O2-treated cells. These findings suggest CNIs, especially Voc, as promising candidates for ND treatment, targeting AChE overactivity and oxidative stress.}, } @article {pmid40952411, year = {2025}, author = {Kanda, A and Rani, A and Mazumder, A}, title = {Exploring precision medicine by utilizing individual genetic information for the management of Alzheimer's disease.}, journal = {Pharmacogenomics}, volume = {26}, number = {10-12}, pages = {455-474}, pmid = {40952411}, issn = {1744-8042}, mesh = {Humans ; *Alzheimer Disease/genetics/therapy/drug therapy ; *Precision Medicine/methods ; Apolipoproteins E/genetics ; Biomarkers ; Methylenetetrahydrofolate Reductase (NADPH2)/genetics ; Genetic Predisposition to Disease ; }, abstract = {Alzheimer's Disease (AD) represents a formidable challenge in neurology, characterized by progressive neurodegeneration and cognitive decline. Traditional therapeutic approaches have failed to deliver significant outcomes, underscoring the need for innovative paradigms such as precision medicine. The review explores integrating genomic, biomarker-driven, and individualized therapeutic strategies to tackle AD. It examines the role of key genetic factors, including APOE and MTHFR polymorphisms, in influencing disease susceptibility and treatment responses. Advances in biomarker technologies, such as blood-based and imaging biomarkers, are highlighted for their potential in early diagnosis and patient stratification. Additionally, the review underscores the importance of tailoring interventions across different stages of AD, incorporating lifestyle modifications and emerging tools like artificial intelligence & recent patented technologies. Precision medicine offers a transformative pathway, aiming to deliver personalized, effective care that addresses the complex and multifactorial nature of AD. The paradigm shift promises improved clinical outcomes and enhanced patient quality of life.}, } @article {pmid40952136, year = {2025}, author = {Frykman, H}, title = {Analytical considerations and clinical utility of plasma phosphorylated Tau217.}, journal = {Critical reviews in clinical laboratory sciences}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/10408363.2025.2551648}, pmid = {40952136}, issn = {1549-781X}, abstract = {Blood-based biomarkers are an easily available and practical tool for Alzheimer's disease (AD) screening and diagnosis. Plasma phosphorylated Tau217 (p-tau217) is the front-runner candidate for AD diagnosis due to its strong correlation with core AD pathology determined either by cerebrospinal fluid biomarker (CSF) and positron emission tomography (PET) or postmortem examination. While plasma p-tau217 is firmly associated with AD pathology, it is crucial to evaluate its performance in distinguishing AD from mixed pathologies, as brain autopsies have shown the coexisting of AD pathology with other related types of dementia. Moreover, the measurement of AD biomarkers will be a crucial element in defining eligibility for disease-modifying treatment in clinical practice. Moreover, plasma p-tau217 is a highly efficacious biomarker in the early detection of Aβ pathology, making it a feasible test for AD screening in clinical practice. Several assays, including the ALZpath p-tau217 assay and the Fujirebio plasma p-tau217 assay, have been made commercially available for research use. A few studies analytically and clinically have validated these immunoassays as laboratory diagnostic tests for AD diagnosis and differentiating from non-AD neurodegenerative disorders in clinical practice.}, } @article {pmid40951935, year = {2025}, author = {Wei, Y and Li, H}, title = {The Efficacy and Safety of Amyloid Beta-Directed Monoclonal Antibodies for Alzheimer's Disease: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials.}, journal = {Human psychopharmacology}, volume = {40}, number = {5}, pages = {e70017}, doi = {10.1002/hup.70017}, pmid = {40951935}, issn = {1099-1077}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Randomized Controlled Trials as Topic ; *Antibodies, Monoclonal/adverse effects/pharmacology/administration & dosage/therapeutic use ; Clinical Trials, Phase III as Topic ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of mortality worldwide. One of the newer treatments for AD is amyloid beta (Aβ) directed monoclonal antibodies (mAbs). This systematic review and meta-analysis aimed to assess the efficacy and safety of this class of drugs. METHODS: A comprehensive literature search was conducted across Scopus, Web of Science, PubMed, and the Cochrane Library until January 30, 2025, focusing on phase III randomized controlled trials (RCTs) evaluating anti-Aβ mAbs. RESULTS: Twelve RCTs with 24 arms were included. Anti-Aβ mAbs significantly reduced the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score (mean difference (MD): -0.16, 95% confidence interval (CI) (-0.29, -0.04)), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score (MD: -0.87, 95% CI (-1.13, -0.60)), and amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR) (MD: -0.11, 95% CI (-0.19, -0.02)). They also significantly increased the Mini-Mental State Examination (MMSE) score (MD: 0.31, 95% CI (0.15, 0.46)) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score (MD: 1.21, 95% CI (0.89, 1.53)). However, they were associated with a significant increase in complications, including amyloid-related imaging abnormalities-edema/effusion (ARIA-E) (odds ratio (OR): 10.20, 95% CI (7.17, 14.50)), ARIA-hemosiderosis or microhemorrhage (ARIA-H) (OR: 1.75, 95% CI (1.22, 2.50)), and any adverse events (OR: 1.22, 95% CI (1.08, 1.38), I[2]: 48.59%)). The subgroup analysis showed that treatment administered in the early/preclinical stages of AD resulted in a greater reduction in CDR-SB and ADAS-Cog scores, as well as in amyloid burden. CONCLUSIONS: Anti-Aβ mAbs offer modest clinical benefits, and pose some serious complications, necessitating a cautious approach to their prescription.}, } @article {pmid40951730, year = {2025}, author = {Besin, V and Humardani, FM and Yudiarto, FL and Ong, PA and Putra, SED and Ningrum, RA}, title = {Amyloid-Related Imaging Abnormality (ARIA) Beyond the APOE-ε4 Allele.}, journal = {Chronic diseases and translational medicine}, volume = {11}, number = {3}, pages = {186-196}, pmid = {40951730}, issn = {2589-0514}, abstract = {Monoclonal antibodies (mAbs) have made significant progress in the treatment of Alzheimer's disease (AD). However, mAbs are associated with adverse effects, including Amyloid-Related Imaging Abnormality (ARIA), which manifests as edema or effusion (ARIA-E) and hemorrhage (ARIA-H). The mechanisms behind these effects are not yet fully understood. Moreover, spontaneous ARIA has been insufficiently explored, and mAb therapies, particularly lecanemab, have mainly focused on patients with the APOE-ε4 allele carrier. This review aims to address this gap by examining the mechanisms of spontaneous ARIA, ARIA induced by mAbs, and the influence of genetic variants on ARIA development. The autoantibody-Aβ-mediated immune response targets excessive Aβ deposits, increasing immune activity through microglial reactivity. The heightened immune response, driven by Aβ accumulation in blood vessels, promotes angiopathy and inflammation, potentially contributing to spontaneous ARIA. The APOE-ε4 allele carrier is more strongly associated with ARIA-E because it redistributes Aβ deposition from the brain to blood vessels, influencing microglial reactivity. The redistribution enhances vascular integrity and reduces the risk of ARIA-H. However, it also increases the likelihood of ARIA-E due to Aβ accumulation in the vasculature, triggering inflammation. In contrast, the development of ARIA-H is linked to increased TREM2 expression and microglial reactivity, leading to impaired vascular integrity and disrupted matrix remodeling, which worsens the condition. Additionally, the adverse effects of mAbs may extend beyond the APOE-ε4 allele, possibly impacting other genetic variants involved in microglial reactivity, Aβ redistribution, and vascular integrity.}, } @article {pmid40951709, year = {2025}, author = {Cui, CX and Shao, XN and Li, YY and Qiao, L and Lin, JT and Guan, LH}, title = {Therapeutic potential of mesenchymal stem cells in neurodegenerative diseases.}, journal = {World journal of stem cells}, volume = {17}, number = {8}, pages = {107717}, pmid = {40951709}, issn = {1948-0210}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, are characterized by the progressive loss of neuronal function and structure, leading to severe morbidity and mortality. Current therapeutic approaches are ineffective at stopping or reversing disease progression. Stem cell therapy has emerged as a promising candidate in research and treatment. Mesenchymal stem cells (MSCs) are considered ideal candidates for regenerative medicine because of their high proliferation rate and multi-differentiation potential. MSCs can differentiate into neurons and glial cells, modulate immune responses, and reduce inflammation, and their exosomes can promote neural repair and regulate neuronal function; thus, MSCs offer unique advantages for treating neurodegenerative diseases. However, challenges remain in optimizing cell delivery methods, ensuring the long-term survival and integration of transplanted cells, and fully understanding their therapeutic effects. This article primarily outlines the functions of MSCs in neurodegenerative diseases, with the intention that further research will fully harness their potential and translate these findings into clinical applications, offering new hope for patients suffering from neurodegenerative diseases.}, } @article {pmid40951706, year = {2025}, author = {Shan, XQ and He, MH and Gao, WL and Li, YJ and Liu, SZ and Liu, Y and Wang, CL and Zhao, L and Xu, SX}, title = {Mesenchymal stem cell-derived exosomes: Shaping the next era of Alzheimer's disease treatment.}, journal = {World journal of stem cells}, volume = {17}, number = {8}, pages = {109006}, pmid = {40951706}, issn = {1948-0210}, abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disease for which effective disease-modifying therapies are lacking. Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as a promising therapeutic approach due to their unique biological functions and favorable biocompatibility. This review systematically explores the mechanism of action of MSC-Exos in AD therapy, including the removal of β-amyloid via the delivery of degradative enzymes, modulation of neuroinflammation, and promotion of neural regeneration. Meanwhile, this paper summarizes recent advances in preclinical and clinical studies, and analyzes the challenges in production standardization, safety assessment, and long-term efficacy validation of exosome therapies. Finally, several innovative strategies are proposed to enhance the therapeutic potential of MSC-Exos, including exosome functionalization and targeting optimization, gene editing techniques. This aims to promote the translation of exosomes from basic research to clinical application.}, } @article {pmid40951469, year = {2025}, author = {Widaja, E and Pawitan, JA and Ramli, Y}, title = {Therapeutic potential of hUC-MSC secretome preconditioned with IFN-γ and/or TNF-α: An in vitro study on Alzheimer's neuronal cell models.}, journal = {Narra J}, volume = {5}, number = {2}, pages = {e2281}, pmid = {40951469}, issn = {2807-2618}, mesh = {Humans ; *Interferon-gamma/pharmacology ; *Alzheimer Disease/therapy ; *Mesenchymal Stem Cells/metabolism ; *Tumor Necrosis Factor-alpha/pharmacology ; *Neurons/drug effects ; *Secretome/metabolism ; Umbilical Cord/cytology ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disease that is characterized by toxic Amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). Treatment options include the use of human umbilical cord mesenchymal stem cell (hUC-MSC)-based therapy. Its secretome contains healing substances such as neprilysin (CD10), which breaks down Aβ42; anti-inflammatory cytokines, which lower inflammation; and growth factors, which promote neuronal regeneration. The aim of this study was to produce hUC-MSC secretomes preconditioned with tumor necrosis factor-alpha (TNF-α) and/or interferon-gamma (IFN-γ) to enhance the secretion of these healing substances. hUC-MSCs were sub-cultured in T-25 flasks at a seeding density of 5×103 cells/cm[2] in 10 mL xeno-free medium. hUC-MSCs were preconditioned with TNF-α only, IFN-γ only, and a combination of TNF-α and IFN-γ. This study used 10 ng/mL TNF-α and 20 ng/mL IFN- γ. The secretome was harvested after 48 hours of preconditioning and then filtered through a 0.22 µm filter. In vitro tests were conducted to assess the effects of the secretome on neuronal survival using the neuroblastoma SH-SY5Y cell line. These cells were differentiated with retinoic acid (RA) and then exposed to Aβ42 to mimic Alzheimer's disease neurons. Secretome therapy was applied at concentrations of 5%, 10%, and 20% to evaluate neuroprotective effects. Four types of secretome were tested: unpreconditioned, TNF-α preconditioned, IFN-γ preconditioned, and a combination of TNF-α and IFN-γ. High levels of CD10 (neprilysin) expression were observed in hUC-MSCs treated with IFN-γ and TNF-α, although they did not release sufficient soluble neprilysin (sNEP). Viability results indicated that secretomes preconditioned with IFN-γ at 10% and 20% concentrations provided the highest increase in cell viability after 72 hours post-therapy. The combination of TNF-α and IFN-γ preconditioned secretome exhibited synergistic effects, particularly at 5% and 10% doses at 24- and 72-hours post- therapy. In conclusion, preconditioned hUC-MSC secretome represents a promising therapeutic approach for Alzheimer's disease, as it enhances neuronal cell viability and promotes neuronal regeneration. However, further studies are required to optimize sNEP release and maximize therapeutic efficacy in in vivo models.}, } @article {pmid40950425, year = {2025}, author = {Brown, CA and Cousins, KAQ and Korecka, M and McGrew, E and Chen-Plotkin, A and Detre, JA and McMillan, CT and Lee, EB and Das, SR and Mechanic-Hamilton, D and Yushkevich, PA and Nasrallah, IM and Shaw, LM and , and Wolk, DA}, title = {Temporal Modeling of Amyloid and Tau Trajectories in Alzheimer's Disease using PET and Plasma Biomarkers.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40950425}, support = {P01 AG084497/AG/NIA NIH HHS/United States ; RF1 AG069474/AG/NIA NIH HHS/United States ; R25 NS065745/NS/NINDS NIH HHS/United States ; R01 AG072796/AG/NIA NIH HHS/United States ; R01 AG055005/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG056014/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVE: To compare PET and plasma-based temporal modeling of amyloid and tau biomarkers in Alzheimer's disease. METHODS: Longitudinal amyloid PET, [18]F-flortaucipir tau-PET, and Fujirebio Lumipulse plasma p-tau217 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and University of Pennsylvania Alzheimer's Disease Research Center (Penn ADRC) were used to generate biomarker trajectory models using Sampled Iterative Local Approximation (SILA). SILA models using plasma p-tau217 were compared to amyloid and tau PET-based models to estimate tau onset age (ETOA) and estimate amyloid onset age (EAOA), and factors influencing ETOA and time from ETOA to dementia were evaluated for PET and plasma-based models. RESULTS: Plasma-based models generated similar results to PET for EAOA and ETOA, with stronger model agreement for ETOA than EAOA. Accuracy of estimated onset age compared to actual onset age was high within modality with slightly greater error when comparing across modalities (i.e. plasma to PET). For both plasma and PET models, earlier ETOA was associated with younger EAOA, female sex, and ≥1 ApoE ε4 allele. Earlier dementia onset after ETOA was associated with later ETOA for both plasma and PET models, while male sex was associated with shorter tau to dementia gap in plasma models. INTERPRETATION: Temporal modeling of plasma biomarkers provides comparable information to PET-based models, particularly for tau onset age. Plasma-based temporal modeling can serve as a widely accessible tool for clinical assessment of biological disease duration that places the patient on the disease timeline, which may allow for improved discussion of prognosis and treatment decisions.}, } @article {pmid40950166, year = {2025}, author = {Wang, Y and Anchipolovsky, S and Bhuiyan, P and Sato, L and Liang, G and Chuang, DM and Wei, H}, title = {Lithium Chloride Inhibits Iron Dysregulation and Ferroptosis in Induced Pluripotent Stem Cells with ApoE4/E4 from a sporadic Alzheimer's disease patient.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40950166}, issn = {2692-8205}, support = {R01 AG061447/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD), particularly its sporadic form (SAD, 95% AD patients), is strongly associated with the apolipoprotein E4 ApoE4 genotype and characterized by oxidative stress, iron dysregulation, and increased susceptibility to ferroptosis. Lithium, a well-established neuroprotective agent, has shown potential to mitigate several pathological mechanisms in AD, including ferroptosis. This study investigates the therapeutic potential of lithium chloride in human induced pluripotent stem cells (iPSCs) derived from a SAD patient with ApoE4/E4 genotype, and compared effects with those of isogenic gene-edited ApoE3/E3 control. Lithium treatment significantly improved cell viability in ApoE4/E4 iPSCs. It also reversed key ferroptosis phenotypes, including elevated cytosolic Fe[[2+]], increased expression of divalent metal transporter 1, reduced level of glutathione peroxidase 4, enhanced lipid peroxidation, and excessive ROS production. Moreover, lithium normalized mitochondrial respiration and reduced proton leak, indicating preservation of mitochondrial function and protection against mitochondrial damage and cell death. Lithium also reduced the expression of type 1 InsP3 receptor (InsP3R-1) protein, a Ca[[2+]] channel located on the endoplasmic reticulum (ER) membrane. Together, these findings highlight lithium's inhibition of ferroptosis through modulation of iron metabolism, antioxidant defenses, and inhibition of disrupted Ca[2+] signaling. Given its demonstrated efficacy in reversing ApoE4-driven cellular vulnerabilities, lithium salt warrants further investigation for the treatment of AD.}, } @article {pmid40950069, year = {2025}, author = {Simpson, D and Morrone, CD and Wear, D and Khani, A and Liu, F and Gutierrez, J and Yu, WH}, title = {Brain large artery dilatation increases the risk for Alzheimer's disease pathology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.08.29.672901}, pmid = {40950069}, issn = {2692-8205}, abstract = {Alzheimer's disease (AD) and related dementia cases are increasing globally, emphasizing the urgent need to clarify disease mechanisms for translational application in diagnoses and treatment. Vascular alterations represent a major pathological feature of AD, and beyond the well-established roles of small vessel disease and large artery atherosclerosis, our group has previously demonstrated that brain large artery dilatation is associated with elevated risk of dementia and Alzheimer pathology. The most severe manifestation of this non-atherosclerotic arterial phenotype is dolichoectasia, an enlargement of large blood vessels (Gutierrez et al., 2019; Melgarejo et al., 2024). Despite consistent epidemiological evidence across populations, the mechanistic link between arterial dilatation and AD remains poorly understood. To address this gap, we induced dolichoectasia in App [NL-G-F] mice, a model of amyloid pathology, by injecting elastase into the cisterna magna. After three months, brains were examined using biochemical and immunohistochemical methods. Elastase-treated mice exhibited a significant increase in amyloid plaques in the hippocampus (p = 0.021) and cortex (p = 0.029) compared with vehicle-treated controls. Neuronal loss was evident in the CA1 region of the hippocampus (p = 0.036), with a trend towards neurodegeneration in CA3 (p = 0.055). We also observed elevated p62 in the hippocampus and cortex (p = 0.009 and p = 0.001 , respectively), suggesting impaired protein or autophagic-lysosomal clearance. Although no overt increase in neuroinflammation or astrogliosis was detected at this time point, matrix metalloproteinase-9 (MMP-9) levels were trending towards elevated levels (p = 0.058). Combined, these findings indicate successful elastase-induced brain arterial dilatation accelerates AD-related pathology in App [NL-G-F] mice, providing mechanistic evidence that large artery dilatation may contribute directly to Alzheimer's disease progression.}, } @article {pmid40949788, year = {2025}, author = {Alzenaidi, F and Aldoweesh, O and Alghofaili, S and Fadel, A and Ali Awad Lasloom, R and Alharbi, D and Almalki, F and Ahmad Alkhairi, A and Alharbi, M and Ahmed Alhamdan, N and Azzam, AY}, title = {Selective serotonin reuptake inhibitors and glucose metabolism in Alzheimer's disease and related dementias: A systematic review and meta-analysis of brain metabolic and adverse event data.}, journal = {Metabolism open}, volume = {27}, number = {}, pages = {100389}, pmid = {40949788}, issn = {2589-9368}, abstract = {INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression in Alzheimer's disease (AD), however their effects on glucose metabolism remain poorly understood. We conducted a systematic review and meta-analysis to evaluate SSRI effects on brain glucose metabolism and metabolic adverse events in AD patients. METHODS: Following PRISMA 2020 guidelines, we searched multiple databases up to July 11, 2025 for studies investigating SSRI effects on glucose-related outcomes in AD patients. Despite significant heterogeneity in study designs and populations, we performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. We performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. Advanced Bayesian hierarchical modeling and Markov simulations projected long-term metabolic outcomes. RESULTS: Twelve studies with total included 7143 participants met our inclusion criteria, including nine randomized controlled trials and three observational studies. Brain FDG-PET revealed SSRI use restored dorsal raphe nucleus hypometabolism (standardized mean difference 0.87, 95 % CI: 0.52-1.22, P-value = 0.001). Meta-analysis demonstrated increased gastrointestinal adverse events (risk ratio 2.15, 95 % CI: 1.68-2.76, P-value<0.001, with moderate between-study heterogeneity), with sertraline showing highest rates. Citalopram 30 mg provided significant weight loss protection (risk ratio 0.13, 95 % CI: 0.02-0.98, P-value = 0.02), though this exceeds the recommended 20 mg maximum dose for elderly patients due to cardiac safety considerations. Long-term diabetes incidence showed no increased risk (hazard ratio 0.75, 95 % CI: 0.50-1.12, P-value = 0.15). Bayesian modeling revealed 85 % probability of beneficial brain metabolic effects and 89 % probability of citalopram superiority for weight protection. CONCLUSIONS: SSRIs restore brain glucose metabolism in AD patients while causing manageable peripheral metabolic effects. Citalopram appears the best for weight-sensitive patients, while sertraline requires gastrointestinal monitoring. These findings support SSRI safety for metabolic outcomes in AD treatment, however longer-term studies with controlled metabolic outcomes are needed to confirm our findings. The observed citalopram weight protection benefit was documented at 30 mg daily, which exceeds recommended dosing limits for elderly patients due to cardiac safety concerns.}, } @article {pmid40949676, year = {2025}, author = {Cai, H and Hu, J and Zhao, C and Lin, J}, title = {Wearable devices in neurological disorders: a narrative review of status quo and perspectives.}, journal = {Annals of translational medicine}, volume = {13}, number = {4}, pages = {46}, pmid = {40949676}, issn = {2305-5839}, abstract = {BACKGROUND AND OBJECTIVE: Neurological disorders are a group of diseases involving motor, sensory, cognitive, and autonomic functions, among which stroke, Alzheimer's disease (AD), and Parkinson's disease (PD) are prevalent. Their management, especially in conditions with chronic courses or long-term sequelae, remains a substantial unmet need. With the growing comprehension of neuroscience, the development of digital technology, and the rising demand for quality of life, wearable devices offer a promising solution for disease management. The review aimed to evaluate the application and prospect of wearable devices in neurological disorders. METHODS: We conducted the review by searching papers on the application of wearable devices and wearable technology in neurology and neurological disorders using multiple databases. We summarized the present development status of wearable devices, and outlined the potential value and future direction for further research. KEY CONTENT AND FINDINGS: Existing wearable devices for neurological diseases can be applied to diagnosis and follow-up, as an electronic biomarker detector capturing subtle and objective changes in motor, sensory, and cognitive function. The devices can also be utilized for treatment and rehabilitation, mainly through exoskeletons and brain-computer interface. The application of wearable devices in neurology currently faces several critical limitations, including technical bottlenecks in the detection of fine motor and sensory functions, a lack of industry standards, and a limited sample size. CONCLUSIONS: This review demonstrates the potential of wearable technology in people with neurological disorders, enabling disease management and clinical trials outside clinical settings in the future. Nevertheless, further research is required to develop lighter, more user-friendly devices with various functions. It is believed that with increasing demand and technical support, wearable devices would have a promising range of applications.}, } @article {pmid40949612, year = {2025}, author = {Gao, L and Wang, J and Bi, Y}, title = {Nanotechnology for Neurodegenerative Diseases: Recent Progress in Brain-Targeted Delivery, Stimuli-Responsive Platforms, and Organelle-Specific Therapeutics.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {11015-11044}, pmid = {40949612}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism/drug effects ; *Drug Delivery Systems/methods ; Nanomedicine/methods ; Nanoparticles/chemistry ; Organelles/drug effects/metabolism ; Liposomes/chemistry ; *Nanoparticle Drug Delivery System/chemistry ; Drug Carriers/chemistry ; }, abstract = {Neurodegenerative diseases-including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis-are characterized by progressive neuronal loss and complex pathological mechanisms such as protein aggregation, mitochondrial dysfunction, and neuroinflammation. Conventional therapies offer limited efficacy due to the blood-brain barrier (BBB) and lack of targeted delivery. Nanotechnology has emerged as a transformative strategy for precise brain-targeted treatment. This review summarizes recent advances in nanoparticle-based drug delivery systems, including polymeric nanoparticles, liposomes, inorganic nanomaterials, and biomimetic carriers, highlighting their design features, BBB-penetration mechanisms, and disease-specific applications. Emphasis is placed on stimuli-responsive nanocarriers that react to pH, reactive oxygen species, or enzyme activity, enabling site-specific drug release. Additionally, organelle-targeting strategies-particularly those directed at mitochondria and lysosomes-are explored for their role in subcellular precision therapy. The integration of diagnostic and therapeutic modalities in theranostic nanoplatforms is also discussed. By consolidating preclinical progress and emerging technologies, this review offers insights into the future of nanomedicine in treating neurodegenerative diseases and lays the groundwork for clinical translation.}, } @article {pmid40949219, year = {2025}, author = {Van, DTT and Hoang, TLH and Tran, TVT and Le, TH and Le, LS and Nguyen, QM and Nguyen, THH and Bich, TTN and Nguyen, THC and Phan, CU and Nguyen, CC}, title = {Structural Characterizations and In Vitro Bioactivities of a d‑Fructose-Rich Polysaccharide from Gymnopetalum cochinchinense as a Potential Candidate for Alleviating Alzheimer's Disease.}, journal = {ACS omega}, volume = {10}, number = {35}, pages = {40342-40353}, pmid = {40949219}, issn = {2470-1343}, abstract = {The presented investigation attempts to unveil the structural characteristics, bioactivities, and potential application of Gymnopetalum cochinchinense-derived d-fructose-rich heteropolysaccharide (denoted as PS-HB5) for the treatment of Alzheimer's disease (AD). Structural analyses of the PS-HB5 evaluated by FT-IR, GC-MS, and NMR techniques reveal a novel repeating unit composed of d-glucose and d-fructose linked through (1 → 6)-glucosyl, (2 → 6)-fructosyl, and (2 → 4)-fructosyl bonds, and possesses a molecular weight of 1.217 × 10[5] Da. The PS-HB5 exhibits strong antioxidant activity, as evidenced by its DPPH and ABTS radical scavenging rates of 84.12% and 74.14%, associated with the IC50 values of 0.80 and 3.06 mg.mL[-1], respectively. In addition, the PS-HB5 shows an inhibition rate of 78.37% (IC50 = 221.96 μg.mL[-1]) toward nitric oxide (NO) production in LPS-stimulated macrophages. Cytotoxicity assays indicate selective inhibition of the PS-HB5 against HepG2 and KB cancer cell lines (IC50 = 449.95 and 408.34 μg/mL), with minimal impact on MCF-7 and SK-LU-1. Interestingly, PS-HB5 demonstrates an outstanding AChE inhibitory effect, achieving 41.01% inhibition at 500 μg.mL[-1], placing it among the most active AChE-inhibitory polysaccharides. These findings unveil the PS-HB5 potential as a candidate for the treatment of Alzheimer's Disease.}, } @article {pmid40949132, year = {2025}, author = {Han, X and Meng, X and Wu, Y and Xia, W and Xue, S and Liu, X and Lyu, C and Li, Z and Yan, X and Won Jung, H and Zhang, S}, title = {Systems pharmacology identifies ajugol-mediated NF-κB/caspase-3 inhibition and isoacteoside-driven p62/mTOR-mediated autophagy as key mechanisms of Rehmanniae Radix and its processed form in Alzheimer's treatment.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1644847}, pmid = {40949132}, issn = {1663-9812}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the deposition of senile plaques, neurofibrillary tangles, and neuronal dysfunction, resulting in severe cognitive and memory decline. The root of the Scrophulariaceae plant Rehmannia glutinosa (Gaertn.) DC. (Rehmanniae radix; RR) and its product Rehmanniae radix praeparata (RRP) possess high nutritional and medicinal value. Both show therapeutic potential for AD in traditional medical settings. However, the differences in their bioactive components and the mechanisms of action underlying their anti-AD effects remain unclear. METHODS: In this study, APP/PS1 mice were used as the animal model of AD. Ultra-high-performance liquid chromatography coupled with Q-Exactive tandem mass spectrometry (MS/MS) (UPLC-QE-MS/MS), network pharmacology, proteomics, molecular docking, and 16S rRNA sequencing were used to investigate the differences in the medicinal components of RR and RRP and their mechanisms of action in the treatment of AD. The mechanisms of action of two identified critical components, ajugol and isoacteoside, were further verified in the D-galactose/AlCl3-induced Institute of Cancer Research (ICR) mouse model of AD-with cognitive function evaluated using the Morris water maze and open-field tests-and the amyloid-beta (Aβ)-induced BV2 cell model of inflammation. RESULTS: Ajugol and isoacteoside were identified as the key anti-AD bioactive compounds in RR and RRP, respectively, through UPLC-QE-MS/MS. Integrated network pharmacology, proteomics, and 16S rRNA sequencing implicated neuroinflammation, apoptosis, and autophagy as critical pathways for their anti-AD effects. Subsequently, in vivo and in vitro experiments demonstrated that ajugol exerted its effects mainly by modulating the TLR/NF-κB/NLRP3 and BCL-2/BAX/cytochrome C/caspase-3 pathways, while isoacteoside primarily acted via the LC3-Ⅱ/P62/p-mTOR/mTOR pathway. Ajugol and isoacteoside mitigated cognitive impairment in AD models, decreased Aβ plaque accumulation in hippocampal tissues, and attenuated inflammatory injury-induced cytotoxicity in BV2 microglia, thereby suppressing AD progression. CONCLUSION: In this work, we systematically elucidated the differential mechanisms underlying the anti-AD effects of ajugol and isoacteoside. We found that ajugol primarily acts via the TLR/NF-κB/NLRP3 and BCL-2/BAX/cytochrome C/caspase-3 pathways, while isoacteoside acts via the LC3-II/P62/p-mTOR/mTOR pathway. These findings establish a foundation for developing RRP-based complementary medicines and functional foods.}, } @article {pmid40948811, year = {2025}, author = {Imiruaye, OE and Perez, IG and Carson, BC and Crouzet, C and Garcia, J and Han, D and Bhattacharya, S}, title = {Spatiotemporal differential regulation of extrasynaptic GluN2B receptor subunits and PSA-NCAM in brain aging and Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1649625}, pmid = {40948811}, issn = {1662-4548}, abstract = {INTRODUCTION: Extrasynaptic GluN2B N-methyl-D-aspartate receptors (ES-GluN2B) are localized outside synapses and promote excitotoxic signaling, apoptosis, and long-term depression (LTD) in Alzheimer's disease (AD). Polysialylated neural cell adhesion molecule (PSA-NCAM) physiologically inhibits ES-GluN2B activity, and its downregulation is associated with impaired synaptic plasticity. However, the spatiotemporal changes of ES-GluN2B and PSA-NCAM during brain aging versus AD remain poorly understood. METHODS: We investigated GluN2A, GluN2B, ES-GluN2B, and PSA-NCAM expression across brain regions in young and old Tg2576 AD and wild-type (WT) mice. Additional experiments included PSD-95 pulldown assays, analysis of GluN2B phosphorylation at Ser1480, CRISPRa-driven ST8Sia4 upregulation in IMR-32 neuroblastoma cells, and Aβ treatment to assess effects on PSA-NCAM biosynthetic enzymes. RESULTS: Normal aging was associated with decreased GluN2B, increased GluN2A, stable ES-GluN2B, and elevated PSA-NCAM levels. In contrast, AD aging showed elevated ES-GluN2B and reduced PSA-NCAM, particularly in the hippocampus and cortex, with no change in total NCAM expression. PSD-95 pulldown revealed increased extrasynaptic GluN2B in aged AD brains. AD aging was associated with elevated phosphorylation of GluN2B at Ser1480 by casein kinase 2 (CK2), promoting GluN2B redistribution to extrasynaptic sites. CRISPRa-driven ST8Sia4 upregulation increased PSA-NCAM and reduced pGluN2B expression supporting a direct regulatory role for PSA-NCAM in GluN2B trafficking. Additionally, Aβ suppressed PSA-NCAM biosynthetic enzymes ST8Sia4 and UDP-E linking Aβ to impaired polysialylation. DISCUSSION: These findings highlight distinct regulatory patterns of ES-GluN2B and PSA-NCAM in AD versus normal aging and support a model in which impaired PSA-NCAM buffering facilitates pathological ES-GluN2B signaling and plasticity loss in AD progression.}, } @article {pmid40948809, year = {2025}, author = {Kynigopoulos, D and Fella, E and Shahabian, L and Christodoulou, CC and Papacharalampous, R and Diskos, K and Vagiaki, LE and Sidiropoulou, K and Pipis, M and Kleopa, KA and Panayiotou, E}, title = {Systemic lipid and glucose modulation differentially affects cognitive function and neuroinflammation in a mouse model of Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1636624}, pmid = {40948809}, issn = {1662-4548}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and cognitive decline. Increasing evidence implicates systemic metabolic dysregulation in AD pathogenesis, yet it remains unclear whether modulation of peripheral lipid and glucose metabolism can alter disease progression. METHODS: We investigated the effects of two FDA-approved metabolic agents-Alirocumab, a PCSK9 inhibitor that lowers LDL cholesterol, and Gliclazide, a sulfonylurea that enhances insulin secretion-in male 5xFAD mice, a transgenic model of AD. Animals received chronic treatment for five months. Behavioral testing, hippocampal electrophysiology, ELISA, lipidomics, and adipokine profiling were performed to assess cognitive, synaptic, and molecular outcomes. RESULTS: Alirocumab significantly improved spatial working memory, restored hippocampal long-term potentiation, and normalized synaptophysin expression. Gliclazide reduced neuroinflammation and partially preserved glial and neuronal markers. Both treatments decreased amyloid burden and modulated adipokine levels, with Alirocumab elevating leptin and omentin in brain and serum. Lipidomic profiling of visceral adipose tissue revealed distinct lipid remodeling and highlighted candidate pathways linking systemic metabolism to central nervous system outcomes. DISCUSSION: These findings demonstrate that systemic modulation of lipid and glucose metabolism can influence neurodegenerative and synaptic processes in AD. The results support metabolic interventions as a potential strategy to modify AD progression through peripheral-central metabolic crosstalk.}, } @article {pmid40948808, year = {2025}, author = {Cansiz, B and Ilhan, HO and Aydin, N and Serbes, G}, title = {Olfactory EEG based Alzheimer disease classification through transformer based feature fusion with tunable Q-factor wavelet coefficient mapping.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1638922}, pmid = {40948808}, issn = {1662-4548}, abstract = {INTRODUCTION: Alzheimer's disease has been considered one of the most dangerous neurodegenerative health problems. This disease, which is characterized by memory loss, leads to conditions that adversely affect daily life. Early diagnosis is crucial for effective treatment and is achieved through various imaging technologies. However, these methods are quite costly and their results depend on the expertise of the specialist physician. Therefore, deep learning techniques have recently been utilized as decision support tools for Alzheimer's disease. METHODS: In this research, the detection of Alzheimer's disease was investigated using a deep learning model applied to electroencephalography signals, taking advantage of olfactory memory. The dataset comprises three categories: healthy individuals, those with amnestic mild cognitive impairment, and Alzheimer's disease patients. The proposed model integrates three distinct feature types through a transformer-based fusion approach for classification. These feature vectors are derived from the Common Spatial Pattern, Covariance matrix-Tangent Space and a Tunable Q-Factor wavelet coefficient mapping. RESULTS: The results demonstrated that subject-based classification of rose aroma attained a 93.14% accuracy using EEG-recorded olfactory memory responses. CONCLUSION: This output has demonstrated superiority over EEG-based results reported in the literature.}, } @article {pmid40948654, year = {2025}, author = {Cui, S and Zhao, Y and Wang, X and Huang, Y and Ye, J and Deng, Z and Li, Y and Qin, H and Wang, L and Li, Y and Wang, K and Zheng, G and Qin, Q}, title = {Evaluating the clinical evidence of TCM in Alzheimer's disease: an evidence map perspective.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1571361}, pmid = {40948654}, issn = {1664-2295}, abstract = {OBJECTIVE: This systematic review aimed to synthesize current clinical evidence from randomized controlled trial (RCT) and meta-analyses on the efficacy and safety of TCM in the treatment of Alzheimer's Disease (AD). METHODS: Systematic searches across eight biomedical databases (PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang, VIP, SinoMed) through October 26, 2024 yielded an evidence matrix, which was analyzed through integrated narrative-graphic synthesis. RESULTS: Our analysis encompassed 187 studies (141 RCTs and 46 systematic reviews/meta-analyses), demonstrating cyclical publication growth with recent contraction. Study characteristics included sample sizes of 50-100 participants and intervention durations of 4-24 weeks. Interventions included acupuncture, herbal decoctions, and proprietary medicines. Outcomes focused on clinical efficacy, scale scores, TCM syndrome scores, and safety. While TCM demonstrated therapeutic potential, prescription heterogeneity and diagnostic ambiguity constrained specificity. Methodological quality was generally low, with few high-quality systematic reviews or meta-analyses. CONCLUSION: While TCM shows therapeutic potential in Alzheimer's disease, methodological limitations persist. Subsequent research requires enhanced trial designs with standardized outcome metrics and rigorous bias control protocols.}, } @article {pmid40947745, year = {2025}, author = {Ogunsuyi, OB and Oluokun, OO and Ademiluyi, AO and Oboh, G and Akeeb, RA and Umar, HI and Olagoke, OC}, title = {Synergistic effects of curcumin-donepezil therapy in a Drosophila Alzheimer's disease model.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/17582024.2025.2558428}, pmid = {40947745}, issn = {1758-2032}, abstract = {BACKGROUND: Despite emerging therapeutic options, Alzheimer´s disease (AD) management remains suboptimal due to multimodal pathogenesis. We investigated curcumin-donepezil combination therapy, as curcumin demonstrates antioxidant, anti-inflammatory, and anti-amyloidogenic properties that may complement donepezil's cholinesterase inhibition. RESEARCH DESIGN AND METHODS: We employed the elav-Gal4/UAS-hAPP-BACE-1 Drosophila melanogaster model alongside molecular docking simulation and ADMET prediction to evaluate curcumin-donepezil combination versus monotherapy. Fruit flies received the treatment regimen, and were tested for survival, memory performance, and biochemical markers, including BACE-1 activity and oxidative stress parameters. RESULTS: Combination therapy significantly improved survival rates and memory performance compared to individual treatment. The combination effectively modulated multiple AD-related pathways, demonstrating reduced BACE-1 activity and decreased oxidative stress markers. Molecular docking confirmed favorable drug interactions, and ADMET profiles supported therapeutic viability. CONCLUSIONS: Curcumin-donepezil combination therapy shows promise as a multi-target approach for AD management. However, translation to clinical applications requires validation in higher-order models and human trials.}, } @article {pmid40947724, year = {2025}, author = {Aljabali, AAA and Alkaraki, A and Obeid, MA}, title = {MAPT Haplotype Variation and Alzheimer's Disease Risk: A Narrative Review with Focus on the Jordanian Population.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X371971250818110608}, pmid = {40947724}, issn = {1875-6190}, abstract = {INTRODUCTION: Genetic variations in the microtubule-associated protein tau (MAPT) gene play a central role in Alzheimer's disease (AD) pathogenesis. Two major MAPT haplotypes, H1 and H2, show differential associations with tau expression and AD risk. However, data from Middle Eastern populations remain limited, restricting our understanding of population-specific disease susceptibility patterns and therapeutic responses. METHODS: We conducted a comprehensive literature review using PubMed, Scopus, and Web of Science databases. Search terms included "MAPT haplotype," "Alzheimer's disease," "H1 H2," "tau pathology," and "pharmacogenetics." We analyzed peer-reviewed articles published between 2000 and 2024, focusing on studies reporting haplotype frequencies, MAPT expression levels, APOE interactions, and clinical outcomes. This review synthesizes published data without generating new experimental results. RESULTS: The H1 haplotype consistently associates with increased MAPT expression, tau accumulation, and elevated AD risk, particularly in APOE ε4 noncarriers. Conversely, the H2 haplotype appears protective, correlating with reduced tau burden and slower cognitive decline. Notably, recent reports reveal significant overrepresentation of the H2 haplotype in the Jordanian population compared to European and East Asian cohorts, where H2 frequency is substantially lower or absent. This distinct genetic architecture suggests altered regional AD risk profiles. DISCUSSIONS: The elevated H2 frequency in Jordan represents a unique population-specific genetic signature that may influence regional AD susceptibility patterns. These findings challenge current risk models predominantly based on European populations and suggest the need for populationtailored approaches in neurodegenerative disease research. The naturally H2-enriched Jordanian cohort provides an exceptional opportunity to investigate protective mechanisms against tau pathology. CONCLUSION: MAPT haplotype distributions show significant population variation with important implications for AD risk assessment and therapeutic targeting. The high H2 frequency in Jordan warrants integration into personalized medicine frameworks and population-specific disease models, potentially informing more effective regional prevention and treatment strategies.}, } @article {pmid40947692, year = {2025}, author = {Manubolu, K and Peeriga, R}, title = {Revolutionizing Neurodegenerative Disease Management: The Synergy of AI and Pharmacy.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098375978250820220024}, pmid = {40947692}, issn = {1874-6128}, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS), represent major healthcare challenges worldwide. Despite advances in diagnosis and treatment, these conditions remain incurable, and there is a need for more effective management strategies. The integration of artificial intelligence (AI) in healthcare has emerged as a promising solution, offering new approaches to diagnosis, personalized treatment, and patient care. This paper explores the potential of AI to revolutionize the management of neurodegenerative diseases, with a focus on its synergistic role in pharmacy. By leveraging AI in drug discovery, personalized treatment plans, and clinical decision-making, AI can enhance therapeutic outcomes and improve patient quality of life. The study reviews the current landscape of AI applications in neurodegenerative disease management, with a focus on pharmacy-related interventions. The review includes AI-driven approaches in genomics, biomarkers, drug repurposing, and clinical trials. It also examines AI's role in optimizing pharmaceutical care, improving medication adherence, and tailoring treatments based on individual genetic profiles. AI has demonstrated its capability to analyze vast datasets, from genetic information to clinical records, to identify novel drug targets and predict patient responses to specific therapies. The use of AI in precision medicine has enabled more accurate diagnosis and has facilitated the development of personalized treatments for neurodegenerative diseases. Additionally, AI tools are enhancing medication management by providing personalized therapy adjustments and improving adherence. AI offers transformative potential for the future of neurodegenerative disease management. Its integration into pharmacy practice promises more effective, individualized treatments, accelerating drug discovery, and optimizing patient care. As AI technologies continue to advance, their role in managing complex neurological disorders will become increasingly vital.}, } @article {pmid40947660, year = {2025}, author = {Noguchi, Y and Masuda, R and Yoshimura, T}, title = {Sequence Symmetry Analysis of the Interrelationships Between Ramelteon and Parkinson's Disease.}, journal = {Journal of pineal research}, volume = {77}, number = {5}, pages = {e70080}, doi = {10.1111/jpi.70080}, pmid = {40947660}, issn = {1600-079X}, support = {//This study was supported by JSPS KAKENHI, 22K12890./ ; }, mesh = {*Parkinson Disease/epidemiology/drug therapy ; Humans ; *Indenes/adverse effects/therapeutic use ; Female ; Male ; Aged ; Middle Aged ; }, abstract = {Parkinson's disease is the second most frequent neurodegenerative disease after Alzheimer's disease, and the most common neurodegenerative disease that causes movement dysfunction. Without innovations in prevention and treatment, the incidence and prevalence of Parkinson's disease is projected to increase by > 30% by 2030, making the development of new treatments an urgent priority. We previously investigated the association between melatonin receptor agonists and Parkinson's disease using the US Food and Drug Administration's Adverse Event Reporting System (FAERS). The results showed that ramelteon may reduce the incidence of Parkinson's disease. However, since the US FAERS relies on spontaneous reports, which are susceptible to reporting bias, further validation using real-world data is required. This study investigated the association between ramelteon use and risk of developing Parkinson's disease using the DeSC database, a Japanese claims database reported to be representative of the general Japanese population. The association was evaluated using sequence symmetry analysis, with the adjusted sequence ratio (ASR) serving as the evaluation index. Our DeSC database analysis showed a negative association between ramelteon use and Parkinson's disease (ASR: 0.959, 95% confidence interval: 0.955-0.964). Our results support previous reports suggesting that ramelteon may help suppress the onset of Parkinson's disease. However, even though this study used real-world data, these results should be interpreted with caution, as a sequence symmetry analysis cannot be adjusted for covariates. Therefore, additional pharmacoepidemiological studies are needed to further verify the potential risk of Parkinson's disease associated with ramelteon use.}, } @article {pmid40947402, year = {2025}, author = {Ghosh, D and Xu, X and Luo, S and , }, title = {Power and Sample Size Calculation for Multivariate Longitudinal Trials Using the Longitudinal Rank Sum Test.}, journal = {Statistics in medicine}, volume = {44}, number = {20-22}, pages = {e70261}, pmid = {40947402}, issn = {1097-0258}, support = {P30 AG072958/AG/NIA NIH HHS/United States ; R01 AG064803/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; R01AG064803/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Longitudinal Studies ; Sample Size ; Alzheimer Disease/therapy/drug therapy ; Parkinson Disease/therapy/drug therapy ; Multivariate Analysis ; *Clinical Trials as Topic/methods/statistics & numerical data ; Computer Simulation ; Models, Statistical ; Treatment Outcome ; Statistics, Nonparametric ; }, abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's often exhibit complex, multivariate longitudinal outcomes that require advanced statistical methods to comprehensively evaluate treatment efficacy. The Longitudinal Rank Sum Test (LRST) offers a nonparametric framework to assess global treatment effects across multiple longitudinal endpoints without requiring multiplicity corrections. This study develops a robust methodology for power and sample size estimation specific to the LRST, integrating theoretical derivations, asymptotic properties, and practical estimation techniques under large sample conditions. Validation through numerical simulations demonstrates the accuracy of the proposed methods, while real-world applications to clinical trials in Alzheimer's disease (AD) and Parkinson's disease (PD) highlight their practical significance. This framework facilitates the design of efficient, well-powered trials, advancing the evaluation of treatments for complex diseases with multivariate longitudinal outcomes.}, } @article {pmid40946953, year = {2025}, author = {Sun, C and Cai, X and Jiang, X and Wen, F and Wan, L}, title = {Neuroprotective alpha-linolenic acid derived from black pepper targets PGK1 and activates the Nrf2 pathway in PC12 cells and mice.}, journal = {European journal of pharmacology}, volume = {1006}, number = {}, pages = {178154}, doi = {10.1016/j.ejphar.2025.178154}, pmid = {40946953}, issn = {1879-0712}, mesh = {Animals ; PC12 Cells ; *NF-E2-Related Factor 2/metabolism ; *alpha-Linolenic Acid/pharmacology/therapeutic use/isolation & purification ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Male ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Hydrogen Peroxide/pharmacology ; Mice, Inbred C57BL ; Apoptosis/drug effects ; }, abstract = {BACKGROUND: Oxidative stress is a significant contributor to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Nuclear factor E2-related factor 2 (Nrf2), a pivotal regulator of antioxidant responses, is an emerging therapeutic target for these conditions. Our study assessed the neuroprotective effects of monomeric compounds derived from black pepper against hydrogen peroxide (H2O2)-induced damage in neuron-like PC12 cells. Alpha-linolenic acid (ALA) demonstrated superior protective effects. PURPOSE: The aim of this study was to investigate the mechanism underlying the neuroprotective activity of ALA derived from black pepper. METHODS: H2O2 induces oxidative stress in vitro, and MPTP induces Parkinson's syndrome in vivo. Proliferation and apoptosis assays, fluorescent dye staining, Western blotting, real-time PCR, immunofluorescence, luciferase reporter assays, behavioural experiments, and immunohistochemistry were performed to investigate the effects of ALA and the underlying mechanism in vitro and in vivo. RESULTS: Our findings indicate that the ROS-scavenging and cytoprotective properties of ALA are likely mediated through Nrf2 activation and the upregulation of phase II antioxidant enzymes, including HO-1 and NQO1. Drug affinity responsive target stability (DARTS) assays revealed that ALA interacts with the PGK1 protein, potentially inhibiting its activity to promote Nrf2 activation. In vivo, the oral administration of ALA (60 and 120 mg/kg) significantly mitigated the behavioural deficits associated with Parkinson's disease, preserved dopaminergic neurons in an MPTP-induced mouse model of PD, and relieved nerve inflammation. CONCLUSION: Our data suggest that ALA may be a candidate neuroprotective agent for the treatment of neurodegenerative diseases, offering novel insights and potential therapeutic targets for future interventions.}, } @article {pmid40945030, year = {2025}, author = {Tang, P and Zhao, D and Lin, H and Li, X and Shi, C and Li, P and Chen, H}, title = {Potential modulation of microglial ferroptosis by Linggui Zhugan decoction in Alzheimer's disease through IL-17 and TNF pathways.}, journal = {International immunopharmacology}, volume = {165}, number = {}, pages = {115489}, doi = {10.1016/j.intimp.2025.115489}, pmid = {40945030}, issn = {1878-1705}, mesh = {*Ferroptosis/drug effects ; Animals ; *Alzheimer Disease/drug therapy/immunology/metabolism ; *Microglia/drug effects/metabolism ; Signal Transduction/drug effects ; Mice ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Tumor Necrosis Factor-alpha/metabolism ; *Interleukin-17/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Mice, Inbred C57BL ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Peptide Fragments ; }, abstract = {Alzheimer's Disease (AD) is a neurodegenerative condition marked by cognitive decline and memory loss, with ferroptosis, an iron-dependent form of regulated cell death, emerging as a contributing factor. This study explored the potential modulatory effects of key components of the traditional Chinese medicine (TCM) formula Linggui Zhugan Decoction (LZD) on microglial ferroptosis in AD, focusing on IL-17 and TNF signaling pathways. Using single-cell RNA sequencing, we observed alterations in microglial populations and ferroptosis-related gene expression in AD mice. Network pharmacology and in vitro experiments indicated that LZD components might influence ferroptosis-related pathways, coinciding with reduced IL-17 and TNF levels in Aβ1-42-treated microglia. In vivo, LZD administration was associated with improved behavioral outcomes and modulation of ferroptosis markers. Although our findings suggest a correlation between LZD treatment and attenuation of ferroptosis-associated pathology, further mechanistic validation is necessary to establish causal links. This study provides preliminary evidence supporting the therapeutic potential of TCM in AD via inflammatory pathway modulation.}, } @article {pmid40944899, year = {2025}, author = {Sharma, DK}, title = {Nanotechnology-driven approaches for the early detection and targeted treatment of Alzheimer's disease.}, journal = {Journal of drug targeting}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/1061186X.2025.2561788}, pmid = {40944899}, issn = {1029-2330}, abstract = {A neurodegenerative condition called Alzheimer's disease (AD) is brought on by the buildup of beta-amyloid plaques in the brain. As of right now, AD has no known cure. The only thing the medications on the market can do is slow their development. Nonetheless, nanotechnology has demonstrated its superiority in its application in medicine. It has great promise for AD therapy, mostly in diagnosing the ailment and offering a different treatment method. Penetrating and bypassing the blood-brain barrier (BBB) increases the effectiveness of drug delivery. The most recent advancements in AD diagnosis using nanotechnology based on nanoparticles with optical sensing, electrochemical sensing, and imaging approaches are summarised in this study. When treating AD, nanocarriers help deliver the targeted medication. Since one of the newest and most active treatments for AD is nanomedicines, the main goal of this review is to comprehend the sophisticated application of nanocarriers for targeted drug delivery in AD treatment.}, } @article {pmid40943807, year = {2025}, author = {Rajič Bumber, J and Rački, V and Mežnarić, S and Pelčić, G and Mršić-Pelčić, J}, title = {Clinical Significance of APOE4 Genotyping: Potential for Personalized Therapy and Early Diagnosis of Alzheimer's Disease.}, journal = {Journal of clinical medicine}, volume = {14}, number = {17}, pages = {}, pmid = {40943807}, issn = {2077-0383}, support = {uniri-iskusni-biomed-23-82//University of Rijeka/ ; }, abstract = {Apolipoprotein E (APOE) remains the most robust and widely replicated genetic risk factor for late-onset Alzheimer's disease (AD) susceptibility, with the ε4 allele (APOE4) demonstrating profound associations with accelerated symptom manifestation, enhanced disease trajectory, and modified therapeutic responsiveness. This comprehensive review synthesizes contemporary evidence regarding the clinical utility of APOE4 genotyping, emphasizing its integration into personalized therapeutic frameworks and early diagnostic paradigms. The APOE4 variant exerts pathogenic influence through impaired amyloid-β clearance, enhanced tau pathology, and compromised neuronal repair mechanisms that alter disease phenotype. We systematically examine available genotyping methodologies, encompassing polymerase chain reaction (PCR) and next-generation sequencing (NGS) platforms, and evaluate their practical implementation within clinical environments. Recent investigations demonstrate that APOE4 status profoundly influences therapeutic efficacy, particularly with anti-amyloid interventions such as lecanemab, where carriers exhibit enhanced treatment response alongside increased adverse event susceptibility. Emerging gene therapeutic approaches show promise in mitigating APOE4-associated risks through targeted molecular interventions. The integration of APOE4 genotyping with fluid biomarkers and neuroimaging techniques enables refined patient stratification and enhanced diagnostic precision, facilitating earlier intervention windows that optimize therapeutic outcomes before irreversible neuronal damage occurs. This review underscores APOE4 testing as a transformative component of precision medicine in AD management, emphasizing its contribution to diagnostic refinement, clinical decision support, and targeted therapeutic interventions.}, } @article {pmid40943686, year = {2025}, author = {Bishara, H and Cohen, H and Hadar, D and Specktor, P}, title = {Ethnic Differences in Dementia Diagnosis and Treatment in Israel.}, journal = {Journal of clinical medicine}, volume = {14}, number = {17}, pages = {}, pmid = {40943686}, issn = {2077-0383}, abstract = {Background/Objectives: Lifestyle and socioeconomic disparities influence dementia prevalence and treatment across ethnic groups worldwide. Our study aimed to examine differences in the diagnosis, work-up, and treatment of mild cognitive impairment (MCI) as well as various types of dementia provided to Arab and Jewish participants in Israel. Methods: Data were collected retrospectively and anonymously between 1 January 2010 and 12 September 2021, by Clalit Health Services' research department. Ethnicity was determined based on residence, including only cities with a 99% majority of either Jewish or Arab participants, according to the Central Bureau of Statistics (CBS). Subjects over the age of 60 with an MCI or dementia diagnosis were analyzed. Results: Of 212,091 diagnosed individuals, 14,742 were of a definite ethnicity as defined. The mean age at diagnosis was significantly younger for Arab participants (75.78 ± 10.28) compared to Jewish participants (80.14 ± 9.45) (p < 0.001). The gender distribution was similar (42.5% male). The most common diagnosis was Alzheimer's disease (AD), affecting 2495 (29.8%) of Jewish participants and 2387 (38%) of Arab participants (p < 0.001). Vascular dementia (VD) was also more prevalent in Arab participants, 12.6%, vs. 6.42% in Jewish participants (p < 0.001). MCI was more common in Jewish participants, 26.2%, compared to 10.3% in Arab participants (p < 0.001). Conclusions: Arab participants were diagnosed with dementia at a younger age and showed higher rates of AD and VD diagnosis compared to Jewish participants, but were significantly less likely to be diagnosed with MCI. Efforts to understand and address these underlying causes are warranted to promote health equity.}, } @article {pmid40943548, year = {2025}, author = {Yudaev, P and Aleksandrova, Y and Neganova, M}, title = {Recent Insights into the Creation of Histone Deacetylase Inhibitors for the Treatment of Human Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943548}, issn = {1422-0067}, support = {25-73-20033//Russian Science Foundation/ ; }, mesh = {Humans ; *Histone Deacetylase Inhibitors/therapeutic use/chemistry/pharmacology ; Histone Deacetylases/metabolism ; Neoplasms/drug therapy ; Cardiovascular Diseases/drug therapy ; Animals ; Autoimmune Diseases/drug therapy ; Nervous System Diseases/drug therapy ; Hydroxamic Acids/therapeutic use/chemistry/pharmacology ; }, abstract = {This review examines publications over the past two years devoted to histone deacetylase inhibitors for the treatment of cancer, diseases of the nervous, cardiovascular, digestive, and respiratory systems, and autoimmune diseases. The review covers various classes of histone deacetylase inhibitors depending on the zinc-binding group, in particular hydroxamic acids, benzamides, hydrazides, carboxylic acids, and cyclic peptides. The review pays special attention to the mechanisms of development of pathologies involving various isoforms of histone deacetylases. The review shows that, for the treatment of cancer, nervous, cardiovascular, respiratory systems, and autoimmune diseases, the most promising compounds are hydroxamic acids, and for the treatment of diseases of the digestive system, they are hydrazides and cyclic peptides. Variation in the linker and cap group of hydroxamic acids will allow the creation of an inhibitor selective for a specific histone deacetylase isoform. The review may be useful for molecular biologists, medical workers, and pharmacologists involved in the design of new drugs.}, } @article {pmid40943460, year = {2025}, author = {Del Rio, EA and Valenzano, MC and DiGuilio, KM and Rybakovsky, E and Kjelstrom, S and Montone, G and Mercogliano, G and Newman, G and Wong, P and Albert, N and Burris, V and Szymanski, K and Rodriguez, A and Hollis, E and Kossenkov, A and Mullin, JM}, title = {Orally Administered Zinc Gluconate Induces Tight Junctional Remodeling and Reduces Passive Transmucosal Permeability Across Human Intestine in a Patient-Based Study.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943460}, issn = {1422-0067}, support = {2023-02//Sharpe-Strumia Research Foundation of the Bryn Mawr Hospital/ ; }, mesh = {Humans ; *Gluconates/administration & dosage/pharmacology ; *Tight Junctions/drug effects/metabolism ; *Intestinal Mucosa/metabolism/drug effects ; Administration, Oral ; Male ; Female ; Adult ; Permeability/drug effects ; Middle Aged ; Tight Junction Proteins/metabolism ; Gastrointestinal Microbiome/drug effects ; Zinc ; }, abstract = {This study focuses on the issue of whether orally administered zinc (gluconate) (26 mg BID) can induce the remodeling of gastrointestinal barrier function and reduce passive leak across the human intestinal mucosal barrier in situ. Increased transmucosal leak has been implicated in diseases as diverse and seemingly unconnected as Inflammatory Bowel Disease (IBD), Celiac Disease, Autism Spectrum Disorders and Alzheimer's Dementia. Our current investigation represents the first patient-based study to examine the effect of zinc on gastrointestinal epithelial tight junctions and gastrointestinal barrier leak in otherwise healthy test subjects. Using independent test subject groups for each endpoint, three separate molecular analyses indicated that zinc treatment can achieve a positive outcome: (1) RNA-seq analyses of intestinal biopsies showed salutary patterns of gene transcription changes dealing with not only transcripts of junctional proteins but also transcripts mitigating the proinflammatory state, as well as dedifferentiation (both modulators of tight junction permeability); (2) Western immunoblot analyses of intestinal tissue indicated that tight junctional protein expression was being modified by the administered zinc, most notably Claudin-2 and Tricellulin; (3) zinc treatment induced a reduction in serum levels of a functional marker of passive intestinal leak, namely the GI microbiome metabolite D-Lactate. The data collectively suggest that orally administered zinc can induce remodeling of the intestinal epithelial barrier, resulting in the reduction in GI barrier leak. The overall safety and economy of supplement levels of zinc suggest that this micronutrient could be efficacious as an adjuvant therapy to reduce the condition known as leaky gut, and possibly therefore be protective regarding diseases postulated to involve leaky gut.}, } @article {pmid40943200, year = {2025}, author = {Zhao, D and Ma, L and Brownlie, J and Tonissen, K and Pan, Y and Feng, Y}, title = {Neuroprotective Potential of Major Alkaloids from Nelumbo nucifera (Lotus): Mechanisms and Therapeutic Implications.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943200}, issn = {1422-0067}, mesh = {Humans ; *Nelumbo/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; *Alkaloids/pharmacology/chemistry/therapeutic use ; Animals ; Benzylisoquinolines/pharmacology/chemistry ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Nelumbo nucifera (lotus) has long been used in traditional medicine across Asia, and its bioactive alkaloids have recently garnered attention for their neuroprotective properties. This review summarizes the current research on the mechanisms by which lotus-derived alkaloids, particularly neferine, nuciferine, liensinine, and isoliensinine, protect neural tissues. These compounds exhibit a wide range of pharmacological activities, including antioxidant and anti-inflammatory effects, regulation of calcium signaling and ion channels, promotion of neurogenesis, and modulation of key neurotransmitter systems, such as dopaminergic, cholinergic, and GABAergic pathways. Notably, they attenuate tau hyperphosphorylation, reduce oxidative stress-induced neuronal apoptosis, and enhance neurotrophic signaling via BDNF-related pathways. While antioxidant and anti-inflammatory actions are the most extensively studied, emerging evidence also highlights their roles in autophagy modulation and mitochondrial protection. Together, these findings suggest that lotus alkaloids are promising candidates for the prevention and treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Further investigation is warranted to explore the synergistic mechanisms and potential clinical applications of these compounds.}, } @article {pmid40943177, year = {2025}, author = {Bowirrat, A and Pinhasov, A and Bowirrat, A and Badgaiyan, R}, title = {Navigation Between Alzheimer's Disease (AD) and Its Various Pathophysiological Trajectories: The Pathogenic Link to Neuroimmunology-Genetics and Neuroinflammation.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943177}, issn = {1422-0067}, mesh = {*Alzheimer Disease/genetics/pathology/metabolism/physiopathology/immunology/etiology ; Humans ; *Neuroinflammatory Diseases/pathology/genetics ; Blood-Brain Barrier/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Brain/pathology/metabolism ; Animals ; Inflammation ; }, abstract = {One hundred and eighteen years have passed since Alzheimer's disease (AD) was first diagnosed by Alois Alzheimer as a multifactorial and complex neurodegenerative disorder with psychiatric components. It is inaugurated by a cascade of events initiating from amnesic-type memory impairment leading to the gradual loss of cognitive and executive capacities. Pathologically, there is overwhelming evidence that clumps of misfolded amyloid-β (Aβ) and hyperphosphorylated tau protein aggregate in the brain. These pathological processes lead to neuronal loss, brain atrophy, and gliosis culminating in neurodegeneration and fueling AD. Thus, at a basic level, abnormality in the brain's protein function is observed, causing disruption in the brain network and loss of neural connectivity. Nevertheless, AD is an aging disorder caused by a combination of age-related changes and genetic and environmental factors that affect the brain over time. Its mysterious pathology seems not to be limited to senile plaques (Aβ) and neurofibrillary tangles (tau), but to a plethora of substantial and biological processes, which have also emerged in its pathogenesis, such as a breakdown of the blood-brain barrier (BBB), patients carrying the gene variant APOE4, and the immuno-senescence of the immune system. Furthermore, type 2 diabetes (T2DM) and metabolic syndrome (MS) have also been observed to be early markers that may provoke pathogenic pathways that lead to or aggravate AD progression and pathology. There are numerous substantial AD features that require more understanding, such as chronic neuroinflammation, decreased glucose utilization and energy metabolism, as well as brain insulin resistance (IR). Herein, we aim to broaden our understanding and to connect the dots of the multiple comorbidities and their cumulative synergistic effects on BBB dysfunction and AD pathology. We shed light on the path-physiological modifications in the cerebral vasculature that may contribute to AD pathology and cognitive decline prior to clinically detectable changes in amyloid-beta (Aβ) and tau pathology, diagnostic biomarkers of AD, neuroimmune involvement, and the role of APOE4 allele and AD-IR pathogenic link-the shared genetics and metabolomic biomarkers between AD and IR disorders. Investment in future research brings us closer to knowing the pathogenesis of AD and paves the way to building prevention and treatment strategies.}, } @article {pmid40943145, year = {2025}, author = {Öztan, G and İşsever, H and İşsever, T}, title = {The Role of miRNAs in the Differential Diagnosis of Alzheimer's Disease and Major Depression: A Bioinformatics-Based Approach.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943145}, issn = {1422-0067}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Alzheimer Disease/diagnosis/genetics/metabolism ; *Depressive Disorder, Major/diagnosis/genetics/metabolism ; *Computational Biology/methods ; Diagnosis, Differential ; Biomarkers/metabolism ; Gene Expression Profiling ; Gene Regulatory Networks ; Transcriptome ; Gene Expression Regulation ; Signal Transduction ; }, abstract = {Alzheimer's disease (AD) and major depressive disorder (MDD) are prevalent central nervous system (CNS) disorders that share overlapping symptoms but differ in underlying molecular mechanisms. Distinguishing these mechanisms is essential for developing targeted diagnostic and therapeutic strategies. In this study, we integrated multi-tissue transcriptomic datasets from brain and peripheral samples to identify differentially expressed microRNAs (miRNAs) in AD and MDD. Functional enrichment analyses (KEGG, GO) revealed that dysregulated miRNAs in AD were associated with MAPK, PI3K-Akt, Ras, and PD-1/PD-L1 signaling, pathways linked to synaptic plasticity, neuroinflammation, and immune regulation. In contrast, MDD-associated miRNAs showed enrichment in Hippo signaling and ubiquitin-mediated proteolysis, implicating altered neurogenesis and protein homeostasis. Network analysis highlighted key disease- and tissue-specific miRNAs, notably hsa-miR-1202 and hsa-miR-24-3p, with potential roles in neuronal survival and molecular network regulation. These findings suggest that miRNAs may serve as non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring in both disorders. While therapeutic targeting of miRNAs offers promise, challenges such as blood-brain barrier penetration and tissue-specific delivery remain. This integrative approach provides a translational framework for advancing miRNA-based strategies in CNS disease research.}, } @article {pmid40943059, year = {2025}, author = {Nojima, H and Yamamoto, M and Kamada, J and Hamanaka, T and Aoyagi, K}, title = {Fully Automated Measurement of GFAP in CSF Using the LUMIPULSE[®] System: Implications for Alzheimer's Disease Diagnosis and Staging.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943059}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; *Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Male ; Aged ; Female ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; tau Proteins/cerebrospinal fluid ; Cognitive Dysfunction/cerebrospinal fluid/diagnosis ; Aged, 80 and over ; Peptide Fragments/cerebrospinal fluid ; ROC Curve ; Immunoenzyme Techniques/methods ; }, abstract = {Glial fibrillary acidic protein (GFAP) has been shown to be a reliable biomarker for detecting neurological disorders. Recently, we developed the Lumipulse G GFAP plasma assay, which is a commercially available tool. Compared to existing assays, the LUMIPLSE G platform offers the high-throughput, rapid, and fully automated quantification of biomarkers, enabling more standardized and accessible clinical study. In this study, we evaluated this assay using cerebrospinal fluid (CSF) samples. Assessing GFAP in CSF may provide more direct insights into central nervous system pathology than plasma and could improve the characterization of Alzheimer's disease (AD) stages and support treatment monitoring. The LUMIPULSE G system is a chemiluminescent enzyme immunoassay (CLEIA) platform equipped with full automation, utilizing specialized cartridges to process samples within 30 min. The assay, which employs a pair of proprietary monoclonal antibodies targeting GFAP, was evaluated for clinical performance using 30 CSF samples from patients diagnosed with AD, patients with mild cognitive impairment (MCI), and cognitively unimpaired (CU) individuals, with 10 samples from each group. In addition, levels of β-amyloid 1-40 (Aβ40), β-amyloid 1-42 (Aβ42), and pTau181 were simultaneously measured. The Lumipulse G GFAP assay significantly differentiated (p < 0.05) between the amyloid accumulation and non-amyloid accumulation groups, as classified based on the CSF Aβ test. Furthermore, GFAP showed a moderate correlation with pTau181 (r = 0.588), as determined based on Spearman's rank correlation coefficient. Moreover, receiver operating characteristic (ROC) analysis was performed to determine the performance of GFAP in distinguishing amyloid-positive and amyloid-negative subjects, with an area under the curve (AUC) of 0.72 (0.50-0.93). When stratified by CSF pTau181 positivity, GFAP demonstrated an improved diagnostic accuracy, achieving an AUC of 0.86 (95% CI: 0.68-1.00). This study demonstrates that the Lumipulse G GFAP assay, when applied to CSF samples, has the potential to differentiate AD from non-AD cases, particularly suggesting its utility in detecting tau-related pathology. While GFAP has previously been established as a biomarker for AD, our findings highlight that combining GFAP with other biomarkers such as Aβ40, Aβ42, and pTau181 may enhance the understanding of AD pathogenesis, disease staging, and possibly treatment responses. These findings suggest that GFAP may serve as a complementary biomarker reflecting astroglial reactivity associated with tau positivity, alongside established biomarkers such as Aβ40, Aβ42, and pTau181. However, since GFAP levels may also be elevated in other neurological disorders beyond AD, further investigation into these conditions is required.}, } @article {pmid40942908, year = {2025}, author = {Mbue, ND and Tabei, F and Williams, K and Olanrewaju, K}, title = {Innovative Sensor-Based Approaches for Assessing Neurodegenerative Diseases: A Brief State-of-the-Art Review.}, journal = {Sensors (Basel, Switzerland)}, volume = {25}, number = {17}, pages = {}, pmid = {40942908}, issn = {1424-8220}, support = {2024 TARC Pitch//2024 Texas A&M Engineering Experiment Station Annual Research Conference (TARC)./ ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; *Biosensing Techniques/methods ; Artificial Intelligence ; Nanotechnology ; Alzheimer Disease/diagnosis ; Parkinson Disease/diagnosis ; }, abstract = {Sensor-based approaches are transforming the diagnosis and treatment of neurodegenerative diseases by offering more sensitive, non-invasive tools and are capable of real-time monitoring. Integrating advanced materials, nanotechnology, and artificial intelligence presents promise for earlier detection, enhanced disease management, and improved patient outcomes. From a clinical perspective, these technologies facilitate the shift toward precision medicine by enabling early intervention strategies, real-time treatment monitoring, and more refined patient stratification in practice and research contexts. This review provides an overview of recent advancements in sensor-based technologies aimed at enhancing the diagnosis and monitoring of neurodegenerative diseases (NDDs) such as Alzheimer's and Parkinson's, among others. Sensor-based technologies are adjunct tools and integral components of a next-generation framework for diagnosing, monitoring, and understanding neurodegenerative disorders.}, } @article {pmid40942040, year = {2025}, author = {Charissopoulos, E and Pontiki, E}, title = {Targeting Metal Imbalance and Oxidative Stress in Alzheimer's Disease with Novel Multifunctional Compounds.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {17}, pages = {}, pmid = {40942040}, issn = {1420-3049}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; *Oxidative Stress/drug effects ; *Metals/metabolism ; Animals ; *Antioxidants/pharmacology/therapeutic use/chemistry ; *Chelating Agents/therapeutic use/pharmacology/chemistry ; Brain/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is considered to be one of the most common types of dementia, threatening the health of elderly individuals. Enhancing the brain's cholinergic activity is currently the primary therapeutic strategy for treating AD patients. Acetylcholine and butyrylcholine are key targets in this approach, as they function as neuromodulators within the cerebrum-particularly in its various cholinergic regions responsible for essential functions like memory, thought, inspiration, and excitement. Oxidative stress and free radicals are considered to play a crucial role in the pathogenesis of AD and may be key factors in its etiology. Additionally, oxidants and oxidative stress-induced products can upregulate amyloid precursor protein (APP) expression, promoting Aβ aggregation. Another major factor in the pathogenesis of AD is the imbalance of metal homeostasis in the brain. Notably, the mammalian brain contains significantly higher concentrations of Cu, Zn, and Fe ions compared to other tissues. The present review focuses on novel bifunctional metal chelators with potential antioxidant activity for the treatment of AD.}, } @article {pmid40942007, year = {2025}, author = {Li, H and Shen, X and Zhang, B and Zhu, Z}, title = {Biologics as Therapeutical Agents Under Perspective Clinical Studies for Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {17}, pages = {}, pmid = {40942007}, issn = {1420-3049}, mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy/metabolism ; *Biological Products/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Clinical Trials as Topic ; Genetic Therapy/methods ; tau Proteins/metabolism ; Oligonucleotides, Antisense/therapeutic use ; Animals ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, synaptic loss, and multifaceted pathology involving amyloid-β (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, and impaired proteostasis. In recent years, biologic therapies, such as monoclonal antibodies, vaccines, antisense oligonucleotides (ASOs), and gene therapies, have gained prominence as promising disease-modifying strategies. In this review, we provide a comprehensive synthesis of current biologic approaches under clinical evaluation for AD. Drawing on data curated from ClinicalTrials.gov (as of 2025), we systematically summarise the molecular targets, therapeutic modalities, mechanisms of action, trial phases, and sponsors of over 60 biologic agents. These include Aβ-directed antibodies targeting distinct conformers such as protofibrils, pyroglutamate-modified species, and soluble oligomers; tau-targeted immunotherapies and RNA-based interventions; and emerging platforms focused on neuroimmune modulation, peptide hormones, and microbiota-based strategies. Gene and RNA therapeutics, particularly ASOs and small interfering RNAs (siRNAs) delivered intrathecally or via lipid nanoparticles, are also reviewed for their potential to modulate intracellular targets with high specificity. We also analyse the historical landscape of biologic candidates that failed to reach approval, discussing key reasons for trial discontinuation, including lack of clinical efficacy, safety concerns (e.g., amyloid-related imaging abnormalities), or inadequate biomarker responses. These cases offer crucial insights for refining future drug design. Looking ahead, we highlight major challenges and evolving perspectives in AD biologic therapy: expanding therapeutic targets beyond Aβ and tau, overcoming delivery barriers to the brain, designing prevention-oriented and genetically stratified trials, and navigating regulatory and ethical considerations. Together, these efforts signal a paradigm shift in AD drug development, from symptomatic treatment to mechanism-based precision biologics. By integrating real-time clinical trial data with mechanistic insight, this review aims to inform both translational research and therapeutic innovation in AD.}, } @article {pmid40941958, year = {2025}, author = {Rodríguez-Escobar, ML and Martínez-Francés, V and Ríos, S and Feresin, GE and Borges, WS and Bastida, J and Torras-Claveria, L and Tallini, LR}, title = {Alkaloid Profile of Fifteen Different Species of Narcissus L. (Amaryllidoideae) Collected in Spain.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {17}, pages = {}, pmid = {40941958}, issn = {2223-7747}, abstract = {Molecular diversity is a key component of overall biodiversity, playing a vital role in evolution. It results from the adaptation of organisms to various habitats, which impacts their survival. The Amaryllidoideae subfamily is a significant group of monocotyledonous plants known for producing an exclusive and still-expanding group of molecules with diverse biological activities. Galanthamine (Gal), the most renowned metabolite from Amaryllidoideae subfamily, has been marketed for the palliative treatment of Alzheimer's disease since 2001 due to its ability to inhibit the acetylcholinesterase enzyme. Due to the high cost and low yield of its synthesis, pharmaceutical companies extract this drug from Amaryllidoideae plants, such as Narcissus pseudonarcissus cv. Carlton in Europe and Lycoris radiata in China. The aim of this study was to describe the alkaloid profile of fifteen different species of Narcissus L. (commonly known as daffodils) collected in Spain using gas chromatography coupled with mass spectrometry. Fifty-one alkaloids were identified and quantified within these species through our private library of Amaryllidaceae alkaloids (AA) built over the last four decades, while thirty structures remained not identified in thirteen of these species. The highest concentration of these nitrogenate metabolites was quantified in N. confusus, 541 μg Gal·100 mg[-1] DW, which also exhibited a notably high concentration of Gal, 301 μg Gal·100 mg[-1] DW, which represents about 55% of the alkaloids identified in this species. The species N. bujei was also found to contain a significant quantity of this compound, amounting to 103.2 μg Gal·100 mg[-1] DW. The plant N. assoanus harbored a total of seven unidentified compounds, indicating that this species could be a potentially important source of novel alkaloids. In conclusion, this study facilitates a direct comparison of alkaloid profiles for fifteen Narcissus plant species. This serves as a valuable tool for identifying possible new sources of galanthamine, as well as other novel medicinal alkaloids. Finally, this work presents the first alkaloid profile of the species N. minor and N. nevadensis.}, } @article {pmid40941620, year = {2025}, author = {Altıntop, ÇG}, title = {Enhancing Diagnostic Accuracy of Neurological Disorders Through Feature-Driven Multi-Class Classification with Machine Learning.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {17}, pages = {}, pmid = {40941620}, issn = {2075-4418}, abstract = {Background/Objectives: Neurological disorders (ND) are a global health challenge, affecting millions and greatly reducing quality of life. Disorders such as Alzheimer's disease, mild cognitive impairment (MCI), schizophrenia, and depression often share overlapping symptoms, complicating diagnosis and treatment. Early detection is crucial for timely intervention; however, traditional diagnostic methods rely on subjective assessments and costly imaging, which are not universally accessible. Addressing these challenges, this study investigates the classification of multiple ND using electroencephalography (EEG) signals. Methods: Various feature extraction methods were employed, and the Least Absolute Shrinkage and Selection Operator (Lasso) algorithm was utilized for effective feature selection. Two-class (disease-disease and healthy control-disease), three-class (healthy control and two ND, as well as three ND), and four-class (healthy control and three ND) classifications were conducted using different machine learning algorithms with the selected features. An EEG dataset comprising 40 Alzheimer's patients, 43 healthy controls, 42 schizophrenia patients, 28 MCI patients, and 28 depression patients served as the experimental benchmark. Results: The Linear Discriminant Analysis (LDA) classifier achieved the highest accuracy, distinguishing between healthy controls and Alzheimer's with 100% accuracy and demonstrating strong performance in other comparisons. Multi-class classification reached 84.67% accuracy for distinguishing depression, MCI, and schizophrenia, while four-class classification achieved 57.89%, highlighting the complexity of differentiating among multiple ND. The frequent selection of frontal lobe channels across ND indicates their critical role in classification. Conclusions: This study contributes to the literature by emphasizing disease-to-disease classification over the traditional control-versus-patient framework, highlighting the potential for more effective diagnostic tools in clinical settings.}, } @article {pmid40941175, year = {2025}, author = {Jeong, H and Choi, H and Park, YS}, title = {Neuroprotective Potential of Broccoli Sprout Extract in Scopolamine-Induced Memory-Impaired Mice.}, journal = {Foods (Basel, Switzerland)}, volume = {14}, number = {17}, pages = {}, pmid = {40941175}, issn = {2304-8158}, support = {P0025365//Ministry of Trade, Industry and Energy/ ; }, abstract = {Alzheimer's disease is characterized by progressive cognitive decline associated with oxidative stress, neuroinflammation, and impaired neurotrophic signaling. Sulforaphane, a bioactive compound found in broccoli, has demonstrated neuroprotective effects by activating NRF2 and inhibiting NF-κB. However, the efficacy of whole-food-derived sulforaphane remains unclear. This study evaluated the neuroprotective potential of broccoli sprout extract using a scopolamine-induced mouse model of memory impairment. Mice were orally administered broccoli sprout extract once daily at doses of 100 mg/kg or 200 mg/kg for four weeks prior to behavioral and biochemical assessments. Treatment with broccoli sprout extract significantly improved scopolamine-induced deficits in long-term memory, as determined by the passive avoidance test. The spatial working memory remained unaffected. High doses of broccoli sprout extract restored hippocampal brain-derived neurotrophic factor levels and reduced cortical lipid peroxidation, suggesting antioxidant and neurotrophic benefits. Additionally, the low dose preserved striatal choline acetyltransferase expression and reduced systemic tumor necrosis factor-alpha and hippocampal cyclooxygenase-2 levels, indicating its anti-inflammatory and cholinergic protective effects. No significant changes in acetylcholinesterase activity or glutathione levels were observed. Overall, these results imply that broccoli sprout extract has multi-targeted neuroprotective effects, possibly involving redox and inflammatory regulation. Therefore, it may be a safe dietary strategy to support cognition in neurodegenerative conditions.}, } @article {pmid40940798, year = {2025}, author = {Li, L and Zheng, X and Ma, H and Zhu, M and Li, X and Sun, X and Feng, X}, title = {TREM2 in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential.}, journal = {Cells}, volume = {14}, number = {17}, pages = {}, pmid = {40940798}, issn = {2073-4409}, mesh = {Humans ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Microglia/metabolism ; Phagocytosis ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), represent significant global health challenges, affecting millions and straining healthcare systems. These disorders involve progressive neuronal loss and cognitive decline, with incompletely elucidated underlying mechanisms. Chronic neuroinflammation is increasingly recognized as a critical contributor to disease progression. The brain's resident immune cells, microglia, are central to this inflammatory response. When overactivated, microglia and other immune cells, such as peripheral macrophages, can exacerbate inflammation and accelerate disease development. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily that demonstrates high expression on microglia in the central nervous system. TREM2 serves a vital role in regulating phagocytosis, synaptic pruning, and energy metabolism. This review examines the functions of TREM2 in neurodegenerative diseases and its potential as a therapeutic target, aiming to inform future treatment strategies.}, } @article {pmid40940766, year = {2025}, author = {Kochman, U and Sitka, H and Kuźniar, J and Czaja, M and Kozubek, P and Beszłej, JA and Leszek, J}, title = {Neuronal Death and Biomolecular Condensates: Are There Any New Treatment Options for Alzheimer's Disease?.}, journal = {Cells}, volume = {14}, number = {17}, pages = {}, pmid = {40940766}, issn = {2073-4409}, mesh = {Humans ; *Alzheimer Disease/pathology/drug therapy/metabolism/therapy ; *Neurons/pathology/metabolism/drug effects ; *Biomolecular Condensates/metabolism ; Animals ; tau Proteins/metabolism ; Cell Death ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is marked by the pathological aggregation of amyloid β (Aβ) and tau proteins. Emerging research reveals that these proteins undergo liquid-liquid phase separation (LLPS), forming biomolecular condensates that promote aggregation and neurotoxicity. These phase-separated structures reshape the intracellular environment, facilitating protein misfolding and spreading. This review highlights recent advances in understanding the role of condensates in AD pathogenesis and explores novel therapeutic strategies targeting condensate dynamics. Promising approaches include small molecules that disrupt LLPS, epigenetic drugs influencing nuclear condensates, and compounds like DDL 920 and RI AG03 that modulate tau phase separation and neuroinflammation, respectively. Additionally, anti-inflammatory agents, such as nucleotide reverse transcriptase inhibitors (NRTIs), offer potential for upstream intervention. Targeting biomolecular condensates presents a next-generation strategy for AD treatment. Future research should focus on in vivo profiling of condensate composition, biomarker development, and the development of patient-specific therapies to enable early, disease-modifying interventions.}, } @article {pmid40940699, year = {2025}, author = {Fazio-Eynullayeva, E and Mystkowski, P and Lv, L and Aly, A and Cotton, S and Grant, N and Johnson, W and Mattke, S}, title = {A Real-World Analysis of the Clinical Journey, Diagnosis, and Monitoring Patterns of Patients With Alzheimer Disease by Stage in the United States.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {40}, number = {}, pages = {15333175251375378}, pmid = {40940699}, issn = {1938-2731}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; Cross-Sectional Studies ; United States ; Female ; Male ; Aged ; Severity of Illness Index ; *Cognitive Dysfunction/diagnosis ; Middle Aged ; Disease Progression ; *Physicians, Primary Care/statistics & numerical data ; Aged, 80 and over ; }, abstract = {This study aimed to describe the clinical journey of patients with different stages of Alzheimer disease (AD). This was a cross-sectional survey of US primary care physicians (PCPs)/specialists and patients using the Adelphi Real World AD Disease Specific Programme™ (December 2022 - September 2023). Patients were stratified by disease severity and data are presented as the mean (SD) or frequencies/percentages. In the overall sample (N = 990), mean time from symptom onset to first evaluation was 31.4 (40.6) weeks and mean time from evaluation to diagnosis was 14.2 (29.0) weeks (mild cognitive impairment due to AD, 12.0 [22.7] weeks; mild AD dementia, 15.7 [31.6] weeks; moderate AD dementia, 14.0 [29.9] weeks; severe AD dementia, 5.1 [9.6] weeks). 74.5% of the overall sample was initially evaluated by their PCP and 13.8% by a neurologist. Patients with AD experience many barriers during the diagnostic journey; however, PCPs and neurologists play key roles in early diagnosis.}, } @article {pmid40940304, year = {2025}, author = {Francis, E and Paylor, S and Van, C and Mathews, B and Sobhanian, MJ and Mansour, DZ and Hennawi, G and Brandt, NJ}, title = {Review of anti-amyloid-beta (Aβ) monoclonal antibodies for the treatment of Alzheimer's disease.}, journal = {Expert review of clinical pharmacology}, volume = {18}, number = {12}, pages = {1063-1078}, doi = {10.1080/17512433.2025.2556122}, pmid = {40940304}, issn = {1751-2441}, mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology ; *Amyloid beta-Peptides/immunology ; *Antibodies, Monoclonal/adverse effects/pharmacology/administration & dosage ; Animals ; Disease Progression ; Risk Assessment ; Precision Medicine ; Apolipoprotein E4/genetics ; Drug Development ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) remains a major public health challenge, with growing prevalence and limited treatment options that modify disease progression. Recent advances have led to the development and approval of Anti-amyloid-β (Aβ) monoclonal antibodies, which represent a paradigm shift from symptomatic management to targeted disease modification. AREAS CCOVERED: Agents such as lecanemab and donanemab selectively bind aggregated forms of Aβ and have demonstrated modest but statistically significant slowing of cognitive and functional decline in early AD. However, these therapies are associated with amyloid-related imaging abnormalities (ARIA), particularly in individuals carrying the APOE ε4 allele, necessitating close monitoring and individualized risk assessment. Implementation challenges, including high treatment burden, cost, and real-world applicability, have limited broad clinical adoption. This review examines the mechanistic differences, clinical trial outcomes, and safety considerations of Aβ monoclonal antibodies, while also highlighting emerging therapies and the need for inclusive, precision-guided approaches. EXPERT OPINION: As research continues to evolve, balancing clinical benefits with safety and accessibility will be critical in defining the role of anti-amyloid-β therapies within the broader landscape of AD care.}, } @article {pmid40940223, year = {2025}, author = {Liu, C and Zhao, Y and Dao, JJ and Zhang, W and Liu, J and Ma, YK and Qiao, CM and Cui, C and Chen, SX and Shen, YQ and Zhao, WJ}, title = {Targeted ErbB4 receptor activation ameliorates neuronal deficits via DOCK3 signaling in a transgenic mouse AD model.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {22}, number = {6}, pages = {e00739}, pmid = {40940223}, issn = {1878-7479}, mesh = {Animals ; *Receptor, ErbB-4/metabolism/agonists ; *Alzheimer Disease/metabolism/drug therapy/genetics/pathology ; Mice ; Mice, Transgenic ; Signal Transduction/drug effects/physiology ; *Neurons/metabolism/drug effects ; Disease Models, Animal ; Hippocampus/metabolism/drug effects ; Male ; Mice, Inbred C57BL ; Humans ; }, abstract = {Accumulating evidence has highlighted the critical involvement of ErbB4 receptor in the onset and progression of Alzheimer's disease (AD). Utilizing a small molecule ErbB4 receptor agonist (E4A) identified through virtual screening, it was observed that activation of ErbB4 receptor significantly ameliorated the cognitive behavioral deficits in APP/PS1 mice. Additionally, E4A treatment enhanced the expression of DOCK3 and SIRT3, leading to improvements in synaptic and mitochondrial dysfunction within the hippocampus of these mice. E4A also attenuated the activation of the TLR4-NF-κB-NLRP3 pathway, thereby reducing neuroinflammation and the formation of β-amyloid (Aβ) plaques. In vitro studies revealed that E4A partially mitigated the impact of hippocampal neuronal damage on microglial inflammation, which was partly compromised by the silencing of DOCK3. Collectively, our data suggest that targeted activation of ErbB4 receptor may treat AD via DOCK3 signaling by inhibiting neuronal damage and subsequent neuroinflammation, thereby offering a viable strategy for this neurodegenerative disease.}, } @article {pmid40939527, year = {2025}, author = {Pagan, FL and Torres-Yaghi, Y and Hebron, ML and Wilmarth, B and Liu, X and Ahn, J and Moussa, C}, title = {Safety, tolerability and potential biomarkers of vodobatinib in patients with dementia with Lewy bodies.}, journal = {Parkinsonism & related disorders}, volume = {140}, number = {}, pages = {108020}, doi = {10.1016/j.parkreldis.2025.108020}, pmid = {40939527}, issn = {1873-5126}, mesh = {Humans ; Female ; *Lewy Body Disease/drug therapy/cerebrospinal fluid ; Aged ; Male ; Double-Blind Method ; Aged, 80 and over ; Biomarkers/cerebrospinal fluid/blood ; Amyloid beta-Peptides/cerebrospinal fluid ; *Protein Kinase Inhibitors/adverse effects/administration & dosage/therapeutic use ; Peptide Fragments/cerebrospinal fluid ; }, abstract = {INTRODUCTION: Activation of the tyrosine kinase Abelson (Abl) was suggested in the pathogenesis of neurodegenerative diseases. We investigated the effects of a potent and highly specific Abl kinase inhibitor vodobatinib (K0706) in patients diagnosed with dementia with Lewy bodies (DLB). We determined safety, tolerability and potential biomarkers following oral administration of vodobatinib versus placebo in DLB patients. METHODS: Participants were randomized 1:1:1 into vodobatinib 192 mg, or 384 mg or matching placebo in a single-center, double-blind study. Study drug was taken orally once daily for 3 months followed by one-month wash-out. RESULTS: Twenty-nine individuals were enrolled, 3 were women (10.3 %), age 76.3 ± 6 years (mean ± SD). Vodobatinib was safe and well-tolerated and more adverse events were noted in the placebo (56) vs vodobatinib 192 mg (19) or 384 mg (6) groups. The number of falls were reduced in the vodobatinib 192 mg (6) and 384 mg (0) compared to placebo (28) groups. The only potential significant change in cerebrospinal fluid (CSF) biomarkers was Aβ42/Aβ40 in 192 mg vodobatinib (p = 0.0002) and 384 mg (0.0121) compared to placebo. There was no change in homovanillic acid, a biomarker of dopamine level, or other potential CSF and plasma biomarkers of DLB. Exploratory clinical outcomes were not different between baseline and 3 months in vodobatinib compared to placebo. CONCLUSIONS: Vodobatinib appears to be safe and tolerated, but larger trials and longer treatment periods are needed to determine its effects on biomarkers and clinical outcomes.}, } @article {pmid40939126, year = {2025}, author = {Boccalini, C and Mathoux, G and Hristovska, I and Ribaldi, F and Peretti, DE and Arnone, A and Scheffler, M and Frisoni, GB and Hansson, O and Vogel, JW and Garibotto, V}, title = {Visual Classification of Tau-PET Detects 4 Subtypes With Different Long-Term Outcomes.}, journal = {Neurology}, volume = {105}, number = {7}, pages = {e213950}, pmid = {40939126}, issn = {1526-632X}, mesh = {Humans ; Male ; Female ; *tau Proteins/metabolism ; Aged ; *Positron-Emission Tomography/methods ; *Alzheimer Disease/diagnostic imaging/classification/metabolism ; Prospective Studies ; Aged, 80 and over ; *Brain/diagnostic imaging/metabolism ; Middle Aged ; Carbolines ; }, abstract = {BACKGROUND AND OBJECTIVES: Tau accumulation pattern shows substantial variability in Alzheimer disease (AD), and 4 distinct spatiotemporal trajectories were distinguished using a data-driven approach called the Subtype and Stage Inference (SuStaIn). A visual method to validate and identify these subtypes is a requirement for their clinical translation. Our study aimed to provide a standardized topographic method for identifying tau patterns visually using tau-PET in a clinical setting. METHODS: Participants in this prospective study were included from the memory clinic of Geneva University Hospital. Inclusion criteria required participants to have undergone at least 1 [18]F-Flortaucipir tau-PET scan and a Mini-Mental State Examination (MMSE) within a 1-year time frame. All scans were classified into different tau subtypes (limbic [S1], medial temporal lobe-sparing [S2], posterior [S3], and lateral temporal [S4]) using both visual rating and SuStain algorithm. A subgroup underwent amyloid-PET and clinical follow-up. Cohen's κ tested the agreement between raters and between visual and automated subtypes. Chi-squared and Kruskal-Wallis tests assessed differences in clinical and biomarker features between subtypes, whereas differences in cognitive trajectories were tested using linear mixed-effects models, controlling for age, sex, and clinical and tau stages. RESULTS: A total of 245 tau-PET scans of individuals ranging from cognitively unimpaired to mild dementia (mean age: 68.25 years, 52% women) were included and classified into different tau pattern subtypes. A substantial agreement between raters was found in visually interpreting tau subtypes (κ > 0.65, p < 0.001) and a fair agreement between visual and automated subtypes (κ = 0.39, p < 0.001), with the automated approach more likely to classify a scan as tau negative and lower agreement between methods in more severe cases and AD clinical variants. Regarding the visual classification, individuals with S2 subtype were younger than S1 and S3, had lower MMSE and verbal fluency scores than S4 and S1, showed higher global tau burden than other subtypes, and a steeper cognitive decline. DISCUSSION: Visual classification reliably identified 4 tau patterns that differ in global tau load, clinical features, and long-term outcomes, suggesting its clinical usefulness for the detection of higher-risk AD variants. A clinically implementable classification of subtypes with faster decline is paramount for personalized diagnosis, accurate prognosis, and treatment.}, } @article {pmid40939031, year = {2025}, author = {Chun, H and Yoon, ML and Lee, HW and Lee, JY and Hong, SB and Ha, SS and Yoon, KJ}, title = {The Efficacy and Safety of Transcranial Photobiomodulation for Mild Cognitive Impairment Due to Alzheimer's Disease: A Randomized, Double-Blind, Sham-Controlled Study.}, journal = {Photobiomodulation, photomedicine, and laser surgery}, volume = {43}, number = {9}, pages = {411-416}, doi = {10.1177/15578550251369575}, pmid = {40939031}, issn = {2578-5478}, mesh = {Humans ; *Alzheimer Disease/complications ; *Cognitive Dysfunction/etiology/therapy ; *Low-Level Light Therapy/methods ; Male ; Aged ; Female ; Double-Blind Method ; Treatment Outcome ; Aged, 80 and over ; Middle Aged ; }, abstract = {Background: Transcranial photobiomodulation (tPBM) is a promising noninvasive neuromodulation modality with potential therapeutic benefits for neurodegenerative diseases. Infrared light delivered by a tPBM device penetrates the cortex, stimulating neuronal activity by increasing mitochondrial adenosine triphosphate production and enhancing regional cerebral blood flow. Objective: This study investigated the efficacy and safety of a self-administered, at-home, wearable tPBM device for improving cognitive function in individuals with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Methods: Individuals with MCI due to AD, diagnosed according to the National Institute on Aging and Alzheimer's Association criteria, with a Korean version of Mini-Mental State Examination-2 (K-MMSE2) score of 23-27 and a global Clinical Dementia Rating (CDR) score of 0.5-1.0 were enrolled. Subjects self-administered tPBM six times per week for 12 weeks. Assessments were conducted at weeks 7 and 13 using the Korean version of the Montreal Cognitive Assessment (K-MoCA), K-MMSE2, the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease, and the Geriatric Depression Scale. Results: A total of 26 participants were enrolled. The treatment group showed a statistically significant improvement in K-MoCA scores at week 13 (p < 0.05) compared with the sham group. Although K-MMSE2 scores improved in the treatment group, the difference was not statistically significant. No serious adverse events were reported. Conclusion: Findings suggest that tPBM is an effective and safe home-use intervention for individuals with MCI, with promising therapeutic and preventative roles in Alzheimer's dementia.}, } @article {pmid40938652, year = {2025}, author = {Tho Chu, TQ and Morimoto, K and Kowa, H}, title = {Cognitive performance and blood biomarkers: Insights into their relationship and predicting high Amyloid Probability Score in cognitively impaired older adults.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {4}, pages = {1661-1673}, doi = {10.1177/13872877251372958}, pmid = {40938652}, issn = {1875-8908}, mesh = {Humans ; Aged ; Male ; Female ; *Cognitive Dysfunction/blood/psychology/diagnosis ; Biomarkers/blood ; Aged, 80 and over ; Neuropsychological Tests ; Mental Status and Dementia Tests ; Middle Aged ; *Cognition/physiology ; Cohort Studies ; Japan ; *Amyloid beta-Peptides/blood ; Alzheimer Disease/blood ; }, abstract = {BackgroundUnderstanding associations between cognitive performance and blood biomarkers supports diagnosis and treatment of Alzheimer's disease (AD); however, this relationship remains unclear.ObjectiveExploring associations between the Amyloid Probability Score (APS; PrecivityAD® blood test) and cognitive performance, and between Mini-Mental State Examination (MMSE) and Cogstate Brief Battery (CBB) in cognitively impaired older adults.MethodsOlder adults aged ≥ 60 years with MMSE from 10 to 27, recruited from a cohort in Japan, were assessed with the CBB, and plasma biomarkers to calculate APS. We used Spearman correlation to explore relationships; receiver operating curves and cross-validation to identify the best model for predicting high APS.ResultsAmong 46 participants (mean age = 78.3 ± 5.9; mean MMSE = 20.3 ± 4.6), 39.1% did not complete at least one test in the CBB. Lower MMSE were observed in those who were non-completers. MMSE correlated with Detection (Psychomotor function), Identification (Attention), and their composite (r = 0.34-0.52; p < 0.05; 95%CI excluding null value). Higher APS was seen in those who did not complete the One Card Learning (OCL-visual learning and short-term memory). The best model for predicting High APS included OCL completion status, MMSE and Years of Education, achieving accuracy = 0.808 and kappa = 0.606 in participants with MMSE < 21.ConclusionsOur findings suggest a consideration of incompletion when using CBB in cognitively impaired older adults and a potential approach to differentiate High APS group among those with moderate to severe dementia based on visual learning and short-term memory, global cognition and education level.}, } @article {pmid40938517, year = {2025}, author = {Xie, F and Zhou, L and Yu, M}, title = {Dihuang Yinzi Ameliorates Cognitive Impairments and Inhibits Ferroptosis in APP/PS1 Mice.}, journal = {Biochemical genetics}, volume = {}, number = {}, pages = {}, pmid = {40938517}, issn = {1573-4927}, support = {2024CCCX259//Anhui Traditional Chinese Medicine Inheritance and Innovation Research Project/ ; 2021byzd058//Bengbu Medical University Key Project/ ; Chinese Medicine Education Letter (2022) No. 75//National Administration of Traditional Chinese Medicine National Famous Traditional Chinese Medicine Expert Inheritance Studio Construction Project/ ; Project No. 202204295107020034//Clinical Medical Research Translation Special Project of Anhui Provincial Science and Technology Department/ ; 81803984//National Natural Science Foundation of China/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss. Ferroptosis, a form of regulated cell death driven by iron overload and lipid peroxidation, has been implicated in AD pathology. DiHuangYinZi (DHYZ), a traditional Chinese herbal remedy, has been suggested to ameliorate cognitive impairments and reduce ferroptosis in AD models. This study aimed to investigate the effects of DHYZ on learning, memory, ferroptosis markers, and neuronal integrity in APP/PS1 transgenic mice. Six-month-old APP/PS1 transgenic mice were treated with DHYZ or donepezil for four weeks. Learning and memory functions were evaluated using the Morris Water Maze (MWM) and open field test. Neuronal integrity was assessed through Hematoxylin and Eosin (H&E) and Nissl staining. Ferroptosis markers, including superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), and the GSH/GSSG ratio, were measured in hippocampal tissues. Ferroptosis-related protein expressions, such as ferritin, DMT1, FPN1, Nrf2, and GPX4, were analyzed using Western blot. DHYZ treatment significantly improved learning and memory deficits in APP/PS1 mice, as evidenced by reduced escape latency and increased platform crossings in the MWM. DHYZ also reversed anxiety-like behavior in the open field test. Histological analysis showed that DHYZ treatment restored neuronal integrity, as indicated by better cellular arrangement and staining compared to untreated APP/PS1 mice. DHYZ inhibited ferroptosis by reducing iron overload, increasing SOD and GSH levels, and normalizing the GSH/GSSG ratio. Moreover, DHYZ modulated the expression of ferroptosis-related proteins, restoring FPN1 levels while reducing ferritin and DMT1 expressions. Nrf2 and GPX4 levels, which were reduced in APP/PS1 mice, were significantly increased after DHYZ treatment. DHYZ effectively improved cognitive deficits, inhibited ferroptosis, and restored neuronal integrity in APP/PS1 mice. These findings suggest that DHYZ may have therapeutic potential for AD by targeting ferroptosis and regulating iron metabolism.}, } @article {pmid40938483, year = {2025}, author = {Comert Onder, F and Ural, K and Onder, A and Ozpolat, B and Ay, M}, title = {Boron Containing Curcumin-Like Compound as an Acetylcholinesterase Inhibitor and Anticancer Agent: Synthesis, Biological Evaluation, and Computational Insights.}, journal = {Cell biochemistry and biophysics}, volume = {}, number = {}, pages = {}, pmid = {40938483}, issn = {1559-0283}, abstract = {Alzheimer's disease (AD) and cancer are significant global health challenges that highlight the need for the development of new therapeutics. Targeting biological mechanisms involved in both AD and cancer could be an effective treatment strategy for developing novel inhibitors. In this study, we investigated the effect of a newly synthesized boron containing curcumin-like compound as a potential acetylcholinesterase (AChE) inhibitor along with its cytotoxic effects on breast and colorectal cancer cell lines. Compound A exhibited a potent AChE inhibitory activity (IC50 = 22.89 ± 2.32 nM), demonstrating that it was more effective than the known inhibitors donepezil (IC50 = 28.32 ± 3.27 nM) and tacrine. Compound A showed a moderate cytotoxic activity on MCF-7 and BT20 cells with the IC50 values 40.70 ± 2.31 μM and 41.71 ± 4.51 μM, respectively. Throughout molecular dynamics (MD) simulations, the RMSD value of the protein was calculated as 1.56 ± 0.20 Å and 1.65 ± 0.19 Å for the complexes of compound A and curcumin, respectively. The interactions with specific amino acid residues such as Tyr124, Tyr337, and Trp86 for AChE, and Trp82, His438, and Tyr332 for BChE were obtained. Additionally, MM/GBSA calculations demonstrated that Compound A had the highest binding free energies (-88.89 ± 8.34 kcal/mol for AChE and -73.25 ± 8.83 kcal/mol for BChE) compared to curcumin (-67.87 ± 5.48 kcal/mol for AChE and -51.68 ± 5.28 kcal/mol for BChE) and tacrine (-56.67 ± 2.22 kcal/mol for BChE) were calculated. Overall, these findings suggest that Compound A is a promising agent with its potent AChE inhibitory activity and anticancer potential, making it a valuable candidate for further research in neurodegenerative diseases and cancer therapy.}, } @article {pmid40937962, year = {2025}, author = {Hillerstrom, H and Das, A and Janicki, MP and Rozas, NS and Santoro, SL}, title = {Specialists' perceptions of clinical instruments, practices, and staging of DS-AD: Results from an international survey.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70356}, pmid = {40937962}, issn = {1552-5279}, support = {//LuMind IDSC Foundation/ ; /DP/NCCDPHP CDC HHS/United States ; 1NU58DP006782-01-00//Healthy Brain Initiative/ ; //Eli Lilly and Company/ ; //Rainwater Charitable Foundation/ ; }, mesh = {Humans ; *Down Syndrome/complications/diagnosis ; *Alzheimer Disease/diagnosis ; Surveys and Questionnaires ; Cognitive Dysfunction/diagnosis ; Male ; Female ; Neuropsychological Tests ; }, abstract = {INTRODUCTION: Diagnosing and staging Down syndrome-associated Alzheimer's disease (DS-AD) is hindered by the lack of standardized criteria, complicating clinical decision making, trial participation, and access to advanced therapies. This study aimed to explore perceptions of these issues. METHOD: An international survey of 42 clinicians and researchers specializing in DS-AD gathered perspectives on instruments, symptomatic staging, clinical practices, and research priorities. RESULTS: Respondents noted that key domains of impairment in mild cognitive impairment in Down syndrome and DS-AD dementia included memory, executive functioning, personality, social behavior, attention, mood, and language. Among the 10 assessment tools evaluated, informant-based interviews were noted as critical for individuals with severe intellectual disability (ID), while direct assessments were noted as useful for those with mild to moderate ID. Common diagnostic confounders like hypothyroidism and sleep disorders were identified. DISCUSSION: Behavioral assessments provide a valuable function; however, future efforts should integrate behavioral assessments with biomarkers and develop standardized staging frameworks to improve diagnostic reliability, care planning, and treatment strategies for DS-AD. HIGHLIGHTS: Personality, social behavior, language, mood/affect, memory, executive functioning, and attention are recognized as key domains of impairment in both mild cognitive impairment in Down syndrome (MCI-DS) and Down syndrome-associated Alzheimer's disease (DS-AD). Ten prominent informant and direct assessment tools were noted as appropriate for individuals with DS and mild to moderate intellectual disability (ID) for identifying both MCI-DS and DS-AD; however, for individuals with severe/profound ID, there was less assurance of applicability. Harmonizing recommended tools in a standardized list was identified as a strategy to promote consistency across clinical and research contexts.}, } @article {pmid40937948, year = {2025}, author = {Zhao, J and Chen, J and Lu, J and Shi, Q and Wang, Q and Gao, Z and Zeng, L and Liu, Q}, title = {Nitration of Tyrosine Residue Y10 of Aβ1-42 Ameliorates Aβ1-42-Induced Neurotoxicity and Memory Impairment In Vitro and In Vivo.}, journal = {Journal of neurochemistry}, volume = {169}, number = {9}, pages = {e70218}, doi = {10.1111/jnc.70218}, pmid = {40937948}, issn = {1471-4159}, support = {22377027//National Natural Science Foundation of China/ ; 2022C03034//Key R&D Program Project of Zhejiang/ ; 2023SHIBS0003//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; LTGD23C050001//Zhejiang Provincial Natural Science Foundation of China/ ; }, mesh = {*Amyloid beta-Peptides/toxicity/metabolism ; Animals ; *Peptide Fragments/toxicity/metabolism ; *Tyrosine/metabolism ; Mice ; Humans ; Male ; Cell Line, Tumor ; *Memory Disorders/chemically induced/metabolism ; Alzheimer Disease/metabolism ; Mice, Inbred C57BL ; Hippocampus/drug effects/metabolism ; }, abstract = {The abnormal generation and aggregation of Aβ has been considered the central pathogenic mechanism of Alzheimer's disease (AD). Soluble Aβ tends to aggregate into toxic oligomers, which initiate neuronal dysfunction. Therefore, attenuation of Aβ oligomer formation might be an effective therapeutic strategy for AD. It has been reported that Aβ can be nitrated at tyrosine 10. Our previous study found that nitration of Y10 in Aβ significantly inhibits its aggregation and reduces its toxicity. However, the effects of Aβ nitration on its neurotoxicity remain unclear. Here, we used SH-SY5Y cells and a mouse model of AD induced by intrahippocampal Aβ1-42 oligomer injection to investigate the effects of tyrosine nitration on the neurotoxicity of Aβ1-42. The results of dot blot, gel electrophoresis analysis, transmission electron microscopy, atomic force microscopy, and dynamic light scattering indicated that nitration of Y10 in Aβ1-42 inhibits its oligomerization. Aβ1-42 treatment perturbed the integrity of intracellular membranes, eventually leading to apoptosis of SH-SY5Y cells. In contrast, nitrated Aβ1-42 exhibited little neurotoxicity toward SH-SY5Y cells. Additionally, mice injected with Aβ1-42 oligomer developed cognitive impairment in behavioral tests. Aβ1-42 oligomer caused neurotoxicity in the hippocampus of the mice, possibly through triggering apoptosis and neuroinflammation and promoting aberrant amyloid processing. As expected, nitrated Aβ1-42 also had little effect on physiological and cognitive capacities. These results further confirm that nitration of Y10 in Aβ can significantly inhibit its neurotoxicity. Moreover, our findings contribute to the understanding of the role of Aβ in the development of AD.}, } @article {pmid40937337, year = {2025}, author = {Han, SH and Jeong, HB and Lee, SJ and Jeong, HT and Shin, HW and Park, CY and Ahn, SW and Park, KY and Kim, HR and Youn, YC}, title = {Therapeutic Potential of Porcine Brain-Derived Peptide Mixture (PBDP) in Alzheimer's Disease: An Exploratory Study on Quantitative Electroencephalography (qEEG) Changes.}, journal = {Neuropsychiatric disease and treatment}, volume = {21}, number = {}, pages = {1981-1992}, pmid = {40937337}, issn = {1176-6328}, abstract = {BACKGROUND: This exploratory study investigates the therapeutic potential of Porcine Brain-Derived Peptide Mixture (PBDP) in Alzheimer's Disease (AD) by examining changes in quantitative electroencephalography (qEEG) parameters following treatment. METHODS: We analyzed qEEG data from 27 AD patients treated with 2-weeks of PBDP treatment and compared them to a control group of 20 patients at 2-month follow-up, all of whom were previously on donepezil therapy. RESULTS: EEG modifications were noted within two weeks of PBDP administration, including improvements in EEG patterns such as reduced Theta/Beta (4.437 ± 3.979 to 3.859 ± 3.587, p = 0.442), Theta/Alpha ratio (1.815 ± 1.637 to 1.578 ± 1.304, p < 0.05), and Delta/Alpha ratio (2.365 ± 2.471 to 2.105 ± 2.402, p < 0.05) across various brain regions, suggesting enhanced cortical activity. Post-intervention, 55% of patients showed caregiver-reported improvements in mood and daily activities. CONCLUSION: PBDP could serve as a viable therapeutic approach for managing AD, and qEEG could serve as a monitoring biomarker for acute drug effects, warranting further investigation into its long-term benefits and mechanistic pathways.}, } @article {pmid40936998, year = {2025}, author = {Duehring, JA and Jacobs, DM and Thomas, ML and Dodge, HH and Feldman, HH and Edland, SD}, title = {Implications of practice effects for the design of Alzheimer clinical trials.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70154}, pmid = {40936998}, issn = {2352-8737}, abstract = {INTRODUCTION: Practice effects (PEs) are a well-known potential confound in natural history studies of longitudinal cognitive decline in aging and early-stage Alzheimer's disease. The implication of PEs on Alzheimer's disease clinical trials is less well understood, although we have previously speculated that a "run-in" period of repeated cognitive assessments prior to randomization may improve the efficiency of clinical trials [Jacobs et al. Alzheimer's & Dementia 2017;3(4):531-535]. We have also described how the performance of composite outcome measures depends on parameters that may be influenced by PEs. METHODS: To investigate this, we used the cognitive battery within the National Alzheimer's Coordinating Center (NACC) Uniform Data Set to characterize the potential impact of PEs on clinical trial design and outcome measures. The analysis restricted to N = 1094 amnestic mild cognitively impaired participants with 3 years of follow-up data. Linear mixed effects models estimate the magnitude of PEs observed in aMCI participants. Power calculations informed by the pattern of progression in the NACC sample were used to describe the net impact of PEs on trials with and without a run-in phase. Weighting parameters of optimal composite measures constructed from the NACC battery were also compared. RESULTS: PEs were large, often exceeding the magnitude of annual rate of change observed in later assessments. Annualized rate of change, and therefore target treatment effect sufficient to achieve a specified percentage reduction in rate of decline, was larger after run-in. Sample size projections for the run-in design were a fraction of those required for trials without run-in. Weighting parameters that optimize composite outcome performance were also different for the two designs, underscoring the importance of considering design in the construction of composite outcomes. DISCUSSION: Clinical trials randomizing after a run-in period measure treatment efficacy relative to decline unbiased by PEs, and require smaller sample size. HIGHLIGHTS: In the National Alzheimer's Coordinating Center (NACC), amnestic mild cognitive impairment (aMCI) cohort practice effects often exceed annualized rate of change.Run-in clinical trial designs can be used to extinguish practice effects.Rate of decline after run-in is faster and unbiased by practice effects.Run-in designs correctly target the most clinically relevant outcome signal.Practice effects also impact weighting of optimal composite measures.}, } @article {pmid40936458, year = {2025}, author = {Paul, I and Roy, A and Ray, S and Pyne, S and Saha, M and Ray, S}, title = {Exploring the novel protein drug target BAG33339.1 of Porphyromonas gingivalis: an integrative subtractive proteomics and structural dynamics study.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-45}, doi = {10.1080/07391102.2025.2553155}, pmid = {40936458}, issn = {1538-0254}, abstract = {Porphyromonas gingivalis, a gram-negative, bacterium interacts favourably with host subgingival biofilms to cause adult tooth decay and loss. Consequently, the host is infested with an uncontrollable microbial community and a compromised immune system, ultimately leading to tissue damage and bone resorption. P. gingivalis has also been known to cause cardiovascular and metabolic diseases, Alzheimer's disease, depression, prostate and digestive system cancer, rheumatoid arthritis, and adverse pregnancy outcomes with high detection frequencies. Rising concerns in the recent past, highlight the inefficiency of antibiotics and antiseptics in the treatment of P. gingivalis-related infections. Hence, the current scenario impels the discovery of an alternative therapeutic avenue against P. gingivalis-infections. To elucidate the unidentified bacterial mechanisms of infection, we screened a non-homolog of the host and gut microbiome as a novel druggable target from 173 essential hypothetical proteins of P.gingivalis (BAG33339.1). BAG33339.1 was an inner membrane protein with a hydrophobic N-terminal transmembrane helix and a primarily reconfiguring C-terminal helical region (Y36 to E52) while the residues (downstream of Lys45) lay in the disordered region. Frustration index coupled with the mutation matrix showed the steadiness of the transmembrane helix and dynamicity of the C-terminal residues finally yielding a 'U'-shaped protein conformation. The tendency of the disordered C-terminal residues was to generate P. gingivalis variants. The overall conformational stability was determined by equilibrating RMSD, Rg and SASA values corroborated by increasing H-bonds and helix settling. Targeting the ligand binding pockets of BAG33339.1 would guide future endeavours to tackle P. gingivalis interaction with host systems.}, } @article {pmid40936007, year = {2025}, author = {Tskhakaia, I and Lema, D and Tsibadze, N and Lam, JR and Subramanian, A and Lau, A}, title = {Proton pump inhibitors in systemic sclerosis: should we exercise caution? Insights from a large-scale data analysis.}, journal = {Clinical rheumatology}, volume = {44}, number = {10}, pages = {4061-4070}, pmid = {40936007}, issn = {1434-9949}, mesh = {Humans ; *Proton Pump Inhibitors/adverse effects/therapeutic use ; *Scleroderma, Systemic/complications/drug therapy ; Female ; Male ; Retrospective Studies ; Middle Aged ; *Gastroesophageal Reflux/drug therapy/complications ; *Renal Insufficiency, Chronic/epidemiology/chemically induced ; Aged ; Osteoporosis/epidemiology/chemically induced ; Adult ; Alzheimer Disease/epidemiology ; }, abstract = {BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disorder often accompanied by gastroesophageal reflux disease (GERD), necessitating frequent use of proton pump inhibitors (PPIs). While PPIs mitigate GERD symptoms and protect against lung injury, concerns about their long-term safety, particularly regarding chronic kidney disease (CKD), osteoporosis, and Alzheimer's disease, are growing. This study aimed to assess whether the adverse effects of PPI are amplified in patients with scleroderma. METHODS: This was a retrospective observational analysis that utilized the TriNetX research network, including over 130 million patients globally. The study population comprised 6800 SSc patients on PPIs and 1,889,433 GERD patients on PPIs. Outcomes were evaluated pre- and post-propensity score matching for demographic and clinical factors. Risks of CKD (including stages 3, 4, 5, ESRD, hemodialysis dependence), osteoporosis, vascular dementia, and Alzheimer's disease were assessed. RESULTS: The SSc cohort exhibited higher risks of developing CKD (attributable risk [AR] 2.8%, p < 0.01) and osteoporosis (AR 9%, p < 0.01) after matching, compared to the GERD cohort. Notably, CKD stages 4 and 5 showed minimal differences between groups. SSc patients on PPI had lower risks of Alzheimer's disease (AR - 0.7%, p < 0.01). While the findings highlight an amplified risk of CKD and osteoporosis in SSc patients, the differences in advanced renal disease were modest. CONCLUSION: PPI therapy remains indispensable in SSc management. While potentially associated with a slight but significant increase in the risks of CKD and osteoporosis, these adverse effects do not negate the critical role of PPIs in mitigating GERD and its serious pulmonary complications. A strategy of targeted monitoring is recommended to maximize safety. Key Points • Identified Amplified Risks in SSc: This large-scale study reveals that SSc patients on PPIs face significantly higher risks of chronic kidney disease and osteoporosis compared to GERD patients on PPIs, suggesting SSc pathophysiology amplifies PPI-associated adverse effects. • Uncovered Neuroprotective Association: Contrary to general population trends, SSc patients on PPIs showed a reduced risk of Alzheimer's disease, potentially linked to immunosuppressant use, closer monitoring, or unique disease mechanisms-a finding warranting further investigation. • Provided Real-World Safety Evidence: Leveraging global data (> 130 million patients), this study offers robust real-world evidence on PPI safety in SSc, reinforcing PPIs' vital role in GERD/ILD management while advocating vigilant monitoring for CKD/osteoporosis. • Informed Risk-Benefit Clinical Strategy: The findings underscore the need to balance PPI benefits (reducing GERD/aspiration-related lung injury) against amplified renal/bone risks in SSc, guiding individualized treatment and monitoring protocols despite causal limitations of retrospective data.}, } @article {pmid40935607, year = {2025}, author = {Yoo, HB and Kang, SK and Shin, SA and Kim, D and Choi, H and Kim, YK and Yi, D and Byun, MS and Lee, DY and Lee, JS and , }, title = {Artificial Intelligence-Powered Quantification of Flortaucipir PET for Detecting Tau Pathology.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {66}, number = {11}, pages = {1827-1833}, pmid = {40935607}, issn = {1535-5667}, mesh = {Humans ; *Positron-Emission Tomography ; *tau Proteins/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Carbolines ; Male ; Female ; *Artificial Intelligence ; Aged ; Image Processing, Computer-Assisted/methods ; }, abstract = {We developed and evaluated an artificial intelligence (AI)-powered approach for easier quantification of tau PET uptake without requiring structural MR to aid earlier tracking of Alzheimer disease (AD). Methods: We implemented a deep neural network model that normalizes [18]F-AV1451 (tau) PET images to a standard template without requiring MR, using transfer learning from a model pretrained on amyloid PET. This model was integrated into an MR-free pipeline for tau PET quantification and validated on external dataset (Alzheimer Disease Neuroimaging Initiative). We examined correlations between model-derived tau uptake estimates and cognitive measures, including AD stage and episodic memory performance (n = 666). Longitudinal analyses were conducted to assess whether baseline tau deposition predicted future cognitive decline (n = 168). Results: The AI-powered pipeline achieved robust performance with intraclass correlation coefficients exceeding 0.97 for regional uptake estimation compared with MR-based ground truth. We also showed that the tau deposition in metatemporal regions was significantly correlated with Mini-Mental State Examination and Montreal Cognitive Assessment scores. Elevated tau PET uptake in the entorhinal cortex and inferior temporal gyrus predicted future cognitive decline. Conclusion: The proposed AI-powered pipeline enhances the clinical accessibility of tau PET by reducing scan costs and streamlining the uptake quantification, achieving high performance without requiring structural MR. We further demonstrated that the pipeline yields cognitively relevant outcome measures for early diagnosis and monitoring of AD progression to aid more personalized treatment strategies targeting AD biomarkers.}, } @article {pmid40935215, year = {2026}, author = {Huang, H and Lu, W and Huang, Y and Su, Y and Luo, R and Zeng, Y and Yuan, C and Jia, Z and Wang, X}, title = {Bazi Bushen improves cognitive dysfunction in 5×FAD mice by targeting amyloid pathology, neuroinflammation and cellular senescence.}, journal = {Journal of ethnopharmacology}, volume = {355}, number = {Pt A}, pages = {120586}, doi = {10.1016/j.jep.2025.120586}, pmid = {40935215}, issn = {1872-7573}, mesh = {Animals ; *Cellular Senescence/drug effects ; Mice ; Mice, Transgenic ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Cognitive Dysfunction/drug therapy/pathology/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Disease Models, Animal ; Aspartic Acid Endopeptidases/metabolism ; *Neuroinflammatory Diseases/drug therapy/pathology ; Male ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism/genetics ; Hippocampus/drug effects/metabolism/pathology ; Cognition/drug effects ; Maze Learning/drug effects ; Plaque, Amyloid/drug therapy/pathology ; }, abstract = {Bazi Bushen (BZBS), a Traditional Chinese Medicine (TCM) formula, is composed of fourteen herbal ingredients, including classic tonics such as Ginseng Radix et Rhizoma and Cistanches Herba. Traditionally used to combat fatigue and promote vitality in aging individuals, BZBS is rooted in TCM principles of kidney essence replenishment and brain function enhancement. Recent pharmacological studies have begun to validate its efficacy in age-related cognitive decline, but its effects and mechanisms in Alzheimer's disease (AD) remain unclear. AIM OF THE STUDY: This study aimed to evaluate the potential therapeutic effects of BZBS in 5 × FAD transgenic mice, a commonly used Alzheimer's disease model, and to shed light on its possible mechanisms of action. METHODS: Four- and six-month-old 5 × FAD mice were treated with BZBS to examine how it might influence cognitive performance. Behavioral assessments were carried out using Y-Maze and the Morris Water Maze. To investigate the biological changes and uncover the mechanisms involved, we used a range of techniques-Thioflavin S staining, immunofluorescence, Western blotting, and qPCR-to look at Aβ plaque accumulation, Amyloid Precursor Protein C-terminal Fragments (APP-CTF) and β-secretase 1 (BACE1) expression levels, markers of inflammation, and indicators of cellular aging in hippocampus and motor cortex. RESULTS: In the 4-month group, where treatment was started before severe pathology developed, BZBS improved learning and memory performance. It also reduced amyloid deposition in the cortex and hippocampus, and lowered the levels of APP-CTFs and BACE1. In addition, we observed decreased mRNA expression of IL-1α, IL-6, and NF-κB, along with reduced microglial activation in the hippocampus of BZBS-treated mice. Similarly BZBS downregulated key markers of cellular senescence, including p16, p21, and senescence-associated β galactosidase (SA-β-gal) activity. In the 6-month group, which already showed signs of amyloid pathology, BZBS still had beneficial effects-improving cognition, lowering Aβ load, and reducing microglial activity-suggesting that it may be effective even after disease onset. CONCLUSION: These findings demonstrate that BZBS exerts significant therapeutic effects in 5 × FAD mice, including improved cognitive improvement, reduced Aβ deposition, suppressed microglial activation, and attenuated hippocampal cellular senescence. Notably, BZBS was effective whether administered from the early stage of pathology (at four months of age) or after established amyloidosis (at six months of age), highlighting its dual potential as both a preventive and disease-modifying intervention for Alzheimer's disease (AD).}, } @article {pmid40935202, year = {2026}, author = {Yang, X and Hu, D and Zhao, S and Wan, J and Chen, L and Bao, Q and Zhang, Y and Wang, Q and Huang, Z}, title = {Neuroprotective effects of butyrolactone II from Aspergillus terreus via Nrf-2/SKN-1 pathway modulation in Caenorhabditis elegans.}, journal = {The Journal of nutritional biochemistry}, volume = {147}, number = {}, pages = {110107}, doi = {10.1016/j.jnutbio.2025.110107}, pmid = {40935202}, issn = {1873-4847}, mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism/genetics ; *Aspergillus/chemistry/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *NF-E2-Related Factor 2/metabolism/genetics ; *4-Butyrolactone/pharmacology/analogs & derivatives ; *Transcription Factors/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; *DNA-Binding Proteins/metabolism/genetics ; Signal Transduction/drug effects ; Longevity/drug effects ; }, abstract = {Fourteen compounds were isolated from the fermentation broth of Aspergillus terreus, all of which were isolated from A. terreus for the first time. Among them, butyrolactone II (A9) had excellent DPPH radical scavenging activity, with an EC50 value of 42.05 µM superior to positive control drug BHT. Further neuroprotective activity evaluation of in Caenorhabditis elegans CL2355 revealed that butyrolactone II could alleviate Aβ, causing chemotaxis disorder, prolonging lifespan of C. elegans, and reducing 5-HT sensitivity. Butyrolactone II treatment significantly elevated the chemotaxis index of genotyped nematode CL2355 by 15.06% (P<0.05), and reduced the sensitivity of nematodes to 5-HT, decreasing the paralysis rate by 9.8% (P<0.05). Moreover, it significantly increased median lifespan and maximum lifespan by 20% and 26% respectively. In the RNA transcriptome, Butyrolactone II caused upregulation of 277 differentially expressed genes and downregulation of 171 differentially expressed genes, inducing the entry of transcription factor SKN-1 into the nucleus and changes in its downstream genes. The annotation and enrichment of GO and KEGG pathways indicated that differentially expressed genes might be related to pathways such as metabolic detoxification, oxidative stress, and lysosomal autophagy. The qRT-PCR validation of gene expression was consistent with transcriptomics. Butyrolactone II could significantly increase the expression of mitochondrial fission factor (mff-2), downstream genes related to SKN-1 (dod-17, gst-38), heat shock protein genes (hsp-17, hsp-12.6), and oxidative stress related genes (cyp-14A5) in nematodes, while having no significant effect on the expression level of gst-33 gene. Taken conclusion, butyrolactone II exerts neuroprotective effects by modulating the Nrf-2/SKN-1 pathway and regulating metabolic pathways, underscoring its potential as a therapeutic strategy for Alzheimer's disease and other related neurodegenerative disorders.}, } @article {pmid40934766, year = {2025}, author = {Xin, X and Zong, T and Hu, Z and Jin, L and Zhou, W and Sun, J and Li, G}, title = {Discovery of natural compounds and their derivatives against neuroinflammation: Pharmacological mechanisms and structure-activity relationship.}, journal = {Bioorganic chemistry}, volume = {165}, number = {}, pages = {108934}, doi = {10.1016/j.bioorg.2025.108934}, pmid = {40934766}, issn = {1090-2120}, mesh = {Humans ; Structure-Activity Relationship ; *Biological Products/chemistry/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; *Neuroinflammatory Diseases/drug therapy ; Molecular Structure ; *Drug Discovery ; *Neuroprotective Agents/chemistry/pharmacology ; }, abstract = {Neuroinflammation refers to the inflammatory response within the central nervous system mediated by immune and glial cells, constitutes a pivotal mechanism in the pathological progression of neurodegenerative diseases. Alzheimer's disease (AD) serves as a paradigmatic example of neuroinflammation role in driving cytokine-mediated neuronal damage and perpetuating of disease progression. AD, which is characterized by memory decline and progressive cognitive impairment as its core clinical manifestations, currently has no effective treatment. Recent advances have underscored natural products as promising candidates for the development of safer and more effective anti-AD agents, particularly through the targeting of neuroinflammatory pathways that have emerged as central pathological mechanisms in the progression of AD. This review aims to elucidate the pathogenesis of neuroinflammation in AD and provides a comprehensive overview of anti-AD drugs currently in clinical research as well as those already available on the market. Additionally, this paper highlights natural compounds and their derivatives discovered over the past decade that exhibit anti-AD neuroinflammatory properties, analyzing the structure-activity relationships of selected compounds and their permeability across the blood-brain barrier. The goal is to offer valuable insights and references for drug developers.}, } @article {pmid40934542, year = {2025}, author = {Liu, T and Zhang, W and Bao, W and Wang, X and Zhang, F and Guo, J and Li, M}, title = {Aβ impairs bone vascular homeostasis in APP/PS1 mice via disrupting the mitochondrial fission-efferocytosis axis in macrophages.}, journal = {International immunopharmacology}, volume = {165}, number = {}, pages = {115526}, doi = {10.1016/j.intimp.2025.115526}, pmid = {40934542}, issn = {1878-1705}, mesh = {Animals ; *Mitochondrial Dynamics/drug effects ; *Macrophages/metabolism/physiology/drug effects ; Mice ; Homeostasis ; Mice, Transgenic ; Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/metabolism/immunology/pathology ; Phagocytosis ; c-Mer Tyrosine Kinase/metabolism ; *Bone and Bones/blood supply/pathology/metabolism ; Amyloid beta-Protein Precursor/genetics ; Endothelial Cells ; Humans ; ADAM17 Protein/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Presenilin-1/genetics ; Apoptosis ; Reactive Oxygen Species/metabolism ; Dynamins/metabolism ; Male ; Efferocytosis ; }, abstract = {Alzheimer's disease (AD) is associated with progressive bone loss, but the underlying mechanisms remain unclear. This study focused on how amyloid-β (Aβ) disrupted bone vascular homeostasis by impairing macrophage efferocytosis in APP/PS1 mice. We found that Aβ accumulation in bone tissue impaired MerTK-mediated macrophage efferocytosis and promoted excessive accumulation of apoptotic endothelial cells (ECs). Mechanistically, Aβ triggered excessive mitochondrial fission via GSK-3β-mediated DRP1 phosphorylation, resulting in elevated reactive oxygen species (ROS) and subsequent ADAM17 activation. ADAM17 cleaved MerTK, a critical efferocytosis receptor, impairing apoptotic cells (ACs) clearance. Pharmacological inhibition of GSK-3β (LiCl and TDZD-8) or mitochondrial fission (Mdivi-1) restored MerTK expression, improved efferocytosis, and reduced inflammatory cytokine release (such as TNF-α, IL-6), while enhancing vascular endothelial growth factors (VEGFs). In vivo, LiCl treatment ameliorated bone loss and vascular dysfunction in APP/PS1 mice. These findings revealed that Aβ disrupted the mitochondrial fission-efferocytosis axis in macrophages, contributing to AD-related bone pathology, and highlighted GSK-3β as a potential therapeutic target for preserving bone vascular homeostasis in AD.}, } @article {pmid40933919, year = {2025}, author = {Song, B and Yue, D and Yan, H and Feng, L and Li, M}, title = {Traditional Chinese Medicine Natural Products Targeting Shared Mechanisms of T2DM and AD: Potential Therapeutic Insights.}, journal = {Drug design, development and therapy}, volume = {19}, number = {}, pages = {7681-7705}, pmid = {40933919}, issn = {1177-8881}, mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Medicine, Chinese Traditional ; *Biological Products/pharmacology/therapeutic use/chemistry ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Animals ; Oxidative Stress/drug effects ; }, abstract = {As highly prevalent chronic diseases globally, AD (Alzheimer's disease) and T2DM (type 2 diabetes mellitus) not only severely affect the quality of life of patients but also impose a significant burden on their families. Numerous studies have gradually revealed that T2DM and AD are bidirectional risk factors, each capable of exacerbating the other. There is a notable correlation in their pathological mechanisms, primarily manifested in insulin resistance, OS (oxidative stress), and inflammatory responses. Currently, available drugs can only delay the progression of AD, such as Donepezil, Galantamine, and Carbamylcholine, making complete cures challenging to achieve. TCM (Traditional Chinese medicine) natural products exhibit characteristics such as multi-targeting, multi-pathway interactions, diverse biological activities, and relatively mild side effects, enabling synergistic intervention in both diseases. In recent years, TCM natural products have garnered increasing attention in research concentrated on the prevention and management of AD and T2DM. This article aims to comprehensively elucidate the collective pathogenic mechanism of AD and T2DM, and explore the progress of TCM natural products based on these mechanisms in the prevention and treatment of both diseases, thereby providing a theoretical foundation for the advancement of innovative treatment tactics.}, } @article {pmid40933857, year = {2025}, author = {Li, H and Zhu, J and Li, J and Wu, Y and Luo, C and Huang, Y and Wu, J and Liu, W and Wang, H and Mo, Z}, title = {Human brain organoids: an innovative model for neurological disorder research and therapy.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1658074}, pmid = {40933857}, issn = {1662-5102}, abstract = {The emergence of human brain organoids (hBOs) has transformed how we study brain development, disease mechanisms, and therapy discovery. These 3D in vitro neural models closely mimic the cellular diversity, spatial structure, and functional connectivity of the human brain, providing a groundbreaking platform that outperforms traditional 2D cultures and animal models in studying neurodevelopment and neurological disorders. To further explore the potential of hBOs technology, we review current literature focusing particularly on its applications for diagnosing and treating major neurological diseases such as Alzheimer's disease, Parkinson's disease, and other related neurological disorders. Using patient-derived induced pluripotent stem cells combined with cutting-edge gene-editing technologies, hBOs enable highly precise mechanistic studies and scalable drug screening. Moreover, we further discuss the advantages and current limitations of hBOs. Despite these challenges, hBOs remain a transformative platform for the development of targeted neurotherapeutics. Collectively, this review offers a solid foundation for advancing neuroscience research and fostering innovative treatment strategies for neurological disorders.}, } @article {pmid40933625, year = {2025}, author = {Hean, AC and Jones, J and Arena, M and Kavanagh, K}, title = {Memantine leading to physical aggression in the treatment of chronic catatonia secondary to schizophrenia: A case report.}, journal = {The mental health clinician}, volume = {15}, number = {4}, pages = {218-221}, pmid = {40933625}, issn = {2168-9709}, abstract = {INTRODUCTION: Memantine is a noncompetitive N-methyl-D-aspartate receptor antagonist approved by the FDA for moderate to severe Alzheimer's dementia. Memantine is also recommended as an off-label treatment in current catatonia clinical guidelines when benzodiazepines alone are inadequate. CASE: A 37-year-old male with a history of schizophrenia on psychiatric conservatorship, stimulant use disorder, and traumatic brain injury was stabilized on risperidone 4 mg twice daily, diphenhydramine 50 mg twice daily, divalproex delayed release 500 mg twice daily, and lorazepam 1 mg twice daily for catatonia. Lorazepam was titrated for unresolved chronic catatonic symptoms but was not tolerated beyond 5 mg total per day due to hemodynamic instability. Owing to barriers in initiating clozapine or electroconvulsive therapy, the patient was started on memantine to address residual catatonia symptoms. After the addition of memantine, the patient began to spontaneously speak in multiple languages and engage in discharge planning, but shortly after a dose increase to 15 mg daily also displayed increased aggressive behaviors. The aggression improved after decreasing the dose to 10 mg daily, and the patient was discharged. CONCLUSIONS: This case adds to the body of evidence for memantine in catatonia with underlying schizophrenia and, to our knowledge, is the first described case of memantine uncovering aggression during catatonia treatment.}, } @article {pmid40933191, year = {2025}, author = {Zhao, Y and Wang, X and Zhang, J and Zhao, Y and Li, Y and Shen, J and Yuan, Y and Li, J}, title = {Plasma FGF2 and YAP1 as novel biomarkers for MCI in the elderly: analysis via bioinformatics and clinical study.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1663276}, pmid = {40933191}, issn = {1662-4548}, abstract = {The contemporary consensus firmly emphasizes the urgent need to reorient research efforts toward the early detection of preclinical Alzheimer's disease (AD) or mild cognitive impairment (MCI). However, there is still a notable absence of novel biomarkers that are both efficient, minimally invasive, and cost-effective in real-world clinical settings. To address this gap, datasets GSE29378 and GSE12685 were selected to screen differentially expressed genes (DEGs), and hub genes were identified by different algorithms. A total of 350 DEGs were identified in bioinformatics data mining. Functional enrichment analysis showed that fibroblast growth factor 2(FGF2) and yes-associated protein 1(YAP1) protein levels were highly expressed in AD samples, indicating their potential regulatory roles in AD. Between October and November 2024, a total of 146 elderly individuals diagnosed with MCI and 54 healthy elderly subjects were successfully recruited. Enzyme linked immunosorbent assay (ELISA) was used to detect plasma hub gene protein concentration. The results showed that the expression levels of plasma FGF2 and YAP1 proteins in the MCI group were significantly higher compared to the control group. Logistic regression analysis indicated that high plasma FGF2 and YAP1 expression levels were independently associated with MCI in the elderly. The Area under the curve (AUC) of FGF2 model and YAP1 model were 0.907 and 0.972, respectively. Therefore, the high expression of plasma FGF2 and YAP1 proteins may be independent predictive risk factors for MCI in the elderly. Our findings may provide targets for the development of early minimally invasive, efficient, and convenient screening tools, and even for the treatment of AD in the future.}, } @article {pmid40933041, year = {2025}, author = {He, C and Chen, B and Yan, C and Zhou, X}, title = {Stem cell and CRISPR/Cas9 gene editing technology in Alzheimer's disease therapy: from basic research to clinical innovation.}, journal = {Frontiers in genome editing}, volume = {7}, number = {}, pages = {1612868}, pmid = {40933041}, issn = {2673-3439}, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by Aβ plaques, tau protein neuronal fiber tangles, and neuroinflammation, poses a significant global health problem, and current therapies focus on the symptoms rather than the cause. This paper gives a new multidimensional therapeutic form to AD treatment by exploring the integrated application of stem cell therapy and CRISPR/Cas9 gene editing technology. The study comprehensively dissected the roles of neural stem cells (NSCs), induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) in neural replacement, neuroinflammation modulation and neuroplasticity enhancement, and also explored the application of CRISPR/Cas9 in modifying the pathogenic variants of AD-related genes (APP, PSEN1 and PSEN2). The key findings suggest that gene-edited iPSCs can reduce abnormal Aβ and tau protein accumulation in AD models, improve cognitive function, and provide a platform for disease modeling and drug screening. Stem cell transplantation promotes neurogenesis and synaptic plasticity by secreting neurotrophic factors to improve the brain microenvironment. Despite the challenges of off-target effects, immune rejection, and long-term safety, the synergistic application of these two technologies offers a breakthrough solution for AD treatment. This paper highlights the translational potential of combining stem cells with gene editing technology, which is expected to drive clinical applications in the next 5-10 years. The integration of these advanced technologies not only addresses the limitations of current AD treatments, but also paves the way for a personalized medical approach that is expected to revolutionize the AD treatment landscape and bring new hope to patients worldwide.}, } @article {pmid40932994, year = {2025}, author = {Katel, S and Cicalo, J and Vasciaveo, V and Vecchio, LM and Carrion, J and Mahadeo, L and Huerta, PT and Choksi, JD and Aubert, I and Marambaud, P and Giliberto, L and d'Abramo, C}, title = {AAV-mediated peripheral scFv's administration to reduce cerebral tau in adult P301S transgenic mice: Mono-vs. combination therapy.}, journal = {Molecular therapy. Methods & clinical development}, volume = {33}, number = {3}, pages = {101563}, pmid = {40932994}, issn = {2329-0501}, support = {P01 AI073693/AI/NIAID NIH HHS/United States ; P01 AI102852/AI/NIAID NIH HHS/United States ; R01 AG061381/AG/NIA NIH HHS/United States ; }, abstract = {Tau is a primary target for immunotherapy in Alzheimer's disease (AD). Recent studies have shown the potential of anti-tau fragment antibodies in lowering pathological tau levels in vitro and in vivo. Here, we compared the effects of single-chain variable fragments (scFvs) derived from the well-characterized monoclonal antibodies PHF1 and MC1. We used adeno-associated virus 1 (AAV1) to deliver scFvs to skeletal muscle cells in 8-week-old P301S tau transgenic mice. We evaluated motor and behavioral functions at 16 and 23 weeks of age and measured misfolded, soluble, oligomeric, and insoluble brain tau species. Monotherapy with scFv-MC1 improved motor and behavioral functions more effectively than scFv-PHF1 or combination therapy. Brain glucose metabolism also benefited from scFv-MC1 treatment. Surprisingly, combining scFvs targeting early (MC1) and late (PHF1) tau modifications did not produce additive or synergistic effects. These results confirm that intramuscular AAV1-mediated scFv-MC1 gene therapy holds promise as a potential treatment for AD. Our findings also suggest that combining scFvs targeting different tau epitopes may not necessarily enhance efficacy if administered together in a prevention paradigm. Further research is needed to explore whether other antibodies' combinations and/or administration schedules could improve the efficacy of scFv-MC1 alone.}, } @article {pmid40931963, year = {2025}, author = {Nardi Cesarini, E and Falcicchio, G and Librizzi, L and Sciaccaluga, M and Assenza, G and Galimberti, CA and Giorgi, FS and DiFrancesco, JC and Costa, C and , }, title = {Etiological diagnosis of late-onset epilepsy: A key priority for Italian epileptologists - Insights from a LICE survey.}, journal = {Epilepsia open}, volume = {10}, number = {5}, pages = {1639-1647}, pmid = {40931963}, issn = {2470-9239}, mesh = {Humans ; Italy/epidemiology ; *Epilepsy/etiology/diagnosis/epidemiology ; Cross-Sectional Studies ; Electroencephalography ; Male ; Middle Aged ; Magnetic Resonance Imaging ; Female ; Surveys and Questionnaires ; *Neurologists ; Age of Onset ; Aged ; Adult ; }, abstract = {OBJECTIVE: The incidence of epilepsy rises markedly after age 50. While late-onset epilepsy (LOE) is often linked to structural brain abnormalities, non-structural factors, such as infections, autoimmune disorders, and neurodegenerative diseases, also contribute. Approximately 20% of LOE cases remain of unknown etiology (LOEU). This study evaluated the diagnostic and therapeutic strategies employed by Italian epileptologists in managing LOE and LOEU, with the ultimate goal of proposing a standardized diagnostic algorithm. METHODS: Data were collected through a cross-sectional online survey administered to neurologists who are formal members of the Italian Chapter of the International League Against Epilepsy (LICE). Descriptive statistics were used to summarize responses, and inferential statistics were applied to derive meaningful conclusions. RESULTS: Sixty-five epilepsy centers across 19 of the 20 Italian regions participated in the survey. EEG (100%; n = 65) and brain MRI (92.31%; n = 60) were routinely employed in the diagnostic evaluation of LOE. In over half of the centers (58.46%; n = 38), sleep-activated or sleep-influenced EEGs were also used. For LOEU cases, neuropsychological assessments were performed in 60% of centers. More than 30% of centers employed additional diagnostic tools, including lumbar puncture, FDG-PET, and serum antibody testing for neural autoantibodies. The most commonly prescribed anti-seizure medications (ASMs) for LOE were levetiracetam (86.15%; n = 56), lacosamide (81.54%; n = 53), and lamotrigine (61.54%; n = 40). SIGNIFICANCE: These findings suggested that Italian epileptologists frequently evaluate patients with LOE during routine outpatient visits. LOEU is increasingly recognized as a distinct subtype of LOE that may warrant a targeted diagnostic approach due to the potential involvement of autoimmune and neurodegenerative mechanisms. There is a pressing need for focused cross-sectional or prospective multicenter studies to refine the diagnostic strategies for LOE, particularly for LOEU, and to enhance the characterization of its clinical and etiological features. PLAIN LANGUAGE SUMMARY: After age 50, epilepsy rates rise, often linked to brain changes but sometimes with no clear cause (LOEU). We surveyed Italian epilepsy specialists and found that routine EEG and MRI are widely used, yet about 20% of cases require advanced tests to identify rare or autoimmune causes. Our findings will inform patient-focused diagnostic and treatment guidelines and underscore the need for standardized care pathways and further research in adult-onset epilepsy.}, } @article {pmid40931717, year = {2025}, author = {Rogers, EA and Diorio, TC and Beauclair, T and Martinez, J and Mufti, SJ and Kim, D and Krishnan, N and Rayz, V and Shi, R}, title = {Concussive injuries induce neuronal stress-dependent tau mislocalization to dendritic spines with acrolein and functional network alteration in TBI-on-a-chip.}, journal = {Lab on a chip}, volume = {25}, number = {20}, pages = {5203-5220}, pmid = {40931717}, issn = {1473-0189}, support = {UL1 TR002529/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; *Acrolein/metabolism ; *tau Proteins/metabolism ; Mice ; *Dendritic Spines/metabolism/pathology ; *Lab-On-A-Chip Devices ; *Brain Concussion/metabolism/pathology ; *Neurons/metabolism/pathology ; Oxidative Stress ; }, abstract = {Traumatic brain injuries (TBIs) are a risk factor for Alzheimer's disease (AD), and share several important pathological features including the development of neurofibrillary tangles (NFT) of tau protein. While this association is well established, the underlying pathogenesis is poorly defined and current treatment options remain limited, necessitating novel methods and approaches. In response we developed "TBI-on-a-chip", an in vitro trauma model utilizing murine cortical networks on microelectrode arrays (MEAs), capable of reproducing clinically relevant impact injuries while providing simultaneous morphological and electrophysiological readout. Here, we incorporate a digital twin of the TBI-on-a-chip model to resolve cell-scale mechanical deformation via shear stresses and demonstrate direct connections between impact forces with aberrations in tau and synaptic deficits, and correlate these changes with elevations of oxidative stress, a suspected key contributor to both trauma and neurodegeneration. This multi-disciplinary investigation combines computational modeling, electrophysiology, and imaging, to explore tau mislocalization and functional deficits as a function of force, in the context of a potential mechanism via acrolein. We hope that this novel, integrative approach will help improve our mechanistic understanding of trauma and neurodegeneration, solo and in concert, and ultimately assist in generating more effective treatment options.}, } @article {pmid40931680, year = {2025}, author = {Stone, WJ and Pair, FS and Ekkatine, R and Gannon, M and Scholz, K and Pattanayak, R and Syed, R and Yacoubian, TA}, title = {14-3-3 Proteins Negatively Regulate Microglial Activation via Inhibition of the NF-κB Pathway.}, journal = {Journal of neurochemistry}, volume = {169}, number = {9}, pages = {e70228}, pmid = {40931680}, issn = {1471-4159}, support = {R01NS112203/NH/NIH HHS/United States ; R01 NS112203/NS/NINDS NIH HHS/United States ; F31 ES034985/ES/NIEHS NIH HHS/United States ; F31ES034985/NH/NIH HHS/United States ; //Parkinson Association of Alabama/ ; }, mesh = {*Microglia/metabolism/drug effects ; *14-3-3 Proteins/metabolism/antagonists & inhibitors ; Animals ; Mice ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Signal Transduction/physiology/drug effects ; Lipopolysaccharides/pharmacology ; Mice, Inbred C57BL ; Cells, Cultured ; }, abstract = {Microglia, the resident immune cells of the central nervous system (CNS), are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson's disease (PD). 14-3-3 proteins act as molecular hubs to regulate protein-protein interactions, which are involved in numerous cellular functions, including cellular signaling, protein folding, and apoptosis. We previously revealed decreased 14-3-3 levels in the brains of human subjects with neurodegenerative diseases. In this study, we examined the role of 14-3-3 proteins in the microglial proinflammatory response to lipopolysaccharide (LPS). We found that LPS treatment induced 14-3-3 protein levels within 6 hours. With the use of BV02 and dimeric fourteen-three-three peptide inhibitor (difopein), a small molecule and peptide inhibitor of 14-3-3 protein-protein interactions, respectively, we found a dramatic increase in microglial activation markers in both immortalized BV-2 microglial cells and in primary mouse microglia. Both 14-3-3 inhibitors also increased LPS-induced microglial phagocytosis, lysosomal proteolysis, and cytokine release in primary microglia. In contrast, chemotaxis toward the cellular damage stimulus, adenosine triphosphate (ATP), was diminished with 14-3-3 inhibition. Inhibition of 14-3-3's hastened LPS-induced activation of the nuclear factor-kB (NF-κB) signaling pathway, as measured by its nuclear translocation. 14-3-3's reduced activation of the NF-κB pathway by binding and inhibiting the release of IκB kinase beta (IKKβ). Disruption of 14-3-3's binding to IKKβ with BV02 or difopein increased the downstream phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα). Collectively, our findings suggest 14-3-3 proteins play a critical role in the regulation of inflammatory responses in microglia and may serve as potential targets for immunotherapy of CNS diseases.}, } @article {pmid40931359, year = {2025}, author = {Ramonet, D and Daerr, A and Hallbeck, M}, title = {Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer's disease mouse model.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {190}, pmid = {40931359}, issn = {2051-5960}, support = {2019-01016//Swedish Research Council/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics/drug therapy ; Mice ; *Endosomes/metabolism/drug effects/pathology ; Disease Models, Animal ; *Synapses/metabolism/drug effects/pathology ; Mice, Transgenic ; *Vesicular Transport Proteins/metabolism/genetics ; Protein Transport/drug effects/physiology ; Humans ; }, abstract = {Disruptions in synaptic transmission and plasticity are early hallmarks of Alzheimer's disease (AD). Endosomal trafficking, mediated by the retromer complex, is essential for intracellular protein sorting, including the regulation of amyloid precursor protein (APP) processing. The VPS35 subunit, a key cargo-recognition component of the retromer, has been implicated in neurodegenerative diseases, with mutations such as L625P linked to early-onset AD. Despite growing evidence for retromer dysfunction in AD, its role in synaptic pathology and neuroinflammation remains incompletely understood. Here, we investigate the acute molecular effects of retromer stabilization in the 5xFAD mouse model of AD using the pharmacological chaperones R55 and R33, previously identified to enhance VPS35 stability. Following intracranial stereotaxic injections, we performed transcriptomic profiling, quantitative histology, and immunohistochemistry to assess synaptic function, neuroinflammation, and endosomal trafficking. Our findings reveal that retromer stabilization reverses multiple AD-associated molecular changes. R55 treatment significantly reduced Aβ-related pathology, normalized synaptic gene expression, and restored long-term potentiation (LTP)-associated pathways, including Gria1 (AMPA receptors), Grip1, and semaphorin/plexin signaling. Additionally, retromer stabilization counteracted dysregulated calcium signaling by modulating Ryr2 and L-type calcium channel expression. Beyond synaptic effects, we observed broad transcriptional and structural changes in the endosomal system. Notably, R55 treatment decreased VPS13 family gene expression, implicated in membrane contact site regulation, while increasing RAB7 levels, suggesting enhanced late-endosomal recycling. VPS35-positive vesicles were redistributed away from the nucleus, indicating restored intracellular trafficking dynamics. In the neuroinflammatory domain, retromer stabilization modulated microglial activation, shifting towards a profile characterized by balanced pro-inflammatory (Il1, Nfkb2) and anti-inflammatory (Il4r, Il13ra1, Stat6) markers, consistent with disease-associated microglia (DAM) phenotypes. Together, these findings demonstrate that retromer dysfunction contributes to key AD pathologies, including synaptic dysfunction and neuroinflammation, and that pharmacological retromer stabilization can restore cellular homeostasis. Given that 5xFAD mice lack direct VPS35 mutations, our results suggest that retromer-targeting strategies may be applicable to both familial and sporadic AD, offering a promising therapeutic avenue for modifying disease progression.}, } @article {pmid40931113, year = {2025}, author = {Hu, M and Kang, X and Liu, Z and Wang, S and Liu, S and Li, C and Lu, D and Qin, Q and Liu, Y and Yi, H and Yuan, L and Liu, Q and Lu, Z and Cai, W}, title = {Senescent-like border-associated macrophages regulate cognitive aging via migrasome-mediated induction of paracrine senescence in microglia.}, journal = {Nature aging}, volume = {5}, number = {10}, pages = {2039-2054}, pmid = {40931113}, issn = {2662-8465}, support = {82271348//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *Microglia/metabolism/physiology ; *Cellular Senescence/physiology ; Mice ; *Paracrine Communication/physiology ; *Macrophages/physiology/metabolism ; *Cognitive Aging/physiology ; Apoptosis ; Mice, Inbred C57BL ; *Aging ; Cell Movement ; Male ; Amyloid beta-Peptides/metabolism ; Brain/pathology ; Humans ; }, abstract = {Aging is a major risk factor for various neurological disorders, including Alzheimer's disease, and is associated with the accumulation of senescent cells, which can themselves propagate the senescence process through paracrine signaling. Migrasomes are organelles that form during cellular migration, detach from parent cells and mediate intercellular communication. Here we demonstrate that border-associated macrophages (BAMs) acquire senescence-associated properties during early brain aging, possibly due to prolonged exposure to amyloid beta. Senescent-like BAMs show elevated production of migrasomes, which convey senescence-associated signals including the apoptosis inhibitor of macrophage to neighboring cells. We show that microglia are prominent recipients of senescent-like BAM-derived migrasomes, and that through activation of CD16 in recipient cells, the apoptosis inhibitor of macrophage inhibits apoptosis and promotes senescence induction. Blocking migrasome induction in senescent-like BAMs through treatment with Tspan4-targeting siRNA-encapsulated liposomes ameliorates cognitive deficits in aged mice. Our findings suggest that migrasomes are potent vehicles of senescence-regulatory signals and represent a promising target for senomorphic therapy.}, } @article {pmid40930236, year = {2025}, author = {Zhang, F and Ding, K and Zhang, LM and Liu, DY and Dong, X and Wang, MN and Zhou, FL and Sun, YW and Zhang, WK and Yan, Y and He, J and Xu, JK}, title = {The role of the gut microbiota in neuropsychiatric disorders and therapy.}, journal = {Ageing research reviews}, volume = {112}, number = {}, pages = {102894}, doi = {10.1016/j.arr.2025.102894}, pmid = {40930236}, issn = {1872-9649}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Mental Disorders/therapy/microbiology ; Animals ; *Dysbiosis/microbiology ; Fecal Microbiota Transplantation ; Probiotics/therapeutic use ; Brain ; Brain-Gut Axis/physiology ; Prebiotics ; }, abstract = {The vast microbial community residing in the gut is known as the gut microbiota (GM). Alterations in the compositional equilibrium of the GM, a phenomenon termed GM dysbiosis, have been increasingly associated with the pathogenesis of various diseases, particularly neuropsychiatric disorders. The microbiota-gut-brain axis (MGBA) serves as a bidirectional communication system that connects the gut to the brain. Notably, several prevalent neuropsychiatric disorders, including depression, Alzheimer's disease (AD), and Parkinson's disease (PD), collectively affect over one billion individuals globally. Emerging scientific evidence has consistently demonstrated the presence of GM dysbiosis in various neuropsychiatric disorders, suggesting a potential etiological role of GM in these conditions through MGBA-mediated mechanisms. In this comprehensive review, we systematically discussed the GM and MGBA, and presented evidence from both animal and human studies that highlighted the significance of GM in the occurrence and development of neuropsychiatric disorders. Subsequently, we emphasized the potential impact of GM and its metabolites on neuropsychiatric disorders. Next, we summarized the drugs used to treat diseases by regulating the GM. Finally, we proposed strategies to ameliorate the malignant progression of neuropsychiatric disorders by manipulating the composition of the GM. These strategies encompass the application of probiotics, prebiotics and synbiotics, postbiotics, fecal microbiota transplantation (FMT), and dietary interventions. Collectively, targeted GM therapy has the potential to be an effective treatment for neuropsychiatric disorders.}, } @article {pmid40929163, year = {2025}, author = {Schwertner, K and Basílio, J and Hoffmann-Sommergruber, K and Ellinger, I and Geiselhart, S}, title = {Global transcriptional analysis of human FHs 74 Int intestinal epithelial cells after exposure to advanced glycation end products.}, journal = {PloS one}, volume = {20}, number = {9}, pages = {e0331325}, pmid = {40929163}, issn = {1932-6203}, mesh = {Humans ; *Glycation End Products, Advanced/pharmacology ; *Intestinal Mucosa/metabolism/cytology/drug effects ; *Epithelial Cells/metabolism/drug effects ; S100A12 Protein/pharmacology ; *Transcriptome/drug effects ; Gene Expression Profiling ; Cell Line ; Gene Expression Regulation/drug effects ; Cell Proliferation/drug effects ; }, abstract = {Advanced glycation end products (AGEs) and reactive intermediates, such as methylglyoxal, are formed during thermal processing of foods and have been implicated in the pathogenesis of a series of chronic inflammatory diseases. AGEs are thought to directly interact with the intestinal epithelium upon ingestion of thermally processed foods, but their effects on intestinal epithelial cells are poorly understood. This study investigated transcriptomic changes in human intestinal epithelial FHs 74 Int cells after exposure to AGE-modified human serum proteins (AGE-HS), S100A12, a known RAGE ligand, and unmodified human serum proteins (HS). In contrast to previous studies employing cancer cell lines, RNA sequencing of FHs 74 Int cells treated with AGE-HS did not reveal transcriptional changes associated with increased proliferation, increased expression of tight junction proteins or proinflammatory responses. Surprisingly, neither AGE-HS nor S100A12 treatments resulted in significant differential gene expression at standard analysis thresholds, while unmodified HS induced minor transcriptional changes. Gene set enrichment analysis revealed that AGE-HS treatment induced downregulation of gene sets linked to MYC, interferon responses, and oxidative phosphorylation, as well as pathways related to neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, paralleling some effects observed with S100A12. This is the first global transcriptomic analysis of FHs 74 Int cells and the first unbiased investigation of signaling pathway alterations in intestinal epithelial cells exposed to AGEs. In contrast to previous studies, this analysis did not reveal any significantly differentially expressed genes, thus challenging previous reports of robust AGE-induced inflammatory and proliferative effects and emphasizing the importance of an isolated experimental setting and rigorous endotoxin testing.}, } @article {pmid40928812, year = {2025}, author = {Taragano, F and Seinhart, D and Epstein, P and Sylvestre, V and Barañano, C and Otero Castro, V and Sánchez, V and Kilstein, A and González, R and Franco-Trecu, V and Costa-Urrutia, P}, title = {A real-world study on the safety and efficacy of therapeutic plasma exchange in patients with Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {129-141}, pmid = {40928812}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; Male ; Aged ; *Plasma Exchange/methods/adverse effects ; Treatment Outcome ; Aged, 80 and over ; Middle Aged ; Neuropsychological Tests ; Mental Status and Dementia Tests ; Argentina ; }, abstract = {BackgroundTherapeutic plasma exchange (TPE) with albumin replacement has emerged as a potential treatment for Alzheimer's disease (AD). The AMBAR trial showed that TPE could slow cognitive and functional decline, along with changes in core and inflammatory biomarkers in cerebrospinal fluid.ObjectiveTo evaluate the safety and effectiveness of TPE in a real-world setting in Argentina.MethodsFrom 2022 to 2024, 32 patients with mild-to-moderate AD received TPE and were compared to a historical control group (2008-2018, n = 194) matched for inclusion criteria and cognitive assessments. The protocol included six weekly intensive sessions followed by at least 10 monthly maintenance sessions. Outcomes were measured using the Mini-Mental State Examination (MMSE), and tests of memory, language, executive function, and attention. Linear models were used for analysis.ResultsPatients had a mean age of 72.1 years; 42.4% were female. Baseline MMSE scores ranged from 15 to 26. A total of 514 procedures were performed; 81.5% were uneventful. Mild-to-moderate adverse events occurred in 18.5% of sessions, mainly related to venipuncture; no severe events were reported. Mean plasma exchange volumes were 88.2% and 49.8% of estimated plasma volume during the intensive and maintenance phases, respectively. TPE significantly slowed MMSE decline (45% less than controls, p < 0.001) and reduced memory deterioration (88% less in immediate recall, p < 0.001; 74% in delayed recall, p = 0.04). Other domains were also better preserved.ConclusionsTPE appears to be a safe and effective intervention for slowing cognitive decline in AD, supporting the AMBAR findings.}, } @article {pmid40928277, year = {2025}, author = {Fu, JX and Wang, WP and Wang, YD and Wang, PC}, title = {Beams of Hope: Shedding New Light on Alzheimer's Treatment with Low-Dose Radiation Therapy.}, journal = {Biomedical and environmental sciences : BES}, volume = {38}, number = {8}, pages = {1001-1002}, doi = {10.3967/bes2025.100}, pmid = {40928277}, issn = {2214-0190}, } @article {pmid40928009, year = {2025}, author = {Weden, MM and Frank, L and Dick, AW and Wang, Z and Peschin, S and Bovenkamp, DE and Rossi, SL and Sciullo, D and Hillerstrom, H and Fisher, RA}, title = {Investment in Alzheimer's disease research for the next generation of adults with Down syndrome will yield health benefits for future generations.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70348}, pmid = {40928009}, issn = {1552-5279}, support = {//LuMind IDSC Foundation/ ; //Alliance for Aging Research/ ; //BrightFocus® Foundation/ ; //National Down Syndrome Society/ ; }, mesh = {Humans ; *Down Syndrome/economics/complications/epidemiology/therapy ; *Alzheimer Disease/economics/therapy/epidemiology ; Life Expectancy ; Adult ; *Biomedical Research/economics ; Caregivers/economics ; }, abstract = {Recent innovations in Alzheimer's disease (AD) treatment highlight critical gaps in knowledge about how to support healthy aging of adults with Down syndrome (DS). RAND researchers updated demographic and epidemiological evidence about the DS population to assess the impact of increased investment in treatment innovations for DS-associated Alzheimer's disease (DS-AD). They estimated life expectancy at birth in 2020 to be 55 years, with ≈ 5 years of DS-AD. They found that the results of investment were dramatic. Between 2020 and 2070, adult years of life are expected to increase by 5 years without any increase in unhealthy years of life with DS-AD. Caregiving hours for individuals with DS-AD are expected to be reduced by 40%, which will generate large annual savings. The new evidence underscores the magnitude of the impact that investment in DS-AD treatments could have for individuals with DS, their families, and caregivers. HIGHLIGHTS: Evidence is sparse about treatment for Down syndrome (DS)-associated Alzheimer's disease (DS-AD) and healthy aging of DS adults. This population simulation model estimates DS-AD caregiving costs at ≈ $1 billion per year. DS-AD innovations could increase life expectancy by 5 years and reduce caregiving by 40% by 2070. This better forecasting can improve policy and service planning. DS-AD research investment could yield dramatic gains for individuals and families.}, } @article {pmid40927759, year = {2025}, author = {Aggarwal, A and Rajalekshmi, R and Aggarwal, A and Agrawal, DK}, title = {Plants, Pills, and the Brain: Exploring Phytochemicals and Neurological Medicines.}, journal = {International journal of plant, animal and environmental sciences}, volume = {15}, number = {3}, pages = {90-114}, pmid = {40927759}, issn = {2231-4490}, support = {R25 AI179582/AI/NIAID NIH HHS/United States ; }, abstract = {Neurological disorders, such as Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injuries, and traumatic brain injuries, represent substantial global health challenges due to their chronic and often progressive nature. While allopathic medicine offers a range of pharmacological interventions aimed at managing symptoms and mitigating disease progression, it is accompanied by limitations, including adverse side effects, the development of drug resistance, and incomplete efficacy. In parallel, phytochemicals-bioactive compounds derived from plants-are receiving increased attention for their potential neuroprotective, antioxidant, and anti-inflammatory properties. This review will explore the therapeutic landscape of neurological diseases by providing a comprehensive overview of prevalent conditions and the current allopathic treatments available. Furthermore, this review will investigate specific phytochemicals, including flavonoids, alkaloids, and terpenoids, that exhibit promise in modulating various disease pathways. Emphasis will be placed on the interactions between plant-derived compounds and prescription medications, highlighting both potential synergistic effects and possible adverse interactions. A thorough understanding of these interactions is essential for the development of integrative treatment approaches that enhance therapeutic efficacy while minimizing harm. By bridging traditional herbal medicine with contemporary pharmacotherapy, this review aims to promote a more holistic perspective on the management of neurological diseases, while also encouraging further research into safe and effective combinatory therapies.}, } @article {pmid40927393, year = {2025}, author = {Ning, G and Fan, X and Juan, D and Wenxue, Z and Sijia, W and Meinei, C and Xiaolong, D and Yiming, Q}, title = {The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1637671}, pmid = {40927393}, issn = {1663-4365}, abstract = {The intramembrane aspartic protease, γ-secretase, is a heterotetrameric protein complex composed of four integral membrane proteins: presenilin (PSEN), nicastrin (NCT), Anterior pharynx defective-1 (APH-1), and presenilin enhancer 2 (PEN-2). These components are sequentially assembled into a functional complex. γ-secretase is ubiquitously expressed in all cells and tissues and exhibits enzymatic activity akin to "molecular scissors" by cleaving various type I transmembrane proteins. The primary substrates of this complex include amyloid precursor protein (APP) and Notch. The role of APP in the pathogenesis of Alzheimer's disease (AD) has been extensively investigated. Although γ-secretase inhibitors (GSIs) have been evaluated for their therapeutic potential in AD, their clinical application is limited due to significant toxic side effects. Recently, γ-secretase modulators (GSMs) have emerged as promising alternatives, offering new opportunities for the treatment of AD, especially the inherent γ-secretase modulatory proteins (GSMPs) within cells. Research on GSMPs has ushered in a new era for mitigating the side effects of AD drugs. In this review, we systematically summarize recent advancements in the study of γ-secretase in relation to AD and provide an overview of GSMs and GSMPs, thereby offering potential insights for the development of therapeutic strategies for AD.}, } @article {pmid40927301, year = {2025}, author = {Heller, LI and Lowe, AS and Del Rosario Hernández, T and Gore, SV and Chatterjee, M and Creton, R}, title = {Target the Heart: A New Axis of Alzheimer's Disease Prevention.}, journal = {Journal of dementia and alzheimer's disease}, volume = {2}, number = {2}, pages = {}, pmid = {40927301}, issn = {3042-4518}, support = {R01 GM136906/GM/NIGMS NIH HHS/United States ; }, abstract = {BACKGROUND/OBJECTIVE: Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer's disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved compounds using Z-LaP Tracker revealed that some heart medications produce a similar behavioral profile, suggesting these drugs may exert calcineurin-inhibitor-like effects relevant to prevent-ing or ameliorating Alzheimer's disease. METHODS: Screening a large library of FDA-approved drugs using Z-LaP Tracker, a neural network model, revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. Fourteen of these drugs were heart medications, including angiotensin receptor blockers, beta blockers, al-pha-adrenergic receptor antagonists, and a statin. RESULTS: Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. Other studies have shown that many of these heart medica-tions drugs directly or indirectly inhibit the calcineurin-NFAT pathway, like cyclo-sporine A, providing a potential mechanism. CONCLUSIONS: Co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for preventing Alzheimer's disease occurrence and simultaneously treating cardiovascular dysfunction, while mitigating the side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer's disease in many patients, physicians may be able to create a treatment regimen that addresses both con-ditions. Our results suggest that a calcineurin inhibitor combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol is the most promising candidate for future exploration.}, } @article {pmid40926822, year = {2025}, author = {Guo, W and Dong, L and Lu, Q and Xie, M and Yang, Y and Zhang, Y and Lu, X and Yu, Q}, title = {Association Between Cannabis Use and Neuropsychiatric Disorders: A Two-sample Mendelian Randomization Study.}, journal = {Alpha psychiatry}, volume = {26}, number = {4}, pages = {46108}, pmid = {40926822}, issn = {2757-8038}, abstract = {BACKGROUND: The progressive legalization and widespread use of cannabis has led to its use as a treatment for certain neuropsychiatric disorders. Traditional epidemiological studies suggest that cannabis use has an effect on some neurocognitive aspects. However, it is unclear whether cannabis use is causally related to common neuropsychiatric disorders. The present study was conducted to illustrate the causal relationships of genetically predicted cannabis use with common neuropsychiatric disorders. METHODS: We used a two-sample Mendelian randomization method using genome-wide association study (GWAS) summary statistics obtained from publicly available databases on lifetime cannabis use and 10 neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), epilepsy, generalized epilepsy, focal epilepsy, migraine, migraine with aura, migraine without aura, schizophrenia (SCZ), anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), and Parkinson's disease (PD) were studied with a two-sample Mendelian randomization method for GWAS summary statistics. The inverse variance weighted (IVW) method was used as the main analysis model. RESULTS: Our study suggests that lifetime cannabis use is associated with an increased risk of developing PD (odds ratio (OR) = 1.782; 95% CI 1.032-3.075; p = 0.038) and an increased risk of ADHD in female participants (OR = 1.650; 95% CI 1.051-2.590; p = 0.029). CONCLUSIONS: Cannabis intake may cause adverse effects relating to certain neuropsychiatric disorders. Therefore, special attention should be paid to the side effects of addictive drugs during clinical treatment to avoid harmful effects on the brain and neurocognition.}, } @article {pmid40926795, year = {2025}, author = {Zhang, Y and Silang, Q and Wang, Y and Wang, N and Gesang, L and Tang, L and Liu, L}, title = {Integrated Gut Microbiota, Metabolomics, and Network Pharmacology to Investigate the Anti-Alzheimer's Mechanism of Tripterygium Glycoside.}, journal = {Neuropsychiatric disease and treatment}, volume = {21}, number = {}, pages = {1911-1933}, pmid = {40926795}, issn = {1176-6328}, abstract = {BACKGROUND: Tripterygium glycoside (TG) has been reported to have the effect of ameliorating Alzheimer's disease (AD)-like symptoms in mice model. However, the underlying mechanism is largely unknown. This study aimed to investigate the potential mechanism of TG against AD by integrating metabolomics, 16s rRNA sequencing, network pharmacology, molecular docking, and molecular dynamics simulation. METHODS: Memory and cognitive functions were assessed in mice via the Morris water maze. The pathological changes were assessed using hematoxylin and Nissl's straining. Pathological changes in p-Tau and Aβ1-42 were assessed using immunohistochemistry, immunofluorescence, ELISA, and Western blotting. 16S rRNA sequencing and metabolomics were performed to analyze alterations in the structure of gut microbiota and hippocampus metabolites. Network pharmacology, molecular docking, and molecular dynamics simulation were performed to determine the putative molecular regulatory mechanism of TG in treating AD. RESULTS: TG significantly could inhibit neuron loss, improved cognitive and memory functions, and significantly reduce the expression of p-Tau and Aβ1-42. In addition, 16s rRNA analysis revealed that TG could reverse AD-induced gut microbiota dysbiosis in AD model mice by reducing the abundance of Alistipes. Furthermore, metabolomic analysis revealed that TG may reverse AD-induced metabolic disorders by regulating glycerophospholipid metabolism. And spearman analysis revealed that glycerophospholipids metabolism might closely related to Alistipes. Moreover, network pharmacology, molecular docking, and molecular dynamics simulation analyses indicated that TG might regulate lipid metabolism-related pathways via SRC for the treatment of AD. CONCLUSION: TG may serve as a potential therapeutic drug for preventing AD via the microbiota-gut-brain axis.}, } @article {pmid40926603, year = {2025}, author = {Porwal, S and Malviya, R and Sridhar, SB and Wadhwa, T and Shareef, J and Meenakshi, DU}, title = {Trends and Advancements in Smart Electrospun Food Fibers for the Management of Neurological Disorders.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273375873250829060106}, pmid = {40926603}, issn = {1996-3181}, abstract = {Neurological disorders are complex conditions characterized by impairment of the nervous system, affecting motor, cognitive, and sensory functions. Current treatments meet substantial obstacles, primarily due to the difficulty of transporting drugs across the blood-brain barrier and ineffective therapy for nerve regeneration. Emerging technologies, such as electrospinning, offer innovative solutions to overcome these challenges. The study explores the potential of electrospun food fibers in managing and treating neurological disorders, concentrating on their role in drug delivery and nerve tissue regeneration. Electrospinning allows for the generation of nanofibers from diverse natural and synthetic polymers that imitate the extracellular matrix and stimulate brain healing. These fibers may be loaded with therapeutic drugs, permitting controlled, localized drug release while limiting systemic toxicity. For instance, electrospun fibers loaded with neuroprotective drugs, such as donepezil and levodopa, have exhibited better drug stability, enhanced bioavailability, and prolonged therapeutic efficacy in treating syndromes such as Alzheimer's and Parkinson's diseases. Furthermore, the biodegradable and biocompatible nature of food-based polymers like chitosan, cellulose, and zein makes them great candidates for medicinal applications, minimizing the risk of inflammation and unfavorable immunological reactions. In conclusion, electrospun food fibers show tremendous promise in resolving the issues of drug delivery and nerve regeneration in neurological illnesses. Their capacity to boost therapeutic results via targeted and regulated drug release makes them a possible alternative to established treatment procedures, bringing renewed hope to patients suffering from neurodegenerative disorders.}, } @article {pmid40926398, year = {2025}, author = {Nie, RZ and Zhang, QL and Tan, XR and Hu, SS and Zhou, XT and Jiang, WK and Guo, BW and Cao, X and Yuan, DH and Long, Y and Hong, H and Tang, SS}, title = {Cholinergic G protein-coupled bile acid receptor 1 (TGR5/GPBA) in the medial septal orchestrates adult hippocampal neurogenesis and cognition in Alzheimer's disease mice.}, journal = {British journal of pharmacology}, volume = {182}, number = {21}, pages = {5409-5429}, doi = {10.1111/bph.70185}, pmid = {40926398}, issn = {1476-5381}, support = {82071202//National Natural Science Foundation of China/ ; 82173805//National Natural Science Foundation of China/ ; 82373860//National Natural Science Foundation of China/ ; 2024YFA1308200//National Key Research and Development Program of China/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Receptors, G-Protein-Coupled/metabolism/genetics ; *Neurogenesis ; *Hippocampus/metabolism ; Mice ; *Cognition/physiology ; Male ; Mice, Transgenic ; Disease Models, Animal ; Mice, Inbred C57BL ; Cholinergic Neurons/metabolism ; }, abstract = {BACKGROUND AND PURPOSE: The pathological role of the bile acid receptor TGR5/GPBA in Alzheimer's disease (AD) is not fully understood. We investigated the pharmacological effects and mechanisms of TGR5 in AD model mice. EXPERIMENTAL APPROACH: TGR5 expression was assessed in AD mice using immunofluorescence and immunoblotting. Bidirectional modulation of TGR5 expression was achieved via stereotaxic delivery of adeno-associated virus vectors, while localized pharmacological activation was conducted through intracerebral cannula implantation. Cognition was evaluated using the Morris water maze and novel object recognition test. Adult hippocampal neurogenesis was assessed via immunofluorescence. Neuronal activity was analysed using immunofluorescence, fibre photometry and chemogenetics-coupled fibre photometry. Acetylcholine dynamics were monitored using fibre photometry, both alone and in combination with chemogenetic manipulation. KEY RESULTS: TGR5 expression was selectively decreased in the medial septal (MS) cholinergic neurons during middle-late AD stages. Bidirectional genetic regulation of TGR5 in MS cholinergic neurons significantly affected cognition and adult hippocampal neurogenesis in mice. Pharmacological activation of TGR5 in the MS not only increased cholinergic neuronal activity and acetylcholine release, but also enhanced DG glutamatergic neuronal activity, acetylcholine levels and neurogenesis in AD mice. TGR5 modulated cognition and neurogenesis via the MS[cholinergic(ChAT)]→ DG[glutamatergic(Glu)] circuit. Furthermore, α7 nAChRs in the DG were involved in TGR5-mediated improvements in cognition and neurogenesis. CONCLUSION AND IMPLICATIONS: Our findings demonstrate that TGR5 in MS cholinergic neurons is critical during the middle-late stage of AD and provide valuable insights into the underlying neuronal circuit mechanisms. TGR5 (GPBA) represents a potential therapeutic target for AD treatment.}, } @article {pmid40925485, year = {2026}, author = {Prokop-Millar, S and Di Passa, AM and Yaya, H and McIntyre-Wood, C and Farzan, F and Terpstra, AR and Fein, A and Vandehei, E and MacKillop, E and MacKillop, J and Duarte, D}, title = {Predictive and mechanistic biomarkers of treatment response to Transcranial Magnetic Stimulation (TMS) in Psychiatric and Neurocognitive Disorders, identified via TMS-Electroencephalography (EEG) and Resting-State EEG: A systematic review.}, journal = {Journal of affective disorders}, volume = {393}, number = {Pt A}, pages = {120194}, doi = {10.1016/j.jad.2025.120194}, pmid = {40925485}, issn = {1573-2517}, mesh = {Humans ; *Transcranial Magnetic Stimulation/methods ; *Electroencephalography/methods ; Biomarkers ; *Mental Disorders/therapy/physiopathology ; Bipolar Disorder/therapy/physiopathology ; Schizophrenia/therapy/physiopathology ; *Neurocognitive Disorders/therapy/physiopathology ; Treatment Outcome ; Alzheimer Disease/therapy/physiopathology ; }, abstract = {Electroencephalography (EEG) is a comparatively inexpensive and non-invasive recording technique of neural activity, making it a valuable tool for biomarker discovery in transcranial magnetic stimulation (TMS). This systematic review aimed to examine mechanistic and predictive biomarkers, identified through TMS-EEG or resting-state EEG, of treatment response to TMS in psychiatric and neurocognitive disorders. Nineteen articles were obtained via Embase, APA PsycInfo, MEDLINE, and manual search; conditions included, unipolar depression (k = 13), Alzheimer's disease (k = 3), bipolar depression (k = 2), and schizophrenia (k = 2). Two mechanistic biomarkers were identified: one TMS-EEG marker, reductions in N100 post-dorsolateral prefrontal cortex (DLPFC) repetitive TMS or intermittent theta burst stimulation (iTBS) in unipolar depression (n = 120; k = 2), and one resting-state marker, reductions in theta connectivity post-DLPFC repetitive TMS in unipolar and bipolar depression (n = 89; k = 2). Whereas one predictive TMS-EEG biomarker was isolated: greater baseline N100 was predictive of unipolar depression improvement in DLPFC repetitive TMS and iTBS (n = 113; k = 2). Promising markers were briefly discussed for future research in Alzheimer's disease and schizophrenia. In conclusion, across the psychiatric and neurocognitive disorders considered in this study, TMS-EEG and resting-state mechanistic and predictive biomarkers of depression appear to hold the most promise. Further research is needed to validate the biomarkers identified in depression, to help guide treatment plans and advance precision medicine in psychiatry.}, } @article {pmid40925435, year = {2025}, author = {Liu, Y and Wang, Y and Liang, Y and Yang, S and Deng, Y and Zeng, S and Wang, Y and Shu, Z and Shuai, Y and Guo, H}, title = {Transcriptomics and metabolomics revealed the effects of Polygonatum Rhizoma polysaccharide on delaying C. elegans senescence and ameliorating Alzheimer's disease.}, journal = {International journal of biological macromolecules}, volume = {327}, number = {Pt 2}, pages = {147375}, doi = {10.1016/j.ijbiomac.2025.147375}, pmid = {40925435}, issn = {1879-0003}, mesh = {Animals ; *Caenorhabditis elegans/drug effects/genetics/metabolism ; *Polysaccharides/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Polygonatum/chemistry ; *Metabolomics/methods ; *Aging/drug effects/genetics ; *Rhizome/chemistry ; Oxidative Stress/drug effects ; *Transcriptome/drug effects ; Gene Expression Profiling ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; }, abstract = {We explored the role of Polygonatum Rhizoma polysaccharide (PRP) in delaying aging and improving Alzheimer's disease (AD) and revealed its potential molecular mechanism. Through chemical characterizations to clarify the physicochemical properties of PRP, it was found that PRP mainly consists of mannose, glucose, galactose, and arabinose, with molecular weights ranging from 7.4 × 10[4] to 9.1 × 10[4] Da; using Caenorhabditis elegans (C. elegans) models, its anti-AD activity was verified by combining approaches using pharmacodynamics, molecular biology, metabolomics, and transcriptomics sequencing. The results of this study showed that PRP significantly extended the lifespan of C. elegans, reduced the accumulations of lipofuscin and increased the ability of C. elegans to resist oxidative stress, and reduced the aggregation of Aβ protein in the AD model C. elegans, and improved neuromuscular dysfunction. Transcriptomic analysis revealed that PRP modulated the expression of genes involved in key processes, including anti-stress and senescence (daf-12, skn-1, gst-4, ctl-1, sod-3, age-1, gcs-1), autophagy (unc-51, bec-1, lgg-1), and mitochondrial function (clk-1, mev-1, isp-1). Metabolomic analysis revealed that PRP improved metabolic disorders in C. elegans by regulating phenylalanine/purine metabolism pathway. These results indicated that PRP exerted its effects through multiple pathways to delay C. elegans aging and improve AD symptoms, providing a strong theoretical basis for the development of AD treatment drugs based on traditional Chinese medicine.}, } @article {pmid40924554, year = {2025}, author = {Zhao, ZQ and Liang, L and Hu, LF and He, YT and Jing, LY and Liu, Y and Chen, BZ and Guo, XD}, title = {Correction to "Subcutaneous Implantable Microneedle System for the Treatment of Alzheimer's Disease by Delivering Donepezil".}, journal = {Biomacromolecules}, volume = {26}, number = {10}, pages = {7222-7223}, doi = {10.1021/acs.biomac.5c01588}, pmid = {40924554}, issn = {1526-4602}, } @article {pmid40923675, year = {2025}, author = {Evans, RC and Dar, NJ and Chen, L and Na, R and O'Connor, JC and Jiang, J and Zheng, S and Ran, Q}, title = {Inhibition of Hippo Signaling Through Ablation of Lats1 and Lats2 Protects Against Cognitive Decline in 5xFAD Mice via Increasing Neuronal Resilience Against Ferroptosis.}, journal = {Aging cell}, volume = {24}, number = {11}, pages = {e70218}, pmid = {40923675}, issn = {1474-9726}, support = {R01 AG086496/AG/NIA NIH HHS/United States ; S10 OD030311/OD/NIH HHS/United States ; I01 BX003507/BX/BLRD VA/United States ; R01 AG064078/AG/NIA NIH HHS/United States ; P30 CA054174/CA/NCI NIH HHS/United States ; R01AG064078/AG/NIA NIH HHS/United States ; R01AG086496/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Mice ; *Neurons/metabolism/pathology ; *Cognitive Dysfunction/metabolism/genetics/pathology ; Hippo Signaling Pathway ; *Tumor Suppressor Proteins/metabolism/genetics ; *Ferroptosis/genetics ; Signal Transduction ; Disease Models, Animal ; Mice, Transgenic ; Humans ; *Alzheimer Disease/genetics/metabolism ; }, abstract = {The Hippo signaling pathway is a key regulator of cell growth and cell survival, and hyperactivation of the Hippo pathway has been implicated in neurodegenerative diseases such as Huntington's disease. However, the role of Hippo signaling in Alzheimer's disease (AD) remains unclear. We observed that hyperactivation of Hippo signaling occurred in the AD model 5xFAD mice. To determine how inhibition of Hippo signaling might affect disease pathogenesis, we generated 5xFAD mice with conditional neuronal ablation of Lats1 and Lats2, the gatekeepers of Hippo signaling activity. Our results indicated that 5xFAD mice with ablation of Lats1 and Lats2 were protected against cognitive decline compared with control 5xFAD mice, and this protection was correlated with a marked reduction in neurodegeneration. Interestingly, primary culture neurons with ablation of Lats1 and Lats2 had significantly increased survival following treatment with chemical inducers of ferroptosis and exhibited reduced lipid peroxidation, the driving force of ferroptotic cell death. Moreover, 5xFAD mice with ablation of Lats1 and Lats2 showed reduced lipid peroxidation, and transcriptomic analysis revealed that 5xFAD mice with ablation of Lats1 and Lats2 had enriched metabolic pathways associated with ferroptosis. These results indicate that inhibition of Hippo signaling activity confers neural protection in 5xFAD mice by augmenting resilience against ferroptosis.}, } @article {pmid40923656, year = {2025}, author = {Li, Q and He, B and Xiong, Y}, title = {Calycosin attenuates neuronal ferroptosis in Alzheimer's disease mice by activating the Nrf2/HO-1 pathway.}, journal = {General physiology and biophysics}, volume = {44}, number = {5}, pages = {363-375}, doi = {10.4149/gpb_2025021}, pmid = {40923656}, issn = {0231-5882}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Ferroptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; Mice ; *Neurons/drug effects/metabolism/pathology ; *Isoflavones/pharmacology/administration & dosage ; *Heme Oxygenase-1/metabolism ; Signal Transduction/drug effects ; Male ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Membrane Proteins ; }, abstract = {In this study, we investigated the therapeutic potential of calycosin (from Astragalus) in Alzheimer's disease (AD), focusing on ferroptosis modulation. APP/PS1 mice received 40 mg/kg calycosin for 3 months. Cognitive function was assessed via Morris water maze test. Tau hyperphosphorylation and amyloid-β (Aβ) aggregation were analyzed using immunofluorescence and Western blotting. In vitro, Aβ1-42-treated HT22 neuronal cells were exposed to calycosin. Ferroptosis-related phenotypes were assessed in vivo and in vitro using Prussian blue staining, commercial kits, and Western blotting. The nuclear factor-erythroid factor 2-related factor 2 (Nrf2) signaling was examined by Western blotting. Calycosin treatment significantly improved cognitive deficits in APP/PS1 mice and inhibited Tau hyperphosphorylation and Aβ aggregation. Calycosin attenuated neurotoxicity and Tau hyperphosphorylation in Aβ1-42-treated HT22 cells. Moreover, calycosin inhibited ferroptosis in vivo and in vitro by decreasing iron aggregation and lipid peroxidation, downregulating transferrin receptor expression, and upregulating ferroportin, cystine/glutamate antiporter, and glutathione peroxidase 4 expression. Mechanistically, the anti-ferroptosis effects of calycosin were linked to the activation of the Nrf2-mediated pathway. These findings suggest that calycosin may exhibit neuroprotective effects against neuronal ferroptosis in AD, indicating its potential as a therapeutic candidate for further investigation in AD.}, } @article {pmid40922888, year = {2025}, author = {Kademani, A and Avraam, C and Montenegro, D and Paloh, A and Somannagari, N and Gupta, A and Lafi, AW and Algaba, AE and Islam, R and Fahima, C and Siddiqui, HF}, title = {Exploring the Emerging Role of Stem Cell Therapy in Neurodegenerative Diseases and Spinal Cord Injury: A Narrative Review.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e89629}, pmid = {40922888}, issn = {2168-8184}, abstract = {Neurodegenerative diseases and spinal cord injuries (SCI) pose a significant burden on the healthcare system globally. Diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease precipitate cognitive, motor, and behavioral deficits. Parallelly, spinal cord injuries produce sensory and motor deficits, which are burdensome psychologically, socially, and economically. Current management strategies focus only on symptomatic relief, with no definitive cure. Stem cells have been explored for regenerative therapy. This review focuses on developments, limitations, and future potential of stem cell therapy. Stem cells affect the central nervous system via neuroprotective mechanisms, immunomodulatory effects, and mitigation of oxidative stress. The clinical implications of stem cell therapy in treating neurodegenerative diseases and SCI are debatable due to varied outcomes. Challenges related to sample size, long-term follow-up, and assessment of adverse effects should be mitigated in future research. Researchers are currently exploring optimal stem cell types along with various transplantation strategies. Biomaterials integrated with stem cells are a novel approach for treating neurodegenerative diseases and spinal cord injuries. Certain genetic modifications have shown improved results. Screening patients to ascertain better responses to therapy has proven to be a challenge. Other complications include graft vs. host reaction and degeneration of transplanted neurons due to pathogenesis and tumorigenesis. However, the majority of the potential stem cell therapeutic avenues are in the preclinical stage and are being tested on animal models. Guidelines pertaining to ethical concerns and regulatory frameworks need to be established to unfold the full potential of stem cell therapy in the clinical setting. Recent advances also show an increased need to formulate patient-specific approaches to treatment, ranging from stem cell selection to the technique of transplantation. Ongoing clinical trials can address the current challenges and leverage emerging technologies, leading to definitive treatments for neurodegenerative diseases and spinal cord injuries.}, } @article {pmid40922863, year = {2025}, author = {Murali, A and Muddappa, SC and Rajan, RR and Joseph, A and Ravi, AB}, title = {Barriers to Geriatric Oral Health: A Multifaceted Public Health Issue.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e89604}, pmid = {40922863}, issn = {2168-8184}, abstract = {Oral health is important for the overall health of an individual, particularly older adults. However, a number of obstacles frequently prevent older people from receiving timely and appropriate dental care. These obstacles are intricate and multifaceted, involving systemic diseases, cognitive elements, and psychological, financial, and educational issues. Dementia and Alzheimer's disease are examples of cognitive impairments that can make it difficult for an elderly person to seek or cooperate with dental treatment. Additional psychological factors that decrease care-seeking behaviour include anxiety, fear of dental treatments, depression, and a general lack of motivation. Financial constraints are major deterrents, such as low income and no dental insurance. Furthermore, polypharmacy and multimorbidity not only make treatment planning more difficult, but they also deprive oral health of priority. The problem is made worse by systemic healthcare barriers like inadequate referral systems, a lack of geriatric-focused dentists, and poor integration between dental and medical services. Neglect is also exacerbated by older adults' and their caregivers' perceived lack of need for dental care. A comprehensive, multidisciplinary strategy is needed to address these issues, one that incorporates training dental professionals in geriatric care, better public health regulations, caregiver education, and the creation of easily accessible, reasonably priced services. Improving the general and oral health of the elderly requires an understanding of and commitment to removing these obstacles.}, } @article {pmid40922111, year = {2025}, author = {Vitali, F and Torrandell-Haro, G and Arias, JC and French, SR and Zahra, S and Brinton, RD and Weinkauf, C}, title = {Carotid endarterectomy mitigates Alzheimer's disease and non-Alzheimer's disease dementia risk linked to asymptomatic carotid stenosis.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70674}, pmid = {40922111}, issn = {1552-5279}, support = {R01AG070987/AG/NIA NIH HHS/United States ; R01AG057931/AG/NIA NIH HHS/United States ; P01AG026572/AG/NIA NIH HHS/United States ; //Arizona Alzheimer's Consortium/ ; CTR056056//Arizona Biomedical Research Commission/ ; //Richard and Jan Highberger Award/ ; //Health Sciences, University of Arizona/ ; /DDCF/Doris Duke Charitable Foundation/United States ; }, mesh = {Humans ; *Endarterectomy, Carotid/statistics & numerical data ; *Alzheimer Disease/epidemiology/prevention & control ; *Carotid Stenosis/surgery/complications/epidemiology ; Male ; Female ; Aged ; Retrospective Studies ; Propensity Score ; United States/epidemiology ; Stents ; *Dementia/epidemiology/prevention & control ; Risk Factors ; Incidence ; Middle Aged ; }, abstract = {INTRODUCTION: Asymptomatic extracranial carotid artery disease (aECAD) is associated with increased Alzheimer's disease (AD) and non-AD dementia risk. aECAD treatment includes carotid endarterectomy (CEA) and carotid artery stenting (CAS) for stroke prevention, but their impact on dementia incidence is poorly studied. METHODS: Propensity score matching was used in a retrospective cohort study of United States-based insurance claims (2010-2022) in 487,676 patients with aECAD to evaluate the effect of CEA and CAS on AD and non-AD dementia incidence. RESULTS: After matching, 37,317 patients underwent CEA or CAS. CEA was associated with a significantly lower AD risk (relative risk = 0.93; 95% confidence interval, 0.86-0.99; P < 0.05), whereas CAS was associated with a slight but non-significant increase. Similar trends were observed for non-AD dementia. DISCUSSION: CEA, but not CAS, may confer a protective effect against AD and non-AD dementia in patients with aECAD, a common cerebrovascular disease affecting up to 15% of adults over age 60. HIGHLIGHTS: Asymptomatic extracranial carotid artery disease (aECAD) is associated with increased Alzheimer's disease (AD) and non-AD dementia risk. Limited studies have evaluated the role of carotid endarterectomy (CEA) and (carotid artery stenting (CAS) on dementia outcomes. Using United States-based insurance claims data, 487,676 patients with aECAD were evaluated. After propensity score matching, CEA was significantly associated with reduced AD risk. CAS was not significantly associated with a change in AD risk.}, } @article {pmid40922100, year = {2025}, author = {Floud, S and Hermon, C and Whiteley, W and Fitzpatrick, KE and Reeves, GK}, title = {Hypertension in pregnancy and in midlife and the risk of dementia: prospective study of 1.3 million UK women.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70595}, pmid = {40922100}, issn = {1552-5279}, support = {A29186/CRUK_/Cancer Research UK/United Kingdom ; CAF/17/01//Chief Scientist's Office/ ; //Health Data Research UK/ ; //BHD Data Science Centre/ ; /ALZS_/Alzheimer's Society/United Kingdom ; CAF/17/01//Chief Scientist Office, Scottish Government Health and Social Care Directorate/ ; }, mesh = {United Kingdom/epidemiology ; *Hypertension/complications/epidemiology/psychology ; *Dementia/epidemiology/etiology ; *Hypertension, Pregnancy-Induced/epidemiology/psychology ; Risk Factors ; Humans ; Female ; Pregnancy ; Middle Aged ; Proportional Hazards Models ; Alzheimer Disease/epidemiology/etiology ; Dementia, Vascular/epidemiology/etiology ; Age Factors ; Prospective Studies ; Causality ; }, abstract = {INTRODUCTION: Midlife hypertension is associated with dementia risk, although uncertainties remain regarding its association with subtypes and regarding the effect of pregnancy-related hypertension on dementia risk. METHODS: In the Million Women Study, 1,363,457 women (mean age 57) were asked about current treatment for hypertension and hypertension in pregnancy and were followed for first hospital record with any mention of dementia. Cox regression yielded hazard ratios (HRs) adjusted for socioeconomic, lifestyle, and metabolic factors. RESULTS: With 84,729 dementia cases over 21 years, midlife hypertension was positively associated with dementia (HR 1.17, 95% confidence interval [CI] 1.15 to 1.19); higher for vascular dementia (VaD) (HR 1.50; 95% CI 1.45 to 1.56) than Alzheimer's disease (AD) (HR 1.01; 95% CI 0.98 to 1.04). Hypertension in pregnancy but not in midlife was only weakly associated with dementia (HR 1.04; 95% CI 1.01 to 1.06). DISCUSSION: Midlife hypertension is a strong risk factor for dementia, largely through VaD. Hypertension during pregnancy does not appear to materially affect dementia risk. HIGHLIGHTS: Midlife hypertension was associated with long-term all-cause dementia risk. Midlife hypertension was associated with VaD, not AD. Hypertension in pregnancy has little effect on dementia risk.}, } @article {pmid40922096, year = {2025}, author = {Ottoy, J and Owsicki, N and Bilgel, M and Binette, AP and Salvadó, G and Kang, MS and Cash, DM and Ewers, M and La Joie, R and Wisse, LEM and Goubran, M and Betthauser, T}, title = {Recent advances in neuroimaging of Alzheimer's disease and related dementias.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70648}, pmid = {40922096}, issn = {1552-5279}, support = {CIHR-PJT-190220//Canadian Institutes for Health Research/ ; CIHR-187890//Canadian Institutes for Health Research/ ; ALZ23-05//Alzheimer Society of Canada/ ; ALZ26-021//Alzheimer Society of Canada/ ; 24AARF-1242638/ALZ/Alzheimer's Association/United States ; 22AARF-972612/ALZ/Alzheimer's Association/United States ; SG-666374-UK/ALZ/Alzheimer's Association/United States ; AARG-22-926899/ALZ/Alzheimer's Association/United States ; AS-DRL-23-005//Alzheimer's Society Dementia Research Leaders Fellowship/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; 101061836//European Union's Horizon 2020 Research and Innovation Program/ ; //Strategic Research Area MultiPark/ ; A2024012F//BrightFocus Foundation/ ; A2024007F//BrightFocus Foundation/ ; R01AG080766//National Institutes of Health National Institute on Aging/ ; P30AG062715//National Institutes of Health National Institute on Aging/ ; R01AG027161//National Institutes of Health National Institute on Aging/ ; P30AG062422//National Institutes of Health National Institute on Aging/ ; 24AARF-1242638//Brain Canada/ ; AF-980942//Alzheimerfonden/ ; AF-994514//Alzheimerfonden/ ; AF-1012218//Alzheimerfonden/ ; BMBF//ERAPerMed/ ; 01KU2203//ERAPerMed/ ; //Alzheimer's Society Research Program/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Neuroimaging/methods/trends ; Biomarkers ; *Brain/diagnostic imaging/pathology ; *Dementia/diagnostic imaging ; Positron-Emission Tomography ; Disease Progression ; tau Proteins/metabolism ; }, abstract = {This review covers recent advances (2023-2024) in neuroimaging research into the pathophysiology, progression, and treatment of Alzheimer's disease (AD) and related dementias (ADRD). Despite the rapid emergence of blood-based biomarkers, neuroimaging continues to be a vital area of research in ADRD. Here, we discuss neuroimaging as a powerful tool to topographically visualize and quantify amyloid, tau, neurodegeneration, inflammation, and vascular disease in the brain. We examine the utility of neuroimaging for (1) tracking the spatiotemporal progression of pathology, (2) serving as the reference standard for validating novel fluid biomarkers, (3) characterizing disease heterogeneity, (4) exploring the role of brain networks in ADRD progression, and (5) evaluating biomarkers for better individualized estimates of treatment benefit. Finally, we discuss advances in radiotracer development and AD risk factors. By reviewing the most promising breakthroughs in the neuroimaging field, we hope to spark new ideas for future discoveries that will deepen our understanding of ADRD. HIGHLIGHTS: The diagnostic and staging criteria for Alzheimer's disease (AD) were updated in 2024. Despite robust harmonization methods for amyloid beta positron emission tomography (PET), parallel efforts for tau PET remain challenging. Larger anti-amyloid drug effects were seen at lower levels of amyloid and tau PET. Phosphorylated tau217 (p-tau217) is currently the most promising plasma biomarker to detect AD pathology. There are new tracer developments for alpha-synuclein, primary tauopathies, and inflammation.}, } @article {pmid40921933, year = {2025}, author = {Sehlin, D and Aguilar, X and Cortés-Canteli, M and Syvänen, S and Lopes van den Broek, S}, title = {Brain-penetrating peptide and antibody radioligands for proof-of-concept PET imaging of fibrin in Alzheimer's disease.}, journal = {EJNMMI radiopharmacy and chemistry}, volume = {10}, number = {1}, pages = {59}, pmid = {40921933}, issn = {2365-421X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a multifactorial disorder with vascular contributions, including a pro-coagulant state marked by fibrin deposition in the brain. Fibrin accumulation may exacerbate cerebral hypoperfusion and neuroinflammation, leading to neurodegeneration. Identifying patients with this pathology could enable targeted anticoagulant therapy. However, current imaging tools lack the specificity and sensitivity to detect fibrin in the brain non-invasively. This study aimed to develop and evaluate brain-penetrating peptide- and antibody-based PET radioligands targeting fibrin to enable individualized treatment strategies in AD. RESULTS: A fibrin-binding peptide (FBP) was conjugated to the antibody fragment scFv8D3, which targets the transferrin receptor (TfR), to facilitate transcytosis across the blood-brain barrier. FBP-scFv8D3 bound TfR and with modest affinity to fibrin. In vivo studies in Tg-ArcSwe mice, that exhibit fibrin along with brain amyloid-β pathology, and wild-type mice showed that [[125]I]FBP-scFv8D3 retained brain-penetrating properties but did not demonstrate significant fibrin-specific retention. In contrast, the monoclonal antibody 1101 and its bispecific, brain penetrant variant 1101-scFv8D3 exhibited higher fibrin selectivity and TfR binding. Both antibodies showed a trend towards higher brain retention in Tg-ArcSwe mice and [[125]I]1101-scFv8D3 showed a higher brain-to-blood ratio compared to [[124]I]1101. PET imaging with [[124]I]1101 and [[124]I]1101-scFv8D3 revealed low global brain uptake. However, ex vivo autoradiography and regional PET quantification (ROI-to-cerebellum ratios) indicated significant cortical and caudate retention of [[124]I]1101-scFv8D3 in Tg-ArcSwe mice, supporting region-specific target engagement. CONCLUSION: This proof-of-concept study demonstrates the feasibility of using bispecific antibody-based PET radioligands to target fibrin in the AD brain. While the FBP-scFv8D3 conjugate showed limited specificity, the bispecific antibody 1101-scFv8D3 exhibited higher brain penetration and fibrin selectivity. These findings support further development of antibody-based imaging tools toward the goal to stratify AD patients who may benefit from anticoagulant therapy.}, } @article {pmid40921720, year = {2025}, author = {Moreira, IP and Vieira-Coelho, MA and Guimarães, J}, title = {Dopamine System Dysfunction in Alzheimer's Disease.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {25}, number = {5}, pages = {e70097}, pmid = {40921720}, issn = {1479-8301}, mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology ; *Dopamine/metabolism ; Animals ; Disease Models, Animal ; Cognitive Dysfunction ; *Receptors, Dopamine/metabolism ; }, abstract = {The dopaminergic system may be at the base of some neurobehavioral symptoms, as apathy and depression, and extrapyramidal symptoms, often seen in Alzheimer's disease patients. It can also have an impact on cognitive decline, as extrapyramidal symptoms, classically linked with dopamine dysfunction, are associated with increased risk of cognitive impairment and Alzheimer's disease progression. We review the knowledge of the dopaminergic system, emphasizing changes in Alzheimer's disease. Both animal models, post-mortem and in vivo human studies, point to a dopaminergic system dysfunction in this disease. Dopamine dysfunction seems more associated with neuronal loss, modification of dopamine receptors and anomalies in terminal function, including irregularities in dopamine metabolism, than with neurofibrillary tangles or β-amyloid plaques depositions. This dysfunction has an impact on both cognitive and non-cognitive symptoms. A better understanding of the dopaminergic system may help in understanding the pathophysiology of Alzheimer's disease and assist in the diagnosis. Clinical trials aimed at modulating the dopaminergic system may be promising in the treatment of symptoms associated with Alzheimer's disease.}, } @article {pmid40920304, year = {2025}, author = {Bhujbal, SP and Hah, JM}, title = {Advances in JNK inhibitor development: therapeutic prospects in neurodegenerative diseases and fibrosis.}, journal = {Archives of pharmacal research}, volume = {48}, number = {9-10}, pages = {858-886}, pmid = {40920304}, issn = {1976-3786}, support = {NRF-RS-2020-NR049583//National Research Foundation of Korea/ ; NRF- RS-2024-00397929//National Research Foundation of Korea/ ; NRF-RS-2024-00333784//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/enzymology/metabolism/pathology ; Animals ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use ; *Fibrosis/drug therapy ; *JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism ; *Drug Development ; }, abstract = {c-Jun N-terminal kinases (JNKs), a subfamily of mitogen-activated protein kinases (MAPKs), are key mediators of cellular responses to environmental stress, inflammation, and apoptotic signals. The three isoforms-JNK1, JNK2, and JNK3 exhibit both overlapping and isoform-specific functions. While JNK1 and JNK2 are broadly expressed across tissues and regulate immune signaling, cell proliferation, and apoptosis, JNK3 expression is largely restricted to the brain, heart, and testis, where it plays a crucial role in neuronal function and survival. Subtle structural variations among the isoforms, particularly within the ATP-binding pocket and activation loop, provide a basis for the developing isoform-selective inhibitors to improve therapeutic precision. JNK3 has been increasingly recognized for its involvement in the pathogenesis of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, through mechanisms involving neuroinflammation, oxidative stress, and neuronal apoptosis. Given the limited efficacy of current therapies, which remain largely symptomatic and do not modify disease progression, covalent inhibitors of JNK3 represent a compelling alternative due to their potential for high selectivity and sustained target engagement. In parallel, JNK signaling contributes to fibrosis, with JNK1 serving as the predominant isoform driving profibrotic pathways such as fibroblast activation and extracellular matrix (ECM) deposition. Current antifibrotic agents provide only partial benefit and lack specificity for downstream effectors like JNK1. PROteolysis TArgeting Chimeras (PROTACs), which induce selective protein degradation via the ubiquitin-proteasome system, represent a promising modality to overcome these limitations. Selective degradation of JNK1 could provide a novel therapeutic avenue for fibrotic diseases. This review highlights therapeutic efforts to date and discusses how emerging approaches-particularly covalent JNK3 inhibitors for neurodegeneration and PROTACs for JNK1 in fibrosis-may advance future treatment paradigms.}, } @article {pmid40920073, year = {2025}, author = {Peng, L and Xie, X and Chen, X and Chen, C}, title = {Electrochemical Biosensors Combined with Nanomaterial Signal Amplification for the Detection of Alzheimer's Disease Biomarkers in Blood.}, journal = {ACS sensors}, volume = {10}, number = {9}, pages = {6380-6405}, doi = {10.1021/acssensors.5c02453}, pmid = {40920073}, issn = {2379-3694}, mesh = {*Alzheimer Disease/blood/diagnosis ; *Biosensing Techniques/methods ; Humans ; Biomarkers/blood ; *Electrochemical Techniques/methods ; *Nanostructures/chemistry ; Amyloid beta-Peptides/blood ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by cognitive decline and behavioral impairments, typically manifesting in the elderly and presenile population. With the rapid global aging trend, early diagnosis and treatment of AD have become increasingly urgent research priorities. The primary pathological features of AD include excessive accumulation of β-amyloid (Aβ) plaques, the formation of neurofibrillary tangles, and neuronal loss. Conventional diagnostic techniques, such as positron emission tomography-computed tomography (PET-CT) and cerebrospinal fluid (CSF) analysis, are limited by their high cost and invasiveness. As a result, there is growing interest in developing blood-based biomarker assays for AD detection. Electrochemical biosensors offer notable advantages in this context, including high sensitivity, low cost, and minimally invasive sampling. However, due to the extremely low concentrations of AD-related biomarkers in blood, signal amplification is necessary. The incorporation of nanomaterials significantly enhances the sensitivity and performance of the electrochemical biosensors. This Perspective highlights the application of various nanomaterial-enhanced electrochemical biosensors in the early diagnosis and disease monitoring of AD, underscoring their potential in advancing AD prevention, diagnosis, and therapeutic strategies.}, } @article {pmid40919318, year = {2025}, author = {Harrison, D and Billinton, A and Bock, MG and Clarke, NP and Digby, Z and Gabel, CA and Lindsay, N and Reader, V and Scanlon, J and Smolak, P and Thornton, P and Wescott, H and Watt, AP}, title = {Profile of NT-0527, a brain penetrant NLRP3 Inflammasome inhibitor suitable as an in vivo tool compound for neuroinflammatory disorders.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {40919318}, issn = {2632-8682}, abstract = {Inhibition of the NLRP3 inflammasome has emerged as a high potential treatment paradigm for the treatment of neuroinflammation, with demonstrated anti-neuroinflammatory effects in Parkinson's disease patients and a strong rationale in Alzheimer's disease and amyotrophic lateral sclerosis. To facilitate further progress in this field, brain penetrant NLRP3 inflammasome inhibitors as leads and tool compounds are required. We discovered a small molecule NLRP3 inflammasome inhibitor, NT-0527 (11), and extensively profiled this to reveal a highly potent, selective and brain penetrant compound. This was shown to be orally bioavailable, efficacious in an in vivo model of inflammation, and with good developability characteristics. However, NT-0527 exhibited CYP 2C19 time-dependent inhibition, which halted development, but this molecule could be employed as a valuable tool compound for the investigation of neuroinflammatory conditions where NLRP3 inflammasome activation is implicated.}, } @article {pmid40919134, year = {2025}, author = {Zheng, K and Huang, HZ and Liu, D and Brazhe, N and Chen, J and Zhu, LQ}, title = {Targeting the miR-96-5p/Cathepsin B Pathway to Alleviate Neuron-Derived Neuroinflammation in Alzheimer's Disease.}, journal = {MedComm}, volume = {6}, number = {9}, pages = {e70368}, pmid = {40919134}, issn = {2688-2663}, abstract = {Alzheimer's disease (AD) is one of the leading causes of dementia in the elderly, and no effective treatment is currently available. Cathepsin B (CTSB) is involved in key pathological processes of AD, but the underlying mechanisms and its relevance to AD diagnosis and treatment remain unclear. In the present study, we found that CTSB expression was abnormally elevated in the hippocampus of 3×Tg mice and was regulated by miR-96-5p. Abnormalities in the miR-96-5p/CTSB signaling pathway were detected in the serum of both mild cognitive impairment and AD patients, and the combination of serum miR-96-5p and CTSB demonstrated strong diagnostic efficacy for cognitive impairment (AUC = 0.7536). Abnormalities in the miR-96-5p/CTSB signaling pathway in AD may be associated with Aβ pathology, and neuronal CTSB can be released extracellularly to reactivate adjacent astrocytes. Ultimately, the reconstitution of the miR-96-5p/CTSB signaling pathway effectively rescued astrocyte reactivity and memory impairment in AD. Our findings suggest that the neuron-derived inflammatory mediator CTSB reactivates adjacent astrocytes and mediates memory impairment in early AD. The combination of serum miR-96-5p and CTSB represents potential serum biomarkers for cognitive impairment, and targeting the neuronal miR-96-5p/CTSB pathway may serve as a promising therapeutic strategy for AD.}, } @article {pmid40918977, year = {2025}, author = {Yang, H and Dong, C and Cai, Y and Zhao, M and Liu, J and Bian, S and Ding, X}, title = {Advances in the use of structural and diffusion magnetic resonance imaging for characterizing SCD and MCI due to Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1596459}, pmid = {40918977}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) has become a great concern for society in general and clinicians specifically because of its high morbidity, relative lack of awareness of its characteristics, and low diagnosis and treatment rates. Worldwide, there is a lack of effective treatments for slowing the progression of AD in clinical practice. Thus, the management of patients in the preclinical phase of AD (PPAD) has been identified to be highly important for addressing this concern. PPAD is considered a preclinical manifestation of the early stages of AD and includes subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Developments in magnetic resonance imaging (MRI) technology have led to its demonstration of great potential in the early identification and progression monitoring of PPAD. Thus, in this review, we summarized the concepts, principles and applications of structural and diffusion MRI in the identification of PPAD to provide potential imaging markers that can be used by clinicians in clinical practice.}, } @article {pmid40918734, year = {2025}, author = {Sun, X and Lu, Y and Hu, J and Meng, S and Wang, X and Jiang, Q}, title = {Tooth loss impairs cognitive function in SAMP8 mice by aggravating pyroptosis of microglia via the cGAS/STING pathway.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1628520}, pmid = {40918734}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a common neurodegenerative disease among the elderly population. It has been posited that the onset and progression of AD are influenced by a combination of various factors. Occlusal support loss due to tooth loss has been reported to be a risk factor triggering cognitive dysfunction. This study aimed to investigate the relationship between tooth loss and cognitive dysfunction and illustrate the role of pyroptosis in advancing Alzheimer's disease. METHODS: Male 5-month-old senescence-accelerated mouse strain P8 (SAMP8) mice were divided into two groups (n = 6): the S (sham-operated) and TL (tooth loss) groups. We assessed spatial memory ability using the Y-maze and Novel Object Recognition (NOR) tests. In addition, we performed pathological and molecular biological assessments of the hippocampus to evaluate pyroptosis-related indicators and changes in cGAS/STING. We further verified the correlation between the two in vitro. RESULTS: The pathological section staining revealed an upregulation of GSDMD, a target protein of pyroptosis, and abnormal activation of the cGAS/STING pathway, particularly in microglia, after tooth loss. In vitro, we demonstrated that the BV2 microglia knockdown STING group improved the inflammatory cascade response and down-regulated the pyroptotic features. DISCUSSION: These data suggest that the occlusal support loss due to tooth loss induces pyroptosis-related protein deposition, which may be intimately associated with the cGAS/STING signaling pathway. This provides new insights into the treatment and prevention of oral health and cognitive behavioural disorders in the elderly population.}, } @article {pmid40918343, year = {2025}, author = {Kaya, B and Çevik, UA and Çiftçi, B and Necip, A and Işik, M and Ay, EN and Yur, S and Özkay, Y and Beydemir, Ş and Kaplancıklı, ZA}, title = {Design, Synthesis, and Molecular Docking Studies of Novel Pyrazoline-Thiazoles as Cholinesterase Dual-Target Inhibitors for the Treatment of Alzheimer's Disease.}, journal = {ACS omega}, volume = {10}, number = {34}, pages = {38427-38439}, pmid = {40918343}, issn = {2470-1343}, abstract = {Ten novel pyrazoline-thiazole derivatives were synthesized and assessed for their potential as acetylcholinesterase and butyrylcholinesterase inhibitors. The structure of the target compounds was characterized by [1]H NMR and [13]C NMR, and purity was determined using HPLC. The in vitro enzyme inhibitory activity assays determined that compounds 3f (IC50 = 0.382 μM) and 3g (IC50 = 0.338 μM) showed good inhibitory activity of acetylcholinesterase (AChE). Compound 3f has a selective inhibitory effect on AChE, while compound 3g has a dual effect, being effective against both AChE and BChE (IC50 = 2.087 μM). The molecular docking results of compound 3g with high inhibitory activity for AChE experimentally showed that it has a strong inhibitory effect close to that of the reference inhibitor tacrine. The compound 3g was found to have the highest activity in its interaction with the BChE (4BDS) protein with a low docking score (-5.555 kcal/mol). Furthermore, the prediction of ADME properties of compounds 3f and 3g was determined through Swiss ADME.}, } @article {pmid40917662, year = {2025}, author = {Sun, Z and Li, Y and Qu, X and Wang, L and Zhu, S and Sun, X and Yang, L and Sun, X}, title = {Research trend of functional magnetic resonance imaging in diabetes mellitus research: a visualization and bibliometric analysis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1539995}, pmid = {40917662}, issn = {1664-2295}, abstract = {BACKGROUND: Understanding the neurological complications associated with diabetes mellitus is essential for developing comprehensive treatment strategies. Functional magnetic resonance imaging (fMRI) is a powerful tool for investigating brain functional and structural changes associated with various conditions, including diabetes mellitus. OBJECTIVES: To analyze the application trends, research hotspots, and emerging frontiers of fMRI in diabetes mellitus research through a comprehensive bibliometric analysis. METHODS: A systematic literature search was conducted utilizing the Web of Science Core Collection (WoSCC) database. Bibliometric tools, including VOSviewer (version 1.6.20), CiteSpace (version 6.3.R1), and R (version 4.3.3), were employed for data analysis. RESULTS: A total of 706 articles about fMRI and diabetes mellitus were published from 1987 to 2024. The United States of America (USA) ranks first (n = 931), followed by China (n = 756) and Germany (n = 270) regarding total publications. Harvard University ranks first in terms of total publications. Among the top ten institutions regarding publications, the majority of articles originated from the USA. The journal Diabetes has the highest number of publications. The author SHAO YI ranks first in total publications, while FRITSCHE ANDREAS ranks first in total citations. The top five keywords identified are "dementia," "risk," "brain," "Alzheimer's disease," and "functional connectivity." Keyword burst analysis indicates that the recent research hotspots included "impairment," "dysfunction," and "diagnosis." CONCLUSION: Cognitive impairment and dysfunction related to diabetes mellitus, along with Alzheimer's disease and dementia, and their diagnosis were identified as focal areas of research. Future investigations should concentrate on predicting and early diagnosing cognitive function in patients with diabetes mellitus using fMRI. The findings of this study provide a valuable reference for researchers and clinicians seeking to explore the neurological dimensions of diabetes mellitus and develop targeted therapeutic approaches.}, } @article {pmid40917568, year = {2025}, author = {Yoon, DM and Plante, DT and Fleming, V and Handen, B and Lao, P and Peven, J and Christian, B and Okonkwo, O and Laymon, C and Ances, B and Hom, C and Helsel, B and Hartley, SL}, title = {Preliminary investigation of obstructive sleep apnea and Alzheimer's disease in down syndrome.}, journal = {Sleep advances : a journal of the Sleep Research Society}, volume = {6}, number = {3}, pages = {zpaf044}, pmid = {40917568}, issn = {2632-5012}, support = {R01 AG070028/AG/NIA NIH HHS/United States ; F31 AG085730/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; P50 HD105353/HD/NICHD NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; K01 AG083130/AG/NIA NIH HHS/United States ; U01 AG051406/AG/NIA NIH HHS/United States ; }, abstract = {This study provided a preliminary examination of indices of obstructive sleep apsnea (OSA) and sleep disruptions in adults with Down syndrome (DS), and their associations with Alzheimer's disease (AD) pathology and symptomatology. A total of 93 adults with DS (aged 25-61 years) from the Alzheimer Biomarker Consortium-DS completed cognitive assessments, MRI and positron emission tomography (PET) scans (assessing amyloid-beta [Aβ] and tau), and a one-night home sleep study using the WatchPAT-300 device. Study partners also reported on depressive symptoms and diagnoses. Correlational analyses examined relationships between sleep variables, PET biomarkers, and AD symptomatology (cognitive functioning and depressive mood), controlling for sociodemographics. A total of 81 participants (87 per cent) completed valid WatchPAT data. Of these, 60 (74 per cent) screened positive for OSA, and an additional 11 had a prior OSA diagnosis and used CPAP during the test night. Nearly half (45 per cent) of those screening positive for OSA had no prior diagnosis, indicating under-detection. Among the 22 participants using OSA treatment, 50 per cent continued to show sleep-disordered breathing, suggesting suboptimal treatment effectiveness. Higher wake percentage and shorter total sleep time were associated with greater Aβ and tau burden. Cognitive performance was negatively associated with wake percentage, total sleep time, and oxygenation indices (minimum oxygen, desaturation, and time ≤ 88 per cent oxygen). Depressive symptoms were negatively related to total sleep time. These findings add preliminary evidence linking sleep disruption and OSA with AD-related pathology and symptomatology. Larger, longitudinal studies are needed to confirm these associations and evaluate whether improving sleep quality and treating OSA may help delay AD onset in this high-risk population.}, } @article {pmid40917296, year = {2025}, author = {Önder, S and Biberoğlu, K and Tacal, Ö}, title = {Thionine modulates tau phosphorylation in an Alzheimer's disease cell culture model.}, journal = {Turkish journal of biology = Turk biyoloji dergisi}, volume = {49}, number = {4}, pages = {400-408}, pmid = {40917296}, issn = {1303-6092}, abstract = {BACKGROUND/AIM: Tau protein, which is crucial for sustaining the cytoskeletal network by assisting microtubule construction, contributes significantly to the pathophysiology of Alzheimer's disease (AD). The hyperphosphorylation of tau causes it to detach from microtubules (MTs), leading to the formation of neurofibrillary tangles (NFTs) in neurons, which ultimately results in cell death. Thionine (TH), a cationic phenothiazine-structured compound, has been the topic of extensive research due to its interesting physicochemical properties. It is a common biological dye, especially useful in histology due to its strong affinity for biological membranes. Furthermore, TH serves as a photosensitizer in phototherapy. It has a phenothiazine pharmacophore, which makes it selective against microbial and tumor cells. Our prior studies demonstrated that TH inhibits human plasma butyrylcholinesterase (BChE) by acting as a nonlinear inhibitor and also affects amyloid precursor protein (APP) metabolism in PS70 cells. In the current research, we investigated whether TH modulates the phosphorylation of tau in N2a/APPSwe cells. MATERIALS AND METHODS: Using flow cytometry, we identified the dose range and treatment time of TH that did not affect the viability of N2a/APPSwe cells. The western blot method was used to investigate the effects of TH on total tau and four key tau phosphorylation sites. RESULTS: The results indicated that TH reduces tau phosphorylation at residues Ser202/Thr205, Ser396, Ser396/Ser404, and Thr181, which contribute to NFT formation. CONCLUSION: When all these findings are evaluated together, TH may have a therapeutic potential against AD.}, } @article {pmid40916557, year = {2025}, author = {Feng, X and Wang, H}, title = {Antibody Therapies for Alzheimer's Disease: A New Strategy for Targeted Therapy and Blood-Brain Barrier Delivery.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3450-3464}, doi = {10.1021/acschemneuro.5c00484}, pmid = {40916557}, issn = {1948-7193}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/diagnosis/therapy ; *Blood-Brain Barrier/metabolism/drug effects ; Animals ; *Antibodies/therapeutic use/administration & dosage ; *Drug Delivery Systems/methods ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment and neuronal loss, with pathological hallmarks including Aβ plaque deposition and tau tangles. At present, the early diagnosis and treatment of AD still face great challenges, such as limited diagnostic methods, difficulty in blood-brain barrier (BBB) penetration, complex disease mechanisms, and lack of highly effective targeted therapies. Antibody drugs have shown broad prospects in the field of AD due to their high specificity, engineering and multifunctional therapeutic potential, include targeted Aβ clearance, tau pathological regulation, imaging probes, and blood biomarkers. In the future, with the development of antibody engineering technologies (such as PROTAC-antibody conjugates and antibody-based gene therapies), the precision diagnosis and treatment of AD is expected to usher in new breakthroughs. This article systematically reviews the latest advances in the treatment and diagnosis of AD and discusses their potential for clinical translation.}, } @article {pmid40916410, year = {2025}, author = {Algazzawi, H and Abujamai, J and Alshanberi, AM and Satar, R and Ansari, SA}, title = {Role of GSK-3 Inhibition in Alzheimer's Disease Therapy.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050400781250904082943}, pmid = {40916410}, issn = {1875-5828}, abstract = {A serine/threonine kinase with a wide variety of substrates, Glycogen Synthase Kinase-3 (GSK-3) is widely expressed. GSK-3 is a key player in cell metabolism and signaling, modulating numerous cellular functions and playing significant roles in both healthy and diseased states. The two histopathological features of Alzheimer's disease, the intracellular neurofibrillary tangles composed of hyperphosphorylated tau, and the extracellular senile plaques composed of beta-amyloid, have been linked to GSK-3. It alters multiple tau protein locations found in neurofibrillary tangles. Additionally, GSK-3 can react to this peptide and regulate the production of beta-amyloid. The overexpression of GSK-3 in several transgenic models has been linked to tau hyperphosphorylation, neuronal death, and a reduction in cognitive function. It has been shown that lithium, a medication commonly used to treat affective disorders, inhibits GSK-3 at therapeutically relevant concentrations and stops tau phosphorylation. In this review, we provide an overview of the most recent research on the potential of GSK-3 inhibitors for treating Alzheimer's disease.}, } @article {pmid40916051, year = {2025}, author = {Le, HT and Lau, ECY and Lu, CY and Hilmer, SN and Jeon, YH and Low, LF and Nguyen, TA and Tan, ECK}, title = {Treatment modifiers and predictors of risperidone response in dementia: An individual participant data meta-analysis of six randomized controlled trials.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70665}, pmid = {40916051}, issn = {1552-5279}, mesh = {Humans ; *Risperidone/therapeutic use ; Randomized Controlled Trials as Topic ; *Dementia/drug therapy ; *Antipsychotic Agents/therapeutic use ; Aggression/drug effects ; Treatment Outcome ; Male ; Female ; Aged ; }, abstract = {INTRODUCTION: Risperidone is approved for behaviors and psychological symptoms of dementia (BPSD), despite modest efficacy and known risks. Identifying responsive symptoms, treatment modifiers, and predictors is crucial for personalized treatment. METHOD: A one-stage individual participant data meta-analysis of six randomized controlled trials (risperidone: n = 1009; placebo: N = 712) was conducted. Mixed-effects models assessed treatment effects, modifiers, and predictors, with BPSD measured via the Behavioral Pathology in Alzheimer's Disease scale. RESULTS: Risperidone showed modest 8 week benefits for aggression (standardized mean difference [SMD]: -0.22; p < 0.001), psychosis (SMD: -0.23; p = 0.001), and anxiety/phobias (SMD: -0.19; p = 0.014), but not for activity, affective, or sleep disturbances. Pharmacokinetic/pharmacodynamic-related factors (e.g., body mass index, endocrine disease, race/ethnicity) potentially modified treatment effects. Week 2 response predicted week 8 improvement (odds ratio: 4.46; p < 0.001). DISCUSSION: Risperidone provided symptom-specific benefits in reducing aggression, psychosis, and anxiety/phobias. Week 2 response predicted treatment outcomes, while certain patient characteristics may modify treatment response. Further research is needed to optimize the benefit-risk balance and individualize treatment. HIGHLIGHTS: Risperidone modestly reduces symptoms of psychosis, aggression, and anxiety/phobias. Risperidone shows no effect on activity, affective, or sleep disturbances. Patient factors (body mass index, endocrine disease, race/ethnicity) may affect response. Positive response by week 2 predicts significant improvement later.}, } @article {pmid40915373, year = {2026}, author = {Lei, HP and Yang, X and Hu, YT and Wu, LN and Wei, AH and Yu, L and Liu, TT and Ji, XH and Liu, J and Jin, H and Zhou, SY and Jin, F}, title = {Gastrodin alleviates mitochondrial energy metabolism dysfunction via activating β-catenin/c-Myc/MCT2 signaling in Alzheimer's disease models.}, journal = {Journal of ethnopharmacology}, volume = {354}, number = {}, pages = {120548}, doi = {10.1016/j.jep.2025.120548}, pmid = {40915373}, issn = {1872-7573}, mesh = {Animals ; *Glucosides/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; beta Catenin/metabolism ; Male ; Proto-Oncogene Proteins c-myc/metabolism ; Mice ; Signal Transduction/drug effects ; *Mitochondria/drug effects/metabolism ; Disease Models, Animal ; *Benzyl Alcohols/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology ; Energy Metabolism/drug effects ; Mice, Transgenic ; Cell Line ; Mice, Inbred C57BL ; }, abstract = {Gastrodia elata, also known as Chijian, belongs to the Orchidaceae family of plants. The "Compendium of Materia Medica" records that Gastrodia elata treats "confused speech, excessive fear, and loss of willpower". Gastrodin (GAS) is the main bioactive component of Gastrodia elata. Research has shown that GAS possesses protective effects on multiple animal models of Alzheimer's disease (AD). However, the exact molecular mechanism of GAS-mediated neuroprotection in AD pathology remains unclear. AIM OF THE STUDY: This study aims to determine whether GAS exerts neuroprotective effects on AD models through regulating β-catenin/c-Myc/MCT2 signaling axis. MATERIALS AND METHODS: Behavioral and histopathological tests, including Morris water maze test, Nissl staining, and NeuN immunofluorescence staining in 3 × Tg-AD male mice, were used to assess the pharmacological effect of GAS on AD. To investigate the neuroprotective mechanisms of GAS, we established an in vitro AD model using Aβ25-35-treated HT22 cells. The expressions of proteins and mRNA related to the β-catenin/c-Myc signaling axis were determined by western blotting and quantitative PCR. The change in energy metabolism was evaluated by measuring pyruvate, cellular ATP production, and mitochondrial membrane potential (MMP). The molecular mechanism of GAS-mediated neuroprotection was further explored using pharmacological and genetic interventions targeting β-catenin and c-Myc. Transcriptional regulation was interrogated through β-catenin chromatin immunoprecipitation (ChIP) coupled with JASPAR-based motif prediction, while ligand-receptor interactions were characterized by AutoDock-based molecular docking validated through drug affinity responsive target stability (DARTS) assay and cellular thermal shift assay (CETSA). RESULTS: In vivo experimental results revealed that GAS ameliorated cognitive impairment in 3 × Tg-AD mice, attenuated neuronal damage, and markedly inhibited the downregulation of active-β-catenin, c-Myc, and MCT2 in the hippocampal tissues. In Aβ25-35-challenged HT22 cells, the relevant protein levels of β-catenin/c-Myc signaling axis were reduced, with both mRNA and protein expressions of MCT2 declining, alongside reductions in pyruvate and ATP concentrations. GAS treatment reversed these pathological alterations, while this effect was antagonized by β-catenin and c-Myc inhibitors. Additionally, lentiviral-mediated β-catenin overexpression markedly increased MCT2 mRNA and protein expression in HT22 cells. The results of chromatin immunoprecipitation assay coupled with quantitative PCR and JASPAR-based motif prediction revealed that β-catenin bound to the MCT2 promoter region. Autodock Vina simulation demonstrated that GAS binds to β-catenin with a binding energy of less than -5 kcal/mol. Both DARTS and CETSA experiments showed that the binding of GAS to β-catenin protects the β-catenin protein from degradation. CONCLUSION: This study demonstrates that GAS plays a protective role in experimental AD models through enhancing MCT2 expression and improving mitochondrial energy metabolism function by activation of the β-catenin/c-Myc/MCT2 signaling axis.}, } @article {pmid40913913, year = {2025}, author = {Lee, H and Hossain, MK and Lee, HY and Kumar, V and Shin, SJ and Kim, BH and Park, HH and Son, JG and Moon, M and Kim, HR}, title = {Taurine suppresses Aβ aggregation and attenuates Alzheimer's disease pathologies in 5XFAD mice and patient-derived cerebral organoids.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {191}, number = {}, pages = {118527}, doi = {10.1016/j.biopha.2025.118527}, pmid = {40913913}, issn = {1950-6007}, mesh = {*Taurine/pharmacology ; Animals ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Humans ; Mice ; *Organoids/drug effects/metabolism/pathology ; tau Proteins/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Doublecortin Protein ; *Peptide Fragments/metabolism ; Phosphorylation/drug effects ; Hippocampus/drug effects/metabolism/pathology ; Neurogenesis/drug effects ; *Neuroprotective Agents/pharmacology ; Cell Line ; Male ; }, abstract = {Alzheimer's disease (AD) is marked by amyloid-beta (Aβ) plaque buildup, tau hyperphosphorylation, neuroinflammation, neuronal loss, and impaired adult hippocampal neurogenesis (AHN). Taurine has shown protective effects in various cellular and animal models of AD, though the molecular mechanisms of free taurine and its effects in patient-derived models remain underexplored. This study evaluates taurine's therapeutic potential using integrated in silico, in vitro, in vivo, and ex vivo approaches. In vitro aggregation assays revealed that taurine (10-100 μM) inhibited Aβ42 fibril formation, with transmission electron microscopy showing looser, amorphous fibrils, particularly at higher doses. Computational simulations further supported that taurine binds stably to Aβ peptide fragments and facilitates the dissociation of Aβ dimers. In HT22 cells, taurine protected against Aβ-induced cytotoxicity. In 5XFAD mice, oral administration of taurine (1000 mg/kg, 4 weeks) significantly reduced Aβ accumulation and hyperphosphorylation of tau at Ser202/Thr205 in the dorsal subiculum. Furthermore, taurine attenuated microgliosis, as evidenced by decreased Iba-1 immunoreactivity, protected against neurodegeneration demonstrated by preserving NeuN-positive neurons, and ameliorated deficit of AHN shown by increasing DCX-positive cells in the subgranular zone of the dentate gyrus. Importantly, in cerebral organoids derived from an AD patient carrying the APOE ε4/ε4 genotype, taurine treatment attenuated Aβ accumulation, decreased tau phosphorylation. These findings highlight taurine's multi-target therapeutic potential targeting amyloid aggregation, tau pathology, neuroinflammation and neurogenesis. Our data support taurine emerges as a promising therapeutic candidate for AD.}, } @article {pmid40913683, year = {2025}, author = {Smoller, C and Schiller, E and Yamashita, K and Silverglate, BD and Grossberg, GT}, title = {Current and Emerging Pharmacological Approaches to Agitation in Alzheimer's Disease: A Narrative Review of New and Repurposed Therapies.}, journal = {Drugs}, volume = {85}, number = {11}, pages = {1391-1411}, pmid = {40913683}, issn = {1179-1950}, mesh = {Humans ; *Alzheimer Disease/drug therapy/complications ; *Psychomotor Agitation/drug therapy/etiology ; Drug Repositioning ; *Antipsychotic Agents/therapeutic use ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; Antidepressive Agents/therapeutic use ; Anticonvulsants/therapeutic use ; Hypnotics and Sedatives/therapeutic use ; }, abstract = {This narrative review explores current pharmacological treatments for agitation in Alzheimer's disease (AD). Agitation, a common and difficult-to-manage symptom in AD, often requires targeted intervention. While nonpharmacological methods, such as behavioral therapy and environmental modifications, are considered first line, they may not always be effective. In cases where these approaches fail, pharmacological treatment can become a necessary component of care. Historically, antipsychotics have been the mainstay of pharmacological treatment for agitation in AD; however, safety and efficacy concerns have prompted exploration into alternative treatments. The purpose of this narrative review is to synthesize current literature on pharmacological treatments for agitation in AD with a focus on new and repurposed drugs. It also examines agents that have failed to demonstrate clinical benefit, offering insights into the ongoing challenges of drug development in this area. This review synthesizes recent findings on various drug classes, including anticonvulsants, antipsychotics, selective serotonin reuptake inhibitors (SSRIs), atypical antidepressants, sedatives, anti-dementia drugs, dextromethorphan, and cannabinoids. Both brexpiprazole and risperidone have demonstrated efficacy and received approval from government agencies, including brexpiprazole in the USA and risperidone in parts of Europe. Despite these advances, concerns remain regarding their long-term use and safety profiles. As a result, multiple other therapies are currently being studied as possible alternative solutions. However, no other pharmacological agents are currently approved, underscoring the need for further research on safe and effective options for this vulnerable population.}, } @article {pmid40913351, year = {2025}, author = {Peng, D and Wei, P and Li, Z and Wei, R and Li, H and Li, S}, title = {The Role of P62/Nrf2/Keap1 Signaling Pathway in Lead-Induced Neurological Dysfunction.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {9}, pages = {e70566}, pmid = {40913351}, issn = {1755-5949}, support = {82160626//National Natural Science Foundation of China/ ; 81803281//National Natural Science Foundation of China/ ; }, mesh = {*Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/metabolism ; Animals ; *Signal Transduction/drug effects/physiology ; *Lead/toxicity ; *Sequestosome-1 Protein/metabolism ; Male ; Oxidative Stress/drug effects/physiology ; Mice ; Reactive Oxygen Species/metabolism ; Neurons/drug effects/metabolism ; Cells, Cultured ; Rats ; Autophagy/drug effects ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Lead (Pb) exposure is recognized for its contribution to the development of neurodegenerative diseases. However, the precise mechanisms underlying Pb-induced neurological dysfunction remain elusive. This study aimed to investigate the role of oxidative stress and the autophagy-related P62/kelch like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in neuronal impairment caused by Pb. METHODS: By employing both in vivo and in vitro approaches, we explored the involvement of the P62/Nrf2/Keap1 pathway in Pb-induced neurotoxicity. RESULTS: Our findings demonstrated that Pb exposure triggers excessive production of reactive oxygen species (ROS), upregulates Keap1 protein expressions, promotes Nrf2 degradation, and inhibits expression of antioxidant proteins such as heme Oxygenase-1 (HO-1) and glutathione peroxidase (GPx), resulting in oxidative damage in neurons. Furthermore, we observed that the autophagy protein P62 disrupts the normal autophagy process by interacting with the Nrf2/Keap1 axis, leading to an accumulation of Tau, a protein associated with Alzheimer's disease (AD), ultimately resulting in neurodegeneration. However, treatment with the antioxidant N-acetylcysteine, Nrf2 activator Artemisitene, and autophagy activator Rapamycin attenuated these detrimental changes. CONCLUSION: The P62/Nrf2/Keap1 pathway mediates Pb-induced neuronal dysfunction and highlights its potential as a therapeutic target for mitigating the neurodegenerative effects associated with Pb exposure.}, } @article {pmid40912996, year = {2025}, author = {Greeley, D and Nash, M and Herskowitz, B and Kim, F and Rock, J and Prins, N and Kim, S and Xi, T and Busam, JA and Tete, B and Choung, JJ and Sha, SJ}, title = {A phase 2 randomized, placebo-controlled study on the efficacy and safety of AR1001, a phosphodiesterase-5 inhibitor, in patients with mild-to-moderate Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {9}, pages = {100337}, pmid = {40912996}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Aged ; Male ; Double-Blind Method ; Female ; Middle Aged ; *Phosphodiesterase 5 Inhibitors/therapeutic use/adverse effects/administration & dosage ; Aged, 80 and over ; Treatment Outcome ; tau Proteins/blood ; Amyloid beta-Peptides ; Cognition/drug effects ; Biomarkers/blood ; }, abstract = {BACKGROUND: AR1001 is a phosphodiesterase-5 inhibitor that produces improved cognitive performance and reduces amyloid-β and phosphorylated tau burdens in preclinical models of Alzheimer's disease (AD). OBJECTIVES: To evaluate the safety and efficacy of AR1001 in participants with mild-to-moderate Alzheimer's disease (AD). DESIGN: Randomized, double-blind, placebo-controlled phase 2 trial conducted at 21 sites in the United States. PARTICIPANTS: Adults aged 55-80 years with mild-to-moderate dementia as determined by National Institutes of Aging-Alzheimer's Association (NIA-AA) stage 4 or 5 and Mini-mental State Exam (MMSE) score 16-26. INTERVENTION: Once daily oral administration of placebo, 10 mg AR1001, or 30 mg AR1001 for 26 weeks followed by 26 weeks optional extension. MEASUREMENTS: Co-primary efficacy endpoints were changes from baseline at Week 26 in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog 13) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included measures of cognition, daily living, and depression. Levels of plasma biomarkers pTau-181, pTau-217, Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were also examined. RESULTS: A total of 210 participants were enrolled and 82% completed 26 weeks of treatment. AR1001 10 mg and 30 mg were well-tolerated with a similar safety profile compared to placebo. After 26 weeks, there were no differences in ADAS-Cog13, ADCS-CGIC, or in secondary efficacy endpoints between groups. Levels of plasma biomarkers pTau-181, pTau-217, and GFAP were improved in the 30 mg AR1001 group compared to placebo. CONCLUSION: AR1001 was safe and well tolerated. Although primary efficacy endpoints were not met after 26 weeks of treatment, participants receiving 30 mg AR1001 showed favorable changes in AD-related plasma biomarkers compared to placebo. TRIAL REGISTRATION: clinicaltrials.gov; NCT03625622.}, } @article {pmid40912535, year = {2025}, author = {Cheng, F and Gao, H and Yan, B and Chen, F and Lei, P}, title = {From disinfectant to neurodegeneration: Integrating machine learning and mendelian randomization reveals triclosan as a novel environmental risk factor for Alzheimer's disease.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {385}, number = {}, pages = {127068}, doi = {10.1016/j.envpol.2025.127068}, pmid = {40912535}, issn = {1873-6424}, mesh = {*Triclosan/toxicity/adverse effects ; *Alzheimer Disease/epidemiology/chemically induced ; *Machine Learning ; Humans ; Risk Factors ; Mendelian Randomization Analysis ; *Disinfectants/toxicity ; *Environmental Exposure/statistics & numerical data ; }, abstract = {This study systematically investigated the association between triclosan (TCS) exposure and Alzheimer's disease (AD) risk via integrated bioinformatics approaches. TCS-AD-related genes were identified using bioinformatics tools and public databases, followed by the screening of key genes through multi-model machine learning algorithms (LASSO, SVM-RFE, RF) to mitigate random errors in small sample sizes. DRD2 was confirmed as the most robust core gene by LASSO confidence interval analysis and SHAP evaluation, while APP and SLC6A3 were validated through cross-method intersection. Findings from functional enrichment analysis, Mendelian randomization, and molecular docking demonstrated that TCS may affect AD pathogenesis through these key genes. Moreover, a stable AD risk scoring model and predictive formula were developed via logistic regression analysis of T-A-Key Genes. This study constitutes an innovative and transformative research endeavor. Building upon the understanding of TCS-induced neurotoxicity, it extends to the clinical translational direction of predicting AD onset risk, thereby establishing a quantitative association model of "environmental exposure-core genes-disease risk. " It not only provides novel evidence for the potential role of TCS neurotoxicity as an environmental pathogenic factor in AD, emphasizing the necessity of prioritizing risk management of daily chemical exposure in AD prevention and treatment, but also offers a scientific foundation for the formulation of public health policies aimed at preventing long-term TCS exposure.}, } @article {pmid40912368, year = {2025}, author = {Wang, J and Qiao, Z and Cao, X and Li, H and Wang, Y and Jiao, Q and Chen, X and Du, X}, title = {G Protein-coupled receptors: key targets for maintaining the function of basal ganglia-thalamus-cortical circuits in Parkinson's disease.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 2}, pages = {117303}, doi = {10.1016/j.bcp.2025.117303}, pmid = {40912368}, issn = {1873-2968}, mesh = {*Parkinson Disease/metabolism/drug therapy/physiopathology ; Humans ; *Receptors, G-Protein-Coupled/metabolism/antagonists & inhibitors ; *Basal Ganglia/metabolism/drug effects ; Animals ; *Cerebral Cortex/metabolism/drug effects ; *Nerve Net/metabolism/drug effects ; *Drug Delivery Systems/methods ; }, abstract = {Parkinson's Disease (PD), the second most common neurodegenerative disease after Alzheimer's disease, is clinically characterized by resting tremor, rigidity and postural balance disorder. Its pathological essence is the progressive degenerative death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to a significant decrease in striatal dopamine (DA) levels. This results in the dysfunction of basal ganglia-thalamus-cortex (BGTC) circuit. This circuit is the core neural circuit of motor control, and its abnormality not only directly causes the motor symptoms of PD, but also participates in the cascade of disease progression through the disorder of neurotransmitter signals. At present, DA replacement therapy and DA receptors (DARs) agonists are still the main methods of clinical treatment, but single therapy cannot fully correct the imbalance of other neurotransmitter systems, which has significant limitations in long-term efficacy and symptom management. G protein-coupled receptors (GPCRs), as the largest family of membrane proteins, have become important targets for PD treatment due to their extensive participation in physiological regulatory networks and excellent drug development potential. These transmembrane signaling molecules play important roles in multiple key nodes in the pathological process of PD by precisely regulating the release of neurotransmitters, the maintenance of synaptic plasticity and the dynamic balance of neural circuits. Here, we review the transition of BGTC in the context of PD and then focus on the pathological cascade of GPCRs mediating PD in this loop. Finally, we update the clinical trials or approvals of GPCR drugs under investigation for the treatment of PD.}, } @article {pmid40912064, year = {2025}, author = {Ali, N and Al-Rejaie, SS and Babu, MA and Nayak, P and VenuPrasad, KD and Mohany, M and Singh, TG and Akhter, MS and Fareed, M and Tyagi, Y and Bansal, N and Puri, S}, title = {Exploring the bioactive constituents from spices targeting N-methyl-d-aspartate receptors: An in silico and in vitro approach to identify druggable leads against neurological disability.}, journal = {Bioorganic & medicinal chemistry}, volume = {130}, number = {}, pages = {118378}, doi = {10.1016/j.bmc.2025.118378}, pmid = {40912064}, issn = {1464-3391}, mesh = {*Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; Molecular Docking Simulation ; Humans ; *Spices/analysis ; *Curcumin/chemistry/pharmacology ; Structure-Activity Relationship ; Molecular Structure ; *Neuroprotective Agents/chemistry/pharmacology ; Dose-Response Relationship, Drug ; Quercetin/chemistry/pharmacology ; }, abstract = {N-methyl-d-aspartate (NMDA) receptors are validated druggable targets for the treatment of Alzheimer's and other associated neurological conditions, particularly in individuals with disabilities. Considering the excitotoxicity associated with NMDA receptors, which leads to neuronal damage, cognitive impairment, and limitations of current therapeutic regimens, better therapeutic candidates are required. One of the validated drug discovery approaches is computer-assisted drug discovery, supplemented by molecular docking, mechanics, and dynamics. To this end, we curated 134 bioactive constituents derived from spices. These were subjected to high-throughput virtual screening (HTVS) considering the pharmacophoric features of the NMDA receptor. Molecular docking, followed by molecular mechanics and dynamics, indicated that curcumin and quercetin could plausibly bind to the NMDA receptor in comparison to memantine. In vitro ELISA-based analysis revealed that curcumin may inhibit the NMDA receptor with an IC50 of 2.36 μM compared to memantine's 736.48 nM, employed as a positive control. However, targeting the neuronal receptor NMDA requires that the ligand efficiently cross the blood-brain barrier (BBB). To overcome this challenge, we performed a rational bioisosteric replacement strategy to potentially optimize the pharmacokinetic features of curcumin without affecting its NMDA binding. We generated 150 bioisosteres of curcumin, and through extensive computational analyses, the top 5 scoring molecules were further validated via a molecular dynamics approach. However advantageous, in the present work, curcumin or its proposed derivatives have not been corroborated by extensive biological investigation. It is a prototype study to identify the druggable leads from the spices that have the potency to interact and inhibit NMDA. Owing to this, the mechanism of action is not fully elucidated. Further, the work upon validation (biologically) may serve as a useful pharmacophore (tool molecule) using which NMDA may be downregulated. The designed derivatives thus open avenues to synthesize and biologically test them against NMDA inhibition, plausibly establishing their roles in Alzheimer's and related disabilities.}, } @article {pmid40911712, year = {2025}, author = {Wang, G and Li, Y and McDade, E and Xiong, C and Hartz, SM and Bateman, RJ and Morris, JC and Schneider, LS and , }, title = {Clinical progression on CDR-SB©: Progression-free time at each 0.5 unit level in dominantly inherited and sporadic Alzheimer's disease populations.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70643}, pmid = {40911712}, issn = {1552-5279}, support = {R01AG046179//National Institute on Aging of the National Institutes of Health/ ; R01AG068319//National Institute on Aging of the National Institutes of Health/ ; R01 AG068319/AG/NIA NIH HHS/United States ; SG-20-690363-DIAN//National Institute on Aging (NIA), the Alzheimer's Association/ ; U01 AG024904/AG/NIA NIH HHS/United States ; U01 AG059798/AG/NIA NIH HHS/United States ; U01 AG024904/NH/NIH HHS/United States ; R01 AG046179/AG/NIA NIH HHS/United States ; U01AG042791//National Institute on Aging of the National Institutes of Health/ ; 1U01AG059798//National Institute on Aging of the National Institutes of Health/ ; R01AG053267-S1//National Institute on Aging of the National Institutes of Health/ ; R01AG053267//National Institute on Aging of the National Institutes of Health/ ; U19 AG032438/AG/NIA NIH HHS/United States ; U01 AG052564/AG/NIA NIH HHS/United States ; P30AG066530//National Institute on Aging of the National Institutes of Health/ ; HI21C0066//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; P30 AG066530/AG/NIA NIH HHS/United States ; U01AG042791-S1//National Institute on Aging of the National Institutes of Health/ ; R01 AG053267/AG/NIA NIH HHS/United States ; U19AG032438//The Dominantly Inherited Alzheimer Network/ ; U01AG052564//National Institute on Aging of the National Institutes of Health/ ; W81XWH-12-2-0012//Department of Defense/ ; U01 AG042791/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy/diagnosis ; *Disease Progression ; Female ; Male ; Aged ; *Mental Status and Dementia Tests ; Cohort Studies ; Middle Aged ; Neuropsychological Tests ; }, abstract = {INTRODUCTION: Clinical Dementia Rating Sum of Boxes (CDR-SB) is a reliable and clinically meaningful composite for assessing treatment effects in Alzheimer's disease (AD) clinical trials. Small CDR-SB differences at the end of a trial often lead to controversy in deriving clinically meaningful interpretations. METHODS: We estimated progression-free time (PFT) participants remained at each 0.5 unit CDR-SB increment in dominantly inherited AD (DIAD) and sporadic AD populations, evaluating its potential as an alternative measure of treatment effects. RESULTS: PFT is longer at CDR-SB ≤ 2.0 (1-2 years) and shorter at CDR-SB ≥ 5 (≤ 0.33) in the Alzheimer's Disease Neuroimaging Initiative cohort. The DIAD cohort showed similar but shorter times. Using PFT, continuous lecanemab treatment for 3 years is estimated to delay disease progression by 0.62 years in the sporadic population. DISCUSSION: PFT provides a benchmark for expressing clinical progression and treatment effects and can be applied particularly during open-label extensions and single-arm trials without placebo comparisons. HIGHLIGHTS: We estimated the progression-free time at each 0.5 unit Clinical Dementia Rating Sum of Boxes increment in dominantly inherited Alzheimer's disease (AD) and sporadic AD populations. We proposed using progression-free time to estimate treatment effects in open-label extension or single-arm studies. If further validated, progression-free time could serve as a benchmark for assessing clinical progression and treatment effects.}, } @article {pmid40911700, year = {2025}, author = {Maria, and Khan, A and Ajaj, R and Rauf, A and , and Shah, ZA and Ahmad, Z and Hemeg, HA and Rashid, U}, title = {Secondary metabolites isolated from Fernandoa adenophylla (Wall. ex G.Don) steenis as multitarget inhibitors of cholinesterases for the treatment of Alzheimer's Disease, followed by molecular docking studies.}, journal = {PloS one}, volume = {20}, number = {9}, pages = {e0331119}, pmid = {40911700}, issn = {1932-6203}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/isolation & purification ; Molecular Docking Simulation ; *Alzheimer Disease/drug therapy/enzymology ; Butyrylcholinesterase/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; Humans ; *Plant Extracts/chemistry/pharmacology ; Secondary Metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder categorized by the progressive loss of cognitive function, with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as key therapeutic targets. In this study, we report the isolation, characterization, and evaluation of the cholinesterase inhibitory potential of phytochemicals from Fernandoa adenophylla (Wall. ex G. Don) Steenis, a plant known for its medicinal properties. Using in-vitro enzyme inhibition assays, we identified five bioactive compounds, including lapachol (1), α-lapachone (2), peshawaraquinone (3), dehydro-α-lapachone (4), and an indanone derivative (5), which demonstrated significant inhibition of AChE and BuChE. The compounds exhibited varied inhibitory potency, with peshawaraquinone (3) showing the most promising AChE (IC50 = 0.90 ± 0.04 µM) and BuChE (IC50 = 8.39 ± 0.14 µM) inhibition, followed by dehydro-α-lapachone (4), which exhibited an AChE IC50 value of 2.64 ± 0.08 µM. Further, the selectivity index (SI) for AChE over BuChE was highest for dehydro-α-lapachone (SI = 21.1), suggesting its potential as a selective inhibitor. Molecular docking studies provided insights into the binding interactions between these compounds and the enzyme active sites, highlighting key interactions that may contribute to their inhibitory activity. These findings suggest that phytochemicals from F. adenophylla possess significant cholinesterase inhibition potential and may serve as leads for the development of novel therapeutic agents for Alzheimer's disease.}, } @article {pmid40911470, year = {2025}, author = {Yamamoto, N and Yuzu, K and Morishima, K and Inoue, R and Sugiyama, M and Koyama, D and Chatani, E}, title = {Targeting Both Monomer and Oligomer with Fibrinogen Efficiently Suppresses Amyloid Fibril Formation and Cell Toxicity of Amyloid β 1-42.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3623-3630}, pmid = {40911470}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; *Fibrinogen/pharmacology/metabolism ; Humans ; *Peptide Fragments/metabolism/toxicity ; Animals ; *Amyloid/metabolism ; Cattle ; Microscopy, Atomic Force ; Alzheimer Disease/metabolism ; Cell Survival/drug effects ; }, abstract = {The development of drugs for Alzheimer's disease, which accounts for over half of all dementia cases, remains challenging. Amyloid β 1-42 (Aβ42) is widely recognized for its deposition in the brains of patients with Alzheimer's disease. Furthermore, Aβ42-induced cell toxicity likely plays a role in disease onset. Molecular species present in the early stages, such as monomers and oligomers, are appropriate therapeutic targets for suppressing amyloid fibril formation and cell toxicity. In this study, we investigated the effects of bovine fibrinogen (bFg) and human fibrinogen (hFg) since these molecules have been known to exhibit chaperone-like activities. Our findings indicate that bFg exerts a strong inhibitory effect on amyloid fibril formation. Dot blot assays, analytical ultracentrifugation (AUC), and atomic force microscopy (AFM) suggest that bFg interacts with both Aβ42 monomers and oligomers. In contrast, human fibrinogen (hFg), which interacts only with oligomers, exhibits a weaker inhibitory effect on amyloid fibril formation. Moreover, bFg significantly rescued cells from Aβ42-induced toxicity, whereas hFg provided only partial protection. These findings underscore the potential of molecules targeting early stage Aβ42 species as promising candidates for Alzheimer's disease treatment.}, } @article {pmid40911101, year = {2025}, author = {Qian, J and Ren, S and Ren, T and Shi, R and Qiao, L and Kang, J}, title = {Astrocyte Autophagy in Neurodegenerative Diseases: Current Progress in Mechanisms and Therapeutics.}, journal = {Neurochemical research}, volume = {50}, number = {5}, pages = {287}, pmid = {40911101}, issn = {1573-6903}, support = {202310472004//the College Students' Innovation and Entrepreneurship Training Program/ ; 82071326//the National Natural Science Foundation of China/ ; 232102310288//Key Technologies R&D Program of Henan Province/ ; 252300421395//Natural Science Foundation of Henan/ ; 505511, XYBSKYZZ202124, 506017//Doctoral Scientific Research Foundation of Xinxiang Medical University/ ; }, mesh = {Humans ; *Autophagy/physiology/drug effects ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy/therapy ; *Astrocytes/metabolism/pathology/drug effects ; Animals ; Oxidative Stress/physiology ; }, abstract = {Astrocytes, the most abundant and functionally diverse glial cell type in the brain, play a crucial role in maintaining cellular homeostasis and promoting neuronal survival. Autophagy is the process of transferring senescent, denatured, or damaged proteins and organelles from cells to lysosomes for degradation. However, recent research on autophagy in the central nervous system has focused on neurons. In this paper, we reviewed the latest findings on astrocyte autophagy and its mechanisms in regulating neurodegenerative disorders. It influences the pathological processes of Alzheimer's disease, Parkinson's disease, Huntington's disease, and other synucleinopathies (including dementia with Lewy bodies and Parkinson's disease dementia) by regulating oxidative stress and inflammatory responses, as well as aberrant protein aggregation and folding. Furthermore, we listed medications that can prevent or treat neurodegenerative disorders by modulating astrocyte autophagy pathways, providing new insights into preventive and therapeutic strategies for neurodegenerative diseases.}, } @article {pmid40910917, year = {2025}, author = {Xin, YX and Xiao, YL}, title = {[Research progress on the relationship between traumatic brain injury and neurogenic lower urinary tract dysfunction].}, journal = {Zhonghua nan ke xue = National journal of andrology}, volume = {31}, number = {7}, pages = {650-653}, pmid = {40910917}, issn = {1009-3591}, mesh = {Humans ; *Brain Injuries, Traumatic/complications ; *Urinary Bladder, Neurogenic/etiology ; Risk Factors ; }, abstract = {Urinary dysfunction caused by central nervous system or peripheral nerve disease represents a significant global medical and social problem. Neurologic abnormalities, including traumatic brain injury (TBI), stroke, Alzheimer's disease, and Parkinson's disease, have been identified as potential risk factors for neurogenic urinary tract dysfunction. The relationship between TBI and neurogenic lower urinary tract dysfunction (NLUTD) will be introduced in this article, with the mechanisms, clinical manifestations, diagnostic methods, and treatment strategies of NLUTD after TBI being evaluated as well, which provides a reference for the diagnosis and treatment.}, } @article {pmid40910390, year = {2025}, author = {Frederiksen, KS and Gramkow, MH and Hasselbalch, SG and Law, I and Waldemar, G}, title = {[Anti-amyloid antibodies for the treatment of early-stage Alzheimer's disease].}, journal = {Ugeskrift for laeger}, volume = {187}, number = {35}, pages = {}, doi = {10.61409/V03250217}, pmid = {40910390}, issn = {1603-6824}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/immunology ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; }, abstract = {Alzheimer's disease is the most common neurodegenerative dementia disorder and is associated with several negative health outcomes. Current treatment consists of symptomatic treatment and supportive measures. However, advances have led to the development of antibodies towards beta-amyloid, which likely plays a pivotal role in the pathophysiology. Lecanemab and donanemab have shown efficacy in the early stages of Alzheimer's disease but are also associated with a risk of cerebral haemorrhages and oedema. The introduction of these antibodies will require adjustment of diagnostic and management pathways as discussed in this review.}, } @article {pmid40910338, year = {2025}, author = {Navarra, AN and Wang, LA and Al-Sahlani, H and Liu, AJ and Doraiswamy, PM}, title = {Severe Persistent Urinary Retention Following Treatment With Intravenous Lecanemab.}, journal = {Pharmacotherapy}, volume = {45}, number = {10}, pages = {702-705}, doi = {10.1002/phar.70060}, pmid = {40910338}, issn = {1875-9114}, mesh = {Humans ; *Urinary Retention/chemically induced ; Male ; Alzheimer Disease/drug therapy ; Aged ; Administration, Intravenous ; }, abstract = {Lecanemab is an amyloid-targeted antibody indicated for treating patients with amyloid-confirmed early Alzheimer's Disease in mild dementia or mild cognitive impairment stages. We report here a case of a subject with early stage of Alzheimer's Disease dementia, amyloid positive, who developed severe acute urinary retention following his first dose of intravenous lecanemab. His urinary retention resolved after a week but recurred following the second intravenous dose 2 weeks later. Lecanemab was discontinued, but the urinary retention has persisted for 8 months indicating possible permanent adverse impact on the bladder. The Naranjo causality probability score was 6. The incidence of urinary retention with intravenous lecanemab is not known but given that elderly patients with dementia may have multiple risks for bladder dysfunction, clinicians should remain vigilant. It is hoped that newer formulations, such as subcutaneous lecanemab, may prove safer in such patients.}, } @article {pmid40910212, year = {2025}, author = {Zhang, YY and Cheng, YY and Guan, W}, title = {Betaine, a Potential Therapeutic Alternative for the Treatment of Depression.}, journal = {Current drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113894501394957250818110931}, pmid = {40910212}, issn = {1873-5592}, abstract = {Depression is a debilitating psychiatric disorder characterized by loss of interest, anhedonia, and social isolation, which is projected to become the leading cause of disability worldwide by 2030. Despite the greater economic and social burden imposed by depression, the precise pathophysiology underlying the development of depression remains elusive. Betaine (N, N, N-trimethylglycine), an amino acid derivative, is widely distributed in various animals and plants and has been shown to have numerous beneficial effects, including antioxidant activities, anti-inflammatory functions, regulation of energy metabolism, and reduction of endoplasmic reticulum stress. It has been used to treat Alcohol-Associated Liver Disease (AALD), type 2 diabetes, cancer, obesity, and Alzheimer's Disease (AD). Interestingly, accumulating evidence has shown that betaine exerts a significant role in alleviating depressive-like behavior in patients and animals resulting from chronic stress. Although the antidepressant effects of betaine have not been compared with traditional antidepressants with insufficient verification, based on the neurobiological mechanisms of depression, it may be a potential alternative medicine for the treatment of depression. This is the first review aiming to provide a comprehensive overview of the remarkable effects of betaine in the pathophysiology of depression. These pieces of evidence are of great importance for deepening our understanding of the antidepressant mechanism of betaine, so as to develop betaine supplements for the supplementary treatment of depression.}, } @article {pmid40910023, year = {2025}, author = {Shahid, SB and Kaikaus, M and Kabir, MH and Yousuf, MA and Azad, AKM and Al-Moisheer, AS and Alotaibi, N and Alyami, SA and Bhuiyan, T and Moni, MA}, title = {Novel deep learning for multi-class classification of Alzheimer's in disability using MRI datasets.}, journal = {Frontiers in bioinformatics}, volume = {5}, number = {}, pages = {1567219}, pmid = {40910023}, issn = {2673-7647}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is one of the most common neurodegenerative disabilities that often leads to memory loss, confusion, difficulty in language and trouble with motor coordination. Although several machine learning (ML) and deep learning (DL) algorithms have been utilized to identify Alzheimer's disease (AD) from MRI scans, precise classification of AD categories remains challenging as neighbouring categories share common features. METHODS: This study proposes transfer learning-based methods for extracting features from MRI scans for multi-class classification of different AD categories. Four transfer learning-based feature extractors, namely, ResNet152V2, VGG16, InceptionV3, and MobileNet have been employed on two publicly available datasets (i.e., ADNI and OASIS) and a Merged dataset combining ADNI and OASIS, each having four categories: Moderate Demented (MoD), Mild Demented (MD), Very Mild Demented (VMD), and Non Demented (ND). RESULTS: Results suggest the Modified ResNet152V2 as the optimal feature extractor among the four transfer learning methods. Next, by utilizing the modified ResNet152V2 as a feature extractor, a Convolutional Neural Network based model, namely, the 'IncepRes', is proposed by fusing the Inception and ResNet architectures for multiclass classification of AD categories. The results indicate that our proposed model achieved a standard accuracy of 96.96%, 98.35% and 97.13% for ADNI, OASIS, and Merged datasets, respectively, outperforming other competing DL structures. DISCUSSION: We hope that our proposed framework may automate the precise classifications of various AD categories, and thereby can offer the prompt management and treatment of cognitive and functional impairments associated with AD.}, } @article {pmid40909873, year = {2025}, author = {Wang, X and Dong, B and Gan, Q and Li, J and Wu, P and Guan, Y and Wang, J}, title = {Unraveling the Vicious Cycle: Oxidative Stress and Neurotoxicity in Neurodegenerative Diseases.}, journal = {FASEB bioAdvances}, volume = {7}, number = {8}, pages = {e70041}, pmid = {40909873}, issn = {2573-9832}, abstract = {Oxidative stress is characterized by an imbalance between the production and elimination of free radicals, where the rate of free radical generation surpasses the rate of their removal. This imbalance can lead to tissue and organ damage, contributing to the pathogenesis of various diseases. The nervous system, due to its high oxygen consumption, is particularly susceptible to oxidative stress. Numerous neurotoxins can induce neurotoxicity through oxidative stress, thereby contributing to the onset of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Furthermore, neurotoxicity can exacerbate oxidative stress by disrupting mitochondrial metabolism and impairing the activity of antioxidant enzymes, thereby intensifying neurotoxic effects. This review examines the mechanisms underlying the interaction between oxidative stress and neurotoxicity and explores strategies to mitigate neurotoxicity by reducing oxidative stress, with the aim of informing future clinical approaches for the treatment of neurodegenerative diseases.}, } @article {pmid40908886, year = {2025}, author = {Singh, T and Yadav, R and Hazra, S}, title = {Atomically Dispersed Ru Catalyst Locked in Knitting Aryl Network Polymers: A Robust Heterogeneous Catalyst for Borrowing Hydrogenation in Aqueous Micelles.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {37}, pages = {52024-52036}, doi = {10.1021/acsami.5c09711}, pmid = {40908886}, issn = {1944-8252}, abstract = {Fabrication of water-stable and atomically dispersed ruthenium catalysts for sustainable borrowing hydrogenation (BH) reactions is a long-standing challenge. Herein, we developed an atomically dispersed Ru catalyst that has been successfully employed for BH reactions in aqueous micelles under mild conditions. The micellar cooperativity with the hydrophobic knitted aryl polymers (KAPs) led to the formation of microconfinements, which act as the confined space for catalysis in water. The catalyst was characterized by using various techniques such as transmission electron microscopy (TEM), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (AC-HAADF-STEM), X-ray photoelectron spectroscopy (XPS), and X-ray absorption spectroscopy (XAS). Confocal laser scanning microscopy (CLSM) and fluorescence lifetime imaging microscopy (FLIM) have been used to understand the role of micelles, reagents, and materials in the generation of confined space in water. The catalyst was found to be recyclable for five cycles without a significant loss of its catalytic activity. We have also demonstrated a 1 g scale reaction for the alkylation of acetophenone and synthesis of Donepezil, a marketed drug for the treatment of Alzheimer's disease, using our method.}, } @article {pmid40908772, year = {2025}, author = {Faysal, M and Zehravi, M and Sutradhar, B and Al Amin, M and Shanmugarajan, TS and Arjun, UVNV and Ethiraj, S and Durairaj, A and Dayalan, G and Ahamad, SK and Rab, SO and Raman, K and Emran, TB}, title = {The Microbiota-Gut-Brain Connection: A New Horizon in Neurological and Neuropsychiatric Disorders.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {9}, pages = {e70593}, pmid = {40908772}, issn = {1755-5949}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Mental Disorders/microbiology/metabolism/therapy ; *Nervous System Diseases/microbiology/metabolism/therapy ; *Brain/metabolism ; Animals ; Dysbiosis ; *Brain-Gut Axis/physiology ; Probiotics ; }, abstract = {INTRODUCTION: The microbiota-gut-brain axis (MGBA), a complex two-way connection between the gut microbiota and the brain, has become a key regulator of neurological and neuropsychiatric disorders. Neurological disorders and gut microbiota dysbiosis are linked to these diseases. Changes in gut microbiota can lead to neurotransmitter imbalances, oxidative stress, and neuroinflammation. Gut dysbiosis may contribute to the development of diseases such as depression, autism, schizophrenia, bipolar disorder, Parkinson's disease, Alzheimer's disease, dementia, multiple sclerosis, epilepsy, anxiety, and autism spectrum disorders through immunological regulation, neuroinflammation, and neurotransmitter metabolism changes. METHOD: This review systematically sourced articles related to microbiota gut brain axis, neurological disorders, neuropsychiatric disorders and clinical studies from major medical databases, including Scopus, PubMed, and Web of Science. RESULTS: This review explores the molecular processes underlying MGBA interactions, including vagus nerve signaling, systemic immunological responses, and metabolites produced by microorganisms. The discussion explores the potential of microbiome-targeted treatments like fecal microbiota transplantation, probiotics, and prebiotics as effective treatment methods. The comprehension of the MGBA can revolutionize neurology and psychiatry, introducing innovative diagnostic and therapeutic approaches. Multiple elements, including diet, metabolism, age, stress, and medications, shape the human gut microbiota, and intestinal imbalances can lead to CNS diseases. The MGBA interacts with gut bacteria, and gut dysbiosis is associated with neurological disorders. CONCLUSIONS: The review demonstrates the correlation between gut microbiota and neurologically associated diseases, highlighting its importance in neurogenesis, mental development, emotions, and behaviors. MGBA, mediated by microbial metabolites, affects brain function and neuroinflammation. Interventions like fetal microbiota transplantation, probiotics, and prebiotics can improve microbial balance, but more clinical research is needed.}, } @article {pmid40908698, year = {2025}, author = {Singh, A and Maheshwari, S and Ansari, VA and Verma, A and Ansari, TM and Akhtar, J and Ahsan, F and Vishwakarma, VK and Wasim, R}, title = {Dendrimers: Advancing Therapeutic Strategies for Dementia.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098343913250818112618}, pmid = {40908698}, issn = {1874-6128}, abstract = {Dementia, characterized by a progressive decline in cognitive function, poses a significant challenge to global healthcare systems, with current therapeutic approaches offering limited efficacy. The development of nanotechnology-based drug delivery systems has introduced promising avenues for enhancing the treatment of neurodegenerative disorders such as Alzheimer's disease. Dendrimers, with their highly branched, nanoscale structure, provide an innovative platform for targeted drug delivery to the brain. Dendrimers serve as nanoscale drug carriers that facilitate controlled drug release, enhance bioavailability, and improve penetration across the blood-brain barrier (BBB), leading to superior therapeutic efficacy in neurodegenerative disorders. In particular, dendrimers can encapsulate both hydrophilic and hydrophobic drugs, increasing their stability and minimizing systemic side effects. This review explores the unique properties of dendrimers, focusing on their potential as drug delivery vehicles in dementia treatment. We also highlight advancements in the design and application of dendrimer-based therapeutics, emphasizing their role in targeting key pathological mechanisms underlying dementia. Through these approaches, dendrimers represent a promising strategy for developing more effective and personalized treatment modalities for patients suffering from cognitive impairment and dementia.}, } @article {pmid40908696, year = {2025}, author = {Paul, S and Tiwari, P and Dubey, S}, title = {Precision Enzyme: Targeted Drug Discovery in Neurodegenerative Disorders.}, journal = {Protein and peptide letters}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298665391103250825102319}, pmid = {40908696}, issn = {1875-5305}, abstract = {INTRODUCTION: Neurodegenerative disorders such as Alzheimer's, Parkinson's, and ALS are characterized by progressive neuronal dysfunction with limited therapeutic options. Recent advances in molecular biology and drug development have highlighted the therapeutic promise of precision enzyme targeting, offering novel strategies for disease modulation and symptom management. METHODS: A comprehensive literature review spanning recent/current was conducted using PubMed, Scopus, and ScienceDirect. Studies focusing on enzyme-based targets, high-throughput screening, and molecular docking in neurodegeneration were included. Thematic synthesis was employed to categorize findings based on enzyme class, disease relevance, and therapeutic outcomes. RESULTS: Key enzyme families such as kinases, proteases, and oxidoreductases were identified as pivotal modulators in disease progression. Emerging enzyme-targeted compounds demonstrated enhanced bioavailability, blood-brain barrier permeability, and disease-specific efficacy. Novel screening platforms and computational modeling enabled the precise selection of inhibitors, significantly improving the therapeutic index and reducing off-target effects. DISCUSSION: Targeting enzymes implicated in neuroinflammation, oxidative stress, and protein misfolding has shown disease-modifying potential. Integrating precision drug discovery tools, such as AI-assisted modeling and enzyme kinetics, supports rational drug design. However, translational challenges persist due to variability in enzyme expression and disease heterogeneity. CONCLUSION: Future research should focus on refining enzyme inhibitors and integrating biomarkers to facilitate personalized treatment strategies for neurodegenerative disorders. As the understanding of enzymatic roles in neurodegeneration deepens, precision enzyme-targeted drug discovery holds significant promise in transforming neurotherapeutic approaches.}, } @article {pmid40908524, year = {2025}, author = {Oba, GMJ and Sahu, R and Shah, K and Paliwal, D and Kumar Sah, A and Thakur, A}, title = {Current Developments in the Pharmacological Activities and Synthesis of Carbazole Derivatives.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575407122250822095143}, pmid = {40908524}, issn = {1875-5607}, abstract = {The growing prevalence of multidrug resistance and its detrimental effects pose a significant threat to public health, which is one reason for the current interest in the introduction of novel agents. To combat this adverse effect and drug resistance, numerous drugs have been developed over time, and their safety is still being evaluated; derivatives or medications based on the carbazole moiety are one of the key contributors. Therefore, this review explores carbazole-based derivatives as possible drugs to treat Alzheimer's, diabetes, inflammation, cancer, and many more, along with their synthetic schemes, SARs, and activity. Some of the carbazole-based drugs available in the market and under clinical trials are also tabulated. By integrating this insight, describe how these compounds are being reinvented as targeted therapeutic agents. This comprehensive analysis is designed to guide researchers in developing next-generation drugs to address various challenges and leverage the unique pharmacological properties of carbazole-derived drugs.}, } @article {pmid40908201, year = {2025}, author = {Jung, JH and Kong, N and Lee, S and , }, title = {Pulse pressure as a predictor of Alzheimer's disease biomarkers and cognitive decline: The moderating role of APOE ε4.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {10}, pages = {100363}, pmid = {40908201}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/genetics/physiopathology/diagnosis/diagnostic imaging ; *Apolipoprotein E4/genetics ; Male ; *Cognitive Dysfunction/genetics/physiopathology/diagnosis ; Female ; Biomarkers/metabolism ; Aged ; Amyloid beta-Peptides/metabolism ; *Blood Pressure/physiology ; tau Proteins/metabolism ; Prospective Studies ; Positron-Emission Tomography ; Aged, 80 and over ; Longitudinal Studies ; }, abstract = {BACKGROUND: Elevated pulse pressure (PP), indicative of arterial stiffness, has been implicated in cognitive impairment and Alzheimer's disease (AD) pathology. However, its role in preclinical AD and interactions with genetic risk factors like apolipoprotein E ε4 (APOE4) remain unclear. OBJECTIVES: To investigate the association between baseline PP and AD biomarkers (amyloid-beta (Aβ) and tau) and cognitive decline, and to determine whether APOE4 carrier status moderates these relationships. DESIGN: Prospective cohort study and secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) randomized clinical trial SETTING: Multicenter observational cohort and randomized clinical trial conducted at 67 sites across the United States, Canada, Australia, and Japan. PARTICIPANTS: This study included 1690 cognitively unimpaired older adults from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Participants underwent baseline PP assessment, Aβ and tau PET imaging, and cognitive testing with longitudinal follow-up over 240 weeks. MEASUREMENTS: Blood pressure was measured at baseline, with PP calculated as the difference between systolic and diastolic pressures. AD pathologies were assessed through Aβ PET imaging using 18F-Florbetapir, and regional tau deposition in inferior temporal and meta-temporal regions using 18F-Flortaucipir PET imaging. Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite (PACC). RESULTS: Higher baseline PP was significantly associated with increased Aβ (β = 0.078; p = 0.001), inferior temporal tau (β = 0.110; p = 0.032), and meta-temporal tau deposition (β = 0.116; p = 0.022). In longitudinal analyses, elevated PP predicted greater decline in PACC scores (β = -0.020; p < 0.001). APOE4 status moderated these associations, with significant effects of PP on tau deposition and cognitive decline observed exclusively among APOE4 carriers. Mediation analysis indicated that tau deposition significantly mediated the association between PP and cognitive decline (indirect effect β = -0.068; 95 % CI [-0.126, -0.011]). CONCLUSIONS: Elevated PP is associated with increased AD biomarker burden and accelerated cognitive decline in cognitively unimpaired older adults, particularly among APOE4 carriers. Our study suggests that arterial stiffness may contribute to AD pathogenesis and progression via tau pathology. These results highlight the potential of vascular health management as an early intervention target for AD prevention, especially in genetically at-risk populations.}, } @article {pmid40907816, year = {2025}, author = {Rai, S and Nair, A and Saleem, Z and Ray, SK and Kanwar, JR and Mukherjee, S}, title = {Advancing nanotheranostics for neuro-immunological disorders: current status and future prospects.}, journal = {Neuroscience}, volume = {585}, number = {}, pages = {233-248}, doi = {10.1016/j.neuroscience.2025.08.051}, pmid = {40907816}, issn = {1873-7544}, mesh = {Humans ; Animals ; *Theranostic Nanomedicine/methods/trends ; *Nervous System Diseases/drug therapy/immunology/therapy ; *Immune System Diseases/drug therapy/therapy ; *Neuroinflammatory Diseases/drug therapy ; }, abstract = {Neuroimmunological disorders involve complex interactions between the nervous and immune systems, leading to various severe neurological conditions such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. These disorders are characterized by immune-mediated damage or inflammation within nervous tissue, resulting in cognitive deficits, movement issues, sensory impairments, and other neurological problems. They can affect people of all ages, but incidence increases significantly with advancing age, making them a growing public health concern. As the global population ages, the prevalence of neuroimmunological diseases is expected to rise sharply. Projections indicate that by 2050, approximately 150 million individuals worldwide may suffer from dementia-related disorders alone, with an economic burden reaching around $10 trillion. Current therapies mainly focus on symptom management, aiming to slow disease progression and improve quality of life. Emerging therapeutic strategies show promise, particularly nanomedicine, which employs nanoscale materials to deliver drugs precisely to affected tissues. This targeted approach reduces side effects and increases treatment effectiveness. Additionally, natural products and plant-based compounds are gaining attention for their neuroprotective effects, as they can modulate pathways involved in neuronal survival, repair, and immune regulation. Future research aims to deepen understanding of the molecular and genetic mechanisms underlying these disorders through advanced experimental models and technologies. These insights will facilitate the development of innovative therapies targeting neuroinflammation and immune dysregulation, with the goal of preventing disease progression or even achieving cures. Continued progress in neuroimmunology offers hope for improved treatment outcomes, reduced disease burden, and transformative advances in neurological healthcare worldwide.}, } @article {pmid40907613, year = {2025}, author = {Li, K and Qiu, X and Yang, Q and Wang, Z}, title = {Histone modifications: Key players in Alzheimer's disease.}, journal = {Mechanisms of ageing and development}, volume = {228}, number = {}, pages = {112102}, doi = {10.1016/j.mad.2025.112102}, pmid = {40907613}, issn = {1872-6216}, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Histones/metabolism ; Animals ; tau Proteins/metabolism ; *Histone Code ; Amyloid beta-Peptides/metabolism ; Acetylation ; }, abstract = {Alzheimer's disease (AD) is one of the most prevalent diseases in the older population. AD causes progressive cognitive and behavioral impairment, but current treatments are unable to slow or prevent the progression of this disease. Thus, identification of novel biomarkers and therapeutic targets is urgently needed. We previously described the roles of histone acetylation, crotonylation, and lactylation in the accumulation of amyloid beta and hyperphosphorylation of Tau protein, which are the hallmarks of AD. In this review, we summarize and discuss the current knowledge of the role of histone modifications in AD, with a particular emphasis on its association with characterized pathological alterations, including amyloid plaques, Tau tangles, neuroinflammation, and synaptic dysfunction. This review provides novel insights into the central role of histone modifications in AD pathogenesis and evaluates histone-modifying enzymes as potential therapeutic targets for the treatment of AD.}, } @article {pmid40907541, year = {2025}, author = {Wu, N and Wu, Z and Wang, P and Zhang, C and Wu, C and Huo, X and Zhang, G}, title = {Three-dimensional magnetic field measurement of transcranial magnetic stimulation using a printed circuit board-based miniature orthogonal coil array.}, journal = {Biomedical physics & engineering express}, volume = {11}, number = {5}, pages = {}, doi = {10.1088/2057-1976/ae0340}, pmid = {40907541}, issn = {2057-1976}, mesh = {*Transcranial Magnetic Stimulation/instrumentation ; Equipment Design ; Humans ; *Magnetic Fields ; Miniaturization ; Printing, Three-Dimensional ; }, abstract = {Objective. Transcranial magnetic stimulation (TMS) is a promising neuromodulation therapy for treating diseases such as depression and Alzheimer's disease. However, its efficacy depends on precise magnetic field targeting. Current measurement methods face a trade-off between accuracy and complexity. Their intricate designs limit miniaturization, and they are typically confined to one-dimensional detection.Approach. This study proposes a miniaturized printed circuit board (PCB)-integrated coil array (11.10 mm × 9.10 mm × 1.60 mm) as a novel solution to replace complex probe systems for the synchronous measurement of three-dimensional magnetic field components (Bx,By,Bz) generated by a figure-8 coil.Results. Using this approach, we simulated and measured the magnetic field distribution produced by a self-made figure-8 coil, demonstrating consistency with relative errors below 5%, 10%, and 15% along the line of interest (LOI) in thex,y,zdirections, respectively. Variations in magnetic flux density from a commercial figure-8 coil were also measured at two specific spatial positions, showing consistent trends.Significance. The presented measurement probe enables feasible characterization of TMS-induced magnetic flux, with measured values aligning closely with simulated results. By integrating orthogonal coils into a compact PCB, it overcomes the traditional accuracy-complexity trade-off. Clinically, it assists in precise coil positioning during treatment, reducing off-target side effects via magnetic field validation. Technologically, its compact and cost-effective design accelerates testing of novel TMS coils, advancing the development of efficient neuromodulation devices.}, } @article {pmid40906916, year = {2025}, author = {Kakoty, V and Kang, JH and Lee, OH and Oh, DH and Ko, YT}, title = {Grueneberg Ganglion: An Unexplored Site for Intranasal Drug Delivery in Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3425-3437}, doi = {10.1021/acschemneuro.5c00376}, pmid = {40906916}, issn = {1948-7193}, mesh = {Animals ; Administration, Intranasal/methods ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Delivery Systems/methods ; Humans ; Mice ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {Neurological disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis pose significant challenges for treatment. Reasons for the difficulty in finding cures for these conditions include complications in early diagnosis, progressive and irreversible neuronal damage, and the presence of the blood-brain barrier (BBB), which hinders the delivery of drugs to the affected areas of the brain. Intranasal (INL) drug administration has increasingly gained popularity among researchers for targeting neurological conditions, because of its ability to bypass the BBB. However, chronic INL administration leads to nasal mucosa irritation. Additionally, rapid mucociliary clearance, a lack of targeted drug delivery, increased enzymatic degradation, and tight junctions that obstruct drug transport limit the clinical applicability of the INL route. To overcome these challenges, a unique region in the rodent nose, known as the Grueneberg Ganglion (GG), can be considered to be a novel site for INL drug administration. GG is a small structure housed under the snout cartilage of the nasal septum, approximately 1.5 mm from the nasal opening in mice. It is directly connected to the main olfactory bulb through axons. This Perspective aims to expand knowledge on why GG may be a viable option for INL delivery to combat neurological conditions. For better understanding, we have explained the INL administration in GG, using Alzheimer's Disease and INL insulin therapy as a role model for the current review.}, } @article {pmid40904621, year = {2025}, author = {Castilhos, RM and Formoso, CR and Borelli, WV and Teixeira, EC and Dousseau, GC and Chaves, MLF and Brucki, SMD}, title = {Anticholinergic burden and polypharmacy in patients referred from primary care to tertiary dementia centers in Brazil.}, journal = {Dementia & neuropsychologia}, volume = {19}, number = {}, pages = {e20240246}, pmid = {40904621}, issn = {1980-5764}, abstract = {UNLABELLED: Anticholinergic burden (ACB) and polypharmacy are poorly studied in the context of primary care in Brazil. OBJECTIVE: To evaluate the ACB and polypharmacy of individuals with suspected dementia referred from primary care to tertiary dementia outpatient clinics in Brazil. METHODS: We performed a cross-sectional study in two tertiary dementia clinics. We included individuals with suspected dementia referred from primary care. Sociodemographic variables, number of drugs, ACB score, disease duration, Mini Mental State Examination (MMSE) were collected in the first evaluation. Final diagnosis received was also collected. RESULTS: A total of 921 individuals were included, with a median (IQR) age of 72 [64-78] years, 57.8% (532) women, 4 [2-7] years of formal education and 15 [10-20] points in MMSE. Most patients had a final diagnosis of dementia (66%, 616) and Alzheimer's disease (21.4%, 197), psychiatric disorders (16%, 147) and multifactorial dementia (14.8%, 136) were the most common diagnoses. Most individuals (68.1%, 627) were using at least one medication with anticholinergic effect, and in 44.6% (411) there was polypharmacy. ACB total score correlated with MMSE (rho=-0.13) and with total number of medications (rho=0.52). In multivariate regression, ACB score ≥1 was associated with MMSE and polypharmacy. CONCLUSION: Most individuals referred from primary care in Brazil were using at least one medication with anticholinergic effect and this was correlated with cognitive severity. Educational measures for primary care physicians, focusing on the management of pharmacological treatment, are essential to reduce the anticholinergic load in this context.}, } @article {pmid40904419, year = {2025}, author = {Mullins, GR and Ardayfio, P and Gueorguieva, I and Anglin, G and Bailey, J and Chua, L and Zimmer, JA and Evans, CD and Nery, ESM and Wang, H and Khanna, R and Brooks, DA and Sims, JR}, title = {Donanemab immunogenicity in participants with early symptomatic Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70149}, pmid = {40904419}, issn = {2352-8737}, abstract = {INTRODUCTION: Donanemab is an immunoglobulin G1 antibody that targets an N-terminal truncated form of amyloid beta present in mature plaques. Treatment-emergent (TE) anti-drug antibodies (ADAs) were quantified in donanemab-treated participants from two pivotal clinical trials, and effects of TE ADAs on donanemab pharmacokinetics, efficacy, and safety were assessed. METHODS: Data were pooled from the phase 2 TRAILBLAZER-ALZ (NCT03367403) and phase 3 TRAILBLAZER-ALZ 2 trials (NCT04437511). Eligible participants were randomized 1:1 to donanemab (700 mg for the first three doses, 1400 mg thereafter) or placebo intravenously every 4 weeks up to 72 weeks. TE ADA-evaluable participants had a non-missing baseline ADA result and ≥ 1 non-missing post-baseline ADA result. TE ADA incidence and effect of titer on pharmacokinetics, amyloid plaque reduction, clinical efficacy (measured by change from baseline of integrated Alzheimer's Disease Rating Scale [iADRS] score and Clinical Dementia Rating Scale Sum of Boxes [CDR-SB]), and safety were assessed. RESULTS: Of 922 TE ADA-evaluable donanemab-treated participants, 56 (6.1%) had ADAs detected at baseline, and 812 (88.1%) were TE ADA positive. Donanemab clearance increased linearly with logarithm of ADA titer; however, titer did not affect maximum donanemab concentration. Amyloid plaque level was significantly reduced with donanemab versus placebo, irrespective of titer (P < 0.001 for all). No association was found between ADA presence or titer and donanemab efficacy by iADRS or CDR-SB. Eighty-four of 984 (8.5%) donanemab-treated participants and 4 of 999 (0.4%) placebo-treated participants reported infusion-related reactions (IRRs). All donanemab-treated participants reporting immediate IRRs developed ADAs at some point during the study; however, 90.5% of TE ADA-positive participants did not experience IRRs. DISCUSSION: Most participants were TE ADA positive. TE ADAs increased donanemab clearance but did not have clinically meaningful impact on plaque reduction or efficacy. While all participants reporting IRRs developed ADAs at some point during the study, the majority of participants with ADAs did not experience IRRs. HIGHLIGHTS: In pivotal trials, most donanemab-treated participants were treatment-emergent anti-drug antibody (TE ADA) positive.TE ADAs increased donanemab clearance but did not impact plaque reduction/efficacy.All participants reporting infusion-related reactions (IRRs) developed ADAs at some point during the study.However, the majority of participants with ADAs did not experience IRRs.}, } @article {pmid40904199, year = {2025}, author = {Isik, S and Osman, S and Yeman-Kiyak, B and Shamshir, SRM and Sanchez, NME}, title = {Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {9}, pages = {e70577}, pmid = {40904199}, issn = {1755-5949}, mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods/trends ; *Clinical Trials as Topic/methods ; }, abstract = {AIM: This review provides a systematic evaluation of 94 stem cell clinical trials to treat neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. METHODS: Data were collected from using relevant search terms, focusing exclusively on stem cell therapy. Of the 8000+ participants in these trials, nearly 70% were enrolled in AD-related studies. Only three Phase 3 studies were conducted, and most trials were in the early phases (Phases 1 and 2). Mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, and embryonic stem cells are used the most to treat neurodegenerative diseases. This review also explores the emerging fields of preclinical and clinical investigations of stem cell-derived exosome-based therapies for neurodegenerative diseases. RESULTS: Exosomes can cross the blood-brain barrier to deliver therapeutic molecules directly to the brain, offering a less invasive alternative to stem cell transplantation. Mesenchymal stem cell-derived exosomes, in particular, have demonstrated significant potential in preclinical models by reducing neuroinflammation, oxidative stress, and promoting neuronal regeneration. Additionally, recent advances in exosome engineering, including surface modifications, therapeutic agent loading, and transgenic modifications, have improved targeting, stability, blood-brain barrier delivery, and neural cell interactions, enabling targeted and effective treatment. Exosome-based therapies are in the preliminary phases of clinical investigation, with only three clinical trials. CONCLUSION: Given the increasing interest in exosome therapy, clinical investigations are expected to increase. This growth will be driven by ongoing advancements in exosome technology, a deeper understanding of their therapeutic potential, and escalating demand for innovative treatment strategies for neurodegenerative diseases.}, } @article {pmid40904091, year = {2025}, author = {Hu, WQ and Gao, HY and Yang, L and Wang, YX and Cheng, HJ and Yang, SY and Zhang, MY and Sun, J}, title = {[Characterization of hippocampal components of Danzhi Xiaoyao Formula based on HPLC-Q-TOF-MS/MS and network pharmacology and assessment of its therapeutic potential for nervous system diseases].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {14}, pages = {4053-4062}, doi = {10.19540/j.cnki.cjcmm.20250426.201}, pmid = {40904091}, issn = {1001-5302}, mesh = {*Drugs, Chinese Herbal/chemistry/administration & dosage ; Animals ; Rats ; *Hippocampus/drug effects/chemistry/metabolism ; Network Pharmacology ; Chromatography, High Pressure Liquid ; Tandem Mass Spectrometry ; Rats, Sprague-Dawley ; Male ; *Nervous System Diseases/drug therapy/metabolism/genetics ; Humans ; Signal Transduction/drug effects ; }, abstract = {In this study, the pharmacodynamic components and potential pharmacological functions of Danzhi Xiaoyao Formula in treating nervous system diseases were investigated by hippocampal component characterization and network pharmacology. After rats were administrated with Danzhi Xiaoyao Formula by gavage, high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(HPLC-Q-TOF-MS/MS) was employed to explore the components in the hippocampus of rats. Fifty-seven components were identified in the hippocampus of rats by comparing the extract of Danzhi Xiaoyao Formula, herbal components in the hippocampus after administration, and blank samples. KEGG and GO analyses predicted 74 core targets including GSK3B, MAPK1, AKT, IL6. These targets were involved in PI3K/Akt, NF-κB, MAPK, JAK/STAT, Wnt, and other signaling pathways. The results indicated that Danzhi Xiaoyao Formula may ameliorate other nervous system diseases enriched in DO, such as neurodegenerative diseases, cerebrovascular diseases, and mental and emotional disorders by mediating target pathways, inhibiting inflammation, reducing neuronal damage, and alleviating hippocampal atrophy. The relevant activities exhibited by this formula in nervous system diseases such as Alzheimer's disease, Parkinson's disease, and diabetic neuropathy have extremely high development value and are worthy of further in-depth research. This study provides a theoretical basis and practical guidance for expanding the application of Danzhi Xiaoyao Formula in the treatment of nervous system diseases.}, } @article {pmid40904084, year = {2025}, author = {Pu, YZ and Chen, HF and Wang, XY and Su, C}, title = {[Caffeoylquinic acids from Erigeron breviscapus ameliorates cognitive impairment and mitochondrial dysfunction in AD by activating PINK1/Parkin-mediated mitophagy].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {14}, pages = {3969-3979}, doi = {10.19540/j.cnki.cjcmm.20250219.402}, pmid = {40904084}, issn = {1001-5302}, mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/metabolism/physiopathology/psychology ; *Mitophagy/drug effects ; *Mitochondria/drug effects/metabolism/genetics ; Caenorhabditis elegans/drug effects/genetics/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Cognitive Dysfunction/drug therapy/metabolism/genetics/physiopathology ; Rats ; *Protein Kinases/metabolism/genetics ; Humans ; Male ; Disease Models, Animal ; Caenorhabditis elegans Proteins/metabolism/genetics ; *Drugs, Chinese Herbal/administration & dosage ; }, abstract = {This study aimed to investigate the effects of caffeoylquinic acids from Erigeron breviscapus(EBCQA) on cognitive impairment and mitochondrial dysfunction in Alzheimer's disease(AD), and to explore its underlying mechanisms. The impacts of EBCQA on paralysis, β-amyloid(Aβ) oligomerization, and mRNA expression of mitophagy-related genes [PTEN-induced putative kinase 1(PINK1) homolog-encoding gene pink-1, Parkin homolog-encoding gene pdr-1, Bcl-2 interacting coiled-coil protein 1(Beclin 1) homolog-encoding gene bec-1, microtubule-associated protein 1 light chain 3(LC3) homolog-encoding gene lgg-1, autophagic adapter protein 62(p62) homolog-encoding gene sqst-1] were examined in the AD Caenorhabditis elegans CL4176 model, along with mitochondrial functions including adenosine triphosphate(ATP) content, enzyme activities of mitochondrial respiratory chain complexes Ⅰ,Ⅲ, and Ⅳ, and mitochondrial membrane potential. Additionally, the effects of EBCQA on the green fluorescent protein(GFP)/red fluorescent protein from Discosoma sp.(DsRed) ratio, the expression of phosphatidylethanolamine-modified and GFP-labeled LGG-1(PE-GFP::LGG-1)/GFP-labeled LGG-1(GFP::LGG-1), and GFP-labeled SQST-1(GFP::SQST-1) proteins were investigated in transgenic C. elegans strains. The effect of EBCQA on paralysis was further evaluated after RNA interference(RNAi)-mediated suppression of the pink-1 and pdr-1 genes in CL4176 strain. An AD rat model was established through intraperitoneal injection of D-galactose and intragastric administration of aluminum trichloride. The effects of β-nicotinamide mononucleotide(NMN) and EBCQA on learning and memory ability, neuronal morphology, mitophagy occurrence, mitophagy-related protein expression(PINK1, Parkin, Beclin 1, LC3-Ⅱ/LC3-Ⅰ, p62), and mitochondrial functions(ATP content; enzyme activities of mitochondrial respiratory chain complexes Ⅰ, Ⅲ, and Ⅳ; mitochondrial membrane potential) were investigated in this AD rat model. The results showed that EBCQA delayed paralysis onset in the CL4176 strain, reduced Aβ oligomer formation, and upregulated the mRNA expression levels of lgg-1, bec-1, pink-1, and pdr-1, while downregulating sqst-1 mRNA expression. EBCQA also enhanced ATP content, mitochondrial membrane potential, and the activities of mitochondrial respiratory chain complexes Ⅰ, Ⅲ, and Ⅳ. Furthermore, EBCQA improved the PE-GFP::LGG-1/GFP::LGG-1 ratio, reduced GFP::SQST-1 expression, and decreased the GFP/DsRed ratio. Notably, the ability of EBCQA to delay paralysis was significantly reduced following RNAi-mediated suppression of pink-1 and pdr-1 in CL4176 strain. In AD rats, the administration of NMN or EBCQA significantly improved learning and memory, restored neuronal morphology in the hippocampus, increased autophagosome numbers, and upregulated the expression of PINK1, Parkin, Beclin 1, and the LC3-Ⅱ/LC3-Ⅰ ratio, while reducing p62 expression. Additionally, the treatment with NMN or EBCQA both elevated ATP content, mitochondrial respiratory chain complex Ⅰ, Ⅲ, and Ⅳ activities, and mitochondrial membrane potential in the hippocampus. The above findings indicate that EBCQA improves cognitive impairment and mitochondrial dysfunction in AD, possibly through activation of PINK1/Parkin-mediated mitophagy.}, } @article {pmid40903965, year = {2025}, author = {Parikh, A and Cholavaram, A and Chitti Babu, AK and Deepankumar, K and Vijayan, M}, title = {Role of voltage-dependent anion channel 1 in neurodegeneration: Mechanisms, implications, and therapeutic potential.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00368}, pmid = {40903965}, issn = {1673-5374}, abstract = {Voltage-dependent anion channel 1 is an integral outer membrane protein of the mitochondria that governs apoptosis, enables metabolite exchange, and influences mitochondrial activity. In neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease, oxidative stress, neuroinflammation, and mitochondrial dysfunction are frequent features. Voltage-dependent anion channel 1 is a key regulator of these processes. This review described the structure, membrane topology, and physiological function of voltage-dependent anion channel 1 in neurons and glial cells. We emphasize how it affects mitophagy, oxidative damage, and changes in mitochondrial permeability. Special attention is focused on how voltage-dependent anion channel 1 interacts with pathogenic proteins that damage mitochondrial integrity and cause neurotoxicity, including mutant huntingtin, phosphorylated tau, α-synuclein, amyloid-beta, and TAR DNA-binding protein 43. Furthermore, the paper examines the function of voltage-dependent anion channel 1 in astrocytic dysfunction and microglial activation, highlighting its impact on neuroinflammation. In a nutshell, we assess treatment strategies that target voltage-dependent anion channel 1, such as VBIT-4, a selective inhibitor of voltage-dependent anion channel 1 oligomerization, and newer methods, including structure-based drug design and CRISPR/Cas9 regulation. Improved knowledge of the hinter voltage-dependent anion channel 1 of the molecular mechanism may allow for new therapeutic approaches in neurodegenerative diseases.}, } @article {pmid40903964, year = {2025}, author = {Wu, S and Guo, T and Zheng, X and Gu, C and Hu, Y and Gu, X and Zhou, X}, title = {Integrated machine learning-based RNA sequencing and single-cell analysis reveal RNA methylation regulation patterns in the immune microenvironment of Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01650}, pmid = {40903964}, issn = {1673-5374}, abstract = {Alterations in RNA methylation may affect the initiation and development of Alzheimer's disease. However, the exact nature of the relationship between RNA methylation and Alzheimer's disease remains unclear. In this study, RNA methylation levels were analyzed by bulk transcriptomic and single-cell RNA sequencing. The expression levels of RNA methylation regulators were confirmed using molecular biology techniques. Co-expression network analysis was used to identify relevant long non-coding RNAs. Molecular subtypes related to RNA methylation were classified, and variations in clinical characteristics, biological behavior, and immune signatures between subtypes were assessed. Machine learning approaches were applied to identify methylation-associated long noncoding RNAs, which were used to construct a risk model and nomogram for Alzheimer's disease. Potential therapeutic agents for different risk groups were predicted, and in vitro experiments were conducted to identify key RNA methylation events. Single-cell analysis demonstrated enhanced RNA methylation in patients with Alzheimer's disease, particularly within T cells, B cells, and NK cells. Quantitative reverse transcription-polymerase chain reaction and western blot confirmed alterations in RNA methylation regulators in neurons treated with amyloid-β oligomers in vitro . This evidence supported the classification of patients with Alzheimer's disease into heterogeneous subtypes. Specifically, subtype 1 was identified as the immune-active subtype, while subtype 2 was characterized by a metabolic phenotype. Machine learning algorithms identified five significant methylation-associated long non-coding RNAs -LINC01007, MAP4K3-DT, MIR302CHG, VAC14-AS1, and TGFB2-OT1-that accurately predict clinical outcomes for patients with Alzheimer's disease. These patients were classified into low- and high-risk categories; the latter group displayed higher immune infiltration, upregulated immune regulatory gene expression, and elevated immune scores and responded better to treatment with arachidonic-trifluoroethane. These findings suggest that dysregulated RNA methylation alters the immune microenvironment in Alzheimer's disease and is closely associated with its progression. This phenomenon provides novel insights into potential therapeutic strategies for Alzheimer's disease that target RNA methylation.}, } @article {pmid40903963, year = {2025}, author = {Fan, F and Zhao, N and Guo, M}, title = {Lymphatic-venous anastomosis: Cracking the code of Alzheimer's disease treatment?.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00540}, pmid = {40903963}, issn = {1673-5374}, } @article {pmid40903956, year = {2025}, author = {Chen, Y and Yin, P and Chen, Q and Zhang, Y and Tang, Y and Jin, W and Yu, L}, title = {Neurodegenerative diseases and immune system: From pathogenic mechanism to therapy.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00274}, pmid = {40903956}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are a class of disorders with the gradual loss of the central nervous system and peripheral nervous system. Neurodegenerative diseases manifest primarily as cognitive and behavioral disorders that adversely affect the lives of millions of people worldwide. Therefore, it is necessary to elucidate the mechanism of neurodegenerative diseases further and find effective new therapies. In recent years, increasing evidence has shown that the immune system plays a significant role in the pathophysiology of neurodegenerative diseases and regulates this process. The central and peripheral immune systems exert different roles in the disease progression. The development of neurodegenerative diseases is influenced by interactions between them. This review focuses on how the immune system, including microglia mediated nucleotide-binding oligomerization domainlike receptor protein 3 inflammation activation and T cell-mediated neuroinflammation, interactions with neurodegenerative diseases by modulating protein aggregation and blood-brain barrier permeability. Besides, we gave particular attention to glial cell-centered multicellular interactions and the inflammatory signaling pathway. Insight into the immune system's functions and cellular interactions is essential for progressing disease research. In addition, the functions and mechanisms of these immune cells also suggest new ideas and targets for treatment. Therefore, this review summarizes some of the existing treatment strategies for amyloid-beta, tau, neuroinflammation, α-synuclein, associated microbiota, immune modulation, and neural injury repair. In addition, this review summarizes and compares animal models of different common neurodegenerative diseases and clinical research progress. In view of the current research status, new research directions and suggestions are proposed.}, } @article {pmid40903950, year = {2025}, author = {Liu, Y and Tang, T and Cai, H and Liu, Z}, title = {Bidirectional communication between the gut microbiota and the central nervous system.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00434}, pmid = {40903950}, issn = {1673-5374}, abstract = {In recent years, an increasing number of researchers have become interested in the bidirectional communication between the gut microbiota and the central nervous system. This communication occurs through the microbiota-gut-brain axis. As people age, the composition of the gut microbiota undergoes considerable changes, which are now known to play an important role in the development of many neurodegenerative diseases. This review aims to investigate the complex bidirectional signaling pathways between the gut and the brain. It summarizes the latest research findings on how the gut microbiota and its metabolites play critical roles in regulating inflammation, maintaining gut health, and influencing the development of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The review also analyzes the current clinical applications of gut microbiota-based treatments for neurological disorders, including fecal microbiota transplantation, probiotics, and prebiotics. Many studies show that the gut microbiota affects the brain in several ways. For example, it can produce substances such as short-chain fatty acids and activate inflammatory pathways. Studies involving animals and laboratory models have demonstrated that adjusting the gut microbiota can help improve behavior and reduce neurological problems. Recent metagenomic and metabolomics studies have shown that the microbiota plays a crucial role in maintaining the organism's health. Microorganisms primarily colonize the gut and are involved in host nutrient metabolism, maintaining the structural integrity of the intestine, preserving the intestinal mucosal barrier, and modulating the immune system. The gut microbiota communicates with the brain through a bidirectional microbiota-gut-brain axis. The composition of the gut flora changes considerably with age, and ecological dysregulation has been recognized as one of the twelve most recent hallmarks of aging. Recent studies have linked these changes to a variety of age-related neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, and Huntington's disease. Specifically, the gut microbiota influences the brain through the production of key metabolites such as short-chain fatty acids and the activation of inflammatory and other relevant signaling pathways. In preclinical studies, targeted modulation of the gut microbiota, through methods such as fecal microbiota transplantation, probiotics, and prebiotics, has demonstrated potential in improving host behavioral outcomes. Therefore, gut microbiotabased treatments offer new hope for the treatment of nervous system diseases. However, due to the complexity of the gut microbiota and the potential adverse reactions associated with these therapies, researchers need to carefully assess their safety and efficacy before widespread clinical application.}, } @article {pmid40903895, year = {2026}, author = {Higgins, A and Tewolde, S and Page, SD and Rubenstein, E}, title = {The Occurrence of Obstructive Sleep Apnea and Its Association With Alzheimer Dementia in Medicaid-Enrolled Adults With Down Syndrome, 2011-2019.}, journal = {American journal of medical genetics. Part A}, volume = {200}, number = {1}, pages = {129-136}, pmid = {40903895}, issn = {1552-4833}, support = {R01 AG073179/AG/NIA NIH HHS/United States ; R01AG073179/AG/NIA NIH HHS/United States ; R01AG073179/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Down Syndrome/complications/epidemiology ; *Sleep Apnea, Obstructive/epidemiology/complications ; *Alzheimer Disease/epidemiology/complications/etiology ; Male ; Female ; United States/epidemiology ; Adult ; Medicaid ; Middle Aged ; Prevalence ; Aged ; Risk Factors ; }, abstract = {Down syndrome is a condition caused by trisomy of chromosome 21 and is the most common genetic cause of intellectual disability. Due to distinct body and facial morphology, people with Down syndrome appear to be at increased risk for obstructive sleep apnea (OSA). Additionally, adults with Down syndrome are at increased risk for Alzheimer dementia at younger ages than the general population, and OSA has been identified as a risk factor for Alzheimer dementia in the general population. This study aims to explore the prevalence of diagnosed OSA, as well as the association between OSA and Alzheimer dementia, in adults with Down syndrome using Medicaid claims data from2011 to 2019. Of 118,539 adults with Down syndrome who met inclusion criteria, 23,785 had at least one OSA claim from2011 to 2019 (20.1%, 95% CI 19.8%-20.3%). After weighting for age, sex, dual enrollment, race, ethnicity, and region, adults with Down syndrome and OSA claims had 1.08 times the hazard of having a claim for Alzheimer dementia compared to those without OSA claims (95% CI 1.05-1.10). OSA is common in adults, and our findings have clinical implications for its evaluation and treatment in those with Down syndrome.}, } @article {pmid40903623, year = {2025}, author = {Anzai, Y and Minoshima, S}, title = {The role of brain MR and FDG-PET in the diagnosis of neurodegenerative disease.}, journal = {European radiology}, volume = {}, number = {}, pages = {}, pmid = {40903623}, issn = {1432-1084}, abstract = {Alzheimer disease (AD) is the most common dementing disorder, affecting 55 million people worldwide. Brain MRI plays an integral role in the diagnostic evaluation of patients with cognitive symptoms. When interpreting brain MRI for cognitive impairment, radiologists should assess the following four key features: (1) white matter ischemic burden, (2) structural changes to suggest normal pressure hydrocephalus, (3) locoregional pattern of brain atrophy, and (4) presence of microhemorrhage or superficial siderosis, particularly for determining eligibility for anti-amyloid monoclonal antibody (MAB) treatment when appropriate. The recent approval and clinical adoption of anti-amyloid MAB expanded the role of neuroradiologists in evaluating eligibility and monitoring ARIA (amyloid-related imaging abnormality) among patients receiving anti-amyloid MAB. This advancement underscores the importance of standardized imaging protocols and effective communication between neuroradiologists and cognitive neurologists. Depending on the severity of ARIA and patients' symptoms, treatment may need to be suspended or discontinued. This review article explores brain MRI and FDG-PET/CT imaging abnormalities in patients with major cognitive and movement disorders associated with dementia. It aims to assist radiologists in providing differential diagnoses within a clinical context. Finally, the article emphasizes the importance of recognizing co-pathologies, since patients may have more than one neurodegenerative disease rather than viewing these neurodegenerative diseases as being mutually exclusive. KEY POINTS: Question Traditional regional patterns of brain atrophy on MRI by neuroradiologists may not be effective given the recent advances in understanding of neurodegenerative disease and recognition of co-pathologies. Findings The locoregional atrophy and the patterns of metabolic abnormality help in the differential diagnosis of neurodegenerative disease. Remember that brain MRI determines eligibility for anti-amyloid immunotherapy. Clinical relevance Understanding clinical history is vital for interpreting brain MRI for patients with cognitive impairment or memory loss. Newly recognized entities such as limbic-predominant age-related TDP43 encephalopathy (LATE) can mimic Alzheimer disease among extremely elderly patients with amnestic symptoms with mesial temporal lobe atrophy.}, } @article {pmid40903613, year = {2025}, author = {Horn, A and Neumann, WJ}, title = {From adaptive deep brain stimulation to adaptive circuit targeting.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {10}, pages = {556-566}, pmid = {40903613}, issn = {1759-4766}, mesh = {Humans ; *Deep Brain Stimulation/methods ; Parkinson Disease/therapy ; *Brain/physiology/physiopathology ; }, abstract = {Deep brain stimulation (DBS) substantially improves motor symptoms and quality of life in people with movement disorders such as Parkinson disease and dystonia, and it is also being explored as a treatment option for other brain disorders, including treatment-resistant obsessive-compulsive disorder, Alzheimer disease and depression. Two major developments are currently driving progress in DBS research: first, the framework of adaptive DBS, which senses brain activity to infer the momentary state of the symptoms of a patient and reacts by adapting stimulation settings, and second, the concept of connectomic DBS, which identifies brain circuits that should optimally be stimulated to reduce specific symptoms. In this Perspective, we propose a unified framework that combines these two concepts. Our approach, termed adaptive circuit targeting, decodes symptom severity from brain signals and adaptively activates the most relevant symptom-response circuits. We discuss the state of the art in the adaptive and connectomic DBS fields and the research gaps that need to be addressed to unify these concepts.}, } @article {pmid40903459, year = {2025}, author = {Zhang, B and Zhang, S and Guo, Z and Hong, C and Zhang, F and Lin, H}, title = {Nesfatin-1 ameliorates blood-brain barrier dysfunction in Alzheimer's disease by targeting VEGF-R1 and reducing cellular senescence in brain vascular endothelial cells.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {341}, pmid = {40903459}, issn = {2158-3188}, mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects/physiopathology ; *Nucleobindins/metabolism ; *Cellular Senescence/drug effects ; *Alzheimer Disease/metabolism/physiopathology ; Mice ; *Endothelial Cells/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; Peptide Fragments ; Brain/metabolism ; Mice, Transgenic ; Male ; Disease Models, Animal ; Humans ; }, abstract = {Cellular senescence and associated endothelial permeability are crucial factors in the dysfunction of the blood-brain barrier (BBB) in neurodegenerative diseases, including Alzheimer's disease (AD). Nesfatin-1 (NF-1), a neuropeptide involved in regulating appetite and energy homeostasis, has not been extensively studied for its pathophysiological role in AD. In this study, we found that NF-1 treatment improved cellular senescence in brain vascular endothelial bEnd.3 cells by restoring the expression of hTERT and TERF2 against oligomerized Aβ1-42. Additionally, NF-1 reduced p53 and p21 protein levels in bEnd.3 cells exposed to oligomerized Aβ1-42. Notably, NF-1 reduced oligomerized Aβ1-42-induced endothelial monolayer permeability by maintaining transendothelial electric resistance (TEER) and the levels of tight junction proteins claudin 5 and ZO-1. Furthermore, NF-1 suppressed the expression of VEGF-R1 but not VEGF-R2 in bEnd.3 cells exposed to oligomerized Aβ1-42. Overexpression of VEGF-R1 negated the protective effects of NF-1 against oligomerized Aβ1-42-induced cellular senescence and increased endothelial monolayer permeability, indicating the involvement of VEGF-R1 in this process. Using a transgenic (Tg APPswe/PSEN1dE9) AD mouse model, we demonstrated that NF-1 administration lowered VEGF-R1 expression in the brain cortex of AD mice. Moreover, NF-1 mitigated BBB dysfunction and enhanced the expression of claudin 5 and ZO-1 in the brains of AD mice. Our results suggest that NF-1 may be a potential therapeutic strategy for treating AD.}, } @article {pmid40902672, year = {2025}, author = {Sharma, S and Bashir, B and Kolekar, KA and Acharya, A and Gupta, M and Jena, R and Vishwas, S and Kaur, J and Gupta, G and Kumbhar, PS and Patle, D and Chaitanya, M and Gulati, M and Singh, SK}, title = {Tailoring the biomarkers of Alzheimer's disease using a gut microbiome-centric approach: Preclinical, clinical, and regulatory perspectives.}, journal = {Ageing research reviews}, volume = {112}, number = {}, pages = {102888}, doi = {10.1016/j.arr.2025.102888}, pmid = {40902672}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/microbiology/diagnosis ; *Gastrointestinal Microbiome/physiology ; Biomarkers/metabolism ; Probiotics/therapeutic use ; Animals ; Fecal Microbiota Transplantation/methods ; Dysbiosis ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, poses significant therapeutic challenges due to its complex etiology and limited treatment options. Traditional pharmacotherapies targeting amyloid-β (Aβ) and cholinergic pathways offer modest benefits and are often associated with adverse effects. Emerging evidence implicates gut dysbiosis and the gut-brain axis in the pathogenesis and progression of AD. This review explores the multifactorial pathophysiology of AD and evaluates the therapeutic potential of gut-based interventions such as probiotics, prebiotics, synbiotics, metabiotics, postbiotics, and fecal microbiota transplantation (FMT) in mitigating disease pathology. Emphasis has also been given on role of miRNA released from FMT in management of AD. Preclinical and clinical studies demonstrate that these strategies can restore microbial homeostasis, reduce neuroinflammation, enhance gut barrier integrity, and improve cognitive outcomes. The regulatory aspects with use of probiotics based products and FMT is also highlighted. The modulation of neuroimmune, neuroendocrine, and neural pathways through microbiota-derived metabolites offers a promising avenue for AD management. Despite encouraging findings, further research is needed to address interindividual microbiome variability, delivery challenges, and the requirement for large-scale, randomized trials. Personalized gut-targeted approaches may open new horizons for the prevention and treatment of AD.}, } @article {pmid40901302, year = {2025}, author = {Stothart, G and Alderman, S and Hermann, O and Creavin, S and Coulthard, EJ}, title = {A passive and objective measure of recognition memory in mild cognitive impairment using Fastball memory assessment.}, journal = {Brain communications}, volume = {7}, number = {5}, pages = {fcaf279}, pmid = {40901302}, issn = {2632-1297}, abstract = {As viable pharmacotherapies and blood biomarkers emerge for dementia treatment and screening, there remains a great need for accurate, sensitive biomarkers of cognitive function. We have previously demonstrated that Fastball, a new Electroencephalography (EEG) method for the passive and objective measurement of recognition memory that requires no behavioural memory response or task comprehension, is sensitive to cognitive dysfunction in Alzheimer's disease. Here we present new evidence that Fastball is sensitive to amnestic dysfunction in an earlier stage of the dementia lifecourse, Mild Cognitive Impairment (MCI). 53 MCI patients and 54 healthy older adult (HOA) controls completed a 3-min Fastball task in which they passively viewed rapidly presented images while EEG captured their automatic ability to differentiate between images based on previous exposure. They also completed neuropsychological assessments of memory (Delayed Match to Sample-48), sustained attention (Psychomotor Vigilance Task), and general cognitive function (Addenbrookes Cognitive Exam-iii). Participants were re-tested after 1 year to establish the test-retest reliability of Fastball in HOAs, and the sensitivity of Fastball to cognitive decline in MCI patients, over a 1 year period. Amnestic MCI patients showed significantly reduced Fastball responses compared with non-amnestic MCI patients (P = 0.001, Cohen's d = 0.98) and HOA controls (P = 0.005, Cohen's d = 0.64). Regression analyses showed that Fastball EEG responses were selectively predictive of neuropsychological measures of recognition memory and not attention. Between baseline and year one follow-up Fastball showed moderate to good test-retest reliability in HOA controls, and the six MCI-dementia converters showed a trend for lower Fastball responses at baseline which will be confirmed with further longitudinal assessment. Fastball is further validated as a viable method for testing recognition memory in cognitively impaired populations. We have demonstrated that it is selectively predictive of memory dysfunction and not attention or other cognitive functions. It is passive, non-invasive, quick to administer and uses cheap, scalable EEG technology. Fastball is a viable functional biomarker that can help to advance cognitive assessment in MCI.}, } @article {pmid40899945, year = {2025}, author = {Saido, TC and Iwata, N}, title = {The tale of donanemab: God is in the details.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {4}, pages = {1364-1373}, pmid = {40899945}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; Animals ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; }, abstract = {Alzheimer's disease is a major cause of dementia, that affects approximately 7-8% of people aged 65 years and older (according to WHO & Alzheimer's Disease International) and thus is a major concern in public health world-wide. This review chronicles the foundational research and translational trajectory leading to the development of donanemab, a monoclonal antibody targeting pyroglutamyl amyloid-β (Aβ3pE-X) peptides, recently approved for the treatment of early Alzheimer's disease (AD). We trace a 30-year arc from the biochemical identification of Aβ species to the recognition of Aβ3pE-42 as a predominant pathological isoform in AD and Down syndrome brains-a fact still underrecognized among clinicians and researchers. We highlight key breakthroughs in antibody generation, Aβ peptide biochemistry, and resistance to enzymatic degradation. Mechanistic distinctions between donanemab (Kisunla[®]), and lecanemab (Leqembi[®]) are also explored, along with therapeutic implications for targeting specific Aβ species at preclinical stages of disease. The review emphasizes how persistent biochemical research, fueled by intellectual curiosity, serendipity, and rigorous experimentation, has culminated in clinical proof-of-concept for the amyloid hypothesis. In addition to its molecular specificity, donanemab's development underscores a critical shift toward precision medicine in Alzheimer's care. Its clinical validation, though limited in scope, reinforces the need for scalable and affordable interventions that can address the growing global burden of dementia. We expect these therapeutic antibodies to contribute to reducing the global burden by ceasing the disease progression in a preclinical stage now that new methods for fluid biomarkers are becoming available. As the global population ages, understanding and addressing AD has become a top priority in neuroscience and public health.}, } @article {pmid40899340, year = {2025}, author = {Zamanian, MY and Khachatryan, LG and Heidari, M and Darabi, R and Golmohammadi, M and Al-Aouadi, RFA and Akkol, EK}, title = {The Therapeutic Potential of Flavonols in Alzheimer's Disease: Inhibiting Amyloid-β, Oxidative Stress, and Neuroinflammation.}, journal = {BioFactors (Oxford, England)}, volume = {51}, number = {5}, pages = {e70047}, doi = {10.1002/biof.70047}, pmid = {40899340}, issn = {1872-8081}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; Oxidative Stress/drug effects ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors/genetics ; *Flavonols/pharmacology/therapeutic use ; Animals ; Kaempferols/pharmacology ; Flavonoids/pharmacology ; *Neuroprotective Agents/pharmacology ; Quercetin/pharmacology ; Mice ; Humans ; Male ; Mitochondria/drug effects ; *Neuroinflammatory Diseases/drug therapy ; Signal Transduction/drug effects ; Amyloid Precursor Protein Secretases/genetics/metabolism ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, oxidative stress, and neuroinflammation, remains a significant global health challenge. This study investigates the therapeutic potential of flavonols-quercetin, kaempferol, myricetin, and fisetin-in targeting Aβ aggregation and mitigating AD pathology through diverse molecular mechanisms. Our findings reveal that flavonols effectively inhibit Aβ oligomerization and fibril formation, reduce oxidative stress via Nrf2/HO-1 pathway activation, and suppress neuroinflammation by modulating microglial polarization. Additionally, these compounds enhance mitochondrial function, promote autophagy-mediated clearance of Aβ aggregates, and regulate key enzymes such as β-secretase (BACE1) and α-secretases (ADAM10/17), favoring non-amyloidogenic pathways. Quercetin demonstrated neuroprotective effects by activating TrkB signaling, reducing tau phosphorylation, and enhancing synaptic plasticity. Kaempferol prevented Aβ-induced apoptosis via the ER/ERK/MAPK pathway and inhibited acetylcholinesterase activity, improving cognitive outcomes. Myricetin ameliorated mitochondrial dysfunction and oxidative damage through GSK3β/ERK2 signaling modulation and showed enhanced brain bioavailability when delivered via nanostructured lipid carriers. Fisetin reduced Aβ burden by upregulating neprilysin expression, suppressed neuroinflammation, and improved synaptic function by restoring synaptic protein levels. Overall, flavonols exhibit multi-targeted therapeutic potential against AD by addressing its complex pathogenesis. Their ability to cross the blood-brain barrier and low toxicity profiles position them as promising candidates for further clinical development. This study underscores the potential of flavonols as natural agents for AD treatment and highlights their role in advancing multi-mechanistic therapeutic strategies.}, } @article {pmid40898925, year = {2025}, author = {Park, HA and Amjad, E and Burnett, G and Ferdous, KA and Scott, M and Jansen, J and Bannerman, S and Scott, M and Correll, RN and Ciesla, L and Ellis, A}, title = {Oral supplementation of fucoxanthin regulates gene expression in the brain of middle-aged rats.}, journal = {The British journal of nutrition}, volume = {134}, number = {6}, pages = {451-461}, doi = {10.1017/S0007114525104996}, pmid = {40898925}, issn = {1475-2662}, mesh = {Animals ; *Xanthophylls/pharmacology/administration & dosage ; Male ; Rats, Sprague-Dawley ; Oxidative Stress/drug effects ; Rats ; *Brain/metabolism/drug effects ; *Dietary Supplements ; *Aging ; Antioxidants/pharmacology/administration & dosage ; *Gene Expression Regulation/drug effects ; Lipid Peroxidation/drug effects ; Administration, Oral ; Neurons/drug effects/metabolism ; }, abstract = {Age is the main risk factor for many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and frontotemporal dementia. Despite our limited understanding of cellular mechanisms of ageing-associated neuronal loss, an increasing number of studies demonstrate that oxidative stress and inflammation are key drivers. Epidemiological studies indicate that diet during middle adulthood can influence the risk of developing neurodegenerative diseases later in life, so it is important to investigate dietary interventions to combat oxidative stress and inflammation. In this study, we hypothesised that treatment with fucoxanthin, a marine carotenoid with strong antioxidant properties, prevents ageing-associated oxidative stress that is known to be related to natural brain ageing. Treatment with fucoxanthin protected rat primary hippocampal neurons against oxidative stress and ageing in vitro. In our in vivo study, middle-aged male Sprague-Dawley rats were gavaged with fucoxanthin (1 mg/kg, 5 d/week, n 6) or vehicle (n 6) for 4 weeks. After supplementation was completed, brain samples were harvested and subjected to quantitative and bioinformatic analyses. Fucoxanthin was detected and shown to decrease lipid peroxidation in the brains of the animals supplemented with fucoxanthin. Microarray analysis showed that treatment with fucoxanthin changed 5602 genes. Together, our results suggest that treatment with fucoxanthin prevents ageing-associated oxidative stress and is capable of regulating genes that potentially ameliorate age-related changes to the brain.}, } @article {pmid40898264, year = {2025}, author = {Drinkall, NJ and Siersma, V and Lathe, R and Waldemar, G and Janbek, J}, title = {Herpesviruses, antiviral treatment, and the risk of dementia - systematic review and meta-analysis.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {201}, pmid = {40898264}, issn = {1758-9193}, mesh = {Humans ; *Antiviral Agents/therapeutic use ; *Dementia/epidemiology/virology ; *Herpesviridae Infections/drug therapy/complications/epidemiology ; *Herpesviridae ; Risk Factors ; }, abstract = {INTRODUCTION: The aim of this systematic review and meta-analysis was to synthesize the evidence on the association between herpesviruses, antiviral treatment, and the risk of dementia. We also aimed to explore the impact of time between herpesviruses and dementia on the reported associations. METHODS: PubMed and Web of Science were searched along with reference lists of the included studies. We included studies that looked at clinical episodes or serology (IgG/IgM) of herpes simplex virus type 1/2 (HSV1/2) and/or varicella zoster virus (VZV), antiviral treatment and incident dementia (all-cause dementia, Alzheimer's disease, and vascular dementia). Study results were pooled with random effect meta-analyses. RESULTS: We included 32 studies. The pooled hazard ratio for all-cause dementia was 1.36 [95% CI: 1.01, 1.83] following a clinical episode of HSV1/2, and 1.12 [95% CI: 1.00, 1.25] following a clinical episode of VZV. The pooled estimate for all-cause dementia following antiviral treatment and VZV was 0.88 [95% CI: 0.81, 0.96]. CONCLUSIONS: The present review of the scientific literature generally shows little evidence of an association between herpesviruses and risk of dementia. However, the review shows evidence of an association between antiviral treatment and a decreased risk of dementia. Because of considerable heterogeneity, future investigations could advantageously target certain subgroups.}, } @article {pmid40896959, year = {2025}, author = {Yun, J and Moon, M and Yang, J and Yeom, HD and Lee, MH and Lee, G and Lee, JH}, title = {Molecular regulation and subtype-specific effects of naringenin and naringin on nicotinic acetylcholine receptors expressed in Xenopus oocytes.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {191}, number = {}, pages = {118494}, doi = {10.1016/j.biopha.2025.118494}, pmid = {40896959}, issn = {1950-6007}, mesh = {*Flavanones/pharmacology ; Animals ; *Receptors, Nicotinic/metabolism/genetics ; Xenopus laevis ; *Oocytes/metabolism/drug effects ; Molecular Docking Simulation ; Humans ; Mutagenesis, Site-Directed ; Female ; Dose-Response Relationship, Drug ; *Nicotinic Antagonists/pharmacology ; }, abstract = {Naringenin and naringin, bioactive flavonoids from citrus fruits, exhibit neuroprotective effects, showing promise for neurodegenerative diseases like Alzheimer's and Parkinson's. Additionally, they demonstrate significant anticancer potential, modulating key signaling pathways involved in tumor growth, apoptosis, and metastasis, thus expanding their therapeutic applications in cancer treatment. These compounds interact with nicotinic acetylcholine receptors (nAChRs), a class of ligand-gated ion channels critical for modulating neurotransmission within the central nervous system. In this study, naringenin and naringin were found to selectively inhibit specific subtypes of nAChRs in a concentration-dependent, reversible, and noncompetitive manner. These effects were examined using two-electrode voltage-clamp recordings in Xenopus laevis oocytes heterologously expressing various human nAChR subtypes, and further analyzed by site-directed mutagenesis and molecular docking simulations to identify key binding residues. Mutational analyses, supported by molecular docking, revealed that certain mutations in nAChRs eliminate naringin's inhibitory effect, highlighting a selective binding affinity. This inhibition was observed selectively in α3β2 and α3β4 nAChR subtypes, which are significant within the autonomic nervous system, while α7 and α4β2 nAChRs, often implicated in neurodegenerative processes, remained unaffected. These findings suggest that naringenin and naringin could be developed as targeted modulators of nAChRs, offering therapeutic potential.}, } @article {pmid40896796, year = {2025}, author = {Dirir, AM and Ali, A and Hachem, M}, title = {Recent Advancements in Lipid Nanoparticles-Based Phytoactives Delivery Systems for Neurodegenerative Diseases.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {10279-10300}, pmid = {40896796}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Animals ; *Phytochemicals/administration & dosage/pharmacokinetics/chemistry ; *Nanoparticles/chemistry ; *Neuroprotective Agents/administration & dosage/pharmacokinetics/chemistry ; *Lipids/chemistry ; Drug Carriers/chemistry ; *Drug Delivery Systems/methods ; }, abstract = {Neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, pose a significant and continuous burden on the healthcare system, urging the search for innovative therapeutical approaches targeting the central nervous system. Nowadays, no definitive treatment can effectively modulate the neuronal degeneration associated with such diseases. The current line of therapies is primarily symptomatic and suffers several drawbacks. Among these, phytochemicals are emerging for their potential in the management of neurodegenerative disorders. Indeed, plants produce secondary metabolites that provide defensive functions against abiotic and biotic stresses. These metabolites can target the neurons and represent a promising therapeutic intervention for neurological disorders. However, the polar nature of phytochemicals and their large size hinder their passage through the blood-brain barrier, a selective barrier separating blood and the brain. Emerging studies have shown that the therapeutic efficiency of phytochemicals has been enhanced following their encapsulation with engineered nanocarriers such as lipid nanoparticles. Recent research indicates that delivering phytochemicals through lipid nanoparticles improves their physiological stability, promotes their passage across the blood-brain barrier, and enhances their accumulation in brain tissue-resulting in more effective neuroprotective effects than their free, unencapsulated form. Hence, the aim of the present review is to highlight the application of lipid nanoparticles as carriers for phytoactives with neuroprotective properties, discuss the current challenges associated with such nanocarriers, and provide insights into potential future research work.}, } @article {pmid40896259, year = {2025}, author = {Xu, J and Jin, H and Li, X and Jiang, Z and Meng, F and Wang, W and Li, WY}, title = {ADAM17 Inhibition Protects Cognition in Intermittent Hypoxia: The Role of TREM2.}, journal = {Nature and science of sleep}, volume = {17}, number = {}, pages = {1915-1928}, pmid = {40896259}, issn = {1179-1608}, abstract = {PURPOSE: The triggering receptor expressed on myeloid cells 2 (TREM2) is a new therapeutic target in Alzheimer's disease. However, its role in obstructive sleep apnea (OSA)-related cognitive impairment is still unclear. This study aimed to investigate the effect and regulatory mechanism of TREM2 on cognitive impairment related to OSA. METHODS: Since intermittent hypoxia (IH) is the primary pathophysiologic characteristic of OSA, we conducted IH animal and BV2 cell model to investigate the mechanism. Trem2 knockdown and Trem2 overexpression cells were created by Lentivirus transfection. A disintegrin and metalloprotease 17 (ADAM17) is the primary enzyme for TREM2 shedding, we used TAPI-1 to inhibit its activity. Morris water maze, Nissl staining, real-time PCR, immunofluorescence, Western blotting, fluorometric assay kit, and enzyme-linked immunosorbent assay were used to explore the molecular mechanism. RESULTS: The TREM2 levels were decreased in BV2 cells exposed to IH for 24 hours. IH elevated the levels of IL-1β, TNF-α and CD86 in BV2 cells, as well as the levels of p-Tau in conditioned media-cultured HT-22 cells. Conversely, IH reduced the levels of IL-10 and CD206 in BV2 cells. However, these effects were exacerbated in BV2 cells with Trem2 knockdown, whereas they were mitigated in those with Trem2 overexpression. Additionally, the ADAM17 activity and soluble TREM2 (sTREM2) levels were increased in BV2 cells subjected to IH. Treatment with TAPI-1, suppressed ADAM17 activity and restored TREM2 expression both in vitro and in vivo. Inhibition of ADAM17 led to a reduction in the expression of CD86, IL-1β, TNF-α and p-Tau levels, while enhancing the expression of CD206, IL10 and cognitive functions. CONCLUSION: TREM2 played a protective role in IH-induced neuroinflammation and neuronal injury by promoting microglia M2 polarization. IH caused excessive activation of ADAM17 and resulted in augmented degradation of TREM2. Restoring TREM2 expression by inhibiting ADAM17 indicates a potentially promising therapeutic strategy for cognitive impairment in OSA.}, } @article {pmid40895811, year = {2025}, author = {Tysinger, B and Wei, Y and Heun-Johnson, H and Zissimopoulos, JM}, title = {Long-term value of lecanemab to individuals and families.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70151}, pmid = {40895811}, issn = {2352-8737}, abstract = {INTRODUCTION: An assessment of the value of lecanemab for patients living with Alzheimer's disease (AD) and their care partners provides them and their health-care providers important information for deciding treatment initiation. METHODS: We used data from a nationally representative sample of middle aged and older Americans combined with data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) on AD progression and data on lecanemab treatment effects from Clarity AD clinical trials. We use dynamic microsimulation modeling to quantify the long-term health and economic value of lecanemab for persons living with AD and their care partners. RESULTS: We quantified five measures of value: quality of life of the persons living with AD and their care partners, medical costs, caregiving costs, and earnings, and estimated that lecanemab had a value of $21,398 relative to no treatment after 4 years and $37,943 after 10 years. Extending the treatment to 48 months resulted in a value of $42,821 relative to no treatment after 4 years and $95,311 after 10 years. Forty-eight months of a similar next-generation therapy but with 50% efficacy in slowing cognitive and functional decline resulted in a value of $82,116 relative to no treatment after 4 years and $189,691 after 10 years. DISCUSSION: Over time, lecanemab treatment reduced medical costs, hours of care required from care partners, and improved quality of life. There is much value to be gained with next-generation treatments that have a larger impact on slowing decline. Considering a wider range of outcomes in future assessments will provide a more complete understanding of value to support decision making about treatment initiation and about reimbursement for payers. HIGHLIGHTS: There is significant value of lecanemab for persons with mild cognitive impairment or mild dementia.Over time, lecanemab reduces medical costs, caregiver hours, and improves the quality of life of persons living with Alzheimer's disease (AD) and their care partners.A next-generation treatment for AD with similar features to lecanemab but higher efficacy, more than doubles the value.Assessing therapy value supports decision making by patients and their health-care providers.}, } @article {pmid40895150, year = {2025}, author = {Chen, G and Su, Y and Chen, S and Lin, T and Lin, X}, title = {Polyphenols and Alzheimer's Disease: A Review on Molecular and Therapeutic Insights With In Silico Support.}, journal = {Food science & nutrition}, volume = {13}, number = {9}, pages = {e70496}, pmid = {40895150}, issn = {2048-7177}, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation resulted the cognitive memory loss. Despite extensive research, effective therapeutic treatment remains elusive. Polyphenols, naturally occurring bioactive compounds, have emerged as promising neuroprotective agents due to their potent antioxidant, anti-inflammatory, and amyloid-modulating properties. Research indicated that these bioactive compounds have potent antioxidant and anti-inflammatory properties, have garnered significant attention for their potential role in combating AD by targeting its key pathological mechanisms. Preclinical studies highlight the efficacy of various polyphenols, such as resveratrol, curcumin, and epigallocatechin gallate, in improving cognitive function and reducing neurodegeneration. Moreover, in silico approaches, displayed polyphenols mechanistic interactions with key AD targets to reduce pathogenesis. These computational models accelerate drug discovery by predicting binding affinities, optimizing structural modifications, and identifying novel polyphenol derivatives with enhanced therapeutic potential. This review explores the multifaceted role of polyphenols in AD mitigation, emphasizing their impact on oxidative stress and neuroinflammation while integrating in silico evidence to reinforce their therapeutic relevance. Convincingly, through the suppression of key mediators of AD, including oxidative stress, neuroinflammation, amyloid-beta and tau proteins, polyphenols exhibited outstanding therapeutic potential to treat AD.}, } @article {pmid40894925, year = {2025}, author = {He, G and Huang, J and Zeng, Z and Sun, H and Wu, C and Xu, Q and Hu, C and Jin, B and Tong, M and Wang, C}, title = {Stem cell therapy offers new hope for the treatment of Alzheimer's disease.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1650885}, pmid = {40894925}, issn = {2296-634X}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory impairment and cognitive decline, for which no curative treatment is currently available. Existing therapeutic strategies, such as cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, can only provide limited symptomatic relief and fail to halt disease progression. In recent years, stem cell therapy has emerged as a promising approach for AD due to its multifaceted mechanisms of action. The therapeutic effects of stem cells in AD are mainly attributed to their ability to differentiate into functional neurons or glial cells, thereby replacing damaged cells and repairing neural networks. In addition, stem cells secrete neurotrophic and anti-inflammatory factors that contribute to the improvement of the brain microenvironment. Furthermore, they can regulate neuroinflammation, promote the clearance of β-amyloid (Aβ) deposits, and suppress neuroinflammation, thus potentially slowing disease progression. However, several challenges remain, including low cell survival rates, immune rejection, tumorigenic risks, and difficulties in crossing the blood-brain barrier. Looking ahead, the integration of advanced technologies such as organoid models, gene editing, artificial intelligence, and multi-omics approaches may drive substantial progress in the clinical translation of stem cell therapies for AD. Although still in its early stages, the future of this therapeutic strategy holds great promise.}, } @article {pmid40894255, year = {2025}, author = {Hu, N and Chen, L and Hu, G and Ma, R}, title = {Advancements in extracellular vesicle therapy for neurodegenerative diseases.}, journal = {Exploration of neuroprotective therapy}, volume = {5}, number = {}, pages = {}, pmid = {40894255}, issn = {2769-6510}, support = {R01 DA043138/DA/NIDA NIH HHS/United States ; R01 MH112848/MH/NIMH NIH HHS/United States ; R21 DA042704/DA/NIDA NIH HHS/United States ; R21 DA046831/DA/NIDA NIH HHS/United States ; }, abstract = {Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.}, } @article {pmid40894003, year = {2025}, author = {Kridawati, A and Indrawati, L and Hadisaputra, S and Adawiyah, AR}, title = {The preventive role of tempeh isoflavones on menopausal women's cognitive function: A multiple mechanism pathway.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251371284}, pmid = {40894003}, issn = {2542-4823}, abstract = {Cognitive dysfunction in the elderly is not only a disease but also could be considered a preclinical condition of Alzheimer's disease (AD), one of the most common types of dementia in the elderly. Therefore, treatment such as early detection and management of risk factors that could slow and prevent the onset of dementia is necessary for the elderly. Estrogen reduces the risk of AD in postmenopausal women. It has also been shown to reduce amyloid-β (Aβ) pathology in animal models of AD and suppress Aβ secretion from neuronal tissue. Estrogen receptors are involved in cognitive processes such as learning and memory, the formation of the hippocampus, the amygdala, and the cerebral cortex. Hormone replacement therapy (HRT) could improve cognition and thus delay the development of AD. Giving HRT after 9 years has been shown to increase the risk of breast cancer two-fold and cardiovascular disease. Phytoestrogens are hormones found in plants that can be an alternative to HRT. One of the foods that contains phytoestrogens and is widely consumed in Indonesia is tempeh. Isoflavone is a dominant phytoestrogen, structurally an estrogen-like substance, and functionally similar to 17β-estradiol. In this review article, we will discuss the role of tempeh isoflavones in a mechanism pathway on cognition.}, } @article {pmid40893997, year = {2025}, author = {Mokwenye, RC}, title = {A thematic analysis of Lay knowledge and beliefs about dementia among first-generation Black African immigrants from West Africa living in London: Informed by a grounded theory approach.}, journal = {Journal of public health research}, volume = {14}, number = {3}, pages = {22799036251368446}, pmid = {40893997}, issn = {2279-9028}, abstract = {BACKGROUND: Many Black Africans live in the UK. More than 850,000 people live with dementia in the UK, and more than 25,000 people with dementia are from Black and minority ethnic groups. The study explores themes of lay knowledge and beliefs about dementia. DESIGN AND METHODS: This study employs a qualitative research design and methods to explore lay knowledge and beliefs about dementia amongst Black African populations living in London. The research is philosophically underpinned by social constructionism and sociological and anthropological lay concepts of health and illness. The researcher interviewed 31 adult respondents, male and female, from the Black African community in London to generate rich data. Participants were first-generation immigrants from West Africa living in London and were mainly carers. Thematic data analysis informed by a grounded theory approach was used to analyse the data. RESULTS: The findings show that dementia is a complex biopsychosocial phenomenon. Four key themes with subthemes emerged and were developed: (i) Traditional views, (ii) Disease and illness, (iii) Help-seeking, and (iv) Caregiving and treatment. The group's understanding of dementia evolved from traditional views to a more medical perspective. This study added witchcraft to the dementia literature on BAME in the UK. CONCLUSIONS: The study concluded that the group does not lack knowledge of dementia. Their understanding and beliefs about dementia are evolving, and further efforts are needed to enhance awareness through education, training, and outreach to support individuals with dementia and their families within the Black African community.}, } @article {pmid40893935, year = {2025}, author = {Wu, H and Shi, J and Wang, X and Yang, M and Cai, J}, title = {A rare intronic c.2654+1G>A mutation in CSF1R-microglial encephalopathy: a case report.}, journal = {Frontiers in genetics}, volume = {16}, number = {}, pages = {1593964}, pmid = {40893935}, issn = {1664-8021}, abstract = {OBJECTIVE: We report a case of CSF1R-microglial encephalopathy associated with a rare intronic c.2654 + 1G>A mutation, featuring negative diffusion-weighted imaging (DWI) findings and a cerebrospinal fluid (CSF) biomarker profile indicative of Alzheimer's disease-related changes, and we explore the associations between genetic mutations, CSF biomarker alterations, and neuroimaging manifestations. METHODS: This study documents the demographic data, detailed medical history, and clinical manifestations of a patient with CSF1R-microglial encephalopathy. The medical histories of some family members were collected, and the proband underwent whole-exome sequencing (WES) for diagnostic confirmation. RESULTS: The patient, a 53-year-old woman, presented with early-onset cognitive decline, personality changes, and behavioral abnormalities. Neuropsychological testing revealed severe cognitive impairment, and the CSF biomarker profile suggested Alzheimer's disease-related changes. Cranial MRI showed bilateral, symmetric deep white matter changes, brain atrophy (including corpus callosum thinning), and low signal intensity on DWI. Family history revealed that 3 out of 19 individuals across four generations, including the proband, her aunt, and her sister, developed dementia and progressed to severe cognitive impairment rapidly. WES analysis revealed a heterozygous c.2654 + 1G>A variant in the CSF1R gene (NM_005211.3), confirming a diagnosis of CSF1R-microglial encephalopathy caused by a dominant autosomal mutation in exon 20 of the CSF1R gene. CONCLUSION: CSF1R-microglial encephalopathy is a progressive disorder with diverse early clinical presentations, making it prone to misdiagnosis and delayed treatment. This case suggests that, contrary to previous findings, negative DWI results should not exclude CSF1R-microglial encephalopathy. In addition, CSF biomarker profiles in patients with CSF1R-microglial encephalopathy may exhibit Alzheimer's disease-related changes. Early genetic testing is critical, and for genetically linked diseases, testing other family members can help ensure early diagnosis and intervention.}, } @article {pmid40893870, year = {2025}, author = {Kwak, MG and Mao, L and Zheng, Z and Su, Y and Lure, F and Li, J}, title = {A Cross-Modal Mutual Knowledge Distillation Framework for Alzheimer's Disease Diagnosis: Addressing Incomplete Modalities.}, journal = {IEEE transactions on automation science and engineering : a publication of the IEEE Robotics and Automation Society}, volume = {22}, number = {}, pages = {14218-14233}, pmid = {40893870}, issn = {1545-5955}, support = {P30 AG072980/AG/NIA NIH HHS/United States ; R01 AG069453/AG/NIA NIH HHS/United States ; R42 AG053149/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Early detection of Alzheimer's Disease (AD) is crucial for timely interventions and optimizing treatment outcomes. Integrating multimodal neuroimaging datasets can enhance the early detection of AD. However, models must address the challenge of incomplete modalities, a common issue in real-world scenarios, as not all patients have access to all modalities due to practical constraints such as cost and availability. We propose a deep learning framework employing Incomplete Cross-modal Mutual Knowledge Distillation (IC-MKD) to model different sub-cohorts of patients based on their available modalities. In IC-MKD, the multimodal model (e.g., MRI and PET) serves as a teacher, while the single-modality model (e.g., MRI only) is the student. Our IC-MKD framework features three components: a Modality-Disentangling Teacher (MDT) model designed through information disentanglement, a student model that learns from classification errors and MDT's knowledge, and the teacher model enhanced via distilling the student's single-modal feature extraction capabilities. Moreover, we show the effectiveness of the proposed method through theoretical analysis and validate its performance with simulation studies. In addition, our method is demonstrated through a case study with Alzheimer's Disease Neuroimaging Initiative (ADNI) datasets, underscoring the potential of artificial intelligence in addressing incomplete multimodal neuroimaging datasets and advancing early AD detection.}, } @article {pmid40893127, year = {2025}, author = {Lai, Z and Ke, L and Zhao, W}, title = {Naringenin as a neurotherapeutic agent in Alzheimer's disease: epigenetic signatures, gut microbiota alterations, and molecular neuroprotection.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1647967}, pmid = {40893127}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) remains a major neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) aggregation, tau pathology, oxidative stress, and chronic neuroinflammation. In recent years, the dietary flavonoid naringenin, abundant in citrus fruits, has gained attention as a multi-target neuroprotective agent with potential application in AD therapy. Preclinical studies demonstrate that naringenin exhibits robust antioxidant activity, notably through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway, which reduces ROS and preserves mitochondrial integrity. Furthermore, naringenin upregulates AMPK-mediated autophagy, aiding in the clearance of toxic Aβ peptides and promoting neuronal survival. Inflammatory cascades are significantly downregulated following naringenin treatment. Additionally, naringenin modulates estrogen receptor and PI3K/Akt signaling, contributing to enhanced neuronal viability and reduced apoptosis. Notably, its ability to inhibit acetylcholinesterase suggests promise for restoring cholinergic neurotransmission. Despite these benefits, naringenin's poor solubility and limited oral bioavailability hinder clinical translation. To address these challenges, advanced nanocarrier-based delivery systems have been engineered to facilitate blood-brain barrier penetration and sustained brain targeting, markedly improving cognitive outcomes in animal models. Safety profiles in rodents indicate low toxicity at therapeutic doses, reinforcing its viability as a candidate compound. This review highlights the multifaceted mechanisms and delivery strategies of naringenin in AD, and underscores the need for well-designed clinical trials to confirm its efficacy and safety in humans.}, } @article {pmid40893125, year = {2025}, author = {Gu, Z and Ge, B and Wang, Y and Gong, Y and Qi, M}, title = {Artificial intelligence technologies for enhancing neurofunctionalities: a comprehensive review with applications in Alzheimer's disease research.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1609063}, pmid = {40893125}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition that impairs memory and cognition, presenting a growing global healthcare burden. Despite major research efforts, no cure exists, and treatments remain focused on symptom relief. This narrative review highlights recent advancements in artificial intelligence (AI), particularly machine learning (ML) and deep learning (DL), which enhance early diagnosis, predict disease progression, and support personalized treatment strategies. AI applications are reshaping healthcare by enabling early detection, predicting disease progression, and developing personalized treatment plans. In particular, AI's ability to analyze complex datasets, including genetic and imaging data, has shown promise in identifying early biomarkers of AD. Additionally, AI-driven cognitive training and rehabilitation programs are emerging as effective tools to improve cognitive function and slow down the progression of cognitive impairment. The paper also discusses the potential of AI in drug discovery and clinical trial optimization, offering new avenues for the development of AD treatments. The paper emphasizes the need for ongoing interdisciplinary collaboration and regulatory oversight to harness AI's full potential in transforming AD care and improving patient outcomes.}, } @article {pmid40893124, year = {2025}, author = {Kayano, M}, title = {Exploring efficient and effective mammalian models for Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1652754}, pmid = {40893124}, issn = {1663-4365}, abstract = {The aim of this study was to explore and discuss efficient and effective mammalian models for Alzheimer's disease (AD). In this study, efficient AD models are characterized by a small body size, a short lifespan, and rapid development of the main pathology including amyloid plaque formation. Effective AD models are expected to exhibit not only the main pathology, but also co-pathology associated with other neurodegenerative diseases (e.g., Lewy body dementia), systemic disturbances such as disrupted central-peripheral homeostasis, and sleep-circadian failures. This reflects recent findings indicating that AD is far more multifactorial than previously assumed. Although further investigation is required, non-human primates, particularly common marmosets (Callithrix jacchus), and dogs (Canis lupus familiaris) are candidates of promising and effective AD models. Tree shrews (Tupaia belangeri), guinea pigs (Cavia porcellus), and evolutionary related species including degus (Octodon degus) constitute an alternative group of AD models that remain underexplored but potentially efficient and effective. These mammalian models, together with hypothesis-driven mouse models and advances in data science technologies including omics and imaging analyses, may lead to breakthroughs in AD research, resulting in the development of effective prevention and treatment for AD.}, } @article {pmid40891144, year = {2025}, author = {Pascali, V and Tosoni, D and Altieri, S and Protti, N}, title = {Capture-enhanced neutron irradiation to treat Alzheimer's disease: Design of a small animal set-up for future in-vivo experiments.}, journal = {Medical physics}, volume = {52}, number = {9}, pages = {e18062}, pmid = {40891144}, issn = {2473-4209}, support = {964934//European Commission/ ; }, mesh = {*Alzheimer Disease/radiotherapy ; Animals ; Mice ; Monte Carlo Method ; *Boron Neutron Capture Therapy/instrumentation/methods ; *Neutrons/therapeutic use ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of β $\beta$ -Amyloid and τ $\tau$ proteins in the brain that causes dementia. To date, there is no cure capable of eradicating AD, so it is necessary to study a performing therapy. The NECTAR project aims to investigate an extension of the conventional Boron Neutron Capture Therapy principles as a possible treatment for AD at different scales (protein, cells, animal). PURPOSE: The present study focuses on a macroscopic scale and wants to propose an irradiation set-up for mice in the thermal column (TC) of the Triga Mark II reactor of Pavia University, in view of the forthcoming in vivo irradiation of healthy and transgenic AD mouse models. METHODS: Monte Carlo simulations were carried out with the MCNP6 code to test different irradiation positions and study the least toxic treatment possible by modeling neutron shielding to preserve healthy tissue. A shielding prototype was built and tested by means of neutron activation measurements. A geometrical mouse model was developed with the aim of computing the dose-rates induced in each radiosensitive organ and thus to estimate possible irradiation times for future in vivo experiments. RESULTS: The computational study showed that the safest irradiation condition involves placing the shielding 20 cm from the TC entrance and that the best performing shielding material is 6 Li $^{6} {\rm Li} $ enriched lithium carbonate. Furthermore, taking into account the tolerance doses of each organ, the maximum animal irradiation time in an AD context is 45 min. The proposed set-up could also be used for preclinical studies on brain tumors; in this context, the maximum estimated irradiation time is 11 min. CONCLUSION: The proposed work is pivotal in the study of a possible treatment for AD in a neutron irradiation context, paving the way for the next phase of the NECTAR project involving in vivo irradiation of AD mouse models and thus making it possible to assess its efficacy and its possible future extension to the human brain.}, } @article {pmid40891036, year = {2025}, author = {Wang, B and Wang, ZX and Lv, LM and Wang, X and Lu, JC and Zhao, YF and Jiang, R and Li, QF and Kong, Y and Yang, XW and Luo, J and Xiao, ZC and Li, AP and Yang, G and Ma, QH and Shao, L}, title = {Tenascin-R aggravates Aβ production in the perforant pathway by regulating Nav1.6 activity in APP/PS1 mice.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70633}, pmid = {40891036}, issn = {1552-5279}, support = {82471464 to L.S.//National Natural Science Foundation of China/ ; 82301700 to B.W.//National Natural Science Foundation of China/ ; 82503370 to G.Y.//National Natural Science Foundation of China/ ; 2024-MS-157 to B.W.//Liaoning Province Natural Science Foundation/ ; ZR2023QH126 to X.W.//Shandong Provincial Natural Science Foundation/ ; LJ222510161002 to L.S.//Leading Talents Team Project of Liaoning Provincial Department of Education/ ; }, mesh = {Animals ; *NAV1.6 Voltage-Gated Sodium Channel/metabolism ; Mice ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Tenascin/metabolism/genetics ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Alzheimer Disease/metabolism/genetics ; Disease Models, Animal ; Hippocampus/metabolism ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) neuropathology exhibits early accumulation of amyloid beta (Aβ) plaques within the perforant pathway. This study explores how tenascin-R, a myelin-associated protein at nodes of Ranvier (NORs), modulates Aβ generation through Nav1.6 within this cortico-hippocampal circuit. METHODS: We integrated genetic, electrophysiological, and microdialysis techniques in APP/PS1 mice and constructed tenascin-R gene fragments and GEDC motif to identify potential therapeutic sequences for AD treatment. RESULTS: Stimulating the entorhinal cortex increased Aβ1-42 release along the perforant pathway through Nav-dependent mechanisms. Reducing tenascin-R decreased Aβ deposition and alleviated cognitive deficits. Overexpressing tenascin-R enhanced Nav1.6 currents and upregulated amyloid precursor protein and β-secretase. The GEDC motif within tenascin-R's epidermal growth factor-like domain controlled Nav1.6 activity. DISCUSSION: Our findings demonstrate that NORs signaling modulates Aβ processing independently of synaptic mechanisms. Tenascin-R regulates Aβ pathogenesis via Nav1.6 at NORs, underscoring myelin proteins and Nav1.6 as therapeutic targets. The GEDC motif represents a potential peptide-based compound for AD therapy. HIGHLIGHTS: Nodes of Ranvier-associated tenascin-R (Tn-R) regulate amyloid beta (Aβ) production in the perforant pathway of APP/PS1 mice. Tn-R enhances Nav1.6-mediated sodium currents, promoting amyloid precursor protein (APP) transcription and Aβ generation. Genetic downregulation of Tn-R mitigates Aβ deposition, restores synaptic integrity, and improves cognition. The conserved GEDC motif within Tn-R's epidermal growth factor-like domain is critical for modulating Nav1.6 activity and amyloidogenesis. The Tn-R/Nav1.6 axis represents a novel therapeutic target for Alzheimer's disease, with GEDC-derived peptides offering translational potential.}, } @article {pmid40890909, year = {2025}, author = {Maheta, P and Patel, C and Parmar, D and Beladiya, J and Patel, S and Sheth, D and Dholakia, S}, title = {Neuroprotective Effects of a 3-Amino Quinazoline Derivative via Keap1-Nrf2 Pathway Activation in an ICV-STZ-Induced Rat Model of Sporadic Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3611-3622}, doi = {10.1021/acschemneuro.5c00540}, pmid = {40890909}, issn = {1948-7193}, mesh = {Animals ; *NF-E2-Related Factor 2/metabolism/drug effects ; *Kelch-Like ECH-Associated Protein 1/metabolism/drug effects ; *Neuroprotective Agents/pharmacology ; *Alzheimer Disease/metabolism/drug therapy/chemically induced ; Rats ; Male ; Streptozocin ; Disease Models, Animal ; *Quinazolines/pharmacology ; Signal Transduction/drug effects ; Hippocampus/drug effects/metabolism ; Rats, Wistar ; }, abstract = {The Keap1-Nrf2 pathway has emerged as a promising target for Alzheimer's disease (AD). This study employed in silico modeling to identify Nrf2 activators through Keap1 inhibition. The most promising quinazoline derivative, LMDP10, was then evaluated in a rat model of sporadic AD induced by Intracerebroventricular (ICV) streptozotocin (STZ). ICV STZ-induced rats were treated with LMDP10 (5-50 mg/kg, orally). Behavioral changes were assessed using the Morris water maze (MWM) and novel object recognition (NOR) tests. Additionally, neurochemical marker (oxidant/antioxidant), proinflammatory cytokine (TNF-α) levels, Nrf2 levels, and histopathological alterations were analyzed in both the hippocampus and cortex. An oral toxicity study of LMDP10 was performed according to the OECD Guideline 425. LMDP10 treatment (50 mg/kg/day) significantly improved memory performance (increased percentage time spent in target quadrant in the MWM test and increased discrimination index in the NOR test; P < 0.001 for both). Notably, this dose also significantly increased Nrf2, SOD, and GSH levels while attenuating elevated MDA and TNF-α levels in both brain regions compared to those in vehicle-treated STZ rats. LMDP10 emerged as a potential therapeutic candidate for AD. LMDP10 improved memory function and increased Nrf2 signaling and antioxidant defenses while reducing neuroinflammation. These findings suggest that the neuroprotective effects of LMDP10 may involve Keap1-Nrf2 pathway activation, warranting further investigation of its therapeutic potential in AD.}, } @article {pmid40890872, year = {2025}, author = {Yuan, M and Nguyen, TTT and Gibb, AJ and Xian, YF and Xu, HX}, title = {Potential of phytochemicals in the treatment of Alzheimer disease by modulating lysosomal dysfunction: a systematic review.}, journal = {Chinese medicine}, volume = {20}, number = {1}, pages = {138}, pmid = {40890872}, issn = {1749-8546}, support = {82204723//National Natural Science Foundation of China/ ; }, abstract = {Alzheimer disease (AD) is a primary international health dilemma, especially in elderly populations, due to its progressive nature and its adverse cognitive impact. The dysfunction of lysosomes, which impairs protein degradation and leads to toxic accumulation in neurons, is a pivotal factor in AD. We explore phytochemicals that specifically target lysosomal dysfunction via the activation of autophagy, phagocytosis, and lysosome function, exhibiting anti-inflammatory and antioxidant properties. This study involves extracting and evaluating phytochemicals by exploring multiple databases, Google Scholar, PubMed, the Science Citation Index Expanded (SCIE), and the China National Knowledge Infrastructure (CNKI), integrating contemporary biochemical evidence with TCM principles-highlighting the interconnected roles of deficiency, stasis, and phlegm-to provide a comprehensive therapeutic framework. Key phytochemicals-magnolol, trehalose, and salidroside- demonstrate notable promise in enhancing lysosomal function, reducing amyloid beta accumulation, and improving cognitive outcomes. Addressing traditional theory and modern science, we underline the potential for future research by clarifying the mechanisms of compounds and their effectiveness, which may delay the disease process.}, } @article {pmid40889776, year = {2025}, author = {Cemali, SH and Poyraz, S and Belveren, S and Taş, S and Tamer, MA and Döndaş, NY and Döndaş, HA and Sansano, JM}, title = {Recent Insights in Multi-Target Drugs in Pharmacology and Medicinal Chemistry.}, journal = {ChemMedChem}, volume = {20}, number = {18}, pages = {e202500447}, pmid = {40889776}, issn = {1860-7187}, support = {TSA-2022-15050//Çukurova University/ ; TSA-2021-13814//Çukurova University/ ; FYL-2023-15939//Çukurova University/ ; TSA-2023-16116//Çukurova University/ ; TYL-2024-17047//Çukurova University/ ; }, mesh = {Humans ; Alzheimer Disease/drug therapy ; Antineoplastic Agents/pharmacology/chemistry/chemical synthesis ; *Chemistry, Pharmaceutical/trends ; *Drug Design ; Molecular Structure ; Neoplasms/drug therapy ; Parkinson Disease/drug therapy ; }, abstract = {Many of the drugs used in treatment today have been designed based on the "specificity paradigm". Resistance has developed against drugs designed using this approach, leading to a decrease in their effectiveness. In addition, it is well-documented in the literature that diseases with complex etiologies, such as Alzheimer's, Parkinson's, and cancer are influenced by multiple genetic and/or environmental factors. As a result, specificity paradigm is often insufficient for treating these diseases. Therefore, there is a need to develop drugs that interact with multiple targets simultaneously through different mechanisms. This review aims to provide an overview of the methods used in multitarget drug design, the reactions employed in the synthesis of these drugs, their applications, and recent research conducted in this field.}, } @article {pmid40889628, year = {2025}, author = {Çam Özünlü, SA and Uysal, F and Tatlı Doğan, H and Parlar, A and Çetinkaya, A and Arslan, SO}, title = {Thymoquinone ameliorates cognitive impairment and neuroinflammation in an amyloid-beta-induced rat model of Alzheimer's disease.}, journal = {Brain research}, volume = {1866}, number = {}, pages = {149918}, doi = {10.1016/j.brainres.2025.149918}, pmid = {40889628}, issn = {1872-6240}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Benzoquinones/pharmacology/therapeutic use ; Male ; Amyloid beta-Peptides/toxicity ; Rats ; Rats, Wistar ; *Cognitive Dysfunction/drug therapy/metabolism ; Disease Models, Animal ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; Neuroprotective Agents/pharmacology ; Peptide Fragments ; Maze Learning/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Amyloid-beta (Aβ) peptide accumulation is one of the most important chatacteristics of AD that cause neuronal damage and neuroinflammation. Thymoquinone (TQ), a bioactive compound derived from Nigella sativa, has shown neuroprotective properties in previous studies. This study aimed to evaluate the ameliorative effects of TQ in an Aβ1-42-induced AD rat model. Male Wistar-Albino rats were divided into four groups: Control, AD, TQ-10 (10 mg/kg TQ), and TQ-30 (30 mg/kg TQ). TQ was administered orally for 7 days before and 10 days after Aβ1-42 injection into the hippocampus. Cognitive functions were assessed using the Passive Avoidance (PA) and Morris Water Maze (MWM) tests. After behavioral experiments, hippocampal cytokine (tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)) levels, as well as astrocyte and microglial activation, are evaluated. TQ treatment reversed memory impairements in the AD group. Hippocampal TNF-α and IL-1β levels were elevated in the AD and reduced in TQ-treated groups. Immunohistochemical analysis revealed that the increased reactivity of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1) in the AD group was significantly attenuated by TQ treatment. Both 10 mg/kg and 30 mg/kg doses of TQ administration improved cognitive performance, reduced neuroinflammation, and mitigated glial activation in an Aβ-induced AD rat model. These findings suggest that TQ may serve as a promising neuroprotective agent for AD. Further studies are required to elucidate its molecular mechanisms and therapeutic potential in clinical settings.}, } @article {pmid40889010, year = {2025}, author = {Gote, S and Dubey, S and Nargund, SL and Thapa, S}, title = {A systematic review of natural products targeting Nrf2-Keap1-ARE pathway and their influence on neurodegenerative disorders.}, journal = {Inflammopharmacology}, volume = {33}, number = {9}, pages = {5097-5111}, pmid = {40889010}, issn = {1568-5608}, mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Biological Products/pharmacology ; *Kelch-Like ECH-Associated Protein 1/metabolism ; Animals ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Neuroprotective Agents/pharmacology ; *Antioxidant Response Elements/drug effects/physiology ; }, abstract = {Neurodegenerative disease represents a significant public health concern, with conditions, such as Alzheimer's disease and Parkinson's disease, being among the most prevalent. The primary risk factor for these neurodegenerative diseases is the process of aging. Key factors, such as oxidative stress and mitochondrial dysfunction, play a crucial role in initiating neurodegeneration. The progressive deterioration and neuronal loss in both the central and peripheral nervous systems are hallmark features of neurodegenerative diseases. Plant-derived natural products and their bioactive components, such as curcumin, resveratrol, genistein, marine algae, quercetin, apigenin, and luteolin, have shown promise as therapeutic agents for treating neurodegenerative diseases. There are various medications approved for the management of neurodegenerative diseases; their usage is primarily limited to providing symptomatic relief. The utilization of natural products holds significant promise for the prevention and treatment of neurodegenerative diseases (ND). The review provides evidence that natural products and their bioactive compounds could be beneficial in the treatment of neurodegenerative disorders. This article delineates the Keap1-Nrf2-ARE pathway's role in ND progression, shedding light on the therapeutic efficacy of natural products and their bioactive constituents that have demonstrated neuroprotective properties.}, } @article {pmid40888949, year = {2025}, author = {Tang, L and Liu, F and Sun, X and Yang, J and Liu, Y and Pan, X and Hao, L and Lou, F and Su, J}, title = {The Janus face of CaMKII: from memory consolidation to neurotoxic switch in Alzheimer's disease.}, journal = {Archives of toxicology}, volume = {99}, number = {12}, pages = {4829-4868}, pmid = {40888949}, issn = {1432-0738}, support = {32271160//Natural Science Foundation of China/ ; 2021M693914//China Postdoctoral Science Foundation/ ; 2022JH2/20200069//Scientific Research Project of Liaoning Province/ ; xtcx2019-11//Medical Electrophysiological Key Lab Foundation of Sichuan Province/ ; KeyME-2019-07//Key Laboratory Foundation of Medical Electrophysiology of Ministry of Education/ ; }, mesh = {*Alzheimer Disease/physiopathology/pathology/enzymology/metabolism ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Humans ; Animals ; Amyloid beta-Peptides/metabolism ; *Memory Consolidation/physiology ; Calcium Signaling ; Neuronal Plasticity ; Calcium/metabolism ; tau Proteins/metabolism ; Long-Term Potentiation ; }, abstract = {Alzheimer's disease (AD), a neurodegenerative "memory killer" demanding urgent global intervention, has long been shrouded in mystery regarding its core pathological mechanisms. Although the traditional amyloid-β (Aβ) hypothesis remains dominant, recent groundbreaking research has revealed that early activation of aberrant calcium (Ca[2][+]) signaling pathways serves as the "initiating trigger" of AD pathogenesis-preceding even the formation of classical Aβ plaques-a discovery that fundamentally overturns the existing cognitive framework. This study systematically deconstructs, for the first time, the cascading regulatory network of the Ca[2][+]/CaM-CaMKII signaling axis in AD pathology, elucidating its potential links with core AD mechanisms, including the Aβ hypothesis, tau hyperphosphorylation, Ca[2][+] dyshomeostasis, synaptic dysfunction, and neuronal loss. Furthermore, this pathway not only triggers neurotoxic cascades through spatiotemporally specific regulation of synaptic Ca[2][+] overload but also directly disrupts neuroplasticity-the physical basis of memory encoding-by reshaping the dynamic equilibrium between long-term potentiation (LTP) and long-term depression (LTD).Crucially, the research uncovers the dual role of CaMKII as a "molecular switch": while physiologically maintaining memory consolidation via Thr286 autophosphorylation, its pathological overactivation due to Ca[2][+] dyshomeostasis leads to a "memory solidification-toxicity cycle." These findings establish a theoretical foundation for developing innovative therapies based on precise calcium signaling modulation-including Ca[2][+] homeostasis intervention and CaMKII allosteric modulators-offering a potential breakthrough in overcoming the long-standing limitation of "symptom relief without targeting root causes" in AD treatment.}, } @article {pmid40888418, year = {2025}, author = {Tansir, G and Rastogi, S and Gounder, MM}, title = {Repurposing nirogacestat, a gamma secretase enzyme inhibitor in desmoid tumors.}, journal = {Future oncology (London, England)}, volume = {21}, number = {23}, pages = {2985-2993}, pmid = {40888418}, issn = {1744-8301}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Drug Repositioning ; *Amyloid Precursor Protein Secretases/antagonists & inhibitors ; *Desmoid Tumors/drug therapy/mortality/pathology ; *Enzyme Inhibitors/therapeutic use/pharmacology ; Tetrahydronaphthalenes ; Valine/analogs & derivatives ; }, abstract = {The gamma secretase (GS) enzyme controls cell-cell adhesion, neural stem cell proliferation, neo-angiogenesis, spinal maturation, and metabolism of amyloid precursor proteins (APP). Pathological production of abnormal amyloid-beta isoforms and senile plaques serves as the basis for pathogenesis of Alzheimer's disease (AD). GS enzyme inhibitors such as semagacestat and avagacestat were explored in AD but the studies were paused because of adverse events attributed to their influence on the Notch pathway.Crosstalk between Notch and Wnt signaling pathways created a potential role for GS inhibitors in the treatment of malignancies such as glioblastoma multiforme, pancreatic, and breast cancers. In a phase I study on nirogacestat among refractory solid malignancies, overall response rate (ORR) of 71.4% was observed in desmoid tumor (DT). The pivotal DeFi phase III trial established superiority of nirogacestat in terms of progression-free survival and ORR, reducing the likelihood of progression by 71%. Emphasis was placed on patient-reported outcomes (PRO) including the DT-specific tool, GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom Scale (GODDESS).Nirogacestat received Food and Drug Administration (FDA) approval in November 2023 and European Commission approval in August 2025 for adults with progressing desmoid tumors (DT) who require systemic treatment. Further studies are underway to investigate other GS inhibitors such as AL-102 in the management of DT.}, } @article {pmid40887393, year = {2025}, author = {Hsu, JL and Park, KH and Panegyres, PK and Huang, YH and Eom, YI and Prusty, V and Tan, LS and Shea, YF}, title = {Early Alzheimer's disease (mild cognitive impairment or mild dementia): Prevalence, diagnostics, treatment options, and guidelines in Asia, Australasia, and Pacific nations countries.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {9}, pages = {100362}, pmid = {40887393}, issn = {2426-0266}, mesh = {Humans ; *Cognitive Dysfunction/epidemiology/diagnosis/therapy ; *Alzheimer Disease/epidemiology/diagnosis/therapy ; Australasia/epidemiology ; Prevalence ; Asia/epidemiology ; Early Diagnosis ; Practice Guidelines as Topic ; }, abstract = {Early diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) with mild dementia is becoming increasingly important to enable patients to receive appropriate treatment with available amyloid-targeting therapies. Reviews of AD prevalence and diagnostic and treatment patterns typically focus on global or western populations, but the situation in Asia, Australasia, and Pacific Nations (AAPN) countries is less clear. We performed a narrative review of literature for AD in several AAPN countries, focusing on patients with MCI or mild dementia who may benefit from early treatment. Published information regarding AD incidence and prevalence and current practice in AAPN countries is limited and the nature of available information differs between countries. However, AAPN countries include some of the most rapidly aging populations and show the associated increasing trend of all-cause dementia prevalence observed globally. Although lecanemab and donanemab are now approved for AD with MCI and mild dementia in several AAPN countries, the most appropriate diagnostic pathway for patients with MCI and early AD is not established. Even though the AAPN region includes countries with routine access to advanced technologies, concerns have already been raised about the ability of healthcare systems in Australia, New Zealand, and Korea to respond to approvals of new AD therapies, including the need to ensure availability of biomarker testing and dementia specialists to allow patients to receive the early diagnosis required to enable appropriate treatment. Guidelines and national policies also need updating to differentiate between dementia subtypes and include amyloid-targeting therapies for eligible patients with early AD.}, } @article {pmid40887244, year = {2025}, author = {Yamashita, C}, title = {[Development of Drug Delivery Systems Based on New Concepts].}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {145}, number = {9}, pages = {747-763}, doi = {10.1248/yakushi.25-00023}, pmid = {40887244}, issn = {1347-5231}, mesh = {*Drug Delivery Systems/trends ; Humans ; Alzheimer Disease/drug therapy ; Nanoparticles ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Administration, Inhalation ; Animals ; *Drug Development/trends ; Lipids ; Liposomes ; }, abstract = {This review is a partial summary of the author's 40 years of research and development at Otsuka Pharmaceutical Co., Ltd. and the Faculty of Pharmaceutical Sciences, Tokyo University of Science. The author has consistently addressed issues of clinical significance and developed drug delivery systems based on new concepts through a change in thinking, free from preconceptions and stereotypes. In this review, the following research and development projects that the author has been involved in are described: a new concept inhalation system applicable to proteins and created based on a patient's perspective; a radical treatment for chronic obstructive pulmonary disease using a nuclear transfer strategy combining lipid nanoparticles and nuclear transfer signals for alveolar regeneration; a glycosylated Nose-to-Brain system for the development of innovative therapeutic agents for Alzheimer's disease.}, } @article {pmid40887228, year = {2025}, author = {Kawaguchi, Y and Takei, K}, title = {[Aβ Receptor PirB and its regulation by LOTUS].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {160}, number = {5}, pages = {318-323}, doi = {10.1254/fpj.25018}, pmid = {40887228}, issn = {0015-5691}, mesh = {Humans ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Neuronal Plasticity ; *Receptors, Immunologic/metabolism/physiology ; }, abstract = {Over the years, research has accumulated a vast amount of knowledge about the pathogenesis of dementia, including Alzheimer's disease (AD). However, fundamental treatments for AD have not yet been established. In this article, we discuss an Aβ receptor, paired immunoglobulin like receptor B (PirB) and its endogenous regulator lateral olfactory tract usher substance (LOTUS), which are completely different novel drug target from existing drugs, and the possibility of endogenous inhibitors of PirB. PirB expressed in neurons is a negative regulator of neuronal plasticity, as loss or inhibition of PirB increases neuronal plasticity, leading to increased spine density and improved cognitive function. Furthermore, PirB is known to function as a receptor for Aβ, leading to reduced neuronal plasticity and cell death. These findingss suggest that PirB can be positioned as a novel drug target for the treatment of AD. The neuronal circuit-forming factor LOTUS, which binds to PirB and functions as an endogenous antagonist, has been shown to inhibit the neurotoxic effects of Aβ mediated by PirB. Namely, LOTUS is an endogenous molecule that inhibits Aβ receptor function of PirB and may have medicinal effects against Aβ pathology.}, } @article {pmid40886864, year = {2026}, author = {Su, Y and Shang, C and Cao, B and Ma, H and Wang, P and Song, J and Xie, Z and Zhang, Z}, title = {Ferulic acid derived from Huanshaodan improves cognitive deficits in Alzheimer's disease model through regulating APP proteolytic processing via downregulation of SIRT2 expression.}, journal = {Journal of ethnopharmacology}, volume = {354}, number = {}, pages = {120508}, doi = {10.1016/j.jep.2025.120508}, pmid = {40886864}, issn = {1872-7573}, mesh = {Animals ; *Coumaric Acids/pharmacology/therapeutic use/isolation & purification ; *Alzheimer Disease/drug therapy/metabolism ; *Sirtuin 2/genetics/metabolism ; Down-Regulation/drug effects ; Mice ; Disease Models, Animal ; *Drugs, Chinese Herbal/pharmacology/chemistry/therapeutic use ; *Amyloid beta-Protein Precursor/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Humans ; Proteolysis/drug effects ; Mice, Transgenic ; }, abstract = {Huanshaodan (HSD) is a Traditional Chinese Medicine Compound Prescription, traditionally used in the clinical treatment of Alzheimer's disease (AD) in China. Nevertheless, its bioactive constituents and mechanistic basis remain poorly understood. AIM OF THE STUDY: To identify the components derived from HSD that inhibit SIRT2 and investigate the underlying mechanisms in mitigating AD pathogenesis. MATERIALS AND METHODS: A luciferase reporter gene assay was employed to screen HSD for components that downregulate SIRT2 expression. The neuroprotective effects and the mechanisms of the screened component, ferulic acid (FA), was evaluated both in SAMP8 mice and HT22-APPswe cell using behavioral tests, H&E, immunohistochemistry, transmission electron microscopy, ELISA, MTT, Western blot, RT-qPCR, immunofluorescence and Co-immunoprecipitation, to assess its effect on SIRT2 expression, SIRT2-APP interaction, as well as the expression of proteins associated with APP proteolytic processing. SIRT2-overexpressing plasmids were transfected to assess FA's neuroprotection via SIRT2 modulation. RESULTS: As a component in HSD, FA inhibited SIRT2 promoter-driven transcription, ameliorated cognitive deficits, protected neuronal and synaptic structures, reduced Aβ deposition in SAMP8 mice and Aβ level in HT22-APPswe cells. FA suppressed SIRT2 expression, inhibited SIRT2-APP interaction, modulated the expression levels of proteins involved in APP proteolytic processing, namely ADAM10, sAPPα, BACE1, sAPPβ, and CTFα in vitro and in vivo. Notably, the regulatory effects of FA on APP proteolytic processing in HT22-APPswe cells were completely abolished upon SIRT2 overexpression. CONCLUSIONS: This study demonstrates that FA is an active component in HSD that mitigates AD pathology, potentially by modulating APP proteolytic processing through SIRT2 downregulation.}, } @article {pmid40886227, year = {2025}, author = {da Silva, AMP and Falcão, L and Ribeiro Gonçalves, O and Virgilio Ribeiro, F and Machado Magalhães, PL and Lee Han, M and Łajczak, P and Letícia de Bastos Maximiano, M and Cal, H and de Souza Franco, E and de Sousa Maia, MB}, title = {Brexpiprazole for the Treatment of Agitation in Older Adults with Alzheimer's Disease: A Systematic Review, Bayesian Meta-analysis, and Meta-regression.}, journal = {CNS drugs}, volume = {39}, number = {11}, pages = {1071-1082}, pmid = {40886227}, issn = {1179-1934}, mesh = {Humans ; *Alzheimer Disease/drug therapy/complications ; *Psychomotor Agitation/drug therapy/etiology ; *Thiophenes/therapeutic use/adverse effects/administration & dosage ; Randomized Controlled Trials as Topic ; Bayes Theorem ; Aged ; *Quinolones/therapeutic use/adverse effects/administration & dosage ; }, abstract = {BACKGROUND: Agitation is a common and distressing neuropsychiatric symptom in Alzheimer's disease (AD), affecting up to half of patients and contributing to faster cognitive decline and caregiver burden. Brexpiprazole, a serotonin-dopamine modulator, has been evaluated for this indication, but uncertainties remain regarding its efficacy, safety, and appropriate use in older adults. OBJECTIVE: We aimed to assess the efficacy and safety of brexpiprazole for the treatment of agitation in older adults with AD through a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines and the Cochrane Handbook, we included RCTs comparing brexpiprazole (0.5-3 mg/day) with placebo in older adults with a clinical diagnosis of AD. Primary outcomes were agitation severity (measured using the Cohen-Mansfield Agitation Inventory [CMAI]), clinical impression (clinical global impression-severity scale [CGI-S]), neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]), and adverse events. Risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were pooled using a random-effects model. Random-effects meta-analyses were performed using frequentist and Bayesian models in R (version 4.3.0). RESULTS: A total of five RCTs (N = 1770) met the inclusion criteria. Brexpiprazole was associated with a modest reduction in agitation CMAI (MD - 5.79; 95% CI - 9.55 to - 2.04; prediction interval: - 14.07 to 2.49) and improved CGI-S scores (MD - 0.23; 95% CI - 0.32 to - 0.13; prediction interval: - 0.39 to - 0.06). No significant differences were found in NPI scores. Adverse events such as extrapyramidal symptoms and daytime somnolence occurred more frequently with brexpiprazole but with wide and nonsignificant intervals. Meta-regression did not identify dose or duration as effect modifiers. CONCLUSIONS: Brexpiprazole may offer modest short-term benefits for agitation in AD without cognitive worsening, but safety signals remain imprecise. However, prediction intervals indicate considerable uncertainty, and its use should be individualized and closely monitored. Future trials should prioritize long-term outcomes and patient-centered measures. CRD 42025646060.}, } @article {pmid40885501, year = {2026}, author = {Rahamouz-Haghighi, S and Akaberi, M and Emami, SA and Tayarani-Najaran, Z}, title = {Biochemical profiling and protective effects of Scutellaria litwinowii against AlCl3-Induced neurotoxicity in PC12 cells.}, journal = {Journal of ethnopharmacology}, volume = {354}, number = {}, pages = {120504}, doi = {10.1016/j.jep.2025.120504}, pmid = {40885501}, issn = {1872-7573}, mesh = {Animals ; PC12 Cells ; Aluminum Chloride ; Rats ; *Plant Extracts/pharmacology/isolation & purification ; *Neuroprotective Agents/pharmacology/isolation & purification ; *Scutellaria/chemistry ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Cell Survival/drug effects ; Reactive Oxygen Species/metabolism ; Antioxidants/pharmacology/isolation & purification ; *Aluminum Compounds/toxicity ; *Chlorides/toxicity ; *Cholinesterase Inhibitors/pharmacology/isolation & purification ; Acetylcholinesterase/metabolism ; Glutathione/metabolism ; }, abstract = {Scutellaria litwinowii Bornm. & Sint., native to Iran, belongs to the Lamiaceae family, Scutellaria species are widely used in traditional medicine for treating inflammation, infections, and Neurological diseases. AIM OF THE STUDY: This research aimed to assess the neuroprotective effects of S. litwinowii fractions, focusing on anti-acetylcholinesterase (anti-AChE), antioxidant, and anti-apoptotic activities. MATERIALS AND METHODS: Oxidative stress and apoptosis were created utilizing aluminum chloride (AlCl3) in PC12 cells. The neuroprotective effect was assessed using resazurin assays, while reactive oxygen species (ROS), AChE and glutathione (GSH) were assessed using DCF-DA and Ellman's Reagent, respectively. Apoptotic cells, and lactate dehydrogenase (LDH) release were also evaluated. Western blot analysis detected the expression of β-Catenin, Survivin, and phosphorylated SAPK JNK/SAPKJNK. A dichloromethane (DCM) root fraction underwent HPLC and LC-ESI-MS profiling to identify active anti-AChE compounds. RESULTS: 48 h treatment with 5 mM AlCl3 decreased cell viability by 27 %. Pretreatment with the DCM fraction at 6.25 and 12.5 μg/ml significantly improved viability, reduced ROS and LDH release, and prevented GSH depletion, comparable to the antioxidant N-acetylcysteine (p < 0.001). At a 12.5 μg/ml, the DCM fraction inhibited AChE activity by 63.61 %, while 12.5 μM baicalein showed 59.11 % inhibition. The DCM fraction and baicalein significantly reduced AlCl3-induced apoptosis (p < 0.001), increased of β-Catenin, Survivin expression and decreased p-JNK/JNK ratio (p < 0.001). In the active time window, baicalein and wogonin were detected. CONCLUSION: This research suggests that S. litwinowii and baicalein may serve as protective agents against oxidative stress and apoptosis-related cell damage.}, } @article {pmid40885031, year = {2026}, author = {Majie, A and Karmakar, V and Ghosh, A and Chakraborty, S and Apurva, and Layek, B and Gorain, B}, title = {Advanced intranasal peptide delivery systems for improved management of Alzheimer's disease.}, journal = {Biomaterials advances}, volume = {178}, number = {}, pages = {214474}, doi = {10.1016/j.bioadv.2025.214474}, pmid = {40885031}, issn = {2772-9508}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Administration, Intranasal ; *Peptides/administration & dosage/therapeutic use/chemistry ; Animals ; *Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism ; Nanoparticles/chemistry ; Brain/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline, memory loss, and impairment in daily functioning, making up nearly 60 % of all dementia cases. Current treatments primarily manage symptoms rather than address the disease itself, underscoring the need for more effective solutions. Therapeutic peptides have emerged as promising candidates, targeting critical pathological processes in AD. Additionally, intranasal delivery offers significant advantages, including non-invasiveness, enhanced stability, rapid absorption, and the ability to bypass the blood-brain barrier. This review explores the potential of intranasal peptide delivery for AD treatment, beginning with an overview of the disease's mechanisms and existing therapies. We discuss the challenges of targeting the brain, examine nose-to-brain delivery pathways, and highlight recent advancements in delivery techniques, including the role of nanoparticles in improving efficacy. Our goal is to encourage further research into these innovative delivery strategies that could improve patient compliance and treatment outcomes. While preclinical studies indicate substantial promise, advancing these findings into clinical applications remains crucial to overcoming drug delivery challenges and ensuring long-term safety.}, } @article {pmid40884977, year = {2026}, author = {Kong, X and Yu, Z and Sun, Q and Liu, Y and Yin, ZZ}, title = {An integrative and efficient microbiosensor for β-amyloid42 based on a molecularly imprinted layer coordinating built-in hemin on the acupuncture needle.}, journal = {Bioelectrochemistry (Amsterdam, Netherlands)}, volume = {167}, number = {}, pages = {109095}, doi = {10.1016/j.bioelechem.2025.109095}, pmid = {40884977}, issn = {1878-562X}, mesh = {*Amyloid beta-Peptides/analysis ; *Hemin/chemistry ; *Biosensing Techniques/methods/instrumentation ; *Molecular Imprinting ; *Peptide Fragments/analysis ; Humans ; *Needles ; *Electrochemical Techniques/methods ; Limit of Detection ; Polymers/chemistry ; Nanotubes, Carbon/chemistry ; }, abstract = {Monitoring beta-amyloid1-42 (Aβ42) is vital and challenging, which is a typical biomarker of Alzheimer's disease. Here, a novel electrochemical microbiosensor is developed to detect Aβ42 on an acupuncture needle. Hemin is well known for its characteristics, including its ability to self-assemble on single-walled carbon nanotube (SWCNT), the molecular interaction with Aβ42, and the intrinsic electroactive signal. These properties are exploited to anchor and respond to Aβ42 after integrating a molecularly imprinted surface polymer (SMIP). The SMIP layer of polydopamine/poly (ionic liquid) can be prepared by electropolymerization on an acupuncture needle microelectrode (ANME), which undergoes growth and formation of a polymeric structure around the anchored Aβ42. Interestingly, the imprinted cavities express a fluent signal of built-in hemin after eluting the templates, and show a highly selective and sensitive hindrance response for the recombined Aβ42. Under optimized conditions, the microbiosensor displays a linear range of 100 to 1 × 10[10] fM with a limit of detection of 0.05 fM. There are development and advances for the discipline of electroanalysis after comparing the technique and important indicators with the electrochemical biosensors reported of Aβ42. The microbiosensor also exhibited excellent selectivity, good stability, and reproducibility, which was effectively used to detect Aβ42 in real spiked samples. The improved behavior of the developed microbiosensor can be attributed to its superficial highly matched imprinted cavities, built-in hemin label, and electronic barrier without signal of the nonimprinted surface to outside molecules. This microbiosensor has a scientific and reference value for directly sensing non-electroactive biomarkers, functionalizing microelectrodes, and electron transport cavities. It would also be amazing if this new microbiosensor could combine with the unclear and magical property of acupuncture in the treatment of neurological disorders.}, } @article {pmid40883746, year = {2025}, author = {Holmes, BB and Weigel, TK and Chung, JM and Kaufman, SK and Apresa, BI and Byrnes, JR and Kumru, KS and Vaquer-Alicea, J and Gupta, A and Rose, IVL and Zhang, Y and Nana, AL and Alter, D and Grinberg, LT and Spina, S and Leung, KK and Miller, BL and Condello, C and Kampmann, M and Seeley, WW and Coutinho-Budd, JC and Wells, JA}, title = {β-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {96}, pmid = {40883746}, issn = {1750-1326}, support = {R35 GM122451/GM/NIGMS NIH HHS/United States ; P30AG062422/NH/NIH HHS/United States ; K24 AG053435/AG/NIA NIH HHS/United States ; ZEN-22-969903/ALZ/Alzheimer's Association/United States ; R01 NS121101/NS/NINDS NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; Shenandoah Community Foundation//Shenandoah Community Foundation/ ; P01 AG019724/AG/NIA NIH HHS/United States ; P01AG019724/NH/NIH HHS/United States ; U01AG057195/NH/NIH HHS/United States ; R01NS121101/NS/NINDS NIH HHS/United States ; RF1AG061874/NH/NIH HHS/United States ; BrightFocus Foundation//BrightFocus Foundation/ ; R35GM122451/GM/NIGMS NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; Brain Institute, University of Virginia//Brain Institute, University of Virginia/ ; U19 AG063911/AG/NIA NIH HHS/United States ; RF1 AG061874/AG/NIA NIH HHS/United States ; U19AG063911/NH/NIH HHS/United States ; K08 NS133290/NS/NINDS NIH HHS/United States ; K24AG053435/NH/NIH HHS/United States ; 1K08NS133290/NS/NINDS NIH HHS/United States ; }, abstract = {UNLABELLED: To define how Aβ pathology alters microglia function in Alzheimer’s disease, we profiled the microglia surfaceome following treatment with Aβ fibrils. Our findings reveal that Aβ-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). Glial GPC4 expression exacerbates motor deficits and reduces lifespan in a Drosophila amyloidosis model, implicating GPC4 in a toxic neurodegenerative program. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. In human Alzheimer’s disease brain, microglial GPC4 expression surrounding Aβ plaques correlates with neuritic tau pathology, supporting a pathological link between amyloid, GPC4, and tau. These studies define a mechanistic pathway by which Aβ primes microglia to promote tau pathology via HSPGs and APOE. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00883-4.}, } @article {pmid40883512, year = {2025}, author = {Hanumanthappa, D and Kumar, BS and Shajan, SRO and Sadashivappa, NM and Walikar, SK and Hosur Dinesh, BG and Ganjipete, S and Kunjiappan, S and Theivendren, P and Chidamabaram, K and Ammunje, DN and Pavadai, P}, title = {Computational insights and experimental breakthroughs in identifying next-generation acetylcholinesterase inhibitors.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {31901}, pmid = {40883512}, issn = {2045-2322}, mesh = {Animals ; *Cholinesterase Inhibitors/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/pathology ; Rats ; Molecular Docking Simulation ; *Acetylcholinesterase/metabolism/chemistry ; Neuroprotective Agents/pharmacology/chemistry ; Male ; Nanoparticles/chemistry ; Brain/drug effects/pathology ; Disease Models, Animal ; Molecular Dynamics Simulation ; Humans ; }, abstract = {The study aimed to identify the potential acetylcholinesterase (AChE) inhibitors for effective Alzheimer's treatment from existing FDA-approved drugs through a drug repurposing technique via computational tools. Further, to evaluate the anti-Alzheimer's potency of the identified drug with the help of a suitable drug delivery system through in vivo pharmacological studies. The molecular docking and dynamics simulation studies indicated that letrozole has a significant binding affinity of -9.6 kcal/mol and a better interaction with AChE. The physicochemical properties of letrozole-encapsulated solid lipid nanoparticles (L-SLNs) were characterized and confirmed. Initially, acute toxicity tests of L-SLNs were performed according to OECD 423 guidelines. Biochemical studies revealed that L-SLNs significantly decreased brain Acetylcholine esterase activity induced by scopolamine, but L-SLNs significantly increased AChE activity compared to the Shaam control group. Histopathological evaluation of brain regions revealed significant insights into the neuroprotective potential of L-SLNs in an Alzheimer's disease (AD) rat model. Treatment with L-SLNs demonstrated dose-dependent neuroprotection across all studied brain regions. At a low dose of L-SLNs (2.5 mg/kg), neuronal and glial cells in the cortical and hippocampal regions showed improved regularity, although some disorganization persisted. At a mid-dose of L-SLNs (5 mg/kg), the histopathological architecture further normalized, with neurons and glial cells exhibiting regular arrangement and morphology akin to normal cells. The high dose of L-SLNs (10 mg/kg) provided the most significant protection, with neuronal and glial cells displaying near-normal arrangement and morphology in the cortical, hippocampal, and Substantia Nigra regions. This study highlights the importance of SLNs-based drug delivery systems in improving the efficacy of existing therapeutic agents in neurodegenerative conditions.}, } @article {pmid40859005, year = {2025}, author = {Toledano, RS and Akirav, I}, title = {Cannabidiol prevents cognitive and social deficits in a male rat model of Alzheimer's disease through CB1 activation and inflammation modulation.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {50}, number = {13}, pages = {1916-1927}, pmid = {40859005}, issn = {1740-634X}, support = {993/20//Israel Science Foundation (ISF)/ ; }, mesh = {Animals ; *Cannabidiol/pharmacology/therapeutic use ; Male ; *Alzheimer Disease/metabolism/chemically induced/drug therapy ; Rats ; *Receptor, Cannabinoid, CB1/metabolism ; Disease Models, Animal ; *Social Behavior ; Streptozocin ; Rats, Sprague-Dawley ; Hippocampus/drug effects/metabolism ; Neuroinflammatory Diseases ; *Cognitive Dysfunction/prevention & control/metabolism ; Receptor, Cannabinoid, CB2/metabolism ; Inflammation/metabolism ; }, abstract = {Cognitive decline is a hallmark of Alzheimer's disease (AD). Cannabidiol (CBD), a non-intoxicating phytocannabinoid with immunomodulatory properties, shows promise in alleviating AD symptoms. This study examined the effects of chronic CBD treatment in a male rat model of sporadic AD induced by intracerebroventricular streptozotocin (ICV-STZ) and explored its impact on neuroinflammatory genes and cannabinoid signaling. STZ rats showed impaired performance in object location and recognition tasks, along with reduced social behavior. STZ exposure also affected AD-related hippocampal markers, leading to increased levels of amyloid β-protein (Aβ) and tau phosphorylation (p-Tau) and elevated mRNA levels of triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E4 (APOEε4). Additionally, STZ increased hippocampal neuroinflammatory markers, including mRNA levels of Tumor Necrosis Factor α (TNF-α), nuclear factor kappa B subunit 1 (NF-κB1), and interleukin (IL)-1β. It also altered cannabinoid receptor expression, with cannabinoid receptor 1 (cnr1) and 2 (cnr2) genes upregulated in the dentate gyrus (DG), whereas in the CA1, cnr2 was upregulated and cnr1 downregulated. Chronic CBD treatment restored the STZ-induced behavioral deficits, reduced neuroinflammatory marker expression, and mitigated AD-associated changes. Importantly, the CB1 receptor antagonist AM251, but not CB2 antagonist AM630, blocked the beneficial effects of CBD on performance in object location and social tasks in STZ-treated rats, highlighting CB1 receptor activation as a key mechanism. These findings suggest that CBD holds promise as a therapeutic agent for inflammation-induced AD, with the potential to ameliorate cognitive deficits and prevent disease onset through mechanisms involving CB1 receptor activation and modulation of neuroinflammation.}, } @article {pmid40858778, year = {2025}, author = {Yan, J and Yang, X and Li, G and Ramirez, OA and Hagenston, AM and Chen, ZY and Bading, H}, title = {The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer's disease.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {40858778}, issn = {1476-5578}, support = {FOR 2289//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; BA1007/20-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; Advanced Grant 233024//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; BMBF 180051//Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (Federal Ministry for Education, Science, Research and Technology)/ ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by cognitive decline and neuronal degeneration. The formation of amyloid β plaques and neurofibrillary tangles are key morphological features of AD pathology. However, the specific molecules responsible for the cell destruction triggered by amyloid β and tau proteinopathies in AD has not yet been identified. Here we use the 5xFAD mouse model of AD to investigate the role of a recently discovered death signaling complex which consists of the extrasynaptic N-methyl-D-aspartate receptor (NMDAR) and the transient receptor potential cation channel subfamily M member 4 (TRPM4). The NMDAR/TRPM4 death complex is responsible for toxic signaling of glutamate, which has been implicated in AD pathogenesis. We detected an increase in NMDAR/TRPM4 death complex formation in the brains of 5xFAD mice. This increase was blocked by the oral application of FP802, a small molecule TwinF interface inhibitor that can disrupt and thereby detoxify the NMDAR/TRPM4 death complex. FP802 treatment prevented the cognitive decline of 5xFAD mice assessed using a series of memory tasks. It also preserved the structural complexity of dendrites, prevented the loss of synapses, reduced amyloid β plaque formation, and protected against pathological alterations of mitochondria. These results identify the NMDAR/TRPM4 death complex as a major promoter of AD disease progression, amplifying potentially self-perpetuating pathological processes initiated by amyloid β. TwinF interface inhibitors offer a novel therapeutic avenue, serving as an alternative or complementary treatment to antibody-mediated clearing of amyloid β from AD brains.}, } @article {pmid40854422, year = {2025}, author = {Płoska, A and Radulska, A and Siekierzycka, A and Cieślik, P and Santocki, M and Dobrucki, IT and Kalinowski, L and Wierońska, JM}, title = {Allosteric modulation of M1 or M4 muscarinic receptors restores eNOS expression and L-arginine metabolism in dementia models and synergizes with NO releasers.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {256}, number = {}, pages = {174085}, doi = {10.1016/j.pbb.2025.174085}, pmid = {40854422}, issn = {1873-5177}, mesh = {Animals ; Mice ; *Arginine/metabolism ; Male ; *Nitric Oxide Synthase Type III/metabolism/biosynthesis/genetics ; Allosteric Regulation/drug effects ; *Nitric Oxide/metabolism ; *Receptor, Muscarinic M1/metabolism/agonists ; *Receptor, Muscarinic M4/metabolism/agonists ; Disease Models, Animal ; *Dementia/metabolism/drug therapy ; Dizocilpine Maleate/pharmacology ; Scopolamine/pharmacology ; Drug Synergism ; Mice, Inbred C57BL ; Amidohydrolases/metabolism ; }, abstract = {BACKGROUND: Positive allosteric modulators (PAMs) of muscarinic receptors (M) have been shown to effectively prevent cognitive dysfunctions associated with dementias, but little is known about their impact on NO֗-dependent pathways, in particular eNOS expression, L-arginine metabolism and its derivatives (ADMA/SDMA/NMMA) production. METHODS: Biochemical studies were performed in frontal cortices, hippocampi and plasma samples from mice that were administered with MK-801 (schizophrenia-related dementa) or scopolamine (Alzheimer's disease model) for 14 days alone or together with muscarinic receptors modulators: VU0357017 (M1) and VU0152100 (M4). Western blot was used to measure eNOS, DDAH1 and PRMT5, while mass spectrometry was used to measure the levels of L-arginine derivatives. Behavioral studies aimed to investigate the procognitive effects of the combined administration of PAMs with NO[•] releasers, spermineNONOate or DETANONOate were performed in novel object recognition (NOR) test, in scopolamine- or MK-801- induced amnesia. RESULTS: Our results indicate that MK-801 or scopolamine disturb eNOS, DDAH1, PRMT5 expression, and L-arginine bioavailability. VU0357017 or VU0152100 prevented scopolamine or MK-801-induced eNOS dysfunction, but L-arginine derivatives synthesis was inhibited only in MK-801 model. Synergistic effect with NO֗ releasers was observed in NOR. CONCLUSIONS: eNOS expression and L-arginine bioavailability may contribute to antipsychotic action of VU0357017 or VU0152100. The antialzheimer's effect to a lesser extend involves normalization of L-arginine metabolism. The joint administration of the compounds with NO֗ releaser could be proposed as synergistic treatment for both schizophrenia and Alzheimer's disease.}, } @article {pmid40884807, year = {2025}, author = {Ding, MR and Xia, CY and Qu, YJ and Zhang, LM and Zhang, MX and Zhen, RR and Zhang, T and Chen, JF and Hu, B and An, HM}, title = {Identification of Flavonoid Compounds in Treating Alzheimer's Disease Based on Network Medicine Framework Strategy.}, journal = {The American journal of Chinese medicine}, volume = {53}, number = {7}, pages = {2167-2198}, doi = {10.1142/S0192415X25500806}, pmid = {40884807}, issn = {1793-6853}, mesh = {*Alzheimer Disease/drug therapy/genetics ; Animals ; Rats ; PC12 Cells ; *Flavonoids/pharmacology/therapeutic use/isolation & purification ; *Neuroprotective Agents/pharmacology ; Apoptosis/drug effects ; *Network Pharmacology ; Apigenin/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Microglia/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Flavanones/pharmacology ; Quercetin/pharmacology/therapeutic use ; Luteolin/pharmacology/therapeutic use ; *Phytotherapy ; }, abstract = {Alzheimer's disease (AD) currently lacks effective therapeutics, but blood-brain-barrier-penetrating flavonoids show promising therapeutic potential. To address this critical need, we employed a novel network medicine framework to systematically identify flavonoid compounds for AD therapy by quantifying their network proximity to AD targets. Our systematic screening identified 48 potential anti-AD flavonoids, of which luteolin, quercetin, apigenin (API), and baicalein demonstrated significant neuroprotective effects in A[Formula: see text]25-35-induced rat pheochromocytoma (PC12) cell models. Of these, API emerged as the most promising candidate. A network pharmacological analysis revealed that API likely exerts its anti-AD effects through modulating apoptosis and inflammatory response, and AKT1 and NFKBIA were identified as key therapeutic targets. Experimental validation demonstrated that API treatment impeded the H2O2-induced decline in the mitochondrial membrane potential of PC12 cells, suppressed apoptosis, and mitigated neuronal damage. Furthermore, API downregulated the AKT/NF-[Formula: see text]B signal pathway, promoted microglial M2 polarization, and attenuated LPS-induced neuroinflammation in BV2 cells. API also alleviated the toxic effects of M1 microglia on neurons. This network-based screening strategy provides an innovative approach for developing new AD therapeutics.}, } @article {pmid40882479, year = {2025}, author = {Chen, T and Li, X}, title = {ResGSNet: Enhanced local attention with Global Scoring Mechanism for the early detection and treatment of Alzheimer's Disease.}, journal = {Computers in biology and medicine}, volume = {197}, number = {Pt A}, pages = {110951}, doi = {10.1016/j.compbiomed.2025.110951}, pmid = {40882479}, issn = {1879-0534}, mesh = {*Alzheimer Disease/diagnostic imaging/therapy ; Humans ; *Magnetic Resonance Imaging ; *Brain/diagnostic imaging ; Early Diagnosis ; Female ; Male ; Aged ; *Neural Networks, Computer ; }, abstract = {Recently, Transformer has been widely used in medical imaging analysis for its competitive potential when given enough data. However, Transformer conducts attention on a global scale by utilizing self-attention mechanisms across all input patches, thereby requiring substantial computational power and memory, especially when dealing with large 3D images such as MRI images. In this study, we proposed Residual Global Scoring Network (ResGSNet), a novel architecture combining ResNet with Global Scoring Module (GSM), achieving high computational efficiency while incorporating both local and global features. First, our proposed GSM utilized local attention to conduct information exchange within local brain regions, subsequently assigning global scores to each of these local regions, demonstrating the capability to encapsulate local and global information with reduced computational burden and superior performance compared to existing methods. Second, we utilized Grad-CAM＋＋ and the Attention Map to interpret model predictions, uncovering brain regions related to Alzheimer's Disease (AD) Detection. Third, our extensive experiments on the ADNI dataset show that our proposed ResGSNet achieved satisfactory performance with 95.1% accuracy in predicting AD, a 1.3% increase compared to state-of-the-art methods, and 93.4% accuracy for Mild Cognitive Impairment (MCI). Our model for detecting MCI can potentially serve as a screening tool for identifying individuals at high risk of developing AD and allow for early intervention. Furthermore, the Grad-CAM＋＋ and Attention Map not only identified brain regions commonly associated with AD and MCI but also revealed previously undiscovered regions, including putamen, cerebellum cortex, and caudate nucleus, holding promise for further research into the etiology of AD.}, } @article {pmid40877951, year = {2025}, author = {Jiao, HS and Ge, YJ and Huang, LY and Liu, Y and Wu, BS and Lian, PP and Hao, YN and Han, SS and Li, YT and Wu, KM and Wu, CY and Cheng, TL and Yuan, P and Yu, JT}, title = {MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer's disease model.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {94}, pmid = {40877951}, issn = {1750-1326}, support = {82071201//National Natural Science Foundation of China/ ; 32371036//National Natural Science Foundation of China/ ; 2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 2023SHZDZX02//Shanghai Municipal Science and Technology Major Project/ ; 2022JC01//Shanghai Municipal Health Commission Emerging Interdisciplinary Research Project/ ; 22TQ019//Shanghai Pilot Program for Basic Research - FuDan University 21TQ1400100/ ; LG-QS-202203-09//Lingang Laboratory/ ; }, mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; *Microglia/metabolism/pathology ; Humans ; Animals ; Mice ; Genome-Wide Association Study ; Disease Models, Animal ; *Inflammation/metabolism/genetics/pathology ; Male ; Female ; Mice, Transgenic ; Neuroprotection/physiology ; Membrane Proteins ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia. Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidences indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied. METHODS: We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis. RESULTS: We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures. CONCLUSIONS: Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.}, } @article {pmid40877781, year = {2025}, author = {Poulet, PE and Tran, M and Tezenas du Montcel, S and Dubois, B and Durrleman, S and Jedynak, B and , }, title = {Prediction-powered inference for clinical trials: application to linear covariate adjustment.}, journal = {BMC medical research methodology}, volume = {25}, number = {1}, pages = {204}, pmid = {40877781}, issn = {1471-2288}, mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; *Machine Learning ; Alzheimer Disease ; Sample Size ; Disease Progression ; Algorithms ; Prognosis ; Linear Models ; Models, Statistical ; }, abstract = {Prediction-powered inference (PPI) (Angelopoulos et al., Science 382(6671):669-674, 2023) and its subsequent development called PPI++ (Angelopoulos et al., 2023) provide a novel approach to standard statistical estimation, leveraging machine learning systems, to enhance unlabeled data with predictions. We use this paradigm in clinical trials. The predictions are provided by disease progression models, providing prognostic scores for all the participants as a function of baseline covariates. The proposed method would empower clinical trials by providing untreated digital twins of the treated patients while remaining statistically valid. The potential implications of this new estimator of the treatment effect in a two-arm randomized clinical trial (RCT) are manifold. First, it leads to an overall reduction of the sample size required to reach the same power as a standard RCT. Secondly, it advocates for an imbalance of controls and treated patients, requiring fewer controls to achieve the same power. Finally, this technique directly transfers any disease prediction model trained on large cohorts to practical and scientifically valid use. In this paper, we demonstrate the theoretical properties of this estimator and illustrate them through simulations. We show that it is asymptotically unbiased for the Average Treatment Effect and derive an explicit formula for its variance. We then compare this estimator to a regression-based linear covariate adjustment method. An application to an Alzheimer's disease clinical trial showcases the potential to reduce the sample size.}, } @article {pmid40877780, year = {2025}, author = {Brosch, JR and Summanwar, D and Fowler, NR and Hammers, DB and Perkins, AJ and Higbie, A and Swartzell, K and Willis, DR}, title = {An innovative health systems approach to support early detection of cognitive impairment in primary care - the brain health navigator.}, journal = {BMC primary care}, volume = {26}, number = {1}, pages = {271}, pmid = {40877780}, issn = {2731-4553}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; *Primary Health Care/organization & administration ; Aged ; Male ; Female ; Early Diagnosis ; Aged, 80 and over ; Referral and Consultation ; *Dementia/diagnosis ; Feasibility Studies ; }, abstract = {BACKGROUND: Patients and providers experience barriers to early detection of mild cognitive impairment (MCI) and dementia. We developed a new primary care-based role, the Brain Health Navigator (BHN), who is trained to assess patients for cognitive impairment, identify addressable causes, suggest appropriate diagnostic testing, connect patients to resources, and assist patients in accessing disease-modifying treatments and dementia care management. This study describes the BHN role, the feasibility of implementing the BHN in Primary Care (PC) clinics, and the initial patients' outcomes for those who saw the BHN. METHODS: Patients ≥65 years were screened with a Digital Cognitive Assessment (DCA) in seven PC clinics from June 1, 2022, to May 31, 2023. Patients who scored likely cognitively impaired or borderline for impairment were eligible for referral to the BHN. Clinics and providers could determine if referrals were automatic or on a patient-by-patient basis. The BHN encounter included a comprehensive assessment of standardized tools and suggested laboratory and imaging studies to facilitate the diagnostic process and connect patients to resources, care and treatment, and research opportunities. RESULTS: 466 of 861 patients with likely impaired or borderline impaired DCA results were referred to the BHN.More patients with likely impaired scores (62.7%) were referred to the BHN compared to those with borderline scores (47.6%). Of the 466 referred patients, 28.9% with likely impaired scores and 23.5% with borderline scores completed a BHN visit. Patients who were seen by the BHN had a significantly higher likelihood of receiving a new diagnosis of MCI than patients who did not see the BHN and were more likely to have orders for diagnostic tests, such as vitamin B12 thyroid function and Magnetic Resonance Imaging of the head and neck. Referrals to both neurology and neuropsychology were significantly more common among patients who completed the BHN visit. CONCLUSIONS: A BHN enhances follow-up care and monitoring for patients with abnormal cognitive screening tests. A BHN visit increases the rate of evidence-based diagnostic evaluation for MCI and dementia in PC. TRIAL REGISTRATION: This study was designated as exempt by the Indiana University Institutional Review Board (#15281).}, } @article {pmid40872731, year = {2025}, author = {Vitturini, C and Cerquetella, M and Spaterna, A and Bazzano, M and Marchegiani, A}, title = {Diagnosis of Canine Cognitive Dysfunction Syndrome: A Narrative Review.}, journal = {Veterinary sciences}, volume = {12}, number = {8}, pages = {}, pmid = {40872731}, issn = {2306-7381}, abstract = {Many recent progresses in the overall quality of life have allowed for an increase in life expectancy, both in humans and in dogs. In addition, long-lived individuals may develop neurodegenerative disorders, and one of the most important in human medicine is Alzheimer's disease (AD). In veterinary medicine, the AD counterpart is Canine Cognitive Dysfunction Syndrome (CCDS), which, generally, affects elderly dogs from 8 years of age. These cognitive disorders are becoming frequently encountered conditions and, despite researchers' attention towards pathogenesis, treatment and diagnosis, more efforts are required to outline which clinical and laboratory evaluations must be carried out to reach a presumptive antemortem diagnosis of CCDS. The biggest need is the establishment of standardized protocols and guidelines for a correct clinical and diagnostic approach towards dogs with clinical signs referrable to CCDS. In this narrative review, we examined the up-to-date scientific literature on the topic, focusing our attention on sensitive and reliable markers for clinical antemortem CCDS diagnosis. Even if some parameters analyzed are interesting and promising, more investigations are needed to confirm the results obtained so far. This is crucial because a correct diagnosis is fundamental to determine the best treatment and, thus, to guarantee animals' health and welfare.}, } @article {pmid40872614, year = {2025}, author = {Marinescu, M and Zalaru, C}, title = {Benzimidazole-Pyrimidine Hybrids: Synthesis and Medicinal Properties.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {8}, pages = {}, pmid = {40872614}, issn = {1424-8247}, abstract = {Background: Heterocyclic compounds represent a key class of compounds in medicinal chemistry. Both benzimidazoles and pyrimidines are essential heterocycles in medicinal chemistry, with various therapeutic properties. Recent literature presents a series of hybrid heterocyclic compounds, as their medicinal properties are generally improved compared to those of single heterocyclic rings. Methods: A literature search was conducted across relevant scientific literature from peer-reviewed sources, using keywords, including "benzimidazole", "pyrimidine", "Biginelli", "benzimidazole-pyrimidine hybrids", "anticancer", "antiviral", "antimicrobial", and "anti-inflammatory". Results: In this review, benzimidazole-pyrimidine hybrids are reported as anticancer, antimicrobial, antiviral, anti-inflammatory, analgesic, antiulcer, antidepressant, anti-Alzheimer's, or antioxidant agents, with activities even better than those of existing drugs. The IC50 values for these anticancer hybrids are in the nanomolar range, which signifies potent anticancer agents. It can be mentioned here that the anticancer hybrid Abemaciclib, as a CDK4/6 inhibitor for the treatment of certain types of breast cancer, was approved in 2017. The antimicrobial activity of these hybrids proved especially potent against a broad variety of infections, with MIC values in the range of µM or even nM. Moreover, these hybrids exhibited good antiviral properties against SARS-CoV-2, HIV-1, and the hepatitis C virus. The hybrids also functioned as JAK3 inhibitors, COX-1 inhibitors, and MAO-A inhibitors. Conclusions: This review presents synthesis methods of benzimidazole-pyrimidine hybrids, their medicinal properties, and SAR studies reported in the last 20 years. For almost every therapeutic activity, SAR studies have revealed the essential presence of a substituent on the aromatic rings or between the two benzimidazole and pyrimidine nuclei.}, } @article {pmid40872509, year = {2025}, author = {Kruk-Słomka, M and Kuceł, D and Małysz, M and Machnikowska, A and Orzelska-Górka, J and Biała, G}, title = {New Approaches to the Treatment of Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {8}, pages = {}, pmid = {40872509}, issn = {1424-8247}, abstract = {Alzheimer's disease (AD) is one of the most common chronic neurodegenerative disorders worldwide. It is characterized by progressive memory loss and cognitive decline, leading to dementia. The pathogenesis of the disease is primarily attributed to two pathological protein structures: amyloid-beta (Aβ) plaques and tau protein neurofibrils. The current treatment strategies for AD are mainly symptomatic, highlighting the urgent need for the development of new, more effective therapies for the disease. The purpose of this paper is to provide a comprehensive and scientific review of the latest research regarding novel therapeutic options in the treatment of AD. In recent years, research has focused on more advanced and diversified strategies, including immunotherapy, gene therapy, tyrosine kinase inhibitors, therapies targeting mitochondrial function, and neurogenesis-related process modulation. One of the most promising treatment strategies for AD is immunotherapy. Intensive research is currently underway on both passive immunization, which involves the administration of monoclonal antibodies, and active immunization through vaccinations that stimulate the body to produce specific antibodies. Further research into novel therapeutic directions is essential, particularly concerning the role of the immune system in the pathogenesis of AD. Immunization appears to be a highly promising approach to developing effective methods for preventing AD or delaying the progression of this disease.}, } @article {pmid40871729, year = {2025}, author = {Vegh, C and Walach, G and Dube, K and Dobson, B and Talukdar, R and Wear, D and Jayawardena, H and Dufault, K and Culmone, L and Srikantha, S and Okaj, I and Huggard, R and Cohen, J and Pandey, S}, title = {Investigation into Efficacy and Mechanisms of Neuroprotection of Ashwagandha Root Extract and Water-Soluble Coenzyme Q10 in a Transgenic Mouse Model of Alzheimer's Disease.}, journal = {Nutrients}, volume = {17}, number = {16}, pages = {}, pmid = {40871729}, issn = {2072-6643}, mesh = {Animals ; *Ubiquinone/analogs & derivatives/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Mice, Transgenic ; *Plant Extracts/pharmacology ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; Mice ; Oxidative Stress/drug effects ; *Plant Roots/chemistry ; Male ; Autophagy/drug effects ; Cognition/drug effects ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Alzheimer's Disease (AD) is one of the most prevalent neurodegenerative disorders and the most common form of dementia. Although current treatments examine disease progression, many have side effects and primarily target symptomatic relief as opposed to halting further neurodegeneration. OBJECTIVE: The current study aims to determine the neuroprotective effects of water-soluble coenzyme Q10 (Ubisol-Q10) and an ethanolic Ashwagandha extract (E-ASH) on a transgenic mouse model of AD. METHODS: A variety of immunofluorescence staining of biomarkers was conducted to assess mechanisms commonly implicated in the disease. Additionally, spatial and non-spatial memory tests evaluated cognitive functions at two timepoints throughout the progression of the disease. RESULTS: A substantial reduction in microglial activation and amyloid-β (Aβ) plaques when treated with a combination of natural health products (NHPs), Ubisol-Q10 and E-ASH. Moreover, activation of autophagy was upregulated in both the Ubisol-Q10 and combination (Ubisol-Q10+E-ASH given as a combined "Tonic" solution) groups. Oxidative stress was decreased across treated groups, while astrocyte activation was elevated in both the E-ASH and Tonic group. The Tonic group expressed an elevation in the fluorescent intensity of neuronal nuclei (NeuN) and brain-derived neurotrophic factor (BDNF) levels. Interestingly, treatment with E-ASH and Ubisol-Q10 enhanced synaptic vesicle formation compared to controls. Pre-mortem memory tests revealed the treatments to be effective at preserving cognitive abilities. CONCLUSIONS: Based on these findings, the combination of E-ASH and Ubisol-Q10 may effectively mitigate the various mechanisms implicated in AD and ultimately prevent further disease progression.}, } @article {pmid40871707, year = {2025}, author = {Wang, M and Jin, B and Xu, J and Wang, C}, title = {Avenanthramide-C Mitigates High-Fat Diet-Accelerated Alzheimer's Pathologies via NOD1-Driven Neuroinflammation in 5×FAD Mice.}, journal = {Nutrients}, volume = {17}, number = {16}, pages = {}, pmid = {40871707}, issn = {2072-6643}, support = {LQ24H310001//Natural Science Foundation of Zhejiang Province/ ; 2022Z127//Municipal Key R&D Program of Ningbo/ ; 2024010317//Ningbo Top Medical and Health Research Program/ ; NRF-2021R1I1A1A01050493//Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; }, mesh = {Animals ; *Diet, High-Fat/adverse effects ; *Alzheimer Disease/drug therapy/etiology/metabolism/pathology ; Male ; Mice ; *ortho-Aminobenzoates/pharmacology ; Obesity/complications ; Disease Models, Animal ; *Nod1 Signaling Adaptor Protein/metabolism ; *Neuroinflammatory Diseases/drug therapy/etiology ; *Phenylenediamines/pharmacology ; Amyloid beta-Peptides/metabolism ; }, abstract = {Background: Obesity is clinically known to be associated with an increased risk and aggravated pathology of Alzheimer's disease (AD). A high-fat diet (HFD), the major contributor to obesity, induces neuroinflammation and central insulin resistance, both of which are linked to synaptic dysfunction. Our previous studies demonstrated that avenanthramide-C (Avn-C), a natural oat-derived phenolic compound, exerts anti-inflammatory effects and alleviates synaptic dysfunction in conventional AD models. The present study aimed to elucidate the underlying mechanisms of Avn-C in obesity-accelerated AD. Methods: Two-month-old male 5×FAD mice were fed an HFD to induce obesity and then treated with Avn-C. Cognitive performance, synaptic function, and structure were assessed via behavioral tests, electrophysiological recordings, and Golgi-Cox staining, respectively. Cytokine levels were quantified using ELISA and Western blotting. To explore the underlying mechanism, the NOD1 agonist C12-iE-DAP was administered to evaluate its effect on Avn-C-mediated neuroprotection. Results: Avn-C reduced Aβ deposition, enhanced the expression of synapse proteins, and restored synaptic plasticity, thereby improving both spatial and recognition memory in obese 5×FAD mice. Furthermore, Avn-C reduced neuroinflammation by inhibiting the NOD1/RIP2/NF-κB signaling pathway. Co-treatment with C12-iE-DAP abolished the beneficial effects of Avn-C on neuroinflammation, Aβ pathology, and cognitive function. Conclusions: These results suggest that Avn-C mitigates obesity-exacerbated AD-like pathological features by suppressing NOD1/RIP2/NF-κB-mediated neuroinflammation and could be a new potential therapeutic strategy for obesity-associated AD.}, } @article {pmid40871591, year = {2025}, author = {Jelčić, A and Talić, S and Odak, I and Pongrac, P and Štefok, D and Škorić, I}, title = {Photochemically Assisted Synthesis of Thienobenzotriazole-Based Dual Cholinesterase Inhibitors.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {16}, pages = {}, pmid = {40871591}, issn = {1420-3049}, mesh = {*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; Butyrylcholinesterase/metabolism/chemistry ; *Triazoles/chemistry/chemical synthesis/pharmacology ; Acetylcholinesterase/metabolism/chemistry ; Humans ; Structure-Activity Relationship ; Animals ; Molecular Structure ; Photochemical Processes ; Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry ; }, abstract = {BACKGROUND: It has been shown previously that thienobenzo-1,2,3-triazoles exhibit very good selective inhibition toward butyrylcholinesterase (BChE), while the same derivatives converted into salts also display inhibitory activity against acetylcholinesterase (AChE), enzymes relevant to Alzheimer's disease therapy. They show even better BChE inhibition potential than neutral analogs. METHODS: This study presents the synthesis and biological evaluation of a novel series of charged thienobenzo-1,2,3-triazolinium salts (1-17) as inhibitors of AChE and BChE. The basic skeleton of the targeted compounds was synthesized via a photochemical method and subsequently converted into corresponding bromide salts. Their structures were confirmed using NMR and HRMS analyses. RESULTS: In vitro testing showed that all synthesized compounds exhibit moderate to strong BChE inhibition and, to a lesser extent, AChE inhibition. Compounds 8 and 11 emerged as the most potent AChE inhibitors (IC50 ~ 2.6-3.2 µM), while compounds 1, 2, and 8 demonstrated excellent and selective BChE inhibition (IC50 ~ 0.3-0.4 µM), outperforming the reference drug galantamine. Anti-inflammatory evaluation revealed limited activity, with compound 17 slightly reducing LPS-induced TNF-α production at the highest tested concentration. CONCLUSIONS: These findings highlight the role of the electric charge and substituent type in modulating biological activity and confirm the therapeutic potential of these molecules as dual cholinesterase inhibitors for further development in neurodegenerative disease treatment.}, } @article {pmid40871020, year = {2025}, author = {Renteros, MS and Barreto-Abanto, R and Huapaya, DC and Tovar-Cobos, M and Alvarado-Ramos, RD and Rivera-Lozada, O and Barboza, JJ}, title = {The Efficacy of Solanezumab in Patients with Alzheimer's Disease: A Systematic Review and Meta-Analysis of Clinical Trials.}, journal = {Pharmaceutics}, volume = {17}, number = {8}, pages = {}, pmid = {40871020}, issn = {1999-4923}, abstract = {Background/Objectives: Solanezumab is a humanized monoclonal antibody designed to bind soluble amyloid-beta (Aβ) and facilitate its clearance from the brain, aiming to slow the progression of Alzheimer's disease (AD). Methods: A systematic search was applied in four medical databases through October 2024 to identify phase 2 or 3 randomized controlled trials evaluating solanezumab in patients aged ≥50 years with mild AD or in preclinical stages. The primary outcomes were changes in cognitive and functional scales, including ADAS-cog14, MMSE, ADCS-ADL, and CDR-SB. Data were pooled using a random-effects model, and certainty of evidence was assessed using GRADE. Results: Seven trials involving 4181 participants were included. Solanezumab did not significantly reduce cognitive decline based on ADAS-cog14 (MD = -0.75; 95% CI: -2.65 to 1.15; very low certainty) or improve functional scores on ADCS-ADL (MD = 0.85; 95% CI: -1.86 to 3.56; very low certainty) and CDR-SB (MD = -0.15; 95% CI: -0.89 to 0.60; very low certainty). A modest but statistically significant improvement was observed in MMSE scores (MD = 0.59; 95% CI: 0.33 to 0.86; moderate certainty). Conclusions: While solanezumab may offer slight benefits in general cognitive performance, its overall impact on clinically meaningful outcomes remains limited. The results do not support its use as a disease-modifying therapy for Alzheimer's disease in either preclinical or symptomatic stages.}, } @article {pmid40870510, year = {2025}, author = {Bougea, A and Debasa-Mouce, M and Gulkarov, S and Castro-Mosquera, M and Reiss, AB and Ouro, A}, title = {From Better Diagnostics to Earlier Treatment: The Rapidly Evolving Alzheimer's Disease Landscape.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {8}, pages = {}, pmid = {40870510}, issn = {1648-9144}, support = {AWD00004772//The Alzheimer's Foundation of America Award/ ; //The Herb and Evelyn Abrams Family Amyloid Research Fund/ ; IN607A2022/07//Xunta de Galicia/ ; PI22/00938//Instituto de Salud Carlos III/ ; PI21/00727//Instituto de Salud Carlos III/ ; RD21/0006/0005//Instituto de Salud Carlos III/ ; CB22/05/00067//CIBERNED/ ; EAPA_791/2018_ NEUROATLANTIC project//INTERREG Atlantic Area/ ; 0624_2IQBIONEURO_6_E//INTER-REG V A España Portugal/ ; }, mesh = {*Alzheimer Disease/diagnosis/therapy/genetics ; Humans ; Biomarkers/analysis/blood ; Amyloid beta-Peptides/analysis ; tau Proteins/analysis ; Early Diagnosis ; Neuropsychological Tests ; Genome-Wide Association Study/methods ; }, abstract = {Background and Objectives: Over the past few years, there has been a significant shift in focus from developing better diagnostic tools to detecting Alzheimer's disease (AD) earlier and initiating treatment interventions. This review will explore four main objectives: (a) the role of biomarkers in enhancing the diagnostic accuracy of AD, highlighting the major strides that have been made in recent years; (b) the role of neuropsychological testing in identifying biomarkers of AD, including the relationship between cognitive performance and neuroimaging biomarkers; (c) the amyloid hypothesis and possible molecular mechanisms of AD; and (d) the innovative AD therapeutics and the challenges and limitations of AD research. Materials and Methods: We have searched PubMed and Scopus databases for peer-reviewed research articles published in English (preclinical and clinical studies as well as relevant reviews and meta-analyses) investigating the molecular mechanisms, biomarkers, and treatments of AD. Results: Genome-wide association studies (GWASs) discovered 37 loci associated with AD risk. Core 1 biomarkers (α-amyloid Aβ42, phosphorylated tau, and amyloid PET) detect early AD phases, identifying both symptomatic and asymptomatic individuals, while core 2 biomarkers inform the short-term progression risk in individuals without symptoms. The recurrent failures of Aβ-targeted clinical studies undermine the amyloid cascade hypothesis and the objectives of AD medication development. The molecular mechanisms of AD include the accumulation of amyloid plaques and tau protein, vascular dysfunction, neuroinflammation, oxidative stress, and lipid metabolism dysregulation. Significant advancements in drug delivery technologies, such as focused Low-Ultrasound Stem, T cells, exosomes, nanoparticles, transferin, nicotinic and acetylcholine receptors, and glutathione transporters, are aimed at overcoming the BBB to enhance treatment efficacy for AD. Aducanumab and Lecanemab are IgG1 monoclonal antibodies that retard the progression of AD. BACE inhibitors have been explored as a therapeutic strategy for AD. Gene therapies targeting APOE using the CRISPR/Cas9 genome-editing system are another therapeutic avenue. Conclusions: Classic neurodegenerative biomarkers have emerged as powerful tools for enhancing the diagnostic accuracy of AD. Despite the supporting evidence, the amyloid hypothesis has several unresolved issues. Novel monoclonal antibodies may halt the AD course. Advances in delivery systems across the BBB are promising for the efficacy of AD treatments.}, } @article {pmid40869897, year = {2025}, author = {Akbar, A and Haider, R and Agnello, L and Noor, B and Maqsood, N and Atif, F and Ali, W and Ciaccio, M and Tariq, H}, title = {CRISPR in Neurodegenerative Diseases Treatment: An Alternative Approach to Current Therapies.}, journal = {Genes}, volume = {16}, number = {8}, pages = {}, pmid = {40869897}, issn = {2073-4425}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/genetics ; *CRISPR-Cas Systems/genetics ; *Gene Editing/methods ; *Genetic Therapy/methods ; Animals ; *Clustered Regularly Interspaced Short Palindromic Repeats ; RNA, Guide, CRISPR-Cas Systems/genetics ; }, abstract = {Neurodegenerative diseases (NDs) pose a major challenge to global healthcare systems owing to their devastating effects and limited treatment options. These disorders are characterized by progressive loss of neuronal structure and function, resulting in cognitive and motor impairments. Current therapies primarily focus on symptom management rather than on targeting the underlying causes. However, clustered regularly interspaced short palindromic repeat (CRISPR) technology offers a promising alternative by enabling precise genetic modifications that could halt or even reverse ND progression. CRISPR-Cas9, the most widely used CRISPR system, acts as a molecular scissor targeting specific DNA sequences for editing. By designing guide RNAs (gRNAs) to match sequences in genes associated with NDs, researchers can leverage CRISPR to knockout harmful genes, correct mutations, or insert protective genes. This review explores the potential of CRISPR-based therapies in comparison with traditional treatments for NDs. As research advances, CRISPR has the potential to revolutionize ND treatment by addressing its genetic underpinnings. Ongoing clinical trials and preclinical studies continue to expand our understanding and application of this powerful tool to fight debilitating conditions.}, } @article {pmid40869269, year = {2025}, author = {Zhang, YM and Yang, F and Li, Q and Zhang, JN}, title = {Role of Histone Lactylation in Neurological Disorders.}, journal = {International journal of molecular sciences}, volume = {26}, number = {16}, pages = {}, pmid = {40869269}, issn = {1422-0067}, support = {82371321 82271240 82301604//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Histones/metabolism ; *Nervous System Diseases/metabolism/genetics ; Animals ; Epigenesis, Genetic ; *Protein Processing, Post-Translational ; *Lactic Acid/metabolism ; }, abstract = {Lactate is not only the end product of glycolysis but also plays a key role in epigenetic regulation. Recently, lactate-derived histone lactylation has been identified as a novel epigenetic modification that can directly influence gene transcription. Histone lactylation has been associated with various pathological conditions and shows significant therapeutic potential. However, studies on histone lactylation in central nervous system diseases are still quite limited. In this review, we summarize the latest research progress on histone lactylation, detailing the specific mechanisms and sites of histone lactylation, including lactylation and delactylation. We also discuss the role of histone lactylation in Alzheimer's disease (glycolysis/H4K12la/PKM2 feedback loop), depression (neuronal excitation), neuroinflammation (anti-inflammatory/pro-inflammatory balance of microglia), aging, stroke (infarct volume), and glioblastoma (activation of oncogenes), pointing out the research directions for the future. This may provide new ideas for the diagnosis and treatment of neurological diseases.}, } @article {pmid40869160, year = {2025}, author = {Faustman, DL and Davis, M and Kuhtreiber, WM}, title = {TNFR2 Agonism: Basic Science and Promising Treatment for Multiple Sclerosis and Related Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {16}, pages = {}, pmid = {40869160}, issn = {1422-0067}, support = {001-20//Iacocca Foundation/ ; }, mesh = {Humans ; *Multiple Sclerosis/drug therapy/metabolism/immunology ; *Receptors, Tumor Necrosis Factor, Type II/agonists/metabolism ; Animals ; T-Lymphocytes, Regulatory/immunology/metabolism/drug effects ; }, abstract = {The three pathological hallmarks of multiple sclerosis (MS) are inflammation, demyelination, and progressive neurodegeneration. None of the approved disease-modifying therapies for MS counters all three pathologies, and, more specifically, none is approved for neuroprotection. Axonal loss is the most significant contributor to chronic and irreversible disability in MS. A tantalizing molecular target has emerged to uniquely counter all three MS pathologies: tumor necrosis factor receptor 2 (TNFR2). Agonism or activation of TNFR2 has been shown in MS models to induce immunosuppression, oligodendrocyte precursor differentiation, and neuroprotection. Further, in basic science studies stemming from the past 15 years, TNFR2 agonism is known to be a strong inducer of T-regulatory cells (Tregs). Treg cells, and especially those expressing TNFR2, are known to confer the strongest suppression per cell type. TNFR2 is even more attractive as a therapeutic target because of its restricted expression by only a handful of CNS and immune cell subsets, thereby minimizing the likelihood of systemic and other adverse effects. Recent antibody design work suggests many of the hurdles of Treg agonism may have been overcome. This review covers the current treatment landscape for MS, the basic science of TNFR2, the rationale for and evidence behind TNFR2 agonism to treat multiple sclerosis, the design of potent TNFR2 agonist antibodies, and the treatment applications for other neurological, autoimmune, or inflammatory diseases.}, } @article {pmid40869046, year = {2025}, author = {Koga-Batko, J and Antosz-Popiołek, K and Nowakowska, H and Błażejewska, M and Kowalik, EM and Beszłej, JA and Leszek, J}, title = {Nanoparticles as an Encouraging Therapeutic Approach to Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {16}, pages = {}, pmid = {40869046}, issn = {1422-0067}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Nanoparticles/chemistry/therapeutic use ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; Neuroprotective Agents/therapeutic use/chemistry ; Drug Carriers/chemistry ; }, abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease of the central nervous system, responsible for 60-80% of dementia. Its pathogenesis is mainly based on the accumulation of beta-amyloid and tau proteins. Current pharmacological treatment includes acetylcholinesterase inhibitors, NMDA receptor antagonists, and monoclonal antibodies. However, their effect is limited by the blood-brain barrier (BBB). A new and promising way for different drugs to cross the BBB is the use of nanoparticles such as liposomes, micelles, solid lipid nanocarriers, polymeric nanoparticles, dendrimers, nanoemulsions, and inorganic nanoparticles as their carriers. Additionally, some nanoparticles present anti-inflammatory or neuroprotective effects. Some of them can also be used to treat cerebral amyloid angiopathy (CAA) by aiming at amyloid deposits in brain arterioles. All the properties of nanoparticles listed and discussed in the article allow us to hope that there will be more effective treatment in the future, which is extremely important as the number of patients with AD is still growing.}, } @article {pmid40868857, year = {2025}, author = {Tahiroglu, V and Karagecili, H and Aslan, K and Gulcin, İ}, title = {Polyphenolic Profiling and Evaluation of Antioxidant, Antidiabetic, Anti-Alzheimer, and Antiglaucoma Activities of Allium kharputense and Anchusa azurea var. azurea.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {8}, pages = {}, pmid = {40868857}, issn = {2075-1729}, abstract = {The genera Allium (Liliaceae) and Anchusa (Boraginaceae) are flowering plant genera with a rich diversity, also including the Allium kharputense Freyn & Sint. and Anchusa azurea Mill. var. azurea species. The antioxidant, anti-Alzheimer's disease (AD), antidiabetic, and antiglaucoma effects of the Allium kharputense Freyn & Sint. and Anchusa azurea Mill. var. azurea species, which are commonly eaten foods in the Southeast of Türkiye in the treatment of several diseases, were studied. To interpret the antioxidant capacities of ethanol extract of two plant species, aerial parts were analyzed by ABTS and DPPH assays. The IC50 values of A. kharputense and A. azurea ethanol and water extracts for ABTS[•+] activities were recorded in the range of 30.93 to 33.94 µg/mL and 33.45 to 33.78 µg/mL, respectively. Also, DPPH[•] activities were measured at 30.78 to 36.87 µg/mL and 31.67 to 32.45 µg/mL, respectively. The best of the IC50 values was measured in the ethanol extract of A. kharputense as 30.78 µg/mL for DPPH scavenging activity. The total phenolic and flavonoid quantities in A. kharputense and A. azurea plants were measured. The highest phenolic and flavonoid contents of A. kharputense and A. azurea species were recorded in amounts of 445.52 and 327.35 mg GAE/g in ethanol extracts, respectively, and 332.88 and 234.03 mg QE/g in ethanol extracts, respectively. The effects of A. kharputense and A. azurea on diabetes, AD, and glaucoma were studied on the target enzymes of diseases. The most efficient IC50 values were recorded at 10.72 μg/mL against α-glycosidase, 35.01 μg/mL against AChE, 38.05 μg/mL against BChE, 9.21 μg/mL towards hCA I, and 81.02 μg/mL towards hCA II isoenzymes. The kinds and amounts of phenolic compounds in A. kharputense and A. azurea were determined using LC-MS/MS against 53 standards. A. kharputense and A. azurea plants have prospective use in enhancing glaucoma, diabetes, AD, Parkinson's disease, epilepsy, and cancerous disorders.}, } @article {pmid40868760, year = {2025}, author = {Georgieva, D and Bogdanova, I and Mihaylova, R and Alexandrova, M and Bozhilova, S and Christova, D and Kostova, B}, title = {Orodispersible Hydrogel Film Technology for Optimized Galantamine Delivery in the Treatment of Alzheimer's Disease.}, journal = {Gels (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {40868760}, issn = {2310-2861}, abstract = {Alzheimer's disease is the most widespread neurodegenerative disease in the world. Galantamine hydrobromide (GH) is one of the drugs used to treat mild to moderate dementia of the Alzheimer type. Due to the fact that the specificity of the disease requires maximally facilitated intake, orodispersible films present such an opportunity. In the present study orodispersible films based on poly(2-ethyl-2-oxazoline) as well as partially hydrolyzed poly(2-ethyl-2-oxazoline) were prepared and studied as delivery systems for GH. Two samples of partially hydrolyzed PEtOx were synthesized-one of relatively low degree of hydrolysis and another one of relatively high degree of hydrolysis, and studied by Nuclear Magnetic Resonance (NMR). Cytotoxicity assay was performed that validated the low hydrolyzed derivative as biocompatible polymer that maintained desirable physicochemical characteristics without compromising the safety, thereby it was selected for further research. The films were prepared by the solution casting method and characterized by different methods. FTIR was used to determine the potential interactions between the galantamine molecule and the film components. Based on the Thermogravimetric Analysis (TGA) conducted, it was concluded that all films were sufficiently thermally stable, as the component decomposition stage (after initial solvent removal) began above 180 °C. The polymer films were further characterized with the determination of Shore hardness and the results showed that the films containing glycerol as a plasticizer exhibited higher hardness compared to those with PEG as a plasticizer. The disintegration time of the films was determined visually using Petri dishes and it was found that the films disintegrated within the range of 0.52 to 1.58 min, fully meeting the pharmacopoeial requirements. GH release profiles in PBS at 37 °C were obtained, and it was found that by the second minute, 80-90% of the drug were released from the different films, and the release followed an anomalous diffusion mechanism (Case II).}, } @article {pmid40867632, year = {2025}, author = {Han, L and Wei, S and Wang, R and Liu, Y and Zhong, Y and Fu, J and Luo, H and Bao, M}, title = {Apelin-13-Mediated Upregulation of METTL3 Ameliorates Alzheimer's Disease via Inhibiting Neuroinflammation Through m6A-Dependent Regulation of lncRNA BDNF-AS.}, journal = {Biomolecules}, volume = {15}, number = {8}, pages = {}, pmid = {40867632}, issn = {2218-273X}, support = {82100040//National Natural Science Foundation of China/ ; 2024JJ5054//Natural Science Foundation of Hunan Province/ ; 2022JJ30640//Natural Science Foundation of Hunan Province/ ; 23A0666//Scientific Research Foundation of Hunan Provincial Education Department/ ; 2022CYY012//ESI Special Project of Changsha Medical University/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/drug therapy/pathology ; Rats ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; Male ; *Intercellular Signaling Peptides and Proteins/pharmacology ; Up-Regulation/drug effects ; *Methyltransferases/genetics/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; Amyloid beta-Peptides ; PC12 Cells ; Rats, Sprague-Dawley ; Hippocampus/metabolism/pathology/drug effects ; Disease Models, Animal ; Peptide Fragments ; *Neuroinflammatory Diseases/metabolism/genetics ; Signal Transduction ; }, abstract = {Apelin-13, a neuropeptide, has been recognized for its neuroprotective properties. Our previous study found apelin-13 improves cognitive function in Alzheimer's disease (AD) rats by inhibiting neuroinflammation through upregulation of BDNF/TrkB signaling pathway. However, the precise mechanism by which apelin-13 modulates BDNF remains unclear. Thus, this study aimed to unravel the specific regulatory mechanism by which apelin-13 regulates BDNF. Bilaterally intracerebroventricular injection with Aβ25-35 was used to establish an in vivo model of AD. For the generation of METTL3 KO rats, the Crispr/Cas9 method was applied. PC12 cells were treated with Aβ25-35 to establish an in vitro model of AD. The cognitive function of the rats was evaluated with the Morris water maze and the novel object recognition test. Hippocampal damage and neuron loss were detected through H&E and immunofluorescent staining. METTL3, BDNF, TrkB, and p-TrkB were examined by Western blotting. Inflammation-related cytokines, IBA1, GFAP, IL-1β, and TNF-α were detected by Western blotting, immunofluorescent staining, ELISA, and qRT-PCR. m6A modification level was evaluated through MeRIP. A flow cytometer was applied to evaluate cell apoptosis. Cell proliferation was examined using MTT. m6A methylation inhibitor DAA reverses the improvement effect of apelin-13 on cognitive function, hippocampal nerve damage, neuron loss, and neuroinflammation in Aβ25-35-treated rats. Further results showed that apelin-13 upregulated METTL3, BDNF-AS m6A methylation, inhibited BDNF-AS expression, and subsequently upregulated BDNF/TrkB signaling pathway and reduced neuroinflammation in in vivo and in vitro AD models in a dose-dependent manner. Knockdown of METTL3 abolished apelin-13's improvement effect in AD rats. Apelin-13-mediated upregulation of METTL3 enhances neuroinflammation inhibition and BDNF/TrkB signaling pathway via m6A-dependent downregulation of lncRNA BDNF-AS, thus ameliorating AD. Our study offers novel insights into the pathogenesis of AD and identifies potential drug targets for its treatment.}, } @article {pmid40867293, year = {2025}, author = {Arendash, GW}, title = {The Evidence That Brain Cancers Could Be Effectively Treated with In-Home Radiofrequency Waves.}, journal = {Cancers}, volume = {17}, number = {16}, pages = {}, pmid = {40867293}, issn = {2072-6694}, support = {9 R44 AG073096-02A1//National Institute of Health/ ; }, abstract = {There is currently no effective therapeutic capable of arresting or inducing regression of primary or metastatic brain cancers. This article presents both pre-clinical and clinical studies supportive that a new bioengineered technology could induce regression and/or elimination of primary and metastatic brain cancers through three disease-modifying mechanisms. Transcranial Radiofrequency Wave Treatment (TRFT) is non-thermal, non-invasive and self-administered in-home to safely provide radiofrequency waves to the entire human brain. Since TRFT has already been shown to stop and reverse the cognitive decline of Alzheimer's Disease in small studies, evidence is provided that three key mechanisms of TRFT action, alone or in synergy, could effectively treat brain cancers: (1) enhancement of brain meningeal lymph flow to increase immune trafficking between the brain cancer and cervical lymph nodes, resulting in a robust immune attack on the brain cancer; (2) rebalancing of the immune system's cytokines within the brain or brain cancer environment to decrease inflammation therein and thus make for an inhospitable environment for brain cancer growth; (3) direct anti-proliferation/antigrowth affects within the brain tumor microenvironment. Importantly, these mechanisms of TRFT action could be effective against both visualized brain tumors and those that are yet too small to be identified through brain imaging. The existing animal and human clinical evidence presented in this perspective article justifies TRFT to be clinically tested immediately against both primary and metastatic brain cancers as monotherapy or possibly in combination with immune checkpoint inhibitors.}, } @article {pmid40867182, year = {2025}, author = {Jensen-Kondering, U and Kuhn, V and Schacht, H and Neumann, A and Royl, G and Schramm, P}, title = {Cerebral Microbleeds with a Venous Connection on 3 Tesla Susceptibility-Weighted Imaging in Persons with Alzheimer's Disease and Healthy Aging Controls.}, journal = {Brain sciences}, volume = {15}, number = {8}, pages = {}, pmid = {40867182}, issn = {2076-3425}, abstract = {Introduction: It has been recently demonstrated that some cerebral microbleeds (CMBs) are connected to cerebral veins in patients with cerebral small vessel disease (CSVD) including cerebral amyloid angiopathy (CAA). We sought to demonstrate the presence of CMB at 3 Tesla using susceptibility-weighted imaging and speculated that it was more prevalent in persons with Alzheimer's disease (AD), another amyloid-related disease, than in healthy ageing controls. Material and Methods: We included persons from the publicly available OASIS3-database. Persons were included if they had a structural MRI including a susceptibility-weighted sequence (SWI) and relevant clinical data. Two raters assessed the presence and location of CMBs and CMBs with a venous connection (CMBven). Results: A total of 571 persons (AD, n = 140, healthy controls, n = 431) were included. In total, 367 CMBs were detected, encompassing 26/571 persons (4.5%) who had a total of 40/367 (10.9%) CMBs with a CMBven, though there was no difference between persons with AD and healthy controls (AD 6.6%, healthy controls 7.4%, p = 0.773). Persons with CMBven had a higher total CMB load, were more likely female, displayed an APOE ε2/2 genotype and had antithrombotic treatment more often. Logistic regression revealed a higher number of CMB (OR (95% CI) = 1.351 (1.161-1.688), p < 0.0014) and a lower MoCA score (OR (95% CI) = 0.862 (0.762-0.982), p = 0.018), indicating a statistically significant association with the presence of CMBven. Discussion: CMBven are not an uncommon finding in persons with AD and healthy ageing controls. Our results highlight the potential venous contribution to CSVD. Histopathological studies will be needed to assess these further.}, } @article {pmid40867162, year = {2025}, author = {Cont-Richter, C and Stute, N and Galli, A and Schulte, C and Wojtecki, L}, title = {Transcranial Pulse Stimulation in Alzheimer's: Long-Term Feasibility and a Multifocal Treatment Approach.}, journal = {Brain sciences}, volume = {15}, number = {8}, pages = {}, pmid = {40867162}, issn = {2076-3425}, abstract = {BACKGROUND/OBJECTIVES: Neuromodulation is under investigation as a possibly effective add-on therapy in Alzheimer's disease (AD). While transcranial pulse stimulation (TPS) has shown positive short-term effects, long-term effects have not yet been fully explored. This study aims to evaluate the long-term feasibility, safety, and potential cognitive benefits of TPS over one year in patients with Alzheimer's disease, focusing on domains such as memory, speech, orientation, visuo-construction, and depressive symptoms. METHODS: We analyzed preliminary data from the first ten out of thirty-five patients enrolled in a prospective TPS study who completed one year of follow-up and were included in a dedicated long-term database. The protocol consisted of six initial TPS sessions over two weeks, followed by monthly booster sessions delivering 6000 pulses each for twelve months. Patients underwent regular neuropsychological assessments using the Alzheimer Disease Assessment Scale (ADAS), Mini-Mental Status Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Beck Depression Inventory (BDI-II). All adverse events (AEs) were documented and monitored throughout the study. RESULTS: Adverse events occurred in less than 1% of stimulation sessions and mainly included mild focal pain or transient unpleasant sensations, as well as some systemic behavioral or vigilance changes, particularly in patients with underlying medical conditions, with some potentially related to the device's stimulation as adverse device reactions (ADRs). Cognitive test results showed significant improvement after the initial stimulation cycle (ADAS total improved significantly after the first stimulation cycle (M_pre = 28.44, M_post = 18.56; p = 0.001, d = 0.80, 95% CI (0.36, 1.25)), with stable scores across all domains over one year. Improvements were most notable in memory, speech, and mood. CONCLUSIONS: TPS appears to be a generally safe and feasible add-on treatment for AD, although careful patient selection and monitoring are advised. While a considerable number of participants were lost to follow-up for various reasons, adverse events and lack of treatment effect were unlikely primary causes. A multifocal stimulation approach (F-TOP2) is proposed to enhance effects across more cognitive domains.}, } @article {pmid40867144, year = {2025}, author = {Dong, Y and Shi, L and Ma, Y and Liu, T and Sun, Y and Jin, Q}, title = {Gender Differences in the Effects of Exercise Interventions on Alzheimer's Disease.}, journal = {Brain sciences}, volume = {15}, number = {8}, pages = {}, pmid = {40867144}, issn = {2076-3425}, support = {2016YFD0400603//The National Key Research and Development project in China/ ; Project No. KYCX25_3954//The Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory loss, cognitive decline, and structural brain atrophy. Substantial sex differences have been observed in its incidence, clinical trajectory, and response to treatment. Women are disproportionately affected, exhibiting faster progression and more severe cognitive impairment. Exercise has emerged as a promising non-pharmacological intervention to mitigate AD-related decline, yet growing evidence reveals that its benefits vary by sex. This review synthesizes current findings from human and animal studies, focusing on how exercise impacts AD differently in males and females. In women, exercise is more strongly associated with improvements in cognitive function, neurotrophic support, and emotional regulation. In men, benefits tend to involve structural preservation and oxidative adaptations. Underlying mechanisms include differential hormonal profiles, inflammatory responses, and neuroplastic signaling pathways. These findings underscore the need to consider sex as a biological variable in AD research. Developing sex-specific exercise strategies may enhance therapeutic outcomes and support more individualized approaches in AD prevention and care.}, } @article {pmid40864805, year = {2025}, author = {Klein, BY and Gofrit, ON and Greenblatt, CL}, title = {BCG Impact on PD-1/PD-L1 Expression in Peripheral Immunocytes of Cancer Patients-A Potential Explanation for Its Activity in Preventing Alzheimer's Disease.}, journal = {Current issues in molecular biology}, volume = {47}, number = {8}, pages = {}, pmid = {40864805}, issn = {1467-3045}, abstract = {We found, retrospectively, that BCG therapy in non-muscle invasive bladder cancer (NMIBC) reduces the rate of Alzheimer's disease. Blockade of the ligand PD-L1 or its checkpoint receptor PD-1 has been shown to improve cognitive function and reduce brain pathology features in a mouse model of Alzheimer's disease (AD). Given that peripheral blood mononuclear cells (PBMCs) are involved in aging brain pathology and thus represent a potential AD therapeutic target, we analyzed the impact of BCG on the expression of PD-1, PD-L1, and inflammation modulators in PBMCs. Cryopreserved PBMCs pre- and post-BCG-treated six melanoma and six NMIBC patients were repurposed for immunoelectrophoretic analysis of PBMC-extracted proteins. PBMCs, post-BCG treatment in melanoma patients, were harvested only 4 months after the start of treatment (short BCG period), whereas the PBMCs of NMIBC patients were harvested 24 to 52 months after starting the BCG treatment. In melanoma PBMCs, BCG upregulated PD-L1 (p = 0.052) while downregulating PD-1 (insignificantly, p = 0.16). In contrast, in NMIBC patients, BCG downregulated PD-L1 (insignificantly, p = 0.67), while upregulating PD-1 (p = 0.0082). PD-L1 positive correlation with p-IkB (r = 0.7228) under BCG is inverted to that of PD-L1 against IkB (p = -0.9491). The difference between these opposite correlations is significant (p = 0.011), indicating that PD-L1 is upregulated early after BCG treatment, in association with p-IKB, which enables inflammation. This association subsided later, and for PD-1, did not occur at the short or long BCG periods. Experiments with a larger number of patients may substantiate the hypothesis that an increase in PD-1 by BCG relative to PD-L1 may protect against AD.}, } @article {pmid40864789, year = {2025}, author = {Szala-Rycaj, J and Zagaja, M and Szewczyk, A and Polak, J and Andres-Mach, M}, title = {Neuroprotective Potential of Phytocompounds in the Treatment of Dementia: The State of Knowledge from the Scopolamine-Induced Animal Model of Alzheimer's Disease.}, journal = {Current issues in molecular biology}, volume = {47}, number = {8}, pages = {}, pmid = {40864789}, issn = {1467-3045}, abstract = {Dementia is a broad category of neurodegenerative pathologies characterized by a progressive decline in two or more cognitive domains, including memory, language, executive and visuospatial functions, personality, and behavior, resulting in the loss of the ability to perform instrumental and/or basic daily activities. One of the most common types of dementia is Alzheimer's disease. Current approved treatments for Alzheimer's disease are mainly limited to alleviating cognitive, behavioral, and psychological deficits. To date, four drugs belonging to two families have been approved for the treatment of Alzheimer's disease: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and antiglutamatergic drugs (memantine). Drugs delay the progression of the disease, but they cause a number of side effects. Many scientific studies have focused on finding natural products with potential neuroprotective properties and no or minimal cytotoxicity that can support current drug therapy. The main objective of this review is to analyze and describe the neuroprotective potential of selected groups of natural substances (polyphenols, alkaloids, terpenoids) in one of the commonly performed in vivo studies, the scopolamine-induced animal model of Alzheimer's disease. The article is a review of literature reports from the last 5 years, and the information collected indicates that the neuroprotective activity of natural compounds may prove to be a potential alternative or add-on for Alzheimer's disease therapy.}, } @article {pmid40882298, year = {2025}, author = {Sobha, A and Krishnan, L and Shaik, S and Pai, A and Purushothaman, J and Alaganandam, K and Somappa, SB}, title = {Targeting Alzheimer's pathology: Tetralone- and thiochromanone-based benzyl pyridinium derivatives as promising multi-target-directed ligands.}, journal = {Bioorganic & medicinal chemistry}, volume = {130}, number = {}, pages = {118369}, doi = {10.1016/j.bmc.2025.118369}, pmid = {40882298}, issn = {1464-3391}, mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Ligands ; *Tetralones/chemistry/pharmacology ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Pyridinium Compounds/chemistry/pharmacology/chemical synthesis ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology/chemical synthesis ; Cell Line, Tumor ; Acetylcholinesterase/metabolism ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Monoamine Oxidase/metabolism ; Structure-Activity Relationship ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Molecular Structure ; }, abstract = {The lack of therapeutics that can fully halt the progression of Alzheimer's disease (AD) has prompted us to design and synthesize a series of tetralone/thiochromanone-based benzyl pyridinium salts (4a-4s) aimed at modulating multiple pathological targets associated with AD. Preliminary screening for cholinesterase and monoamine oxidase inhibition identified compounds 4e and 4g as the most potent inhibitors (AChE IC50: 2.17 ± 0.13 μM and 2.29 ± 0.15 μM; MAO-B IC50: 0.89 ± 0.07 μM and 0.92 ± 0.16 μM, respectively). Both compounds also demonstrated anti-neuroinflammatory activity by reducing pro-inflammatory cytokines (TNF-α and IL-6) and downregulating COX-2 and NF-κB signalling pathways. Additionally, 4e exhibited significant ROS scavenging ability by mitigating oxidative stress and conferred neuroprotection in SH-SY5Y cells by attenuating Aβ1-42-induced mitochondrial dysfunction and apoptosis. Collectively, these findings position compound 4e as a promising multi-target-directed ligand (MTDL) for the treatment of AD.}, } @article {pmid40882223, year = {2025}, author = {Jiang, X and Wu, L and Zhou, R and Quan, M and Xiang, X}, title = {Galanthamine promotes neuronal differentiation and neurite outgrowth of neural progenitor/stem cells by up-regulating IGF-2.}, journal = {Biochemistry and cell biology = Biochimie et biologie cellulaire}, volume = {103}, number = {}, pages = {1-9}, doi = {10.1139/bcb-2025-0058}, pmid = {40882223}, issn = {1208-6002}, mesh = {*Galantamine/pharmacology ; *Neural Stem Cells/drug effects/cytology/metabolism ; Animals ; *Cell Differentiation/drug effects ; *Up-Regulation/drug effects ; *Insulin-Like Growth Factor II/metabolism/genetics ; *Neuronal Outgrowth/drug effects ; Cells, Cultured ; *Neurons/cytology/drug effects/metabolism ; Signal Transduction/drug effects ; Mice ; *Neurites/drug effects/metabolism ; Neurogenesis/drug effects ; Rats ; }, abstract = {Galanthamine, an alkaloid derived from the Amaryllidaceae family, serves as an acetylcholinesterase inhibitor. Due to its central cholinergic properties, this compound is being actively studied as a potential treatment for Alzheimer's disease. However, the broader scope of its biological effects remains poorly understood. In this study, we explored the therapeutic potential of galanthamine in promoting neuronal differentiation and enhancing neurite outgrowth in neural stem and progenitor cells (NSPCs). Our detailed analysis demonstrated notable changes in neuronal morphology and complexity during maturation following galanthamine exposure. Notably, the compound significantly increased the proportion of neurons with multiple neurites, indicating its ability to stimulate neurite formation and foster the development of complex neuronal networks. Furthermore, galanthamine treatment led to a marked rise in the number of mature-appearing neurons, distinguished by elongated and intricate dendrites, highlighting its potential to enhance neural plasticity and repair mechanisms. Importantly, we also identified that galanthamine facilitates neuronal differentiation in NSPCs by up-regulating the insulin-like growth factor 2 signaling pathway. Collectively, these findings provide valuable insights into galanthamine's role in Alzheimer's disease and emphasize its promise as a therapeutic agent for this neurodegenerative disorder.}, } @article {pmid40881368, year = {2025}, author = {Zhao, J and Dong, X and Liu, B and Peng, Y and Yao, Z}, title = {Cognitive function enhancement in Alzheimer's disease through traditional Chinese medicine rehabilitation nursing: meta-analysis.}, journal = {Frontiers in psychiatry}, volume = {16}, number = {}, pages = {1631589}, pmid = {40881368}, issn = {1664-0640}, abstract = {Alzheimer's disease (AD) manifests as progressive cognitive deterioration with significant impact on patient independence and quality of life. While conventional treatments offer limited efficacy, Traditional Chinese Medicine (TCM) rehabilitation nursing presents a complementary approach deserving systematic evaluation. To synthesize existing evidence on the efficacy of TCM rehabilitation nursing for cognitive enhancement in AD through comprehensive meta-analysis. We conducted systematic searches across multiple electronic databases (PubMed, Embase, CNKI, Wanfang, and VIP) for controlled studies published from 2010 to present examining TCM rehabilitation nursing interventions for AD patients. Methodological quality was assessed using the Cochrane Risk of Bias 2.0 tool. Primary outcomes included Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), and treatment efficacy rates. Statistical synthesis employed RevMan 5.3 with random or fixed effects models based on heterogeneity assessment. Nine eligible studies encompassing 864 participants (432 intervention, 432 control) met inclusion criteria. Meta-analysis revealed significantly improved cognitive function in the TCM rehabilitation nursing group compared to conventional care, with MMSE scores showing substantial enhancement (mean difference = 4.63, 95% confidence interval: 3.74-5.53, P<0.00001). Treatment response analysis demonstrated higher rates of marked clinical improvement (risk ratio = 2.78, 95% CI: 1.65-4.70, P=0.0001) and substantially reduced treatment failure rates (85% reduction, P<0.00001). Though ADL scores showed positive trends, these did not reach statistical significance (P=0.07). TCM rehabilitation nursing demonstrates significant efficacy in enhancing cognitive function and treatment outcomes in AD patients. These findings support its integration into comprehensive care strategies, though additional research with standardized protocols is warranted for optimal implementation.}, } @article {pmid40881206, year = {2025}, author = {Parchwani, D and Singh, R and Patel, D}, title = {Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance.}, journal = {World journal of methodology}, volume = {15}, number = {3}, pages = {102709}, pmid = {40881206}, issn = {2222-0682}, abstract = {The mitochondrial DNA copy number (mtDNAcn) plays a vital role in cellular energy metabolism and mitochondrial health. As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation, maintaining an appropriate mtDNAcn level is vital for the overall cellular function. Alterations in mtDNAcn have been linked to various diseases, including neurodegenerative disorders, metabolic conditions, and cancers, making it an important biomarker for understanding the disease pathogenesis. The accurate estimation of mtDNAcn is essential for clinical applications. Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations. Clinically, mtDNAcn serves as a valuable indicator for early diagnosis, disease progression, and treatment response. For instance, in oncology, elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy. In neurodegenerative diseases such as Alzheimer's and Parkinson's, altered mtDNAcn patterns provide insights into disease mechanisms and progression. Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields. As research continues to uncover the implications of mtDNAcn alterations, its potential as a clinical biomarker is likely to expand, thereby enhancing our ability to diagnose and manage complex diseases.}, } @article {pmid40880849, year = {2025}, author = {Fu, L and Luo, T and Hao, Z and Pan, Y and Xin, W and Zhang, L and Lai, Z and Zhang, H and Liu, H and Wei, W}, title = {Exploring novel roles of lipid droplets and lipid metabolism in regulating inflammation and blood-brain barrier function in neurological diseases.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1603292}, pmid = {40880849}, issn = {1662-4548}, abstract = {The blood-brain barrier (BBB) is a critical structure that maintains the brain's homeostasis by regulating the transport of molecules and protecting it from harmful substances. However, in neurological diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, the integrity and function of the BBB can be significantly compromised. In these conditions, BBB disruption leads to increased permeability, which facilitates neuroinflammation, exacerbates neuronal damage, and accelerates disease progression. Recent research has highlighted the potential of lipid-based carriers, including liposomes and lipid droplets (LDs), in modulating the BBB's integrity and function in various neurological diseases. Liposomes, with their ability to cross the BBB via mechanisms such as receptor-mediated transcytosis and carrier-mediated transport, are emerging as promising vehicles for the targeted delivery of therapeutic agents to the brain. These properties allow liposomes to effectively reduce infarct size and promote neuroprotection in ischemic stroke, as well as deliver drugs in the treatment of neurodegenerative diseases. Furthermore, LDs-dynamic regulators of lipid metabolism and cellular energy-play an essential role in maintaining cellular homeostasis, particularly during periods of stress when BBB function is compromised. These LDs help sustain cellular energy needs and modulate inflammatory responses, which are key factors in maintaining BBB integrity. Surface modifications of liposomes can further enhance their targeting efficiency, enabling them to selectively bind to specific brain cell types, including neurons, astrocytes, and microglia. This customization improves the precision of therapeutic delivery and supports the development of more tailored treatments. However, challenges such as immune responses, rapid clearance, and complement activation-related toxicity continue to hinder the broader application of liposomes and LDs in clinical settings. This review will focus on the roles of liposomes and LDs in regulating BBB integrity across a range of neurological diseases, discussing their potential for targeted drug delivery, neuroprotection, and the modulation of neuroinflammation. Additionally, we will explore the strategies being developed to address the limitations that currently restrict their clinical use.}, } @article {pmid40879893, year = {2025}, author = {Serio, MA and Dethloff, DR and Curry, GC and Beesley, ML and Shekoohi, S and Kaye, AD}, title = {Emerging Concepts in Diagnosis, Pathologic Features, and Treatment of Limbic-Predominant Amnestic Neurodegenerative Syndrome (LANS): A Narrative Review.}, journal = {Advances in therapy}, volume = {42}, number = {11}, pages = {5300-5312}, pmid = {40879893}, issn = {1865-8652}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/therapy/pathology/physiopathology ; *Alzheimer Disease/diagnosis/therapy/pathology/physiopathology ; *Amnesia/therapy/diagnosis/pathology ; *TDP-43 Proteinopathies/therapy/diagnosis/pathology/physiopathology ; }, abstract = {INTRODUCTION: Neurodegenerative disorders (NDs) are characterized by progressive loss of function and destruction of the central and peripheral nervous systems. These disorders result in devastating irreversible cognitive decline and affect millions of people worldwide. Alzheimer's disease (AD) is a common cause of dementia that increases in incidence with increasing age. Limbic-predominant amnestic neurodegenerative syndrome (LANS) is another common etiology of amnestic symptoms and often affects the "oldest-old" of the population. The two disorders share many similarities yet are clearly pathologically distinct. Establishing robust classifications to distinguish these two disorders is key to future management and care of an aging population. The present investigation explored the pathophysiology of neurodegenerative disorders (NDs), specifically Alzheimer's disease (AD), limbic-predominant amnestic neurodegenerative syndrome (LANS), and limbic-predominant age-related TDP-43 encephalopathy (LATE). METHODS: We performed a comprehensive narrative review of the literature, covering studies from database inception through November 2024. We searched PubMed/MEDLINE, Embase, Web of Science, Cochrane Library, and Google Scholar for relevant publications. We also reviewed reference lists of key articles. Two authors independently screened titles/abstracts for relevance and extracted data on study design, patient population, neuropathologic findings, imaging/biomarker methods, and clinical features. Discrepancies were resolved by discussion. This review synthesized findings on the need for LANS criteria and compared LANS to AD and LATE across clinical, imaging, pathologic, and biomarker domains. RESULTS: A comprehensive analysis of the key pathologic features and distinctions among selected neurodegenerative syndromes was carried out using peer-reviewed literature. CONCLUSIONS: Recently proposed clinical criteria for LANS are a milestone in the characterization and further treatment of neurodegenerative disease. Understanding the minute differences in pathophysiology among various NDs allows for pioneering more targeted disease-modifying treatments. This narrative review provides concise reflection between AD and other NDs involving LATE-NC changes.}, } @article {pmid40879814, year = {2025}, author = {Lei, J and Li, J and Wu, W and Xiong, R and Liu, Y and Tang, Y}, title = {Neuroprotective effects of Yangming-Kaixin-Yizhi formula in Alzheimer's disease: dual regulation of PI3K/Akt and p38 MAPK signaling via network pharmacology and experimental approaches.}, journal = {Metabolic brain disease}, volume = {40}, number = {7}, pages = {254}, pmid = {40879814}, issn = {1573-7365}, support = {2024ZYQN017//Joint Project of Chongqing Health Commission and Science and Technology Bureau/ ; 82405150//National Natural Science Foundation of China/ ; 2025ZNSFSC0740//Sichuan Provincial Science and Technology Support Program/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Mice ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; Network Pharmacology/methods ; Phosphatidylinositol 3-Kinases/metabolism ; Mice, Transgenic ; Male ; Signal Transduction/drug effects ; *MAP Kinase Signaling System/drug effects ; Molecular Docking Simulation ; Disease Models, Animal ; }, abstract = {As a neurodegenerative disease characterized by progressive cognitive decline, the pathogenesis of Alzheimer's disease (AD) is still poorly understood, and there is no effective cure currently available. Traditional Chinese medicine (TCM) prescription Yangming-Kaixin-Yizhi formula (YKY) has been clinically applied for the treatment of memory loss related disorders for more than 300 years with remarkable efficacy, but its pharmacological mechanism remains unclear. This study aimed to investigate the therapeutic effects of YKY on AD and its molecular mechanisms. We evaluated YKY's ameliorative effects on the AD phenotype in 3xTg-AD mice using the Morris water maze, histopathological staining, and immunofluorescence assays. The major chemical components of YKY were identified by UPLC-QTOF-MS/MS. Network pharmacology was employed to analyze the molecular mechanisms of YKY in treating AD, followed by validation of its regulatory effects on key pathways through immunofluorescence experiments and molecular docking. The results showed that YKY could significantly improve learning and memory ability, neuronal loss, β-amyloid deposition and glial cell activation in 3xTg-AD mice. 48 chemical components were identified from YKY, and network pharmacology analysis of them showed that YKY may improve AD by regulating apoptosis, PI3K/Akt and MAPK pathways. Immunofluorescence and molecular docking results also confirmed the regulatory effect of YKY on key targets of apoptosis, PI3K/Akt and p38 MAPK pathways. In conclusion, by integrating animal experiments and network pharmacology, the present study revealed the mechanism of YKY in inhibiting neuronal apoptosis by regulating PI3K/Akt and p38 MAPK pathways, which providing modern scientific evidence for the traditional clinical application of YKY.}, } @article {pmid40879672, year = {2025}, author = {Farajpour, N and Soraya, H}, title = {Neuroprotective effects of ivermectin on Alzheimer's model induced by streptozotocin in rats.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/17582024.2025.2554374}, pmid = {40879672}, issn = {1758-2032}, abstract = {BACKGROUND: Alzheimer's disease is a neurodegenerative condition characterized by memory deficits and cognitive decline. Ivermectin, an antiparasitic agent, has shown neuroprotective effects. The present study was conducted to determine the protective effects of ivermectin in a streptozocin-induced Alzheimer's model in rats. METHODS: Alzheimer's model was induced by bilateral intracerebroventricular injection of streptozocin (3 mg/kg BW, 2 doses). Ivermectin was administered intraperitoneally at a dose of 2 mg/kg. On day 19, after behavioral memory and learning tests, the samples were collected for histological and enzymatic studies. RESULTS: Ivermectin reduced the histopathological changes, including pyknotic and dead neurons and the accumulation of Aβ plaques. Ivermectin administration also reduced serum (p < 0.0001) and brain tissue (p < 0.01) acetylcholinesterase activity as well as improved learning (p < 0.05) and spatial memory (p < 0.0001). CONCLUSIONS: Ivermectin demonstrates protective effects in the STZ-induced Alzheimer's model by reducing pathological changes and Aβ plaques, acetylcholinesterase activity, as well as improving memory and learning.}, } @article {pmid40879647, year = {2025}, author = {Fabrik, I and Kupcik, R and Fabrikova, D and Chvojkova, M and Holubova, K and Hakenova, K and Horak, M and Soukup, J and Manethova, M and Rusina, R and Matej, R and Ryska, A and Soukup, O}, title = {Memantine Administration Enhances Glutamatergic and GABAergic Pathways in the Human Hippocampus of Alzheimer's Disease Patients.}, journal = {Proteomics}, volume = {25}, number = {15}, pages = {42-49}, pmid = {40879647}, issn = {1615-9861}, support = {24-10026S//Grantová Agentura České Republiky/ ; 00064190//Ministerstvo Zdravotnictví Ceské Republiky/ ; 00179906//Ministerstvo Zdravotnictví Ceské Republiky/ ; Cooperatio-Neurosciences//Univerzita Karlova v Praze/ ; CZ.02.01.01/00/22_008/0004562//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; LX22NPO5107//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; }, mesh = {Humans ; *Memantine/pharmacology/administration & dosage/therapeutic use ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Hippocampus/metabolism/drug effects/pathology ; Male ; Female ; Aged ; *Glutamic Acid/metabolism ; Proteome/metabolism ; Proteomics/methods ; Aged, 80 and over ; Signal Transduction/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; *Excitatory Amino Acid Antagonists/pharmacology ; Receptors, GABA/metabolism ; }, abstract = {One of the traditional treatments in Alzheimer's disease (AD) is administration of memantine, the NMDA receptor antagonist. However, the molecular mechanism of the complex memantine action and the impact on the hippocampal proteome in humans is unknown. In this study, hippocampal proteins extracted from formalin-fixed paraffin-embedded post mortem tissues obtained from healthy donors (n = 15), AD patients not treated with memantine (n = 11), and AD patients treated with memantine (n = 8) were investigated using tandem mass tag (TMT)-based quantitative proteomics. Memantine medication induced subtle but distinct changes in the hippocampal proteome in AD patients. Although it did not prevent the metabolic and physiologic decline associated with AD pathology, memantine administration upregulated several mitochondrially encoded proteins and mitigated the proteomic pattern of activated phagocytes. Furthermore, memantine specifically enhanced the expression of postsynaptic glutamatergic and GABAergic receptors and components of the respective pathways without affecting presynaptic proteome. This suggests that memantine treatment in AD patients not only alleviates excitotoxic stress by inhibiting NMDA receptor activity, but also triggers broader adaptations in the synaptic signaling and plasticity.}, } @article {pmid40879417, year = {2025}, author = {Zheng, J and Liu, G and Wang, Q and Liang, Y}, title = {Insights into CYP450 polymorphisms and their impact on drug metabolism in Alzheimer's disease therapy.}, journal = {Drug metabolism reviews}, volume = {57}, number = {4}, pages = {523-534}, doi = {10.1080/03602532.2025.2552786}, pmid = {40879417}, issn = {1097-9883}, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; Polymorphism, Genetic ; Pharmacogenetics ; Precision Medicine ; Animals ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder that poses significant therapeutic challenges. Currently available treatments offer symptomatic relief but often yield suboptimal outcomes due to inter-individual variability in drug metabolism. Cytochrome P450 (CYP450) enzymes, particularly those exhibiting genetic polymorphisms, play a central role in the hepatic metabolism of many AD medications. This review focuses on the influence of CYP450 polymorphisms-specifically in CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4-on the pharmacokinetics, efficacy, and safety of approved anti-AD drugs. We discuss how variability in CYP450 expression and activity affects drug response, and examine the implications for adverse drug reactions, therapeutic failure, and dosage optimization. In addition, we evaluate current evidence for CYP450-mediated interactions with traditional Chinese medicines, which are increasingly used in complementary AD therapy. The potential for CYP450 genotyping and phenotyping to guide personalized treatment strategies is critically assessed. We argue that integrating pharmacogenomics into clinical practice may enhance therapeutic precision, reduce adverse outcomes, and improve quality of life in patients with AD. This review provides updated insight into the clinical significance of CYP450 polymorphisms in AD therapy and outlines future directions for personalized medicine approaches.}, } @article {pmid40879416, year = {2025}, author = {Chen, J and Lin, B and Seow, E and Kim, S and Bajaj, PS and Mattke, S}, title = {Prediction of infusion capacity to deliver Alzheimer's disease treatments in the United States relative to expected demand.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {4}, pages = {1567-1574}, doi = {10.1177/13872877251372129}, pmid = {40879416}, issn = {1875-8908}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; United States/epidemiology ; Infusions, Intravenous ; *Health Services Needs and Demand/trends ; *Health Services Accessibility/trends/statistics & numerical data ; }, abstract = {BackgroundCapacity to deliver intravenous Alzheimer's disease (AD) treatments could constitute an obstacle to access in addition to AD specialist and PET scan capacity.ObjectiveWe aim to estimate the overall capacity for AD treatment infusions compared to expected demand in the United States.MethodsWe used published data and a survey of infusion sites to estimate the capacity to deliver AD treatments in physician offices, hospitals, standalone centers and at patients' homes from 2024 to 2033 relative to demand.ResultsCapacity for intravenous AD treatments is predicted to increase from 370,000 in 2024 to 5.2 million infusions in 2033. Nevertheless, a significant shortfall of over 13 million infusions remains in 2033, which would imply delayed access for 2.2 million patients.ConclusionsLimited infusion capacity could impede AD treatment access and result in avoidable disability progression. Expansion of capacity is needed in the short run until treatments with alternative routes of administration become available.}, } @article {pmid40877101, year = {2026}, author = {Lahmar, T and Thuau, F and Pinard, G and Boutoleau-Bretonniere, C and Perrot, P and Lancien, U}, title = {Brain lymphatic drainage pathways, deep cervical lymphatic surgery, and current insights: A systematic review.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {1}, pages = {100335}, doi = {10.1016/j.tjpad.2025.100335}, pmid = {40877101}, issn = {2426-0266}, mesh = {Humans ; *Lymphatic Vessels/surgery ; *Brain/metabolism ; *Glymphatic System/surgery ; *Lymphedema/surgery ; }, abstract = {The discovery of the glymphatic system and the later rediscovery of the meningeal lymphatic network have significantly changed our understanding of central nervous system (CNS) waste clearance. Aging is linked to a gradual decline in these clearance pathways, resulting in waste buildup. As a result, therapeutic strategies targeting cerebral lymphatic function have garnered growing interest, with lymphatic surgery emerging as a promising option. We conducted a review until July 2025, providing an overview of the potential of lymphatic surgical techniques to enhance CNS metabolic waste clearance pathways as a therapeutic approach for brain lymphatic system disorders. Currently available data are limited, nine publications addressing this approach. These studies explore an innovative technique involving lymphatico-venous anastomoses (LVA) targeting deep cervical lymphatic vessels to promote clearance for the treatment of Alzheimer's or Parkinson's diseases. Cerebral lymphatic drainage is critical for effective brain waste elimination such as amyloid-β, phosphorylated tau, and α-synuclein, which are linked to neurodegenerative diseases. Viewing these lymphatic dysfunctions as a form of "cerebral lymphedema," LVA, already used in treating peripheral lymphedema, shows potential as a therapeutic approach. Although clinical evidence is still limited, lymphatic supermicrosurgery presents promising therapeutic possibilities for neurodegenerative diseases and other conditions related to impaired CNS lymphatic outflow.}, } @article {pmid40874776, year = {2025}, author = {Chen, Y and Dong, C and Chen, J and Li, Q}, title = {Clinical observations on treating Alzheimer's disease with umbilical cord blood mononuclear cells.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {4}, pages = {1430-1436}, doi = {10.1177/13872877251366669}, pmid = {40874776}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Male ; Aged ; Female ; *Leukocytes, Mononuclear/transplantation ; Activities of Daily Living ; Treatment Outcome ; Neuropsychological Tests ; Middle Aged ; Aged, 80 and over ; Mental Status and Dementia Tests ; *Fetal Blood/cytology ; *Cord Blood Stem Cell Transplantation/methods ; }, abstract = {BackgroundThere are currently no relevant clinical research reports on the application of human umbilical cord blood mononuclear cells (hUCBMCs) treatment for Alzheimer's disease (AD) in humans.ObjectiveTo observe the clinical efficacy of intravenous transplantation of hUCBMCs in patients with AD.MethodsEleven AD patients with Clinical Dementia Rating (CDR) scores of 1 (mild) or 2 (moderate) were selected. Patients continued standard AD medication and received three intravenous infusions of UCBMCs, spaced seven days apart. Neurological and psychological assessments, including MMSE, ADAS-Cog, ADL, and PSQI scores, were conducted by neurologists at baseline and 1, 3, and 6 months post-treatment. The impact of UCBMCs on cognitive function, daily living activities, sleep disorders, and any adverse reactions were monitored. Repeated measures ANOVA and LSD-t post-hoc tests were used to analyze score changes.ResultsRepeated measures ANOVA revealed differences in MMSE, ADAS-Cog, ADL, and PSQI scores across the evaluated time points. Pairwise comparisons indicated substantial improvements, with MMSE scores increasing at 1, 3, and 6 months post-treatment, while ADAS-Cog scores decreased. ADL scores showed improvement at 1 and 3 months, and PSQI scores decreased consistently at all post-treatment intervals. Notably, MMSE and ADL scores peaked at 3 months before gradually declining, ADAS-Cog scores reached their lowest point at 3 months before increasing, and PSQI scores were lowest at 1 month, followed by a gradual rise.ConclusionsIntravenous infusion of UCBMCs can temporarily improve cognitive function, enhance daily living activities, and alleviate sleep disorders in AD patients, with a high safety profile.}, } @article {pmid40873665, year = {2025}, author = {Parks, AL and Thacker, A and Dohan, D and Gomez, LAR and Gale, SA and Johnson, KG and Ritchie, CS and Shah, SJ and Paladino, J}, title = {Characterizing clinician communication with patients about lecanemab: A qualitative study of clinicians across seven academic medical centers.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70150}, pmid = {40873665}, issn = {2352-8737}, support = {K76 AG083304/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Anti-amyloid monoclonal antibodies (mAbs) slow cognitive decline in Alzheimer's disease but may cause amyloid-related imaging abnormalities (ARIA), which can rarely be disabling or fatal. This qualitative study investigates how clinicians communicate the benefits and risks of mAbs to patients and caregivers. METHODS: Semi-structured interviews with clinicians who prescribe mAbs at seven academic medical centers. Hybrid inductive-deductive thematic analysis by interdisciplinary researchers. RESULTS: In 27 clinician interviews (women [n = 17], White individuals [n = 19], neurologists [n = 17]), three themes emerged. First, clinicians varied in techniques used and concepts emphasized, including using analogies, discussing statistics, and emphasizing versus de-emphasizing risks. Second, patient contextual factors (e.g., comorbidities), hopes, and fears shaped communication. Third, clinician communication varied by training, personal style, and ambivalence. While clinicians honor patients' choices to pursue treatment, many do not "recommend" it (but may recommend against it). DISCUSSION: Preliminary insights about how clinicians communicate tradeoffs can guide future shared decision-making interventions for mAbs. HIGHLIGHTS: This qualitative study among 27 clinicians across seven academic medical centers examined how clinicians communicate with people with Alzheimer's disease about risks and benefits of anti-amyloid therapy, which can influence treatment decisions.Clinicians varied in what techniques they employed and how they portrayed risks and benefits, and whether they incorporated patients' values.They cited comorbidities, eligibility criteria fit, and degree of social support or family involvement in decisions as factors used in framing discussions, while fewer used patients' goals to guide discussion.The professional training, individual practice style, and personal sense of ambivalence of clinicians shaped conversations.These findings can guide future interventions to improve communication and shared decision-making.}, } @article {pmid40873639, year = {2025}, author = {Huang, G and Liu, Y and Zhu, X and He, L and Chen, T}, title = {Exploring the Neuroprotective Role of Selenium: Implications and Perspectives for Central Nervous System Disorders.}, journal = {Exploration (Beijing, China)}, volume = {5}, number = {4}, pages = {e20240415}, pmid = {40873639}, issn = {2766-2098}, abstract = {Selenium (Se) is a crucial element in selenoproteins, key biomolecules for physiological function in vivo. As a selenium-rich organ, the central nervous system can express all 25 kinds of selenoproteins, which protect neurons by reducing oxidative stress and inflammatory response. However, decreased Se levels are prevalent in a variety of neurological disorders, which is not conducive to the treatment and prognosis of patients. Thus, the biological study of Se has emerged as a focal point in investigating the pivotal role of trace elements in neuroprotection. This paper presents a comprehensive review of the pathogenic mechanism of neurological diseases, the protective mechanism of Se, and the neurological protective function of selenoproteins. Additionally, the application of Se as a neuroprotective agent in neurological disorder therapy, including ischemic stroke, Alzheimer's, Parkinson's, and other neurological diseases, is summarized. The present review aims to offer novel insights and methodologies for the prevention and treatment of neurological disorders with trace Se, providing a scientific basis for the development of innovative Se-based neuroprotectants to promote their clinical application against neurological diseases.}, } @article {pmid40871270, year = {2025}, author = {Zhao, Z and Wu, X and Liu, W and Zheng, L and Tang, C}, title = {Effects of Treadmill Exercise on Gut Microbiota in Alzheimer's Disease Model Mice and Wild-Type Mice.}, journal = {Microorganisms}, volume = {13}, number = {8}, pages = {}, pmid = {40871270}, issn = {2076-2607}, support = {(no.S202410542224)//The Hunan Normal University Undergraduate Innovative Experiment Project and Entrepreneurship Program/ ; }, abstract = {There is a growing body of research showing that Alzheimer's disease (AD) is related to enteric dysbacteriosis. Exercise can be effective in alleviating AD, but the effects that exercise has on the gut microbiota in AD patients needs to be further studied. Through this study, we aimed to investigate the differences in the diversity of gut microorganisms between AD model mice and wild-type mice and the effect that treadmill exercise has on the composition of the gut microbiota in both types of mice. C57BL/6 wild-type mice were randomly divided into a sedentary control group (WTC) and an exercise group (WTE); APP/PS1 double transgenic mice were also randomly divided into a sedentary control group (ADC) and an exercise group (ADE). After the control group remained sedentary for 12 weeks and a 12-week treadmill exercise intervention was adopted for the exercise group, the rectal contents were collected so that they could undergo V3-V4 16S rDNA sequencing, and a comparative analysis of the microbial composition and diversity was also performed. The alpha diversity of the gut microbiota in AD mice was lower than that in wild-type mice, but exercise increased the gut microbial diversity in both types of mice. At the phylum level, the dominant microorganisms in all four groups of mice were Bacteroidetes and Firmicutes. There was an increase in the Bacteroidetes phylum in AD mice. Treadmill exercise reduced the abundance of Bacteroidetes in both groups of mice, whereas the abundance of Firmicutes increased. At the genus level, Muribaculaceae, the Lachnospiraceae_NK4A136_group, Alloprevotella, and Alistipes were in relatively high abundance. Muribaculaceae and Alloprevotella were in greater abundance in AD mice than in wild-type mice, but both decreased after treadmill exercise. Through performing linear discriminant analysis effect size (LEfSe), we found that the dominant strains in AD mice were Campilobacterota, Helicobacteraceae, Escherichia-Shigella, and other malignant bacteria, whereas exercise resulted in an increase in probiotics among the dominant strains in both types of mice. Although gut microbial diversity decreases and malignant bacteria increase in AD mice, treadmill exercise can increase gut microbial diversity and lead to the development of dominant strains of probiotics in both types of mice. These findings provide a basis for applying exercise as a treatment for AD.}, } @article {pmid40870360, year = {2025}, author = {Ozen Koca, R and Solak Gormus, ZI and Solak, H and Gultekin, B and Ozdemir, A and Eroglu Gunes, C and Kurar, E and Kutlu, S}, title = {Agomelatine Ameliorates Cognitive and Behavioral Deficits in Aβ-Induced Alzheimer's Disease-like Rat Model.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {8}, pages = {}, pmid = {40870360}, issn = {1648-9144}, support = {201218004//NEU Scientific Research Projects Coordinator/ ; }, mesh = {*Alzheimer Disease/complications/drug therapy/pathology/physiopathology ; Neuroprotective Agents/pharmacology/therapeutic use ; *Antidepressive Agents/pharmacology/therapeutic use ; Rats, Wistar ; Disease Models, Animal ; *Cognitive Dysfunction/drug therapy/etiology/physiopathology ; Behavior, Animal/drug effects/physiology ; Brain/drug effects/pathology/physiopathology ; *Learning/drug effects/physiology ; *Memory/drug effects/physiology ; Cognition/drug effects ; Amyloid beta-Peptides/administration & dosage/toxicity ; Male ; Animals ; Rats ; Acetamides ; Naphthalenes ; Peptide Fragments ; }, abstract = {Background and Objectives: Alzheimer's disease (AD) has become a serious health problem. Agomelatine (Ago) is a neuroprotective antidepressant. This study aimed to assess how Ago influences behavioral outcomes in AD-like rat model. Materials and Methods: Forty-eight Wistar albino rats were allocated into four groups: Control (C), Alzheimer's disease-like model (AD), Alzheimer's disease-like model treated with Ago (ADAgo), and Ago alone (Ago). Physiological saline was injected intrahippocampally in C and Ago animals, whereas Aβ peptide was delivered similarly in AD and ADAgo rats. On day 15, 0.9% NaCl was administered to the C and AD groups, and Agomelatine (1 mg/kg/day) was infused into ADAgo and Ago rats via osmotic pumps for 30 days. Behavioral functions were evaluated using Open Field (OF), Forced Swim (FST), and Morris Water Maze (MWM) tests. Brain tissues were examined histopathologically. Neuritin, Nestin, DCX, NeuN, BDNF, MASH1, MT1, and MT2 transcripts were quantified by real-time PCR. Statistical analyses were performed in R 4.3.1, with p < 0.05 deemed significant. Results: In the FST, swimming, climbing, immobility time, and mobility percentage differed significantly among groups (p < 0.05). In the MWM, AD rats exhibited impaired learning and memory that was ameliorated by Ago treatment (p < 0.05). DCX expression decreased in AD rats but was elevated by Ago (p < 0.05). Nestin levels differed significantly between control and AD animals; MT1 expression varied between control and AD cohorts; and MT2 transcript levels were significantly lower in AD, ADAgo, and Ago groups compared to C (all p < 0.05). Conclusions: Ago exhibits antidepressant-like activity in this experimental AD model and may enhance cognitive function via mechanisms beyond synaptic plasticity and neurogenesis.}, } @article {pmid40865469, year = {2025}, author = {Gurram, PC and Manandhar, S and Satarker, S and Nassar, A and Begum, F and Mudgal, J and Arora, D and Nampoothiri, M}, title = {Substance P mitigates lipopolysaccharide induced cognitive impairment in rats in a dose dependent manner.}, journal = {Neuropeptides}, volume = {113}, number = {}, pages = {102551}, doi = {10.1016/j.npep.2025.102551}, pmid = {40865469}, issn = {1532-2785}, mesh = {Animals ; Lipopolysaccharides ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Substance P/pharmacology/administration & dosage ; Male ; Rats ; Dose-Response Relationship, Drug ; Hippocampus/metabolism/drug effects ; Disease Models, Animal ; Acetylcholinesterase/metabolism ; Alzheimer Disease/metabolism/chemically induced ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/drug effects ; Rats, Sprague-Dawley ; Cyclic AMP Response Element-Binding Protein/metabolism ; Maze Learning/drug effects ; }, abstract = {Neuroinflammation contributes to cognitive decline in Alzheimer's disease (AD), and the neurokinin pathway has been implicated in the pathophysiology of AD. Although Substance P (SP), an endogenous ligand to the neurokinin 1 receptor (NK1R), is primarily known as a neurotransmitter, but emerging evidence indicates it has shown both pro and anti-inflammatory actions. However, the dose-dependent nature of the SP-NK1R axis's functional role remains to be fully elucidated. In this study, we examined the effects of SP in a rat model of AD induced by lipopolysaccharide (LPS). A dose of 150 μg/10 μl of LPS was administered through intracerebroventricular injection to induce cognitive impairment in the rats. Two doses of SP, 50 μg/kg and 500 μg/kg were administered intraperitoneally once a day for 21 days. Behavioral assessments included the Morris water maze test and novel object recognition test to investigate cognitive defects, and the open field test evaluated locomotion. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), amyloid-beta (Aβ), acetylcholinesterase (AChE), lipid peroxidation, and catalase were estimated in the frontal cortex and hippocampus. The cAMP-responsive element-binding (CREB) protein levels in the whole brain were estimated by western blot. The LPS treatment significantly impaired cognition, increased levels of cytokines, Aβ, oxidative stress, and AChE, while decreasing CREB levels. Notably, the lower dose of SP (50 μg/kg) restored cognitive performance and markers of AD. In contrast, the higher dose of SP (500 μg/kg) failed to reverse spatial memory impairment and neuroinflammation. Thus, our data propose the dose-dependent effect of SP on neuroinflammation-induced cognitive deficits in AD.}, } @article {pmid40865297, year = {2025}, author = {Araújo, R and Reis Carneiro, D and Nunes Rato, R and Massano, J}, title = {Time-saved and time-invested with anti-amyloid treatments in early Alzheimer's disease: practical considerations.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {141}, number = {}, pages = {111584}, doi = {10.1016/j.jocn.2025.111584}, pmid = {40865297}, issn = {1532-2653}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Female ; Male ; Aged ; Time Factors ; *Amyloid beta-Peptides/antagonists & inhibitors ; }, abstract = {Anti-amyloid treatments for early Alzheimer's disease very effectively remove amyloid deposits from the brain and have shown an approximately 30 % less worsening in cognitive functions compared to placebo. Some additional metrics, such as time-saved, i.e. the additional time people may live independently, have been suggested to better inform patients and the general public about the benefits and risks of these medications. Some authors report 4-6 months, and others 10-13 months, depending on the treatment period, time of follow-up, and the methodology used. Taking into consideration that these drugs' regimens are monthly or bi-weekly intravenous infusions requiring clinical supervision, and the necessary brain MRIs for follow-up, we argue that the time spent travelling by the patients and their family members should also be taken into consideration when proposing anti-amyloid treatments, and specifically, when discussing the amount of time saved. In this study, we report that nearly half of the possible eligible patients for anti-amyloid treatments experience a reduction in motivation after receiving the information about the number of times required to come to the hospital, especially those travelling long distances (average time: 60 min for one-way). We propose a rough estimate for the additional time patients and their family members are likely to spend in these arrangements and suggest these additional calculations should be part of the decision-making process.}, } @article {pmid40863632, year = {2025}, author = {Toulis, V and Marfany, G and Mirra, S}, title = {Marine Derived Strategies Against Neurodegeneration.}, journal = {Marine drugs}, volume = {23}, number = {8}, pages = {}, pmid = {40863632}, issn = {1660-3397}, support = {2021SGR-01093//Generalitat de Catalunya/ ; PID2022-140957OB-I00//MCIN/ AEI/10.13039/501100011033 / "ERDF A way of making Europe"/ ; }, mesh = {Humans ; Animals ; *Aquatic Organisms/chemistry ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification ; *Biological Products/pharmacology/therapeutic use/isolation & purification ; Alzheimer Disease/drug therapy ; Genetic Therapy/methods ; }, abstract = {Marine ecosystems are characterized by an immense biodiversity and represent a rich source of biological compounds with promising potential for the development of novel therapeutic drugs. This review describes the most promising marine-derived neuroprotective compounds with strong potential for the treatment of neurodegenerative disorders. We focus specifically on the retina and brain-two key components of the central nervous system-as primary targets for therapeutic interventions against neurodegeneration. Alzheimer's disease and retinal degeneration diseases are used here as a representative model of neurodegenerative disorders, where complex molecular processes such as protein misfolding, oxidative stress, and neuroinflammation drive disease progression. We also examine gene therapy approaches inspired by marine biology, with particular attention to their application in retinal diseases, aimed at preserving or restoring photoreceptor function and vision.}, } @article {pmid40863627, year = {2025}, author = {Debi, PR and Barua, H and Ahmmed, MK and Bhowmik, S}, title = {Therapeutic Potential of Sea Cucumber-Derived Bioactives in the Prevention and Management of Brain-Related Disorders: A Comprehensive Review.}, journal = {Marine drugs}, volume = {23}, number = {8}, pages = {}, pmid = {40863627}, issn = {1660-3397}, mesh = {Humans ; *Sea Cucumbers/chemistry ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification ; *Neurodegenerative Diseases/drug therapy ; *Brain Diseases/drug therapy/prevention & control ; *Biological Products/pharmacology/therapeutic use ; }, abstract = {The popularity of bioactive compounds extracted from sea cucumbers is growing due to their wide application in the pharmaceutical industry, particularly in the development of drugs for neurological disorders. Different types of compounds, such as saponins, phenolic compounds, cerebrosides, and glucocerebrosides, are being studied intensively for their efficacy in assessing the treatment of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and brain tumors, among others. Positive results have been observed in the upregulation in the content of p-CREB, p-PL3K, BDNF, SOD, and MDA. Furthermore, the neuroprotective mechanism of the compounds against Alzheimer's disease revealed that suppressing the phosphorylation of tau protein by the PI3K/Akt/GSK3β pathway leads to improved synaptic plasticity and reduced nerve fiber tangles. This comprehensive review explores recent findings on the therapeutic potential of sea cucumber bioactives in the treatment of brain-related disorders.}, } @article {pmid40863573, year = {2025}, author = {Farup, PG and Hestad, K and Engedal, K}, title = {Personalised Prevention of Falls in Persons with Dementia-A Registry-Based Study.}, journal = {Geriatrics (Basel, Switzerland)}, volume = {10}, number = {4}, pages = {}, pmid = {40863573}, issn = {2308-3417}, abstract = {BACKGROUND/OBJECTIVES: Multifactorial prevention of falls in persons with dementia has minimal or non-significant effects. Personalised prevention is recommended. We have previously shown that gait speed, basic activities of daily living (ADL), and depression (high Cornell scores) were independent predictors of falls in persons with mild and moderate cognitive impairment. This study explored person-specific risks of falls related to physical, mental, and cognitive functions and types of dementia: Alzheimer's disease (AD), vascular dementia (VD), mixed Alzheimer's disease/vascular dementia (MixADVD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). METHODS: The study used data from "The Norwegian Registry of Persons Assessed for Cognitive Symptoms" (NorCog). Differences between the dementia groups and predictors of falls, gait speed, ADL, and Cornell scores were analysed. RESULTS: Among study participants, 537/1321 (40.7%) reported a fall in the past year, with significant variations between dementia diagnoses. Fall incidence increased with age, comorbidity/polypharmacy, depression, and MAYO fluctuation score and with reduced physical activity, gait speed, and ADL. Persons with VD and MixADVD had high fall incidences and impaired gait speed and ADL. Training of physical fitness, endurance, muscular strength, coordination, and balance and optimising treatment of comorbidities and medication enhance gait speed. Improving ADL necessitates, in addition, relief of cognitive impairment and fluctuations. Relief of depression and fluctuations by psychological and pharmacological interventions is necessary to reduce the high fall risk in persons with DLB. CONCLUSIONS: The fall incidence and fall predictors varied significantly. Personalised interventions presuppose knowledge of each individual's fall risk factors.}, } @article {pmid40862941, year = {2025}, author = {Gao, F and Hou, Y and Wang, Y and Liu, L and Yi, X and Xia, N}, title = {Photothermal and Photodynamic Strategies for Diagnosis and Therapy of Alzheimer's Disease by Modulating Amyloid-β Aggregation.}, journal = {Biosensors}, volume = {15}, number = {8}, pages = {}, pmid = {40862941}, issn = {2079-6374}, support = {2023AYSYKYCXTD03//Program for Innovative Research Team of Science and Technology in Anyang Normal University/ ; }, mesh = {*Alzheimer Disease/therapy/diagnosis ; Humans ; *Amyloid beta-Peptides/metabolism ; *Photochemotherapy ; *Photothermal Therapy ; Photosensitizing Agents/therapeutic use ; Reactive Oxygen Species/metabolism ; Protein Aggregates ; }, abstract = {Amyloid-β (Aβ) aggregates are considered as the important factors of Alzheimer's disease (AD). Multifunctional materials have shown significant effects in the diagnosis and treatment of AD by modulating the aggregation of Aβ and production of reactive oxygen species (ROS). Compared to traditional surgical treatment and radiotherapy, phototherapy has the advantages, including short response time, significant efficacy, and minimal side effects in disease diagnosis and treatment. Recent studies have shown that local thermal energy or singlet oxygen generated by irradiating certain organic molecules or nanomaterials with specific laser wavelengths can effectively degrade Aβ aggregates and depress the generation of ROS, promoting progress in AD diagnosis and therapy. Herein, we outline the development of photothermal therapy (PTT) and photodynamic therapy (PDT) strategies for the diagnosis and therapy of AD by modulating Aβ aggregation. The materials mainly include organic photothermal agents or photosensitizers, polymer materials, metal nanoparticles, quantum dots, carbon-based nanomaterials, etc. In addition, compared to traditional fluorescent dyes, aggregation-induced emission (AIE) molecules have the advantages of good stability, low background signals, and strong resistance to photobleaching for bioimaging. Some AIE-based materials exhibit excellent photothermal and photodynamic effects, showing broad application prospects in the diagnosis and therapy of AD. We further summarize the advances in the detection of Aβ aggregates and phototherapy of AD using AIE-based materials.}, } @article {pmid40862772, year = {2025}, author = {de Munter, JPJM and Tsoy, A and Sitdikova, K and Wolters, EC and Chaprov, K and Yenkoyan, KB and Torosyan, H and Askarova, S and Anthony, DC and Strekalova, T}, title = {Therapeutic Effects of Neuro-Cells on Amyloid Pathology, BDNF Levels, and Insulin Signalling in APPswe/PSd1E9 Mice.}, journal = {Cells}, volume = {14}, number = {16}, pages = {}, pmid = {40862772}, issn = {2073-4409}, support = {(AP23485236//the Ministry of Higher Education and Science of the Re-public of Kazakhstan/ ; BR24992841//the Ministry of Higher Education and Science of the Re-public of Kazakhstan/ ; 21T-3A327 and 24YSMU-CON-I-3A//the Higher Education and Science Committee of the Republic of Armenia/ ; 101007642//European Union's H2020-MSCA-RISE-2020/ ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; Mice, Transgenic ; Mice ; Signal Transduction ; *Alzheimer Disease/therapy/pathology/metabolism ; *Insulin/metabolism ; Disease Models, Animal ; *Plaque, Amyloid/pathology/metabolism ; *Neurons/metabolism ; Male ; Amyloid beta-Protein Precursor/metabolism ; }, abstract = {Stem cell therapies, including mesenchymal (MSCs) and haematopoietic stem cells (HSCs), have shown promise in neurodegenerative diseases. Here, we investigated the therapeutic effects of a defined combination of unmanipulated MSCs and CD34[+] HSCs, termed Neuro-Cells (NC), in a murine model of Alzheimer's disease (AD), the APPswe/PS1dE9 mouse. At 12 months of age, mice received intracisternal injections of NC (1.39 × 10[6] MSCs + 5 × 10[5] HSCs) or vehicle. After 45 days, behavioural testing, immunohistochemical analyses of amyloid plaque density (APD), and cortical gene expression profiling were conducted. NC-treated APP/PS1 mice exhibited preserved object recognition memory and reduced anxiety-like behaviours, contrasting with deficits observed in untreated transgenic controls. Histologically, NC treatment significantly reduced the density of small amyloid plaques (<50 μm[2]) in the hippocampus and thalamus, and total plaque burden in the thalamus. Gene expression analysis revealed that NC treatment normalised or reversed disease-associated changes in insulin receptor (IR) signalling and neurotrophic pathways. Specifically, NC increased expression of Bdnf, Irs2, and Pgc-1α, while attenuating aberrant upregulation of Insr, Igf1r, and markers of ageing and AD-related pathology (Sirt1, Gdf15, Arc, Egr1, Cldn5). These findings indicate that NC therapy mitigates behavioural and molecular hallmarks of AD, potentially via restoration of BDNF and insulin receptor-mediated signalling.}, } @article {pmid40859865, year = {2025}, author = {Mello-Hortega, JV and de Oliveira, CS and de Araujo, VS and Furtado-Alle, L and Tureck, LV and Souza, RLR}, title = {Cannabidiol and Alzheimer Disease: A Comprehensive Review and In Silico Insights Into Molecular Interactions.}, journal = {The European journal of neuroscience}, volume = {62}, number = {4}, pages = {e70229}, pmid = {40859865}, issn = {1460-9568}, support = {//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Cannabidiol/therapeutic use/pharmacology ; Humans ; Animals ; Oxidative Stress/drug effects ; Computer Simulation ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a set of multifactorial conditions that progressively impair memory processing and cognitive function. The study of this pathology is particularly challenging due to its complex etiology, which involves several pathological hallmarks, including amyloid plaque formation, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, and other contributing factors-all leading to neuronal loss. The primary therapeutic approach for AD involves the use of anticholinesterase agents; however, these treatments are associated with adverse effects, and their efficacy has been increasingly questioned. Against this backdrop, researchers have investigated cannabidiol (CBD) as a potential complementary treatment for AD. This study compiles and synthesizes current evidence regarding the therapeutic effects of CBD in the context of AD, examining its impact on the amyloid cascade, tau phosphorylation, neuroinflammation, oxidative stress, the cholinergic pathway, glucose and lipid metabolism, behavioral alterations, and physiological changes. In addition, an in silico analysis was conducted based on studies that identified differential gene expression in response to CBD. Through this analysis, we mapped the gene network and biological pathways involved in CBD's mechanism of action in AD, contributing to the identification of potential gene targets for further research and providing deeper insight into its therapeutic potential.}, } @article {pmid40857536, year = {2025}, author = {Xu, X and Ghosh, D and Luo, S}, title = {A novel longitudinal rank-sum test for multiple primary endpoints in clinical trials: Applications to neurodegenerative disorders.}, journal = {Statistics in biopharmaceutical research}, volume = {}, number = {}, pages = {}, pmid = {40857536}, issn = {1946-6315}, support = {P30 AG072958/AG/NIA NIH HHS/United States ; R01 AG064803/AG/NIA NIH HHS/United States ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD) present a significant global health challenge, characterized by cognitive decline, functional impairment, and other debilitating effects. Current AD clinical trials often assess multiple longitudinal primary endpoints to comprehensively evaluate treatment efficacy. Traditional methods, however, may fail to capture global treatment effects, require larger sample sizes due to multiplicity adjustments, and may not fully utilize the available longitudinal data. To address these limitations, we introduce the Longitudinal Rank Sum Test (LRST), a novel nonparametric rank-based omnibus test statistic. The LRST enables a comprehensive assessment of treatment efficacy across multiple endpoints and time points without the need for multiplicity adjustments, effectively controlling Type I error while enhancing statistical power. It offers flexibility for various data distributions encountered in AD research and maximizes the utilization of longitudinal data. Simulations across realistic clinical trial scenarios, including those with conflicting treatment effects, and real-data applications demonstrate the LRST's performance, underscoring its potential as a valuable tool in AD clinical trials.}, } @article {pmid40853684, year = {2025}, author = {Insel, PS and Mattsson-Carlgren, N and Langford, O and Caruso, VM and Leuzy, A and Young, CB and Boxer, A and Aisen, PS and Sperling, RA and Mormino, EC and Donohue, MC}, title = {Concurrent Changes in Plasma Phosphorylated Tau 217, Tau PET, and Cognition in Preclinical Alzheimer Disease.}, journal = {JAMA neurology}, volume = {82}, number = {10}, pages = {985-993}, pmid = {40853684}, issn = {2168-6157}, mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/diagnostic imaging/blood/psychology ; Aged ; Male ; Female ; Positron-Emission Tomography ; Aged, 80 and over ; Phosphorylation ; Longitudinal Studies ; *Cognition/physiology ; Amyloid beta-Peptides/metabolism ; Aniline Compounds ; Prodromal Symptoms ; Cognitive Dysfunction/diagnostic imaging ; Biomarkers/blood ; Ethylene Glycols ; }, abstract = {IMPORTANCE: Developing disease-modifying treatments is a priority for Alzheimer disease research. OBJECTIVE: To determine the potential of plasma phosphorylated tau 217 (p-tau217) and tau positron emission tomography (PET) to assess disease modification in treatment trials. This diagnostic/prognostic study used longitudinal data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study collected from April 2014 to June 2023. Recruited from 67 sites in the US, Canada, Australia, and Japan, participants included older individuals (age 65-85 years) who were cognitively unimpaired at screening and underwent an amyloid PET scan. Participants without elevated amyloid PET were included from a companion to the A4 study, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. EXPOSURE: 18F-florbetapir PET imaging. MAIN OUTCOMES AND MEASURES: 18F-florbetapir PET imaging was used to classify participants as having elevated amyloid β (Aβ+). Measures of tau included longitudinal plasma p-tau217 and 18F-flortaucipir PET. Cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). RESULTS: A total of 1169 individuals were included from A4 Study and 538 without elevated amyloid PET were included from the LEARN Study. Among these 1707 participants, the baseline mean (SD) age was 71.5 (4.7) years, 1024 (60%) were female, and 683 (40%) male; 1169 participants were Aβ+, and the mean (SD) Mini-Mental State Examination score was 28.8 (1.2). The tau PET substudy included 443 participants; plasma p-tau217 levels were available for 1643 participants. The largest effect size of longitudinal tau PET accumulation at 36 months in Aβ+ participants was in the inferior temporal gyrus. Baseline associations with longitudinal change in PACC score in Aβ+ participants were strongest in the entorhinal cortex (correlation [ρ] = -0.55; 95% CI, -0.63 to -0.45) and plasma p-tau217 levels (ρ = -0.47; 95% CI, -0.56 to -0.37). Tau PET changes in frontoparietal regions were strongly correlated with concurrent cognitive changes. Levels of plasma p-tau217 increased significantly in Aβ+ participants before showing significant deceleration (χ2 = 21.7; P < .001) and were not associated with concurrent cognitive change in the tau PET substudy (ρ = -0.03; 95% CI, -0.23 to 0.16) but were modestly associated with concurrent cognitive changes in the full plasma sample (n = 1119; ρ = -0.24; 95% CI, -0.34 to -0.14). CONCLUSIONS AND RELEVANCE: This study found that tau PET is valuable for both prognostic and real-time tracking of disease progression. Plasma p-tau217 predicts cognitive changes prior to overt cognitive impairment and can efficiently guide participant selection. Imaging-based tau measures may enhance detection of disease-modifying effects and refine therapeutic targets in future Alzheimer disease trials.}, } @article {pmid40851107, year = {2025}, author = {Wang, R and Maloney, B and Beck, JS and Counts, SE and Lahiri, DK}, title = {MicroRNA-153-3p targets repressor element 1-silencing transcription factor (REST) and neuronal differentiation: Implications for Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70399}, pmid = {40851107}, issn = {1552-5279}, support = {P01 AG014449/AG/NIA NIH HHS/United States ; 1R21 AG076202//NIA/NIH/ ; R56 AG051086/AG/NIA NIH HHS/United States ; P30CA082709/GF/NIH HHS/United States ; R21 AG056007/AG/NIA NIH HHS/United States ; R21 AG074539/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; NIA-P30 AG072931//Michigan Alzheimer's Disease Research Center/ ; 2R56 AG051086//NIA/NIH/ ; NIA-P30 AG072976//Indiana Alzheimer's Disease Research Center/ ; UL1TR002529/GF/NIH HHS/United States ; R56 AG072810/AG/NIA NIH HHS/United States ; }, mesh = {*Repressor Proteins/genetics ; Humans ; *Alzheimer Disease/genetics/pathology ; *MicroRNAs/genetics ; *3' Untranslated Regions ; Cell Differentiation ; Neurons/cytology ; Induced Pluripotent Stem Cells/cytology ; Cell Line ; Binding Sites ; Amyloid beta-Protein Precursor/genetics ; alpha-Synuclein/genetics ; Cognitive Dysfunction/genetics/pathology ; }, abstract = {INTRODUCTION: Small non-coding microRNAs (miRNAs) play essential roles in Alzheimer's disease (AD) pathogenesis. Repressor element 1-silencing transcription factor (REST) is involved in AD, though its regulation remains unclear. METHODS: We performed real-time quantitative polymerase chain reaction (qPCR) in autopsied brain tissues to determine miR-153-3p and AD associations. A reporter-based assay measured the activity of REST mRNA 3'-untranslated region (3'-UTR). Induced pluripotent stem cells (iPSC)-derived neurons and human cell lines were applied to determine miR-153-3p regulation of endogenous proteins. RESULTS: Elevation of miR-153-3p is associated with a reduced probability of AD, while elevated REST is associated with a greater probability of AD. The 3'-UTR functional assay pinpointed the miR-153-3p binding sites. miR-153-3p treatment reduced REST, amyloid precursor protein (APP), and α-synuclein (SNCA) 3'-UTR activities and protein levels. miR-153-3p treatment altered REST and neuronal differentiation in iPSC-derived neuronal stem cells. RNA-sequencing and proteomics revealed miR-153-3p-associated networks. DISCUSSION: miR-153-3p reduces REST, APP, and SNCA expression, pointing toward its therapeutic and biomarker potential in neurodegenerative diseases. HIGHLIGHTS: With the increased emphasis on comorbidities of Alzheimer's disease (AD) and other neurodegenerative diseases, we identified that miR-153-3p, as a master regulator, reduced a group of neurodegeneration related proteins: REST, amyloid precursor protein (APP) and α-synuclein (SNCA) levels. The elevation of miR-153-3p levels is associated with reduced probability of AD in posterior cingulate cortex (PCC), while REST, by contrast, is associated with a greater probability of AD. miR-153-3p treatment alters REST protein levels and neuronal differentiation in induced pluripotent stem cells (iPSC) derived neuronal cells. RNA sequencing proteomics and interactome analysis revealed the role of miR-153-3p in axonal guidance.}, } @article {pmid40864415, year = {2025}, author = {Wasim, R}, title = {Bioenergetic failure and oxidative stress: mitochondrial contributions to Alzheimer's disease.}, journal = {Inflammopharmacology}, volume = {33}, number = {9}, pages = {5273-5289}, pmid = {40864415}, issn = {1568-5608}, mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology/drug therapy/pathology ; *Oxidative Stress/physiology ; *Mitochondria/metabolism/pathology ; Animals ; *Energy Metabolism/physiology ; Reactive Oxygen Species/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {The pathophysiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, is greatly impacted by mitochondrial dysfunction. Recent research suggests that a number of interconnected processes, such as elevated oxidative stress, disturbed energy metabolism, compromised calcium homeostasis, and malformed mitochondrial dynamics, all lead to neuronal injury. The mitochondria in AD brains have structural defects and the function of important oxidative phosphorylation-related enzymes is lowered, which results in less ATP being produced. Further exacerbated by mitochondrial dysfunction is the build-up of amyloid-beta (Aβ) peptides and hyperphosphorylated tau proteins, which interact directly with mitochondrial membranes and proteins to cause mitochondrial fragmentation and hinder mitochondrial transport along neuronal axons. These occurrences cause an increase in reactive oxygen species (ROS) generation, which exacerbates oxidative damage and feeds a vicious cycle. In AD, mutations in mitochondrial DNA (mtDNA) and changes in mitochondrial biogenesis have also been documented, indicating a key involvement in the development of the illness. Preclinical models show promise for therapeutic approaches that attempt to maintain mitochondrial function, including antioxidants, drugs that target the mitochondria. It is crucial to comprehend the intricate relationship between mitochondrial dysfunction and other pathological aspects of AD to find new treatment targets and enhance patient outcomes. In addition to underlining its role in the development of AD, this review examines the complex interaction between mitochondrial dysfunction and AD pathogenesis, taking into account its potential as a biomarker and a target for intervention.}, } @article {pmid40864225, year = {2025}, author = {Terpstra, K and Gutiérrez, C and Gui, K and Mirica, LM}, title = {Donepezil and Memantine Derivatives for Dual-Function and Prodrug Applications in Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3591-3602}, pmid = {40864225}, issn = {1948-7193}, support = {RF1 AG083937/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Memantine/pharmacology/analogs & derivatives ; *Alzheimer Disease/drug therapy/metabolism ; *Donepezil/pharmacology ; *Prodrugs/pharmacology ; *Cholinesterase Inhibitors/pharmacology ; Mice ; Amyloid beta-Peptides/metabolism ; Molecular Docking Simulation ; Mice, Transgenic ; Brain/metabolism/drug effects ; Humans ; Plaque, Amyloid/metabolism ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; }, abstract = {The treatment of Alzheimer's disease by acetylcholinesterase (AChE) and N-methyl-d-aspartate receptor (NMDAR) inhibitors is limited by the narrow therapeutic window and adverse side effects of the drugs. This study aims to increase the efficacy and limit the side effects of donepezil, an AChE inhibitor, and memantine, an NMDAR inhibitor, through the addition of amyloid-β (Aβ)-targeting fragments to create dual-function compounds. The incorporation of the amyloid-targeting fragments successfully produced compounds with affinity for Aβ fibrils, and that can stain amyloid plaques in the brains of 5xFAD mice. The donepezil-based compounds showed significant changes in AChE inhibition compared to donepezil due to the incorporation of the Aβ-targeting fragment and as confirmed by molecular docking studies. The memantine-derived compound showed good brain uptake in 5xFAD mice but lacked compatibility with NMDAR inhibition based on in vitro assays and molecular docking. Importantly, the memantine-derived compound acts as a prodrug in vivo, releasing memantine within a pharmacologically relevant time frame. Overall, these findings suggest that dual-function compounds may be useful as drug delivery agents that can be metabolized to release an active drug in areas of the brain rich in amyloid plaques and thus could lead to improved treatments for Alzheimer's disease.}, } @article {pmid40862175, year = {2025}, author = {Azimi, SM and Elhaie, M and Abedi, I and Salehi, H}, title = {Assessing the Diagnostic Utility of FDG-PET and HPLC for Detecting Microglia Activation and Inflammation in Alzheimer's Disease.}, journal = {Advanced biomedical research}, volume = {14}, number = {}, pages = {59}, pmid = {40862175}, issn = {2277-9175}, abstract = {Early and accurate Alzheimer's disease (AD) diagnosis is essential due to its progressive nature and significant impact. This study reviews and analyses FDG-PET and HPLC techniques in detecting inflammation and microglia activation in AD, marking the first comparison of their diagnostic capabilities. Through a literature search of publications from January 2021 to December 2023 across Scopus, Science Direct, and PubMed databases, 31 relevant articles were selected for analysis. FDG-PET and HPLC data on sensitivity, specificity, and inflammation were examined, highlighting their roles in detecting amyloid plaques, microglial activation, and blood/CSF metabolite regulation. Although amyloid PET offers higher sensitivity, FDG-PET uniquely classifies cognitive stages in AD despite its limitations due to glucose metabolism variance. Whereas HPLC provides insight into metabolic profile changes, it is noted for being invasive and costly. The combined use of FDG-PET and HPLC promises a comprehensive AD diagnostic approach by offering unique, complementary insights into functional and molecular brain changes. However, further validation is needed to overcome technical challenges and confirm their effectiveness before widespread adoption. The advancement of these diagnostic tools, alongside ongoing research, could significantly improve early AD detection, monitoring, and treatment. This review provides a novel assessment and comparison of the diagnostic utility of FDG-PET and HPLC techniques for detecting neuroinflammation and microglia activation in Alzheimer's disease by analyzing relevant studies between 2021 and 2023, highlighting their complimentary strengths and limitations.}, } @article {pmid40860878, year = {2025}, author = {Hou, R and Song, W and Nan, Y and Gong, Y and Liu, J and Liu, J}, title = {Cistanche tubulosa glycosides ameliorate cognitive decline in APP/PS1 mice via modulation of gut microbiota and fatty acid metabolism: insights from multi-omics and experimental validation.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1662336}, pmid = {40860878}, issn = {1663-9812}, abstract = {OBJECTIVE: The dried succulent stem of C. tubulosa (Schenk) Wight has long been used as herbal medicine in China and other regions of Asia for its tonifying properties. This study aimed to elucidate the pharmacological mechanisms of the total glycosides from Cistanche tubulosa (GCT) in ameliorating cognitive decline, with a focus on gut microbiota remodeling and metabolic regulation. METHODS: Six-month-old APP/PS1 double-transgenic mice received oral GCT at three doses or donepezil for 60 days. Cognitive function was assessed by the Morris water maze. Aβ burden and inflammatory factors were evaluated by immunohistochemistry and ELISA. Gut microbiota was analyzed using 16S rRNA sequencing. Metabolomic profiles of mice serum and brain were profiled by a targeted metabolomics approach that enabled simultaneous quantitation of 306 metabolites. The effect of GCT on pure-cultured bacterial strain was assessed via growth curve analysis in vitro. RESULTS: GCT treatment significantly improved spatial memory and reduced the protein levels of Aβ and proinflammatory factors in APP/PS1 mice. Multi-omics analyses revealed that GCT rapidly enriched beneficial taxa like Akkermansia and suppresses Firmicutes since the seventh day of intervention, leading to increased neuroprotective short-chain fatty acids (e.g., β-hydroxybutyrate) and decreased pro-inflammatory long-chain fatty acids in both serum and brain. Crucially, in-vitro experiments demonstrated that GCT directly promoted the proliferation of Akkermansia muciniphila, a key probiotic implicated in AD amelioration. CONCLUSION: This work uncovers a novel "gut microbiota-fatty acid metabolism-neuroinflammation" axis as the primary mechanism underlying GCT's anti-AD effects. These findings highlight GCT's therapeutic potential and offer new mechanistic insights into how low-bioavailability phytochemicals exert systemic benefits via the gut-brain axis.}, } @article {pmid40860056, year = {2025}, author = {Kermaninia, S and Mohammadi-Khanaposhtani, M and Şenol, H and Khajeh Mohammadilar, FS and Dastyafteh, N and Moradkhani, F and Saeedi, S and Larijani, B and Dadgar, A and Aktaş, A and Sadeghian, N and Taslimi, P and Mahdavi, M}, title = {New 1E,1'E-hydrazine-bis(phenoxy-1,2,3-triazol-acetamide) derivatives as potent inhibitors against acetylcholinesterase, butyrylcholinesterase, and α-glucosidase.}, journal = {RSC advances}, volume = {15}, number = {36}, pages = {29960-29971}, pmid = {40860056}, issn = {2046-2069}, abstract = {In this study, novel 1E,1'E-hydrazine-bis(phenoxy-1,2,3-triazol-acetamide) derivatives 10a-n were synthesized, and because of their structural features, they were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase. AChE and BChE are two important targets in the treatment of Alzheimer's disease (AD), and α-glucosidase is a carbohydrate-hydrolyzing enzyme with therapeutic importance in diabetes. Furthermore, cell studies were performed on the title compounds against SH-SY5Y neuroblastoma cells as a cancer cell line and HEK293 cells as a normal cell line. In vitro enzymatic evaluations demonstrated that these new compounds were active against the studied enzymes in comparison to standard inhibitors. In this regard, all the synthesized compounds were more potent than the standard inhibitors tacrine and donepezil against BChE, and most of these compounds were more potent than tacrine against AChE. Moreover, most of the target synthesized compounds were more potent than the standard inhibitor acarbose against α-glucosidase. The most potent compound against AChE and BChE was the 2,4-dichloro derivative 10k, and the most potent compound against α-glucosidase was the 2-chloro derivative 10h. Moreover, in vitro cell studies demonstrated that compounds 10k and 10h with a selectivity index of >10 demonstrated more cytotoxic effects on the cancer cell line SH-SY5Y than on the normal cell line HEK293. A docking study showed that the latter compounds attached to the active sites of the target enzymes with binding energies more favorable than those of the selected standard inhibitors. Furthermore, docking studies demonstrated that compound 10k interacted with both the catalytic and peripheral anionic sites of AChE and BChE. This property led to the better efficacy of the compound in the treatment of AD.}, } @article {pmid40859959, year = {2025}, author = {Mao, S and Qiao, R and Wang, Q and Shen, L and Li, D and Huo, X and Wang, J and Liu, K and Chen, W and Zhu, T and Zhang, B and Leng, S and Bai, Y}, title = {Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets.}, journal = {MedComm}, volume = {6}, number = {9}, pages = {e70329}, pmid = {40859959}, issn = {2688-2663}, abstract = {Astrocytes, the most prevalent glial cells in the central nervous system (CNS), play crucial roles in maintaining CNS homeostasis and responding to various pathological stimuli. They play key roles in neural development, neurotransmission, neuroinflammation, metabolic support, and tissue repair. Recent advancements in single-cell sequencing have revealed the remarkable heterogeneity of astrocytes, with distinct subpopulations differentially contributing to disease progression in neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, intracerebral hemorrhage, and multiple sclerosis. In addition, they play an important role in various behavioral neuropsychiatric disorders. This review highlights the dual roles of astrocytes in disease progression, driven by their diverse molecular profiles and functions. It outlines the key molecular mechanisms underlying astrocyte heterogeneity and their impact on neuroinflammation, neuronal support, and ionic balance regulation. Additionally, the review discusses potential therapeutic strategies targeting astrocytes to modulate these processes, aiming to improve treatment outcomes in neurological diseases. By elucidating the specific roles of astrocyte subsets in disease, this review seeks to advance the development of precision medicine for astrocyte-related neurological disorders.}, } @article {pmid40859930, year = {2025}, author = {Gao, JM and Li, WB and Chen, NN and Yi, Y and Wang, ZH and Chen, X and Zhao, YY and Yuan, ZL and Gao, J and Pan, YC and Guo, DS and Gong, QH}, title = {A Single-Molecule Pleuripotent Scaffold for Combinational Therapy of Alzheimer's Disease via Intranasal Administration.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {43}, pages = {e11611}, pmid = {40859930}, issn = {2198-3844}, support = {[2025]030//Central Government-Guided Local S&T Special Project of Guizhou Province/ ; GCC[2023]042//"'hundred"' level of high-level innovative talents in Guizhou Province/ ; //Fundamental Research Funds for the Central Universities/ ; 22371147//National Natural Science Foundation of China/ ; 22201141//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Administration, Intranasal/methods ; Animals ; Mice ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/administration & dosage/pharmacology ; Drug Delivery Systems/methods ; Humans ; Male ; }, abstract = {The intricate pathological mechanisms of Alzheimer's disease (AD), along with the restrictive nature of the blood-brain barrier (BBB) that further impedes the drug brain entry, underscore the pressing need for innovative combinational therapy to achieve effective treatment outcomes. Intranasal administration, capable of bypassing BBB by direct transport through olfactory and trigeminal nerves, provides a promising approach for treating neurological disorders. Herein, the guanidinium-modified calix[5]arene (GC5AY) is developed as a single-molecule pleuripotent scaffold, demonstrating small size, positive charge and desirable amphiphilicity, which facilitate its efficient traverse of nasal mucosal barrier. The multifunctionality of GC5AY, including inhibiting amyloid fibrosis, scavenging reactive oxygen species and drug delivery, enables it to serve as a sophisticated platform for constructing multi-target AD therapeutic agents. In light of this, by loading neuroprotective agent Trilobatin (TLB) into the cavity of GC5AY, intranasal administration of the TLB@GC5AY formulation is verified to effectively attenuate the cognitive impairment of AD mice, demonstrating multifaceted pathological improvements, while also possessing good biocompatibility. In response to the growing appeal for combinational therapy of AD, the approach proposed in this study has provided a readily generalizable strategy to fulfill this pursuit.}, } @article {pmid40858403, year = {2025}, author = {Gomaa, AA and Farghaly, HSM and Ahmed, AM and El-Mokhtar, MA and Hemida, FK}, title = {Corrigendum to "Advancing combination treatment with cilostazol and caffeine for Alzheimer's disease in high fat-high fructose-STZ induced model of amnesia'' [Europ. J. Pharmacol. 921 (2022), 174873].}, journal = {European journal of pharmacology}, volume = {1005}, number = {}, pages = {178074}, doi = {10.1016/j.ejphar.2025.178074}, pmid = {40858403}, issn = {1879-0712}, } @article {pmid40854983, year = {2025}, author = {Zhang, G and Pang, KK and Gao, Q and Chen, X and Huang, F and He, J}, title = {Cholecystokinin-expressing GABA neurons elicit long-term potentiation in the cortical inhibitory synapses and attenuate sound-shock associative memory.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {31220}, pmid = {40854983}, issn = {2045-2322}, support = {CityUHK 11101521//Hong Kong Research Grants Council/ ; CityUHK 11103922//Hong Kong Research Grants Council/ ; CityUHK 11104923//Hong Kong Research Grants Council/ ; CityUHK 11104524//Hong Kong Research Grants Council/ ; GHP_075_19GD//Innovation and Technology Fund of the Hong Kong SAR/ ; 09203656//Hong Kong Health Bureau, Health and Medical Research Fund/ ; 08194106//Hong Kong Health Bureau, Health and Medical Research Fund/ ; }, mesh = {Animals ; *Cholecystokinin/metabolism/genetics ; *Long-Term Potentiation/physiology ; *GABAergic Neurons/metabolism/physiology ; Mice ; *Synapses/metabolism/physiology ; *Memory/physiology ; Pyramidal Cells/metabolism/physiology ; *Auditory Cortex/physiology/metabolism ; Parvalbumins/metabolism ; Somatostatin/metabolism ; Interneurons/metabolism ; Male ; Mice, Transgenic ; }, abstract = {Neuronal interactions between inhibitory and excitatory neurons play a pivotal role in regulating the balance of excitation and inhibition in the central nervous system (CNS). Consequently, the efficacy of inhibitory/excitatory synapses profoundly affects neural network processing and overall neuronal functions. Here, we describe a novel form of long-term potentiation (LTP) induced at cortical inhibitory synapses and its behavioral consequences. We show that high-frequency laser stimulation (HFLS) of GABAergic neurons elicit inhibitory LTP (i-LTP) in pyramidal neurons of the auditory cortex (AC). The selective activation of cholecystokinin-expressing GABA (GABA[CCK]) neurons is essential for the formation of HFLS-induced i-LTP, rather than the classical parvalbumin (PV) neurons and somatostatin (SST) neurons. Intriguingly, i-LTP can be evoked in the AC by adding the exogenous neuropeptide CCK when PV neurons and SST neurons are selectively activated in PV-Cre and SST-Cre mice, respectively. Additionally, we discovered that low-frequency laser stimulation (LFLS) of PV neurons paired with HFLS of GABA[CCK] neurons potentiates the inhibitory effect of PV interneurons on pyramidal neurons, thereby generating heterosynaptic i-LTP in the AC. Notably, light activation of GABA[CCK] neurons in CCK-Cre mice significantly attenuates sound- shock associative memory, while stimulation of PV neurons does not affect this memory in PV-Cre mice. In conclusion, these results demonstrate a critical mechanism regulating the excitation-inhibition balance and modulating learning and memory in cortical circuits. This mechanism might serve as a potential target for the treatment of neurological disorders, including epilepsy and Alzheimer's disease.}, } @article {pmid40856257, year = {2025}, author = {Ghosh, A and Mukhopadhyay, TK and Datta, A}, title = {Two-dimensional materials can inhibit Aβ fibrillation in Alzheimer's disease.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {36}, pages = {19134-19148}, doi = {10.1039/d5cp01461a}, pmid = {40856257}, issn = {1463-9084}, mesh = {*Amyloid beta-Peptides/chemistry/metabolism/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy ; *Graphite/chemistry/pharmacology ; Boron Compounds/chemistry/pharmacology ; Humans ; *Nanostructures/chemistry ; Adsorption ; Protein Aggregates/drug effects ; }, abstract = {Alzheimer's disease (AD) is a major life-limiting neurodegenerative disorder caused by extracellular aggregation of amyloid β (Aβ) peptides. This forms amyloid plaques in the brain resulting in dementia and even causing death. In spite of great efforts towards developing therapies to cure AD, unfortunately, treatment is often ineffective. Herein, we investigate the possibility of state-of-the-art two-dimensional (2D) nanomaterials to treat AD by evaluating their potential to perturb and disrupt Aβ peptide aggregates. The adsorption mechanism for a pre-formed Aβ fibril is carefully studied on five 2D materials, namely graphene, hexagonal boron nitride (h-BN), h2D-C2N, g-C3N3, and g-C3N4. They are screened for their disrupting effects on the peptide aggregate. It is found that disruption of the Aβ fibril is directly related to the strength of its adsorption on the 2D material, which in turn, is dominated by the van der Waals interactions. h-BN shows a profound disruption of the Aβ fibril followed by graphene. The nitrogen-containing carbon-based 2D materials, h2D-C2N, g-C3N3, and g-C3N4, are found to be rather poor in this aspect. Structural disruption parameter ρd is proposed as an index to rank the potency of 2D materials to inhibit Aβ fibrillation. h-BN and graphene are shown to be highly potent towards disruption of misfolded protein aggregates like Aβ fibrils.}, } @article {pmid40856133, year = {2025}, author = {Korkmaz, E and Secerli, J and Erdoğan, H and Güdül Bacanlı, M}, title = {Cracking Amyloid Toxicity: Naringin Rescues Neuronal Cells in a Minimal Alzheimer's Model.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {21}, pages = {4224-4235}, doi = {10.1021/acschemneuro.5c00410}, pmid = {40856133}, issn = {1948-7193}, mesh = {*Flavanones/pharmacology ; Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Neurons/drug effects/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; DNA Damage/drug effects ; Apoptosis/drug effects ; *Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, extracellular amyloid plaque accumulation, and neuronal dysfunction. The diphenylalanine (Phe-Phe) dipeptide, a core self-assembling motif of amyloid-β (Aβ) peptides, has recently gained attention as a simplified and cost-effective model for mimicking amyloid aggregation in vitro. In this study, we established a Phe-Phe-induced AD model in SH-SY5Y neuroblastoma cells to investigate the effects of naringin (NAR), a Citrus-derived flavanone glycoside known for its antioxidative and anti-inflammatory properties, on AD. Following Phe-Phe exposure, cells were treated with NAR at subcytotoxic concentrations. Multiple end points including cytotoxicity, reactive oxygen species (ROS) generation, DNA damage (Comet assay), AD-related biomarkers (acetylcholinesterase (AChE), amyloid beta (Aβ), amyloid precursor protein (APP), tau protein), cytokine levels, caspase activation, and apoptosis were evaluated. NAR treatment significantly attenuated Phe-Phe-induced ROS production, genotoxicity, and inflammatory responses, while reducing apoptotic cell death and restoring biomarker levels toward physiological norms. These findings demonstrate that NAR exerts multitargeted neuroprotective effects and suggest its therapeutic potential in AD. Additionally, the Phe-Phe model was validated as a reproducible and biologically relevant in vitro system for screening anti-amyloid agents.}, } @article {pmid40855593, year = {2025}, author = {Foreman, RM and Rodriguez, M}, title = {Understanding the correlative relationship between obesity and Alzheimer disease.}, journal = {The Nurse practitioner}, volume = {50}, number = {9}, pages = {40-45}, doi = {10.1097/01.NPR.0000000000000355}, pmid = {40855593}, issn = {1538-8662}, mesh = {Humans ; *Alzheimer Disease/nursing/physiopathology/epidemiology/etiology ; *Obesity/complications/physiopathology/nursing/epidemiology ; Risk Factors ; }, abstract = {Current literature suggests obesity can increase the risk of developing dementia, in addition to all-cause mortality. Although cardiovascular disease and metabolic disorders are well-known risks of obesity, the increased risk of Alzheimer disease is lesser known. This article explores the pathophysiologic processes behind obesity and dementia and offers recommendations for identification, treatment, and optimal health planning in primary care.}, } @article {pmid40854864, year = {2025}, author = {Chen, YZ and Wei, YT and Xiao, M and Xie, WT and Yan, XK}, title = {[The mechanism of PI3K/AKT pathway in Alzheimer's disease and the research progress of acupuncture intervention].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {50}, number = {8}, pages = {965-973}, doi = {10.13702/j.1000-0607.20240371}, pmid = {40854864}, issn = {1000-0607}, mesh = {*Alzheimer Disease/therapy/genetics/metabolism/enzymology ; Humans ; *Proto-Oncogene Proteins c-akt/metabolism/genetics ; *Acupuncture Therapy ; *Signal Transduction ; *Phosphatidylinositol 3-Kinases/metabolism/genetics ; Animals ; Autophagy ; }, abstract = {Acupuncture has a definite effect on the treatment of Alzheimer's disease (AD), and its molecular mechanism has been studied more and more deeply. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway is mainly involved in the regulation of cell proliferation, apoptosis, autophagy and synaptic plasticity, and plays an important role in the occurrence and development of AD. In this paper, we reviewed the role of PI3K/AKT pathway in the pathogenesis of AD and the mechanism of acupuncture intervention, and concluded that the abnormal expression of PI3K/AKT signaling pathway can lead to imbalance of cellular oxidative defense system, impairment of mitochondrial structure and function synaptic destruction, abnormal autophagy and energy metabolism disorders, and acupuncture can improve oxidative stress damage, enhance synaptic plasticity, regulate autophagic activity and regulate energy metabolism by regulating PI3K/AKT signaling pathway to cure AD.}, } @article {pmid40854505, year = {2025}, author = {Tidke, B and Itekar, S and Khobragade, R and Vinchurney, M and Trivedi, R and Taksande, B and Umekar, M}, title = {Therapeutic implications of allopregnanolone in Alzheimer's related depression.}, journal = {Behavioural brain research}, volume = {495}, number = {}, pages = {115785}, doi = {10.1016/j.bbr.2025.115785}, pmid = {40854505}, issn = {1872-7549}, mesh = {*Pregnanolone/pharmacology/metabolism/therapeutic use ; Humans ; *Alzheimer Disease/drug therapy/metabolism/complications ; Animals ; *Depression/drug therapy/metabolism/etiology ; *Antidepressive Agents/pharmacology ; Neurosteroids ; }, abstract = {Alzheimer's disease (AD) and depression share common neuropathological mechanisms, with neuroinflammation, mitochondrial dysfunction, and impaired neurosteroid signalling contributing to both conditions. Allopregnanolone (ALLO), a potent neurosteroid, plays a crucial role in modulating mood, cognition, and neuroprotection via its interaction with GABA-A receptors and its ability to promote neurogenesis. Emerging evidence suggests that ALLO levels are significantly altered in AD, correlating with cognitive decline and neuropsychiatric symptoms, including depression. This review explores the pathological connection between AD and depression, highlighting the role of ALLO in mitigating disease progression and depressive symptoms. Preclinical studies demonstrate ALLO's ability to enhance synaptic plasticity, reduce β-amyloid toxicity, and alleviate depressive-like behaviours in AD models. Additionally, clinical trials investigating ALLO's therapeutic potential in AD and depression have shown promising results, though challenges remain in optimizing dosing, delivery, and patient selection. As a neurosteroid with both neuroprotective and antidepressant properties, ALLO represents a novel therapeutic approach that could bridge the gap between neurodegeneration and mood disorders. This review discusses the current understanding of ALLO's mechanistic role, its altered levels in AD and depression, and its potential as a disease-modifying therapy. Furthermore, we evaluate preclinical and clinical evidence supporting ALLO's efficacy, along with its limitations and future therapeutic prospects. By integrating neurosteroid-based strategies into AD treatment paradigms, ALLO may offer a promising avenue for addressing both cognitive decline and neuropsychiatric symptoms in AD-induced depression.}, } @article {pmid40854493, year = {2025}, author = {Huang, Y and Huo, X and Liu, H and Li, D and Yin, Z}, title = {Bile acids and polyphenols inhibit succinic anhydride-induced protein succinylation and amyloid aggregation: Mechanistic insights.}, journal = {Archives of biochemistry and biophysics}, volume = {773}, number = {}, pages = {110601}, doi = {10.1016/j.abb.2025.110601}, pmid = {40854493}, issn = {1096-0384}, mesh = {*Polyphenols/pharmacology/chemistry ; *Bile Acids and Salts/pharmacology/chemistry ; Molecular Docking Simulation ; *Protein Aggregates/drug effects ; *Succinic Anhydrides/chemistry ; *Amyloid/chemistry/metabolism ; Humans ; Protein Processing, Post-Translational/drug effects ; Glucosides/pharmacology ; }, abstract = {Lysine succinylation is a major post-translational modification affecting diverse proteins, and its excessive occurrence can lead to protein misfolding and aggregation-hallmarks of various proteinopathies, such as amyloid-β and Tau tangle formation in Alzheimer's disease and islet amyloid polypeptide aggregation in type 2 diabetes. Here, we investigated the inhibitory effects of bile acid metabolites (deoxycholic acid, glycocholic acid, and taurocholic acid sodium) and natural polyphenols (anthocyanin and salidroside) on succinylation and succinylation-induced amyloid aggregation. Succinylation levels were evaluated using the ninhydrin assay before and after treatment, and aggregation behavior and structural alterations were characterized by SDS-PAGE, inverted fluorescence microscopy, and intrinsic fluorescence spectroscopy. Additionally, fluorescence quenching and molecular docking were used to explore the underlying mechanisms. All five small molecules significantly reduced succinylation in a concentration-dependent manner (p < 0.05). Among bile acids, taurocholic acid sodium exhibited the strongest suppression of aggregation (40.99 %), followed by glycocholic acid (28.32 %) and deoxycholic acid (27.94 %). Anthocyanin showed greater inhibition (33.81 %) than salidroside (26.54 %) (all p < 0.05). The results suggest that these small molecules inhibit succinylation-induced aggregation potentially by interacting with proteins and altering their conformations, thereby preventing excessive succinylation at lysine residues. This study provides new insight into the interplay between bile acid metabolism and protein homeostasis and highlights the therapeutic potential of natural compounds in preventing protein aggregation-related diseases.}, } @article {pmid40854473, year = {2025}, author = {Ibrahim, KS and Colson, TL and Ferguson, SSG and Abd-Elrahman, KS}, title = {Positive allosteric modulation of M1 mAChRs with VU0486846 reverses cognitive deficits in male APPswe/PSEN1ΔE9 alzheimer's mice.}, journal = {Neuropharmacology}, volume = {280}, number = {}, pages = {110654}, doi = {10.1016/j.neuropharm.2025.110654}, pmid = {40854473}, issn = {1873-7064}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Male ; *Receptor, Muscarinic M1/metabolism/agonists/drug effects ; Mice ; Mice, Transgenic ; Presenilin-1/genetics ; *Cognitive Dysfunction/drug therapy/metabolism ; Female ; Disease Models, Animal ; Allosteric Regulation/drug effects ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is an age-associated neurodegenerative disease marked by progressive cognitive deterioration and beta-amyloid (Aβ) protein buildup, which currently lacks therapeutic interventions to decelerate its pathogenesis. The M1 muscarinic acetylcholine receptor (mAChR) is integral to synaptic plasticity and memory processes and has emerged as a critical target for ameliorating AD-associated cognitive deficits. Although M1 mAChR agonists have pro-cognitive potential, their clinical application is limited by significant cholinergic side effects. Our recent findings demonstrate that VU0486846, an M1 mAChR positive allosteric modulator (PAM) devoid of cholinergic toxicity, exhibits therapeutic benefits in a female APPswe/PSEN1ΔE9 (APP/PS1) Alzheimer's disease mouse model. This compound reversed memory deficits, alleviated anxiety-like behaviours, reduced Aβ pathology, and attenuated neuroinflammation in female mice. However, its therapeutic potential in male AD models remains to be fully characterized. In this study, we find that VU0486846 treatment restored cognitive function in male APP/PS1 mice, as evidenced by improved performance in the novel object recognition and Morris water maze tasks, and reduced anxiety-like behaviours in the open field test. VU0486846 ameliorates impaired autophagy signaling in the hippocampus, however, it does not alter hippocampal Aβ oligomer or plaque burden, despite decreasing BACE1 expression. These findings suggest that VU0486846 exerts behavioural and cognitive benefits via Aβ-independent mechanism(s). Collectively, this study highlights the therapeutic potential of VU0486846 in modulating AD pathophysiology, albeit via sex-specific signaling pathways.}, } @article {pmid40854437, year = {2025}, author = {Oh, JM and Shin, WH and Kim, B and Kim, E and Son, HJ and Kim, H}, title = {Farnesiferol B and Kamolonol Isolated from Ferula assa-foetida are Potent BACE1 Inhibitors with Neuroprotective Effects.}, journal = {Planta medica}, volume = {91}, number = {15}, pages = {933-942}, doi = {10.1055/a-2689-8035}, pmid = {40854437}, issn = {1439-0221}, support = {RS-2024-00347522//National Research Foundation of Korea (NRF) grant funded by Korean Government/ ; }, mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Animals ; *Neuroprotective Agents/pharmacology/isolation & purification/chemistry ; Molecular Docking Simulation ; Dogs ; *Ferula/chemistry ; Madin Darby Canine Kidney Cells ; *Aspartic Acid Endopeptidases/antagonists & inhibitors ; Humans ; Cell Line, Tumor ; Molecular Dynamics Simulation ; Amyloid beta-Peptides ; }, abstract = {Five compounds were isolated from Ferula assa-foetida and their beta-secretase 1 inhibitory activities were evaluated. Farnesiferol B and kamolonol showed potent beta-secretase 1 inhibitory activity with IC50 values of 8.11 and 1.00 µM and competitive inhibition patterns against beta-secretase 1 with Ki values of 6.51 and 0.41 µM, respectively. In silico pharmacokinetics showed that farnesiferol B was predicted to have high gastrointestinal absorption and blood-brain barrier permeability. In cell studies, farnesiferol B and kamolonol were nontoxic to normal Madin-Darby canine kidney and neuroblastoma cells, and both showed protective effects on neuroblastoma cells for Aβ42-induced neurotoxicity. In molecular docking simulations, we found that the efficacy of the compounds may be related to their interaction with the flap region and hydrogen bonding with ARG368. In addition, molecular dynamics simulation of kamolonol showed the ligand maintained its stability in interaction with the loop residues. These results show that farnesiferol B and kamolonol are potent beta-secretase 1 inhibitors with neuroprotective effects, suggesting that they are potential candidates for the treatment of neurodegenerative disorders, such as Alzheimer's disease.}, } @article {pmid40847318, year = {2025}, author = {Okafor, M and Faller, P and Vitale, N}, title = {Cell-specific copper dyshomeostasis mechanism in Alzheimer's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {42}, pmid = {40847318}, issn = {2047-9158}, support = {Idex PhD program//Université de Strasbourg/ ; ITI Neurostra program//Université de Strasbourg/ ; ITI Neurostra program//Université de Strasbourg/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology ; *Copper/metabolism ; Humans ; *Homeostasis/physiology ; Animals ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism/pathology ; Oxidative Stress/physiology ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive decline of cognitive functions, yet its underlying aetiology remains elusive. While amyloid-β (Aβ) and tau pathologies have been extensively studied, emerging evidence suggests that metal and especially copper dyshomeostasis may also play a crucial role in the pathogenesis of AD. This review explores the intricate relationship between copper and AD, shedding light on the multifaceted mechanisms through which copper dysregulation contributes to neurodegeneration. We delve into the impact of copper ions on Aβ aggregation, tau phosphorylation, and oxidative stress, providing a comprehensive overview of the molecular pathways involved. Furthermore, we discuss the interplay between different brain cell types and the impact Cu dysregulation may have on them. The therapeutic implications of targeting copper dysregulation for AD treatment are also addressed, emphasizing the potential of copper-modulating agents in ameliorating cognitive decline. In summary, this review discusses copper dyshomeostasis as a central player in the intricate tapestry of AD pathology, offering new insights and avenues for therapeutic interventions.}, } @article {pmid40853487, year = {2025}, author = {Wang, S and Xu, Z and Wang, S and Peng, Q and Zhu, S and Liu, C and Zhang, Y and Duan, R}, title = {Alamandine Rescues Cognitive Impairment and Ameliorates Alzheimer's Disease-Like Neuropathology in APP/PS1 Mice.}, journal = {Neurochemical research}, volume = {50}, number = {5}, pages = {277}, pmid = {40853487}, issn = {1573-6903}, support = {202201030//the International Joint Research and Development Project of Nanjing/ ; 82301609//the National Natural Science Foundation of China/ ; 2022M711666//China Postdoctoral Science Foundation/ ; BK20220196//Natural Science Foundation of Jiangsu Province/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism/pathology ; Oxidative Stress/drug effects ; Male ; Amyloid beta-Protein Precursor/genetics ; *Oligopeptides/therapeutic use/pharmacology ; Mice, Transgenic ; Endoplasmic Reticulum Stress/drug effects ; Maze Learning/drug effects ; Disease Models, Animal ; Mice, Inbred C57BL ; *Neuroprotective Agents/therapeutic use/pharmacology ; Presenilin-1/genetics ; Morris Water Maze Test/drug effects ; }, abstract = {Alzheimer's disease (AD) is on the rise worldwide, consequently driving a growing demand for effective prevention and treatment strategies. Alamandine is a member of the renin-angiotensin system family. Although alamandine exhibits protective effects in the pathophysiology of various disorders, its role in AD remains an unexplored area. This research aims to elucidate the benefits and mechanisms of alamandine in an in vivo model of AD. The mice received intracerebroventricular injections of vehicle or alamandine once daily for 4 weeks. The Morris water maze was conducted to assess spatial learning ability. Nissl staining was performed to evaluate neuronal injury. Important inflammation indictors were detected both by qRT-PCR and ELISA. Representative oxidative stress indicators and Fe[2+] levels were measured using corresponding assay kits. Western blot was employed to detect the expression levels of the related proteins. We found that alamandine mitigates cognitive function and spatial learning impairment in APP/PS1 mice. Alamandine shows positive therapeutic effects by ameliorating the phosphorylation of tau proteins and suppressing neuroinflammation. In addition, alamandine mitigates the oxidative stress, ferroptosis and endoplasmic reticulum stress (ERS) in the brain of APP/PS1 mice. Our research indicates that alamandine alleviates cognitive impairment in APP/PS1 mice and inhibits inflammation, oxidative stress, ferroptosis, and ERS. It may serve as a promising approach to alleviate symptoms and promote remission in AD.}, } @article {pmid40853403, year = {2025}, author = {Parmar, P and Chauhan, H and Modi, P and Israni, D}, title = {Pharmacological Evaluation and In-Silico Study of Sabinene as a Potential Anti-Alzheimer's Drug in AlCl3-Induced Rat Model via BACE-1 and GSK3β Modulation.}, journal = {Neurochemical research}, volume = {50}, number = {5}, pages = {278}, pmid = {40853403}, issn = {1573-6903}, mesh = {Animals ; Male ; *Glycogen Synthase Kinase 3 beta/metabolism ; Rats, Wistar ; *Amyloid Precursor Protein Secretases/metabolism ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; Aluminum Chloride ; *Aspartic Acid Endopeptidases/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; Molecular Docking Simulation ; Disease Models, Animal ; Aluminum Compounds ; Chlorides ; }, abstract = {Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disorder. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and glycogen synthase kinase-3β (GSK3β) contribute to Aβ plaque development, tau hyperphosphorylation, neurofibrillary tangles, and neuronal dysfunction in AD pathogenesis. This study aimed to investigate the neuroprotective potential of sabinene in an Aluminum chloride (AlCl3)-induced model of AD in male Wistar rats. Thirty male Wistar rats were randomly divided into six groups (n = 6 per group). Group I (control) received normal saline for 30 days. Groups II-V were administered only AlCl3 (100 mg/kg, orally) for 20 consecutive days to induce AD-like pathology, which was confirmed through behavioral assessments. Following induction, Group II (AD control) received 1% Tween 80; Group III (standard treatment) was administered rivastigmine (2.5 mg/kg); while Groups IV-VI received sabinene at doses of 5, 10, and 20 mg/kg, respectively, for 10 days 1 h prior to AlCl3. Behavioral evaluations were conducted on days 0, 20, and 31. On the 31st day, animals were sacrificed for biochemical and molecular analyses. In silico molecular docking studies revealed that sabinene exhibited a higher binding affinity towards AD-related targets (BACE1, GSK-3β, TACE, and AChE) compared to rivastigmine. In vivo, sabinene treatment significantly mitigated oxidative stress, restored antioxidant enzyme activities, reduced pro-inflammatory cytokine levels, AChE, BACE1, and GSK3β expression, and ameliorated histopathological alterations in the rat brain. Thus, sabinene exerts potent neuroprotective and disease-modifying effects in AlCl3-induced AD via AchE, BACE-1, and GSK3β Modulation.}, } @article {pmid40850846, year = {2025}, author = {Mattke, S and Chen, J and Reiman, EM}, title = {A preliminary economic evaluation of a potential program for the primary prevention of Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {9}, pages = {100334}, pmid = {40850846}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/prevention & control/economics/genetics ; *Cost-Benefit Analysis ; Aged ; *Primary Prevention/economics/methods ; Middle Aged ; Male ; Female ; Plaque, Amyloid/prevention & control ; Apolipoprotein E4/genetics ; }, abstract = {INTRODUCTION: We evaluated the potential cost-effectiveness of a hypothetical primary prevention screening and treatment program to avert the biological and clinical onset of Alzheimer's disease (AD) in cognitively unimpaired older adults. METHODS: This hypothetical program would use an amyloid plaque-clearing antibody therapy monthly in the first six months and annually thereafter in cognitively unimpaired 55-79 year-old APOE4 carriers and 60-79 year-old non-carriers with a negative AD blood test (sensitivity and specificity of 0.9), averting the onset of moderately frequent neuritic amyloid plaques by 75 %. Lifetime hypothetical treatment outcomes were compared to natural history outcomes to estimate cost-effectiveness. RESULTS: The program would be cost-effective up to a per-dose price of $1173 in APOE4 carriers and $307 in non-carriers or a lifetime cost of $20,167 and $5146, respectively. DISCUSSION: Primary AD prevention could be cost-effective in older adults, especially in those at higher risk. Our findings and assumptions need to be confirmed with actual data.}, } @article {pmid40850200, year = {2025}, author = {Shen, D and Fan, S and Kong, W and Yuan, H and Wei, X and Zheng, K and Cao, S and Huang, L and Chu, L and Ge, L}, title = {Research progress on the interaction of artemisinin and its derivatives with TLR4 receptors in neuroinflammation.}, journal = {International immunopharmacology}, volume = {164}, number = {}, pages = {115402}, doi = {10.1016/j.intimp.2025.115402}, pmid = {40850200}, issn = {1878-1705}, mesh = {*Toll-Like Receptor 4/metabolism ; Humans ; *Artemisinins/therapeutic use/pharmacology/chemistry ; Animals ; *Neuroinflammatory Diseases/drug therapy/immunology ; Signal Transduction/drug effects ; }, abstract = {In recent years, TLR4, as a key member of the TLRs family, has attracted increasing attention for its role in neuroimmune diseases. As a critical immune surveillance molecule, TLR4 is considered a promising target for the modulation of neuroimmune disorders. A growing body of research has confirmed that artemisinin and its derivatives, as natural immunomodulators, participate in the regulation of TLR signaling pathways-particularly showing a close relationship with TLR4 among the TLR family.Recent studies have revealed a novel dual regulatory effect of artemisinin and its derivatives on the TLR4 signaling pathway. These compounds can not only selectively modulate TLR4-mediated inflammatory signaling cascades, such as the NF-κB pathway, effectively suppressing the excessive activation of microglia, but also inhibit TLR4 dimerization and endocytosis, thereby blocking downstream signal transduction and alleviating neuroinflammatory responses. This novel finding provides a molecular basis for targeting TLR4 in the treatment of neuroimmune diseases such as multiple sclerosis (MS) and Alzheimer's disease (AD).Moreover, as naturally derived TLR4 modulators, artemisinin and its derivatives show great potential as new lead compounds for targeted therapies in neuroimmune diseases, offering new avenues and strategies for treatment. Therefore, this review focuses on the molecular structural characteristics of artemisinin and its derivatives, and the TLR4-mediated signaling pathways. It explores their potential mechanisms of action in modulating neuroimmune disorders from multiple perspectives-including drug structural properties, molecular docking simulations, and target regulation. The objective is to identify safe and effective neuroimmune modulators from natural products and provide new research perspectives and strategies for the TLR4-targeted treatment of neuroimmune diseases.}, } @article {pmid40849807, year = {2025}, author = {Cong, C and Cong, H and Yao, Y and Bai, Y and Xu, L}, title = {Copper homeostasis and cuproptosis in Alzheimer's disease (Review).}, journal = {International journal of molecular medicine}, volume = {56}, number = {5}, pages = {}, pmid = {40849807}, issn = {1791-244X}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Copper/metabolism ; *Homeostasis ; Animals ; Oxidative Stress ; Brain/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuroinflammation, synaptic dysfunction and neuronal loss. Research has revealed a connection between copper metabolism and the pathophysiology of AD, particularly through a newly identified form of copper‑dependent cell death referred to as cuproptosis. Cuproptosis is driven by the aggregation of lipoylated proteins and proteotoxic stress caused by excessive copper accumulation, leading to cellular demise, which is a key event in AD. While studies on copper levels in the brain in AD remain inconclusive, there is mounting evidence suggesting that an imbalance in copper homeostasis, particularly elevated labile copper levels, contributes to oxidative damage and neurodegeneration in patients with AD. The present review examines the role of cuproptosis in AD and discusses how targeting this pathway may provide novel therapeutic opportunities. By investigating the underlying mechanisms and potential clinical implications, the present review highlights that regulation of cuproptosis provides a promising approach for modulating disease progression and developing personalized treatment strategies for AD.}, } @article {pmid40849781, year = {2025}, author = {Kurochkina, N and Rudrabhatla, P}, title = {Role of Calmodulin in Neurodegeneration and Neuroprotection.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575403663250812115441}, pmid = {40849781}, issn = {1875-5607}, abstract = {Intracellular calcium (Ca2+) levels are critical in maintaining cellular activities and are tightly regulated. Neuronal degeneration and regeneration rely on calcium-binding proteins. Calmodulin (CaM) is a calcium sensor and the primary regulator of receptors and ion channels that maintain calcium homeostasis. The calmodulin binding domains are present in proteins that serve as risk factors and biomarkers associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and other neurodegenerative diseases, suggesting calmodulin ligands as emerging therapeutic targets for treatment. Inhibiting CaM to develop new therapies has drawbacks, as CaM is a ubiquitous molecule involved in many regulatory pathways. Recently, new strategies for disrupting CaM interactions with its targets have shown promising approaches to treatment. The structures of human CaM, its binding proteins, and inhibitors are well studied, with particular emphasis on the conservation of CaM amino acid sequences and the ability to bind protein fragments of high sequence variability, which exhibit common characteristics of amphipathic helices carrying basic amino acids. In this review, we discuss structural characteristics of CaM and its ligands in the context of transcriptional regulation. Specific binding of CaM to (1) basic region/helix-loop-helix/leucine zipper and (2) helix-turn-helix high mobility group box containing Sox families of transcription factors highlights common features of CaM binding sequences, which suggest their regulatory functions. We describe key proteins involved in neurodegeneration and transcription factors subject to calmodulin regulation that are candidates for the development of new approaches to treating neuronal diseases.}, } @article {pmid40849759, year = {2025}, author = {Maheshwari, S and Kumar, P and Dwivedi, V and Mishra, A and Singh, VK and Singh, A}, title = {Advances in Nanotechnology for Targeted Drug Delivery in Alzheimer's Disease.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098359258250727103551}, pmid = {40849759}, issn = {1874-6128}, abstract = {Alzheimer's Disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and hallmark pathological features, such as amyloid-beta plaques and tau protein tangles. Despite substantial research, current therapeutic strategies remain primarily symptomatic, with limited success in preventing or reversing disease progression. One major challenge is the Blood-Brain Barrier (BBB), which restricts the delivery of therapeutic agents to the brain. Nanotechnology provides innovative solutions to these challenges by enabling the development of targeted drug delivery systems tailored to AD's unique pathophysiology. Nanoparticles offer several advantages for AD therapy, including their small size, surface modifiability, and the ability to traverse the BBB. These carriers can enhance drug stability, prolong systemic circulation, and enable controlled drug release, reducing systemic toxicity while maximizing therapeutic efficacy. Among various approaches, nanoparticles functionalized with ligands targeting AD show promise in promoting the clearance of pathological aggregates, potentially slowing disease progression and alleviating neurotoxicity. Liposomes, polymeric nanoparticles, dendrimers, and exosomes are notable nanocarriers that have been successfully engineered to deliver a range of therapeutic agents, including anti-amyloid drugs, neuroprotective compounds, and gene therapies. Recent advancements also emphasize stimulus-responsive nanocarriers that release drugs in response to specific pathological cues, further enhancing treatment precision. This article delves into the most recent advancements in nanotechnology for AD therapy, and the potential of these innovative systems to overcome long-standing barriers in AD treatment and paving the way for more effective and targeted interventions.}, } @article {pmid40849753, year = {2025}, author = {Souza, FN and David, ES and Lima, HB and Silva, AG and Souto, RNP and Hage-Melim, LIS}, title = {Evidence of the Efficacy of Acetylcholinesterase Inhibitors in In Vivo Studies: A Systematic Review.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273388078250801044226}, pmid = {40849753}, issn = {1996-3181}, abstract = {INTRODUCTION: This systematic review aimed to provide an updated overview of studies using anticholinesterases with in vivo activity for the treatment of Alzheimer's disease. METHODS: A systematic review was conducted using searches in the following databases: PubMed, SciELO (Scientific Electronic Library Online), Web of Science, LILACS (Latin American and Caribbean Literature in Health Sciences), as well as gray literature, through the CAPES and Google Scholar databases of national and international journals. The research was registered on the International Prospective Register of Systematic Reviews (PROSPERO) platform under registration number: CRD42024482117 and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. RESULTS: A total of 1,191 articles were identified in the databases, of which 11 were selected to compose this systematic review, as they met the previously pre-defined selection criteria. The selected articles were published between 2019 and 2023. The substance most commonly used to induce Alzheimer's was scopolamine. As for administration routes, the most used was intraperitoneal. Some of the methods used to evaluate cognitive processes in rats and mice were- Elevated Plus Maze (EPM), Morris water maze (MWZ), Y maze, and passive avoidance tests. DISCUSSION: The reviewed studies demonstrated that the evaluated anticholinesterase agents exhibited anti-Alzheimer activity in animal models, with notable cognitive effects observed in behavioral tests. CONCLUSION: The data indicated that the analyzed anticholinesterase agents have therapeutic potential for Alzheimer's disease, justifying the continuation of preclinical research and future clinical investigations.}, } @article {pmid40848921, year = {2025}, author = {Ma, C and Campbell, K and Kovalenko, A and Li, J and Sandusky-Beltran, LA and Liang, H and Hunt, JB and Calahatian, J and Kallupurackal, M and Pandey, S and Vasisht, M and Watler, M and Quadri, Z and Michalski, C and Fahnestock, M and Papangelis, A and Pedersen, DS and Ulven, T and Nash, K and Selenica, MB and Morgan, D and Bickford, PC and Lee, DC}, title = {Nutrient sensing receptor GPRC6A regulates mTORC1 signaling and Tau biology.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107054}, doi = {10.1016/j.nbd.2025.107054}, pmid = {40848921}, issn = {1095-953X}, support = {R01 AG054559/AG/NIA NIH HHS/United States ; R21 AG055996/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Mechanistic Target of Rapamycin Complex 1/metabolism ; Humans ; *Receptors, G-Protein-Coupled/metabolism ; *tau Proteins/metabolism ; Signal Transduction/physiology ; Mice ; *Alzheimer Disease/metabolism/pathology ; *Tauopathies/metabolism ; Male ; Brain/metabolism ; Mice, Transgenic ; Arginine/metabolism ; Female ; Mice, Inbred C57BL ; }, abstract = {Tauopathies, including Alzheimer's disease (AD), comprise microtubule-associated protein tau aggregates that cause neuronal cell death and clinical cognitive decline. Reducing overall tau abundance remains a central strategy for therapeutics; however, no disease-modifying treatment exists to date. One principal pathway for balancing cellular proteostasis includes the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Recently, arginine emerged as one of the primary amino acids to activate mTORC1 through several intracellular arginine sensors and an extracellular arginine receptor, namely the G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A). Human AD brains were previously reported with elevated mTORC1 signaling; however, it is unclear whether arginine sensing and signaling to mTORC1 plays a role in tauopathies. Herein, we examined arginine sensing associated with mTORC1 signaling in the human AD and animal models of tauopathy. We found that human AD brains maintained elevated levels of arginine sensors with potential uncoupling of arginine sensing pathways. Furthermore, we observed increased GPRC6A and arginine in the brain, accompanied by increased mTORC1 signaling and decreased autophagy in a mouse model of tauopathy (Tau PS19). We also discovered that both supplementing arginine and overexpressing GPRC6A in cell culture models could independently activate mTORC1 and promote tau accumulation. In addition, we found that suppressing GPRC6A signaling by either genetic reduction or pharmacological antagonism reduced tau accumulation, phosphorylation, and oligomerization. Overall, these findings uncover the crucial role of arginine sensing pathways in deregulating mTORC1 signaling in tauopathies and identify GPRC6A as a promising target for future therapeutics in tauopathies and other proteinopathies. SIGNIFICANCE STATEMENT: Tauopathies, including Alzheimer's disease (AD), accumulate pathogenic tau protein inclusions that potentially contribute to the hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling and eventually cause neuronal cell death. Here, we presented novel findings that AD and animal models of tauopathy maintained increased expression of arginine sensors and uncoupling of arginine sensing associated with mTORC1 signaling. We investigated the role of a putative extracellular arginine and basic L-amino acid sensing G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A) in activating mTORC1 and accelerating pathogenic tau phenotypes in several cell models. Additionally, we showed that genetic repression or antagonism of GPRC6A signaling provides a novel therapeutic target for tauopathies and other proteinopathies.}, } @article {pmid40848864, year = {2025}, author = {Rao, J and Zheng, H and Lu, M and Chen, J and Wang, C and Cao, Y}, title = {Yanghuo Sanqi capsule against Alzheimer's disease by upregulating lipid metabolism: Network pharmacology and multi-omics analysis.}, journal = {Fitoterapia}, volume = {186}, number = {}, pages = {106837}, doi = {10.1016/j.fitote.2025.106837}, pmid = {40848864}, issn = {1873-6971}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; *Drugs, Chinese Herbal/pharmacology ; Caenorhabditis elegans/drug effects ; *Lipid Metabolism/drug effects ; Network Pharmacology ; Mice ; Molecular Docking Simulation ; Capsules ; Amyloid beta-Protein Precursor/metabolism ; Up-Regulation ; Amyloid beta-Peptides ; Multiomics ; }, abstract = {Yanghuo Sanqi capsule (YSC) consists of Yingyanghuo (Epimedium brevicornu Maxim., YYH) and Sanqi (Panax notoginseng (Burk.) F.H.Chen, SQ), which is used to treat cardiovascular diseases in Traditional Chinese Medicine (TCM). Additionally, the accumulated evidence suggests that it has the potential to treat Alzheimer's disease (AD). This study tries to elucidate the mechanisms of YSC against AD by combining network pharmacology of absorbed components with multi-omics of Caenorhabditis elegans (C. elegans). Firstly, network pharmacology was used to predict the target of the YSC in the treatment of AD. Then, Caenorhabditis elegans (C. elegans) CL4176 and CL2355 were used to study the effect of YSC on AD, and the mechanism was studied through multi-omics. Finally, potential therapeutic targets and bioactivity ingredients were identified through validation experiments, molecular docking, and molecular dynamics simulation. The network pharmacology of 15 mice blood components suggested that YSC may intervene in AD by regulating lipid metabolism and amyloid precursor protein (APP). In addition, YSC can alleviate Aβ-induced toxicity in both muscle and nerve in C. elegans. Transcriptomic and metabolomic analysis in C. elegans showed that YSC protected against AD by increasing lipid metabolism, which can maintain lipid homeostasis inside and outside the cell and down-regulating APP to alleviate Aβ-induced toxicity. Anhydroicaritin (AHI) is an important bioactive ingredient involved in regulating APP error clipping and lipid metabolism in YSC. This study reveals the mechanism of YSC anti-AD and provides experimental support for expanding its clinical use.}, } @article {pmid40848134, year = {2025}, author = {Mehra, A and Sachdeva, V and Khanna, J and Singh, G and Mahajan, M and Bhardwaj, J and Kaur, M and Bedi, N}, title = {Mirtazapine revisited: new therapeutic perspectives and formulation advances.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40848134}, issn = {1432-1912}, abstract = {Mirtazapine (MTZ) is a Food and Drug Administration-approved medication used primarily for the treatment of severe depression. It is a BCS class II drug having poor aqueous solubility (0.092 mg/mL), low oral bioavailability (50%), and high first-pass metabolism. This narrative review summarizes the ongoing research for the development of MTZ's novel formulations, keeping in view its physicochemical properties and its pharmacokinetic limitations. Owing to its novel pharmacodynamics, MTZ offers considerable potential for the management of various diseases, including schizophrenia, Alzheimer's disease, Parkinson's disease, epilepsy, post-traumatic stress disorder, diabetes, irritable bowel syndrome, and infertility, in addition to its widely established utility in depression. Nevertheless, the literature findings on the usage of MTZ in the aforementioned diseases remain contentious, which can be attributed to the inconsistencies in the research evidence and variable study outcomes. However, promising results of therapeutic effectiveness of MTZ against pruritus, cancer-induced nausea, emesis, and anorexia have been reported from preliminary investigations. Lastly, the present review provides a worthwhile overview of clinical trials and patents, which together put forward substantial evidence suggesting the potential repurposing of MTZ beyond from its use in depression, thereby accelerating advancements in drug delivery technologies.}, } @article {pmid40847656, year = {2025}, author = {Stroud, J and Cummings, JL and Chumki, SR and Such, P and Wang, D and Palma, AM and Zhang, Z and Brubaker, M and Grossberg, GT}, title = {Brexpiprazole for agitation in clinically relevant patient subgroups: a post hoc analysis of efficacy and safety in patients with agitation associated with dementia due to Alzheimer's disease.}, journal = {Current medical research and opinion}, volume = {41}, number = {8}, pages = {1523-1534}, doi = {10.1080/03007995.2025.2552278}, pmid = {40847656}, issn = {1473-4877}, mesh = {Humans ; *Alzheimer Disease/complications/drug therapy ; *Thiophenes/adverse effects/administration & dosage/therapeutic use ; Male ; *Psychomotor Agitation/drug therapy/etiology ; Female ; Aged ; Aged, 80 and over ; *Quinolones/adverse effects/administration & dosage/therapeutic use ; Middle Aged ; Double-Blind Method ; Treatment Outcome ; *Antipsychotic Agents/adverse effects/therapeutic use/administration & dosage ; }, abstract = {OBJECTIVE: To explore the efficacy and safety of brexpiprazole for the treatment of agitation symptoms in clinically relevant subgroups of patients with dementia due to Alzheimer's disease. METHODS: Data were pooled for brexpiprazole (2 or 3 mg/day) and placebo from two international, randomized, double-blind trials in adults with a clinical diagnosis of Alzheimer's dementia with mild-to-severe cognitive dysfunction and with agitation (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Change in agitation frequency over 12 weeks was measured using the Cohen-Mansfield Agitation Inventory (CMAI). Safety measures included treatment-emergent adverse events (TEAEs). In this post hoc analysis, thirteen clinically relevant subgroups were investigated based on care setting (institutionalized, non-institutionalized), severity of cognitive dysfunction (mild/moderate, severe), co-occurring behavioral symptoms (psychosis, depression, anxiety, irritability, sleep disturbance), and use of concomitant medications for dementia (acetylcholinesterase inhibitor, memantine) and psychiatric conditions (antidepressant, benzodiazepine). RESULTS: In the randomized sample (N = 621), mean age was 74 years (range 55-90 years), 344 (55.4%) participants were female, and 277 (44.6%) were male. Over 12 weeks, brexpiprazole showed numerically greater reduction in agitation frequency than placebo in 12 of 13 subgroups. The only exception was "concomitant benzodiazepines", which was a small subgroup (n = 71), but showed efficacy for brexpiprazole in secondary analyses. The largest differences in favor of brexpiprazole versus placebo were for the concomitant antidepressant, co-occurring sleep disorder, and co-occurring psychosis subgroups. The overall incidence of TEAEs was generally consistent across subgroups. CONCLUSION: In these exploratory analyses, brexpiprazole reduced symptoms of agitation across a wide range of patients with agitation associated with dementia due to Alzheimer's disease.}, } @article {pmid40846816, year = {2025}, author = {Akindele, RG and Adebayo, S and Yu, M and Kanda, PS}, title = {AlzhiNet: Traversing from 2D-CNN to 3D-CNN, Towards Early Detection and Diagnosis of Alzheimer's Disease.}, journal = {Interdisciplinary sciences, computational life sciences}, volume = {}, number = {}, pages = {}, pmid = {40846816}, issn = {1867-1462}, support = {E2021202179//Natural Science Foundation of Hebei Province/ ; 42075129//National Natural Science Foundation of China/ ; 21351803D//Hebei Provincial Key Research Projects/ ; SJMYF2022Y06//Hebei Provincial Key Research Projects/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with increasing prevalence among the ageing population, necessitating early and accurate diagnosis for effective disease management. In this study, we present a novel hybrid deep learning framework, AlzhiNet, that integrates both 2D convolutional neural networks (2D-CNNs) and 3D convolutional neural networks (3D-CNNs), along with a custom loss function and volumetric data augmentation, to enhance feature extraction and improve classification performance in AD diagnosis. According to extensive experiments, AlzhiNet outperforms standalone 2D and 3D models, highlighting the importance of combining these complementary representations of data. The depth and quality of 3D volumes derived from the augmented 2D slices also significantly influence the model's performance. The results indicate that carefully selecting weighting factors in hybrid predictions is imperative for achieving optimal results. Our framework has been validated on the magnetic resonance imaging (MRI) from Kaggle and MIRIAD datasets, obtaining accuracies of 98.9% and 99.99%, respectively, with an AUC of 100%. Furthermore, AlzhiNet was studied under a variety of perturbation scenarios on the Alzheimer's Kaggle dataset, including Gaussian noise, brightness, contrast, salt and pepper noise, color jitter, and occlusion. The results obtained show that AlzhiNet is more robust to perturbations than ResNet-18, making it an excellent choice for real-world applications. This approach represents a promising advancement in the early diagnosis and treatment planning for AD.}, } @article {pmid40846207, year = {2025}, author = {Sharma, T and Bashir, B and Sharma, P and Andotra, N and Singh, SK and Singh, TG and Vishwas, S}, title = {Quantum dots in neurotheranostics for the treatment of Alzheimer's disease.}, journal = {Ageing research reviews}, volume = {112}, number = {}, pages = {102876}, doi = {10.1016/j.arr.2025.102876}, pmid = {40846207}, issn = {1872-9649}, mesh = {*Alzheimer Disease/drug therapy/diagnosis/metabolism/therapy ; *Quantum Dots/therapeutic use ; Humans ; *Theranostic Nanomedicine/methods ; Animals ; Blood-Brain Barrier/metabolism ; Biomarkers/metabolism ; }, abstract = {Age-related neurodegeneration is one of the primary causes associated with the pathogenesis of Alzheimer's disease (AD). Currently, there are 5.8 million cases of AD worldwide. With the advancement in technology, the paradigm of treating the disease has shifted from one treatment or diagnosis to simultaneously diagnosing as well as treating the disease. Excellent efforts have been made by the scientists towards the development of nanotheranostics. Among them, quantum dots (QDs) have shown promising results due to their nanometer size, which enables them to cross the blood-brain barrier (BBB) and optical properties which help in imaging the environment/pathology inside the brain. Furthermore, their functionalization with the specific biomolecules or coupling with aptamers/proteins/peptides/antibodies offers site-specific detection of pathological biomarkers. The long-lasting, tunable, and strong fluorescence generated by them within the body helps in the selective detection of biomarkers at very low concentrations. This helps in the accurate and early diagnosis of AD. Their multiplexed sensing of multiple markers at a time due to the tunable property of their emission wavelengths, makes it a more specific and sensitive tool over microarray or other assays. Additionally, real-time tracking of drug delivery and parallel treatment of the disease at the targeted site make them a unique theranostic tool over other techniques. This review consolidates recent advances in QDs-based approaches, encompassing their physicochemical properties, blood-brain barrier (BBB) penetration strategies, synthesis, and functionalization techniques. The roles in targeted drug delivery, bioimaging, and biomarker detection, as well as their intrinsic therapeutic actions, including inhibition of amyloid beta formation and tau aggregation, antioxidative effects, and neuroprotection, have also been discussed. Multiple preclinical studies demonstrate the ability of QDs to enhance drug stability, improve BBB transport, enable high-sensitivity imaging of AD biomarkers, and modulate neuroinflammatory responses.}, } @article {pmid40845962, year = {2025}, author = {Zhou, Q and Zheng, N and Chen, Z and Xie, L and Yang, X and Sun, Q and Lin, J and Li, B and Li, L}, title = {The emerging role of disulfidptosis in Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1005}, number = {}, pages = {178085}, doi = {10.1016/j.ejphar.2025.178085}, pmid = {40845962}, issn = {1879-0712}, mesh = {*Alzheimer Disease/pathology/metabolism/drug therapy ; Humans ; Animals ; *Apoptosis/drug effects ; Oxidative Stress/drug effects ; *Disulfides/metabolism ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Disulfidptosis ; }, abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder primarily characterized by Aβ deposition and tau hyperphosphorylation. Clinically, AD manifests as progressive episodic-memory loss that ultimately erodes global cognition and the ability to perform activities of daily living. Despite decades of investigation, the molecular underpinnings of AD remain incompletely understood and no disease-modifying therapies are available. Recently, disulfidptosis, a novel form of programmed cell death (PCD) caused by disulfide stress with high expression of SLC7A11 (solute carrier family 7 member 11) under glucose starvation conditions, has emerged as a potential contributor to neurodegeneration. This review systematically summarizes the discovery, molecular features, and regulatory mechanisms of disulfidptosis, and critically evaluates its relevance to AD pathogenesis. We show that disulfidptosis can directly or indirectly modulate pivotal disease pathways, including Aβ accumulation, tau hyper-phosphorylation, and oxidative stress, through interconnected molecular cascades. Furthermore, we also delved into its potential application prospects in AD treatment, including inhibiting SLC7A11 activity, regulating NADPH (Nicotinamide Adenine Dinucleotide Phosphate) levels, targeting actin cytoskeleton dynamics, and antioxidant therapy. By integrating disulfidptosis into the AD landscape for the first time, this review offers a novel mechanistic perspective and identifies actionable therapeutic targets, thereby laying the groundwork for precision strategies against disulfidptosis-driven neurodegeneration.}, } @article {pmid40844953, year = {2025}, author = {Lalawat, RS and Kushwaha, N and Bajaj, V and Padhy, PK}, title = {NeuroFormer: A Deep Learning Framework for Alzheimer's Detection Using EEG Signals.}, journal = {IEEE journal of biomedical and health informatics}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/JBHI.2025.3601658}, pmid = {40844953}, issn = {2168-2208}, abstract = {Alzheimer's disease (AD), is a prevalent neurodegenerative disorder, characterized by cognitive decline. Alongside AD, and Frontotemporal dementia (FTD) poses significant challenges in clinical diagnosis due to overlapping symptoms and heterogeneous pathological mechanisms. This overlap often complicates timely and accurate diagnosis, which is crucial for effective intervention and treatment planning. To address this, a novel deep learning architecture, NeuroFormer is proposed for the classification of EEG signals captured through non-invasive neurophysiological measurement instruments into three categories: AD, FTD, and healthy controls (CN). The model integrates spectral processing, neural oscillatory dynamics, hierarchical capsule routing, adaptive normalization, and attention-based feature fusion to effectively extract discriminative spatiotemporal features from raw EEG signals. Advanced mechanisms such as dynamic spectral gating and graph convolutions capture both local and global brain activity patterns, while a multi-scale adaptive feature pyramid enhances feature representation. A lightweight classifier decodes the learned features, achieving a classification accuracy of 95.76%, significantly outperforming benchmark models across all key evaluation metrics. These findings demonstrate the strong potential of NeuroFormer as a measurement-driven diagnostic framework for early and accurate classification of dementia-related disorders using EEG instrumentation.}, } @article {pmid40844208, year = {2026}, author = {Sui, YV and Masurkar, AV and Shepherd, TM and Feng, Y and Wisniewski, T and Rusinek, H and Lazar, M}, title = {Associations Between Hippocampal Transverse Relaxation Time and Amyloid PET in Cognitively Normal Aging Adults.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {63}, number = {1}, pages = {171-180}, pmid = {40844208}, issn = {1522-2586}, support = {P30 AG066512/AG/NIA NIH HHS/United States ; P41 EB017183/EB/NIBIB NIH HHS/United States ; P41 EB017183/EB/NIBIB NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Positron-Emission Tomography/methods ; *Hippocampus/diagnostic imaging ; Aged ; Middle Aged ; Aged, 80 and over ; *Magnetic Resonance Imaging ; *Amyloid beta-Peptides/metabolism ; *Aging ; Longitudinal Studies ; Retrospective Studies ; *Cognition/physiology ; Alzheimer Disease/diagnostic imaging ; }, abstract = {BACKGROUND: Identifying early neuropathological changes in Alzheimer's disease (AD) is important for improving treatment efficacy. Among quantitative MRI measures, transverse relaxation time (T2) has been shown to reflect tissue microstructure relevant in aging and neurodegeneration; however, findings regarding T2 changes in both normal aging and AD have been inconsistent. The association between T2 and amyloid-beta (Aβ) accumulation, a hallmark of AD pathology, is also unclear, particularly in cognitively normal individuals who may be in preclinical stages of the disease. PURPOSE: To investigate longitudinal hippocampal T2 changes in a cognitively normal cohort of older adults and their association with global Aβ accumulation. STUDY TYPE: Retrospective, longitudinal. SUBJECTS: 56 cognitively normal adults between 55 and 90 years of age (17 males and 39 females). FIELD STRENGTH/SEQUENCE: 3 Tesla; multi-echo spin echo sequence for T2 mapping; 18F-florbetaben positron emission tomography for Aβ measurement. ASSESSMENT: Bilateral hippocampal T2 and volume were extracted to relate to Aβ PET measurements. To understand variations in AD risk, participants were separated into Aβ-high and Aβ-low subgroups using a predetermined threshold. STATISTICAL TESTS: Linear mixed-effect models and general linear models were used. A p-value < 0.025 was considered significant to account for bilateral comparisons. RESULTS: Older age was associated with increased T2 in the bilateral hippocampus (left: β = 0.30, right: β = 0.25) and smaller hippocampal volume on the left (β = -0.12). In the Aβ-low subgroup, both longitudinal T2 increase rates (β = 0.65) in the left hippocampus and bilateral cross-sectional T2 (left: β = 0.64, right: β = 0.46) were positively correlated with Aβ PET, independent of hippocampal volume. DATA CONCLUSION: This study provided in vivo evidence linking hippocampal T2 to Aβ accumulation in cognitively normal aging individuals, suggesting that quantitative T2 may be sensitive to microstructural changes accompanying early Aβ pathology, such as neuroinflammation, demyelination, and reduced tissue integrity. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.}, } @article {pmid40844075, year = {2025}, author = {Zhang, Y and Zhang, Y and Liang, R and Zou, J and Pei, R and Chen, X}, title = {Targeted ROS Scavenging for Disease Therapies Using Nanomaterials.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {37}, number = {50}, pages = {e04435}, doi = {10.1002/adma.202504435}, pmid = {40844075}, issn = {1521-4095}, support = {NUHSRO/2020/133/Startup/08//National University of Singapore/ ; NUHSRO/2023/008/NUSMed/TCE/LOA//National University of Singapore/ ; NUHSRO/2021/034/TRP/09/Nanomedicine//National University of Singapore/ ; MOH-001388-00//National Medical Research Council/ ; MOH-001041//National Medical Research Council/ ; CG21APR1005//National Medical Research Council/ ; MOH-001127-01//National Medical Research Council/ ; MOH-001500-00//National Medical Research Council/ ; MOH-001609-00//National Medical Research Council/ ; MOE-000387-00//Singapore Ministry of Education/ ; NRF-000352-00//National Research Foundation/ ; 52203205//National Natural Science Foundation of China/ ; 22405291//National Natural Science Foundation of China/ ; BE2023731//Natural Science Foundation of Jiangsu Province/ ; }, mesh = {*Reactive Oxygen Species/metabolism ; Humans ; *Nanostructures/chemistry/therapeutic use ; Animals ; *Free Radical Scavengers/chemistry/therapeutic use ; Neoplasms/drug therapy/metabolism ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Reactive oxygen species (ROS) are essential by-products of cellular metabolism and serve as key mediators in cell signaling and homeostasis. Excessive ROS production is associated with cellular damage and various diseases. Therefore, targeted ROS scavenging may enhance therapeutic efficacy and minimize side effects. With significant progress in nanotechnology, various nanomaterials with targeted ROS-scavenging properties have been developed to modulate ROS levels in biological microenvironments. In this review, the mechanisms underlying ROS generation and elimination in humans and in ROS-related diseases are first outlined. The latest advancements in ROS-scavenging nanomaterials, particularly their mechanisms and composition-based classifications, are then focused on. Strategies for improving the targeting ability of ROS-scavenging nanomaterials and their application in the therapeutics of ROS-induced diseases such as Alzheimer's disease, rheumatoid arthritis, acute kidney injury, diabetic wounds, and cancer are highlighted. Finally, the challenges faced by ROS-targeted nanotherapeutics are discussed, and possible alternatives to accelerate their clinical translation are proposed.}, } @article {pmid40843440, year = {2025}, author = {Phelps, J and Orr, A and Elvira, KS and Willerth, SM}, title = {Extracellular Vesicles for the Treatment of Alzheimer's Disease: A Systematic Review.}, journal = {Journal of extracellular biology}, volume = {4}, number = {8}, pages = {e70077}, pmid = {40843440}, issn = {2768-2811}, abstract = {The development of novel treatments that restore brain function and improve patient outcomes for Alzheimer's disease (AD) is necessary, given the complications and lack of improvement in recently approved amyloid beta (Aβ)-targeting drugs. Cell-derived extracellular vesicles (EVs) have been found to improve cognitive function through reduced inflammation, oxidative stress, and apoptosis, restoring neuronal and blood-brain barrier function, and inhibiting Aβ and phosphorylated tau build-up in the brain. Given the recent emergence of EVs into clinical trials, it is essential to provide the field with an update on proposed mechanisms of action, gaps in knowledge for further study, and recommendations for producing EVs with high therapeutic efficacy to ensure success in subsequent clinical trials. This systematic review summarizes original research to date that reports effects of mammalian cell-derived EVs for the treatment of AD. Evidence of therapeutic benefits and reported mechanisms of action are discussed. Further, methods for engineering EVs to increase their therapeutic efficacy and produce high-quality EVs relevant to the AD field are outlined. The quality of evidence is discussed in terms of reporting guidelines from the Minimal Information for Studies of Extracellular Vesicles (MISEV). The review further discusses current preclinical AD models and provides direction to improve the quality of AD models for testing novel therapeutics.}, } @article {pmid40843131, year = {2025}, author = {Xia, M and Liu, Q and Zhang, W and Ge, J and Mei, Z}, title = {Spatiotemporal Dynamics of Central Nervous System Diseases: Advancing Translational Neuropathology via Single-Cell and Spatial Multiomics.}, journal = {MedComm}, volume = {6}, number = {9}, pages = {e70328}, pmid = {40843131}, issn = {2688-2663}, abstract = {Central nervous system (CNS) diseases, a leading cause of global disability and mortality, encompass a wide range of brain disorders such as stroke, Alzheimer's disease, Parkinson's disease, and so on. These diseases are characterized by dynamic cellular heterogeneity and disrupted intercellular crosstalk, yet their molecular drivers remain incompletely resolved. Single-cell RNA sequencing (scRNA-seq) dissects transcriptional diversity at cellular resolution, while spatial transcriptomics (ST) maps niche-specific interactions within tissue architecture-complementary approaches that have revealed disease-associated subpopulations, neural-glial communication, and microenvironmental remodeling. However, standalone omics layers inadequately capture the genetic, epigenetic, and functional cascades underlying CNS pathologies. Here, we highlight the transformative potential of integrating scRNA-seq and ST with multiomic profiling to delineate spatially orchestrated molecular networks. Such multiomic convergence enables systematic deconstruction of molecular mechanisms and intercellular communication across disease progression. By correlating these signatures with clinical phenotypes, this strategy accelerates biomarker discovery, patient stratification, and therapeutic target identification. We further discuss challenges in data harmonization, subcellular spatial resolution, and computational scalability that must be addressed to realize personalized CNS medicine. This synthesis advocates for interdisciplinary frameworks to translate multiomic insights into mechanistically grounded diagnostics and therapies, ultimately bridging the gap between molecular discovery and precision clinical intervention.}, } @article {pmid40842924, year = {2025}, author = {Ella, FA and Ambamba, BDA and Njayou, FN and Moundipa, PF}, title = {Khaya grandifololia exerts multitarget neuroprotective potential against neurodegenerative disorders: In vitro and in silico studies.}, journal = {IBRO neuroscience reports}, volume = {19}, number = {}, pages = {400-408}, pmid = {40842924}, issn = {2667-2421}, abstract = {BACKGROUND: Treatment for complex multifactorial neurological disorders may benefit more from multifunctional chemicals. Dysregulation of monoaminergic pathways and neuroinflammation are typical confluence points in a range of neuropsychiatric and neurodegenerative illnesses. Polypharmacological medications that affect neuroinflammatory and monoaminergic pathways were investigated as potential targets for these diseases. The aim of this study was to investigate the in vitro and in silico multi-target neuroprotective activity of Khaya grandifololia. METHODS: Decoction and hydro-ethanolic extracts were prepared and screened for their ability to inhibit enzymes related to inflammation (15-lipoxygenase, LOX), neurodegeneration (monoamine oxidase, MAO), and protein glycation and fibrillation using enzymological fluorimetric assays and docking simulations. RESULTS: All extracts were able to strongly inhibit the activity of MAO as well as the glycation and fibrillation activities. Also, these extracts moderately inhibited 15-LOX activity. CONCLUSION: These results extend the knowledge on the potential use of Khaya grandifololia to combat multifactorial disorders, giving new approaches into therapeutic avenues for neurodegenerative disease such as Alzheimer's disease.}, } @article {pmid40842786, year = {2025}, author = {Jaramillo Ramos, JJ and Galindo Pupo, NM and Mena, D and Solis, RP and Bedoya Jaramillo, JE and Vega Solano, M}, title = {Cognitive Decline in Chronic Inflammatory Conditions: Exploring Links Between Systemic Inflammation and Neurodegeneration.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e88397}, pmid = {40842786}, issn = {2168-8184}, abstract = {Chronic inflammatory diseases (CIDs), such as rheumatoid arthritis (RA), obesity, type 2 diabetes mellitus (T2DM), systemic lupus erythematosus (SLE), fibromyalgia (FM), and chronic infection, are risk factors for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This review synthesizes evidence from longitudinal cohort studies and clinical trials, highlighting the contrasting evidence to explain the complex association between systemic inflammation and neurodegeneration. These important mechanisms are disruption of the blood-brain barrier, microglial activation, cytokine-related neurotoxicity (e.g., IL-6, TNF-alpha), lysosomal maladaptation, and metabolic imbalance (e.g., insulin resistance, hyperglycemia). Disease-specific correlations present study outcomes that are paradoxical, including that RA has genetic protection against PD but an increased risk of AD, whereas obesity and T2D associations are the same across studies, persistent associations of these terms with worsened cognitive decline. The risk of dementia is worsened by autoimmune diseases, such as SLE and FM, involving neuroinflammation caused by autoantibodies and central sensitization in the latter, respectively. The new markers, such as glial fibrillary acidic protein (GFAP) (neuroinflammation) and neurofilament light (NfL) (axonal injury), have prospects in early detection, but there is a need for validation in future studies. Therapeutic approaches emphasize the need for immunomodulation (e.g., disease-modifying antirheumatic drugs {DMARDs} in RA), glycemic control in T2DM, and lifestyle interventions, with a lack of targeting the non-amyloid pathways. New studies should emphasize longitudinal studies, multiome-based methods, and clinical trials in an attempt to create precision treatment. Considering the inflammatory risk stratification in the prevention of neurodegeneration, this review sheds light on the possibility of early preventative action that may offset the progressive cognitive decline in especially vulnerable groups.}, } @article {pmid40842769, year = {2025}, author = {Faikoglu, G and Saygisever-Faikoglu, K and Ozbasak, H and Ugur, SA and Uskur, T and Akkan, AG and Kelicen-Ugur, P and Ozyazgan, S}, title = {Neuroprotective Effects of Phosphodiesterase Inhibitors on Sestrin-2 (SESN2) Expression and Autophagy in Alzheimer's Disease Model.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e88449}, pmid = {40842769}, issn = {2168-8184}, abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and the accumulation of amyloid-beta (Aβ) peptides. The neuroprotective protein sestrin-2 (SESN2) has been implicated in the cellular response to oxidative stress and autophagy, processes that are disrupted in AD. This study explores the effects of phosphodiesterase inhibitors (PDEIs) roflumilast (RF), rolipram (ROL), and tadalafil (TAD) on SESN2 expression and autophagy in Aβ25-35-treated hippocampal neuron (HT-22) cell cultures. METHODS: The HT-22 cells were exposed to 5 μM Aβ25-35 for 32 hours to induce AD-like pathology. Concurrently, cells were treated with PDEIs (ROL: 10 μM, TAD: 1.53 nM, RF: 5 μM). The SESN2, autophagy-related proteins (ATG5, beclin-1 (BECN1), LC3II), adenosine monophosphate-activated protein kinase (AMPK), and mTOR expression levels were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot techniques. RESULTS: The Aβ25-35 exposure significantly increased SESN2 expression and altered the levels of autophagy-related proteins, resulting in decreased active AMPK (phosphorylated (p)-AMPK) and increased active mTOR (phosphorylated (p)-mTOR). Treatment with PDEIs reduced the elevated SESN2 expression and modulated autophagy-related protein levels, enhancing ATG5, BECN1, and LC3II expression. The PDEIs also restored p-AMPK levels and reduced p-mTOR expression in Aβ25-35-treated cells. CONCLUSION: The PDEIs exhibit neuroprotective effects in an in vitro AD model by reducing SESN2 overexpression and modulating autophagy through the AMPK/mTOR pathway. These findings suggest that PDEIs could be potential therapeutic agents for AD, targeting SESN2 and autophagy pathways to mitigate neurodegenerative damage.}, } @article {pmid40842658, year = {2025}, author = {Mekulu, K and Aqlan, F and Yang, H}, title = {The mild cognitive impairment window for optimal Alzheimer's disease intervention.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251370768}, pmid = {40842658}, issn = {2542-4823}, abstract = {The FDA approval of disease-modifying Alzheimer's disease therapies marks a major shift in treatment but exposes a critical challenge: identifying patients during the mild cognitive impairment (MCI) stage when intervention is most effective. Despite early biological changes, most diagnoses occur after significant decline. Drawing from over 180 stakeholder interviews conducted through the NSF I-Corps program reveal major detection gaps across primary care, specialty access, and available tools. This commentary highlights the consequences of delayed diagnosis and proposes translational strategies to align early detection with therapeutic opportunity, positioning MCI as the critical window for Alzheimer's disease intervention.}, } @article {pmid40842657, year = {2025}, author = {Chen, S and Sun, Y and Yao, L and Peng, Q}, title = {Probable lecanemab-associated pontine hemorrhage following cardiovascular intervention: Clinical implications for lecanemab use.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251366998}, pmid = {40842657}, issn = {2542-4823}, abstract = {We report a 76-year-old patient with mild cognitive impairment and APOE ε3/ε3 genotype who developed a rare pontine hemorrhage following treatment with lecanemab, an anti-amyloid-β monoclonal antibody for Alzheimer's disease. She was initially on clopidogrel and rivaroxaban; rivaroxaban was discontinued prior to lecanemab initiation. After two infusions, lecanemab was paused due to angina. She then underwent coronary stenting and was placed on dual antiplatelet therapy (aspirin and clopidogrel). Pontine hemorrhage occurred after twenty days. This case highlights heightened bleeding risk when lecanemab is combined with intensified antithrombotic therapy, even without APOE ε4 or significant cerebral small vessel disease load.}, } @article {pmid40842647, year = {2025}, author = {Choi, BK and Jin, Y and Lee, H and Kim, SW and Park, S and Hong, I and Baek, MS}, title = {Effect of aspirin use on conversion risk from mild cognitive impairment to Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1603892}, pmid = {40842647}, issn = {1663-4365}, abstract = {BACKGROUND: The potential effect of the antiplatelet and anti-inflammatory properties of aspirin on Alzheimer's disease development, especially its role in the progression from mild cognitive impairment to Alzheimer's disease dementia, remains controversial. To evaluate the association between aspirin, use and the risk of conversion to Alzheimer's disease dementia among individuals diagnosed with mild cognitive impairment. METHODS: In this retrospective population-based cohort study, we used the Korean National Health Insurance Service database to collect data on patients with mild cognitive impairment enrolled between 2013 and 2016 and followed up until 2021. In total, 508,107 patients initially diagnosed with mild cognitive impairment (192,538 with aspirin prescriptions and 315,569 without aspirin prescriptions) were enrolled. Aspirin use was assessed by extracting information from the Korean National Health Insurance Service database using aspirin prescription codes. The primary outcome was newly diagnosed Alzheimer's disease dementia. Hazard ratios and 95% confidence intervals for Alzheimer's disease were analyzed according to aspirin use using Cox proportional hazards regression analysis. Secondary outcomes included ischemic and hemorrhagic stroke risk associated with aspirin use. RESULTS: The data of 508,107 individuals were analyzed (mean [standard deviation] age, 67.6 [10.7] years; 66.8% women and 33.2% men), and 39,318 developed Alzheimer's disease (22,572 controls and 16,746 using aspirin). The rate of conversion to Alzheimer's disease was lower in the aspirin user group, and the time to Alzheimer's disease dementia occurrence was longer than in the nonuser group. A decreased Alzheimer's disease dementia risk was found in patients using aspirin in Model 2 (adjusted hazard ratio, 0.939; 95% confidence interval, 0.920-0.959), with more pronounced effects in individuals aged ≥65 years (Model 2 adjusted hazard ratio, 0.934; 95% confidence interval, 0.914-0.955). For hemorrhagic stroke, the risk increased with aspirin use across all age groups, with the highest risk observed in younger patients (Model 2 adjusted hazard ratio, 5.082; 95% confidence interval, 4.838-5.338). CONCLUSION: Aspirin use was associated with reduced Alzheimer's disease risk in older patients with mild cognitive impairment. Notably, the bleeding risk associated with aspirin use should be considered, and personalized treatment should be provided.}, } @article {pmid40842491, year = {2025}, author = {Bonet Olivares, C and David, MCB and Estrada Obeso, M and Del Giovane, M and Reeves, S and Malhotra, PA}, title = {Cognitive effects of dopaminergic treatment in Alzheimer's disease: Systematic review and meta-analysis.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70142}, pmid = {40842491}, issn = {2352-8737}, abstract = {INTRODUCTION: Despite advances in disease-modifying drugs, better treatments for symptomatic Alzheimer's disease (AD) are needed, with dopaminergic neurotransmission representing a potential target. The objective of this systematic review and meta-analysis was to evaluate the efficacy of drugs with predominantly dopaminergic action in improving cognitive symptoms in AD. METHODS: The MEDLINE, Embase, and ClinicalTrials.gov databases were searched from 1980 to January 2023. We used random effect models to generate pooled effect estimates. RESULTS: We included 19 prospective randomized controlled AD trials (1408 total participants), of which 7 were of "good" quality, 8 "fair," and 4 "poor." All were included in the analysis. The overall pooled effect was small but showed a significant positive effect of dopaminergic drugs compared to placebo (standardized mean difference [SMD]: 0.33, 95% confidence interval [CI]: 0.08 to 0.59, P = 0.01; I [2] = 79%). Significance remained after removing outliers to account for heterogeneity. When exploring subgroups (divided by mechanism of action), 5 trials of dopamine reuptake inhibitors did not show a significant effect on cognition, whereas 12 monoamine oxidase B (MAO-B) inhibitor trials showed a moderately significant positive effect (SMD: 0.52, 95% CI: 0.13 to 0.90, P = 0.01; I [2] = 84%). DISCUSSION: We show evidence of the benefit of dopaminergic medications, specifically MAO-B inhibitors, on cognitive symptoms in AD. Several studies included here also used drugs with both noradrenergic and dopaminergic action, highlighting a potential dual stimulation that could lead to better clinical efficacy. Trials targeting well-defined patient populations, ideally supported by biomarker evidence of dopaminergic dysfunction, are needed to compare noradrenergic and dopaminergic agents-both separately and in combination-on cognitive function to maximize treatment effects. Particularly, further research should explore the impact of MAO-B drugs on specific aspects of cognitive function to better understand their mechanism given the upregulation of MAO-B expression in AD. HIGHLIGHTS: We conducted a meta-analysis investigating the efficacy of dopaminergic drugs in improving cognitive symptoms in Alzheimer's disease (AD).Our findings highlight the potential cognitive benefits of dopaminergic medications, particularly monoamine oxidase B inhibitors, in AD.Future trials are warranted and could focus on biomarker-defined patient groups to enhance effectiveness.}, } @article {pmid40842389, year = {2025}, author = {da Silva, AMP and Falcão, L and Virgilio Ribeiro, F and Ogasawara Donato, K and Machado Magalhães, PL and Nascimento, MDVS and Leite, M and Lee Han, M and Quiroga, DG and de Souza Franco, E and de Sousa Maia, MB}, title = {Efficacy and Safety of Escitalopram and Citalopram for Agitation in Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {8919887251369893}, doi = {10.1177/08919887251369893}, pmid = {40842389}, issn = {1552-5708}, abstract = {BackgroundAgitation is a frequent and distressing neuropsychiatric symptom in patients with Alzheimer's disease (AD), often leading to increased caregiver burden, institutionalization, and healthcare costs. While antipsychotics are commonly prescribed, their use is limited by safety concerns. Selective serotonin reuptake inhibitors (SSRIs), such as citalopram and escitalopram, have emerged as alternative treatments with a more favorable safety profile. This study aimed to evaluate the efficacy and safety of these agents in the management of agitation in AD.MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing citalopram or escitalopram with placebo or other pharmacological treatments in older adults with AD and clinically defined agitation. Primary outcomes included changes in agitation severity, assessed by the Neuropsychiatric Inventory-Clinician Rating (NPI-C) and the Neurobehavioral Rating Scale (NBRS). Secondary outcomes included cognitive function (MMSE), anxiety symptoms, and adverse events. Standardized mean difference (SMD) and risk ratio (RR) were pooled using a random-effects model.ResultsFour RCTs comprising 502 patients were included. Pooled analysis showed no significant improvement in agitation severity (SMD -0.67; 95% CI -2.58, 1.25; I[2] = 98.3%) or cognitive outcomes (SMD 2.43; 95% CI -2.55, 7.41). Rates of serious adverse events (RR 0.85; 95% CI 0.50, 1.45) and treatment discontinuation (RR 1.05; 95% CI 0.80, 1.37) were similar between groups. However, SSRI use was associated with an increased risk of falls (RR 1.78; 95% CI 1.15, 2.75; I[2] = 0%).ConclusionEscitalopram and citalopram do not significantly reduce agitation in AD but are generally well tolerated. Increased fall risk warrants cautious clinical use.Registration PROSPERO protocol numberCRD420251055237.}, } @article {pmid40842219, year = {2025}, author = {Triplett, O and Varda, N and Decourt, B and Sabbagh, MN}, title = {Nonamyloid-beta active immunization for the treatment of Alzheimer's disease.}, journal = {Expert opinion on investigational drugs}, volume = {34}, number = {9}, pages = {685-693}, doi = {10.1080/13543784.2025.2551352}, pmid = {40842219}, issn = {1744-7658}, mesh = {*Alzheimer Disease/therapy/immunology/physiopathology ; Humans ; Animals ; tau Proteins/immunology/metabolism ; Amyloid beta-Peptides/immunology/metabolism ; Cognitive Dysfunction/therapy/immunology ; *Immunotherapy, Active/methods ; Immunity, Innate/immunology ; *Alzheimer Vaccines/administration & dosage/immunology ; Immunization/methods ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by the formation of senile plaques composed of amyloid-beta (Aβ) peptides and the intraneuronal accumulation of neurofibrillary tangles composed of abnormal, hyperphosphorylated tau proteins. These act in concert to drive cognitive decline, but it is widely held that tau spread correlates better with cognitive decline than does amyloid burden. Control of AD neuropathologies with active immunizations is studied as a potential therapeutic avenue because it could build innate immunity. Although most active immunization studies have focused on Aβ targets, tau and other targets continue to be explored. AREAS COVERED: This study aimed to identify and describe non-Aβ active immunization trials for AD treatment. A narrative review was conducted to analyze the current status of non-Aβ active immunization for AD using PubMed as the research database. EXPERT OPINION: The potential of active immunization beyond Aβ was explored as a therapeutic strategy for AD with a focus that targets tau and provides insights into its effectiveness, associated challenges, and limitations. Results from preclinical and clinical studies were examined, highlighting the progress and the hurdles that exist. Active immunization against non-Aβ targets, such as tau, for the treatment of AD remains a promising and expanding field.}, } @article {pmid40842206, year = {2025}, author = {Chen, PH and Bloom, S}, title = {Divergent Synthesis of ΔAA-Peptides Using a Bioorthogonal pro-Amino Acid and Aqueous Flavin Photocatalyst: Green Light Enhances Catalyst Performance and Product Selectivity.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {64}, number = {39}, pages = {e202511832}, doi = {10.1002/anie.202511832}, pmid = {40842206}, issn = {1521-3773}, support = {/GM/NIGMS NIH HHS/United States ; R35GM147169/NH/NIH HHS/United States ; /GM/NIGMS NIH HHS/United States ; R35GM147169/NH/NIH HHS/United States ; }, mesh = {Catalysis ; *Amino Acids/chemistry ; *Light ; *Flavins/chemistry ; *Peptides/chemical synthesis/chemistry ; Photochemical Processes ; Water/chemistry ; Molecular Structure ; Green Light ; }, abstract = {Dehydroamino acids (ΔAAs) are vital building blocks in the design and optimization of peptide drugs. The exact olefin geometry, side chain chemotype, and ancillary β-carbon substituents play a significant role. Unfortunately, general approaches to install these motifs into peptides are lacking, complicated by the instability of unsaturated residues during traditional amide-bond coupling and failure of divergent protocols, such as oxidative Heck and Horner-Wadsworth-Emmons, to accommodate a complete range of substrate classes. Herein, we conceive and interrogate an original bioorthogonal reagent, β-sulfonyldehydroamino acid (ΔSulf), that can be site-specifically encoded into standard peptides through solid- or liquid-phase synthesis. When combined with an aqueous flavin photocatalyst, myriad boronic acids and 525 nm light-a more biologically benign portion of the flavin visible absorption spectra that has not previously been exploited for flavin photoredox catalysis,-this latent residue becomes one of several (Z)-ΔAA variants (aromatic, heteroaromatic, aliphatic) via stereoretentive radical conjugate addition and β-scission. The importance of green light is established through mechanistic studies showing that it tempers radical formation and discourages flavin-catalyzed isomerization, controlling product selectivity. We apply our original reagent and catalytic platform in a brief medicinal chemistry campaign to discover tetrapeptides that modulate Aβ42 aggregation for the treatment of Alzheimer's disease.}, } @article {pmid40841960, year = {2025}, author = {Wu, Q and Yan, J and Zhang, Y and Ming, X and Chen, S and Zou, Z and Feng, N and Xiao, J}, title = {Modulation of Aging Diseases via RAGE Targets: A Dietary Intervention Review.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {38}, pages = {e10242}, pmid = {40841960}, issn = {2198-3844}, support = {32472341//National Natural Science Foundation of China/ ; JCZRJQ202500133//Natural Science Foundation for Youth (Category A) of Hubei Province/ ; 2024AFD281//Natural Science Foundation of Hubei Province/ ; F2023006//Science and Technology Research Project of the Education Department of Hubei Province/ ; }, mesh = {Humans ; *Receptor for Advanced Glycation End Products/metabolism ; *Aging/metabolism ; Glycation End Products, Advanced/metabolism ; Signal Transduction ; Animals ; }, abstract = {With the acceleration of global population aging, effective strategies for the prevention and management of aging-related diseases have become increasingly urgent. The receptor for advanced glycation end products (RAGE), a pattern recognition receptor of the immunoglobulin superfamily, plays a central regulatory role in the pathogenesis of chronic conditions such as diabetes and Alzheimer's disease. By binding to a wide range of ligands (e.g., advanced glycation end products, amyloid beta), RAGE activates key inflammatory and stress-related signaling pathways, including NF-κB and MAPK, positioning it as a critical therapeutic target. This review systematically examines RAGE-ligand interactions and their downstream signaling cascades, and proposes targeted intervention strategies. Special emphasis is placed on the regulatory potential of dietary bioactive compounds, such as polyphenols, polysaccharides, and terpenoids, highlighting the distinct advantages of functional foods in anti-aging applications. In line with the World Health Organization's concept of "preventive aging," dietary-based approaches offer a long-term, safe, and integrative means of providing both nutritional support and disease prevention. This review provides a theoretical foundation for the development of RAGE-targeted dietary interventions and supports a paradigm shift from medical treatment to nutritional prevention in anti-aging strategies.}, } @article {pmid40838403, year = {2025}, author = {Rodríguez Sarmiento, RM}, title = {A Career Long Effort to Discover a Drug to Treat Neurodegenerative Diseases. My Adventures with γ-Secretase for the Treatment of Alzheimer's.}, journal = {Chimia}, volume = {79}, number = {7-8}, pages = {509-515}, doi = {10.2533/chimia.2025.509}, pmid = {40838403}, issn = {0009-4293}, mesh = {*Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy ; Humans ; *Drug Discovery ; *Neurodegenerative Diseases/drug therapy ; Amyloid beta-Peptides/metabolism ; }, abstract = {Neurodegenerative diseases encompass a range of chronic diseases marked by the progressive loss of structure or function of the nervous system, particularly within areas of the brain such as the neurons (or nerve cells). This degeneration leads to a decline in cognitive abilities, motor skills, and other neurological functions. The progression can be gradual, occurring over years or even decades, and often leads to significant disability and, ultimately, death. Alzheimer's disease (AD) is the most prevalent degenerative disease that affects cognition and that rises dramatically with age. It is a progressive, chronic disease that occurs when nerve cells in the brain die. Current treatments largely address symptoms without altering or reversing disease progression. However, recent advancements with amyloid-β (Aβ) antibodies validate Aβ as a therapeutic target for AD. This article details my long-term experience as a medicinal chemist and project leader working on γ-secretase, a key target in AD drug discovery. I will share initial insights from a multi-disciplinary effort to discover a disease modifying treatment for Alzheimer's disease.}, } @article {pmid40836982, year = {2024}, author = {Grados, M and Salehi, M and Lotfi, A and Dua, S and Xie, I}, title = {A selective review of inhibitors of protein kinase C gamma: a neuroplasticity-related common pathway for psychiatric illness.}, journal = {Frontiers in drug delivery}, volume = {4}, number = {}, pages = {1364037}, pmid = {40836982}, issn = {2674-0850}, abstract = {Psychotropics are currently developed and marketed with a limited understanding of their mechanism of action. The notion that protein kinase C (PKC) activity is highly relevant to learning and memory function stems from experiments in the 1980s, which associated protein kinase alpha (pka) and pkc to animal models of associative learning, opening an area of exploration for psychotropic development. The PKC family consists of several isoforms, including PKC alpha, beta1, beta1, gamma, delta and epsilon among others. In particular, PKC gamma (PRKCG) is highly brain-expressed and is singled out as a candidate for modulation in psychiatric illness. With hundreds of identified substrates, PRKCG affects multiple pathways relevant for regulation of neuronal health. In this review, converging lines of evidence are presented in the context of psychotropic drug action, which point to downregulation of PKC activity as a potential common mechanism across several psychiatric disorders. Using this mechanism through more targeted psychotropic action may then be used to develop agents that further ameliorate psychiatric symptom expression. Psychotropics including fluoxetine, tricyclics, lithium, valproate, ketamine and others are explored in relation to their effect of PKC, finding that across all drugs examined, a downregulation with chronic-but not acute-use constitutes their putative effect in ameliorating symptoms. This effect is compounded by findings that suggest that PKCs, and PRKCG in particular, promote neuroplastic effects by their downregulation. This effect is in contrast to PKC activators, which have been used in neurodegenerative disorders such as Alzheimer's disease. Cross-disorder mechanisms need to continue to be explored in neuropsychiatric illness and targeted treatments developed in turn to address treatment-resistant conditions.}, } @article {pmid40836645, year = {2025}, author = {Liu, T and Li, X}, title = {The Crosstalk Between Protective and Detrimental Interleukin (IL)-1 Family of Cytokines in Alzheimer's Disease.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {9}, pages = {e70460}, doi = {10.1002/jbt.70460}, pmid = {40836645}, issn = {1099-0461}, support = {//Project no. (2024 Foshan self-funded science and technology innovation project (2420001004404), Education and Department of Guangdong Province (2024GCZX011))./ ; }, mesh = {*Alzheimer Disease/metabolism/pathology/immunology ; Humans ; *Interleukin-1/metabolism/immunology ; Animals ; }, abstract = {Alzheimer's disease (AD) is a long-term, progressive, degenerative disorder. One of the most important pathological characteristics of AD is the deposition of β-amyliod (Aβ) peptide, which initiates a spectrum of cerebral neuroinflammation. Vascular changes also play an important role in the pathophysiology of the disease. Cytokines, secreted by immune cells, can facilitate cell-to-cell signaling and influence the functions of the central nervous system (CNS). These important mediators of the immune system, which are known to orchestrate various molecular and cellular mechanisms in both physiological and pathological situations, can be upregulated or downregulated, leading to a complex crosstalk with numerous receptors mediating pro-inflammatory and/or anti-inflammatory actions. In particular, the interleukin (IL)-1 family of cytokines has been implicated to significantly correlate with AD pathogenesis among other cytokines in the CNS. The IL-1 family of cytokines is essential in both the innate and adaptive immune responses. This pleiotropic family of cytokines includes IL-1α, IL-1β, IL-1 receptor antagonist (RA), IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36RA, IL-37, and IL-38. Recent studies have demonstrated that the upregulation of pro-inflammatory cytokines, such as IL-1α and IL-1β, or the downregulation of anti-inflammatory mediators, exerts multifaceted influences on both neurodegeneration and neuroprotection. The lack of effective treatment for AD necessitates the search for new drugs that target several processes in the disease's pathology. This review aims to give a comprehensive overview of the emerging roles of the IL-1 family of cytokines in AD pathology and to explain their perspectives on introducing novel strategies for effective therapeutic/neuropsychiatric management of AD in clinical settings by discussing both the pathogenic and protective roles of these cytokines.}, } @article {pmid40836165, year = {2026}, author = {Bayat, A and Mirmomeni, G and Aiken, S and Jafari, Z}, title = {Meta-Analyses of Auditory Evoked Potentials as Alzheimer Biomarkers.}, journal = {Ear and hearing}, volume = {47}, number = {1}, pages = {95-106}, doi = {10.1097/AUD.0000000000001718}, pmid = {40836165}, issn = {1538-4667}, mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology ; *Evoked Potentials, Auditory/physiology ; Biomarkers ; Early Diagnosis ; Electroencephalography ; }, abstract = {OBJECTIVES: Alterations in auditory evoked potential (AEP) parameters have been associated with sensory memory deficits and may serve as biomarkers for cognitive decline. This systematic review and meta-analysis aimed to evaluate the effectiveness of AEPs in the early detection of Alzheimer disease (AD). DESIGN: The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. A comprehensive search was performed across five electronic databases (EMBASE, Scopus, Cochrane Library, Web of Science, PubMed, and CINAHL) from their inception until August 2024, without restrictions on date or language. The methodological quality of evidence was assessed using the Crew Critical Appraisal Tool. Data were extracted on the latency and amplitude of five AEP components, including auditory P50 gating, mismatch negativity, and late-latency responses (N100, N200, P300), comparing patients with AD to age-matched control peers. RESULTS: Out of 437 publications, 54 articles were selected for review, with most rated as having high methodological quality. The analysis revealed a significantly larger P50 gating amplitude (p < 0.001) in patients with AD. Furthermore, patients with AD demonstrated significantly prolonged latencies and reduced amplitudes for N100, N200, and P300 components (p ≤ 0.001) compared with controls. Among all AEPs, P300 latency exhibited the largest effect size. Funnel plot analysis and Egger's regression test showed no evidence of publication bias. CONCLUSIONS: Our findings support the clinical utility of AEPs in early AD detection, with the P300 response identified as the most accurate electrophysiological measure for distinguishing patients with AD from the control group. These results highlight the value of incorporating AEPs into clinical assessment protocols to enhance early-stage AD diagnosis and monitoring, thereby facilitating timely interventions and the development of personalized treatment strategies.}, } @article {pmid40835596, year = {2025}, author = {Molokanova, E and Zhou, T and Vasupal, P and Cherkas, VP and Narute, P and Ferraz, MSA and Reiss, M and Almenar-Queralt, A and Chaldaiopoulou, G and de Souza, JS and Hemati, H and Downey, F and Olajide, OO and Thörn Perez, C and Puppo, F and Mesci, P and Pfaff, SL and Kireev, D and Muotri, AR and Savchenko, A}, title = {Non-genetic neuromodulation with graphene optoelectronic actuators for disease models, stem cell maturation, and biohybrid robotics.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7499}, pmid = {40835596}, issn = {2041-1723}, support = {R01 MH127077/MH/NIMH NIH HHS/United States ; R43 MH124563/MH/NIMH NIH HHS/United States ; R01 MH123828/MH/NIMH NIH HHS/United States ; 1R01ES033636//U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)/ ; 1R43AG076088//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 1R01MH128365//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; 1R43NS122666//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; MH123828//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01 NS123642/NS/NINDS NIH HHS/United States ; S10 OD026929/OD/NIH HHS/United States ; R01 ES033636/ES/NIEHS NIH HHS/United States ; R56 MH128365/MH/NIMH NIH HHS/United States ; R01NS123642//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R43 AG076088/AG/NIA NIH HHS/United States ; R43 NS122666/NS/NINDS NIH HHS/United States ; R01 NS105969/NS/NINDS NIH HHS/United States ; DISC2-13866//California Institute for Regenerative Medicine (CIRM)/ ; R44 DA050393/DA/NIDA NIH HHS/United States ; 5R44DA050393//U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/ ; 1R43MH124563//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; }, mesh = {*Graphite/chemistry ; *Robotics/methods/instrumentation ; Induced Pluripotent Stem Cells/cytology ; Humans ; Organoids/cytology ; Neurons/cytology ; Brain/cytology ; Alzheimer Disease/pathology/therapy ; Optogenetics/methods ; Cell Differentiation ; Animals ; }, abstract = {Light can serve as a tunable trigger for neurobioengineering technologies, enabling probing, control, and enhancement of brain function with unmatched spatiotemporal precision. Yet, these technologies often require genetic or structural alterations of neurons, disrupting their natural activity. Here, we introduce the Graphene-Mediated Optical Stimulation (GraMOS) platform, which leverages graphene's optoelectronic properties and its ability to efficiently convert light into electricity. Using GraMOS in longitudinal studies, we found that repeated optical stimulation enhances the maturation of hiPSC-derived neurons and brain organoids, underscoring GraMOS's potential for regenerative medicine and neurodevelopmental studies. To explore its potential for disease modeling, we applied short-term GraMOS to Alzheimer's stem cell models, uncovering disease-associated alterations in neuronal activity. Finally, we demonstrated a proof-of-concept for neuroengineering applications by directing robotic movements with GraMOS-triggered signals from graphene-interfaced brain organoids. By enabling precise, non-invasive neural control across timescales from milliseconds to months, GraMOS opens new avenues in neurodevelopment, disease treatment, and robotics.}, } @article {pmid40835473, year = {2025}, author = {Naeshiro, Y and Kitani-Morii, F and Kasai, T and Tanaka, E and Kobayashi, F and Ohara, T}, title = {Amyloid Clearance and Transient CSF Aβ40 Reduction in a Case of ARIA-E/H Following Lecanemab Treatment.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {}, number = {}, pages = {}, doi = {10.2169/internalmedicine.6070-25}, pmid = {40835473}, issn = {1349-7235}, abstract = {We herein report a case of amyloid-related imaging abnormality (ARIA)-E/H following lecanemab treatment in a 70-year-old man with mild cognitive impairment due to Alzheimer's disease. Generalized seizures occurred after the third infusion and were accompanied by FLAIR hyperintensity, microbleeds, and a minor acute infarct. Amyloid PET revealed focal clearance of amyloid plaques in the ARIA-affected regions. CSF Aβ40 levels transiently decreased by ~30% during the ARIA episode, whereas Aβ42 remained stable, thereby increasing the Aβ42/40 ratio. These findings suggest that ARIA may facilitate focal amyloid clearance and that CSF Aβ40 reduction may serve as a potential biomarker for ARIA onset and resolution.}, } @article {pmid40833911, year = {2025}, author = {Wei, Y and Abrol, A and Lah, J and Levey, AI and Calhoun, VD}, title = {From Symptomatic to Pre-symptomatic: Adaptive Knowledge Distillation for Early Alzheimer's Detection Using Functional MRI.}, journal = {IEEE transactions on bio-medical engineering}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TBME.2025.3597261}, pmid = {40833911}, issn = {1558-2531}, abstract = {Alzheimer's disease (AD) progresses from asymptomatic changes to clinical symptoms, underscoring the critical need for early detection to facilitate timely treatment. Functional magnetic resonance imaging (fMRI) offers non-invasive biomarkers for detection, but current methods fail to reliably identify pre-symptomatic individuals due to two key challenges: (1) Subtle, anatomically distinct fMRI patterns in pre-symptomatic cases that resemble healthy controls more than symptomatic patients, and (2) Severe class imbalance in real-world data, where healthy controls vastly outnumber pre-symptomatic subjects. To address this, we reconceptualize AD diagnosis as a multi-stage distillation task, where insights from easier-to-detect symptomatic cases guide pre-symptomatic detection. We propose a novel margin-aware knowledge distillation (KD) framework with two innovations: (1) We leverage Unbalanced Optimal Transport (UOT) for Feature Distillation to flexibly adapt to anatomical differences in brain patterns caused by neurodegeneration and ensure effective distillation from later to earlier disease stages. (2) We propose Self-Distillation with Dynamic Margins to combat class imbalance by adaptively refining the classification boundary. We evaluate our proposed framework across four distinct base models and demonstrate its superiority over state-of-the-art KD methods. Additionally, we show the significance of various brain regions in identifying pre-symptomatic subjects, as well as how features are transferred during distillation. These contributions advance the development of more precise diagnostic tools and foster a deeper understanding of early disease manifestations, marking a significant stride towards more reliable and earlier AD diagnosis.}, } @article {pmid40833319, year = {2025}, author = {Agarwal, U and Verma, S and Gandhi, V and Patil, VM and Tonk, RK}, title = {Multitarget 8-methoxypsoralens against Alzheimer's disease: extraction, synthesis, in vitro and in silico studies.}, journal = {Future medicinal chemistry}, volume = {17}, number = {16}, pages = {1945-1957}, pmid = {40833319}, issn = {1756-8927}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism/chemistry ; Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; Butyrylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification/chemical synthesis ; *Methoxsalen/chemistry/pharmacology/isolation & purification/chemical synthesis ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; }, abstract = {AIM: Alzheimer's disease poses a serious global health challenge, and there is an urgent need for novel therapeutic agents, as existing drugs have limited efficacy and notable adverse effects. Chromenones, known for their diverse biological activities, have emerged as promising drug candidates for AD treatment due to their capacity to target multiple enzymes. In this study, investigated the chromenone derivative 8-methoxypsoralen (8-MOP) as a potential multi-target inhibitor of key AD targets, highlighting the importance of the scaffold in target-based drug design. MATERIAL AND METHODS: 8-MOP, a phytochemical extracted and isolated from parsley leaves, was utilized to synthesize new derivatives, which were then screened against enzymes involved in AD progression (BACE1, AChE, BuChE) and targets involved in oxidative pathways (DPPH, NO). In support of the in vitro activity, in silico ADMET predictions and docking experiments were performed. RESULTS AND CONCLUSIONS: Among the synthesized compounds, 3d and 3e demonstrated significant inhibitory effects against the chosen targets, exhibiting IC50 values between 5.8 ± 0.13 μM and 13 ± 0.12 μM. Furthermore, the docking experiments showed important binding interactions of these compounds with BACE1, AChE, and BuChE. The study demonstrates the potential of 8-MOP derivatives for targeting AD drug targets.}, } @article {pmid40832968, year = {2025}, author = {Zhang, X and Chu, S and Huang, Y and Li, Z and Song, J and Wang, P and Su, Y and Zhang, Z and Xie, Z}, title = {Atractylenolide III Mitigates Alzheimer's Disease by Enhancing Autophagy via the YY1-TFEB Pathway.}, journal = {Phytotherapy research : PTR}, volume = {39}, number = {10}, pages = {4474-4490}, doi = {10.1002/ptr.70069}, pmid = {40832968}, issn = {1099-1573}, support = {2024ZY1027//Special Research Project of Henan Province on Traditional Chinese Medicine/ ; 82274612//National Natural Science Foundation of China/ ; 23HASTIT044//Program for Science & Technology Innovation Talents in Universities of Henan Province/ ; 231111312900//Key Research and Development Program of Henan Province/ ; 232301420085//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; 232301420093//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; 242301420019//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Autophagy/drug effects ; Humans ; Mice ; *Sesquiterpenes/pharmacology ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; *YY1 Transcription Factor/metabolism ; *Lactones/pharmacology ; Caenorhabditis elegans/drug effects ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects ; Cell Line, Tumor ; Mice, Transgenic ; Atractylodes/chemistry ; Disease Models, Animal ; Male ; }, abstract = {Autophagy dysregulation serves as a significant pathogenic factor in Alzheimer's disease (AD), with transcription factor EB (TFEB) acting as a pivotal transcription factor that governs the process of autophagy. Atractylenolide III (AT-III), a terpenoid compound found in medicinal Atractylodes macrocephala Koidz, is well-known for its role in antioxidant and anti-inflammatory activities. The purpose of this study is to explore the beneficial impact of AT-III on AD pathology and identify the mechanisms involved. C. elegans CL4176, SH-SY5Y APPSWE, and APP/PS1 mice were used to investigate the efficacy and possible mechanism of AT-III on the treatment of AD. AT-III reduced amyloid protein (Aβ) deposition in C. elegans CL4176 heads, prolonged the paralysis time, and reduced Aβ levels in SH-SY5Y APPSWE cells. AT-III improved the learning and memory ability of APP/PS1 mice and decreased the deposition of Aβ plaques. Transcriptomics and experimental validation showed that AT-III stimulated transcription and translation of autolysosome-associated genes. AT-III enhanced co-localization of LC3 and LAMP2 with Aβ in APP/PS1 mice. Meanwhile, AT-III increased TFEB transcriptional activity, mRNA, and protein levels in the nucleus. Furthermore, AT-III enhanced the expression of Yin Yang 1 (YY1) protein, an upstream regulator of TFEB, and led to the stimulation of autophagy and lysosome biogenesis both in vivo and in vitro. The observed effects were reversed upon silencing YY1. AT-III may regulate the YY1-TFEB pathway, thereby restoring autophagy flux disturbances and ameliorating AD-related pathological changes and cognitive decline. This study provides a promising lead compound for intervention in AD.}, } @article {pmid40832697, year = {2025}, author = {Kang, S and Kafetsouli, D and Ford, J and Wong, J and Bracoud, L and Suhy, J and Giannakopoulou, P and Udeh-Momoh, C and Russ, TC and Ritchie, C and Alexopoulou, Z and Salinas, C and Saad, ZS and Novak, G and Robinson, O and Middleton, LT}, title = {Prevalence and risk factors of cerebral microhemorrhages and superficial siderosis in cognitively unimpaired older adults: analysis from the CHARIOT-PRO SubStudy.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70594}, pmid = {40832697}, issn = {1552-5279}, support = {//Janssen Research & Development, LLC, a Johnson & Johnson company/ ; NIHR200180//NIHR ARC Dementia Fellowship/ ; MR/S03532X/1//UKRI Future Leaders Fellowship/ ; MR/Y02012X/1//UKRI Future Leaders Fellowship/ ; //Takeda/ ; //Merck/ ; //Gates Ventures/ ; }, mesh = {Humans ; Aged ; Female ; Male ; Risk Factors ; Cross-Sectional Studies ; Aged, 80 and over ; *Cerebral Hemorrhage/epidemiology/diagnostic imaging ; Prevalence ; Middle Aged ; Apolipoprotein E4/genetics ; *Siderosis/epidemiology ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/metabolism ; Prospective Studies ; }, abstract = {INTRODUCTION: Cerebral microhemorrhages (CMHs) and superficial siderosis (SS) are relatively common side effects of anti-amyloid immunotherapies, termed amyloid-related imaging abnormalities (ARIA-H). They are also observed in treatment-naïve older adults. This study explored relationships with modifiable and non-modifiable risk factors. METHODS: This cross-sectional study included 1414 cognitively unimpaired, treatment-naïve individuals aged 60 to 85 years from the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy. Relationships between CMHs/SS and cardiovascular risk factors, amyloid beta (Aβ) load, apolipoprotein E (APOE) ε4 status, educational attainment, and white matter hyperintensities were investigated using regression analyses and structural equation modeling. RESULTS: CMHs were observed in 8.3% of participants and SS in 1.3%. Significant risk factors for CMHs included age and hypertension. Higher education attainment appeared to have a protective effect. Elevated amyloid is a risk factor, particularly when adjusting for APOE ε4 status in individuals aged 70 or younger. DISCUSSION: Increasing age and hypertension are significant risk factors of CMHs. Higher educational attainment may offer a protective effect. HIGHLIGHTS: Of the 1414 participants from the CHARIOT-PRO SubStudy (CPSS), CMHs were present in 118 (8.3%), and SS was present in 18 (1.3%). Age and hypertension were identified as significant risk factors for CMHs, and the latter had a stronger association with the presence of CMHs among female participants. Having a bachelor's degree or higher was found to be protective. Elevated brain amyloid burden, particularly when adjusted for APOE ε4 carrier status, was identified as a risk factor in individuals aged 70 years and below.}, } @article {pmid40832432, year = {2025}, author = {, and Boquet-Pujadas, A and Anagnostakis, F and Yang, Z and Tian, YE and Duggan, MR and Erus, G and Srinivasan, D and Joynes, CM and Bai, W and Patel, PJ and Walker, KA and Zalesky, A and Davatzikos, C and Wen, J}, title = {Multi-organ AI Endophenotypes Chart the Heterogeneity of Pan-disease in the Brain, Eye, and Heart.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40832432}, support = {RF1 AG054409/AG/NIA NIH HHS/United States ; RF1 AG092412/AG/NIA NIH HHS/United States ; }, abstract = {Disease heterogeneity and commonality pose significant challenges to precision medicine, as traditional approaches frequently focus on single disease entities and overlook shared mechanisms across conditions[1]. Inspired by pan-cancer[2] and multi-organ research[3], we introduce the concept of "pan-disease" to investigate the heterogeneity and shared etiology in brain, eye, and heart diseases. Leveraging individual-level data from 129,340 participants, as well as summary-level data from the MULTI consortium, we applied a weakly-supervised deep learning model (Surreal-GAN[4,5]) to multi-organ imaging, genetic, proteomic, and RNA-seq data, identifying 11 AI-derived biomarkers - called Multi-organ AI Endophenotypes (MAEs) - for the brain (Brain 1-6), eye (Eye 1-3), and heart (Heart 1-2), respectively. We found Brain 3 to be a risk factor for Alzheimer's disease (AD) progression and mortality, whereas Brain 5 was protective against AD progression. Crucially, in data from an anti-amyloid AD drug (solanezumab[6]), heterogeneity in cognitive decline trajectories was observed across treatment groups. At week 240, patients with lower brain 1-3 expression had slower cognitive decline, whereas patients with higher expression had faster cognitive decline. A multi-layer causal pathway pinpointed Brain 1 as a mediational endophenotype[7] linking the FLRT2 protein to migraine, exemplifying novel therapeutic targets and pathways. Additionally, genes associated with Eye 1 and Eye 3 were enriched in cancer drug-related gene sets with causal links to specific cancer types and proteins. Finally, Heart 1 and Heart 2 had the highest mortality risk and unique medication history profiles, with Heart 1 showing favorable responses to antihypertensive medications and Heart 2 to digoxin treatment. The 11 MAEs provide novel AI dimensional representations for precision medicine and highlight the potential of AI-driven patient stratification for disease risk monitoring, clinical trials, and drug discovery.}, } @article {pmid40832393, year = {2025}, author = {Cohen, BM and Koh, E and Levental, KR and Levental, I and Sonntag, KC}, title = {Specific Lipid Abnormalities Are Inherently Associated with Late-Onset Alzheimer's Disease.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.08.08.25333304}, pmid = {40832393}, abstract = {INTRODUCTION: Lipid abnormalities have been observed in brain, CSF, and blood in association with late-onset Alzheimer's disease (LOAD). It is unknown which abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived neural lines. METHODS: iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Lipidomics analyses were performed on whole cell and mitochondrial extracts. RESULTS: Large reductions in cholesterol esters (CE) and imbalances in fatty acids (FA) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids. DISCUSSION: The findings identify abnormalities in CE and FA as likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD.}, } @article {pmid40832216, year = {2025}, author = {Bartlett, MJ and Erickson, RP and Frye, J and Doyle, KP and Pires, PW and Witte, MH}, title = {Manual lymph drainage massage of the head and neck improves cognition and reduces pathological biomarkers in the 5x-FAD mouse model of Alzheimers disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40832216}, issn = {2692-8205}, support = {R25 NS076437/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) affects 6.9 million people over the age of 65 in the US and is expected to double by 2060. While FDA approved immunotherapies slow cognitive decline in some individuals with AD, they do not improve cognition, are costly, and have significant side-effects. Therefore, new targets, approaches, and treatments for AD are a necessity. There are no FDA approved therapies for AD that target the brain's lymphatic system. It is well established that the toxic protein, amyloid-beta (Aβ), accumulates in the AD brain. Recent studies have shown that Aβ is cleared via interstitial fluid and cerebrospinal fluid through a pathway involving the glymphatic system-meningeal lymphatic vessels-leading to deep and superficial cervical lymphatic vessels and nodes. Therefore, any blockage along this route can cause inefficient drainage and result in pathological buildup of Aβ, which can lead to AD. Here, we propose a new approach to treating AD by manual lymph drainage (MLD), which is a light skin massage traditionally used to reduce fluid accumulation in lymphedema. This therapy has also been demonstrated to be safe in individuals with AD, but its effects on cognition and biomarkers of AD has never been investigated. In this study we demonstrate that repeated MLD of the head and neck, including the superficial cervical lymphatic vessels (scLVs), improves cognitive function in AD as measured in both the Y-maze and nest-building tests. We also show that this coincides with a reduction in plasma levels of neurofilament light chain (NfL), a non-specific biomarker for neuronal cell death and axonal damage. MLD was also shown to reduce Aβ in the hippocampus of these mice. Combined, this data provides compelling proof-of-principle evidence for the potential of MLD as a standalone or adjunct therapy in the treatment of AD.}, } @article {pmid40832110, year = {2025}, author = {Androni, X and Boyd, RJ and Rosenberg, PB and Mahairaki, V}, title = {Psychedelics meet human brain organoids: insights into proteomics and potential for Alzheimer's disease treatment.}, journal = {Frontiers in dementia}, volume = {4}, number = {}, pages = {1605051}, pmid = {40832110}, issn = {2813-3919}, abstract = {Alzheimer's disease (AD) is characterized by a long preclinical phase lasting more than a decade before the onset of its clinical phase of mild cognitive impairment (MCI) or dementia. Recent advances in psychedelic research underscore numerous neuroplastogenic and anti-inflammatory alterations induced by these compounds, making them promising therapeutic candidates for AD. In this mini review, we will briefly summarize the existing literature using human cerebral organoids to study the molecular and metabolic changes caused by various psychedelic compounds, focusing on their potential therapeutic applications for AD.}, } @article {pmid40831503, year = {2025}, author = {Lu, Y and Wang, X and Saibro-Girardi, C and Fitz, NF and Koldamova, R and Lefterov, I}, title = {Decoding the Effects of Bexarotene treatment on brain of AD-like model mice: Single-Cell Transcriptomics and Chromatin Accessibility Analysis.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40831503}, issn = {2693-5015}, support = {R01 AG066198/AG/NIA NIH HHS/United States ; RF1 AG075992/AG/NIA NIH HHS/United States ; R56 AG057565/AG/NIA NIH HHS/United States ; R01 AG057565/AG/NIA NIH HHS/United States ; R01 AG077636/AG/NIA NIH HHS/United States ; }, abstract = {BACKGOUND: Ligand-activated Retinoid X Receptors (RXRs) regulate gene networks essential for neural development, neuroinflammation, and metabolism. Understanding how RXR activation influences chromatin architecture and gene expression may reveal therapeutic strategies for neurodegenerative diseases. METHODS: We used Bexarotene-treated APP/PS1ΔE9 mice to study RXR-mediated regulatory mechanisms. To investigate epigenomic and transcriptional effects, we integrated single-nucleus ATAC-seq (snATAC-seq) with single-cell RNA-seq (scRNA-seq) and validated differentially accessible chromatin peaks using RXR ChIP-seq. Transcription factor (TF) footprinting analysis were performed to map regulatory networks activated by ligand-bound RXR. RESULTS: Our integrated analyses revealed a multilayered transcriptional cascade initiated by a single linear RXR signaling event. We identified RXR-centered regulatory circuits involving heterodimer activation, subsequent upregulation of multiple downstream TFs, and induction of metabolic pathways relevant to neural function. The results of a detailed analysis of TF regulatory networks in neuronal systems suggests that Bexarotene doesn't dismantle the fundamental regulatory scaffold in neurons but rather modulates RXR regulatory role through existing TF networks. CONCLUSIONS: This study demonstrates that combining scRNA-seq, snATAC-seq, and ChIP-seq enables a comprehensive analysis of RXR-mediated transcriptional regulation. RXR activation orchestrates complex gene networks that may help restore brain homeostasis in the context of amyloid pathology, neuroinflammation, and neuronal injury.}, } @article {pmid40831271, year = {2025}, author = {Takakuwa, M and Izuo, N and Chino, K and Yano, Y and Yokose, J and Shigetsura, Y and Nitta, A}, title = {Construction of Shati/Nat8l Plasmid Vectors, and Analysis of Mitochondrial Function Mediated by Shati/Nat8l Against Amyloid β Toxicity.}, journal = {Neuropsychopharmacology reports}, volume = {45}, number = {3}, pages = {e70041}, pmid = {40831271}, issn = {2574-173X}, support = {AdAMS JP22H04922//Japan Society for the Promotion of Science/ ; JP21H02632//Japan Society for the Promotion of Science/ ; JPMJSP2145//Japan Science and Technology SPRING/ ; //Tamura Science and Technology Foundation/ ; //Smoking Research Foundation/ ; //Kobayashi Foundation/ ; }, mesh = {*Amyloid beta-Peptides/toxicity ; Animals ; *Mitochondria/metabolism/drug effects ; Mice ; Plasmids/genetics ; Genetic Vectors ; Humans ; Cell Line, Tumor ; Membrane Potential, Mitochondrial/drug effects ; Peptide Fragments/toxicity ; }, abstract = {In Alzheimer's disease (AD), the accumulation of senile plaques composed of neurotoxic amyloid β (Aβ) is known to be one of the causes. Shati/Nat8l, a gene related to neuropsychiatric disorders, encodes an enzyme that biosynthesizes N-acetyl aspartate (NAA) from aspartate and acetyl CoA. Studies on AD patients and model mice show that NAA and Shati/Nat8l are associated with AD pathology. We previously demonstrated that hippocampal overexpression of Shati/Nat8l in 5xFAD mice, an AD model, improved cognitive suppress without altering the number or size of Aβ plaques. To investigate the cellular mechanisms underlying the neuroprotective effects of Shati/Nat8l on Aβ neurotoxicity, we constructed a vector containing the full-length Shati/Nat8l sequence and transfected it into Neuro-2a cells to produce a stably Shati/Nat8l-overexpressing cell line (N2A-Shati). N2A-Shati cells expressed threefold higher Shati/Nat8l mRNA levels compared with a control cell line (N2A-Control). Treatment with Aβ for 48 h reduced the viability of N2A-Shati and N2A-Control cells at concentrations ≧ 0.03 μM compared to their own vehicle. Exposure to 0.03 μM Aβ for 24 h did not induce any detectable changes in mitochondrial mass or mitochondrial membrane potential in either N2A-Control or N2A-Shati cells. However, N2A-Shati cells demonstrated reduced pyruvate dehydrogenase kinase 1 (Pdk1) mRNA expression and enhanced nuclear respiratory factor 1 (Nrf1) and mitochondrial transcription factor A (Tfam) mRNA expression levels. These results suggest that, although Shati/Nat8l does not significantly affect cell viability, mitochondrial mass, or membrane potential, it could modulate specific intracellular pathways.}, } @article {pmid40831183, year = {2025}, author = {Sampath, R and Baskar, M}, title = {Biomarker extraction-based Alzheimer's disease stage detection using optimized deep learning approach.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {682-698}, doi = {10.1177/13872877251360394}, pmid = {40831183}, issn = {1875-8908}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; Biomarkers ; Magnetic Resonance Imaging/methods ; Algorithms ; Male ; Aged ; Female ; Hippocampus/diagnostic imaging ; Early Diagnosis ; }, abstract = {BackgroundCognitive decline and memory loss in Alzheimer's disease (AD) progresses over time. Early diagnosis is crucial for initiating treatment that can slow progression and preserve daily functioning. However, challenges such as overfitting in prediction models, underutilized biomarker features, and noisy imaging data hinder the accuracy of current detection methods.ObjectiveThis study proposes a novel deep learning-based framework aimed at improving the identification of AD stages while addressing the limitations of existing diagnostic techniques.MethodsStructural MRI scans are employed as the primary diagnostic tool. To enhance image quality, contrast-limited adaptive histogram equalization and wavelet soft thresholding are applied for noise reduction. Biomarker segmentation focuses on ventricular and hippocampal abnormalities, optimized using a firefly algorithm. Dimensionality reduction is performed via Linear Discriminant Analysis to minimize overfitting. Finally, a Deep Belief Network optimized using the Cuckoo Search algorithm is employed for classification and feature learning.ResultsThe proposed framework demonstrates improved performance over existing methods, achieving a 0.66% increase in accuracy and a 0.0345% decrease in error rate for AD stage detection.ConclusionsThis deep learning strategy shows promise as an effective tool for early and accurate AD stage identification. Enhanced segmentation, dimensionality reduction, and classification contribute to its improved performance, offering a meaningful advancement in AD diagnostics.}, } @article {pmid40830489, year = {2025}, author = {de Weerd, L and Hummel, S and Müller, SA and Paris, I and Sandmann, T and Eichholtz, M and Gröger, R and Englert, AL and Wagner, S and Ha, C and Davis, SS and Warkins, V and Xia, D and Nuscher, B and Berghofer, A and Reich, M and Feiten, AF and Schlepckow, K and Willem, M and Lichtenthaler, SF and Lewcock, JW and Monroe, KM and Brendel, M and Haass, C}, title = {Early intervention anti-Aβ immunotherapy attenuates microglial activation without inducing exhaustion at residual plaques.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {92}, pmid = {40830489}, issn = {1750-1326}, mesh = {Animals ; *Microglia/metabolism/drug effects/immunology ; Mice ; *Plaque, Amyloid/pathology/metabolism/immunology ; *Amyloid beta-Peptides/immunology/metabolism/antagonists & inhibitors ; *Immunotherapy/methods ; *Alzheimer Disease/pathology/metabolism/immunology ; Mice, Transgenic ; Disease Models, Animal ; }, abstract = {Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer's disease. Efficient amyloid clearance has been proven in clinical trials testing anti-Aβ antibodies, by their impact on cognitive endpoints correlating with the extent of amyloid removal. However, treatment is associated with adverse side effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model with an intervention paradigm early during amyloidogenesis. Long-term treatment with anti-Aβ results in a robust and dose-dependent lowering of amyloid plaque pathology, with a higher efficiency for reducing diffuse over dense-core plaque deposition. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune-cell-related proteins. Bulk RNA-seq revealed a dose-dependent attenuation of disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around residual plaques remains high, regardless of treatment dose. In addition, microglia surrounding residual plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen-presenting and immune signalling proteins. These findings demonstrate that chronic early intervention by an anti-amyloid immunotherapy leads to a dose-dependent decrease in plaque formation, which is associated with lower brain-wide microglial DAM activation and neurodegeneration. Microglia at residual plaques still display a combined DAM and antigen-presenting phenotype that suggests a continued treatment response.}, } @article {pmid40829311, year = {2025}, author = {Park, S and Park, M and Lee, HJ}, title = {Ginkgolide A enhances cognition and reduces amyloid-β by activating autophagy in the murine 5xFAD Alzheimer's disease model.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {191}, number = {}, pages = {118472}, doi = {10.1016/j.biopha.2025.118472}, pmid = {40829311}, issn = {1950-6007}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/psychology ; *Ginkgolides/pharmacology/therapeutic use ; *Autophagy/drug effects ; Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; *Cognition/drug effects ; Disease Models, Animal ; *Lactones/pharmacology/therapeutic use ; Mice ; Plaque, Amyloid ; Endoplasmic Reticulum Stress/drug effects ; Signal Transduction/drug effects ; Male ; TOR Serine-Threonine Kinases/metabolism ; Neuronal Plasticity/drug effects ; Maze Learning/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Hippocampus/drug effects/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder closely associated with impaired autophagy. Ginkgolide A (GA), a principal bioactive constituent of Ginkgo biloba, has garnered attention for its antioxidant, anti-inflammatory, and autophagy-modulating properties. MAIN TEXT: To evaluate the therapeutic potential of GA, we administered oral GA (20 mg/kg/day) for four weeks to 5xFAD transgenic mice. GA treatment significantly reduced soluble and insoluble forms of amyloid-β (Aβ) in the cortex and hippocampus, and markedly decreased Aβ plaque deposition. Cognitive performance was improved, as evidenced by increased spontaneous alternation in the Y-maze test. GA enhanced synaptic plasticity, indicated by increased expression of the synaptic markers synaptophysin 11 (SP11) and postsynaptic density 95 (PSD95). At the molecular level, GA activated autophagy by modulating PI3K-Akt signaling, relieving endoplasmic reticulum (ER) stress, and enhancing energy stress responses, ultimately leading to mTOR pathway suppression. CONCLUSION: These findings demonstrate that GA is a promising multifunctional therapeutic candidate for AD. Its ability to regulate autophagy and related signaling pathways provides new insights into disease mitigation and cognitive improvement.}, } @article {pmid40829243, year = {2025}, author = {Liu, Z and Huang, X and Zhang, M and Quan, YS and Wang, YL and Liu, JY and Nie, WZ and Zhao, YQ and Guo, HY and Quan, ZS and Li, G and Shen, QK}, title = {Discovery of oleanolic acid derivatives that inhibit tau protein phosphorylation and neuroinflammation induced by Aβ25-35 in vitro and in vivo.}, journal = {Bioorganic chemistry}, volume = {164}, number = {}, pages = {108866}, doi = {10.1016/j.bioorg.2025.108866}, pmid = {40829243}, issn = {1090-2120}, mesh = {*Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Animals ; *Oleanolic Acid/pharmacology/chemistry/chemical synthesis/analogs & derivatives ; *tau Proteins/metabolism/antagonists & inhibitors ; Mice ; *Peptide Fragments/antagonists & inhibitors/metabolism ; Phosphorylation/drug effects ; Humans ; Structure-Activity Relationship ; Molecular Structure ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Alzheimer Disease/drug therapy/metabolism ; Dose-Response Relationship, Drug ; *Drug Discovery ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Male ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder. The primary pathological features of AD are the abnormal deposition of extracellular β-amyloid (Aβ) protein and hyperphosphorylated microtubule-associated protein tau. Excessive Aβ aggregation triggers neuroinflammation. Oleanolic acid (OA) has significant neuroprotective and anti-inflammatory effects. In this study, we designed and synthesized 35 OA derivatives for the treatment of AD, targeting Aβ and hyperphosphorylated tau. The results showed that compound B1, an OA derivative with a tetrazole, had the strongest activity against Aβ25-35-induced cytotoxicity (EC50 = 1.93 ± 0.76 μM), approximately 14.75-fold more potent than OA and could penetrate the BBB. Intracerebroventricular injection of Aβ25-35 to establish an AD-like mouse model, the histopathological results showed that B1 relieved nerve damage, and Morris water maze results showed that B1 improved learning and memory. Mechanistically, B1 reversed the hyperphosphorylation of tau, significantly inhibited the expression of certain immune-related cytotoxic factors, suppressed the MAPK and NF-κB signaling pathways, and significantly inhibited the expression of RAGE and the apoptosis factors Bax/Bcl-2, both in vitro and in vivo. In conclusion, B1 regulates neuroinflammatory mediators in response to Aβ and reverses the hyperphosphorylation of tau, and is a promising multifunctional compound for treating AD.}, } @article {pmid40827126, year = {2025}, author = {Price, BR and Walker, KA and Eissman, JM and Suryadevara, V and Sime, LN and Hohman, TJ and Gordon, MN}, title = {Sex differences and the role of estrogens in the immunological underpinnings of Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70139}, pmid = {40827126}, issn = {2352-8737}, abstract = {UNLABELLED: Alzheimer's disease (AD) affects women more frequently and more severely than men, but the biological mechanisms underlying these sex differences remain poorly understood. This review integrates recent findings from neuroscience, immunology, endocrinology, and genetics to explore how sex steroid hormones, particularly estrogen, shape neuroimmune responses and influence AD risk. We highlight the pivotal roles of microglia and astrocytes, whose inflammatory and neuroprotective actions are modulated by hormonal fluctuations across the female lifespan, including pregnancy, menopause, and menopausal hormone replacement therapy. Key genetic risk factors, such as apolipoprotein E ε4, show sex-specific effects on glial activation, tau pathology, and cognitive decline. Furthermore, life-stage transitions, especially menopause, intersect with changes in brain metabolism, immune signaling, and epigenetic regulation, increasing susceptibility to neurodegeneration in women. We propose a framework for sex-aware, personalized approaches to AD prevention and treatment. By integrating hormone-immune interactions with genetic and glial biology, this review emphasizes the critical need for sex-specific models in AD research. HIGHLIGHTS: Women develop greater tauopathy, with more cognitive and clinical consequences in Alzheimer's disease (AD).Glial activation is adapted by estrogens to shape vulnerability or resilience to AD.Sex differences in innate and adaptive immunity could contribute to AD progression.Effects of menopausal hormone therapy on immunity in AD remain understudied.Future studies to explore sex differences in immune function during AD are needed.}, } @article {pmid40826719, year = {2025}, author = {Ma, W and Yuan, X and Liu, Y and Wang, Q and Zhang, Y and Dong, P and Zhou, C}, title = {Immune regulatory mechanisms of different exercise methods promoting Parkinson's rehabilitation: A narrative review.}, journal = {Medicine}, volume = {104}, number = {33}, pages = {e44035}, pmid = {40826719}, issn = {1536-5964}, support = {YDZX2022091//the central government guides local Sci-tech development funds/ ; ZR2021QH070//the Natural Scientific Foundation of Shandong Province, China/ ; }, mesh = {Humans ; *Parkinson Disease/rehabilitation/immunology ; *Exercise Therapy/methods ; }, abstract = {Parkinson disease (PD) is the second largest and most common neurodegenerative disease globally, following Alzheimer disease. Its pathological features include the deformation and loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, as well as the aggregation of α-synuclein in the form of Lewy bodies. This leads to motor symptoms such as resting tremors, muscle rigidity, bradykinesia, and postural instability, as well as non-motor symptoms including cognitive, emotional, and sleep disorders. Currently, PD is mainly treated by medication and surgery. Medication, though widely used, has limited efficacy and causes adverse reactions. With the intensification of global aging and the annual increase in the incidence of PD, the limitations of existing treatment approaches have become increasingly prominent, and there is an urgent need to explore safer and more effective treatment strategies. Numerous clinical studies have demonstrated that exercise rehabilitation training can not only effectively ameliorate the motor and non-motor symptoms of PD patients, but also promote the generation of neurotrophic factors, neurotransmitters, and hormones, and regulate the dopaminergic system. Therefore, an in-depth exploration of the mechanisms and effects of different exercise rehabilitation training methods in the treatment of PD holds great significance for refining the comprehensive treatment plan for PD and enhancing the quality of life of patients. This article will conduct a comprehensive review of the mechanisms and effects of various exercise rehabilitation training methods in treating PD.}, } @article {pmid40826256, year = {2025}, author = {Langness, VF and Simmons, DA and McHugh, TLM and Butler, RR and Zhou, J and Liu, H and Yang, T and Ellerby, LM and Longo, FM}, title = {Twenty years of therapeutic development in tauopathy mouse models: a scoping review.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70578}, pmid = {40826256}, issn = {1552-5279}, support = {PO1 AG066591/AG/NIA NIH HHS/United States ; T32 AG052374/AG/NIA NIH HHS/United States ; //Taube Philanthropies/ ; P01 AG066591/AG/NIA NIH HHS/United States ; //Jean Perkins Foundation/ ; }, mesh = {Animals ; Humans ; Mice ; *Disease Models, Animal ; Mice, Transgenic ; tau Proteins/genetics ; *Tauopathies/therapy/genetics/drug therapy ; }, abstract = {Tauopathies are neurodegenerative diseases characterized by pathological tau protein inclusions and dementia. Tauopathy mouse models with MAPT mutations replicate tau-related pathologies and are widely used for therapeutic research. This scoping review examines 409 treatment evaluations in MAPT mouse models. We identify trends in therapeutic strategies and frequently used mouse models, treatment routes, and endpoints. We also document treatment effects and when treatment is initiated relative to tau pathology emergence. Many treatments produced positive effects in multiple MAPT mouse models across many endpoints but showed limited success in clinical trials. Potential barriers to mouse-to-human translation include differences between mouse and human studies in the timing of treatment initiation relative to tau pathology onset, predominant testing of a limited number of endpoints, lack of translatable treatment response biomarkers, and the limited ability of individual mouse models to represent the diversity of tauopathies. Addressing these obstacles could improve mouse-to-human translation for tauopathy therapeutics. HIGHLIGHTS: Two decades of therapeutic research in tauopathy mouse models were reviewed. Treatments often began before or at tau pathology onset in tauopathy mouse models. Key endpoints (e.g., cognition and synaptic degeneration) were underassessed. Well-characterized preclinical treatments often had limited success in humans. Single-sex mouse studies and a lack of biomarkers hinder clinical translation.}, } @article {pmid40826098, year = {2025}, author = {Chia, SY and Li, M and Li, Z and Tu, H and Lee, JWL and Qiu, L and Ling, J and Reynolds, R and Albani, S and Tan, EK and Ng, ASL and Chen, J and Zeng, L}, title = {Single-nucleus transcriptomics reveals a distinct microglial state and increased MSR1-mediated phagocytosis as common features across dementia subtypes.}, journal = {Genome medicine}, volume = {17}, number = {1}, pages = {92}, pmid = {40826098}, issn = {1756-994X}, support = {LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; NMRC/OFLCG/002/2018//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; CIRG19may0052//Clinician Scientist Individual Research Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; MOH-STaR19nov-0002//NMRC Awarded Projects Talent Development/ ; MOH-000988//Duke-NUS and SingHealth AMC core funding as well as Singapore Ministry of Health's NMRC under its Centre Grant Program/ ; A*STAR PEC21-H22P0M0003//A*STAR/ ; }, mesh = {*Microglia/metabolism ; Humans ; *Phagocytosis/genetics ; *Dementia/genetics/metabolism/pathology ; *Transcriptome ; Animals ; Mice ; Male ; *Scavenger Receptors, Class A/metabolism/genetics ; Aged ; Female ; Gene Expression Profiling ; Alzheimer Disease/genetics/metabolism ; Aged, 80 and over ; Single-Cell Analysis ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD) collectively represent the majority of dementia cases worldwide. While these subtypes share clinical, genetic, and pathological features, their transcriptomic similarities and differences remain poorly understood. METHODS: We applied single-nucleus RNA-sequencing (snRNA-seq) to prefrontal cortex samples from individuals with non-cognitive impairment control (NCI), and dementia subtypes (AD, DLB, and PDD) to investigate cell type-specific gene expression patterns and pathways underlying pathological similarities and differences across dementia subtypes. SnRNA-seq findings were validated through RNAscope, immunohistochemistry, and additional biochemical analyses in human tissues and cellular models. RESULTS: SnRNA-seq analysis revealed elevated microglial proportions across all dementia subtypes compared to NCI. Further analysis of cell type-specific transcriptomes identified overlapping differentially expressed genes (DEGs) between microglia and oligodendrocytes across all dementia subtypes. While AD showed molecular similarities to NCI, PDD and DLB were clustered more closely together, sharing a greater number of DEGs and related pathways, predominantly associated with microglia. Investigation of interactions between microglia and oligodendrocytes revealed a distinct microglial state in all dementia subtypes. MSR1, a gene encoding a scavenger receptor, was upregulated in microglia across all dementia subtypes, along with its associated gene HSPA1A in oligodendrocytes. RNAscope supported the potential interaction between microglia and oligodendrocytes, where these cells were in closer proximity to each other in human cortical tissues of PDD compared to NCI. MSR1 expression was significantly increased in cortical primary microglia from PD mice compared with non-transgenic (NTg) mice. Additionally, the expression of myelin-associated genes (MBP, MOBP, and PLP1) was significantly upregulated in PD microglia compared to NTg, supporting the presence of the distinct microglia. Furthermore, MSR1-positive microglia colocalised with MBP in cortical tissue of PDD patients, suggesting a functional role of MSR1 in myelin debris clearance. Overexpression of MSR1 in microglial cells enhanced their phagocytic activity toward myelin, and reciprocally, myelin treatment upregulated MSR1 protein levels, indicating enhanced MSR1-mediated myelin phagocytosis. CONCLUSIONS: Our findings provide novel insights into the cell type-specific role of microglial MSR1 in AD, DLB, and PDD, linking its increased phagocytic capacity to myelin defects as a common feature of neurodegenerative dementias.}, } @article {pmid40825623, year = {2025}, author = {Ma, W and Tang, B and Zhang, H and Qu, Y and Luan, J and Wang, K and Chen, W and Wang, X and Liu, X and Zhao, H and Li, H and Luo, M and Luo, Z and Shen, L and Chen, M}, title = {Small-molecule fluorescent probes for imaging intracellular amyloid toxicity induces ferroptosis via HClO fluctuation in Alzheimer's disease.}, journal = {Analytica chimica acta}, volume = {1371}, number = {}, pages = {344485}, doi = {10.1016/j.aca.2025.344485}, pmid = {40825623}, issn = {1873-4324}, mesh = {*Ferroptosis/drug effects ; *Alzheimer Disease/metabolism/diagnostic imaging ; Humans ; *Fluorescent Dyes/chemistry/chemical synthesis/pharmacology ; *Hypochlorous Acid/metabolism/analysis ; *Amyloid beta-Peptides/toxicity/metabolism ; Animals ; *Small Molecule Libraries/chemistry/pharmacology/chemical synthesis ; Optical Imaging ; Mice ; Blood-Brain Barrier/metabolism ; Molecular Structure ; Peptide Fragments/toxicity ; }, abstract = {BACKGROUND: Amyloid toxicity induces ferroptosis play a crucial role in the pathological dysfunction of brains affected by Alzheimer's disease (AD). Despite this, brain probing implements for looking into the relationship between ferroptosis and ROS in the brains of AD victims are currently scarce. Herein, a HClO activated ESIPT fluorescent probe HCC-Br was engineered to investigate the complicated correlations between HClO and AD, achieving in vivo diagnosing and evaluating of AD progression. RESULTS: With this probe, we could also utilize HCC-Br for the visualization and tracking of endogenous HClO production in live cells during Aβ42-induced ferroptosis. More crucially, our findings suggest that tannic acid (TA) shows promise as an effective neuroprotective agent to control MPO-mediated oxidative stress in this stimulated condition. The small molecular structure and suitable lipophilicity endowed HCC-Br with remarkable blood-brain barrier (BBB) permeability, making it enormously applicable to the in vivo detection of HClO variations in AD brains. SIGNIFICANCE AND NOVELTY: Overall, this study presents a versatile fluorescence tool that can help clarify the contributions of HClO production by MPO in the pathogenic mechanisms of AD. Furthermore, it holds tremendous prospects in exploring the function of HClO in ferroptosis-related pathogenesis and treatment of AD.}, } @article {pmid40825553, year = {2025}, author = {Sato, S and Iwata, A and Ishii, K and Kamiki, E and Nishimoto, T}, title = {[Donanemab, an Amyloid β-targeting Antibody for Early Symptomatic Alzheimer's Disease: Summary of Clinical Study Results].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {8}, pages = {907-920}, doi = {10.11477/mf.188160960770080907}, pmid = {40825553}, issn = {1881-6096}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized ; }, abstract = {Alzheimer's disease is an age-related neurodegenerative disorder, and is considered to contribute to dementia in 60%-70% of individuals with dementia. In recent years, a series of amyloid β protein (Aβ)-targeting antibodies that act directly on Aβ aggregates in the brain, one of the factors which contributes to the onset of Alzheimer's disease, have been approved to suppress the clinical progression, and Alzheimer's disease treatment in Japan is changing. This review article focuses on one of these Aβ-targeting antibodies, donanemab, and summarizes its clinical study results. (Received November 1, 2024; Accepted May 7, 2025; Published August 1, 2025).}, } @article {pmid40825453, year = {2025}, author = {Cozza, M and Fimognari, FL and Castagna, A and Boccardi, V}, title = {Antidepressant use in dementia: Assessing effective strategies for a vulnerable population.}, journal = {Neuroscience and biobehavioral reviews}, volume = {177}, number = {}, pages = {106340}, doi = {10.1016/j.neubiorev.2025.106340}, pmid = {40825453}, issn = {1873-7528}, mesh = {Humans ; *Antidepressive Agents/therapeutic use ; *Dementia/drug therapy/complications/psychology ; *Depression/drug therapy ; Vulnerable Populations ; }, abstract = {Depression is closely associated with dementia and may serve as a risk factor, an early symptom, or a prodromal feature, particularly in Alzheimer's disease, the most common form of dementia. It can also emerge during disease progression, not only in Alzheimer's but in other dementias such as vascular dementia, Lewy body dementia, and frontotemporal dementia. Recognizing the timing and context of depressive symptoms is crucial for accurate diagnosis and management. While non-pharmacological interventions and psychosocial approaches are generally recommended as the first line of treatment, clinical practice often sees widespread use of antidepressants in this vulnerable population. However, such usage is not always supported by robust evidence, particularly given the heightened risk of side effects in older adults with cognitive decline. This narrative review seeks to critically examine the role of antidepressants in managing depression among patients with dementia. Rather than dismissing their use outright, we aim to provide a novel perspective on their application, emphasizing the importance of a thorough multidimensional geriatric assessment. The attempt is to help the clinicians in making more individualized, evidence-based decisions that balance the potential benefits and risks, ensuring that treatment is tailored to the unique needs of each patient.}, } @article {pmid40825161, year = {2025}, author = {Kapasi, A and James, BD and Yu, L and Sood, A and Arvanitakis, Z and Bennett, DA and Boyle, P and Schneider, JA}, title = {Mixed Pathologies and Cognitive Outcomes in Persons Considered for Anti-Amyloid Treatment Eligibility Assessment: A Community-Based Study.}, journal = {Neurology}, volume = {105}, number = {5}, pages = {e214004}, pmid = {40825161}, issn = {1526-632X}, mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction/pathology/drug therapy/psychology ; Aged, 80 and over ; *Alzheimer Disease/pathology/drug therapy ; *Amyloid beta-Peptides/metabolism ; Eligibility Determination ; *Brain/pathology ; Positron-Emission Tomography ; }, abstract = {BACKGROUND AND OBJECTIVES: Despite the capability of anti-amyloid monoclonal antibodies to lower β-amyloid (Aβ) brain levels, there is thus far limited clinical efficacy on cognitive outcomes. Among individuals with mild cognitive impairment (MCI) or mild-stage dementia, the cognitive impact of other brain pathologies may limit efficacy of anti-amyloid drugs. This study examined the burden and cognitive associations of mixed brain pathologies among autopsied persons who would have been considered as patients to undergo anti-amyloid treatment eligibility assessment. METHODS: Eligibility was defined based on a Mini-Mental State Examination score ≥20, a clinical diagnosis of MCI or mild-stage Alzheimer dementia, and a level of Aβ pathology at autopsy indicative of having a positive amyloid PET scan (Consortium to Establish a Registry for Alzheimer's Disease score ≥moderate). The number and types of copathologies were examined. Mixed-effects models were used to examine the association of Aβ, tangles, limbic predominant age-related transactive response DNA-binding protein 43 encephalopathy neuropathologic changes (LATE-NC), infarcts, Lewy bodies (LBs), and vessel diseases, with the rate of cognitive decline. RESULTS: Among 428 older autopsied persons (mean age at death = 91 years, 70% women) considered for anti-amyloid treatment eligibility assessment, 58% had MCI and 42% had mild-stage Alzheimer dementia. Although the majority (94%) had a pathologic diagnosis of Alzheimer disease neuropathologic changes (ADNC), only 26% had ADNC without LATE-NC, LB, or infarcts. The majority (68%) had ADNC with ≥1 copathology with ADNC + infarcts and ADNC + LATE-NC being equally common. In mixed-effects models, tangles and arteriolosclerosis were both associated with a faster rate of global cognitive decline. Separately, tangles and LATE-NC were associated with a faster decline in episodic memory, ADNC was associated with faster decline in semantic memory with Aβ being further associated with decline in working memory, and atherosclerosis was associated with a faster decline in perceptual speed. Infarcts and LBs were not associated with decline in global cognition or any cognitive domain. DISCUSSION: Mixed pathologies are common among community-dwelling older persons considered for anti-amyloid treatment eligibility assessment. Beyond Aβ, tangles, LATE-NC, and vessel pathologies drive cognitive decline in this group of individuals, especially episodic memory decline. These findings suggest that, even among those eligible for anti-amyloid therapies, substantial cognitive decline may occur because of the presence of coexisting pathologies.}, } @article {pmid40824894, year = {2025}, author = {Almarri, B}, title = {Deep learning-based Alzheimer's disease detection using magnetic resonance imaging and gene expression data.}, journal = {PloS one}, volume = {20}, number = {8}, pages = {e0330085}, pmid = {40824894}, issn = {1932-6203}, mesh = {*Alzheimer Disease/genetics/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; Gene Expression Profiling ; ROC Curve ; Male ; }, abstract = {Alzheimer's disease (AD) poses significant challenges to healthcare systems across the globe. Early and accurate AD diagnosis is crucial for effective management and treatment. Recent advances in neuroimaging and genomics provide an opportunity for developing multi-modality-based AD diagnosis models using artificial intelligence (AI) techniques. However, the data complexities cause challenges in developing interpretable AI-based AD identification models. In this study, the author built a comprehensive AD diagnostic model using magnetic resonance imaging (MRI) and gene expression data. MobileNet V3 and EfficientNet B7 model was employed to extract AD features from gene expression data. The author introduced a hybrid TWIN-Performer-based feature extraction model to derive features from MRI. The attention-based feature fusion was used to fuse the crucial features. An ensemble learning-based classification model integrating CatBoost, XGBoost, and extremely randomized tree (ERT) was developed to identify cognitively normal (CN) and AD features. The proposed model was validated on diverse datasets. It achieved a superior performance on MRI and gene expression datasets. The area under the receiver operating characteristic (AUROC) scores were consistently above 0.85, indicating excellent model performance. The use of Shapley Additive exPlanations (SHAP) values improved the model's interpretability, leading to earlier interventions and personalized treatment strategies.}, } @article {pmid40824589, year = {2025}, author = {Borioni, MS and Morano, A and De Matteis, AL and Mazzeo, A and Moro, P and Di Bonaventura, C and Irelli, EC}, title = {Neuroglial biomarkers in autoimmune encephalitis: advances in diagnosis, prognosis, and pathophysiological insights.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {10}, pages = {4925-4941}, pmid = {40824589}, issn = {1590-3478}, mesh = {Humans ; Biomarkers/cerebrospinal fluid/blood/metabolism ; Prognosis ; *Encephalitis/diagnosis/cerebrospinal fluid ; *Neuroglia/metabolism ; *Hashimoto Disease/diagnosis/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; }, abstract = {Autoimmune encephalitis (AE) presents with a diverse spectrum of neuropsychiatric symptoms, often leading to diagnostic challenges and delays in treatment. Neuroglial biomarkers may improve AE diagnosis, disease monitoring, and prognostication. This review examines the diagnostic and prognostic value of fluid biomarkers in AE, focusing on markers of neuroaxonal damage, synaptic dysfunction, astroglial activation, and amyloid metabolism. A systematic search of PubMed, Cochrane, and Scopus databases (from inception until November 26, 2024) was performed. Of the 1,270 articles screened, 31 studies met the inclusion criteria. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was the most frequently investigated subtype (70% of studies). Neurofilament light chain (NfL) was the most widely analyzed biomarker, with elevated levels in both cerebrospinal fluid and serum, aiding in the differentiation of AE from primary psychiatric disorders and in the early identification of checkpoint inhibitor-related neurotoxicity. NfL and total tau (t-Tau) were consistently higher in paraneoplastic than non-paraneoplastic AE. Despite some variability across studies, amyloid-beta (Aβ) 42 and Aβ40, as well as phosphorylated tau (p-Tau), were altered in AE compared to controls, although generally to a lesser extent than in Alzheimer's disease. Higher baseline NfL and YKL-40 correlated with disease severity, and NfL reductions post-immunotherapy were linked to treatment response. Despite consistent heterogeneities in sampling timing, these findings highlight the potential of neuroglial biomarkers as diagnostic and prognostic tools in AE. Future studies should explore longitudinal biomarker dynamics and refine their clinical applications.}, } @article {pmid40823879, year = {2025}, author = {Lee, J and Sim, S and Jin, Y and Park, H and Byeon, EY and Kim, SJ and Yun, S and Lee, HE and Jeong, DU and Suh, JM and Lee, IH and Lee, HY and Choi, Y and Bae, YS}, title = {NADPH Oxidase Inhibition Promotes Brain Resilience by Attenuating Tauopathy and Neuroinflammation in Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {42}, pages = {e05495}, pmid = {40823879}, issn = {2198-3844}, support = {20165925//Starting Growth Technological R&D Program/ ; RS-2024-00398295//Korean National Reseach Foundation (NRF)/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; *NADPH Oxidases/antagonists & inhibitors/metabolism ; *Tauopathies/drug therapy/metabolism ; *Brain/drug effects/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; Mice, Transgenic ; Hippocampus/metabolism/drug effects ; Male ; Neurons/drug effects/metabolism ; }, abstract = {Alzheimer's disease (AD) associates closely associated with the activation of NADPH oxidase (Nox) isozymes. CRB-2131, a novel oxadiazole derivative, is identified as a potently suppresses Nox isozymes. It inhibits reactive oxygen species production (ROS) by hippocampal neuronal and microglial cells and reduces microglial activation. Prophylactic (starting at 3.5 months of age) and therapeutic (starting at 6 months of age) oral administration with CRB-2131 for 10 weeks in 5XFAD mice reduced hippocampal superoxide levels, lipid peroxidation, Tau phosphorylation, and neuroinflammation. Prophylactic and therapeutic CRB-2131 treatment of 5XFAD mice restored their impaired cognition as shown by the novel-object recognition, Y-maze, and Morris water-maze tests. CRB-2131 treatment increased mature neurons, reduced apoptotic mature neurons, and elevated immature neurons in the hippocampus. Positron-emission tomography/computed-tomography imaging confirmed that CRB-2131 stimulated neuronal regeneration. CRB-2131 suppresses brain oxidation, tauopathy, and neuroinflammation, thereby preventing mature neuron death and promoting neuron regeneration. Ultimately, this fosters a resilient brain and protects cognition.}, } @article {pmid40823789, year = {2025}, author = {Shwab, EK and Pathak, GA and Harvey, J and Belloy, ME and Fischer, CE and Lutz, MW and Scholz, SW and Cook, N and Reid, DM and Chen, J and Guan, DX and Oliveira, F and Sinclair, LI and Imo, U and Creese, B and Chiba-Falek, O and , }, title = {Leveraging multiomic approaches to elucidate mechanisms of heterogeneity in Alzheimer's disease: Neuropsychiatric symptoms, co-pathologies, and sex differences.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70549}, pmid = {40823789}, issn = {1552-5279}, support = {R01 AG057522/AG/NIA NIH HHS/United States ; RF1 AG077695/AG/NIA NIH HHS/United States ; R00AG078503//National Institutes of Health/National Institute on Aging/ ; R00AG075238//National Institutes of Health/National Institute on Aging/ ; R01AG067015//National Institutes of Health/National Institute on Aging/ ; RF1-NS113548-01A1//National Institute of Neurological Disorders & Stroke/ ; ZIANS003154//National Institute of Neurological Disorders & Stroke/ ; 2U10AA008401/AA/NIAAA NIH HHS/United States ; //Cure Alzheimer's Fund/ ; 2015/10109-5//The State of São Paulo Research Foundation/ ; AARG-24-1027303/ALZ/Alzheimer's Association/United States ; 22-AAIIA-953269/ALZ/Alzheimer's Association/United States ; AARF-22-967171/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Sex Characteristics ; Comorbidity ; Female ; Male ; Sex Factors ; }, abstract = {The heterogeneity of Alzheimer's disease (AD) is multi-dimensional, encompassing clinical features such as neuropsychiatric symptoms (NPS), rate of progression, age of onset, comorbidities, and neuropathological features such as co-pathologies, and represents the diverse outcomes of manifold genetic and environmental risk determinants. These diverse features of AD also vary significantly between sexes and across ancestral backgrounds, but the specific variations and causal mechanisms are not well understood. Recent technological advances, particularly single-cell and spatial omics, have provided new tools to dissect the molecular underpinnings of AD heterogeneity and its multifactorial nature. This perspective review highlights molecular differences, general and sex-specific, that contribute to the heterogeneity of AD in aspects such as NPS, co-pathology prevalence, and general disease trajectories. We further examined the potential for multiomic approaches to direct future translational studies aimed at the development of precision medicine strategies for the treatment of AD in all its diverse forms. HIGHLIGHTS: Alzheimer's disease (AD) represents diverse subtypes characterized by comorbid clinical symptoms and co-pathologies. Integration of bulk, single-cell, spatial multiomics reveals factors underlying AD variation. Multiomics studies indicate shared and distinct mechanisms between major psychiatric disorders and AD. Multiomics data have transformative implications for sex- and population-specific AD therapies. New tailored precision medicine strategies are needed to address the full range of complexity in AD.}, } @article {pmid40823654, year = {2025}, author = {Dougnon, G and Matsui, H}, title = {Lipofuscin autofluorescence confounds intracellular amyloid β detection in the aged mouse brain.}, journal = {Aging brain}, volume = {8}, number = {}, pages = {100148}, pmid = {40823654}, issn = {2589-9589}, abstract = {Intracellular amyloid β (Aβ) accumulation is a contentious feature of Alzheimer's disease (AD), increasingly reported in young adults and aged animal models of AD. However, autofluorescent lipofuscin granules which consist of a mixture of highly oxidized lipids, misfolded proteins, and metals, accumulates with aging in neurons and microglia and renders difficult the interpretation of immunofluorescence-based studies. Here, we show that lipofuscin accumulation in aged wild-type (WT) mouse brains exhibits significant spectral overlap with commonly used antibodies for Aβ detection, leading to potential misinterpretation of intracellular Aβ signals. Through a combination of dye staining, immunohistochemistry (IHC), and confocal microscopy, we show that fluorescence signals resembling intracellular Aβ and commonly reported in aged animal models of AD, may reflect the presence of lipofuscin granules. Importantly, these signals persisted in control sections where primary Aβ antibodies were omitted, but disappeared following TrueBlack autofluorescence quencher. We also performed Aβ immunofluorescence staining using 5xFAD mice as model for AD, revealing that intracellular Aβ in these models can be diminished by TrueBlack treatment, thus confounding the interpretation of true intracellular Aβ signals. Our findings underscore the need for caution in interpreting intracellular Aβ signals in young adults and aged models of Aβ pathology inside neurons or microglia.}, } @article {pmid40822853, year = {2025}, author = {Tiunova, AA and Diffine, EA and Anokhin, KV}, title = {Memory reconsolidation impairment by amyloid beta (1-42) and its prevention by non-competitive antagonists of NMDA receptors.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1629492}, pmid = {40822853}, issn = {1662-5102}, abstract = {In a healthy brain, the reactivation of memories under conditions of novelty leads to their labilization and subsequent reconsolidation. However, if plasticity of the nervous system is reduced reconsolidation mechanisms may be disrupted, leading to weakening and loss of existing memory. We hypothesize that such self-degradation of old memory due to its reactivation in the compromised brain may lead to progressive memory loss in Alzheimer's disease. Preventing memory lability when accessing it, may slow down such engram degradation. To test these hypotheses, we first examined whether beta-amyloid peptide Aβ1-42 can impair reconsolidation of memory in one-trial passive avoidance task in young chicks. Next, we examined the possibility to prevent such reminder-associated amnesia by administering a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 prior to memory reactivation. Finally, we compared the memory protecting effects of two non-competitive NMDA antagonists, MK-801 and memantine which is a clinically used medication for treatment of Alzheimer's disease. We found that administration of Aβ1-42 prior to memory reactivation in passive avoidance task in chicks impaired its subsequent reconsolidation. Concurrent systemic injection of MK-801 or memantine prevented this impairment. Our data thus support the hypothesis about the possible role of impaired reconsolidation in the progressive deterioration of old memories in neurodegenerative diseases, particularly in Alzheimer's disease. This hypothesis offers a new explanation for the protective effects of memantine and suggests the possibility of similar effects with other NMDA receptor antagonists.}, } @article {pmid40822397, year = {2025}, author = {Liu, X and Sun, C and Dai, Y and Duan, F and He, T and Zhen, M and Liang, E and Zhang, S and Xia, Y and Hu, N and Zhan, R and Deng, D and Liu, S}, title = {Study on the improvement of cognitive deficits in APP/PS1 mice by danggui shaoyao san and its disassembled prescriptions through modulation of the gut microbiota.}, journal = {Frontiers in microbiology}, volume = {16}, number = {}, pages = {1620784}, pmid = {40822397}, issn = {1664-302X}, abstract = {BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disorders linked to gut microbiota dysbiosis, may benefit from Traditional Chinese Medicine (TCM) interventions. OBJECTIVES: Danggui Shaoyao San (DSS), a classic traditional Chinese Medicine (TCM) formula. This study investigated whether Danggui Shaoyao San and its disassembled prescriptions could improve cognitive deficits in APP/PS1 mice by modulating the structure of the gut microbiota, thereby providing a theoretical basis for AD treatment and the further development and application of Danggui Shaoyao San. METHODS: Forty APP/PS1 and eight C57BL/6 mice were divided into six groups: DSS (6.4 g/kg/d), QDW (4.6 g/kg/d), DW (1.8 g/kg/d), GV971 (positive control, 40 mg/kg/d), model (saline), and control (saline). After 60 days of treatment, the mice underwent behavioral testing in the open field, novel object recognition, and water maze. Gut microbiota composition, diversity, and function were then analyzed by 16S rRNA sequencing. RESULTS: The results of Behavioral experiment indicate that Danggui Shaoyao San and its disassembled prescriptions can ameliorate spatial memory deficits (Morris water maze), enhance recognition memory (novel object recognition), and reduce anxiety-like behaviors (open field test), with the DSS group demonstrating the most pronounced effects. In addition, through 16S sequencing analysis we predicted DSS and its disassembled prescriptions reduced harmful bacteria (Firmicutes, Akkermansia) while increasing beneficial bacteria (Bacteroidetes, Bifidobacterium, Lactobacillus). DSS restored microbial diversity closest to healthy controls, evidenced by elevated Chao1/Shannon indices and reduced Simpson index. Beta diversity revealed structural divergence between treatment and model groups. Functional predictions highlighted enriched pathways (D-glutamine metabolism, bile acid biosynthesis) and suppressed antibiotic biosynthesis. CONCLUSION: Danggui Shaoyao San and its disassembled prescriptions ameliorate AD-related cognitive impairment and gut dysbiosis, enhance microbial diversity, and modulate metabolic pathways, supporting their therapeutic potential via gut-brain axis regulation. This study elucidates the multi-target mechanisms of DSS in AD treatment, advancing TCM rationalization for neurodegenerative disorders.}, } @article {pmid40822322, year = {2025}, author = {Diniz, JRG and de Almondes, KM and Godeiro, C and Silva, RAE}, title = {Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy: report of two cases.}, journal = {Dementia & neuropsychologia}, volume = {19}, number = {}, pages = {e20240198}, pmid = {40822322}, issn = {1980-5764}, abstract = {UNLABELLED: The polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy-Nasu-Hakola disease-is a hereditary and progressive pathology, which is mainly associated with pre-senile dementia and changes in bone architecture. OBJECTIVE: To report two rare cases of sibling patients treated with early-onset dementia syndrome with genetic etiology, and to review the literature on the topic. METHODS: Review of medical records, interviews and recording of the diagnostic methods to which patients were subjected. From this, a report was prepared of two cases who began behavioral changes in the third decade of life, who developed, at different times, symptoms of similar cognitive impairment. Bibliographic research carried out in the United States National Library of Medicine (PubMed), Medical Literature Analysis and Retrieval System Online (MEDLINE), Latin American and Caribbean Health Sciences Literature (LILACS), UpToDate and Scientific Electronic Library Online (SciELO) databases for bibliographic review. RESULTS: Two clinical cases with genetic confirmation of Nasu-Hakola disease and a brief literature review were described. CONCLUSION: These cases illustrate a presentation of pre-senile dementia syndrome and reinforce the importance of adequate diagnosis for timely treatment, humanized multidisciplinary follow-up aiming to improve quality of life, as well as genetic and family counseling.}, } @article {pmid40822124, year = {2025}, author = {Wang, H and Qiu, M and Wang, C and Zhang, L and Fan, N and Chen, Z and Liu, Y and Li, T and Wang, Z and Zhu, Y and Zhang, Y and Tian, X and Wang, Y and Yang, M and Fan, D and Luo, Q and Jiang, K and Luo, H and Zhang, H}, title = {Light-Triggered Graphene/Black Phosphorus Heterostructure FET Platform for Ultrasensitive Detection of Alzheimer's Disease Biomarkers at the Zeptomole Level.}, journal = {Research (Washington, D.C.)}, volume = {8}, number = {}, pages = {0772}, pmid = {40822124}, issn = {2639-5274}, abstract = {Due to the low concentration of amyloid-beta (Aβ) in plasma and the high content of interfering factors, the conventional detection method for the quantification of Aβ still faces the problem of insufficient limit of detection (LOD). In this work, we propose a new light-triggered graphene-black phosphorus heterostructure (G-BP) field-effect transistor (FET) biosensing platform that achieves a marked reduction in the LOD. The LOD for Alzheimer's disease (AD) biomarker Aβ42 detection using the G-BP FET is as low as 235.1 zM (2.351 × 10[-19] M), which is the lowest value reported to date and is approximately 2 to 3 orders of magnitude lower than other reported biosensing platforms. The G-BP FET platform provides precise, real-time guidance for non-invasive early diagnosis, disease monitoring, and personalized treatment plans for AD. Moreover, this method has good scalability and potential applications in other areas, including early detection of cancer and other major chronic diseases.}, } @article {pmid40821309, year = {2025}, author = {Matsuura, K and Mayahara, T and Katayama, T and Arai, H}, title = {Recurrent Cholinergic Crisis Caused by Therapeutic-Dose Rivastigmine Patch in an Elderly Patient With Alzheimer's Disease: A Case Report.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e87868}, pmid = {40821309}, issn = {2168-8184}, abstract = {Cholinesterase inhibitors (ChEIs) are widely used for the treatment of dementia and other conditions, but may rarely cause cholinergic crisis, a potentially life-threatening complication. We report an elderly female patient with Alzheimer's disease who experienced three episodes of cholinergic crisis over 32 months while receiving a therapeutic dose of transdermal rivastigmine (18 mg/day). Each episode involved vomiting, diarrhea, diaphoresis, and neurological symptoms, with marked reductions in serum cholinesterase levels (53-63 U/L at presentation). During the first two episodes, alternative diagnoses such as acute gastroenteritis and possible pesticide exposure were initially suspected, and cholinergic crisis secondary to rivastigmine was not recognized. After the third episode, rivastigmine was permanently discontinued, resulting in the complete resolution of both acute and chronic mild gastrointestinal and autonomic symptoms. This case highlights the diagnostic challenges of cholinergic crisis in elderly patients receiving ChEIs and underscores the importance of considering this condition when unexplained gastrointestinal or autonomic symptoms occur even during standard therapeutic dosing.}, } @article {pmid40820453, year = {2025}, author = {Sharma, H and Chandra, P}, title = {Development of Ergosterol Nanoliposome-based Delivery System Pertaining Toxicity Evaluation and Therapeutic Potential for Alzheimer's Disease.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273388820250724174247}, pmid = {40820453}, issn = {1996-3181}, abstract = {INTRODUCTION: Alzheimer's disease (AD), a debilitating neurodegenerative disorder, presents a growing global health challenge due to limited therapeutic options. Ergosterol, known for its neuroprotective and antioxidant properties, suffers from poor bioavailability. This study aimed to develop ergosterol-loaded nanoliposomes (ER-NL-2) and evaluate their safety, antioxidant potential, and therapeutic efficacy in animal models of AD. METHODS: ER-NL-2 was formulated using the ultrasonic thin-film dispersion method and characterized via dynamic light scattering (DLS), zeta potential, and TEM. Acute oral toxicity was assessed in Wistar rats and Swiss mice (2000 mg/kg). Two AD models were employed: Streptozotocin (STZ)- induced in Swiss albino mice and AlCl₃-induced in Wistar albino rats. Behavioral studies included actophotometer and elevated plus maze tests. Antioxidant assays measured SOD, CAT, GSH, and LPO levels. Histopathological analysis of brain tissue was conducted. RESULTS: ER-NL-2 exhibited a mean droplet size of ~180 nm, PDI <0.3, and zeta potential of -27.9 mV. TEM confirmed spherical morphology. Toxicity studies showed no abnormalities. In both AD models, ER-NL-2 improved locomotor activity and reduced transfer latency. Biochemical analyses revealed elevated SOD, CAT, GSH and reduced LPO levels. Histopathology showed preserved neuronal integrity and reduced neurofibrillary tangles in treated groups. DISCUSSION: ER-NL-2 demonstrated neuroprotective efficacy through behavioral, biochemical, and histological endpoints, confirming its antioxidative mechanism and brain safety profile. It was comparable to standard therapy (donepezil). CONCLUSION: ER-NL-2 is a safe and promising nanocarrier for Alzheimer's treatment with significant neuroprotective and antioxidant properties. Further studies are warranted to explore its pharmacokinetics and clinical applicability.}, } @article {pmid40819956, year = {2025}, author = {Wang, J and Wang, ZY and Chen, SF and Wang, RZ and Chen, KL and Lu, JY and Xin, JW and Huang, YY and Wang, MY and Xie, F and Cheng, W and Yen, TC and Wischik, CM and Cui, M and Zuo, CT and Zhao, QH and Wang, YJ and Yu, JT}, title = {Role of [18]F-florzolotau PET in diagnostic and therapeutic decision-making for cognitive impairment.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70563}, pmid = {40819956}, issn = {1552-5279}, support = {2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 82371188//National Natural Science Foundation of China/ ; 2023YFC3605400//National Key Research and Development Program of China/ ; }, mesh = {Humans ; *Positron-Emission Tomography/methods ; Male ; Female ; *Cognitive Dysfunction/diagnostic imaging/therapy ; Aged ; Alzheimer Disease/diagnostic imaging ; Middle Aged ; *Carbolines ; Radiopharmaceuticals ; *Clinical Decision-Making ; *Tauopathies/diagnostic imaging ; Brain/diagnostic imaging ; Supranuclear Palsy, Progressive/diagnostic imaging ; Aged, 80 and over ; }, abstract = {INTRODUCTION: The novel positron emission tomography (PET) tracer, [18]F-florzolotau, enables in vivo visualization of tau pathology. METHODS: We evaluated the diagnostic performance of disease-specific spatial patterns of [18]F-florzolotau PET imaging by visual read for tauopathies and its added value in diagnostic and therapeutic decision-making in 1277 participants with cognitive complaints. RESULTS: The disease-specific spatial patterns of [18]F-florzolotau PET imaging demonstrated high diagnostic accuracy in differentiating various tauopathies, with 96.0% for Alzheimer's disease, 94.4% for frontotemporal lobe degeneration, 93.7% for progressive supranuclear palsy, and 97.5% for corticobasal degeneration. Added to a standard diagnostic workup, [18]F-florzolotau PET reading led to diagnostic revisions for 247 participants (19.3%), increased diagnostic confidence from 68.6% to 81.3%, and resulted in medication changes for 284 participants (22.2%). DISCUSSION: Our data advocate for the strategic implementation of [18]F-florzolotau PET in memory clinics, offering transformative potential for patient care and management. HIGHLIGHTS: [18]F-Florzolotau PET imaging presented disease-specific spatial patterns for different tauopathies. The disease-specific spatial patterns of [18]F-florzolotau positron emission tomography (PET) imaging exhibited high diagnostic accuracy in differentiating various tauopathies. Integration of [18]F-florzolotau PET imaging modality to a standard diagnostic workup significantly enhanced diagnostic confidence, enabled diagnostic revisions, and informed adjustments to treatment strategies.}, } @article {pmid40819191, year = {2025}, author = {Ismail, Z and Wilson, M and Khalifa, H and Belovich, D and Shaw, E and Pham, T and McMullen, S and Chen, Y and Sadman, N and Cai, J and Zulkernine, F and Barber, D}, title = {Diagnosis and Management of Alzheimer's Disease in Primary Care: A Real-World Study in Ontario, Canada.}, journal = {Journal of primary care & community health}, volume = {16}, number = {}, pages = {21501319251363156}, pmid = {40819191}, issn = {2150-1327}, mesh = {Humans ; *Alzheimer Disease/diagnosis/drug therapy/therapy ; Female ; *Primary Health Care ; Retrospective Studies ; Male ; Ontario ; Aged ; Aged, 80 and over ; *Practice Patterns, Physicians'/statistics & numerical data ; Cholinesterase Inhibitors/therapeutic use ; Middle Aged ; Electronic Health Records ; Antidepressive Agents/therapeutic use ; Antipsychotic Agents/therapeutic use ; }, abstract = {OBJECTIVE: To understand the real-world clinical practice patterns and variation in Alzheimer's disease (AD) diagnostic and screening tool utilization by primary care physicians (PCPs), including tools used for assessing dementia/AD severity and subsequent treatment patterns. METHODS: This retrospective observational study used de-identified primary care data from electronic medical records (EMR) data provided by the researchers from Queen's University, Ontario, Canada from August 2011 to August 2021. Individuals ≥50 years old with dementia or AD were identified using AD and dementia-related diagnostic codes, medications, and keywords searched using natural language processing (NLP) and Artificial Intelligence (AI) algorithms from EMR chart notes. Diagnostic and screening tools included scales, neuroimaging, and laboratory tests. Medications examined were cholinesterase inhibitors, memantine, antidepressants, and antipsychotics. RESULTS: The study cohort included 417 individuals with all-cause dementia (mean [standard deviation: SD] age: 78.86 [0.19] years), and 71 individuals with AD (mean [SD] age: 76.13 [1.07]). The most-used scale was the Montreal Cognitive Assessment (MoCA; dementia: 53.2%, AD: 84.5%). The mean [SD] frequency of MoCA administration doubled in the year following AD index date compared to the year prior (0.29 [0.82] to 0.67 [1.19] times per patient-year). Severity scores, often unspecified, suggested various stages of cognitive impairment. Among the medications examined, cholinesterase inhibitors were prescribed in 27.8% (n = 116) and 57.8% (n = 41) of people with dementia and AD, respectively. Antidepressants were the most frequently prescribed medication examined (dementia: 49.6%; AD: 71.8%). CONCLUSION: PCPs play an important role in the early detection and management of dementia/AD. As new biomarkers and therapies emerge for early AD, there is a need for connected health system data to guide PCPs through the early diagnostic process.}, } @article {pmid40818921, year = {2025}, author = {Moorthy, DK and Chinnasamy, P and Nagaraj, P}, title = {Optimization enabled ResNet features with transfer learning for Alzheimer's disease detection.}, journal = {Computational biology and chemistry}, volume = {119}, number = {}, pages = {108613}, doi = {10.1016/j.compbiolchem.2025.108613}, pmid = {40818921}, issn = {1476-928X}, mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; *Neural Networks, Computer ; Algorithms ; *Machine Learning ; }, abstract = {Millions of individuals worldwide suffer from Alzheimer's Disease (AD), a debilitating degenerative condition. Early detection of Alzheimer's disease is critical to ensure effective treatment and better patient outcomes. In the past few years, advanced medical imaging techniques, particularly MRI, have shown potential for diagnosing Alzheimer's disease. However, developing accurate and efficient techniques for Alzheimer's disease detection offcuts a demanding duty suitable to the complication of medical images and the limited availability of labelled data. The early detection of Alzheimer's disease is critical for effective treatment and management of this debilitating neurodegenerative condition. The research proposes a novel method for Alzheimer's disease detection using an optimization-enabled ResNet feature extraction technique with transfer learning that is proposed by combining LeNet and VGG networks. The pre-processing was done using image resizing and median filter and the featureextraction was conducted using the proposed Walrus Optimization Algorithm-Residual neural network (WOA-ResNet), where WOA is employed for training ResNet. The conducted experiments with the Alzheimer's dataset achieved a higher accuracy using the proposed LeNet-VGG method. The findings suggest that optimization-enabled ResNet feature extraction with LeNet-VGG networks can significantly improve the accuracy of Alzheimer's disease detection. The presented method achieved maximum accuracy value of 95.37 %, sensitivity value of 97.24 % and specificity value of 93.73 %.}, } @article {pmid40817880, year = {2025}, author = {da Silva, AWR and da Silva, LB and Rambo, DF and Biegelmeyer, R}, title = {Application of zebrafish (Danio rerio) as a model organism for central nervous system disorders screening of natural products.}, journal = {The Journal of pharmacy and pharmacology}, volume = {77}, number = {12}, pages = {1646-1662}, doi = {10.1093/jpp/rgaf067}, pmid = {40817880}, issn = {2042-7158}, support = {PIE0001/2024//Bahia State Research Support Foundation/ ; //National Council for Scientific and Technological Development/ ; //Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES)/ ; }, mesh = {Animals ; *Zebrafish ; *Biological Products/pharmacology/therapeutic use ; *Disease Models, Animal ; *Central Nervous System Diseases/drug therapy ; Humans ; Drug Evaluation, Preclinical/methods ; Neurodegenerative Diseases/drug therapy ; }, abstract = {OBJECTIVES: Natural products (NP) play a crucial role in the development of new compounds, due to their complex chemical structure and pharmacological diversity. Neurodegenerative diseases and other disorders in the central nervous system (CNS) have become a significant problem in the world due to the increase in life expectancy of the elderly population. This increases the risk of developing diseases, such as Parkinson's disease, Huntington's disease, Alzheimer's disease. Therefore, this exploratory review aims to show the applications of zebrafish for NP research and how they can be used in CNS's in vivo studies. METHODS: The present review covers the literature survey until 2023, including the descriptors for zebrafish, natural product and neurodegenerative diseases. The databases used were PubMed, Scopus, Cochrane and Lilacs. KEY FINDINGS: For the development of new medicines, an efficient animal model is required, and the zebrafish has stood out as a promising model due to its small size, low cost of maintenance, ease of handling, and transparency of embryos, which allows real-time observation of development and pathological processes. They possess conserved neurotransmission systems such as glutamatergic, cholinergic, dopaminergic, serotonergic, histaminergic, GABAergic, and purinergic pathways, making them especially relevant for modelling CNS disorders. From literature survey, flavonoids, alkaloids, and phenolic compounds were the most frequently studied, indicating that its influence the pathophysiological mechanisms associated with neurodegenerative diseases. CONCLUSIONS: This current review offers data for further research work with natural products aiming treatment for CNS disorders.}, } @article {pmid40817783, year = {2026}, author = {Torres, VO and Pizzo, ME and Chan, D and Dugas, JC and Huynh, D and Joy, D and Liang, EK and Sarrafha, L and Becerra, I and Chau, R and Chew, KS and Chow, J and Discenza, CB and Earr, TK and Furaso, L and Khoury, N and Lechtenberg, KJ and Leung, AW and Nguyen, HN and Ojo, ES and Roche, E and Simon, MJ and Solanoy, H and Tong, M and Tong, RK and Henne, K and Lewcock, JW and Watts, RJ and Calvert, ME and Thorne, RG and Zuchero, YJY}, title = {Transferrin receptor-mediated transport at the blood-brain barrier is elevated during early development and maintained across aging and in an Alzheimer's mouse model.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {46}, number = {1}, pages = {20-35}, pmid = {40817783}, issn = {1559-7016}, mesh = {Animals ; *Blood-Brain Barrier/metabolism ; *Receptors, Transferrin/metabolism ; *Alzheimer Disease/metabolism/pathology ; *Aging/metabolism ; Mice ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Male ; Female ; Brain/metabolism ; Biological Transport ; }, abstract = {Transferrin receptor (TfR)-targeting of biologics has emerged as a promising strategy to improve drug delivery across the blood-brain barrier (BBB). However, most preclinical studies evaluating TfR-enabled drugs have been conducted in young adult animals. It remains unclear whether age and aging-related diseases impact TfR protein levels and/or BBB transport capacity. Here, we utilized a previously described TfR-targeting antibody transport vehicle (ATV[TfR]) to investigate how healthy aging and disease progression in the 5xFAD mouse model of Alzheimer's disease (AD) impact TfR protein and TfR-mediated brain delivery. ATV[TfR] transport capacity remained stable across 3- to 24-month-old healthy mice and 5xFAD progression did not impair ATV[TfR] brain transport up to 10.5 months, despite significant amyloid burden. Interestingly, neonates exhibited significantly elevated levels of vascular TfR protein and ATV[TfR] brain exposure compared to adult mice. Furthermore, vascular TfR in AD patient brains was similar to age-matched controls, suggesting conserved TfR transport is also likely in human AD. Overall, our data demonstrates broad functional utility for TfR-based brain delivery in both healthy aging and in an AD mouse model. Additionally, elevated TfR-mediated brain delivery during early mouse development highlights the potential of added efficacy in utilizing such platforms in disease treatment of infants and children.}, } @article {pmid40817729, year = {2025}, author = {Xia, S and He, C and Li, Y and Li, H and Wang, B and Xu, L and Zhao, X}, title = {Low-intensity transcranial ultrasound neuromodulation promotes neuronal regeneration: A new hope for noninvasive treatment of neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00113}, pmid = {40817729}, issn = {1673-5374}, abstract = {Neurodegenerative diseases, which are characterized by progressive neuronal loss and the lack of disease-modifying therapies, are becoming a major global health challenge. The existing neuromodulation techniques, such as deep brain stimulation and transcranial magnetic stimulation, show limitations such as invasiveness, restricted cortical targeting, and irreversible tissue effects. In this context, low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity. This review comprehensively assesses the therapeutic mechanisms, efficacy, and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases, with emphasis on its role in promoting neuronal regeneration, modulating neuroinflammation, and enhancing functional recovery. We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms, enhancing neural repair and regeneration, and alleviating symptoms associated with neurodegenerative diseases. Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors (e.g., brain-derived neurotrophic factor), promote autophagy to clear protein aggregates, modulate microglial activation, and temporarily open the blood-brain barrier to facilitate targeted drug delivery. Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-? plaques, improve motor and cognitive deficits, and promote remyelination in various disease models. Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer's disease and alleviate motor symptoms in Parkinson's disease, all while demonstrating a favorable safety profile. Past studies support the notion that by integrating safety, precision, and reversibility, low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease. However, more advancements are necessary for future clinical application of low-intensity transcranial ultrasound, including optimizing parameters such as frequency, intensity, and duty cycle; considering individual anatomical differences; and confirming long-term efficacy. We believe establishing standardized protocols, conducting larger trials, and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard. Future research should focus on translating preclinical findings into clinical practice, addressing technical challenges, and exploring combination therapies with pharmacological or gene interventions.}, } @article {pmid40817268, year = {2025}, author = {Ibrar, W and Khan, MA and Hamza, A and Rubab, S and Alqahtani, O and Alouane, MT and Teng, S and Nam, Y}, title = {A novel interpreted deep network for Alzheimer's disease prediction based on inverted self attention and vision transformer.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {29974}, pmid = {40817268}, issn = {2045-2322}, mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; *Deep Learning ; *Neural Networks, Computer ; Attention ; Aged ; }, abstract = {In the world, Alzheimer's disease (AD) is the utmost public reason for dementia. AD causes memory loss and disturbing mental function impairment in aging people. The loss of memory and disturbing mental function brings a significant load on patients as well as on society. So far, there is no actual treatment that can cure AD; however, early diagnosis can slow down this disease. Deep learning has shown substantial success in diagnosing AZ disease. However, challenges remain due to limited data, improper model selection, and extraction of irrelevant features. In this work, we proposed a fully automated framework based on the fusion of a vision transformer and a novel inverted residual bottleneck with self-attention (IRBwSA) for AD diagnosis. In the first step, data augmentation was performed to balance the selected dataset. After that, the vision model is designed and modified according to the dataset. Similarly, a new inverted bottleneck self-attention model is developed. The designed models are trained on the augmented dataset, and extracted features are fused using a novel search-based approach. Moreover, the designed models are interpreted using an explainable artificial intelligence technique named LIME. The fused features are finally classified using a shallow wide neural network and other classifiers. The experimental process was conducted on an augmented MRI dataset, and 96.1% accuracy and 96.05% precision rate were obtained. Comparison with a few recent techniques shows the proposed framework's better performance.}, } @article {pmid40816573, year = {2025}, author = {Škorić, I and Sviben, M and Mlakić, M and Čadež, T and Maček Hrvat, N and Kovarik, Z}, title = {Photochemistry-driven design of small molecule cholinesterase ligands.}, journal = {Chemico-biological interactions}, volume = {420}, number = {}, pages = {111703}, doi = {10.1016/j.cbi.2025.111703}, pmid = {40816573}, issn = {1872-7786}, mesh = {Ligands ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Humans ; Butyrylcholinesterase/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; *Drug Design ; *Small Molecule Libraries/chemistry/pharmacology ; Animals ; *Cholinesterase Reactivators/chemistry/pharmacology ; Photochemical Processes ; }, abstract = {The development of small-molecule ligands targeting cholinesterases remains a central focus in neuropharmacology, particularly for the treatment of neurodegenerative disorders and organophosphate poisoning. This review highlights the rational design, synthesis, and biological profiling of diverse classes of heterocyclic compounds - including oxazoles, heterostilbenes, triazoles, and bicyclo[3.2.1]octane/octadiene derivatives - as reversible inhibitors and reactivators of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Novel amino-oxazolostilbenes and their photoproducts exhibited selective BChE inhibition, while naphtoxazole and triazole-containing scaffolds demonstrated promising dual-target or BChE-selective profiles. Several uncharged oximes, such as thienostilbene and heterostilbene oximes, showed potential for reactivating cyclosarin-inhibited BChE, supporting their further development as CNS-permeable antidotes. Additionally, resveratrol-based triazoles and carbamates revealed enhanced BChE inhibition, antioxidant activity, and favorable selectivity. Collectively, these findings underscore the therapeutic potential of structurally diverse cholinesterase ligands and provide a framework for the discovery of multifunctional agents for Alzheimer's disease and chemical threat countermeasures.}, } @article {pmid40816274, year = {2025}, author = {Zeng, PM and Sun, XY and Li, Y and Wu, WD and Huang, J and Cao, DD and Qian, PJ and Ju, XC and Luo, ZG}, title = {Thymosin beta 4 as an Alzheimer disease intervention target identified using human brain organoids.}, journal = {Stem cell reports}, volume = {20}, number = {9}, pages = {102601}, pmid = {40816274}, issn = {2213-6711}, mesh = {*Thymosin/metabolism/genetics/pharmacology ; *Organoids/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology/genetics/drug therapy ; Humans ; Animals ; Induced Pluripotent Stem Cells/metabolism/cytology ; *Brain/metabolism/pathology ; Mice ; Neurons/metabolism ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Neurogenesis ; Amyloid beta-Protein Precursor/genetics/metabolism ; }, abstract = {The developmental origin of Alzheimer disease (AD) has been proposed but is arguably debated. Here, we developed cerebral organoids from induced pluripotent stem cells (iPSCs) with mutations in amyloid precursor protein (APP) associated with familial AD (fAD) and analyzed the dynamic changes of cellular states. We found that mature neurons induced in fAD organoids markedly decreased compared to that of health control, accompanied with increased cell senescence and β-amyloid (Aβ) production. Interestingly, the expression level of the gene TMSB4X that encodes thymosin beta 4 (Tβ4) significantly decreased both in fAD organoids' neurons and AD patients' excitatory neurons. Remarkably, the neurodevelopmental deficits and Aβ formation in fAD organoids were rescued by treatment with Tβ4. The beneficial effects of Tβ4 were also revealed in 5xfAD model mice. Thus, this study has identified Tβ4 as a neuroprotective factor that may mitigate altered neurogenesis and AD pathology, highlighting a potential for disease intervention.}, } @article {pmid40815967, year = {2025}, author = {Scuteri, D and Adornetto, C and Greco, G and Nicotera, P and Bagetta, G and Corasaniti, MT}, title = {Pharmacoutilization data-driven artificial intelligence-assisted diagnosis algorithm to improve the pharmacological treatment of pain and agitation in patients suffering from severe dementia.}, journal = {Current opinion in pharmacology}, volume = {84}, number = {}, pages = {102563}, doi = {10.1016/j.coph.2025.102563}, pmid = {40815967}, issn = {1471-4973}, mesh = {Humans ; *Artificial Intelligence ; *Algorithms ; *Dementia/drug therapy/diagnosis ; Aged ; Aged, 80 and over ; *Pain/drug therapy/diagnosis ; *Psychomotor Agitation/drug therapy/diagnosis/etiology ; *Alzheimer Disease/diagnosis/drug therapy ; Retrospective Studies ; Male ; Antipsychotic Agents/therapeutic use ; Middle Aged ; Female ; }, abstract = {The number of diagnoses and drug prescriptions for dementia patients is poorly available. Delay in the diagnosis of Alzheimer's disease (AD), for which missed diagnoses amount to over half cases, and undertreatment of chronic and neuropathic pain mirroring excessive use of harmful antipsychotics and antidepressants is reported. Our study aimed at diagnosing AD through the most advanced artificial intelligence (AI) methodologies even in patients who escaped clinical observation. To this end, pharmacoepidemiology data collected as part of the first retrospective community study in a wide sample of 298,000 individuals, 84,235 aged over 60 years, were used to set up an AI algorithm for the rescue of missed diagnoses of AD. The core of the algorithm consisted in the management of time series represented by pharmacological therapies through a distance matrix and in the use of autoencoders. Patients without a diagnosis of AD based on pharmacotherapy were 114.920, while diagnosed patients were 1.150, mainly aged between 75 and 84 years, pointing at late start of treatment. Increased use of antidepressants, neuroleptics, and mood stabilizers is found in patients treated with acetylcholinesterase inhibitors (AChEIs) and memantine, while nonsteroidal anti-inflammatory drugs, paracetamol-codeine and opioids are mostly prescribed to patients not receiving AChEIs and memantine. The classification model demonstrated good global accuracy at the end of training, equal to 79.12%. Further studies and longitudinal monitoring of patients are needed to improve disease detection and management. The deep learning-based pharmacoutilization algorithm generated in the present study will aid the diagnosis of AD and the understanding of neuropsychiatric symptoms treatment.}, } @article {pmid40815522, year = {2025}, author = {Yun, H and Unruh, MA and Qian, Y and Zhang, Y and Jung, HY}, title = {Clinicians Who Practice Primarily in Nursing Homes and the Quality of Care for Residents With Alzheimer Disease and Related Dementias.}, journal = {JAMA health forum}, volume = {6}, number = {8}, pages = {e252465}, pmid = {40815522}, issn = {2689-0186}, mesh = {Humans ; Retrospective Studies ; Female ; Male ; *Nursing Homes/statistics & numerical data ; *Alzheimer Disease/therapy ; Aged ; United States ; *Quality of Health Care/statistics & numerical data ; Aged, 80 and over ; Medicare/statistics & numerical data ; *Dementia/therapy ; *Skilled Nursing Facilities/statistics & numerical data ; *Physicians/statistics & numerical data ; }, abstract = {IMPORTANCE: The number of physicians and advanced practitioners (APs) whose care is concentrated in nursing homes (often referred to as nursing home or skilled nursing facility specialists [SNFists]) has increased rapidly. Therefore, whether these clinicians provide better care is important. OBJECTIVE: To examine the association between SNFist care and outcomes of long-stay nursing home (NH) residents with Alzheimer disease and related dementias (ADRD). In this retrospective cohort study of 417 378 residents with ADRD in US NHs, claims for a 20% national sample of Medicare fee-for-service beneficiaries between 2013 and 2019 were analyzed. Adjusted estimates were based on a machine learning approach that incorporated a doubly robust procedure using a generalized estimating equation with inverse probability treatment weighting. Three secondary analyses were conducted: (1) stratified analyses for physicians and APs, (2) inclusion of physicians of any specialty and APs, and (3) use of proxy outcomes for in-place deaths. Data were analyzed from June 1, 2024, to May 3, 2025. INTERVENTION: Receipt of care from a SNFist; SNFists included generalist physicians and APs. MAIN OUTCOMES AND MEASURES: Hospitalizations and emergency department (ED) visits for ambulatory care-sensitive (ACS) conditions. Death without an ACS hospitalization and death without any hospitalization were used in secondary analyses. RESULTS: Of the total 417 378 residents, 242 540 received care from SNFists (mean [SD] age, 83.5 [8.7] years), and 174 838 never received care from SNFists (mean [SD] age, 84.8 [8.5] years). Compared with the residents who never received care from SNFists, the residents who received care from SNFists were more likely to be Black (12.6% vs 9.4%; P < .001), dually eligible (77.5% vs 73.1%; P < .001), and have more chronic conditions (eg, anemia, 60.9% vs 57.6%). Compared with non-SNFist clinicians, the SNFist clinicians were more likely to be female (physicians, 37.1% vs 23.3%; APs, 88.1% vs 85.1%), practice at more facilities (mean [SD] number of facilities, 9.4 [8.7] for SNFist physicians vs 6.4 [6.1] for non-SNFist physicians; 8.6 [8.1] for SNFist APs vs 7.1 [6.8] for non-SNFist APs), and less likely to practice in rural areas (physicians, 9.3% vs 25.4%; APs, 8.1% vs 20.2%). In adjusted analyses, receiving care from a SNFist vs non-SNFist was associated with 7% lower odds of an ACS hospitalization (odds ratio [OR], 0.93; 95% CI, 0.90-0.96) and 7% lower odds of an ACS ED visit (OR, 0.93; 95% CI, 0.90-0.96). In stratified analyses, receiving care from a SNFist physician vs a non-SNFist physician was associated with 13% lower odds (OR, 0.87; 95% CI, 0.83-0.90) of an ACS hospitalization and 7% lowers odds of an ACS ED visit (OR, 0.93, 95% CI, 0.88-0.97); comparisons of SNFist APs vs non-SNFist APs were not statistically significant. Estimates from the analysis including physicians of any specialty and APs were consistent with the primary results. SNFist care was associated with increased odds of in-place death. CONCLUSIONS AND RELEVANCE: Findings of this cohort study suggest that the use of SNFists by NHs may enhance the quality of care for residents with ADRD.}, } @article {pmid40814948, year = {2025}, author = {Bujalance-Fernández, J and Carro, E and Antequera, D and Jurado-Sánchez, B and Escarpa, A}, title = {ZIF-8 Microswimmers Self-Fast Dynamic Destruction in Microliter Volumes of Cerebrospinal Fluid Samples: Toward a Selective Assessment of Amyloidosis.}, journal = {Analytical chemistry}, volume = {97}, number = {33}, pages = {18282-18291}, pmid = {40814948}, issn = {1520-6882}, mesh = {*Amyloid beta-Peptides/cerebrospinal fluid ; Humans ; *Peptide Fragments/cerebrospinal fluid ; *Amyloidosis/cerebrospinal fluid/diagnosis ; *Zeolites/chemistry ; *Imidazoles/chemistry ; Alzheimer Disease/diagnosis/cerebrospinal fluid ; Fluorescent Dyes/chemistry ; Magnetite Nanoparticles/chemistry ; Quinine/chemistry ; Biomarkers/cerebrospinal fluid ; }, abstract = {Herein, we describe the synthesis of magnetic zeolitic imidazole framework (ZIF-8) microswimmers for detecting and quantifying the amyloid beta (Aβ1-42) peptide in cerebrospinal fluid (CSF) samples, which are used as a biomarker of amyloidosis for diagnosing Alzheimer's disease (AD). The microswimmers are prepared by external decoration of the ZIF-8 with magnetic Fe3O4 nanoparticles, followed by post internal encapsulation of quinine as fluorescent probe. The magnetic and surface properties of the microswimmers are fine-tuned to obtain tailored structures with an inner porous structure with the loaded fluorescent probe and outer magnetic engines. A macroporous structure was preferred over a microporous structure for quinine encapsulation, increasing the loading efficiency by about 50%, allowing also external decoration of the ferrite to impart the desired magnetic properties to the microswimmer. The principle for detection relies on the specific affinity of target sequence of amino acids in the Aβ1-42 peptide structure toward the Zn units in the ZIF-8, resulting in the self-destruction of the microswimmers and subsequent release of quinine in a concentration-dependent manner. The use of the bioreceptor-free magnetic assisted microswimmers allows for direct assessment of Aβ1-42 peptide in only 10 μL of CSF samples in just 10 min. Excellent analytical performance with a limit of detection of 40 pg/mL and a linear range ranging from 140 to 1200 pg/mL (r = 0.9990), covering the range in the clinical practice, is obtained. An excellent selectivity was also obtained toward the Aβ1-42 peptide which approaches an excellent assessment of amyloidosis in the human brain, as demonstrated by the good correlation obtained (r = 0.97) between the quantitative levels obtained in our microswimmers approach in comparison with the enzyme-linked immunosorbent assay method in diagnosed CSF samples from patients where Tau protein was also determined due to its coexistence with Aβ1-42 peptides. Since CSF biomarkers are currently the only clinically validated biofluid diagnostic test for AD, our approach will drastically reduce the volume required to determine Aβ levels, reducing the impact of the side effects of lumbar puncture in clinical practice. It became a novel bioreceptor-free approach to more easily, less invasively measure Aβ1-42 peptide in CSF, becoming a valuable tool for indirect amyloidosis prediction in brain tissues in the patient's lifetime, opening the possibility for early treatment of the AD.}, } @article {pmid40814010, year = {2025}, author = {Li, Z and Yang, J and Li, J and Zhao, S and Jiang, S and Liu, W and Li, X and Zhang, S and Du, H and Ni, J and Huang, Y and Qing, H and Ruan, S}, title = {Targeted delivery of BACE1 siRNA for synergistic treatment of Alzheimer's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {41}, pmid = {40814010}, issn = {2047-9158}, support = {82302387//Innovative Research Group Project of the National Natural Science Foundation of China/ ; L222128//Beijing Natural Science Foundation grant/ ; XSQD-202121010//Beijing Institute of Technology Research Fund Program for Young Scholars grant/ ; JCYJ20241202130511015//Fundamental Research Project funding from Shenzhen Science and Technology Innovation Committee/ ; JCYJ20230807142704008//Fundamental Research Project funding from Shenzhen Science and Technology Innovation Committee/ ; 2024KCXTD016//Alzheimer's Disease Pathogenesis and Drug Development Innovation Team, Innovation Team Project of Guangdong General Colleges and Universities (Natural Science)/ ; }, mesh = {*Amyloid Precursor Protein Secretases/genetics/metabolism ; *Alzheimer Disease/therapy/genetics/metabolism ; Animals ; *Aspartic Acid Endopeptidases/genetics/metabolism ; *RNA, Small Interfering/administration & dosage ; Mice ; Humans ; Blood-Brain Barrier/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Mice, Inbred C57BL ; Microglia/metabolism ; Genetic Therapy/methods ; Brain/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD. METHODS: We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1). RESULTS: PPR@siBACE1 crossed the blood-brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice. CONCLUSIONS: This study provides a reliable delivery platform for gene therapies for AD.}, } @article {pmid40812721, year = {2025}, author = {Barroso de Sousa, D and Zucato, MCR and Ribeiro, HM and Alexandre-Silva, V and Cominetti, MR}, title = {Interplay between depressive symptoms and Alzheimer's disease dementia: unraveling the potential roles of ADAM10 and Negr1.}, journal = {Neuroscience}, volume = {584}, number = {}, pages = {60-64}, doi = {10.1016/j.neuroscience.2025.08.012}, pmid = {40812721}, issn = {1873-7544}, mesh = {Humans ; *ADAM10 Protein/metabolism ; *Alzheimer Disease/metabolism ; *Amyloid Precursor Protein Secretases/metabolism ; *Depression/metabolism ; Animals ; Brain/metabolism ; Membrane Proteins ; }, abstract = {Late-onset depression (LOD) is closely linked to Alzheimer's disease (AD), marked by shared biological pathways and common risk factors. The neurobiological alterations associated with depression, particularly the dysregulation of amyloid-β (Aβ), play a critical role in the acceleration of disease progression. In individuals suffering from LOD, Aβ peptides - specifically Aβ40 and Aβ42 - exhibit distinct profiles in plasma, cerebrospinal fluid (CSF), and brain tissue, highlighting the substantial influence of AD pathology. Central to this relationship is A Disintegrin and Metalloprotease 10 (ADAM10), an essential α-secretase that exerts a protective effect by decreasing Aβ formation through the non-amyloidogenic processing of the amyloid precursor protein (APP). Furthermore, ADAM10 regulates the shedding of Neuronal Growth Regulator 1 (Negr1), a protein intricately linked to both LOD and AD, thereby enhancing synaptic plasticity and neuronal development - two critical processes in addressing these challenging disorders. Given the rapidly rising prevalence of both depression and dementia in aging populations, understanding these molecular interactions is more urgent than ever. Despite growing evidence, the interplay among LOD, AD, ADAM10, and Negr1 remains insufficiently explored, particularly in diverse populations. This review synthesizes recent advancements that illuminate the complex interactions among LOD, AD, and the regulatory function of ADAM10, particularly concerning one of its substrates, Negr1. By elucidating these fundamental interactions, the study paves the way for innovative treatment approaches aimed at both LOD and AD, advocating for a synergistic strategy to address these multifaceted conditions effectively, meeting a critical and time-sensitive challenge in global brain health.}, } @article {pmid40812585, year = {2025}, author = {Zhou, W and Yin, X and Huang, J and Fu, L and Yadav, H and Yao, W and Chu, D and Wu, F}, title = {Verapamil modulates astrocytic glycolytic dysfunction via TXNIP inhibition in the hippocampus of 3 × Tg-AD mice.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 2}, pages = {117233}, doi = {10.1016/j.bcp.2025.117233}, pmid = {40812585}, issn = {1873-2968}, mesh = {Female ; Animals ; Mice ; *Verapamil/pharmacology/therapeutic use ; *Calcium Channel Blockers/pharmacology/therapeutic use ; *Astrocytes/drug effects ; *Glycolysis/drug effects ; *Hippocampus/drug effects/metabolism ; Thioredoxins/antagonists & inhibitors ; *Cognitive Dysfunction/drug therapy ; Brain/drug effects/metabolism ; Carrier Proteins ; Glucose Transporter Type 1 ; }, abstract = {Alzheimer's disease (AD) is a gradually worsening neurodegenerative condition marked by the accumulation of amyloid-β plaques and a decline in cognitive abilities. Emerging research emphasizes astrocytic metabolic disturbances as contributors to AD development. This study investigates the therapeutic effects of Verapamil (VPM), a clinically approved calcium channel blocker, on astrocytic glycolysis in 3 × Tg-AD mice, focusing on the involvement of the thioredoxin-interacting protein (TXNIP)/glucose transporter 1 (GLUT1) pathway. VPM treatment significantly enhanced glycolytic activity in astrocytes, as evidenced by increased lactate production and improved metabolic function. Western blot and PCR analyses revealed a reduction in TXNIP levels and an upregulation of GLUT1 expression, particularly in the plasma membrane fraction, suggesting enhanced glucose uptake and glycolysis. Additionally, VPM treatment decreased soluble β-amyloid (Aβ) levels and alleviated cognitive impairments in the 3 × Tg-AD mice. These findings indicate that VPM restores glycolytic function in astrocytes through the TXNIP/GLUT1 pathway, offering a promising intervention targeting metabolic disruption and cognitive decline in AD. This study underscores the critical role of glycolysis in glial cells and highlights VPM's therapeutic potential in AD by targeting metabolic dysfunction.}, } @article {pmid40812500, year = {2025}, author = {Su, WS and Wu, MT and Cheng, IH and Yang, FY}, title = {Low-intensity pulsed ultrasound enhances microglial-mediated Aβ clearance and synaptic preservation in an APP transgenic mouse model of Alzheimer's disease.}, journal = {Experimental neurology}, volume = {394}, number = {}, pages = {115420}, doi = {10.1016/j.expneurol.2025.115420}, pmid = {40812500}, issn = {1090-2430}, mesh = {Animals ; *Alzheimer Disease/therapy/metabolism/genetics/pathology ; Mice, Transgenic ; *Microglia/metabolism/radiation effects ; Mice ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Ultrasonic Waves ; Disease Models, Animal ; *Synapses/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Humans ; Hippocampus/metabolism/pathology ; Male ; Maze Learning/physiology ; Plaque, Amyloid/pathology ; }, abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation and neurofibrillary tangles, leading to neuroinflammation, synaptic dysfunction, and cognitive decline. Despite extensive research, current therapies for AD show limited efficacy. Low-intensity pulsed ultrasound (LIPUS) has emerged as a promising non-invasive therapeutic approach due to its neuroprotective and immunomodulatory properties. This study investigates the effects of LIPUS on Aβ pathology, neuroinflammation, and cognitive deficits in a transgenic AD mouse model. Twelve-month-old J20 transgenic mice expressing human amyloid precursor protein (APP) were used to model middle-to-late-stage AD. LIPUS was administered for 30 days, targeting the bilateral hippocampus. Spatial memory was assessed via the Morris water maze (MWM). Aβ plaque burden and synaptic integrity were quantified using immunofluorescence and Thioflavin-S staining. Western blot analysis evaluated neurotrophic factors, inflammatory markers, and synaptic proteins (PSD95). LIPUS treatment significantly improved spatial learning and memory deficits in APP transgenic mice, as evidenced by reduced escape latency and increased platform crossings in the MWM test. LIPUS significantly reduced hippocampal amyloid plaque burden and promoted microglial recruitment to Aβ plaques. Importantly, LIPUS downregulated TNF-α expression without affecting IL-6 levels, suggesting enhanced Aβ clearance without inducing neuroinflammation. Furthermore, LIPUS increased synaptophysin expression in the CA3-mossy fiber and dentate gyrus (DG) regions, while PSD95 levels remained unchanged. Our findings demonstrate that LIPUS enhances microglial-mediated Aβ clearance, preserves synaptic integrity, and improves cognitive function in a transgenic AD model. As a non-invasive modality capable of targeting deep brain structures, LIPUS holds promise as a potential therapeutic strategy for AD.}, } @article {pmid40812427, year = {2025}, author = {Wu, J and Chai, K and Tu, Y and Fang, K and Shi, S and Hu, X and Liu, J and Yao, T}, title = {Multifunctional molecular agent for tau-targeted combinational therapy of Alzheimer's disease.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {9}, pages = {110583}, pmid = {40812427}, issn = {1083-351X}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; *tau Proteins/metabolism/chemistry/antagonists & inhibitors ; Humans ; Copper/metabolism/chemistry ; *Chelating Agents/pharmacology/chemistry/chemical synthesis ; Reactive Oxygen Species/metabolism ; }, abstract = {Tau aggregation inhibitors or neurotoxic-metal chelators have been extensively studied as potential treatment for Alzheimer's disease. However, it is a great challenge to improve their therapeutic effects while reducing neurotoxicity. Herein, we designed and synthesized two new compounds, (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis((3,4,5-trihydroxyphenyl)methanone) (4GA) and (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis((3,4,5-trihydroxyphenyl)methanone) (2GA). Each molecule is composed of a 1,4,7,10-tetraazacyclododecane (cyclen) core as the supramolecular chelator to copper ions, attached by 2 or 4GAllic acid polyphenol arms to capture tau peptide chain like a molecular hairpin. We interestingly found that 4GA and 2GA could inhibit self-aggregation through blocking the misfolding of tau peptide, suppress the promotion of Cu[2+] on tau aggregation by removing Cu[2+] from dyshomeostasis, and clear reactive oxygen species triggered by Cu[2+] using their reductive gallic acid groups. More significantly, the synthesized compounds exhibit remarkable efficiency on both in vitro and at cellular level. Our rational design of multifunctional therapeutic agent that simultaneously targets tau misfolding process, copper dyshomeostasis, and oxidative stress of reactive oxygen species, may hold considerable implications for the treatment of Alzheimer's disease.}, } @article {pmid40811673, year = {2025}, author = {Goodland, MN and Banerjee, S and Niehoff, ML and Young, BJ and Macarthur, H and Butler, AA and Morley, JE and Farr, SA}, title = {Cannabidiol improves learning and memory deficits and alleviates anxiety in 12-month-old SAMP8 mice.}, journal = {PloS one}, volume = {20}, number = {8}, pages = {e0296586}, pmid = {40811673}, issn = {1932-6203}, mesh = {Animals ; *Cannabidiol/pharmacology/therapeutic use/administration & dosage ; Mice ; *Anxiety/drug therapy ; *Memory Disorders/drug therapy ; Male ; Disease Models, Animal ; Maze Learning/drug effects ; Alzheimer Disease/drug therapy ; Memory/drug effects ; *Learning/drug effects ; }, abstract = {Cannabidiol (CBD) has gained a lot of interest in recent years for its purported medicinal properties. CBD has been investigated for the treatment of anxiety, depression, epilepsy, neuroinflammation, and pain. Recently there has been an interest in CBD as a possible treatment for age-related disorders such as Alzheimer's disease and related disorders (ADRD). Here we tested the hypothesis that chronic CBD administration would improve learning and memory in the SAMP8 mouse model of Alzheimer's disease. SAMP8 mice aged 11 months (at the start of the study) were administered vehicle or CBD (3 or 30 mg/Kg) daily via oral gavage for 2 months. Vehicle-treated young SAMP8 mice (age 3 months at the start of the study) served as unimpaired controls. After 30 days of treatment (4 and 12 months of age), learning and memory, activity, anxiety, strength and dexterity were assessed. High dose CBD treatment significantly improved learning and memory of the 12-month-old mice in the T maze. Novel object recognition memory was also improved by CBD in aged CBD treated mice. Aged CBD treated mice also displayed less anxiety in the elevated plus maze test compared to controls. However, activity and strength levels were similar between groups. Biochemical analysis revealed decreased markers of oxidative stress, providing a possible mechanism by which CBD treatment impacts learning, memory, and anxiety. These results highlight the potential use of CBD as a therapeutic for age related cognitive impairment and dementia.}, } @article {pmid40811499, year = {2025}, author = {Fernandez-Mendoza, J}, title = {Insomnia Phenotypes, Cardiovascular Risk and Their Link to Brain Health.}, journal = {Circulation research}, volume = {137}, number = {5}, pages = {727-745}, pmid = {40811499}, issn = {1524-4571}, support = {R01 HL136587/HL/NHLBI NIH HHS/United States ; R01 MH118308/MH/NIMH NIH HHS/United States ; R01 MH136472/MH/NIMH NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Sleep Initiation and Maintenance Disorders/epidemiology/physiopathology/therapy/diagnosis ; *Cardiovascular Diseases/epidemiology/physiopathology ; Phenotype ; *Brain/physiopathology ; Heart Disease Risk Factors ; Risk Factors ; Sleep ; }, abstract = {About 30% to 40% of the general population experiences insomnia symptoms of difficulty initiating or maintaining sleep, and another 10% to 15% of the general population experiences chronic insomnia disorder. The prevalence of insomnia is disproportionately higher in people with cardiometabolic risk factors, cardiovascular diseases, cerebrovascular diseases, and neurocognitive disorders, including vascular cognitive impairment. In fact, recent meta-analytic evidence from epidemiological studies has demonstrated that insomnia, especially when accompanied by objective short sleep duration, is a risk factor for incident hypertension, type 2 diabetes, heart failure, stroke, cognitive impairment, Alzheimer disease, and all-cause mortality. Insomnia should, thus, be part of the prevention and management of these adverse health outcomes. However, randomized clinical trials have not demonstrated whether treatment with cognitive-behavioral therapy for insomnia, the first-line guideline-recommended treatment, or hypnotics/sedatives improves heart- or brain-related outcomes. Studies have also failed to consider insomnia a heterogeneous disorder consisting of distinct phenotypes that result from the relative contribution of biological versus cognitive-behavioral perpetuating factors. Objective short sleep duration has emerged as a marker of physiological hyperarousal in insomnia (ie, dysregulation of the hypothalamic-pituitary axis, increased sympathetic nervous system activation, and increased inflammation), as a predictor of insomnia-related adverse heart and brain health outcomes and, potentially, poor response to cognitive-behavioral therapy for insomnia. This review summarizes the meta-analytic evidence on the association of insomnia with cardiometabolic risk factors, cardiovascular diseases, cerebrovascular diseases, and neurocognitive disorders, including current knowledge on the heterogeneity of the disorder. This review also summarizes the potential pathophysiologic mechanisms that lead to heart and brain morbidity, which vary across insomnia phenotypes based on objective sleep duration. This review suggests that basic and clinical sciences need to unveil the molecular, cellular, and behavioral mechanisms at play across insomnia phenotypes, as the public health and clinical implications of their association with adverse heart and brain health are demanding immediate attention.}, } @article {pmid40810748, year = {2025}, author = {Nabizadeh, A and Rafati, A and Karbalaei, N and Namavar, MR and Hosseinzadeh, S and Moatamed Jahromi, H and Rahimi, A and Naseh, M}, title = {Probiotic effects on cognitive performance, hippocampal oxidative stress, and structural damage induced by icv STZ in Alzheimer-like rat model.}, journal = {Brain structure & function}, volume = {230}, number = {7}, pages = {135}, pmid = {40810748}, issn = {1863-2661}, mesh = {Animals ; *Probiotics/pharmacology ; *Oxidative Stress/drug effects/physiology ; *Hippocampus/drug effects/pathology/metabolism ; Male ; Rats, Sprague-Dawley ; *Alzheimer Disease/chemically induced/pathology/metabolism/drug therapy ; Streptozocin/administration & dosage ; Rats ; Disease Models, Animal ; *Cognition/drug effects ; Lactobacillus acidophilus ; Maze Learning/drug effects ; Limosilactobacillus reuteri ; }, abstract = {Alzheimer's disease (AD) is a deteriorating neurodegenerative disorder defined by cognitive decline and neuronal damage, with oxidative stress and neuroinflammation as central pathological features. Emerging evidence suggests the gut-brain axis is a key modulator in neurodegeneration, highlighting probiotics' potential in mitigating AD progression. This study investigates the effects of Lactobacillus acidophilus ATCC4356, Lactobacillus reuteri DSM 17938, and their combination on cognitive performance, oxidative stress, and hippocampal structure in a streptozotocin (STZ)-induced AD-like rat model. Thirty-Five male Sprague-Dawley rats were randomly assigned to five groups: Sham, AD-like model (STZ), STZ + Ac, STZ + Re, and STZ + Comb. The AD-like model was induced via intracerebroventricular (icv) injection of STZ. Probiotics were administered by gavage for 35 days. Behavioral assessments, including the open field test and Morris water maze, were conducted to evaluate cognitive and anxiety-like behaviors. Hippocampal oxidative stress markers, including malondialdehyde (MDA), glutathione, superoxide dismutase, and catalase , were analyzed biochemically. Additionally, stereological techniques were used to assess hippocampal volume and cellular densities. Behavioral results demonstrated significant improvement in anxiety-like behavior and spatial memory in probiotic-treated groups compared to the STZ group. Biochemical analysis revealed reduced MDA levels and enhanced antioxidant markers following probiotic intervention. Histological and stereological analyses indicated increased neuronal density and reduced glial cell activation in hippocampal subregions (CA1, CA3, DG), though hippocampal volume loss remained unaltered. These findings underscore the neuroprotective potential of probiotics in alleviating AD-related neurodegeneration, possibly through antioxidative and anti-inflammatory mechanisms. Further pre-clinical studies are warranted to optimize probiotic regimens for AD prevention and treatment.}, } @article {pmid40810239, year = {2025}, author = {Jinglei, J and Tao, YU and Yulin, Q and Meng, W}, title = {Understanding the role of microglia in Alzheimer's disease: insights into mechanisms, acupuncture, and potential therapeutic targets.}, journal = {Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan}, volume = {45}, number = {4}, pages = {922-936}, pmid = {40810239}, issn = {2589-451X}, mesh = {Humans ; *Alzheimer Disease/therapy/immunology/genetics/metabolism ; *Microglia/immunology/metabolism ; *Acupuncture Therapy ; Animals ; Amyloid beta-Peptides/metabolism/genetics/immunology ; }, abstract = {Microglia (MG) are immune effector cells in the central nervous system (CNS) and play a pivotal role in the pathogenesis of various CNS diseases. Alzheimer's disease (AD) is defined as a severe chronic degenerative neurological disease in humans. The amyloid cascade hypothesis is a hypothesis on the pathogenesis of AD that suggests that abnormal extracellular aggregation of β-amyloid (Aβ) peptides is the main cause of the disease. Although this hypothesis has been found to be convincing, a growing body of evidence suggests that it does not fully explain the pathogenesis of AD. Neuroinflammation is a crucial element in the pathogenesis of AD, as evidenced by elevated levels of inflammatory markers and the identification of AD risk genes associated with innate immune function. This paper will first summarize the impact of microglia-mediated neuroinflammation on AD, exploring the phenotypic changes that follow microglia activation. Secondly, the interactions between microglia, Aβ, microtubule-associated protein, apolipoprotein E and neurons are thoroughly investigated, with particular focus on the interactive mechanisms. Furthermore, the recent progress and prospects of microglia as a diagnostic and therapeutic target for AD are analysed. A review of the literature on the mechanisms regulating MG for AD at home and abroad revealed that acupuncture modulation of microglia could help to delay the progression of AD. This was followed by an extensive discussion of the clinical possibilities and scientific validity of acupuncture treatment for AD, with the aim of providing new insights for acupuncture modulation of MG targeting for the treatment of AD.}, } @article {pmid40810165, year = {2025}, author = {Jeon, MT and Sung, B and Lee, JW and Hwang, DW and Lee, E and Kim, HK and Kim, DK and Kim, DG and Chang, Y}, title = {Therapeutic Potential of a Gadolinium Chelate Complex Conjugated with Vanillic Acid for Alzheimer's Disease.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {8}, pages = {2725-2735}, pmid = {40810165}, issn = {2575-9108}, abstract = {Magnetic resonance imaging (MRI) is a widely used diagnostic tool for neurodegenerative diseases, including Alzheimer's disease. A gadolinium chelate conjugated with vanillic acid (Gd-DO3A-Va) serves as a contrast agent that specifically targets activated microglia in the brains of Alzheimer's disease animal models, such as the 5XFAD mouse. In this study, we evaluated the therapeutic potential of Gd-DO3A-Va in this model. The 5XFAD mouse exhibits neuroinflammation, characterized by activation of the c-Jun N-terminal kinase signaling pathway, inflammasome activation, and increased amyloid-β (Aβ) production(?)all of which are pathological features of Alzheimer's disease. Treatment with Gd-DO3A-Va reduced inflammatory responses and Aβ deposits. Additionally, the peri-plaque dendritic loss observed in the brains of 5XFAD mice was attenuated following Gd-DO3A-Va treatment. Moreover, Gd-DO3A-Va treatment prevented memory loss, as indicated by the Y-maze test. Taken together, these findings suggest that Gd-DO3A-Va, an MR contrast agent that provides disease-specific signal enhancement in the brains of animal models of Alzheimer's disease, shows promising therapeutic potential for preventing disease progression by suppressing inflammation and inhibiting Aβ production. Therefore, Gd-DO3A-Va could serve as a theranostic agent for Alzheimer's disease.}, } @article {pmid40810164, year = {2025}, author = {Alo, B and Lamers, C}, title = {Crossing Barriers: Advancements in Macromolecular Therapeutics for Neurodegenerative Diseases and Strategies to Overcome the Blood-Brain Barrier.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {8}, pages = {2353-2383}, pmid = {40810164}, issn = {2575-9108}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, present considerable challenges for our societies and health systems due to their progressive nature, the demographic shift toward older populations, and limited treatment options. Recent advances in macromolecular therapeutics, including antibodies, peptides, and proteins, offer novel therapeutic modalities for a broad range of diseases. Their high potency and specificity hold promise for disease-modifying therapies to combat neurodegenerative diseases. However, the blood-brain barrier poses a significant challenge for the effective delivery of these large molecules to the central nervous system. This review discusses the physiological role of the blood-brain barrier and its influence on restricting the exposure of macromolecules in the brain. Furthermore, emerging strategies for enhancing blood-brain barrier permeability to macromolecules are highlighted. This review summarizes modifications designed to utilize receptor-mediated uptake, adsorptive-mediated transcytosis, carrier-mediated transport, and nanoparticle-based delivery systems to overcome the blood-brain barrier. Additionally, we emphasize the importance of testing macromolecular therapeutics for their blood-brain barrier permeability and review the methods for such in vitro and in vivo testing. Finally, we shed light on therapeutics in preclinical and clinical development for neurodegenerative diseases and their challenges.}, } @article {pmid40810098, year = {2025}, author = {Cao, H and Zhong, J and Chen, L}, title = {Alterations of the oral microbiota in mild Alzheimer's disease and the appropriate application of chlorhexidine gluconate.}, journal = {JAR life}, volume = {14}, number = {}, pages = {100024}, pmid = {40810098}, issn = {2534-773X}, abstract = {OBJECTIVE: This study investigated the effect of 0.2 % chlorhexidine gluconate on oral microbiota dysbiosis in Alzheimer's disease (AD) and explored potential links between oral microbiota and cognition, offering new insights into its role in AD treatment. STUDY DESIGN: We assessed the impact of 0.2 % chlorhexidine gluconate on the oral microbiota of patients with AD. One hundred patients were divided into two groups based on oral health score (using a cut-off of 8). Subgingival plaque samples were analyzed using 16S rRNA sequencing; no significant differences in bacterial composition were observed between groups at baseline. RESULTS: Poor oral health correlated with higher oral health scores (P = 0.000), fewer teeth (P = 0.002), lower cognitive levels (P = 0.048), and a higher proportion of patients with diabetes (P = 0.032). After 24 weeks of treatment with 0.2 % chlorhexidine gluconate in a randomized controlled trial, subgingival plaques from 66 patients showed changes in Porphyromonas, Filifactor, Desulfobulbus, Anaeroglobus, Pyramidobacter, Mycoplasma, Dialister, Fretibacterium, and Tannerella (P < 0.05). Treponema and Porphyromonas gingivalis were identified as potential interventional targets. CONCLUSION: Chlorhexidine gluconate effectively alters oral flora, reducing harmful bacteria. Targeting specific microbiota disturbances may offer a promising strategy to delay AD onset or slow its progression. TRIAL REGISTRATION: This research was registered with the Chinese Clinical Trial Registry (ChiCTR; Reference: ChiCTR2000032876). Registered: 14th of May 2020; http://www.chictr.org.cn/showprojen.aspx?proj=53555.}, } @article {pmid40809903, year = {2025}, author = {Koch, G and Assogna, M and Gadola, Y and Alberici, A and Di Lorenzo, F and Bonnì, S and Borghi, I and Cerulli Irelli, E and Mencarelli, L and Maiella, M and Esposito, R and Casula, EP and Pezzopane, V and D'Acunto, A and Candeo, F and Ferraresi, M and Guerrera, G and Battistini, L and Premi, E and Bracca, V and Lucchini, S and Bertagna, F and Romano, P and Ludovici, A and Daniele, A and Motta, C and Ferrari, C and Martorana, A and Borroni, B}, title = {Safety and efficacy of rotigotine in patients with frontotemporal dementia: a phase 2, double-blind, randomized, placebo-controlled, multicenter trial.}, journal = {The Lancet regional health. Europe}, volume = {57}, number = {}, pages = {101409}, pmid = {40809903}, issn = {2666-7762}, abstract = {BACKGROUND: Frontotemporal dementia (FTD) is a common form of dementia with no approved pharmacological treatment. Clinical and experimental evidence suggest that dopaminergic transmission is impaired in FTD. Here we aimed at investigating the clinical impact of treatment with dopaminergic agonists in FTD. METHODS: This was a phase IIa 24-week randomized, double-blind, multicenter, placebo-controlled study, conducted in Italy from June 16th 2021 to April 30th 2023. Patients with a diagnosis of probable behavioral variant FTD (bvFTD) were randomly assigned in a 1:1:1 ratio to receive rotigotine transdermal patches at 4 mg/24 h, rotigotine transdermal patches at 6 mg/24 h, or placebo transdermal patches for 24 weeks. Randomization was centralized and performed using a double-blind covariate-adaptive scheme. The primary outcome was analyzed in the intention-to treat (ITT) population. The primary efficacy outcome measure was the change at 24-weeks from baseline in the Frontal Assessment Battery (FAB). The trial is completed and was registered on the clinicaltrial.gov website (NCT04937452). FINDINGS: A total of 128 patients were screened, of which 75 were randomized. 25 patients were randomized to receive Rotigotine 4 mg, 26 patients to Rotigotine 6 mg, and 24 patients to placebo. The mean age of patients was 66.5 ± 8 of which 31 (41%) were female. A total of 69 patients (92%) completed the study. The estimated mean change from baseline at 24 weeks in the FAB score in the ITT population was 0.18 (95% confidence interval [CI] -0.79 to 1.15) in the rotigotine 4 mg group, 0.89 (95% CI -0.09 to 1.88) in the rotigotine 6 mg group and 1.08 (95% CI 0.19-1.98) in the placebo group (rotigotine 4 mg vs placebo, -0.90; 95% CI -2.22 to 0.42; p = 0.18; rotigotine 6 mg vs placebo, -0.19; 95% CI -1.52 to 1.14; p = 0.77). No significant effect was found on secondary outcome measures. Adverse events were mild in all groups and more common in the rotigotine (4 mg: 4/25; 6 mg: 3/26) than in the placebo (1/24) group. INTERPRETATION: Rotigotine administration may not be a viable therapeutic option for enhancing frontal function, slowing disease progression, mitigating functional decline or ameliorating behavioral disturbances in bvFTD patients. The current findings provide data in a large sample of bvFTD that might be useful for the design of future clinical trials. FUNDING: This trial was funded by a joint grant from the Alzheimer Drug Discovery Foundation (ADDF) and the Association for Frontotemporal Degeneration (AFTD) grant to GK and BB (GFTD-201902-2017958).}, } @article {pmid40808707, year = {2025}, author = {Aydın, B and Aydın, AS and Çeçen, Ö and Yuca, H and Bona, GE and Demirci, B and Bona, M and Karakaya, S}, title = {From Herbal Tea to Science: Phytochemical and Biological Investigation of Ajuga chamaepitys subsp. chia (Lamiaceae) With Molecular Docking Analysis.}, journal = {Food science & nutrition}, volume = {13}, number = {8}, pages = {e70749}, pmid = {40808707}, issn = {2048-7177}, abstract = {The hypothesis that insulin resistance and impaired insulin-like growth factor signaling contribute to Alzheimer's disease (AD) has led to the designation of AD as "type 3 diabetes." Ajuga chamaepitys subsp. chia is traditionally used in Türkiye as an analgesic, tonic, and for the external treatment of hemorrhoids and wound healing. This study evaluates antioxidant, antidiabetic, and anticholinesterase activities of methanolic, aqueous extracts, and essential oils from the flowering aerial parts of A. chamaepitys subsp. chia, along with their phytochemical profiles (GC-MS/MS), morphological-anatomical characteristics, and molecular docking analysis. The essential oil yield was 0.002%, comprising 45 compounds (92.5%), with β-pinene (19.8%), α-pinene (12.8%), and germacrene D (10.0%) as major constituents, dominated by monoterpene (39.8%) and sesquiterpene hydrocarbons (23.5%). The methanolic extract exhibited moderate bioactivity, achieving 28.36% α-amylase inhibition at 5000 μg/mL and 21.85% acetylcholinesterase inhibition at 100 μg/mL, while also demonstrating notable antioxidant activity with 23.013% ABTS[•+] and 8.114% DPPH[•] scavenging. It showed the highest total phenolic (14.261 μg GAE/mg) and tannin content (34.444 μg TAE/mg) among the tested extracts. Morphologically, the plant features hairy stems and tripartite leaves with a cuticle, trichomes, and diacytic stomata, while anatomically, it presents collenchyma, starch-filled parenchyma, and a distinct cambium in the stem. Molecular docking studies revealed that germacrene D exhibited strong binding affinities to acetylcholinesterase, butyrylcholinesterase, α-amylase, and α-glucosidase, suggesting multitarget inhibition potential. These findings support the traditional use of A. chamaepitys subsp. chia and highlight its promise as a natural source for therapeutic agents targeting oxidative stress, diabetes, and neurodegenerative diseases.}, } @article {pmid40808471, year = {2025}, author = {Zhang, L and Cai, L and Lin, H and Wu, W and Zhu, Y and Cai, J and Hu, C and Lin, X and Sun, H and Wei, X}, title = {Two Birds With One Stone: The Protective Role of the Antidiabetic Drug Sodium-Glucose Cotransporter-2 Inhibitor in Neurodegenerative Diseases.}, journal = {The European journal of neuroscience}, volume = {62}, number = {3}, pages = {e70221}, doi = {10.1111/ejn.70221}, pmid = {40808471}, issn = {1460-9568}, support = {2021J01397//Natural Science Foundation of Fujian, China/ ; 2022GGA010//Fujian Provincial Health Technology Project/ ; 2023Y9347//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; 2023Y9298//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; 2023Y9343//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; }, mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; *Neurodegenerative Diseases/genetics/drug therapy ; Polymorphism, Single Nucleotide ; Sodium-Glucose Transporter 2/genetics ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Hypoglycemic Agents/therapeutic use/pharmacology ; Mendelian Randomization Analysis ; Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Parkinson Disease/genetics ; Genome-Wide Association Study ; Protein Interaction Maps ; }, abstract = {The neuroprotective role of sodium-glucose cotransporter-2 inhibitor (SGLT2i) has attracted considerable interest. The purpose of this study was to investigate the role of SGLT2i in several common neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Utilizing drug-target Mendelian randomization (MR) and colocalization, we used single nucleotide polymorphisms (SNPs) proximal to the SLC5A2 gene to analyze the influence of SGLT2i on AD, PD, ALS, and MS. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. Phenome-wide association study (PheWAS) was used to probe the relationship of SGLT2i with other characteristics. Protein-protein interaction (PPI) networks were used to explore how SLC5A2 affects other proteins, and enrichment analysis was used to explore possible biological processes. The MR analysis showed that SGLT2i was negatively associated with AD (OR = 0.77, p = 0.01), PD (OR = 0.52, p = 0.04), ALS (OR = 0.60, p = 0.01), and MS (OR = 0.33, p = 0.027), indicating that SGLT2i could reduce the risk of AD by 23%, PD by 48%, ALS by 40%, and MS by 67%. The colocalization supported this conclusion. The PheWAS showed that SGLT2i was associated with body mass index and systolic blood pressure. SGLT2i is biologically closely related to the development of NDs. This study suggested that SGLT2i was able to reduce the risk of NDs. SGLT2i may perform this process through many mechanisms. This study provides a new perspective on the treatment of NDs; clinical trials and relevant experiments are necessary to further validate the neuroprotective effects of SGLT2i.}, } @article {pmid40808466, year = {2025}, author = {Martinez, B and Peplow, PV}, title = {Amelioration of behavioral and neural deficits in animal models of neurodegenerative disease by nanoformulations of curcumin and quercetin.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00343}, pmid = {40808466}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are increasing in prevalence due largely to aging populations worldwide and improved medical care for the elderly. Currently approved drugs can reduce some of the symptoms of neurodegenerative diseases but cannot cure them. Inflammation is involved in the development and progression of neurodegenerative diseases, and oxidative stress is implicated in neurodegeneration associated with cognitive decline and age-related cognitive impairment. Polyphenols such as curcumin, quercetin, and resveratrol possess potent anti-inflammatory and antioxidant properties. Nanoformulations of curcumin and quercetin can optimize their pharmacological effects in the treatment of neurodegenerative diseases. Nanocarriers play a crucial role in delivering drugs across the blood-brain barrier, thereby lowering the risk of peripheral side effects. Various nanoforms have been developed to induce bioavailability and solubility of curcumin and quercetin, including nanoparticles and nanoemulsions. The studies reviewed included 17 using curcumin nanoformulations and seven with quercetin nanoformulations and were tested in widely used animal models of Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Many of the curcumin and quercetin nanoformulations brought about improvements in learning and memory in behavioral tests of Alzheimer's disease models and were effective in reducing oxidative stress in the brain. Both nanocurcumin and nanoquercetin decreased the levels of inflammatory markers in the brain. Nanocurcumin formulations improved motor behavior, gait, and memory in Parkinson's disease models and increased dopaminergic neurons in the striatum and substantia nigra. Furthermore, nanocurcumin improved locomotor activity, memory, and learning, and the number of dendrites of medium spiny neurons in Huntington's disease models. Nanocurcumin formulations decreased oxidative stress and inflammation in a model of demyelination. Several important limitations were identified in the studies reviewed and these need to be considered in future studies. Also, clinical trials could be performed using the currently available nanoforms of curcumin and quercetin.}, } @article {pmid40808416, year = {2025}, author = {Figueiredo-Pereira, ME and Serrano, PA and Rockwell, P}, title = {Six promising drug repurposing candidates for Alzheimer's disease and their sex-specific mechanisms and efficacy.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00256}, pmid = {40808416}, issn = {1673-5374}, abstract = {Alzheimer's disease is a neurodegenerative disorder that leads to progressive memory loss, cognitive decline, and behavioral changes. Despite ongoing research, its exact causes and effective treatments remain elusive. Traditional approaches have focused on symptom management, but breakthroughs in bioinformatics and high-throughput drug screening are offering new pathways to potential therapies. This review highlights our recent efforts to identify novel drug candidates for Alzheimer's disease by leveraging computational methods and large-scale biological datasets. Our work introduces two key innovations in Alzheimer's disease research: addressing sex-specific differences and leveraging drug repurposing for accelerated treatment discovery. By combining sex-stratified preclinical data with machine learning and in vivo validation, we improve translational relevance and support precision medicine. Using the TgF344-AD rat model, which mimics human Alzheimer's disease spatial memory deficits and pathology, we explored the efficacy of various US Food and Drug Administration- approved and investigational drugs. These included ibudilast, timapiprant, RG2833, diazoxide/ dibenzoylmethane (combined), and BT-11, which targeted key Alzheimer's disease-related molecular pathways such as amyloid-beta plaques, Tau tangles, and neuroinflammation. These drugs, at various stages of development, offer hope for not only managing symptoms but also addressing the underlying mechanisms of Alzheimer's disease. This review underscores the need for a multifaceted approach to Alzheimer's disease treatment, combining symptom relief with disease modification.}, } @article {pmid40808358, year = {2025}, author = {Shelton, M and Kerns, KA and Shirali, S and Castora, FJ and Coleman, RA}, title = {Integrating mitochondrial gene expression data to model the effects of respirasome supercomplex formation on reactive oxygen species production in Alzheimer's disease models.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {734-742}, doi = {10.1177/13872877251362889}, pmid = {40808358}, issn = {1875-8908}, mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; Humans ; *Mitochondria/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; Oxidative Stress/physiology ; Brain/metabolism ; *Genes, Mitochondrial ; Gene Expression ; }, abstract = {BackgroundIn the past decade, Alzheimer's disease (AD) researchers have found that the formation of amyloid aggregates occurs after dysregulation of respiratory chain activity.ObjectiveUsing our developing mathematical model to identify potential therapeutic targets for AD treatment.MethodsWe have constructed a mathematical model for AD that incorporates enzyme activities and kinetics, and protein and mRNA expression levels.ResultsOur analyses of gene expression in AD brains provide complimentary evidence that changes in mitochondrial energy production and biogenesis accompany AD pathogenesis. Using this data, we created a mitochondrial model of electron transport chain supercomplex assembly.ConclusionsBy carrying out sensitivity analyses of responses to oxidative stress and effects of gene expression on energy production, we demonstrate how oxidative stress and energy deficits change the initial antioxidant defense system and impact the progression of AD. We investigated the impact of gene expression changes in 9 genes as new therapeutic options via metabolic flux analysis of supercomplex assembly. Through careful analysis, we propose that UQCRC1 may be an effective therapy option for in vitro AD treatment testing.}, } @article {pmid40808348, year = {2025}, author = {Bhushan, B and Singh, NK and Singh, R}, title = {An Overview of Neuroprotective Effects of Erythropoietin Against Neurological Disorders: Beyond Erythropoiesis.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {9}, pages = {e70442}, doi = {10.1002/jbt.70442}, pmid = {40808348}, issn = {1099-0461}, support = {//The authors received no specific funding for this work./ ; }, mesh = {Humans ; *Erythropoietin/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Erythropoiesis/drug effects ; *Nervous System Diseases/drug therapy/metabolism/pathology ; }, abstract = {Brain related disorders are a set of medical ailments that cause motor incoordination, cognitive and memory problems due to neurodegeneration in the brain. Although current therapies alleviate symptoms, they fail to target the fundamental pathological processes driving the disorders. A hematopoietic growth factor, Erythropoietin, stimulates erythroid cell formation and is therapeutically applied for the treatment of anemia. Furthermore, Erythropoietin has shown improved neurological outcomes in preclinical models and is being investigated as a potential therapeutic agent for neurodegenerative disorders. Erythropoietin is potential target for the regulation of numerous cellular signal pathways to enhance the neuronal survival, promote neuronal differentiation via binding of Erythropoietin-to-Erythropoietin receptor to stimulate the protein Janus-tyrosine kinase 2 followed by regulation of protein kinase B, signal transducer and stimulators of transcription 5, protein tyrosine phosphatases, mitogen-activated protein kinases, nuclear factor kB and Wnt1. Numerous research studies have evaluated the therapeutic potential of Erythropoietin against several neurological disorders including Alzheimer's disease, Parkinson's disease, neuroinflammation and epilepsy and highlight that Erythropoietin exhibits significant neuroprotective effects by counteracting apoptosis, neuroinflammatory process, reactive oxygen species overburden and neuronal death, consequently, prevent the progression of such diseases. However, two major challenges in developing erythropoietin as a neuroprotective agent include optimizing its therapeutic window and addressing safety concerns, particularly its adverse interaction with tissue plasminogen activator, which has been shown to increase the risk of hemorrhagic complications in ischemic stroke patients. In present review, we discuss the neurotherapeutic applications of Erythropoietin against brain related disorders beyond erythropoiesis. In conclusion, it can be assumed that Erythropoietin could be an alternative therapeutic option for the management of neurological disorders.}, } @article {pmid40807333, year = {2025}, author = {Godela, A and Rogacz, D and Pawłowska, B and Biczak, R}, title = {Natural Neuroinflammatory Modulators: Therapeutic Potential of Fungi-Derived Compounds in Selected Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {15}, pages = {}, pmid = {40807333}, issn = {1420-3049}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Fungi/chemistry ; *Biological Products/therapeutic use/pharmacology/chemistry ; Animals ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis remain incurable. Current therapeutic strategies primarily focus on slowing disease progression, alleviating symptoms, and improving patients' quality of life, including the management of comorbid conditions. Over the past few decades, the incidence of diagnosed neurodegenerative disorders has risen significantly. As the number of affected individuals continues to grow, so does the urgent need for effective treatments that can halt or mitigate the progression of these diseases. Among the most promising therapeutic resources are bioactive compounds derived from fungi. The high quality of proteins, polysaccharides, unsaturated fatty acids, triterpenoids, sterols, and secondary metabolites found in fungi have attracted growing interest from researchers across multiple disciplines. One intensively studied direction involves the use of naturally occurring fungi-derived nutraceuticals in the treatment of various diseases, including neurodegenerative conditions. This article provides an overview of recent findings on fungal compounds-such as phenolic compounds, carbohydrates, peptides and proteins, and lipids-that may have potential applications in the treatment of neurodegenerative diseases and the alleviation of their symptoms.}, } @article {pmid40807232, year = {2025}, author = {Chávez-Castillo, M and Gotera, MP and Duran, P and Díaz, MP and Nava, M and Cano, C and Díaz-Camargo, E and Cano, G and Cano, R and Rivera-Porras, D and Bermúdez, V}, title = {Neuroprotective Role of Omega-3 Fatty Acids: Fighting Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {15}, pages = {}, pmid = {40807232}, issn = {1420-3049}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; *Fatty Acids, Omega-3/therapeutic use/pharmacology ; Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; }, abstract = {Alzheimer's disease (AD) is one of the main causes of dementia, with an exponential increment in its incidence as years go by. However, since pathophysiological mechanisms are complex and multifactorial, therapeutic strategies remain inconclusive and only provide symptomatic relief to patients. In order to solve this problem, new strategies have been investigated over recent years for AD treatment. This field has been reborn due to epidemiological and preclinical findings that demonstrate the fact that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) can be promising therapeutic agents because of their anti-inflammatory, antioxidant, and neurogenic-promoting activities, thus allowing us to classify these molecules as neuroprotectors. Similarly, ω-3 PUFAs perform important actions in the formation of characteristic AD lesions, amyloid-β plaques (Aβ) and neurofibrillary tangles, reducing the development of these structures. Altogether, the aforementioned actions hinder cognitive decline and possibly reduce AD development. In addition, ω-3 PUFAs modulate the inflammatory response by inhibiting the production of pro-inflammatory molecules and promoting the synthesis of specialised pro-resolving mediators. Consequently, the present review assesses the mechanisms by which ω-3 PUFAs can act as therapeutic molecules and the effectiveness of their use in patients. Clinical evidence so far has shown promising results on ω-3 PUFA effects, both in animal and epidemiological studies, but remains contradictory in clinical trials. More research on these molecules and their neuroprotective effects in AD is needed, as well as the establishment of future guidelines to obtain more reproducible results on this matter.}, } @article {pmid40806766, year = {2025}, author = {Rebolledo-Pérez, L and Hernández-Bello, J and Martínez-Ramos, A and Castañeda-Arellano, R and Fernández-Quezada, D and Sandoval-García, F and Aguilar-García, IG}, title = {Substance Abuse and Cognitive Decline: The Critical Role of Tau Protein as a Potential Biomarker.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806766}, issn = {1422-0067}, mesh = {Humans ; *tau Proteins/metabolism ; *Substance-Related Disorders/metabolism/complications ; Biomarkers/metabolism ; Animals ; *Cognitive Dysfunction/metabolism/etiology ; Phosphorylation ; Alzheimer Disease/metabolism ; }, abstract = {Tau protein is essential for the structural stability of neurons, particularly through its role in microtubule assembly and axonal transport. However, when abnormally hyperphosphorylated or cleaved, Tau can aggregate into insoluble forms that disrupt neuronal function, contributing to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Emerging evidence suggests that similar Tau-related alterations may occur in individuals with chronic exposure to psychoactive substances. This review compiles experimental, clinical, and postmortem findings that collectively indicate a substance-specific influence on Tau dynamics. Alcohol and opioids, for instance, promote Tau hyperphosphorylation and fragmentation through the activation of kinases such as GSK-3β and CDK5, as well as proteases like caspase-3, leading to neuroinflammation and microglial activation. Stimulants and dissociatives disrupt insulin signaling, increase oxidative stress, and impair endosomal trafficking, all of which can exacerbate Tau pathology. In contrast, cannabinoids and psychedelics may exert protective effects by modulating kinase activity, reducing inflammation, or enhancing neuroplasticity. Psychedelic compounds such as psilocybin and harmine have been demonstrated to decrease Tau phosphorylation and facilitate cognitive restoration in animal models. Although the molecular mechanisms differ across substances, Tau consistently emerges as a convergent target altered in substance-related cognitive disorders. Understanding these pathways may provide not only mechanistic insights into drug-induced neurotoxicity but also identify Tau as a valuable biomarker and potential therapeutic target for the prevention or treatment of cognitive decline associated with substance use.}, } @article {pmid40806624, year = {2025}, author = {Șerban, M and Toader, C and Covache-Busuioc, RA}, title = {The Redox Revolution in Brain Medicine: Targeting Oxidative Stress with AI, Multi-Omics and Mitochondrial Therapies for the Precision Eradication of Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806624}, issn = {1422-0067}, mesh = {Humans ; *Oxidative Stress/drug effects ; *Mitochondria/metabolism/drug effects ; *Neurodegenerative Diseases/metabolism/therapy/drug therapy ; *Artificial Intelligence ; Oxidation-Reduction ; Antioxidants/therapeutic use/pharmacology ; Biomarkers/metabolism ; *Precision Medicine/methods ; Animals ; Reactive Oxygen Species/metabolism ; Brain/metabolism ; Multiomics ; }, abstract = {Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies.}, } @article {pmid40806521, year = {2025}, author = {Szablewski, L}, title = {Human Glucose Transporters in Health and Selected Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806521}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; *Glucose Transport Proteins, Facilitative/metabolism/genetics ; Animals ; Glucose/metabolism ; Alzheimer Disease/metabolism/genetics ; Huntington Disease/metabolism/genetics ; }, abstract = {Glucose is the main source of energy and the source of carbon for the biosynthesis of several molecules, such as neurotransmitters, for most mammalian cells. Therefore, the transport of glucose into cells is very important. There are described three distinct families of glucose transporters: facilitative glucose transporters (GLUTs), sodium-dependent glucose cotransporters (SGLTs), and a uniporter, the SWEET protein. Impaired function and/or expression of these transporters due to, for example, mutations in their genes, may cause severe diseases. Associations with the impaired function of glucose transporters have been described in the case of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, GLUT1-deficiency syndrome, stroke, and traumatic brain injury. Changes in the presence of glucose transporters may be a cause of NDs, and they may be the effect of NDs. On the other hand, in many cases of neurodegenerative diseases, changes in the expression of glucose transporters may be a targeted therapy in the treatment of patients with these diseases.}, } @article {pmid40806469, year = {2025}, author = {Wang, J and Shen, Y and Liao, P and Yang, B and Jiang, R}, title = {Roles of Ion Channels in Oligodendrocyte Precursor Cells: From Physiology to Pathology.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806469}, issn = {1422-0067}, support = {82401445//National Natural Science Foundation of China/ ; 82271249//National Natural Science Foundation of China/ ; 2024M752251//China Postdoctoral Science Foundation/ ; 2024NSFSC1636//Sichuan Science and Technology Program/ ; 2024HXBH013//Post doctor Research Fund of West China Hospital of Sichuan University/ ; ZYYC23002//1-3-5 Project for Disciplines of Excellence of West China Hospital of Sichuan University/ ; GZC20241141//Postdoctoral Fellowship Program of CPSF/ ; }, mesh = {Humans ; *Ion Channels/metabolism ; Animals ; *Oligodendrocyte Precursor Cells/metabolism/pathology ; Oligodendroglia/metabolism ; Cell Differentiation ; }, abstract = {Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer's disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases.}, } @article {pmid40806404, year = {2025}, author = {Yu, Y and Wang, C and Wang, B and Wang, X and Zhao, Q and Yan, Y and Liu, X}, title = {Clusterin Regulates the Mechanisms of Neuroinflammation and Neuronal Circuit Impairment in Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806404}, issn = {1422-0067}, support = {H2024206232//Natural Science Foundation of Hebei Province/ ; ZF2024142//The Hebei Provincial Department of Finance and the Health Commission will fund the 2024 government-funded clinical medicine excellent talent training project/ ; 20252051//Hebei Provincial Health Commission Medical Science Research Project Project/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Clusterin/metabolism ; Animals ; *Neuroinflammatory Diseases/metabolism/pathology ; Astrocytes/metabolism/pathology ; *Neurons/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with a multifaceted pathogenesis, which remains elusive, seriously affecting the quality of life of elderly patients and placing a heavy burden on affected individuals, their families, and society. As third-party synapses in brain networks, astrocytes play an important role in maintaining the normal function of neural networks, which contribute to the abnormal function of networks in AD. In recent years, numerous studies have shown that clusterin, a protein expressed by astrocytes, can participate in the progression of AD. Clusterin plays a significant role in many pathological processes of AD, such as lipid metabolism, AD pathological features, the imbalance in neural circuit excitatory inhibition, and neuroinflammation. Therefore, delving deeper into the association between clusterin and AD will help us to understand the mechanisms of disease better and provide a theoretical basis for early diagnosis and the development of treatment strategies for AD.}, } @article {pmid40806401, year = {2025}, author = {Nunkoo, VS and Jurcau, A and Les, M and Cristian, A and Militaru, M and Marge, C and Iovanovici, DC and Jurcau, MC}, title = {Circulating Biomarkers for the Early Diagnosis of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806401}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Biomarkers/blood ; Early Diagnosis ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Peptide Fragments/blood ; }, abstract = {With a rapidly growing incidence and prevalence, Alzheimer's disease (AD) is rapidly becoming one of the most disabling, lethal, and expensive diseases of the century. To diagnose AD as early as possible, the scientific world struggles to find reliable and non-invasive biomarkers that could predict the conversion of mild cognitive impairment to AD and delineate the ongoing pathogenic vicious pathways to be targeted with therapy. Research supports the use of blood biomarkers, such as Aβ1-42/Aβ1-40 ratio, phosphorylated tau181, and p-tau217 for diagnostic purposes, although the cut-offs are not clearly established and can depend on the assays used. For more accurate diagnosis, markers of neurodegeneration (neurofilament light) and neuroinflammation (glial fibrillary acidic protein) could be introduced in the biomarker panel. The recent approval of the Lumipulse G p-tau217/Aβ1-42 plasma ratio by the FDA for the early detection of amyloid plaques associated with Alzheimer's disease in adult patients, aged 55 years and older, exhibiting signs and symptoms of the disease represents a significant advancement in the diagnosis of Alzheimer's disease, offering a more accessible and less invasive way to diagnose this devastating disease and allow potentially earlier access to treatment options.}, } @article {pmid40805906, year = {2025}, author = {Fereshtehnejad, SM and Lökk, J}, title = {Healthcare Complexities in Neurodegenerative Proteinopathies: A Narrative Review.}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {15}, pages = {}, pmid = {40805906}, issn = {2227-9032}, abstract = {Background/Objectives: Neurodegenerative proteinopathies, such as Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB), are increasingly prevalent worldwide mainly due to population aging. These conditions are marked by complex etiologies, overlapping pathologies, and progressive clinical decline, with significant consequences for patients, caregivers, and healthcare systems. This review aims to synthesize evidence on the healthcare complexities of major neurodegenerative proteinopathies to highlight current knowledge gaps, and to inform future care models, policies, and research directions. Methods: We conducted a comprehensive literature search in PubMed/MEDLINE using combinations of MeSH terms and keywords related to neurodegenerative diseases, proteinopathies, diagnosis, sex, management, treatment, caregiver burden, and healthcare delivery. Studies were included if they addressed the clinical, pathophysiological, economic, or care-related complexities of aging-related neurodegenerative proteinopathies. Results: Key themes identified include the following: (1) multifactorial and unclear etiologies with frequent co-pathologies; (2) long prodromal phases with emerging biomarkers; (3) lack of effective disease-modifying therapies; (4) progressive nature requiring ongoing and individualized care; (5) high caregiver burden; (6) escalating healthcare and societal costs; and (7) the critical role of multidisciplinary and multi-domain care models involving specialists, primary care, and allied health professionals. Conclusions: The complexity and cost of neurodegenerative proteinopathies highlight the urgent need for prevention-focused strategies, innovative care models, early interventions, and integrated policies that support patients and caregivers. Prevention through the early identification of risk factors and prodromal signs is critical. Investing in research to develop effective disease-modifying therapies and improve early detection will be essential to reducing the long-term burden of these disorders.}, } @article {pmid40804109, year = {2025}, author = {Jia, M and Liu, Z and Fan, X and Ahmad, S and Wang, Z and Zhu, X and Ai, H}, title = {Conformation-Dependent Binding Affinity of Small Molecules to Aβ42 Fibrils: Mechanistic Insights into Tracer Design.}, journal = {The journal of physical chemistry. B}, volume = {129}, number = {34}, pages = {8700-8711}, doi = {10.1021/acs.jpcb.5c04444}, pmid = {40804109}, issn = {1520-5207}, mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; *Peptide Fragments/chemistry/metabolism ; Binding Sites ; Humans ; Protein Binding ; Ligands ; *Small Molecule Libraries/chemistry/metabolism ; Protein Conformation ; Alzheimer Disease/metabolism ; }, abstract = {The β-amyloid (Aβ) deposits in Alzheimer's disease (AD) are primarily composed of Aβ42-derived fibrils, and Aβ42 fibrils exhibit polymorphism with diverse molecular structures. While small-molecule-based targeting strategies have achieved phased progress in AD diagnosis and treatment, the distribution and quantity of binding sites on Aβ42 fibrils, as well as the dynamic interaction mechanisms between these sites and different tracers, remain unclear. Additionally, the binding efficacy of small molecules to Aβ42 fibrils with distinct structures and their conformational dependence have not yet been elucidated. In this study, five novel ligands were selected as tracers to investigate their interactions with four representative Aβ42 fibril conformations. The results demonstrated significant differences in the capacities of these molecules to bind Aβ fibrils with varying conformations, revealing a pronounced conformation-dependent relationship. Notably, small molecule 1 (SM1) and SM3 exhibited robust binding affinities across all four Aβ fibril conformations, highlighting their potential as tracers. Furthermore, the binding sites of the υ-type (8EZE) Aβ fibril accommodating small molecules were first identified, and U-type (2BEG), S-type (2NAO), and LS-type (5OQV) Aβ fibrils were found to align with the ones reported previously for other ligands. Notably, strongly bound molecules induce structural deformation of the fibril. These findings provide critical insights for the rational design and modification of existing Aβ42 fibril-targeting ligands, facilitating the development of tracers with enhanced specificity and selectivity.}, } @article {pmid40803539, year = {2025}, author = {Ji, Y and Wang, M and Yang, C}, title = {Neurosteroids for the treatment of neurodegenerative disorders: We still have a long way to go.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {254}, number = {}, pages = {106841}, doi = {10.1016/j.jsbmb.2025.106841}, pmid = {40803539}, issn = {1879-1220}, } @article {pmid40803248, year = {2025}, author = {Esparza-Moltó, PB and Goswami, AV and Bozkurt, S and Münch, C and Newman, LE and Moyzis, AG and Rojas, GR and Guan, D and Jones, JR and Gage, FH and Shadel, GS}, title = {ROS-dependent localization of glycolytic enzymes to mitochondria.}, journal = {Redox biology}, volume = {86}, number = {}, pages = {103812}, pmid = {40803248}, issn = {2213-2317}, support = {P30 AG068635/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Mitochondria/metabolism/enzymology/drug effects ; *Glycolysis ; *Reactive Oxygen Species/metabolism ; HEK293 Cells ; Oxidative Stress ; Alzheimer Disease/metabolism/pathology ; Fibroblasts/metabolism ; }, abstract = {Mitochondrial reactive oxygen species (mtROS) regulate cellular signaling pathways, but also cause oxidative stress when de-regulated during aging and pathological conditions such as neurodegenerative diseases. The dynamic redistribution of proteins between cellular compartments is a common mechanism to control their stability and biological activities. By targeting the BirA∗ biotin ligase to the outer mitochondrial membrane in HEK293 cells, we identified proteins whose labeling increased or decreased in response to treatment with menadione, consistent with a dynamic change in their mitochondrial localization in response to increased mtROS production. These proteins represent potential candidates for future studies of mitochondrial oxidative stress signaling. A subset of glycolytic enzymes was found in this screen and confirmed, by mitochondrial fractionation and imaging, to increase localization to mitochondria in response to menadione, despite no change in their overall abundance. Submitochondrial fractionation studies are consistent with import of a pool of these enzymes to the mitochondrial intermembrane space. Localization of glycolytic enzymes to mitochondria was also increased in cells grown under hypoxia or that express a mitochondria-targeted d-amino-acid oxidase (conditions that induce increased mtROS production), and inhibited basally under normal growth conditions by the mitochondrial antioxidant MnTBAP. Finally, primary Alzheimer's disease fibroblasts also had glycolytic enzymes associated with mitochondria that was reduced by antioxidants, consistent with increased mtROS altering their relative distribution between the cytoplasm and mitochondria. We speculate that the increased mitochondrial localization of glycolytic enzymes is an adaptive response to mtROS that alters glucose flux toward the antioxidant pentose phosphate pathway, creates distinct regulatory pools of mitochondrial metabolites or new metabolic circuits, and/or provides cytoprotection or other adaptive responses via moonlighting functions unrelated to their enzymatic activity.}, } @article {pmid40803039, year = {2025}, author = {Erickson, RP and Bernas, MJ and Witte, MH}, title = {Manual Lymph Drainage for Alzheimer's Dementia: A Clinical Trial Whose Time Has Come?.}, journal = {Lymphology}, volume = {58}, number = {2}, pages = {43-45}, pmid = {40803039}, issn = {2522-7963}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology ; Brain/pathology ; Clinical Trials as Topic ; *Manual Lymphatic Drainage/methods ; }, abstract = {Mounting evidence implicates brain lymphatic drainage in the pathogenesis of Alzheimer's disease and other dementias. Several recent basic and clinical science discoveries have suggested the impact of lymphatic therapy to stimulate lymph flow in the head and neck including improvement in cognition. Manual lymphatic drainage has potential as a simple inexpensive way to promote brain lymph drainage and is worthy of a well-designed clinical trial to evaluate its potential as a primary or adjunctive treatment of Alzheimer's disease at this time.}, } @article {pmid40802200, year = {2025}, author = {Talib, M and Siddiqui, N and Tripathi, PN and Chaudhary, A}, title = {Ameliorative Role of Phosphodiesterase-5 (PDE-5) Inhibitor "Avanafil" via Modulating cAMP & cGMP Pathway Against Alzheimer's Disease.}, journal = {Neurochemical research}, volume = {50}, number = {4}, pages = {258}, pmid = {40802200}, issn = {1573-6903}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Cyclic GMP/metabolism ; Male ; *Cyclic AMP/metabolism ; Rats ; *Phosphodiesterase 5 Inhibitors/therapeutic use/pharmacology ; Rats, Wistar ; Hippocampus/drug effects/metabolism ; *Pyrimidines/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Galactose ; }, abstract = {Alzheimer's disease (AD) is the utmost age-linked neuro-degenerative conditions, marked via gradual deterioration of cognitive abilities and continues to be a significant worldwide health issue. Etiology of AD is linked to neurobehavioral variations, deposition of Aβ, p-Tau, activations of glycogen synthase kinase-3 (GSK-3β), and fluctuations in cyclic nucleotides including cAMP & cGMP. As per evidence, PDE-5 inhibitors are able to boost cAMP & cGMP levels and other etiological hallmarks, which could be a novel AD cure. The main objective of present study was to examine therapeutic potential of Avanafil in a rat model of AD induced by administering 60 mg/kg of D-galactose (D-galac) and 10 mg/kg of Aluminium chloride (AlCl3) for a period of 42 days. Following this, 28 days of therapy with two different doses of Avanafil (3 mg/kg and 6 mg/kg) was given. Towards end of treatment, locomotor activity & Morris water maze were performed. Rats were then euthanized and hippocampus was isolated for biochemical parameters & histological investigation. Results revealed that both neurobehavioral parameters exhibits significant difference in treatment group as compared to toxic group. Alterations in level of AchE, Aβ (1-42), GSK-3β, p-Tau, tumor necrosis factor- alpha (TNF-α), IL-1β, & IL-6, cAMP, cGMP & BDNF, and oxidative stress were significantly reversed towards normal level in the treatment group when compared to toxic rats. Histopathological changes by H&E staining showed significant difference in treatment vs. toxic rats. The current investigation suggested that Avanafil improves memory by improving cAMP and cGMP pathways, implying that it may have therapeutic prospective in cognitive deficiencies linked with Alzheimer's disease.}, } @article {pmid40801914, year = {2025}, author = {Liguori, C}, title = {Sleep disturbances impact cognition and are highly prevalent in memory clinics.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {4}, pages = {1406-1408}, doi = {10.1177/13872877251366660}, pmid = {40801914}, issn = {1875-8908}, mesh = {Humans ; *Sleep Wake Disorders/epidemiology/psychology/complications/diagnosis ; Prevalence ; *Cognitive Dysfunction/epidemiology ; Surveys and Questionnaires ; *Cognition/physiology ; *Memory Disorders/epidemiology ; Female ; }, abstract = {Sleep questionnaires may help understand sleep habits and screen for sleep disorders. However, they can fail in diagnosing obstructive sleep apnea or identifying the chronotype and the total sleep time of patients admitted to a specialized memory clinic. Lam et al. showed the high prevalence of sleep disturbances in patients with cognitive impairment. They also highlighted the importance of combining subjective questionnaires with objective tests to identify sleep problems associated with poor cognitive performance, particularly in women. Consequently, recognizing sleep problems can help clinicians set personalized treatment strategies for improving sleep and preventing or slowing cognitive impairment.}, } @article {pmid40801842, year = {2025}, author = {Xie, F and Ye, Y and Hao, J and Liu, H and Richard, SA and He, S}, title = {Surgical advances in the treatment of Alzheimer's disease: A comprehensive review.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {3}, pages = {899-909}, doi = {10.1177/13872877251364397}, pmid = {40801842}, issn = {1875-8908}, mesh = {*Alzheimer Disease/surgery/therapy ; Humans ; Deep Brain Stimulation/methods ; Genetic Therapy/methods ; *Neurosurgical Procedures/methods ; Animals ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, represents a significant global health challenge with profound implications for patients and their families. Despite decades of intensive research efforts, no curative treatment for AD currently exists. In recent years, surgical interventions have emerged as a promising therapeutic avenue, offering potential for disease modification and symptom management. This comprehensive review critically evaluates the evolving landscape of surgical approaches in AD treatment, encompassing deep brain stimulation, focused ultrasound, gene therapy delivery systems, neural grafting techniques, and lymphatic-venous anastomosis. We systematically analyze the neurobiological mechanisms, clinical efficacy, safety profiles, and technical challenges associated with these interventions. Drawing upon an extensive review of 112 recent studies, this article provides a rigorous assessment of the current state of surgical therapies for AD, while identifying key knowledge gaps and future research directions that could advance the field toward more effective therapeutic strategies.}, } @article {pmid40801602, year = {2025}, author = {de Munter, J and Chaprov, K and Lang, E and Sitdikova, K and Wolters, EC and Svirin, E and Kassenova, A and Tsoy, A and Kramer, BW and Askarova, S and Schroeter, CA and Anthony, DC and Strekalova, T}, title = {Neuro-Cells Mitigate Amyloid Plaque Formation and Behavioral Deficits in the APPswe/PS1dE9 Model of Alzheimer Disease While Also Reducing IL-6 Production in Human Monocytes.}, journal = {Cells}, volume = {14}, number = {15}, pages = {}, pmid = {40801602}, issn = {2073-4409}, support = {101007642//HORIZON, EU/ ; AP23485236, BR24992841//the Ministry of Higher Education and Science of the Republic of Kazakhstan/ ; }, mesh = {*Alzheimer Disease/therapy/pathology/metabolism ; Animals ; *Monocytes/metabolism ; Humans ; *Interleukin-6/metabolism ; *Plaque, Amyloid/pathology/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Behavior, Animal ; Male ; *Neural Stem Cells ; Presenilin-1/metabolism ; }, abstract = {Neuroinflammation is a key feature of Alzheimer's disease (AD), and stem cell therapies have emerged as promising candidates due to their immunomodulatory properties. Neuro-Cells (NC), a combination of unmodified mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), have demonstrated therapeutic potential in models of central nervous system (CNS) injury and neurodegeneration. Here, we studied the effects of NC in APPswe/PS1dE9 mice, an AD mouse model. Twelve-month-old APPswe/PS1dE9 mice or their wild-type littermates were injected with NC or vehicle into the cisterna magna. Five to six weeks post-injection, cognitive, locomotor, and emotional behaviors were assessed. The brain was stained for amyloid plaque density using Congo red, and for astrogliosis using DAPI and GFAP staining. Gene expression of immune activation markers (Il-1β, Il-6, Cd45, Tnf) and plasticity markers (Tubβ3, Bace1, Trem2, Stat3) was examined in the prefrontal cortex. IL-6 secretion was measured in cultured human monocytes following endotoxin challenge and NC treatment. Untreated APPswe/PS1dE9 mice displayed impaired learning in the conditioned taste aversion test, reduced object exploration, and anxiety-like behavior, which were improved in the NC-treated mutants. NC treatment normalized the expression of several immune and plasticity markers and reduced the density of GFAP-positive cells in the hippocampus and thalamus. NC treatment decreased amyloid plaque density in the hippocampus and thalamus, targeting plaques of <100 μm[2]. Additionally, NC treatment suppressed IL-6 secretion by human monocytes. Thus, NC treatment alleviated behavioral deficits and reduced amyloid plaque formation in APPswe/PS1dE9 mice, likely via anti-inflammatory mechanisms. The reduction in IL-6 production in human monocytes further supports the potential of NC therapy for the treatment of AD.}, } @article {pmid40801286, year = {2025}, author = {Huang, J and Perrin, NA and Spira, AP and Szanton, SL and Rebok, GW and Budhathoki, C and Gooneratne, NS and Li, J}, title = {Sleep Disturbance and Cognitive Trajectories Among Older Adults with Subjective Cognitive Decline: The Roles of Age and Sleep Treatment.}, journal = {Sleep}, volume = {}, number = {}, pages = {}, doi = {10.1093/sleep/zsaf234}, pmid = {40801286}, issn = {1550-9109}, abstract = {STUDY OBJECTIVES: Growing evidence indicates that subjective cognitive decline (SCD), characterized by self-reported cognitive deterioration without measurable cognitive impairment, may be an early indicator of Alzheimer's Disease. This study investigated the association between baseline sleep disturbance and a 10-year trajectory of global cognitive performance in adults with SCD and examined if this association was moderated by age (50-64 years and ≥65 years) and sleep treatment. METHODS: Using six waves (2010-2020) of the Health and Retirement Study, we included individuals aged ≥50 years who reported SCD but had no objective cognitive impairment at baseline (2010) and had final wave of cognitive data (n=1,372). Latent growth curve modeling was employed to examine the associations between self-reported sleep disturbance and cognitive trajectories from 2010 to 2020, controlling for sociodemographic and health-related factors. RESULTS: In the full sample, baseline sleep disturbance was not significantly associated with cognitive change. However, a significant interaction between sleep disturbance and age group was found (β=-0.04, 95% CI [-0.08, -0.003]). Stratified analyses showed that poorer sleep was associated with faster cognitive decline in those aged ≥65 years (β=-0.04, 95% CI [-0.07, -0.005]; n=558), and receiving sleep treatment was associated with a reduced impact of sleep disturbance on cognitive decline (β=0.31, 95% CI [0.02, 0.60]). These associations were not significant in those aged 50-64 years (n=814). CONCLUSIONS: Sleep disturbance was an independent risk factor of future cognitive decline in older adults ≥65 years with SCD. Sleep treatment may mitigate this decline, offering a potential intervention strategy.}, } @article {pmid40801268, year = {2025}, author = {Ikanga, J and Patel, SS and Schwinne, M and Obenauf, C and Gikelekele, G and Epenge, E and Tshengele, N and Kavugho, I and Mampunza, S and Mananga, L and Teunissen, CE and Rojas, JC and Yohe, EO and Alonso, A and Gross, AL}, title = {Association between neuropsychiatric symptoms and neurodegeneration-related plasma biomarkers in older adults with and without clinical dementia in the Democratic Republic of the Congo.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70530}, pmid = {40801268}, issn = {1552-5279}, support = {//National Institutes of Health/ ; P30 AG066511/AG/NIA NIH HHS/United States ; R01AG070953 to AG/AG/NIA NIH HHS/United States ; R01AG030153 to AG/AG/NIA NIH HHS/United States ; P30AG066511/AG/NIA NIH HHS/United States ; RF1AG088003 to AG/AG/NIA NIH HHS/United States ; UL1TR002378//National Center for Advancing Translational Sciences/ ; //Emory Goizueta Alzheimer's disease Research Center (ADRC)/ ; }, mesh = {Humans ; Male ; Female ; *Biomarkers/blood ; Aged ; Democratic Republic of the Congo/epidemiology ; *Dementia/blood/psychology ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Neuropsychological Tests/statistics & numerical data ; Neurofilament Proteins/blood ; Psychiatric Status Rating Scales ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/blood ; }, abstract = {INTRODUCTION: Neuropsychiatric symptoms (NPS) are prevalent in dementia, but most studies focus on Western populations. This study examines the association between NPS and neurodegeneration-related plasma biomarkers in older adults with and without dementia in the Democratic Republic of the Congo (DRC). METHODS: Eighty-five individuals (≥65 years) underwent dementia adjudication using the Community Screening Instrument for Dementia (CSID) and Alzheimer's Questionnaire (AQ). Plasma biomarkers (amyloid β [Aβ] 42/40, phosphorylated-tau181 [p-tau181], neurofilament light [NfL], glial fibrillary acidic protein (GFAP), interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α]) were measured. NPS were assessed using the Geriatric Depression Scale (GDS), Beck Anxiety Inventory (BAI), and Neuropsychiatric Inventory Questionnaire (NPI) (for dementia cases). Logistic regressions examined associations between NPS and biomarkers, adjusting for age, sex, and education. RESULTS: NPS were common in dementia cases, with irritability (57.8%) and depression (90.7%) most frequent. GFAP was linked to irritability (odds ratio [OR] = 3.34, p = 0.01), and NfL and GFAP were associated with depressive symptoms (OR = 0.76, p = 0.04; OR = 1.98, p = 0.02, respectively). DISCUSSION: These findings highlight the burden of NPS in the DRC and suggest biomarker-driven mechanisms, emphasizing the need for further research in diverse populations. HIGHLIGHTS: Identifies neuropsychiatric symptoms as early indicators of Alzheimer's disease (AD) progression. Examines associations between depression and AD biomarkers in preclinical and prodromal stages. Highlights the role of amyloid and tau pathology in depression-related cognitive decline. Discusses implications for early intervention and personalized treatment strategies.}, } @article {pmid40801241, year = {2025}, author = {Jin, Z and Lu, Y and Tang, H and Cui, H}, title = {Integrating neuroinflammation biomarkers into the ATN(X) framework: Advances in Alzheimer's pathogenesis, diagnosis, and insights from non-human primate models.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70472}, pmid = {40801241}, issn = {1552-5279}, support = {82074535//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/diagnosis/metabolism/pathology ; Animals ; *Biomarkers/metabolism ; Humans ; Disease Models, Animal ; *Neuroinflammatory Diseases/metabolism/diagnosis ; *tau Proteins/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; Primates ; }, abstract = {The amyloid/tau/neurodegeneration (ATN) biomarker framework has greatly progressed the diagnosis and staging of Alzheimer's disease (AD). However, recent research highlights neuroinflammation as an equally critical factor in AD pathology across humans, rodents, and non-human primates (NHPs). This review evaluates the combined use of ATN and neuroinflammatory biomarkers-such as glial fibrillary acidic protein (GFAP) (astrocytic marker) and triggering receptor expressed on myeloid cells 2 (TREM2)/ ionized calcium-binding adapter molecule 1 (IBA-1) (microglial markers)-in elucidating AD mechanisms, promoting early diagnosis, and shaping therapeutic strategies. It also summarizes the key features and translational potential of NHP models that closely mimic human AD pathology, highlighting the promising prospects of integrating these models with the ATN(X) biomarker system. These insights strengthen the link between biomarkers, NHP research, and clinical practice, opening new avenues for the early detection and treatment strategies of AD. HIGHLIGHTS: Neuroinflammation biomarkers, including glial fibrillary acidic protein (GFAP), triggering receptor expressed on myeloid cells 2 (TREM2)/sTREM2, and YKL-40, show strong clinical potential in Alzheimer's disease (AD). Incorporating neuroinflammation biomarkers into the ATN(X) framework may enhance diagnostic precision. Advanced non-human primate (NHP) models closely replicate human brain pathology, addressing key limitations of mouse models. Measuring ATN(X) biomarkers in NHPs may improve clinical translation and support early diagnosis of AD. Optimizing NHP models-including ApoE4 status, injection protocols, and gene-editing approaches-is crucial for reproducibility and efficiency.}, } @article {pmid40800505, year = {2024}, author = {Dong, M and Xie, L and Das, SR and Wang, J and Wisse, LEM and deFlores, R and Wolk, DA and Yushkevich, PA}, title = {Regional deep atrophy: Using temporal information to automatically identify regions associated with Alzheimer's disease progression from longitudinal MRI.}, journal = {Imaging neuroscience (Cambridge, Mass.)}, volume = {2}, number = {}, pages = {}, pmid = {40800505}, issn = {2837-6056}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; RF1 AG056014/AG/NIA NIH HHS/United States ; R01 AG069474/AG/NIA NIH HHS/United States ; R01 AG055005/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG070592/AG/NIA NIH HHS/United States ; R01 AG040271/AG/NIA NIH HHS/United States ; }, abstract = {Longitudinal assessment of brain atrophy, particularly in the hippocampus, is a well-studied biomarker for neurodegenerative diseases, such as Alzheimer's disease (AD). Estimating brain progression patterns can be applied to understanding the therapeutic effects of amyloid-clearing drugs in research and detecting the earliest sign of accelerated atrophy in clinical settings. However, most state-of-the-art measurements calculate changes directly by segmentation and/or deformable registration of MRI images, and may misreport head motion or MRI artifacts as neurodegeneration, impacting their accuracy. In our previous study, we developed a deep learning method DeepAtrophy that uses a convolutional neural network to quantify differences between longitudinal MRI scan pairs that are associated with time. DeepAtrophy has high accuracy in inferring temporal information from longitudinal MRI scans, such as temporal order or relative interscan interval. DeepAtrophy also provides an overall atrophy score that was shown to perform well as a potential biomarker of disease progression and treatment efficacy. However, DeepAtrophy is not interpretable, and it is unclear what changes in the MRI contribute to progression measurements. In this paper, we propose Regional Deep Atrophy (RDA), which combines the temporal inference approach from DeepAtrophy with a deformable registration neural network and attention mechanism that highlights regions in the MRI image where longitudinal changes are contributing to temporal inference. RDA has similar prediction accuracy as DeepAtrophy, but its additional interpretability makes it more acceptable for use in clinical settings, and may lead to more sensitive biomarkers for disease monitoring and progression understanding in preclinical AD.}, } @article {pmid40799992, year = {2025}, author = {Chu, J and Hu, H and Xu, W and Lu, X and Zhou, H and Hao, M and Wang, L and Li, S and Ji, W and Li, G and Luo, Y and Gao, J and Huang, D and Liu, Y and Yin, Y}, title = {Top-down engineered micron-cell derived nanovesicles encapsulating curcumin targeting the 3R strategy (remove, remodel, repair) for Alzheimer's disease therapy.}, journal = {Materials today. Bio}, volume = {34}, number = {}, pages = {102157}, pmid = {40799992}, issn = {2590-0064}, abstract = {Alzheimer's disease (AD), a global health crisis exacerbated by aging populations, demands innovative therapeutic strategies. Curcumin, a natural compound with anti-aging and anti-inflammatory properties, holds promise for AD treatment but is hindered by poor bioavailability. Here, we developed curcumin-loaded nanovesicles (NV-CUR) derived from brain-homing B16 melanoma cells to overcome these limitations. NV-CUR enhanced the solubility, stability, and blood‒brain barrier (BBB) penetration of curcumin, enabling systemic delivery in aged 3 × Tg AD mice. Our 3R strategy for removing senescent cells, remodeling the neuroinflammatory microenvironment, and repairing neuronal damage was comprehensively validated. NV-CUR effectively cleared p16[INK4a] (P16)-positive senescent microglia, suppressed senescence-associated secretory phenotypes (SASP), and reduced neuroinflammation (IL-1β, IL-6, and TNF-α). Concurrently, NV-CUR diminished amyloid-beta plaques, attenuated Tau hyperphosphorylation, and restored hippocampal neuronal integrity. Cognitive assessments revealed significant improvements in memory and exploratory behavior, whereas biosafety evaluations confirmed that there was no systemic toxicity. This study establishes NV-CUR as a mechanistically innovative, clinically translatable nanomedicine that aligns with the 3R paradigm, offering a multifaceted approach to combat AD pathogenesis.}, } @article {pmid40799764, year = {2025}, author = {Chakkarai, S and Sadowski, M and Yang, Q and Ray, A and Wang, R and Thomas, LF and Fuentes, RP and Tabar, MS and Cui, B and Jian, X and Nyquist, PA and Gill, D and Aiello, AE and Montine, TJ and Bukhari, S and Rogalski, E and Edland, SE and Haan, ME and Kawas, CH and Corrada, MM and Salardini, A and Chen, ZZ and Himali, JJ and Satizabal, CL and Gerszten, RE and Åsvold, BO and Fornage, M and Cruchaga, C and Habes, M and Chasman, DI and Launer, LJ and Flanagan, ME and Brumpton, BM and Georgakis, MK and Zaitlen, N and Ruiz, A and Debette, S and Seshadri, S and Sargurupremraj, M}, title = {Cross-tissue omics-guided drug repurposing triangulates novel targetable mechanisms for Alzheimer's disease and candidate genetic biomarkers for treatment stratification.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40799764}, issn = {2693-5015}, support = {R01 AG082360/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; R21 AG087907/AG/NIA NIH HHS/United States ; RF1 AG063507/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; R25 GM135043/GM/NIGMS NIH HHS/United States ; R01 NS017950/NS/NINDS NIH HHS/United States ; R01 AG021055/AG/NIA NIH HHS/United States ; }, abstract = {White matter hyperintensities (WMH) are covert magnetic resonance imaging (MRI) - markers of microvascular dysfunction and are primary vascular contributors to dementia, emphasizing its importance in prevention strategies. Here, we integrate gene expression and protein levels measured across plasma, cerebrospinal fluid (CSF), brain and multiple other tissues from population-based and biobank-scale data to triangulate druggable genes influencing WMH-burden and Alzheimer's disease (AD) and to map their spatial localization specifically in brain-cell types. Lowering the expression levels of CALCRL, MAP3K11, PKN2 and EPHB4 shows putative causal associations with reduced WMH-burden, and AD risk. These targets of clinically approved drugs, enriched in key cell types of the neurovascular unit and exhibiting cell-type specific effects in peripheral CD4 + T cell subsets, are implicated in regulating neuroimmune interactions and amyloid-β homeostasis. Gene-drug interaction analysis identifies higher levels of GLTPD2 modifying the antidepressants associated increase in dementia risk contributing to a 73.3% risk reduction relative to the use of drugs. Furthermore, pharmagenic pathway studies identify the coagulation cascade as a targetable pathway associated with AD risk (HR: 2.23, 95% CI:1.85-2.69), providing orthogonal support to emerging therapies targeting coagulation components in treating neurodegenerative disorders.}, } @article {pmid40799393, year = {2025}, author = {Araya, P and Niemeyer, B and Schade, K and Dunn, LN and Waugh, K and Busquet, N and Brindley, C and Brown, C and Winkler, C and Lyford, HR and Britton, EC and Ludwig, M and Siegenthaler, J and Galbraith, MD and Espinosa, JM and Sullivan, KD}, title = {Interferon signaling modulates Down syndrome-associated Alzheimer's disease pathology in a mouse model.}, journal = {iScience}, volume = {28}, number = {8}, pages = {113130}, pmid = {40799393}, issn = {2589-0042}, abstract = {Individuals with Down syndrome (DS), caused by trisomy of chromosome 21 (chr21, T21), are strongly predisposed to Alzheimer's disease (AD), due to triplication of the APP gene, with ∼100% penetrance of AD brain pathology by age 40 and variable onset of dementia thereafter. It remains unclear what role other triplicated genes play in the pathophysiology of DS-associated AD (DS-AD). Using mouse models of DS-AD, we demonstrate that triplication of other chr21 genes has paradoxical effects on learning and memory in DS-AD mice, exacerbating some phenotypes and attenuating others. Spatial transcriptomic analysis revealed genome-wide alterations typified by upregulation of interferon (IFN) signatures and elevated levels of disease-associated microglia with concomitant decreases in neurons in DS-AD animals. Finally, systemic treatment with a JAK inhibitor improved cognition and rescued gene expression changes in DS-AD animals, indicating that IFN may be a driver of pathophysiology in DS-AD that could be amenable to therapeutic intervention.}, } @article {pmid40798958, year = {2025}, author = {Zhang, Y and Ke, Z and Luo, J and Chen, Q and Jiang, X and Xiong, J and Deng, L}, title = {Betaine: A Promising Natural Product for Neurological and Psychiatric Diseases.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X375540250718094903}, pmid = {40798958}, issn = {1875-6190}, abstract = {Neurological and psychiatric diseases pose a considerable global burden. Exploring additional potential prevention strategies and therapies is ongoing. As a prevalent natural product and nutraceutical from food, betaine's pharmaceutical applications suggest benefits for both health and disease in multiple organs. Recently, its efficacy on neurological and psychiatric health has been proposed and has drawn considerable attention. This review aims to provide an updated, critical, and comprehensive profile of the promising medicinal roles of betaine in these diseases. In addition to its well-known osmotic protection, due to methyl donation, it regulates metabolism, alleviates oxidative stress, and reduces inflammation. To manifest neurological and psychiatric health benefits, betaine acts by affecting gamma-aminobutyric acid associated with its transporters, related neurotransmitters, downstream and neurological pathways, and other specific mechanisms in the nervous system. Betaine demonstrates therapeutic potential against various neurological and psychiatric diseases, such as epilepsy, neurocognitive disorders (including Alzheimer's disease), Parkinson's disease, stroke, multiple sclerosis, traumatic brain injury, depression, anxiety, schizophrenia, autism spectrum disorder, sleep disorders, fetal alcohol syndrome, syringomyelia, neonatal brain injury, neuropathic pain, and motor dysfunction. Despite the promising role of betaine in the treatment, diagnosis, and prevention of neuropsychiatric disorders, much of the present evidence appears to be fragmentary. Further studies elucidating the underlying mechanisms and direct clinical applications are required to obtain a deeper understanding of betaine and its underutilized potential. Overall, this review highlights the potential of betaine as a promising agent with benefits for neurological and psychiatric diseases, aiming to offer clues to advance this field.}, } @article {pmid40797227, year = {2025}, author = {Liang, J and Li, R and Wong, G and Huang, X}, title = {Lewy body dementia: exploring biomarkers and pathogenic interactions of amyloid β, tau, and α-synuclein.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {90}, pmid = {40797227}, issn = {1750-1326}, support = {32400781//National Natural Science Foundation of China/ ; No. BYYZ25014//President Foundation of Baiyun District People's Hospital of Guangzhou/ ; }, abstract = {Lewy body dementia (LBD) is a neurodegenerative disorder characterized by a combination of progressive dementia and spontaneous parkinsonian symptoms. As the second most prevalent form of neurodegenerative dementia after Alzheimer’s disease (AD), LBD necessitates a deeper understanding of its pathogenesis to enable the development of targeted therapeutic interventions. While numerous reviews focus on documenting the clinical manifestations and therapeutic modalities for LBD, animal models provide valuable insights into the underlying mechanisms and potential therapeutic strategies. In this review, we systematically analyze the hallmarks of LBD pathogenesis, genetic risk factors, clinical features, and treatment strategies. Importantly, we emphasize and critically evaluate the pivotal role of animal models in LBD research in advancing our understanding of this disorder, offering a comprehensive framework to elucidate the interactions among misfolded proteins and their role in LBD pathogenesis. Our review proposes new directions for LBD therapeutic management and facilitates the development of innovative pharmacological interventions.}, } @article {pmid40796907, year = {2025}, author = {Choi, J and Kim, D and Jeong, H and Hwang, J and Ramalingam, M and Han, S and Cho, HH and Kim, BC and Jeong, HS and Jang, S}, title = {A novel miR-4536-3p inhibition ameliorates Alzheimer's disease by reducing Aβ accumulation and tau phosphorylation.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {189}, pmid = {40796907}, issn = {1758-9193}, support = {RS-2020-KH088567//Korea Health Industry Development Institute/Republic of Korea ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *MicroRNAs/antagonists & inhibitors/metabolism/genetics ; *tau Proteins/metabolism ; Mice ; Phosphorylation/drug effects ; *Amyloid beta-Peptides/metabolism ; Humans ; Mice, Transgenic ; Disease Models, Animal ; Male ; Apoptosis/drug effects ; Signal Transduction ; Neuropeptides/metabolism ; Maze Learning ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive decline, amyloid-beta (Aβ) accumulation, and tau hyperphosphorylation. Effective therapies remain limited; therefore, recent studies have explored microRNAs as potential therapeutic targets. METHODS: miR-4536-3p inhibition was investigated using in vitro (SH-SY5Y cells) and in vivo (5xFAD mouse) AD models. Apoptosis, neuronal markers, and signaling pathways were assessed through functional assays. Cognitive effects were evaluated via the Morris water maze. RESULTS: miR-4536-3p inhibition increased an expression of Drebrin1 (DBN1), a key regulator of synaptic plasticity, but it reduced Aβ deposition, tau phosphorylation, and apoptosis. The treatment improved neuronal marker levels and significantly enhanced the spatial learning and memory of 5xFAD mice. Mechanistically, miR-4536-3p inhibition activated the PI3K/Akt/GSK3β signaling pathway, suppressing apoptosis and mitigating AD pathology. CONCLUSION: miR-4536-3p inhibition offers a promising therapeutic strategy for AD by restoring the DBN1 expression, reducing neurodegeneration, and improving cognitive outcomes through PI3K/Akt pathway modulation.}, } @article {pmid40796687, year = {2025}, author = {Kashiyama, R and Watanabe, H and Akasaka, T and Fujimoto, H and Murakami, M and Ooe, K and Toyoshima, A and Nakashima, K and Ono, M}, title = {Feasibility of targeted alpha therapy for Alzheimer's disease using [211]At-labeled agent targeting amyloid-β aggregates.}, journal = {Annals of nuclear medicine}, volume = {39}, number = {12}, pages = {1319-1325}, pmid = {40796687}, issn = {1864-6433}, support = {JP24wm0625512h//Japan Agency for Medical Research and Development/ ; JP25wm0625512h//Japan Agency for Medical Research and Development/ ; }, mesh = {*Alzheimer Disease/radiotherapy/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; Mice ; Feasibility Studies ; *Alpha Particles/therapeutic use ; *Protein Aggregates/radiation effects ; Tissue Distribution ; Benzofurans/chemistry/pharmacokinetics/therapeutic use ; Humans ; *Molecular Targeted Therapy/methods ; Male ; Isotope Labeling ; }, abstract = {OBJECTIVE: Amyloid-β (Aβ) aggregates have been recognized as therapeutic targets for Alzheimer's disease (AD). Targeted alpha therapy (TAT) using α-particles has the potential to be applied as a novel treatment approach for AD by reducing the quantity of Aβ aggregates. In this study, we developed a novel astatine-211-labeled pyridyl benzofuran (PBF) derivative, [[211]At]APBF-2, as a small molecule-based Aβ-TAT agent and evaluated its potential for in vivo use. METHODS: [[211]At]APBF-2 was synthesized in a one-step astatination process using the tributyltin precursor. In the Aβ aggregation inhibition assay, [[211]At]APBF-2 was added to a sample containing Aβ1-42 monomers and thioflavin-T (ThT) and the mixture was incubated for 24 h. The quantity of Aβ aggregates was evaluated by measuring ThT fluorescence intensity. The biodistribution of [[211]At]APBF-2 (25 kBq/100 μL) was evaluated using ddY mice (n = 5). RESULTS: [[211]At]APBF-2 was synthesized in radiochemical yield of 57% with a radiochemical purity of over 95%. In the in vitro assay, [[211]At]APBF-2 showed a dose-dependent decrease in ThT fluorescence intensity, suggesting the ability of [[211]At]APBF-2 to inhibit Aβ aggregation. In the biodistribution study using normal mice, the initial brain uptake of [[211]At]APBF-2 was observed (2.95% injected dose/g at 2 min), demonstrating favorable Blood-brain barrier permeability. CONCLUSIONS: These results suggest the feasibility of using [[211]At]APBF-2 as an Aβ-TAT agent for in vivo applications.}, } @article {pmid40795635, year = {2025}, author = {Zhou, W and Tian, L and Wang, X and Hou, G and Yu, J and Chen, M and Xu, C and Xue, L and Tan, X and Dai, R}, title = {Integrated untargeted and targeted metabolomics to reveal the mechanisms of herbal medicine HLXLD on Alzheimer's disease.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1265}, number = {}, pages = {124746}, doi = {10.1016/j.jchromb.2025.124746}, pmid = {40795635}, issn = {1873-376X}, mesh = {*Metabolomics ; Herbal Medicine ; *Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Animals ; Rats ; Disease Models, Animal ; Aluminum Chloride ; *Neuroprotective Agents/pharmacology/therapeutic use ; Neuroprotection/drug effects ; Male ; Rats, Sprague-Dawley ; Neurotransmitter Agents/analysis/metabolism ; Amino Acids/analysis/metabolism ; Arachidonic Acid/analysis/metabolism ; Lipids/analysis ; Lipid Metabolism ; Hypothalamus/metabolism/pathology ; }, abstract = {Huo-Luo-Xiao-Ling-Dan (HLXLD), a Chinese herbal medicine consisting of 11 herbs, has been shown to be effective in alleviating cognitive and memory impairment in Alzheimer's disease (AD). However, the underlying mechanisms require further investigation. This study aimed to clarify potential therapeutic mechanisms of HLXLD in the treatment of AD from a metabolic perspective. A rat model of AD induced by AlCl3 and D-gal was established, the Morris water maze (MWM) test and hippocampal histopathology were used to evaluate the pharmacological effect of the HLXLD on AD. Subsequently, untargeted metabolomics of brain tissues samples was performed by UHPLC-Q-Exactive-Orbitrap-MS, followed by multivariate statistical analysis. Targeted metabolomics by UHPLC-QQQ-MS was further employed to validate and supplement the untargeted metabolomics finding, involving neurotransmitters, amino acids, arachidonic acid and lipids, to elucidate the relationship between disease, herbal medicine and metabolism pathway. The study found that HLXLD could relieve the progression of AD and regulate metabolic imbalances. The levels of 26 metabolites decreased and 6 increased in brain tissues including lysine, taurine, fumaric acid, prostaglandin E2, choline and so on, these altered metabolites were primarily associated with amino acid metabolism, TCA cycle, arachidonic acid metabolism and lipid metabolism. The targeted metabolomics results showed that compared with the model group, the levels of 8 neurotransmitters, 21 amino acids, 7 arachidonic acids and 16 lipids in brain tissue, 9 neurotransmitters, 20 amino acids, 6 arachidonic acids and 2 lipids in plasma were changed. In summary, HLXLD could improve the levels of endogenous metabolites by regulating multiple metabolic pathways and play a role in energy supply, anti-neuroinflammatory and neuroprotective effects in AD treatment.}, } @article {pmid40794901, year = {2025}, author = {Tavakoli, E and Niciforos, E and Amid, P and Cuperfain, AB and Burhan, AM and Colman, S and Chu, L and Davies, SJC and Derkach, P and Gerretsen, P and Graff-Guerrero, A and Hussain, M and Ismail, Z and Kim, D and Krisman, L and Mulsant, BH and Pollock, BG and Rej, S and Rostas, A and Rajji, TK and Van Bussel, L and Kumar, S and Elmi, S}, title = {The impact of lifetime excessive alcohol use on behavioural and psychological symptoms of dementia.}, journal = {Alcohol and alcoholism (Oxford, Oxfordshire)}, volume = {60}, number = {5}, pages = {}, doi = {10.1093/alcalc/agaf048}, pmid = {40794901}, issn = {1464-3502}, support = {//The Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN)/ ; //Brain Canada Foundation/ ; //Centre for Aging and Brain Health Innovation/ ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Alcoholism/psychology/epidemiology/complications ; Alzheimer Disease/psychology ; Cross-Sectional Studies ; *Dementia/psychology/epidemiology ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION: Excessive alcohol use (EAU) elevates the risk of dementia through various mechanisms, yet its impact on the behavioural and psychological symptoms of dementia (BPSDs) remains uncertain. METHODS: In this exploratory cross-sectional analysis of baseline data from the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov/NCT03672201), we included individuals with Alzheimer's disease and related dementias requiring BPSD treatment. We compared demographic characteristics and presentation of BPSDs (using the total and domain scores on the Neuropsychiatric Inventory-Clinician) in those with and without a lifetime history of EAU. RESULTS: Among 193 participants [mean (SD) age: 80.6 (9.7) years, male: 48.4%], those in the EAU group (n = 17) and in the comparator group (n = 176) had severe and comparable cognitive impairment, with a median Functional Assessment Staging Tool for Dementia score of 6e. Participants with EAU were significantly younger than comparators [mean age (SD): 72.9 (7.1) years vs. 81.4 (9.5) years] (t = -3.678, df = 181, P < .001), and were more frequently male (76.5% [13 of 17] vs. 46.6% [82 of 176]; P = .036). In a sensitivity analysis, there were no differences in the Neuropsychiatric Inventory-Clinician total or individual domain scores between those with EAU and a subsample of those without EAU matched for age, sex, and recruitment site. CONCLUSION: This exploratory study found that among individuals with Alzheimer's disease and related dementias and BPSDs, lifetime history of EAU is more frequent in younger males. Future studies may further examine the impact of EAU in individuals with BPSDs.}, } @article {pmid40794806, year = {2025}, author = {Yoon, DM and Plante, D and Fleming, V and Handen, B and Lao, P and Peven, J and Christian, B and Okonkwo, O and Laymon, C and Ances, B and Hom, C and Helsel, B and Hartley, SL and , }, title = {Preliminary Investigation of Obstructive Sleep Apnea and Alzheimer's Disease in Down Syndrome.}, journal = {Sleep}, volume = {}, number = {}, pages = {}, doi = {10.1093/sleep/zpaf044}, pmid = {40794806}, issn = {1550-9109}, abstract = {This study provided a preliminary examination of indices of obstructive sleep apnea (OSA) and sleep disruptions in adults with Down syndrome (DS), and their associations with Alzheimer's disease (AD) pathology and symptomatology. Ninety-three adults with DS (aged 25-61 years) from the Alzheimer Biomarker Consortium - Down Syndrome completed cognitive assessments, MRI and PET scans (assessing amyloid-beta [Aβ] and tau), and a one-night home sleep study using the WatchPAT-300 device. Study partners also reported on depressive symptoms and diagnoses. Correlational analyses examined relationships between sleep variables, PET biomarkers, and AD symptomatology (cognitive functioning and depressive mood), controlling for sociodemographics. Eighty-one participants (87%) completed valid WatchPAT data. Of these, 60 (74%) screened positive for OSA, and an additional 11 had a prior OSA diagnosis and used CPAP during the test night. Nearly half (45%) of those screening positive for OSA had no prior diagnosis, indicating under-detection. Among the 22 participants using OSA treatment, 50% continued to show sleep-disordered breathing, suggesting suboptimal treatment effectiveness. Higher wake percentage and shorter total sleep time were associated with greater Aβ and tau burden. Cognitive performance was negatively associated with wake percentage, total sleep time, and oxygenation indices (minimum oxygen, desaturation, and time ≤ 88% oxygen). Depressive symptoms were negatively related to total sleep time. These findings add preliminary evidence linking sleep disruption and OSA with AD-related pathology and symptomatology. Larger, longitudinal studies are needed to confirm these associations and evaluate whether improving sleep quality and treating OSA may help delay AD onset in this high-risk population.}, } @article {pmid40794238, year = {2025}, author = {Jellinger, KA}, title = {Comorbid pathologies and their impact on progressive supranuclear palsy: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {40794238}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, abstract = {Progressive supranuclear palsy, a four-repeat tauopathy, is clinically characterized by early postural instability and falls, vertical supranuclear palsy, levodopa poorly-responsive parkinsonism, pseudobulbar palsy, and cognitive impairment. It is morphologically featured by accumulation of hyperphosphorylated tau protein in neurons and glia predominantly in the basal ganglia, brainstem tegmentum and frontal cortex, associated with degeneration of the extrapyramidal system and cortical atrophy. Isolated PSP neuropathology is uncommon, with nearly 70% showing co-neuropathologies including Alzheimer-type, Lewy body, TDP-43 pathologies, argyrophilic grains, and other tauopathies and neurodegenerative disorders (Parkinson disease, amyotrophic lateral sclerosis). The most common comorbid conditions are hypertension, cardiovascular and cerebrovascular diseases, diabetes mellitus, polyneuropathies, muscular and urological disorders. Due the increased prevalence of comorbidities and their eminent impact on the progress and outcome of the disease, clinical trials should account for them in their design and selection. However, currently little is known about co-pathologies in these patients. In view of the eminent burden of comorbidities and resulting therapeutic consequences, the frequency of the different co-pathologies in PSP and their clinical impact will be discussed. It should provide insight into their pathogenic backgrounds as a basis for adequate treatment procedures to improve the quality of life of patients with this fatal disease.}, } @article {pmid40792123, year = {2025}, author = {Zhi, N and Ren, R and Qi, J and Liu, X and Yun, Z and Lin, S and Hu, Y and Li, H and Xie, X and Wang, J and Li, J and Zhu, Y and Gao, M and Yang, J and Wang, Y and Jing, Y and Geng, J and Cao, W and Xu, Q and Yu, X and Zhu, Y and Zhou, Y and Wang, L and Gao, C and Li, B and Chen, S and Yuan, F and Dou, R and Liu, X and Li, X and Yin, Y and Chang, Y and Xu, G and Zhong, Y and Li, C and Wang, Y and Zhou, M and Wang, G}, title = {The China Alzheimer Report 2025.}, journal = {General psychiatry}, volume = {38}, number = {4}, pages = {e102020}, pmid = {40792123}, issn = {2517-729X}, abstract = {With the sustained growth of the economy and significant changes in social demographics, the issue of elderly-related diseases has increasingly drawn attention, particularly. Alzheimer's disease (AD), as a representative disease of neurodegenerative diseases, has become a major challenge, affecting the health and quality of life of the elderly population severely. In recent years, the incidence, prevalence and mortality rates of AD have increased in China, imposing substantial economic burdens on families, society and the entire healthcare system. To proactively address this challenge and respond to the national 'Healthy China Action' initiative, leading experts from authoritative institutions jointly authored the China Alzheimer Report 2025. Building on previous editions, this report updates epidemiological data on AD in China, thoroughly analyses the latest economic burdens of the disease and comprehensively evaluates the current status of AD diagnosis and treatment services, as well as the allocation of public health resources in our country. Its release reflects China's progress in AD research and prevention, underscores societal concern for elderly health and aims to provide scientific guidance and data support for AD prevention, diagnosis and treatment. It also facilitates academic exchanges and cooperation, enhancing public awareness and promoting active participation in elderly healthcare, towards achieving 'healthy ageing' in China.}, } @article {pmid40792047, year = {2025}, author = {Mannai, A and Ressaissi, A and Merghni, A and Chahdoura, H and Mnif, W and Alelyani, Z and Ben-Attia, M and El-Bok, S and Serralheiro, ML}, title = {Phytochemical Profile and Evaluation of Antioxidant Activity, Enzyme Inhibition and Cell Viability of Leaves Extracts of Three Tunisian Varieties of Diospyros kaki L.}, journal = {Food science & nutrition}, volume = {13}, number = {8}, pages = {e70775}, pmid = {40792047}, issn = {2048-7177}, abstract = {Because of their biological qualities, the leaves of Diospyros kaki L., also known as persimmon, have long been used in traditional Chinese medicine for the treatment of ischemic stroke, angina, internal hemorrhage, hypertension, atherosclerosis, and some infectious diseases. It has also been used in cosmetics, as well as in refreshing drink preparations. In the present study, we have compared the aqueous extract effects of the leaves of the three Tunisian varieties of D. kaki, namely Triumph, Jiro, and Rojo Brillante, prepared by decoction and then filtered. The obtained filtrates were lyophilized and kept cold until analysis. Phytochemical profile and biological activities were performed on the freeze-dried fractions of the different varieties of D. kaki. Analysis of the results shows that the leaf extracts of the three varieties are rich in total phenols and flavonoids (ranking: Rojo Brillante > Triumph > Jiro) and have a high antioxidant activity (EC50 values of 3.8, 8.0 and 12.1 μg/mL respectively for Rojo Brillante, Triumph and Jiro). Using a quadrupole time-of-flight interface and high-resolution tandem liquid chromatography, 29 secondary metabolites of D. kaki leaf decoctions were identified in the three varieties, including several polyphenols such as flavonoids, tannins, organic acids, and others. In addition, these extracts were found to inhibit the function of two key enzymes, acetylcholinesterase (IC50 values of 58, 96 and 210 μg/mL respectively for Rojo Brillante, Triumph and Jiro) and inhibition percentages of 3-hydroxy-3-methylglutaryl-CoA reductase were 61.44%, 57.35%, and 46.28% for Jiro, Triumph, and Rojo Brillante, respectively. However, we noted that these different extracts had no cytotoxic effect on human liver or breast cancer cells in culture until 10 μg/mL. The results reveal that the D. kaki leaves are a potential matrix for the launch of future nutraceuticals, cosmetics, and pharmaceutical specialties such as drugs to combat Alzheimer's disease or to reduce cholesterol levels, as well as an attractive source of ingredients beneficial to health. Comparative analysis of D. kaki leaves showed that the Rojo Brillante variety has a higher content of secondary metabolites than the other two varieties, thus increasing its antioxidant activity and enzyme inhibitory effect, although it is not as cytotoxic as the other two varieties.}, } @article {pmid40791780, year = {2025}, author = {Mahendrarajan, V and Lazarus, HPS and Muthukaliannan, GK and Varghese, S and Easwaran, N}, title = {Membrane vesicles from Red Complex bacteria: key players in oral pathogenesis, immune disruption, systemic diseases, and therapeutic insights.}, journal = {Frontiers in oral health}, volume = {6}, number = {}, pages = {1607931}, pmid = {40791780}, issn = {2673-4842}, abstract = {The oral cavity serves as a habitat for a diverse array of microorganisms, each performing distinct functions, thereby constituting a vibrant and intricate ecological community. The most common pathogenic bacteria in the oral ecosystem are the Red Complex group, which includes Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. These bacteria have several ways to inflict damage, such as creating biofilms and secreting nano-sized vesicles from their outer membrane, called Outer Membrane Vesicles (OMV). OMVs are nano structures that carry proteins, lipids, and toxins from the outer membrane of Gram-negative bacteria. The OMVs of Red Complex bacteria play a role in the onset and development of oral pathological conditions such as gingivitis and periodontitis. Additionally, a substantial body of evidence supports the notion that these OMVs may exert influence on systemic pathologies, including atherosclerosis, alzheimer's, rheumatoid arthritis, and diabetes mellitus. This review will discuss the formation and composition of Red Complex bacterial OMVs, their impacts on the oral environment, the immune response, and their correlations with various systemic diseases. The suggested treatment approach by probiotics and bioactives focuses on the genetic elements that induce the production of OMVs by the Red Complex bacteria, offering a potent means to hinder the advancement of diseases propagated through these OMVs.}, } @article {pmid40791767, year = {2025}, author = {Wang, X and Li, J and Fu, Q and Zheng, H and Duan, S and Gao, Y and Luo, H and Xu, Y}, title = {Cerebral Amyloid Angiopathy-Related Inflammation: Clinical Characteristics and Treatment Experience.}, journal = {Clinical interventions in aging}, volume = {20}, number = {}, pages = {1181-1190}, pmid = {40791767}, issn = {1178-1998}, mesh = {Humans ; *Cerebral Amyloid Angiopathy/complications/diagnosis/diagnostic imaging/therapy/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Retrospective Studies ; Aged, 80 and over ; Adult ; *Inflammation/etiology ; Neuroimaging ; Cognitive Dysfunction/etiology ; }, abstract = {OBJECTIVE: The present study aims to analyze the clinical manifestations, laboratory results, neuroimaging features, treatment interventions, and outcomes in a cohort of patients with cerebral amyloid angiopathy-related inflammation (CAA-ri), providing a deeper understanding of this rare subtype of CAA and enhancing diagnostic precision in clinical practice. METHODS: We conducted a systematic retrospective review of clinical records from 13 consecutive patients who met the diagnostic criteria for probable CAA-ri and were evaluated at the First Affiliated Hospital of Zhengzhou University between January 2021 and August 2024. RESULTS: The study cohort comprised 13 patients (7 males, 6 females; mean age 65.2 years, range 42-81), predominantly presenting with subacute onset (53.8%, n=7). Cognitive impairment (61.5%, n=8) emerged as the most frequent clinical manifestation, followed by headache (46.2%, n=6), epileptic seizures (30.8%, n=4), and focal neurological deficits (23.1%, n=3). Neuroimaging findings across all patients demonstrated asymmetric white matter hyperintensities in conjunction with cortical-subcortical cerebral microbleeds. A subset of patients exhibited cortical superficial siderosis lobar hemorrhage, and/or punctate acute infarction. Among the nine patients who underwent lumbar puncture, five showed elevated cerebrospinal fluid (CSF) pressure and protein levels. All four patients assessed for CSF Alzheimer's disease biomarkers showed reduced Aβ42 and Aβ40 levels, alongside elevated total tau and phosphorylated tau levels. Furthermore, over 70% of the patients who treated with immunosuppressive therapy achieved favorable clinical outcomes. CONCLUSION: Clinical manifestations and neuroimaging abnormalities serve as pivotal non-invasive criteria for guiding clinicians in the diagnosis of CAA-ri. Timely initiation of immunosuppressive therapy in CAA-ri patients can lead to favorable outcomes.}, } @article {pmid40791424, year = {2025}, author = {Adaikkan, C and Islam, MR and Bozzelli, PL and Sears, M and Parro, C and Pao, PC and Sun, N and Kim, T and Abdelaal, K and Sedgwick, M and Kellis, M and Tsai, LH}, title = {A multimodal approach of microglial CSF1R inhibition and GENUS provides therapeutic effects in Alzheimer's disease mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40791424}, issn = {2692-8205}, support = {R01 AG069232/AG/NIA NIH HHS/United States ; R01 NS122742/NS/NINDS NIH HHS/United States ; R56 AG069232/AG/NIA NIH HHS/United States ; }, abstract = {The CSF1R inhibitor PLX3397, an FDA-approved treatment for a rare cancer, has been shown to reduce microglia count, lower inflammation, and increase synaptic markers in mouse models of Alzheimer's disease (AD). However, the effects of PLX3397 on neural function in AD remain largely unknown. Here, we characterized the effects of PLX3397 treatment in 5xFAD mice. While PLX3397 increased synaptic density, it reduced the percentage of neurons phase-locked to gamma oscillations. This neural decoupling was closely associated with gene expression changes related to synapse organization. We investigated whether Gamma ENtrainment Using Sensory (GENUS) stimulation could counterbalance the neural circuit alterations induced by PLX3397. GENUS + PLX3397 restored gamma phase-locking, reshaped gene expression signatures, and improved learning and memory better than either treatment alone in 5xFAD mice. These findings suggest that CSF1R inhibitors like PLX3397 may benefit from a multimodal approach combining microglial targeting with non-invasive sensory stimulation to support neural physiology and improve cognitive function in AD.}, } @article {pmid40791064, year = {2025}, author = {Rodrigues, CC and Carvalho, V and Sotero, FD and Mulroy, E and Guedes, LC}, title = {Efficacy and safety of cholinesterase inhibitors and memantine for cognitive symptoms in patients with Huntington's disease: A systematic review.}, journal = {Journal of Huntington's disease}, volume = {14}, number = {4}, pages = {331-339}, doi = {10.1177/18796397251367689}, pmid = {40791064}, issn = {1879-6400}, mesh = {Humans ; *Memantine/therapeutic use/adverse effects/pharmacology ; *Cholinesterase Inhibitors/therapeutic use/adverse effects/pharmacology ; *Huntington Disease/drug therapy/complications ; *Cognitive Dysfunction/drug therapy/etiology ; }, abstract = {BackgroundHuntington's Disease (HD) is an autosomal dominant neurodegenerative disorder. Clinical features encompass a broad spectrum of movement disorders, psychiatric and cognitive symptoms, often progressing to dementia and imposing a substantial burden on patients and their families. While cholinesterase inhibitors and memantine are often used for symptomatic treatment of Alzheimer's Disease and other dementias, there is currently no approved medication for treating cognitive symptoms in HD.ObjectiveWe aim to review, summarize, and appraise evidence from the literature for the use of cholinesterase inhibitors and memantine in the treatment of cognitive symptoms in patients with HD.MethodsA searched was conducted in PubMed and SCOPUS, from inception until February 2024, for Randomized Clinical Trials (RCTs), open-label, and case-control studies. Quality appraisal was performed using ROBINS-I and ROB2 for non-randomized studies and RCTs, respectively.ResultsFive eligible studies (three RCTs, one extension study, and one retrospective case-control), exploring the use of rivastigmine (n = 3), memantine (n = 1), and donepezil (n = 1) were found. Only two had a follow-up period longer than eight months. Previous cognitive functioning was not specified in three out of five studies. Cognitive measures varied widely, with Unified Huntington's Disease Rating Scale and Mini-Mental State Exam being used more frequently. None of the studies showed a significant improvement in cognitive function. Side effects occurred in up to 50% of patients and were usually considered mild.ConclusionsThere is insufficient evidence in the literature to support the use of cholinesterase inhibitors or memantine for cognitive symptoms in patients with HD.}, } @article {pmid40790925, year = {2025}, author = {Dodel, R and Frölich, L}, title = {Donanemab for Alzheimer's disease: from preclinical research to the clinical application.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {10}, pages = {1151-1163}, doi = {10.1080/14737175.2025.2546868}, pmid = {40790925}, issn = {1744-8360}, mesh = {*Alzheimer Disease/drug therapy/physiopathology ; Humans ; Amyloid beta-Peptides/immunology ; *Antibodies, Monoclonal, Humanized/pharmacology/administration & dosage/adverse effects/therapeutic use ; Animals ; Cognitive Dysfunction/drug therapy ; }, abstract = {INTRODUCTION: Donanemab (Kisunla) is a humanized IgG1 monoclonal antibody specifically targeting a modified form of β-amyloid found predominantly within plaques (characterized as N-terminal pyroglutamate Aβ). Recently, it has gained approval for the use in early-stage Alzheimer's disease (AD) encompassing mild cognitive impairment due to AD or mild AD with confirmed brain amyloid pathology. AREAS COVERED: This drug profile discusses donanemab's function, clinical effectiveness, safety, tolerability, health economics, access challenges, and future prospects. This article is based on systematic review that was derived from PubMed. EXPERT OPINION: Donanemab is the third monoclonal antibody introduced for the treatment of individuals in the early stage of AD. While critical dialog continues regarding the potential impacts and role of antibody therapies, its approval signifies considerable progress in addressing the underlying pathology of AD. The authors are confident in the potential of antibodies against Aβ as a promising treatment option and foresee exciting advancements. However, further research is needed on trials extending beyond 18 months of follow-up, postmarketing surveillance, and the application of donanemab in combination with existing treatments and lifestyle interventions. Additionally, significant knowledge gaps and implementation limitations persist and must be addressed.}, } @article {pmid40790613, year = {2025}, author = {Li, B and Wang, S and Kerman, B and Hugo, C and Shwab, EK and Shu, C and Chiba-Falek, O and Arvanitakis, Z and N Yassine, H}, title = {Microglial States Are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease.}, journal = {Aging cell}, volume = {24}, number = {10}, pages = {e70189}, pmid = {40790613}, issn = {1474-9726}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; //Vranos Foundation/ ; P30AG72975/AG/NIA NIH HHS/United States ; R01 AG074003/AG/NIA NIH HHS/United States ; T32 GM087237/GM/NIGMS NIH HHS/United States ; RF1 AG076124/AG/NIA NIH HHS/United States ; R01AG055770/AG/NIA NIH HHS/United States ; R21AG056518/AG/NIA NIH HHS/United States ; R01 AG062335/AG/NIA NIH HHS/United States ; R01AG057522/AG/NIA NIH HHS/United States ; U01 MH119509/MH/NIMH NIH HHS/United States ; RF1 AG054012/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; R01 HG008155/HG/NHGRI NIH HHS/United States ; R01 AG058002/AG/NIA NIH HHS/United States ; //Tiny Foundation/ ; RF1 AG077695/AG/NIA NIH HHS/United States ; //Ms. Lynne Nauss/ ; U01 AG061356/AG/NIA NIH HHS/United States ; UG3 NS115064/NS/NINDS NIH HHS/United States ; R01AG15819/AG/NIA NIH HHS/United States ; R01AG054434/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; UH3 NS115064/NS/NINDS NIH HHS/United States ; R01 AG067063/AG/NIA NIH HHS/United States ; RF1 AG062377/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R01 AG054434/AG/NIA NIH HHS/United States ; AARFD-24-1313939/ALZ/Alzheimer's Association/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R01 AG055770/AG/NIA NIH HHS/United States ; RF1AG076124/AG/NIA NIH HHS/United States ; P30AG066530/AG/NIA NIH HHS/United States ; RF1 AG054321/AG/NIA NIH HHS/United States ; GC-201711-2014197//Alzheimer's Drug Discovery Foundation/ ; U01 NS110453/NS/NINDS NIH HHS/United States ; R01 AG057522/AG/NIA NIH HHS/United States ; RF1AG077695/AG/NIA NIH HHS/United States ; R01AG067063/AG/NIA NIH HHS/United States ; R21 AG056518/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; *Microglia/metabolism/pathology ; Humans ; *Cholesterol/metabolism ; *Cellular Senescence ; }, abstract = {Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the ROSMAP and SEA-AD cohorts to uncover cell type-specific senescence pathologies. In ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex), microglia emerged as central contributors to AD-associated senescence phenotypes among non-neuronal cells. Homeostatic, inflammatory, phagocytic, lipid-processing, and neuronal-surveillance microglial states were associated with AD-related senescence in both ROSMAP (152,459 microglia nuclei from six brain regions) and SEA-AD (82,486 microglia nuclei) via integrative analysis. We assessed top senescence-associated bioprocesses and demonstrated that senescent microglia exhibit altered cholesterol-related processes and dysregulated cholesterol metabolism. We identified three gene co-expression modules representing cholesterol-related senescence signatures in postmortem brains. To validate these findings, we applied these signatures to snRNA-seq data from iPSC-derived microglia（iMGs) exposed to myelin, Aβ, apoptotic neurons, and synaptosomes. Treatment with AD-related substrates altered cholesterol-associated senescence signatures in iMGs. This study provides the first human evidence that dysregulated cholesterol metabolism in microglia drives cellular senescence in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to attenuate AD progression.}, } @article {pmid40790282, year = {2025}, author = {Higuchi, M and Tagai, K and Takahata, K and Endo, H}, title = {Advances in PET imaging of protein aggregates associated with neurodegenerative disease.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {9}, pages = {506-522}, pmid = {40790282}, issn = {1759-4766}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; *Positron-Emission Tomography/methods/trends ; *Protein Aggregates/physiology ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; alpha-Synuclein/metabolism ; *Protein Aggregation, Pathological/diagnostic imaging/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy (MSA) are characterized pathologically by deposition of specific proteins in the brain. Five major neurodegenerative disease-associated proteins - amyloid-β (Aβ), tau, α-synuclein, TAR DNA-binding protein 43 (TDP43) and fused in sarcoma (FUS) - are commonly encountered, and the disease specificity and neurotoxicity of the fibrillar protein assemblies are determined by factors such as the protein type, fibril structure, degree of multimerization and post-translational modifications. This article reviews the latest advances in PET technologies aimed at visualizing neurodegenerative proteinopathies, and highlights the importance of these technologies for emerging diagnostic and therapeutic approaches. PET allows Aβ deposition to be visualized throughout the natural history of AD and following anti-Aβ immunotherapies. However, whether this technology can visualize specific Aβ assembly subspecies primarily targeted by the treatment remains inconclusive. Various PET radiotracers can capture AD-type tau deposits, although only a few are known to react with non-AD tau pathologies, and cryo-electron microscopy has revealed the mode of binding of these compounds to different tau protofibrils. High-contrast PET imaging of α-synuclein lesions in MSA is a recent development in the field, and gradual progress is being made towards visualization of other, less abundant α-synuclein pathologies. Imaging of TDP43 and FUS deposits presents particular challenges, which might be overcome by establishing public-private partnerships focused on biomarker development.}, } @article {pmid40787376, year = {2025}, author = {Gebeş-Alperen, B and Evren, AE and Sağlik Özkan, BN and Karaburun, AC and Gundogdu-Karaburun, N}, title = {Novel Benzofuran-3-yl-methyl and Aliphatic Azacyclics: Design, Synthesis, and In Vitro and In Silico anti-Alzheimer Disease Activity Studies.}, journal = {ACS omega}, volume = {10}, number = {30}, pages = {32829-32843}, pmid = {40787376}, issn = {2470-1343}, abstract = {Neurological disorders represent a significant burden on human health, particularly as global life expectancy continues to rise. Among these conditions, Alzheimer's disease is notably prevalent. Of greater concern, if left untreated or unaddressed, Alzheimer's disease can progress to dementia, leading to severe cognitive decline and a substantial reduction in quality of life. In this study, 15 novel benzofuran-azacyclic hybrids were designed and synthesized. The final compounds were evaluated for their inhibitory potency on AChE and BACE-1 enzymes, and in silico studies were performed to clarify their binding modes. Finally, structure-activity relationships (SARs) were proposed for future studies. The results indicated that the most promising compound is 4m, which contains N-(2-hydroxyethyl)-piperazine and benzofuran moieties. These moieties effectively occupied the substrate channel of the AChE enzyme and the catalytic cleft of the BACE-1 enzyme. Additionally, compounds 4e (benzyl piperidine) and 4h (2-furoyl piperazine) showed dual inhibitory activity on both enzymes. In conclusion, the tubular form with a stopper group shows great potential for the treatment of Alzheimer's disease, as it blocks the entrance cavity of the AChE active pocket for the substrate and increases the stability of the inactive BACE-1 enzyme. Moreover, electrolytes, specifically sodium ions in this case, play a crucial role in stabilizing the 4m-BACE-1 protein complex. For further studies, we suggest that the tubular form with a stopper can serve as a potential pharmacophore and an appropriate starting point for drug development.}, } @article {pmid40786362, year = {2025}, author = {Chowdhury, A and Bhasin, G and Ganti, L}, title = {Bibliometric Analysis of the Epidemiological Research on Alzheimer's Disease Treatment.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e87484}, pmid = {40786362}, issn = {2168-8184}, abstract = {Alzheimer's disease presents a complex global health issue. It is characterized by a decline in cognitive function, starting with memory impairment, and extending to impact reasoning, language abilities, and spatial awareness. Despite decades of research, Alzheimer's disease remains a global challenge lacking long-term treatments. Institutions like the Karolinska Institutet, Columbia University, the University of California San Francisco (UCSF), and the University of Pittsburgh contribute significantly to Alzheimer's research, with a growth in publications in 2022 post-COVID-19. While current treatments offer symptomatic relief, there's a need for disease-modifying therapies targeting its mechanisms. This analysis aims to provide a comprehensive overview of the available research and medical literature on Alzheimer's disease by employing bibliometric methods to identify publication trends, leading research institutions, and the evolving focus from symptomatic treatments to disease-modifying therapies. This paper seeks to analyze the research papers on Alzheimer's disease and catalog the metadata associated with each paper.}, } @article {pmid40785177, year = {2025}, author = {Varshney, H and Gaur, K and Subhan, I and Fatima, J and Jyoti, S and I, M and Shahid, M and -, R and Siddique, YH}, title = {Neuroprotective Effects of Fenugreek Leaf Extract in a Drosophila Model of Alzheimer's Disease Expressing Human Aβ-42.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050385870250721072643}, pmid = {40785177}, issn = {1875-5828}, abstract = {INTRODUCTION: Much emphasis has been given to the biological activities of Fenugreek against various diseased conditions. This study investigated the effect of fenugreek leaf extract on behavioural and cognitive function of transgenic Drosophila having human Aβ-42 expression in the neurons, herein referred to as Alzheimer's disease model flies (AD flies). MATERIALS AND METHODS: AD flies were exposed to four different doses of fenugreek leaf extract (FE) containing i.e., 0.005, 0.010, 0.015 and 0.02 g/ml for 30 days. Thereafter, behavioural and cognitive assessment was done using climbing ability, activity pattern, aversive phototaxis and odour choice indexes. The life span of different groups of flies was also recorded. The effect of FE on the oxidative stress markers, acetylcholinesterase, monoamine oxidase (MAO) and caspase 3 and 9 activities was determined. The deposition of Aβ-42 aggregates in the brain tissue of the flies was studied by performing immunostaining. Also, the metabolic profile of different groups of flies was studied by performing LC-MS/MS. Compared with control flies, 22 selected metabolites were found to be upregulated and downregulated among transgenic AD flies and FE exposed AD flies compared to control. RESULTS: The findings of this study showed the neuroprotective role of fenugreek extract, which could be employed for the treatment of Alzheimer's disease. The AD flies exposed to FE showed a dose-dependent postponement in the decline of climbing ability, activity and cognitive impairments. A significant dose dependent increase in the life span was also noticed in the AD flies exposed to FE. A significant reduction in the oxidative stress, acetylcholinesterase, monoamine oxidase, and caspase-3&9 activities was also observed in a dose dependent manner. The results obtained from the immunostaining suggest the reduction in the deposition of Aβ-42 fibril, which was also confirmed by the docking studies showing the energetically favoured interaction useful for inhibiting the acetylcholinesterase and Aβ-42 aggregates. DISCUSSION: This study demonstrates the neurological potency of fenugreek leaf extract (FE) in a Drosophila model of AD due to its antioxidantive, anti-cholinesterase, and neuroprotective properties. Using a combination of behavioral, biochemical, histological, and metabolomic approaches, we evaluated the therapeutic potential of FE in mitigating AD-like symptoms in transgenic flies expressing Aβ-42. CONCLUSION: Fenugreek leaf extract may serve as a potential natural remedy for slowing down or alleviating the progression of AD.}, } @article {pmid40784967, year = {2025}, author = {Şener, B and Açıcı, K and Sümer, E}, title = {Improving early detection of Alzheimer's disease through MRI slice selection and deep learning techniques.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {29260}, pmid = {40784967}, issn = {2045-2322}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; Early Diagnosis ; Cognitive Dysfunction/diagnostic imaging/diagnosis ; Aged ; Brain/diagnostic imaging/pathology ; Male ; Female ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disorder marked by cognitive decline, memory loss, and behavioral changes. Early diagnosis, particularly identifying Early Mild Cognitive Impairment (EMCI), is vital for managing the disease and improving patient outcomes. Detecting EMCI is challenging due to the subtle structural changes in the brain, making precise slice selection from MRI scans essential for accurate diagnosis. In this context, the careful selection of specific MRI slices that provide distinct anatomical details significantly enhances the ability to identify these early changes. The chief novelty of the study is that instead of selecting all slices, an approach for identifying the important slices is developed. The ADNI-3 dataset was used as the dataset when running the models for early detection of Alzheimer's disease. Satisfactory results have been obtained by classifying with deep learning models, vision transformers (ViT) and by adding new structures to them, together with the model proposal. In the results obtained, while an accuracy of 99.45% was achieved with EfficientNetB2 + FPN in AD vs. LMCI classification from the slices selected with SSIM, an accuracy of 99.19% was achieved in AD vs. EMCI classification, in fact, the study significantly advances early detection by demonstrating improved diagnostic accuracy of the disease at the EMCI stage. The results obtained with these methods emphasize the importance of developing deep learning models with slice selection integrated with the Vision Transformers architecture. Focusing on accurate slice selection enables early detection of Alzheimer's at the EMCI stage, allowing for timely interventions and preventive measures before the disease progresses to more advanced stages. This approach not only facilitates early and accurate diagnosis, but also lays the groundwork for timely intervention and treatment, offering hope for better patient outcomes in Alzheimer's disease. The study is finally evaluated by a statistical significance test.}, } @article {pmid40784648, year = {2025}, author = {Zhang, F and Gou, J}, title = {Using multiple biomarkers for patient enrichment in two-stage clinical designs.}, journal = {Contemporary clinical trials}, volume = {156}, number = {}, pages = {108012}, doi = {10.1016/j.cct.2025.108012}, pmid = {40784648}, issn = {1559-2030}, mesh = {Humans ; *Biomarkers/analysis ; *Research Design ; *Alzheimer Disease/therapy/drug therapy ; *Precision Medicine/methods ; Sample Size ; *Clinical Trials as Topic/methods ; }, abstract = {Enrichment strategies play a critical role in modern clinical trial design, especially as precision medicine advances the focus on patient-specific efficacy. By targeting biomarker-defined populations most likely to benefit, these strategies improve efficiency, reduce sample sizes and costs, accelerate timelines, and minimize unnecessary exposure to treatment-related risks and side effects. Recent developments in enrichment design have introduced biomarker randomness and accounted for the correlation structure between treatment effect and biomarker, resulting in a two-stage threshold enrichment design. However, existing methods are limited to a single continuous biomarker. While incorporating multiple biomarkers can improve the accuracy of target population identification, no study has examined how to incorporate multiple continuous biomarkers into enrichment designs due to the challenges in determining multiple thresholds. To fully utilize information from all relevant biomarkers, we propose novel two-stage enrichment designs capable of handling two or more continuous biomarkers. Our framework accommodates two popular treatment effect metrics including average treatment effect (ATE) and the standardized ATE. We illustrate our method using a hypothetical clinical trial involving early-stage Alzheimer's patients and assess the impact of stage one sample size on threshold estimation through a simulation study. Overall, our proposed two-stage enrichment designs offer researchers greater flexibility in integrating multiple continuous biomarkers. The findings from our study provide valuable insights for the advancement of enrichment trial methodology.}, } @article {pmid40784620, year = {2025}, author = {Liu, L and Jiang, M and Zhang, Y and Lv, L and Wang, X and Yang, X}, title = {Acori Tatarinowii Rhizoma inhibited neuroinflammation in Alzheimer's disease rats by modulating the intestinal flora.}, journal = {Brain research}, volume = {1865}, number = {}, pages = {149878}, doi = {10.1016/j.brainres.2025.149878}, pmid = {40784620}, issn = {1872-6240}, mesh = {Animals ; *Gastrointestinal Microbiome/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; Male ; *Acorus ; Rats, Sprague-Dawley ; Rhizome ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Brain/drug effects/metabolism/pathology ; Drugs, Chinese Herbal/pharmacology ; *Plant Extracts/pharmacology ; Amyloid beta-Peptides ; }, abstract = {Alzheimer's disease (AD) is a degenerative disorder causing neuronal loss and cognitive deficits, which is associated with intestinal flora dysbiosis. Acori Tatarinowii Rhizoma (ATR) is the dried rhizome of Acorus tatarinowii Schott., and exhibits neuroprotective effects. We aimed to investigate the therapeutic mechanism of ATR in AD. AD rat models were constructed by intracerebroventricular injection of Aβ1-42, with gavage of ATR water extract (5, 10, and 20 mg/kg) for 21 days. Behavior tests, HE staining, immunohistochemistry, ELISA, immunofluorescence, and 16S rRNA sequencing were performed. In AD rats, ATR improved cognitive dysfunction and brain histopathological damage, with reduced Aβ1-42, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, malondialdehyde, ionized calcium binding adaptor molecule, and glial fibrillary acidic protein expression, and higher superoxide dismutase activity, indicating inhibition of neuroinflammation by ATR. Moreover, Ruminococcus was strongly associated with ATR treatment for AD, which mainly enriched in Carbohydrate metabolism, Amino acid metabolism, and Lipid metabolism. Meanwhile, Dorea was negatively correlated with behavioural indicators and positively correlated with inflammatory factors, whereas g_Adlercreutzia showed the opposite trend. These findings suggested that ATR may attenuate neuroinflammation and improved AD by modulating intestinal flora and inhibiting microglia and astrocyte activation, providing a scientific basis for its clinical application in AD.}, } @article {pmid40784614, year = {2025}, author = {Yang, Y and Zhang, L and Zhao, Y and Chen, Z and Wang, P and Yang, Z}, title = {Aβ-damaged neural stem cells migration and differentiation through Wnt3a/β-catenin pathway: Protective effects of 17β-E2.}, journal = {Neuroscience letters}, volume = {865}, number = {}, pages = {138350}, doi = {10.1016/j.neulet.2025.138350}, pmid = {40784614}, issn = {1872-7972}, mesh = {Animals ; *Neural Stem Cells/drug effects/metabolism ; *Wnt3A Protein/metabolism ; *beta Catenin/metabolism ; *Cell Movement/drug effects ; Rats, Sprague-Dawley ; *Cell Differentiation/drug effects ; *Amyloid beta-Peptides/toxicity ; Rats ; Female ; Cells, Cultured ; *Peptide Fragments/toxicity ; Signal Transduction/drug effects ; Neurogenesis/drug effects ; Glycogen Synthase Kinase 3 beta/metabolism ; }, abstract = {Alzheimer's disease (AD) is a widespread central nervous system degenerative disease in the elderly population. This study aims to uniquely targets this sex-specific vulnerability by investigating the effects of 17β-E2 on the differentiation and migration capabilities of Aβ-damaged NSCs and its potential mechanisms-a critical gap for female-focused AD therapies. Primary NSCs isolated from neonatal SD rats were treated with Aβ25-35 (60 μM) to mimic AD pathology, followed by 17β-E2 (100 nM) with or without BX795 (a Wnt3a/β-catenin inhibitor). Results showed that Aβ significantly suppressed Wnt3a, LRP6, and β-catenin mRNA/protein levels while increasing GSK-3β expression. 17β-E2 treatment reversed these effects, enhancing phosphorylated GSK-3β (Ser9) and β-catenin, which were abolished by BX795. Transwell assays demonstrated that 17β-E2 rescued Aβ-damaged migration deficits, accompanied by elevated p-MLC and Cdc42 protein levels. Furthermore, 17β-E2 promoted neuronal differentiation, increasing MAP2 + and βIII-tubulin + cells with enhanced dendritic complexity, whereas BX795 counteracted these benefits. These findings indicate that 17β-E2 mitigates Aβ-damaged NSCs dysfunction by activating the Wnt3a/β-catenin pathway via GSK-3β phosphorylation, highlighting its therapeutic potential for AD by enhancing neurogenesis and NSC mobility.}, } @article {pmid40784611, year = {2025}, author = {Maurice, T}, title = {Prevention of memory impairment and hippocampal injury with blarcamesine in an Alzheimer's disease model.}, journal = {Neuroscience letters}, volume = {865}, number = {}, pages = {138349}, doi = {10.1016/j.neulet.2025.138349}, pmid = {40784611}, issn = {1872-7972}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/prevention & control/pathology ; *Memory Disorders/prevention & control ; Mice ; *Hippocampus/drug effects/pathology/metabolism ; Amyloid beta-Peptides/toxicity ; Disease Models, Animal ; Male ; Peptide Fragments/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is the most common dementia, with rising global prevalence, still incomplete pathogenetic understanding and very limited effective therapies. Recent advances in biomarker identification of Aβ peptides and phospho-tau protein, and in anti-Aβ immunotherapy are suggesting that more early intervention will be more effective. Alternative therapeutic strategies to anti-Aß immunotherapy have received comparably less attention, yet one specific approach toward upstream neuroprotection by improvement of intracellular calcium homeostasis, activation of endogenous neuroprotection and restoration of autophagy through sigma-1 receptor activation recently demonstrated positive clinical data with oral blarcamesine in a phase IIb/III trial in 508 patients with early AD. AD-preventive approaches beyond lifestyle interventions become attractive candidates when meeting criteria of: (i) record of effective early intervention in mild disease, (ii) record of human safety, (iii) ease of administration, (iv) scalability to population level, (v) relative cost-effectiveness considering longer-term preventive use at population level. Here, we assessed blarcamesine's efficacy at preventing memory impairment and brain oxidative injury in the mouse preclinical model induced by intracerebroventricular injection of aggregated Aβ25-35 peptide, that permitted a clean preventive approach before administration of the pathology-inducing amyloidogenic Aβ fragment. We observed significant preventions of Aβ25-35-induced memory impairments, for both spatial working and contextual long-term memories, and of Aβ25-35-induced increase in lipid peroxidation in the mouse hippocampi. These new insights, together with blarcamesine's clinical record in early AD render blarcamesine an attractive candidate for AD pharmacological prevention.}, } @article {pmid40784568, year = {2025}, author = {Yang, Y and Guan, PP and Wang, P}, title = {Triptolide induces the secretion of insulin, through which it alleviates the tauopathies of Alzheimer's disease via inhibiting the phosphorylation of tau.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 3}, pages = {117223}, doi = {10.1016/j.bcp.2025.117223}, pmid = {40784568}, issn = {1873-2968}, mesh = {Animals ; *Diterpenes/pharmacology/therapeutic use ; *Alzheimer Disease/metabolism/drug therapy ; *tau Proteins/metabolism/antagonists & inhibitors ; Phosphorylation/drug effects/physiology ; *Phenanthrenes/pharmacology/therapeutic use ; Mice ; *Insulin/metabolism ; Epoxy Compounds/pharmacology/therapeutic use ; Male ; *Tauopathies/metabolism/drug therapy ; Mice, Transgenic ; Mice, Inbred C57BL ; Humans ; }, abstract = {Triptolide (TP) has shown its therapeutic effects on Alzheimer's disease (AD) via decreasing the overloading of β-amyloid protein (Aβ). However, the roles and mechanisms of TP in the pathogenesis of tau have not been revealed until now. To this end, the current study aimed to assess the effects of TP on AD via tau-associated mechanisms. In detail, TP treatment decreases the phosphorylation of tau, which results in attenuating the cognitive decline of PS19 mice. In the mechanisms, we found that TP treatment elevates the levels of insulin, which lowers the blood glucose, leading to superior performance in the glucose tolerance test, inhibition of AMP-activated protein kinase (AMPK), and the change of serum triglycerides and cholesterol. The in vitro studies demonstrating that TP increases insulin production via cAMP-response element binding protein (CREB)- and pancreatic-duodenal homeobox factor 1 (PDX-1)-dependent mechanisms in MIN6 cells further supported the in vivo findings. By enhancing insulin production, TP upregulates protein O-GlcNAc modification and inhibits Ca[2+]/calmodulin-dependent protein kinase 2 (CaMK2) activity to reduce tau phosphorylation in both in vivo and in vitro experiments. Additionally, metabolic changes decrease the activity of the CCAAT/enhancer binding protein beta (C/EBPβ)/asparagine endopeptidase (AEP) signaling pathway, significantly reducing the associated neuroinflammation. Guided by these mechanisms, TP shows inhibitory effects on tau phosphorylation via an insulin secretion-dependent pathway.}, } @article {pmid40784411, year = {2025}, author = {Yang, J and Chen, Y and Dong, G and Ma, Y and Lin, R and Yuan, Y}, title = {Immune-metabolic perspective on the association of seven psychiatric disorders and five common auditory diseases: a bidirectional two-sample Mendelian randomization study and mediation analysis.}, journal = {Journal of affective disorders}, volume = {391}, number = {}, pages = {120044}, doi = {10.1016/j.jad.2025.120044}, pmid = {40784411}, issn = {1573-2517}, mesh = {Humans ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Depressive Disorder, Major/immunology/genetics ; *Mental Disorders/immunology/genetics/metabolism ; Mediation Analysis ; Autism Spectrum Disorder/immunology/genetics ; *Hearing Disorders/immunology/genetics ; Presbycusis/immunology/genetics ; Bipolar Disorder/immunology/genetics ; }, abstract = {INTRODUCTION: Although the relationship between psychiatric disorders and common auditory diseases has been discovered in observational studies, the causal linkage between them remains inconclusive. METHODS: The bidirectional two-sample Mendelian randomization (MR) analysis was performed, drawing on the most recent and expansive genome-wide association studies (GWAS) data for seven psychiatric disorders and five common auditory diseases. Additionally, a mediation analysis was conducted using data on 731 immune cell phenotypes and 1400 metabolite levels to explore potential mediating factors influencing the causal pathways. RESULTS: Autism Spectrum Disorder (ASD) could increase the risk of presbycusis (odds ratio [OR] = 1.161 [95 % confidence interval (CI), 1.042-1.295], P-value = 0.007) through CD25 on CD45RA- CD4 not regulatory T cell (Mediation effect β = 0.017), and Major Depressive Disorder (MDD) could increase the risk of vertigo (OR = 1.215 [95 % CI, 1.043-1.415], P-value = 0.012) through CD33+ HLA DR+ CD14dim Absolute Count (Mediation effect β = 0.007). Alzheimer's Disease (AD) could reduce the risk of presbycusis through four metabolite levels related to lipid metabolism. And Bipolar Disorder I (BD I) could reduce the risk of vertigo, as well as sudden sensorineural hearing loss (SSNHL) could reduce the risk of Post Traumatic Stress Disorder (PTSD). CONCLUSION: This study underscores the intricate causal links between psychiatric disorders and auditory diseases. Mediation analyses indicate that immune cells are facilitators of positive effects, while metabolite levels play a protective role. These insights offer potential pathways for more effective clinical diagnosis and treatment.}, } @article {pmid40784409, year = {2025}, author = {Sing, R and Shikha, D and Goswami, C}, title = {TRPM8 modulation alters uptake of Transferrin-mediated Fe[3+], mitochondrial Fe[2+] and intracellular Ca[2+]-levels in microglia.}, journal = {Neurochemistry international}, volume = {189}, number = {}, pages = {106031}, doi = {10.1016/j.neuint.2025.106031}, pmid = {40784409}, issn = {1872-9754}, mesh = {*Microglia/metabolism/drug effects ; *TRPM Cation Channels/metabolism ; Animals ; Mice ; *Mitochondria/metabolism/drug effects ; *Iron/metabolism ; *Calcium/metabolism ; *Transferrin/metabolism ; Cell Line ; }, abstract = {Microglia play an important role in the immunity of the central nervous system, crucial in maintaining homeostasis. However, under diseased conditions, this cell accumulates Fe[2+/3+], triggering inflammatory and neurotoxic effects that contribute to neurodegenerative disorders such as Alzheimer's and Parkinson's. Hence, the study of dysregulated microglial activation and overload of Fe[2+/3+] is crucial in the context of neurodegenerative conditions. Emerging research has identified cold-sensitive ion channels, i.e., TRPM8 in microglia, which can regulate key subcellular functions. This study explores the regulatory function of the TRPM8 in Fe[2+/3+] metabolism and its implications for potential ferroptosis in BV2 microglial cells. We used highly specific fluorescence probes, pharmacological modulators of TRPM8 and performed life cell imaging to understand the uptake of Transferrin-488, mitochondrial Fe[2+]-level, cellular Ca[2+]-levels in live BV2 cells under different experimental conditions. Our findings reveal that TRPM8 activation leads to enhanced Transferrin-488-mediated cytosolic Fe[3+]-uptake, disrupts mitochondrial superoxide levels, and promotes cell death. Interestingly, under inflammatory conditions induced by LPS treatment, TRPM8 exhibits a distinct functional role. These results position TRPM8 as an important regulator of microglial Fe[2+/3+] metabolism. This study indicates the involvement of TRPM8 in overload of Fe[2+/3+] leading to ferroptosis and potential for M1-M2 polarization in microglia. These findings impose TRPM8 as a potential therapeutic target for neurodegenerative diseases, and aging.}, } @article {pmid40782673, year = {2025}, author = {Sabbagh, MN and Kennedy, J and Majeed, J and Decourt, B}, title = {Alzheimer's disease: Clinical trials to watch.}, journal = {Med (New York, N.Y.)}, volume = {6}, number = {8}, pages = {100771}, doi = {10.1016/j.medj.2025.100771}, pmid = {40782673}, issn = {2666-6340}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Clinical Trials as Topic ; Oligonucleotides, Antisense/therapeutic use ; Glucagon-Like Peptide-1 Receptor Agonists ; Amyloid beta-Peptides/antagonists & inhibitors ; tau Proteins/antagonists & inhibitors ; }, abstract = {Second-generation anti-amyloid therapies (ATTs) offer new options for early Alzheimer's disease treatment, but with modest efficacy and documented adverse events. Here we highlight several ongoing clinical trials, aiming to develop therapeutic agents with higher efficacy and better safety profiles including third-generation ATTs, aggregation inhibitors, Sigma-1 receptor agonists, anti-tau antisense oligonucleotides, and GLP-1 receptor agonists.}, } @article {pmid40782185, year = {2025}, author = {Bergamo, G and Liguori, C}, title = {Are sleep disturbances modifiable risk factors for mild cognitive impairment and dementia? A systematic review of large studies.}, journal = {Sleep & breathing = Schlaf & Atmung}, volume = {29}, number = {4}, pages = {269}, pmid = {40782185}, issn = {1522-1709}, mesh = {Humans ; *Cognitive Dysfunction/epidemiology/diagnosis/etiology ; *Dementia/epidemiology/etiology/diagnosis ; Risk Factors ; *Sleep Wake Disorders/epidemiology/diagnosis/complications ; Aged ; }, abstract = {Studies have shown a connection between sleep disorders, mild cognitive impairment and dementia. In this context, the present systematic review aimed to determine in large studies whether sleep disturbances are modifiable risk factors for cognitive decline. Following the application of inclusion and exclusion criteria, this systematic review selected 15 studies, with large cohort of subjects included (more than 1000 participants), who were longitudinally observed. Studies predominantly used questionnaires and interviews to collect subjective data on sleep. Eleven studies were based on subjective measurements, one was based on the International Classification of Diseases - 9th Edition diagnosis codes, and three based on objective actigraphic measurements. No study used polysomnographic assessments for the evaluation of sleep disorders.The results of this systematic review showed that extreme sleep durations (either too short or too long), daytime sleepiness, circadian sleep-wake cycle disruption, and variation in sleep patterns are factors associated with an increased risk of developing cognitive decline and dementia. Actigraphy, as an objective instrument for monitoring the sleep-wake rhythm, provided further insights into the association between sleep problems and longitudinal cognitive decline. These findings emphasize the strong connection between sleep disturbances, circadian rhythm, and the risk of developing dementia and Alzheimer's disease (AD). Sleep disorders may serve as an early indicator for cognitive decline, also considering that they may represent a modifiable risk factor for dementia. Therefore, recognition and treatment of sleep problems should be included in the prevention strategies against cognitive decline, opening up new opportunities for the prevention and treatment of cognitive impairment and AD.}, } @article {pmid40780474, year = {2025}, author = {Manzoor, M and Iqbal, MO and Dan, W and Barkat, MQ and Iqbal Khan, MS and Syed, W and Al-Rawi, MBA and Ni, F}, title = {Syringaresinol from Cinnamomum cassia (L.) J.Presl ameliorates cognitive deficits and AD pathology via AMPK in a DM-AD mouse model.}, journal = {Journal of ethnopharmacology}, volume = {353}, number = {Pt A}, pages = {120374}, doi = {10.1016/j.jep.2025.120374}, pmid = {40780474}, issn = {1872-7573}, mesh = {Animals ; Male ; *AMP-Activated Protein Kinases/metabolism ; *Cinnamomum aromaticum/chemistry ; Mice ; *Cognitive Dysfunction/drug therapy/etiology ; Disease Models, Animal ; *Lignans/pharmacology/isolation & purification/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/etiology ; Oxidative Stress/drug effects ; *Diabetes Mellitus, Experimental/drug therapy/complications ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Maze Learning/drug effects ; }, abstract = {Syringaresinol (SYR), a major lignan in food analogous TCM (Cinnamomum cassia (L.) J.Presl) possesses antioxidant, anti-inflammatory, antidiabetic, and antiaging effects. However, its protective role and mechanisms in diabetes-related cognitive dysfunction (DM-AD) remain unclear. AIM OF THE STUDY: We aimed to assess the protective effects of SYR on metabolic dysfunction associated cognitive decline through the modulation of oxidative stress, neuroinflammation and AMPK activation. MATERIALS AND METHODS: This study involved extraction of C. cassia bark and isolation of SYR, structurally characterized by HR-MS and [1]H NMR. A DM-AD mouse model was established using HFD and STZ. In vivo assessments included body weight, food intake, fasting glucose, GTT, and ITT. Cognitive function was evaluated using Y-maze, MWM, and NOR tests. SYR's interaction with AMPK was examined through western blotting, molecular docking, and AMPK inhibitor experiments. Oxidative stress markers and neuroinflammatory cytokines were analyzed via biochemical assays and RT-PCR. RESULTS: SYR treatments at 5 and 15 mg/kg significantly improved metabolic parameters by reducing body weight gain, enhancing glucose tolerance and insulin sensitivity, and restoring hepatic lipid balance. It also alleviated cognitive impairments with improved memory and learning. Mechanistically, SYR activated AMPK, supported by phosphorylation and molecular docking (-8.7 kcal/mol). In addition, SYR also enhanced antioxidant defense and suppressed neuroinflammatory and increased anti-inflammatory cytokines in the DM-AD brain. Co-treatment with the AMPK inhibitor abolished SYR's cognitive and anti-inflammatory benefits to confirm AMPK's key role in neuroprotective effects of SYR. CONCLUSIONS: In conclusion, SYR demonstrates metabolic and neuroprotective effects comparable to metformin, primarily through AMPK activation therefore it could be used as a promising natural therapeutic candidate for DM-associated AD.}, } @article {pmid40780467, year = {2025}, author = {Sugandhi, VV and Gattu, K and Mundrathi, V and Khairnar, R and Arshad, T and Kumar, S and Cho, H}, title = {Intranasal delivery of rapamycin via brain-targeting polymeric micelles for Alzheimer's disease treatment.}, journal = {International journal of pharmaceutics}, volume = {683}, number = {}, pages = {126011}, pmid = {40780467}, issn = {1873-3476}, support = {R16 GM154661/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Sirolimus/administration & dosage/pharmacokinetics/chemistry ; Micelles ; *Alzheimer Disease/drug therapy/metabolism ; Administration, Intranasal ; Polyethylene Glycols/chemistry ; *Brain/metabolism/drug effects ; Mice ; Male ; Drug Carriers/chemistry ; Polyesters/chemistry ; Amyloid beta-Peptides/metabolism ; Humans ; *Immunosuppressive Agents/administration & dosage/pharmacokinetics ; Particle Size ; Maze Learning/drug effects ; Drug Delivery Systems ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is a long-term neurological disorder associated with neuroinflammation and amyloid-beta (Aβ) aggregation, which leads to a decline in cognitive and behavioral changes. Rapamycin (Rapa) is an immunosuppressive drug effective in preventing organ rejection after a kidney transplant. In the last few years, orally delivered Rapa has emerged as a potential candidate for improving cognitive function in patients with AD. However, it is evident that long-term oral treatment of Rapa causes systemic toxicity, and although controversial, it may even trigger the aggregation of Aβ deposition. This study investigated the therapeutic potential of intranasally delivered brain-targeting polymeric micelles carrying Rapa. We successfully prepared Fibronectin CS1 peptide-conjugated poly(ethylene glycol)-block-poly(D, L-lactic acid) (FibCS1-PEG-b-PLA) micelles carrying Rapa, which were 98.08 ± 1.15 nm in particle size with a polydispersity index of 0.21 ± 0.01. FibCS1-PEG-b-PLA micelles showed a significant improvement for nasal permeation of Rapa across RPMI-2650 epithelial cells. Behavioral studies such as corner, novel object recognition and Morris Water Maze tests showed promising results towards the improvement of cognitive function in a 3xTg-AD mice model when treated with intranasal FibCS1-PEG-b-PLA micelles carrying RAPA at a dose of 0.2 mg/kg (q4dx5). The western blot and ELISA results of the brain tissues of 3xTg-AD mice treated with intranasal FibCS1-PEG-b-PLA micelles carrying Rapa showed significant reductions in Aβ and two pro-inflammation markers (e.g. interleukin (IL)-1β, tumor necrosis factor (TNF)-α). Here, we conclude that brain-targeting FibCS1-PEG-b-PLA micelles carrying Rapa were effective in reaching the brain via intranasal route, reduced pro-inflammatory markers and Aβ, and improved cognitive function in AD-induced mice.}, } @article {pmid40779804, year = {2025}, author = {Ferjančič Benetik, S and Proj, M and Knez, D and Košak, U and Meden, A and Krajšek, K and Pišlar, A and Horvat, S and Švajger, U and Tešić, N and Pulkrabkova, L and Soukup, O and Skarka, A and Andrys, R and Brazzolotto, X and Igert, A and Nachon, F and Dias, J and Detka, J and Gdula-Argasińska, J and Wyska, E and Szafarz, M and Manik, A and Płachtij, N and Musílek, K and Sałat, K and Obreza, A and Gobec, S}, title = {Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38α Mitogen-Activated Protein Kinase Inhibitors.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {16}, pages = {17378-17411}, pmid = {40779804}, issn = {1520-4804}, support = {U01 AG066722/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Male ; Mice ; Alzheimer Disease/drug therapy ; *Butyrylcholinesterase/chemistry/metabolism ; *Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use ; *Cognitive Dysfunction/drug therapy ; Crystallography, X-Ray ; Lipopolysaccharides ; *Mitogen-Activated Protein Kinase 14/antagonists & inhibitors/metabolism ; Models, Molecular ; *Neuroinflammatory Diseases/drug therapy ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use ; Structure-Activity Relationship ; }, abstract = {The currently approved drugs for the treatment of Alzheimer's disease (AD) fail to address its interconnected pathological processes. Inhibition of butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) offers an innovative dual approach to mitigate two major drivers of neurodegeneration in AD: cholinergic deficit and neuroinflammation. Using structure-based drug design and a library of known p38α MAPK inhibitors, we developed first-in-class, selective dual BChE/p38α MAPK inhibitors with balanced activity against both targets. The X-ray crystal structures of the two most promising molecules bound to both enzymes were solved. Those ligands effectively reduced the production of proinflammatory markers in vitro and ex vivo in phytohemagglutinin/lipopolysaccharide neuroinflammation models. Remarkably, these compounds also significantly improved cognition in scopolamine- and lipopolysaccharide-induced models of cognitive dysfunction in mice. Because our dual-acting inhibitors target both the symptoms and the underlying neuropathology, they offer an innovative and comprehensive strategy to combat AD.}, } @article {pmid40779063, year = {2025}, author = {Bulai, IM and Ferraresso, F and Gladiali, F}, title = {Optimal control of monomers and oligomers degradation in an Alzheimer's disease model.}, journal = {Journal of mathematical biology}, volume = {91}, number = {3}, pages = {27}, pmid = {40779063}, issn = {1432-1416}, support = {20227TRY8H//Italian Ministry for Research and Education/ ; ECS 00000038//Italian Ministry for Research and Education/ ; ECS 00000038//Italian Ministry for Research and Education/ ; EU-CUP-J55F21004240001//Università degli Studi di Sassari/ ; EU-CUP-J55F21004240001//Università degli Studi di Sassari/ ; }, mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors ; Mathematical Concepts ; Brain/metabolism ; Computer Simulation ; Immunotherapy/methods ; *Models, Biological ; Protein Multimerization ; }, abstract = {The aggregation and accumulation of oligomers of misfolded Aβ-amyloids in the human brain is one of the possible causes for the onset of the Alzheimer's disease in the early stage. We introduce and study a new ODE model for the evolution of Alzheimer's disease based on the interaction between monomers, proto-oligomers, and oligomers of Aβ amyloid protein in a small portion of the human brain, based upon biochemical processes such as polymerization, depolymerization, fragmentation and concatenation. We further introduce the possibility of controlling the evolution of the system via a treatment that targets the monomers and/or the oligomers. We observe that a combined optimal treatment on both monomers and oligomers induces a substantial decrease of the oligomer concentration at the final stage. A single treatment on oligomers performs better than a single treatment on monomers. These results shed a light on the effectiveness of immunotherapy using anti-Aβ antibodies, targeting monomers or oligomers. Several numerical simulations show how the oligomer concentration evolves without treatment, with single monomer/oligomer treatment, or with a combined treatment.}, } @article {pmid40778542, year = {2025}, author = {Li, R and Xiong, W and Sun, C}, title = {Hippocampal neural stem cells in Alzheimer's disease: bridging neurogenesis, extracellular vesicles, and multimodal therapeutic paradigms.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-21}, doi = {10.1080/00207454.2025.2540989}, pmid = {40778542}, issn = {1563-5279}, abstract = {Alzheimer's disease (AD) presents a formidable challenge in neurodegenerative medicine because of its complex pathophysiology and the absence of effective disease-modifying therapies. Emerging evidence suggests that impaired adult hippocampal neurogenesis (AHN), a dynamic process essential for cognitive plasticity, is a mechanistic contributor to AD progression. This review highlights the role of hippocampal neural stem cells (NSCs) in the pathogenesis of AD, including the molecular mechanisms underlying the neurogenic decline in AD and their potential impact on cognitive resilience. We summarize current therapeutic approaches, including pharmacological agents and non-pharmacological interventions (e.g. exercise, cognitive training, dietary strategies, and neurostimulation therapies), and explore their influence on neurogenesis. Additionally, we explore the potential application of NSCs in AD treatment, specifically through the use of NSC-derived extracellular vesicles (NSC-EVs) as a novel therapeutic modality. By integrating insights from AHN research and cutting-edge therapeutic advancements, this review emphasizes the therapeutic potential of promoting neurogenesis to address cognitive decline and advance treatment strategies for AD.}, } @article {pmid40778306, year = {2025}, author = {Li, S and Huang, N and Wang, M and Huang, W and Shi, J and Luo, Y and Huang, J}, title = {GLP-1R as a potential link between diabetes and Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1601602}, pmid = {40778306}, issn = {1663-4365}, abstract = {There is growing interest in the relationship between Alzheimer's disease (AD) and diabetes mellitus (DM), and the glucagon-like peptide-1 receptor (GLP-1R) may be an important link between these two diseases. The role of GLP-1R in DM is principally to regulate glycemic control by stimulating insulin secretion, inhibiting glucagon secretion, and improving insulin signaling, thereby reducing blood glucose levels. In AD, GLP-1R attenuates the pathological features of AD through mechanisms such as anti-inflammatory effects, the reduction in amyloid-beta (Aβ) deposition, the promotion of Aβ clearance, and improvements in insulin signaling. Notably, AD and DM share numerous pathophysiological mechanisms, most notably the disruption of insulin signaling pathways in the brain. These findings further underscore the notion that GLP-1R plays pivotal roles in both diseases. Taken together, these findings lead us to conclude that GLP-1R not only plays an important role in the treatment of DM and AD but also may serve as a bridge between these two diseases. Future research should focus on elucidating the detailed molecular mechanisms underlying the actions of GLP-1R in both diseases and exploring the development of GLP-1R agonists with dual therapeutic benefits for AD and DM. This could pave the way for innovative integrated treatment strategies to improve outcomes for patients affected by these intertwined conditions.}, } @article {pmid40778305, year = {2025}, author = {Zhang, X and Wijenayake, S and Hossain, S and Liu, Q}, title = {Estimating progression of Alzheimer's disease with extracellular vesicle-related multi-omics risk models.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1617611}, pmid = {40778305}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's Disease (AD) is heterogeneous and shows complex interconnected pathways at various biological levels. Risk scores contribute greatly to disease prognosis and biomarker discovery but typically represent generic risk factors. However, large-scale multi-omics data can generate individualized risk factors. Filtering these risk factors with brain-derived extracellular vesicles (EVs) could yield key pathologic pathways and vesicular vehicles for treatment delivery. METHODS: A list of 460 EV-related genes was curated from brain tissue samples in the ExoCarta database. This list was used to select genes from transcriptomics, proteomics, and DNA methylation data. Significant risk factors included demographic features (age, sex) and genes significant for progression in transcriptomics data. These genes were selected using Cox regression, aided by the Least Absolute Shrinkage and Selection Operator (LASSO), and were used to construct three risk models at different omics levels. Gene signatures from the significant risk factors were used as biomarkers for further evaluation, including gene set enrichment analysis (GSEA) and drug perturbation analysis. RESULTS: Nine EV-related genes were identified as significant risk factors. All three risk models predicted high/low risk groups with significant separation in Kaplan-Meier analysis. Training the transcriptomics risk models on EV-related genes yielded better AD classification results than using all genes in an independent dataset. GSEA revealed Mitophagy and several other significant pathways related to AD. Four drugs showed therapeutic potential to target the identified risk factors based on Connectivity Map analysis. CONCLUSION: The proposed risk score model demonstrates a novel approach to AD using EV-related large-scale multi-omics data. Potential biomarkers and pathways related to AD were identified for further investigation. Drug candidates were identified for further evaluation in biological experiments, potentially transported to targeted tissues via bioengineered EVs.}, } @article {pmid40778177, year = {2025}, author = {Villeneuve, S and Poirier, J and Breitner, JCS and Tremblay-Mercier, J and Remz, J and Raoult, JM and Yakoub, Y and Gallego-Rudolf, J and Qiu, T and Valdez, AF and Mohammediyan, B and Javanray, M and Metz, A and Sanami, S and Ourry, V and Wearn, A and Pastor-Bernier, A and Edde, M and Gonneaud, J and Strikwerda-Brown, C and Tardif, CL and Gauthier, CJ and Descoteaux, M and Dadar, M and Vachon-Presseau, É and Baril, AA and Ducharme, S and Montembeault, M and Geddes, MR and Soucy, JP and Rajah, N and Laforce, R and Bocti, C and Davatzikos, C and Bellec, L and Rosa-Neto, P and Baillet, S and Evans, AC and Collins, DL and Chakravarty, MM and Blennow, K and Zetterberg, H and Spreng, RN and Binette, AP and , }, title = {The PREVENT-AD cohort: accelerating Alzheimer's disease research and treatment in Canada and beyond.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40778177}, support = {P30 AG048785/AG/NIA NIH HHS/United States ; R01 AG068563/AG/NIA NIH HHS/United States ; R01 EB026299/EB/NIBIB NIH HHS/United States ; }, abstract = {The PREVENT-AD is an investigator-driven study that was created in 2011 and enrolled cognitively normal older adults with a family history of sporadic AD. Participants are deeply phenotyped and have now been followed annually for more than 12 years [median follow-up 8.0 years,SD 3.1]. Multimodal MRI, genetic, neurosensory, clinical, cerebrospinal fluid and cognitive data collected until 2017 on 348 participants who agreed to open sharing with the neuroscience community were already available. We now share a new release including 6 years of additional follow-up cognitive data, and additional MRI follow-ups, clinical progression, new longitudinal behavioral and lifestyle measures (questionnaires, actigraphy), longitudinal AD plasma biomarkers, amyloid-beta and tau PET, magnetoencephalography, as well as neuroimaging analytic measures from all MRI modalities. We describe the PREVENT-AD study, the data shared with the global research community as well as the model we created to sustain longitudinal follow-ups while also allowing new innovative data collection.}, } @article {pmid40778159, year = {2025}, author = {Khorsand, B and Ghanbarian, E and Rabin, L and Sajjadi, SA and Ezzati, A}, title = {Incremental Value of Plasma Biomarkers in Predicting Clinical Decline Among Cognitively Unimpaired Older Adults: Results from the A4 trial.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.07.22.25332015}, pmid = {40778159}, abstract = {OBJECTIVE: To evaluate the predictive utility of baseline plasma biomarkers and neuropsychological measures in identifying cognitively unimpaired older adults at risk of cognitive and functional decline over five years. BACKGROUND: The clinical and biological heterogeneity observed in Alzheimer's disease (AD) complicates design of trials and the identification of appropriate participants. Identifying practical tools to define more homogenous subgroups could enhance clinical trial enrichment and improve early detection. METHODS: We analyzed data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and its companion Evaluation of Amyloid Risk and Neurodegeneration (LEARN) observational study. The sample included 866 cognitively unimpaired, amyloid-positive individuals from the A4 trial (comprising participants randomized to receive Solanezumab or placebo) and 343 cognitively unimpaired, amyloid-negative individuals from LEARN. Cognitive/functional decline was defined as an increase of ≥0.5 in Clinical Dementia Rating-Global Score (CDR-GS) during a 240-week period. Using multiple logistic regression models, we evaluated the predictive value of demographic variables, APOE4 status, amyloid PET SUVR, plasma P-tau217, and Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (ADCS-PACC) in three groups: A4-Solanezumab, A4-placebo and LEARN. In a sub-study including 656 participants with available data, we assessed the incremental value of additional plasma biomarkers (Aβ42/Aβ40 ratio, GFAP, and NfL). RESULTS: Both plasma P-tau217 and ADCS-PACC significantly improved predictive performance over a base model with demographics and APOE4. The full model combining all predictor variables yielded the highest AUCs across A4 Solanezumab (0.80 ± 0.06), A4 Placebo (0.80 ± 0.06), and LEARN (0.78 ± 0.08). Adding other plasma biomarkers yielded small but consistent improvements in AUC (1-3%). CONCLUSIONS: Plasma P-tau217 and ADCS-PACC, individually and in combination, improved prediction of cognitive/functional decline in asymptomatic older adults. Predictive models incorporating these scalable and non-invasive measures improved clinical trial enrichment and earlier identification of at-risk individuals preclinical AD.}, } @article {pmid40778154, year = {2025}, author = {Guarnier, G and Reinelt, J and Molloy, EN and Mihai, PG and Einaliyan, P and Valk, S and Modestino, A and Ugolini, M and Mueller, K and Wu, Q and Babayan, A and Castellaro, M and Villringer, A and Scherf, N and Thierbach, K and Schroeter, ML}, title = {Cascaded Multimodal Deep Learning in the Differential Diagnosis, Progression Prediction, and Staging of Alzheimer's and Frontotemporal Dementia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40778154}, support = {U19 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Dementia is a complex condition whose multifaceted nature poses significant challenges in the diagnosis, prognosis, and treatment of patients. Despite the availability of large open-source data fueling a wealth of promising research, effective translation of preclinical findings to clinical practice remains difficult. This barrier is largely due to the complexity of unstructured and disparate preclinical and clinical data, which traditional analytical methods struggle to handle. Novel analytical techniques involving Deep Learning (DL), however, are gaining significant traction in this regard. Here, we have investigated the potential of a cascaded multimodal DL-based system (TelDem), assessing the ability to integrate and analyze a large, heterogeneous dataset (n=7,159 patients), applied to three clinically relevant use cases. Using a Cascaded Multi-Modal Mixing Transformer (CMT), we assessed TelDem's validity and (using a Cross-Modal Fusion Norm - CMFN) model explainability in (i) differential diagnosis between healthy individuals, AD, and three sub-types of frontotemporal lobar degeneration (ii) disease staging from healthy cognition to mild cognitive impairment (MCI) and AD, and (iii) predicting progression from MCI to AD. Our findings show that the CMT enhances diagnostic and prognostic accuracy when incorporating multimodal data compared to unimodal modeling and that cerebrospinal fluid (CSF) biomarkers play a key role in accurate model decision making. These results reinforce the power of DL technology in tapping deeper into already existing data, thereby accelerating preclinical dementia research by utilizing clinically relevant information to disentangle complex dementia pathophysiology.}, } @article {pmid40778134, year = {2025}, author = {Ackley, SF and Flanders, M and Murchland, A and Chen, R and Wang, J and Shah, SJ and Huey, ED and Glymour, MM}, title = {Evaluation of Amyloid Removal as a Surrogate for Cognitive Decline: Pilot Analysis in Individual-Level Data from the A4 Study of Solanezumab.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40778134}, support = {K00 AG068431/AG/NIA NIH HHS/United States ; R00 AG073454/AG/NIA NIH HHS/United States ; F99 AG083306/AG/NIA NIH HHS/United States ; P01 AG082653/AG/NIA NIH HHS/United States ; K99 AG088369/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Amyloid removal has been used as a surrogate outcome in Alzheimer's disease trials, allowing accelerated approval of aducanumab and lecanemab. The A4 (Alzheimer's Clinical Trial Consortium A4/LEARN) trial's individual-level data supports novel methods to evaluate amyloid's validity as a surrogate for cognitive decline. METHODS: In 812 participants, cognitive and functional change was measured using the CDR-SB score. Instrumental-variable analysis estimated the effect of amyloid reduction; mediation analysis quantified solanezumab's cognitive effect mediated by amyloid reduction. RESULTS: Each 10 centiloid reduction due to randomization to treatment was associated with 0.026 higher CDR-SB (95% CI: -0.013, 0.065). 14.6% of solanezumab's effect on cognition was mediated by amyloid reduction (95% CI: -122%, 208%). DISCUSSION: Estimates showing near-zero effects of amyloid reduction on cognitive decline suggest minimal impact of amyloid reduction in populations with little disease progression. Replication in anti-amyloid trials with larger treatment effects could guide treatment and regulatory decisions.}, } @article {pmid40777911, year = {2025}, author = {Shojapour, M and Asgharzade, S}, title = {Regenerative Medicine in the Treatment of Alzheimer's Disease: A Narrative Review.}, journal = {Iranian journal of public health}, volume = {54}, number = {7}, pages = {1399-1410}, pmid = {40777911}, issn = {2251-6093}, abstract = {Alzheimer's disease (AD) is one of the progressive neurodegenerative diseases, memory impairments and multiple cognitive and behavioral deficits characterize that. We aimed to evaluate the molecular mechanisms involved in the pathogenesis of AD. It introduces the regenerative medicine approach as a novel therapeutic strategy based on the pathogenesis of AD that would be efficient. Our data was collected using databases such as the Web of Science, PubMed, Scopus, and Google Scholar. We summarized the available therapeutic strategies to induce neurodegeneration that can increase the number of neurons and their survival and improve the plasticity of synapses and synaptic activity. There is a different approach to treatment. In first-line treatment, focusing declines the amyloid beta and hypophosphorylated tau protein accumulation. It inhibits acetylcholinesterase, but in regenerative medicine focusing on treatment via gene therapy, cell therapy, and tissue engineering. As a proposed solution for AD in recent years, the use of inhibitors of the pathogenesis of AD is known as a supportive therapeutic approach, but the multi-potential treatment of regenerative medicine has been able to provide promising results in treating neurodegenerative patients.}, } @article {pmid40777747, year = {2025}, author = {Mathew, LS and Marathe, A and Aman, A and Vats, A and Joy, T and Rao, YL}, title = {Bridging the molecular and clinical aspects of resveratrol in Alzheimer's disease: a review.}, journal = {3 Biotech}, volume = {15}, number = {9}, pages = {284}, pmid = {40777747}, issn = {2190-572X}, abstract = {Alzheimer's disease (AD) is a progressive brain disorder that affects neurological functioning specifically targeting cognition, memory and behaviour. Pathology starts with the accumulation of tau proteins which on phosphorylation can be destructive for brain function. With gold standard drugs like Donepezil, there have been several attempts made to discover adjuvant therapeutic molecules such as plant-based products that could not only ease the ill-toward effects of these drugs, but also lead to the betterment of the patients suffering from AD. These are crucial in the management of patients of AD, by associations with psychological vulnerabilities and the overall loss of health of such individuals 'Resveratrol' is one such plant-based molecule which is a stilbene polyphenol present in many of the commonly occurring plants. Resveratrol is reported to have anti-oxidant and anti-inflammatory properties which brings about the neuroprotection. Several studies have also been conducted that targets the signalling cascades involved during the progression of AD. This review attempts to give a collective information of its properties, its synthesis, metabolism and mechanisms that could drive researchers forward for its therapeutic applications during the treatment of Alzheimer's disease.}, } @article {pmid40777460, year = {2025}, author = {Kehmeier, MN and Famiano, A and Cullen, AE and Leonhardt, T and Ferguson, S and Snyder, M and McCurdy, CE and Tyrrell, D and Alkayed, NJ and Walker, AE}, title = {APOE4 genotype negates the benefits of 17β-estradiol on cerebrovascular endothelial and mitochondrial function.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.07.23.666474}, pmid = {40777460}, issn = {2692-8205}, support = {R00 AG068309/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Postmenopausal females who carry an APOEε4 allele are at higher risk of late-onset Alzheimer's Disease compared to age-matched APOEε4 males. Estrogen deficiency predisposes females to an increased risk of vascular, cognitive, and metabolic impairments. While estrogen and APOE genotype are known to impact metabolic and mitochondrial function in the brain, their cerebrovascular effects are less understood. Thus, the purpose of this study was to determine the interaction between APOE genotype and estrogen on cerebrovascular endothelial and mitochondrial function. METHODS: Young female homozygous APOEε3 and APOEε4 mice (n=19-20/group; ~6 months old) fed a high-fat diet were ovariectomized (OVX), OVX and supplemented with 17β-estradiol, or left intact. RESULTS: In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilation, which was rescued by 17β-estradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-estradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-estradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-estradiol in the APOEε4 mice. In cerebral arteries and arterioles, mitochondrial complexes I and I+II respiration were lower in APOEε4 mice compared with APOEε3 mice. 17β-estradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes, and pro-inflammatory factors. In contrast to other outcomes, we found that 17β-estradiol treatment was associated with lower cerebral artery stiffness in APOEε4 but not APOEε3 mice. CONCLUSIONS: Overall, these results indicate that the APOE genotype modulates the impact of estrogen on the cerebral vasculature. We found that 17β-estradiol enhances cerebrovascular endothelial and mitochondrial function in APOEε3 mice but not in APOEε4 mice. The results suggest that 17β-estradiol supplementation has more cerebrovascular benefit for APOEε4 non-carriers. NOVELTY & SIGNIFICANCE: What is known?: Females have twice the risk of Alzheimer's disease compared with males, and the APOE4 genetic variant is associated with a greater risk for Alzheimer's disease compared with the APOE3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction of APOE genotype and estrogens on cognitive function and other brain outcomes. What new information does this article contribute?: Vascular outcomes were not measured in previous studies examining the interaction between APOE genotype and estrogens. As such, we aimed to determine the impact of APOE4 genotype on the cerebrovascular response to estradiol. We found that estradiol improved cerebral artery endothelial function and mitochondrial respiration in APOE3 mice following ovariectomy. In contrast, APOE4 mice were refractory to the beneficial effects of estradiol on cerebrovascular endothelial and mitochondrial function. The broader implication of this research is that APOE genotype may be a consideration when prescribing hormone replacement therapy to menopausal females due to the impact on vascular outcomes.}, } @article {pmid40777445, year = {2025}, author = {Gu, J and Fuller, C and Carbonetto, P and He, X and Zheng, J and Li, H}, title = {Identifying the genetic basis and molecular mechanisms underlying phenotypic correlation between complex human traits using a gene-based approach.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40777445}, issn = {2692-8205}, support = {R01 AG058742/AG/NIA NIH HHS/United States ; R21 AG064357/AG/NIA NIH HHS/United States ; R21 AG071899/AG/NIA NIH HHS/United States ; }, abstract = {Phenotypic correlations between complex human traits have long been observed based on epidemiological studies. However, the genetic basis and underlying mechanisms are largely unknown. Here we developed a gene-based approach to measure genetic overlap between a pair of traits and to delineate the shared genes/pathways, through three steps: 1) translating SNP-phenotype association profile to gene-phenotype association profile by integrating GWAS with eQTL data using a newly developed algorithm called Sherlock-II; 2) measuring the genetic overlap between a pair of traits by a normalized distance and the associated p value between the two gene-phenotype association profiles; 3) delineating genes/pathways involved. Application of this approach to a set of GWAS data covering 59 human traits detected significant overlap between many known and unexpected pairs of traits; a significant fraction of them are not detectable by SNP based genetic similarity measures. Examples include Cancer and Alzheimer's Disease (AD), Rheumatoid Arthritis and Crohn's disease, and Longevity and Fasting glucose. Functional analysis revealed specific genes/pathways shared by these pairs. For example, Cancer and AD are co-associated with genes involved in hypoxia response and P53/apoptosis pathways, suggesting specific mechanisms underlying the inverse correlation between them. Our approach can detect yet unknown relationships between complex traits and generate mechanistic hypotheses and has the potential to improve diagnosis and treatment by transferring knowledge from one disease to another.}, } @article {pmid40777354, year = {2025}, author = {Ramanan, S and Johnson, GV}, title = {A Bioinformatic Analysis of BAG Protein Interactors and Pathways in Alzheimer's and Parkinson's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40777354}, issn = {2692-8205}, support = {R01 AG073121/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders. While the symptoms and general etiology may be different, these two diseases share significant common features in terms of their disease pathogenesis. Within the scope of neurodegenerative disorders, the Bcl-2 associated athanogene (BAG) family proteins and associated interactors have been a key area of focus. The BAG family is a group of proteins that contain at least one evolutionarily conserved BAG domain. Despite this similarity, their interactions and functions can vary widely. So far, research has predominantly scrutinized individual BAG proteins, rather than explore potential cooperative actions among family members. Some BAG family members may function together thereby indicating potential interactions within this family. Although connections among BAG members have been observed, their role in neurodegenerative disorders, such as AD and PD, remains largely uncharacterized. This mini review explores the common pathways, intersections, and differences within these interactions as well as their link to AD and PD. Using computational techniques to mine transcriptomic data, several groupings of pathways that these BAG family members are involved in were identified in the context of AD and PD. Understanding these pathways and their relationships may uncover potential gaps in current research and help identify novel therapeutic targets for the treatment of these neurodegenerative diseases.}, } @article {pmid40776985, year = {2025}, author = {Huang, Y and Lei, W and Shen, J and Sun, J}, title = {Tat-NR2B9c prevent cognitive dysfunction in mice modeling Alzheimer's Disease induced by Aβ1-42 via perturbing PSD-95 interactions with NR2B-subtype receptors.}, journal = {IBRO neuroscience reports}, volume = {19}, number = {}, pages = {317-322}, pmid = {40776985}, issn = {2667-2421}, abstract = {BACKGROUND: Alzheimer's Disease (AD) is one of common progressive and fatal neurodegenerative disorders,and its main clinical symptoms are progressive memory impairment and cognitive dysfunction. The Tat-NR2B9c, a peptide was known as postsynaptic density protein-95(PSD-95) inhibitors, has shown clinical efficacy as a neuroprotective effects in some diseases such as acute stroke and neuropathic pain.The aim of the study is to clarify whether Tat-NR2B9c has the same neuroprotective effects in AD. METHODS: Studies were performed in mice modeling AD induced by Aβ1-42. Animals were treated with drugs after modeling AD for 14 days,and the spatial learning and memory ability were assessed after drug treatment. Then, mice were euthanized for biochemical tests. RESULTS: The levels of PSD-95 and NR2B decreased,and the levels of N-methyl-d-aspartate receptor-postsynaptic density protein-95 interaction increased in hippocampus in AD mice. Tat-NR2B9c can improve spatial learning and memory ability in AD mice by perturbing PSD-95 interactions with NR2B-subtype but not inhibiting PSD-95 levels. CONCLUSION: Tat-NR2B9c can prevent cognitive dysfunction in mice modeling AD induced by Aβ1-42 via perturbing PSD-95 interactions with NR2B-subtype receptors.}, } @article {pmid40776228, year = {2025}, author = {Gao, T and Madanian, S and Templeton, J and Merkin, A}, title = {Clinical Decision Support for Alzheimer's: Challenges in Generalizable Data-Driven Approach.}, journal = {Studies in health technology and informatics}, volume = {329}, number = {}, pages = {1780-1781}, doi = {10.3233/SHTI251211}, pmid = {40776228}, issn = {1879-8365}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Decision Support Systems, Clinical/organization & administration ; Magnetic Resonance Imaging/methods ; *Deep Learning ; Neural Networks, Computer ; Brain/diagnostic imaging ; }, abstract = {This paper reviews the current research on Alzheimer's disease and the use of deep learning, particularly 3D-convolutional neural networks (3D-CNN), in analyzing brain images. It presents a predictive model based on MRI and clinical data from the ADNI dataset, showing that deep learning can improve diagnosis accuracy and sensitivity. We also discuss potential applications in biomarker discovery, disease progression prediction, and personalised treatment planning, highlighting the ability to identify sensitive features for early diagnosis.}, } @article {pmid40775619, year = {2025}, author = {Ren, X and Edwards, L and Mann, E and Horiuchi, S and Tsuchiyagaito, A}, title = {Repetitive negative thinking, self-reflection, and perceived cognitive dysfunction in older adults: a cross-sectional study.}, journal = {BMC psychiatry}, volume = {25}, number = {1}, pages = {773}, pmid = {40775619}, issn = {1471-244X}, support = {P20 GM121312/GM/NIGMS NIH HHS/United States ; 2P20GM121312-06/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Aged ; Cross-Sectional Studies ; *Cognitive Dysfunction/psychology ; *Depression/psychology ; Aged, 80 and over ; *Rumination, Cognitive/physiology ; *Pessimism/psychology ; Japan ; *Thinking ; Middle Aged ; }, abstract = {As the global population ages, understanding cognitive dysfunction, including Alzheimer's Disease and other forms of dementia, is crucial. With the growing prevalence of these disorders, it is essential to identify and understand potential factors that maintain cognitive function and potentially delay severe cognitive dysfunction. This study examined the roles of repetitive negative thinking (RNT) and reflection in subjective cognitive dysfunction among older adults, with an additional consideration of their association with depressive symptoms. RNT, which is common in depression, has been associated with cognitive impairments. However, its unique influence on cognitive dysfunction is unclear. Conversely, reflection, considered to protect against adverse cognitive outcomes, is less explored. Using the Rumination Response Scale (RRS), we hypothesize that RNT may be more strongly linked to cognitive dysfunction than reflection, even when controlling for depressive symptoms. Two-hundred and seventy-six older adults (137 male, 139 female) from Japan participated in the study, providing measures of RRS-brooding (an index of RNT), RRS-reflection (an index of reflection), depressive symptoms, and self-reported cognitive dysfunction. The results showed higher reflection, but not RNT, was associated with greater subjective cognitive dysfunction [β = 0.28, p =.03], even after controlling for depressive symptoms. Importantly, the association between reflection and cognitive dysfunction demonstrated sex differences, with reflection significantly accounting for cognitive dysfunction in female [β = 0.46, p =.01] but not in male. These findings highlight the significance of evaluating specific subtypes of repetitive thoughts and sex differences when investigating the association with perceived cognitive dysfunction. Future research should continue to explore the mechanisms underlying these associations and the prevention and treatment of cognitive dysfunctions.}, } @article {pmid40775373, year = {2025}, author = {Kelleher-Andersson, J and Yoon, E and Green, C and McFarlane, C and Bagheri, D and Thomas, LP and Turner, RS}, title = {First-in-human study of neuron regenerative therapy NNI-362 to evaluate the safety, pharmacokinetics, and pharmacodynamics in healthy aged population.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {185}, pmid = {40775373}, issn = {1758-9193}, support = {U01 AG082687/AG/NIA NIH HHS/United States ; U01AG082687 (PI-Kelleher-Andersson)/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Aged ; Double-Blind Method ; Female ; Middle Aged ; *tau Proteins/blood ; *Nerve Regeneration/drug effects ; Biomarkers/blood ; }, abstract = {BACKGROUND: A placebo-controlled, double-blind Phase 1a trial examined the safety, tolerability, and pharmacokinetics of NNI-362 as well as the pharmacodynamic outcome of plasma phosphorylated tau[181] (p-tau[181]). METHODS: Oral NNI-362 and placebo were randomized in healthy, cognitively-unimpaired individuals (ages 50-72) at a 3:1 ratio, with sponsor, principal investigator, and subjects all blinded. Plasma levels of p-tau[181] were determined in the placebo and the two highest arms of 120 and 240 mg NNI-362. Plasma biomarker was examined for statistical change from baseline. RESULTS: NNI-362 treatment was safe and well tolerated in older individuals. NNI-362, at the two highest multiple doses, significantly reduced plasma p-tau[181] levels compared to pretreatment levels (P < 0.0012 to P < 0.0009), while no change occurred in placebo groups. CONCLUSIONS: These findings suggest in older subjects, oral NNI-362 appeared safe, well tolerated and reduced plasma p-tau[181]. Phase 2 studies of NNI-362 are warranted for Alzheimer's disease and age-related degenerative disorders. TRIAL REGISTRY NUMBER: NCT04074837. First registered: 2019-08-27.}, } @article {pmid40774425, year = {2025}, author = {Markley, AE and Stratton, KM and Cho, GY and Schmidt, NB and Suhr, J and Sheffler, JL and Nguyen, C and Schubert, FT and Quiles, JRG and Potter, MR and Meynadasy, MA and Irvin, SM and Allan, NP}, title = {Study design and protocol for cognitive anxiety sensitivity treatment for anxiety in adults with mild cognitive impairment or dementia.}, journal = {Contemporary clinical trials}, volume = {156}, number = {}, pages = {108044}, doi = {10.1016/j.cct.2025.108044}, pmid = {40774425}, issn = {1559-2030}, mesh = {Humans ; *Cognitive Dysfunction/psychology ; *Cognitive Behavioral Therapy/methods ; *Anxiety/therapy/psychology ; Aged ; Male ; Female ; Randomized Controlled Trials as Topic ; *Caregivers/psychology ; *Dementia/psychology ; Therapy, Computer-Assisted/methods ; Quality of Life ; *Alzheimer Disease/psychology ; }, abstract = {BACKGROUND: Anxiety is prevalent among older adults with mild cognitive impairment (MCI) and mild Alzheimer's disease and related disorders (ADRD) and may contribute to accelerated cognitive decline and increased care partner burden. Computerized Anxiety Sensitivity Treatment (CAST) is a novel, CBT-based intervention targeting anxiety sensitivity, which has not been widely tested in this population. METHODS: This randomized controlled trial (NCT05748613) will compare CAST to a health education control (HEC) in 194 dyads consisting of older adults with MCI/mild ADRD and their care partners. Primary outcomes include reductions in anxiety sensitivity and anxiety symptoms. Secondary outcomes include measures of mental health and well-being symptoms, improved cognitive performance, and decreased care partner burden. Participants will be assessed at baseline, during two intervention sessions, and follow-ups at 1-, 3-, and 6-months post-intervention. EXPECTED OUTCOMES: CAST will significantly lower anxiety sensitivity (AS) post-intervention and reduce anxiety compared to HEC. Secondary hypotheses propose that CAST will reduce other mental symptoms and improve cognitive functioning more effectively than HEC. Additionally, CAST will alleviate care partner distress and improve their quality of life compared to HEC, with the secondary hypothesis suggesting that these effects will be mediated by reductions in AS in older adults. Furthermore, reductions in AS from pre- to post-intervention will account for the effect of CAST on anxiety, and the secondary hypothesis suggesting that reductions in interoceptive fear conditioning will also contribute to the observed anxiety reduction. CLINICALTRIALS: gov registration: #NCT05748613.}, } @article {pmid40773904, year = {2025}, author = {Ahmad, SR and Zeyaullah, M and Zahrani, Y and Khan, MS and Muzammil, K and Dawria, A}, title = {Phytochemicals from Bacopa monnieri as small molecule modulators of MARK4: A multi-modal strategy for preventing Alzheimer's disease-causing tau aggregation.}, journal = {Journal of molecular graphics & modelling}, volume = {140}, number = {}, pages = {109135}, doi = {10.1016/j.jmgm.2025.109135}, pmid = {40773904}, issn = {1873-4243}, mesh = {*Bacopa/chemistry ; *Alzheimer Disease/drug therapy/metabolism/prevention & control ; Humans ; *tau Proteins/chemistry/metabolism ; *Phytochemicals/chemistry/pharmacology ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Thermodynamics ; *Protein Aggregates/drug effects ; }, abstract = {Neurodegenerative tauopathies, such as Alzheimer's disease, are closely associated with the dysregulation of tau phosphorylation, a process regulated in part by the serine/threonine kinase MARK4. In this study, we explored phytochemicals derived from Bacopa monnieri as potential natural inhibitors of MARK4. Using pressurized liquid extraction with an ethanol-water mixture, we efficiently extracted bioactive compounds from Bacopa leaves. LC-MS analysis identified 25 distinct phytoconstituents spanning flavonoids, triterpenoids, cucurbitacins, sterols, and alkaloids. In silico analysis revealed that several compounds, including oroxindin, cucurbitacin B, and bacosine, bind strongly to the catalytic pocket of MARK4. Molecular dynamics simulations confirmed their stability within the MARK4 active site, with oroxindin demonstrating the most favorable thermodynamic and conformational profile. Principal component and free energy landscape analyses further supported their capacity to stabilize MARK4 in low-energy conformations. Microscale thermophoresis further validated high-affinity binding of MARK4 with oroxindin, while other four compounds also show strong interaction with MARK4. MTT assays in SH-SY5Y cells confirmed the non-cytotoxic nature of all five lead compounds across a concentration range of 10 nM to 10 μM. Cellular assays revealed a significant reduction in Tau-GFP aggregates upon treatment with the compounds, particularly oroxindin. These results highlight oroxindin and other Bacopa monnieri phytochemicals as promising natural inhibitors of MARK4, with potential to attenuate tau pathology in neurodegenerative diseases.}, } @article {pmid40773726, year = {2025}, author = {Rajkumar, M and Presley, SID and Govindaraj, P and Girigoswami, K and Meenambigai, K and Deepak, P and Deepika, B and Elbehairi, SEI and Alfaifi, MY and Shati, AA and Menaa, F}, title = {Biomedical Prowess of Clitoria mariana (L.) Flower Methanolic Extract: A Comprehensive In Vitro, Ex Vivo, and In Vivo Evaluation.}, journal = {Chemistry & biodiversity}, volume = {22}, number = {12}, pages = {e01051}, doi = {10.1002/cbdv.202501051}, pmid = {40773726}, issn = {1612-1880}, mesh = {*Plant Extracts/chemistry/pharmacology/isolation & purification ; *Flowers/chemistry/metabolism ; Animals ; Humans ; Zebrafish/embryology ; *Anti-Bacterial Agents/pharmacology/chemistry/isolation & purification ; Methanol/chemistry ; Microbial Sensitivity Tests ; *Clitoria/chemistry ; *Antineoplastic Agents, Phytogenic/pharmacology/chemistry/isolation & purification ; *Antioxidants/pharmacology/chemistry/isolation & purification ; Staphylococcus aureus/drug effects ; *Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; Acetylcholinesterase/metabolism ; Cell Line, Tumor ; Butyrylcholinesterase/metabolism ; *Anti-Inflammatory Agents/pharmacology/chemistry/isolation & purification ; Drug Screening Assays, Antitumor ; Dose-Response Relationship, Drug ; Cell Survival/drug effects ; Cell Proliferation/drug effects ; }, abstract = {Clitoria mariana L., a medicinal plant widely distributed in Asia, has long been used in folk medicine. This study investigates the biomedical potential of its methanolic flower extract. Gas chromatography-mass spectrometry (GC-MS) and phytochemical analyses revealed the presence of alkaloids, phenolic compounds, and flavonoids. The phytoextract elicited significant antioxidant activity, as demonstrated by various assays, and displayed broad-spectrum antibacterial effects, producing the largest zones of inhibition (ZI) against Staphylococcus aureus, Micrococcus luteus, Escherichia coli, and Salmonella typhi, supported by MIC/MBC (minimum inhibition concentration/minimum bactericidal concentration) values indicative of bactericidal action. Notably, the phytoextract demonstrated marked cytotoxicity against various cancer cell lines, with the highest potency against MCF-7, followed by HeLa, A549, and PC-3, based on IC50 (concentration required to inhibit 50%) values. Its anti-inflammatory properties, comparable to aspirin (reference standard), increased with concentration. Additionally, the phytoextract showed promise in Alzheimer's disease (AD) treatment by inhibiting AChE (acetylcholinesterase) and BuChE (butyrylcholinesterase) activities more effectively than galantamine (GA), the standard drug. The zebrafish embryo assay evidenced its excellent biocompatibility. Overall, this study offers the first comprehensive phytochemical and pharmacological evaluation of C. mariana's methanolic extract, underscoring its potential relevance in managing inflammatory conditions.}, } @article {pmid40773100, year = {2025}, author = {Balki, S and Gautam, AS and Balaji, PG and Yadav, AK and Singh, RK}, title = {Montelukast attenuated memory decline, neuroinflammatory and neurodegenerative biomarkers in Aβ1-42 exposed model of alzheimer's disease in mice.}, journal = {Psychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {40773100}, issn = {1432-2072}, support = {Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India//Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India/ ; }, abstract = {Alzheimer's disease (AD) represents major cognitive and memory decline in the elderly patients. Although Montelukast has traditionally been used for the treatment of asthma, its role in prevention of neuropathological changes and memory decline in AD have recently been reported in literature. However, the brain availability through oral administration of Montelukast is limited due to its poor blood-brain barrier permeation. This study has highlighted that the intranasal administration of Montelukast can provide a considerable brain bioavailability of Montelukast in mice. In addition, intranasal administration of Montelukast showed a significant improvement of spatial and cognitive memory, prevention of Aβ accumulation, astrocyte activation, along with improved redox balance and neuronal density in the hippocampus and cortex regions in the amyloid-beta1-42 (Aβ1-42)-induced animal model of AD. These neuroprotective effects were found to be better through intranasal administration of Montelukast in comparison to its oral administration at the equivalent dose. These results suggest that Montelukast may be administered through intranasal route to achieve a significant therapeutic effect in the pathophysiology of AD.}, } @article {pmid40772428, year = {2025}, author = {French, SR and Arias, JC and Zahra, S and Ally, M and Escareno, C and Heitkamp, E and Vazquez, F and Hillis, M and Wiskoski, H and Ainapurapu, K and Culwell, G and Howell, C and Johnson, K and Kraemer, C and Pacanowski, J and Leon, L and Berman, S and Yanquez, F and Balderman, J and Sabat, J and Hung, O and Lucas, L and Vitali, F and Bedrick, EJ and Mushtaq, R and Altbach, M and Trouard, TP and Elahi, FM and Ashton, NJ and Dage, JL and Reiman, EM and Alexander, GE and Weinkauf, CC}, title = {Cognitive impairment and p-tau217 are high in a vascular patient cohort.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70565}, pmid = {40772428}, issn = {1552-5279}, support = {R01AG070987/AG/NIA NIH HHS/United States ; R01 HL159200/HL/NHLBI NIH HHS/United States ; //Doris Duke Foundation/ ; //University of Arizona Health Sciences Career Development Award/ ; //Arizona Alzheimer's Consortium/ ; P30 AG072980/AG/NIA NIH HHS/United States ; //U24 AG082930 Alzheimer Diagnosis in older Adults with Chronic Conditions ADACC Network/ ; CTR056039//Arizona Biomedical Research Commission/ ; CTR056056//Arizona Biomedical Research Commission/ ; U24 AG021886/AG/NIA NIH HHS/United States ; //Health Sciences, University of Arizona/ ; /DDCF/Doris Duke Charitable Foundation/United States ; }, mesh = {Humans ; Female ; Male ; *Cognitive Dysfunction/blood/diagnosis ; *tau Proteins/blood ; Aged ; Biomarkers/blood ; Cohort Studies ; *Alzheimer Disease/blood ; Mental Status and Dementia Tests/statistics & numerical data ; *Cardiovascular Diseases/complications/blood ; Prospective Studies ; Phosphorylation ; Middle Aged ; Aged, 80 and over ; Neuropsychological Tests ; }, abstract = {INTRODUCTION: Vascular comorbidities are modifiable contributors to cognitive impairment and Alzheimer's disease (AD), yet brain health outcomes are rarely evaluated in cardiovascular patients. METHODS: This study prospectively evaluated cognition and AD pathology in 162 community-dwelling adults with asymptomatic cardiovascular disease who did not have a clinical diagnosis of dementia or cognitive impairment. RESULTS: Twenty-nine percent of the cohort had Montreal Cognitive Assessment (MoCA) scores indicative of cognitive impairment or dementia after adjusting for age, sex, and education based on National Alzheimer's Coordinating Center normative data. AD blood biomarker phosphorylated tau217 was elevated in 55% of the cohort, significantly associated with decreased MoCA scores (β = -1.46, 95% confidence interval [CI] -2.53 to -0.39, p < 0.01), and accurately differentiated cognitive impairment (area under the curve 0.94, 95% CI 0.88-0.99). DISCUSSION: This level of undiagnosed cognitive impairment and AD pathology exceeds what would be expected in the general population and highlights a potential need for screening and future work to better identify treatment options. HIGHLIGHTS: Brain health outcomes are rarely evaluated in vascular patients. One hundred sixty-two adults with asymptomatic cardiovascular disease but without diagnoses of cognitive impairment or dementia were evaluated. Phosphorylated tau217 accurately differentiated cognitive impairment in patients with cardiovascular disease. High levels of cognitive impairment and Alzheimer's disease pathology are greatly underdiagnosed in the cardiovascular population.}, } @article {pmid40772264, year = {2025}, author = {Alrikabi, A and Allahyani, W and Shaghath, A and Alrashdi, J and Almoqhem, R and Alasmari, F and Al-Qerem, W and Albasher, G}, title = {Potential therapeutic effects of Ebixa, Ginkgo biloba, and selenium in a cadmium chloride-induced Alzheimer's disease manifestations in rats.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1634601}, pmid = {40772264}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by cognitive decline and neuronal damage. Cadmium exposure has been implicated in AD pathogenesis. This study aimed to investigate the potential therapeutic effects of Ebixa (memantine), Ginkgo biloba, and selenium in a cadmium-induced rat model of AD. Adult male Wistar rats were divided into six groups: control, control + Ginkgo-treated, cadmium chloride (CdCl2), CdCl2 + Ebixa-treated, CdCl2 + Ginkgo, and CdCl2 + Ginkgo + Selenium. Behavioral tests, including the Morris water maze and passive avoidance learning, were conducted. Additionally, biochemical analysis of acetylcholine (Ach), choline acetyltransferase (AchT), and acetylcholinesterase (AChE) levels in brain homogenates was performed. Histological sections of the cerebral cortex, cerebellum, and medulla were examined. Apoptotic assessment was conducted using the TUNEL assay. CdCl2 exposure resulted in cognitive deficits, reduced Ach levels, and neuronal damage, mirroring AD-like characteristics. Ebixa treatment improved spatial memory behavior as well as Ach, AchT and AChE levels in the brain. Ginkgo biloba and selenium co-administration increased the number of crossings in the Morris water maze test, suggesting memory preservation. Additionally, Ginkgo biloba exhibited potential cholinergic system protective effects. Histological analysis revealed neuroprotection in the cerebral cortex, cerebellum, and medulla. TUNEL assays demonstrated anti-apoptotic effects of both Ebixa and the combination of Ginkgo and selenium. Ebixa, Ginkgo biloba, and selenium showed promise in mitigating cognitive deficits and preserving neuronal structures in a CdCl2-induced AD manifestation in rats. These findings provide insights into potential therapeutic strategies for AD and warrant further investigation.}, } @article {pmid40771977, year = {2025}, author = {Park, H and Ni, M and Le, Y}, title = {Neuroinflammation and nutrition in Alzheimer's disease.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1622571}, pmid = {40771977}, issn = {1664-2295}, abstract = {The brain contains approximately 100 billion neurons and over 200 billion glial cells, which are integral to the neuronal networks that support normal brain function in the central nervous system. The complexity of the brain makes the diagnosis and treatment of neurodegenerative disease particularly challenging. Neuroinflammation and neuronal cell death contribute to the development of neurodegenerative diseases such as dementia. Dementia refers to a decline in memory and thinking ability, affecting approximately 55 million people worldwide. Owing to the association of multiple factors, including amyloid-β plaque, tau-fibrillary tangles, neuroinflammation, nutritional defects, and genetic mutations, the exact cause of the most common type of dementia, Alzheimer's disease, remains elusive. These multiple factors may cause damage to neurons and glial cells, leading to neurodegeneration. Very few therapeutics are available for neurodegenerative diseases due to the limited understanding of their pathogenesis, resulting in the lack of biomarkers and drug targets. Recent attention has shifted toward addressing modifiable risk factors such as unhealthy diets and lifestyles to delay the onset of Alzheimer's disease. Unhealthy diets that consist of saturated fatty acids and refined sugars, with other multiple risk factors, increase neuroinflammation and oxidative stress, furthering cognitive decline and progression of neurodegeneration. Mitigating these risk factors with antioxidants, anti-inflammatory-based nutrition, and multidomain lifestyle intervention, which may include physical exercise, cognitive stimulation, and social engagement, may delay the development of neurodegenerative diseases and cognitive decline. In this review, we focus on the role of neuroinflammation in contributing to neurodegeneration and dietary influence in Alzheimer's disease.}, } @article {pmid40771537, year = {2025}, author = {Sagar, R and Huang, Y and Dong, D and Boyd, RJ and Ahmed, W and Witwer, KW and Mahairaki, V}, title = {Profiling RNA Cargo in Extracellular Vesicles From hiPSC-Derived Neurons of Alzheimer's Disease Patients.}, journal = {Journal of extracellular biology}, volume = {4}, number = {8}, pages = {e70074}, pmid = {40771537}, issn = {2768-2811}, support = {RF1 AG083801/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder that affects more than 55 million people, with an incidence that is projected to triple by 2050. Despite continuous advancements in the field, reliable treatment and early detection strategies remain elusive. Extracellular vesicles (EVs) play a major role in cellular communication throughout the body. In this study, we assessed the cargo of neuronal-specific EVs for their potential as AD biomarkers. We isolated EVs released from iPSC-derived excitatory glutamatergic neurons generated from eight AD patients (ADiNEVs) and six healthy controls (iNEVs). We performed RNA-sequencing and identified significant differences in RNA cargo between ADiNEVs and iNEVs. Notably, fewer small nuclear RNAs (snRNAs) were found in ADiNEVs. RNA transcripts significantly more abundant in ADiNEVs included MT-CO1, PRR32 and IGSF8 messenger RNAs. We also observed fewer XIST long noncoding RNAs and miR-7-5p microRNA content in ADiNEVs. These findings suggest that precision medicine approaches, such as characterising the content of EVs from a patient's own cells, could advance early detection and management of AD.}, } @article {pmid40771353, year = {2025}, author = {Moravveji, S and Sadia, H and Doyon, N and Duchesne, S}, title = {Sensitivity analysis of a mathematical model of Alzheimer's disease progression unveils important causal pathways.}, journal = {Frontiers in neuroinformatics}, volume = {19}, number = {}, pages = {1590968}, pmid = {40771353}, issn = {1662-5196}, abstract = {INTRODUCTION: Mathematical models serve as essential tools to investigate brain aging, the onset of Alzheimer's disease (AD) and its progression. By studying the representation of the complex dynamics of brain aging processes, such as amyloid beta (Aβ) deposition, tau tangles, neuro-inflammation, and neuronal death. Sensitivity analyses provide a powerful framework for identifying the underlying mechanisms that drive disease progression. In this study, we present the first local sensitivity analysis of a recent and comprehensive multiscale ODE-based model of Alzheimer's Disease (AD) that originates from our group. As such, it is one of the most complex model that captures the multifactorial nature of AD, incorporating neuronal, pathological, and inflammatory processes at the nano, micro and macro scales. This detailed framework enables realistic simulation of disease progression and identification of key biological parameters that influence system behavior. Our analysis identifies the key drivers of disease progression across patient profiles, providing insight into targeted therapeutic strategies. METHODS: We investigated a recent ODE-based model composed of 19 variables and 75 parameters, developed by our group, to study Alzheimer's disease dynamics. We performed single- and paired-parameter sensitivity analyses, focusing on three key outcomes: neural density, amyloid beta plaques, and tau proteins. RESULTS: Our findings suggest that the parameters related to glucose and insulin regulation could play an important role in neurodegeneration and cognitive decline. Second, the parameters that have the most important impact on cognitive decline are not completely the same depending on sex and APOE status. DISCUSSION: These results underscore the importance of incorporating a multifactorial approach tailored to demographic characteristics when considering strategies for AD treatment. This approach is essential to identify the factors that contribute significantly to neural loss and AD progression.}, } @article {pmid40771197, year = {2025}, author = {Cardillo, M and Katam, K and Suravajhala, P}, title = {Advancements in multi-omics research to address challenges in Alzheimer's disease: a systems biology approach utilizing molecular biomarkers and innovative strategies.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1591796}, pmid = {40771197}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a growing global challenge, representing the most common neurodegenerative disorder and affecting millions of lives. As life expectancy continues to rise and populations expand, the number of individuals coping with the cognitive declines caused by AD is projected to double in the coming years. By 2050, we may see over 115 million people diagnosed with this devastating condition. Unfortunately, while we currently lack effective cures, there are preventative measures that can slow disease progression in symptomatic patients. Thus, research has shifted toward early detection and intervention for AD in recent years. With technological advances, we are now harnessing large datasets and more efficient, minimally invasive methods for diagnosis and treatment. This review highlights critical demographic insights, health conditions that increase the risk of developing AD, and lifestyle factors in midlife that can potentially trigger its onset. Additionally, we delve into the promising role of plant-based metabolites and their sources, which may help delay the disease's progression. The innovative multi-omics research is transforming our understanding of AD. This approach enables comprehensive data analysis from diverse cell types and biological processes, offering possible biomarkers of this disease's mechanisms. We present the latest advancements in genomics, transcriptomics, Epigenomics, proteomics, and metabolomics, including significant progress in gene editing technologies. When combined with machine learning and artificial intelligence, multi-omics analysis becomes a powerful tool for uncovering the complexities of AD pathogenesis. We also explore current trends in the application of radiomics and machine learning, emphasizing how integrating multi-omics data can transform our approach to AD research and treatment. Together, these pioneering advancements promise to develop more effective preventive and therapeutic strategies soon.}, } @article {pmid40771195, year = {2025}, author = {Ahmad, W and Choe, K and Ahmad, R and Park, TJ and Kim, MO}, title = {Ambroxol confers neuroprotection against scopolamine-induced Alzheimer's-like pathology by modulating oxidative stress, neuroinflammation, and cognitive deficits via Nrf-2/JNK/GSK-3β signaling pathways.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1607289}, pmid = {40771195}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is the most common and costly chronic progressive neurodegenerative disorder, with the highest impact on public health worldwide. Pathological hallmarks of AD include progressive cognitive decline and memory impairment, dominantly mediated by oxidative neurodegeneration. Oxidative stress is commonly recognized as a key factor in the pathophysiological progression of AD. Despite significant advancements, a definitive and effective therapeutic intervention for AD remains elusive. In this study, we investigate the neuroprotective potential of ambroxol (Amb), known for its potent anti-inflammatory and antioxidant properties. Given ambroxol's potential neuroprotective effects, we explore the underlying molecular mechanisms, explicitly examining its role in attenuating scopolamine-induced oxidative stress-mediated activation of the c-Jun N-terminal kinase (JNK) pathway, as well as its modulation of Akt and glycogen synthase kinase-3 beta (GSK-3β) signaling, which is a key contributor to neuroinflammation, synaptic dysfunction and neurodegeneration. AD pathology is induced by scopolamine administration, leading to excessive lipid peroxidation (LPO) and reactive oxygen species (ROS) generation, which leads to a decline in critical antioxidant proteins, including nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1). However, ambroxol treatment effectively attenuated oxidative stress by reducing the production of reactive oxidative species while restoring the expression of key antioxidant proteins. Similarly, ambroxol attenuated oxidative stress-induced JNK activation and modulated Akt and GSK-3β alterations. Immunofluorescence and western blot analyses revealed that ambroxol attenuated reactive gliosis by suppressing the expression of GFAP and Iba-1, alongside the downregulation of key pro-inflammatory mediators, such as IL-1β, TNF-α, and phosphorylated NF-κB (p-p65). Scopolamine also compromised synaptic integrity and induced deficits in memory formation and spatial learning. In contrast, ambroxol promoted synaptic integrity by upregulating the expression of SNAP-23 and PSD-95, thereby ameliorating scopolamine-induced impairments in spatial learning and memory.}, } @article {pmid40770916, year = {2025}, author = {Zhu, M and Han, J and Liu, R and Zhu, C and Liang, F and Zhang, G and Ma, L and Jin, Y and Xu, S and Wang, Z}, title = {Blood-Brain Barrier-Crossing Photo-oxygenation Nanocomposite for the Selective Mapping and Disassembly of Amyloid-β Aggregates In Vivo.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {33}, pages = {46759-46770}, doi = {10.1021/acsami.5c11173}, pmid = {40770916}, issn = {1944-8252}, mesh = {*Blood-Brain Barrier/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; Mice ; *Nanocomposites/chemistry ; Alzheimer Disease/metabolism/drug therapy/pathology ; Stilbenes/chemistry/pharmacology ; Humans ; Reactive Oxygen Species/metabolism ; Mice, Transgenic ; }, abstract = {The accumulation of toxic amyloid-β (Aβ) aggregates in the brain underlies neuronal death and subsequent irreversible neurodegeneration in Alzheimer's disease (AD). Currently, optimized theranostic probes targeting Aβ aggregates are still rare. Herein, we synthesized a series of tetraphenylethylene (TPE) derivatives for the selective recognition and photo-oxygenation of Aβ aggregates. Among them, TPE-yne-Indo with a strong electron-withdrawing group (benzo[e]indolium) and an electron-donating group (N,N-dimethylaniline) can selectively recognize Aβ aggregates in solution (Kd = 310.5 nM, S/N = 6.1) and mapping Aβ plaques in brain slices. Theoretical calculations indicated that TPE-yne-Indo engaged in hydrophobic interactions with the amino acid residues Val-18 (V), Ala-21 (A), and His-13 (H) of Aβ. Notably, the binding with Aβ aggregates bestowed TPE-yne-Indo with higher reactive oxygen species (ROS) generation ability, boosting the photodynamic oxidation of Aβ aggregates. Furthermore, therapeutic nanocomposite with the lactoferrin receptor ligand (MSN@Lf&TPE-yne-Indo) was prepared to facilitate the blood-brain barrier (BBB) crossing process. In vivo assays showed that MSN@Lf&TPE-yne-Indo can selectively stain Aβ plaques and reduce Aβ deposition in the brain of APP/PS1 mice, alleviating symptoms of cognitive impairment and memory loss. This study provides a promising tool for the early diagnosis and treatment of AD.}, } @article {pmid40770806, year = {2025}, author = {Zhang, Y and Wang, J and Li, X and Guo, R and Wang, L and Liu, Y and Yu, Y and Kong, L}, title = {Huanglian Jiedu Decoction improves the"central-peripheral"inflammatory microenvironment and enhances the cognitive function of APP/PS1 mice by inhibiting the activation of NLRP3 inflammasome mediated by gut microbiota.}, journal = {Chinese medicine}, volume = {20}, number = {1}, pages = {123}, pmid = {40770806}, issn = {1749-8546}, support = {No. 2024-MSLH-289//Liaoning Provincial Science and Technology Program Joint Plan/ ; No. 320.6750.2024-18-60//the Wu Jieping Medical Foundation Special Research Fund/ ; No. zyzx2301//the Open fund of Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine/ ; 82404867//National Natural Science Foundation of China/ ; No. JYTQN2023471//Basic Research Project of Education Department of Liaoning Province/ ; }, abstract = {BACKGROUND: Huanglian Jiedu Decoction (HLJDD) is a representative formula for clearing heat and removing toxins, and some basic studies indicated that it can improve the learning cognitive ability of Alzheimer's disease (AD) mice, but the underlying molecular mechanism of its improvement in AD mice is still unclear, therefore, this paper delves into the mechanism of HLJDD to improve AD. PURPOSE: This study aims to investigate whether HLJDD can improve the "central-peripheral" inflammatory microenvironment in APP/PS1 mice, and to explore its relationship with gut microbiota and NLRP3 inflammatory vesicles activation. MATERIALS AND METHODS: In this paper, the fingerprint of HLJDD was established by high-performance liquid chromatography (HPLC) and the components of HLJDD were characterized by ultra-performance liquid chromatography-time-of-flight mass spectrometry (UPLC-O-TOF/MS). The potential signaling pathways of HLJDD against AD were preliminarily investigated through network pharmacology. Behavioral assessment, histopathological staining, immunofluorescence staining, immunohistochemical staining, and detection of central and peripheral inflammatory factors were used to explore the improvement of AD by HLJDD, in addition to which we examined the gut microbiota and expression of relevant inflammatory proteins. RESULTS: In this study, 137 chemical constituents, including flavonoids, terpenoids, and alkaloids, were first identified in HLJDD by HPLC fingerprinting and UPLC-Q-TOF/MS. In addition, 49 components were found in the brain tissue of APP/PS1 mice and 48 components were found in the plasma of APP/PS1 mice. Network pharmacology concluded that the relevant pathways for HLJDD treatment of AD include inflammatory pathways. We found that HLJDD was effective in improving the learning memory ability of APP/PS1 mice by in vivo mouse behavioral performance. Histopathological results showed that HLJDD had the effect of reducing AD-like pathological damage, and also found that HLJDD could significantly reduce the proportion of M1 type microglia and A1 type astrocytes, and increase the proportion of M2 type microglia and A2 type astrocytes, and the treatment of HLJDD also suppressed the infiltration of CD4[+] and CD8[+] T-cells in the brain, and inhibited Aβ deposition and reduced the expression of inflammatory factors in the brain, and alleviated central neuroinflammation. In addition, it was also found that HLJDD was able to reduce the expression of inflammatory factors in the peripheral blood and inhibit the peripheral immune response, and the results of gut microbiota also showed changes in gut microbiota after HLJDD treatment and verified the expression of inflammatory vesicle-associated proteins in the intestines, with significant upregulation of the expression of NLRP3, caspase-1, and ASC proteins in the model group, and significant downregulation of ZO-1 and occludin proteins, and reversal of the above changes after HLJDD intervention. CONCLUSION: Therefore, it is hypothesized that HLJDD improves the "central-peripheral" inflammatory microenvironment in APP/PS1 mice by inhibiting the activation of NLRP3 inflammatory vesicles mediated by gut microbiota.}, } @article {pmid40770529, year = {2025}, author = {Nakamichi, S and Yamada, L and Roselle, C and Horikawa, I and June, CH and Harris, CC}, title = {The senescence-inhibitory p53 isoform Δ133p53α: enhancing cancer immunotherapy and exploring novel therapeutic approaches for senescence-associated diseases.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {40770529}, issn = {2509-2723}, abstract = {Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while it does not inhibit, or may even promote, p53-mediated DNA repair. Owing to this selective inhibitory activity that preserves genome stability, Δ133p53α represents a promising target for enhancement in the prevention and treatment of diseases associated with increased senescence of normal cells. These diseases include Alzheimer's and other neurodegenerative diseases, premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS), and idiopathic pulmonary fibrosis (IPF). Current cell-based therapies, which are limited by increased cellular senescence, may also benefit from Δ133p53α-mediated improvements. As an initial application of Δ133p53α in improving therapeutic cells, we here introduce Δ133p53α-armored chimeric antigen receptor (CAR)-T cells. Based on our previous and ongoing studies using various types of senescent human cells in vitro, we also discuss the importance of further exploring the therapeutic potentials of Δ133p53α, with particular focus on HGPS and IPF. The development of mouse models facilitates in vivo evaluation of the therapeutic effects of Δ133p53α, potentially leading to future clinical applications.}, } @article {pmid40770492, year = {2025}, author = {Kim, J and Han, K and Jung, JH and Oh, SY and Park, KA and Min, JH}, title = {Optic neuritis as a link between autoimmunity and dementia risk.}, journal = {Communications medicine}, volume = {5}, number = {1}, pages = {335}, pmid = {40770492}, issn = {2730-664X}, support = {RS-2024-00341030//National Research Foundation of Korea (NRF)/ ; RS-2024-00439930//Korea Health Industry Development Institute (KHIDI)/ ; }, abstract = {BACKGROUND: Our limited understanding of dementia's complex pathogenesis confines treatment options primarily to symptom management rather than targeting underlying disease processes, underscoring the need for innovative treatment and preventive strategies. This study aimed to examine the relationship between optic neuritis (ON), an autoimmune inflammatory condition of the optic nerve, and the risk of developing dementia. METHODS: This nationwide, population-based cohort study was conducted in Korea, analyzing a cohort of 15,286 ON patients newly diagnosed between 2010 and 2017 who were age and sex matched against 76,430 controls without ON. Primary outcomes were incident cases of Alzheimer's disease, vascular dementia, or other types of dementia. Cox proportional hazards regression models were employed to assess the association between ON and dementia risk after adjusting for demographic characteristics, lifestyle factors, and other comorbidities. Dementia risk was assessed through hazard ratios (HRs), with an average follow-up period of 3.06 years. RESULTS: ON patients shows greater risks of all-cause dementia (HR: 1.258) and Alzheimer's disease (HR: 1.264). Associations between ON and dementia are prominent in younger patients and current smokers. CONCLUSION: This research suggests that autoimmunity, particularly in the form of ON, may significantly contribute to dementia development. This study implies that younger ON patients who smoke could be at a high risk of developing dementia, emphasizing the need for preventative strategies and additional research to establish causality. This work broadens the scope of known dementia risk factors and opens new avenues for research into autoimmune mechanisms as targets for therapeutic intervention.}, } @article {pmid40770370, year = {2025}, author = {Zhang, Y and Xu, Y and Song, Y and Wang, Y and Chen, M and Ji, X and Lin, Y and Gu, S}, title = {Lead-induced hypertension and cognitive dysfunction: brain amyloid pathology.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {720}, pmid = {40770370}, issn = {2047-783X}, support = {2022, ZDYF2022SHFZ101//This work was supported by the Key R & D Projects in Hainan Province/ ; }, mesh = {Animals ; Mice ; *Hypertension/chemically induced/pathology/metabolism ; *Brain/pathology/metabolism/drug effects ; *Cognitive Dysfunction/chemically induced/pathology/metabolism/drug therapy ; Mice, Transgenic ; *Lead/toxicity ; Spironolactone/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; *Alzheimer Disease/pathology ; Amlodipine/pharmacology/therapeutic use ; Receptors, Mineralocorticoid/metabolism ; Male ; Disease Models, Animal ; }, abstract = {BACKGROUND: Lead (Pb) exposure is a recognized environmental risk factor for cognitive decline and may aggravate Alzheimer's disease (AD) pathology through hypertension-related mechanisms. However, the specific role of mineralocorticoid receptor (MR) signaling in this process remains unclear. OBJECTIVES: This study investigated whether Pb-induced hypertension exacerbates amyloid pathology via MR activation, and evaluated the therapeutic effects of amlodipine and spironolactone in an AD mouse model. METHODS: APPSwDI transgenic mice were exposed to Pb acetate (25 mg/kg/day) for 8 weeks, with or without concurrent treatment with amlodipine or spironolactone. Cognitive behavior, blood pressure, renal function, neuroinflammation, oxidative stress, and brain amyloid deposition were assessed. RESULTS: Pb exposure significantly increased systolic blood pressure, impaired cognition, elevated IL-1β and IL-6 levels, and enhanced brain amyloid burden. MR expression in brain tissue was upregulated following Pb exposure. Both spironolactone and amlodipine improved cognitive performance and reduced neuroinflammation and oxidative stress. Spironolactone more effectively suppressed MR expression and amyloid deposition, though some group differences did not reach statistical significance. CONCLUSIONS: Pb exacerbates AD-like pathology through MR-related hypertensive and inflammatory mechanisms. MR antagonism by spironolactone offers greater neuroprotection than calcium channel blockade in this context. These findings suggest that targeting MR signaling may be a promising therapeutic strategy for environmentally induced AD risk.}, } @article {pmid40770222, year = {2025}, author = {Abuhantash, F and Welsch, R and Finkelstein, S and AlShehhi, A}, title = {Alzheimer's disease risk prediction using machine learning for survival analysis with a comorbidity-based approach.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {28723}, pmid = {40770222}, issn = {2045-2322}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; FSU-2021-005//Khalifa University of Science, Technology and Research/ ; }, mesh = {Humans ; *Alzheimer Disease/epidemiology/diagnosis ; Aged ; *Machine Learning ; Male ; Female ; Comorbidity ; Cognitive Dysfunction/epidemiology ; Survival Analysis ; Aged, 80 and over ; Neuroimaging ; Disease Progression ; Risk Factors ; }, abstract = {Alzheimer's disease (AD) presents a pressing global health challenge, demanding improved strategies for early detection and understanding its progression. In this study, we address this need by employing survival analysis techniques to predict transition time from Cognitive Normal (CN) to Mild Cognitive Impairment (MCI) in elderly individuals, considering the predictive value of baseline comorbidities. Leveraging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) databases, we construct feature sets encompassing demographics, cognitive scores, and comorbidities. Various machine learning and deep learning methods for survival analysis are employed. Our top-performing model, fast random forest, achieves a concordance index of 0.84 when considering all feature modalities, with comorbidity data emerging as a significant predictor. The top features identified by the best-performing model include one demographic feature (age), seven cognitive scores (ADAS13, RAVLT learning, FAQ, ADAS11, RAVLT immediate, CDRSB, ADASQ4), and two comorbidities (Endocrine & Metabolic, Renal & Genitourinary). Age is highlighted as the most influential predictor, while cognitive scores are crucial indicators of Alzheimer's disease. External validation against the AIBL dataset affirms the robustness of our approach. Overall, our study contributes to a deeper understanding of the role of baseline comorbidities in AD risk prediction and emphasizes the importance of incorporating comprehensive feature assessment in clinical practice for early diagnosis and personalized treatment planning.}, } @article {pmid40770166, year = {2025}, author = {Lee, Y and Han, S and Lee, J and Cho, Y and Kim, JS and Jeon, Y and Cho, H and Yoo, H and Byun, Y and Kim, TK and Hong, JM and Kim, H and Park, SY and Yim, JH and Kim, SH and Jo, DG}, title = {A novel multi-target compound mitigates amyloid plaques, synaptic deficits, and neuroinflammation in Alzheimer's disease models.}, journal = {Archives of pharmacal research}, volume = {48}, number = {7-8}, pages = {745-764}, pmid = {40770166}, issn = {1976-3786}, support = {RS-2021-KS211513//Korea Institute of Marine Science and Technology promotion/ ; RS-2024-00399237//National Research Foundation of Korea/ ; RS-2024-00345742//National Research Foundation of Korea/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Plaque, Amyloid/drug therapy/pathology/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; *Neuroinflammatory Diseases/drug therapy/pathology/metabolism ; *Synapses/drug effects ; Male ; Synaptic Transmission/drug effects ; *Hydrazines/pharmacology/chemistry ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid plaque accumulation, synaptic dysfunction, and neuroinflammation. This study reports the therapeutic potential of (S)-4-amino-5,5-difluoro-N'-methyl-N'-phenylpentanehydrazide hydrochloride (RA-058HM), a novel compound, in ameliorating these pathological features of AD in the 5xFAD mouse model. RA-058HM was administered orally for 8 weeks, and its multi-target effects - including relief from neuroinflammation, normalization of synaptic transmission, reduction of amyloidogenesis (plaque and soluble oligomers, as well as BACE1 levels), and rescue of cognitive function-were evaluated. To our knowledge, RA-058HM is the first compound to demonstrate simultaneous modulation of these key pathways in the 5xFAD model, highlighting its potential as a comprehensive disease-modifying therapy for AD. Behavioural tests revealed marked improvements in spatial and recognition memory in RA-058HM-treated 5xFAD mice, suggesting a reversal of cognitive deficits. At the molecular level, RA-058HM treatment reduced amyloidogenesis, as evidenced by decreased levels of amyloid precursor protein (APP) and β-secretase (BACE1) in the hippocampus, accompanied by reduced plaque formation, as detected by Thioflavin-S staining. Furthermore, synaptic transmission was restored to near-normal levels in RA-058HM-treated neurons, indicating that RA-058HM effectively rescues synaptic deficits without altering synaptic protein levels of PSD95 and synaptophysin. In addition, treatment of RA-058HM downregulated hippocampal levels of the NLRP3 inflammasome, TNF-α, and GFAP, suggesting a decrease in neuroinflammatory signaling and a modulation of glial activity. Restoration of mitochondrial motility in hippocampal neurons further suggests that RA-058HM may improve cellular energy dynamics. Collectively, these findings indicate that RA-058HM has multifaceted effects on AD pathology, targeting amyloid accumulation, synaptic transmission, neuroinflammation, and mitochondrial function. This study highlights RA-058HM as a promising candidate for AD therapy and underscores the potential of multi-targeted approaches in addressing the complex mechanisms underlying AD progression.}, } @article {pmid40770094, year = {2025}, author = {Aron, L and Ngian, ZK and Qiu, C and Choi, J and Liang, M and Drake, DM and Hamplova, SE and Lacey, EK and Roche, P and Yuan, M and Hazaveh, SS and Lee, EA and Bennett, DA and Yankner, BA}, title = {Lithium deficiency and the onset of Alzheimer's disease.}, journal = {Nature}, volume = {645}, number = {8081}, pages = {712-721}, pmid = {40770094}, issn = {1476-4687}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; DP2 AG072437/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; K01 AG051791/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; R01 AG069042/AG/NIA NIH HHS/United States ; R01 AG046174/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/pathology/metabolism/drug therapy/genetics/prevention & control ; Animals ; Mice ; *Lithium/deficiency/metabolism ; Disease Models, Animal ; Humans ; Glycogen Synthase Kinase 3 beta/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Brain/metabolism/pathology/drug effects ; Cognitive Dysfunction/metabolism/pathology ; tau Proteins/metabolism ; Female ; Microglia/pathology/metabolism/drug effects ; Aging/metabolism/pathology ; Transcriptome/drug effects ; Synapses/pathology/metabolism/drug effects ; Myelin Sheath/metabolism/pathology ; Axons/pathology/metabolism ; Aged ; }, abstract = {The earliest molecular changes in Alzheimer's disease (AD) are poorly understood[1-5]. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.}, } @article {pmid40769959, year = {2025}, author = {Shanok, NA and Derbin, B and Muzac, S and Cabeza, E and Leven, S and Rodriguez, R}, title = {The Effects of Deep TMS on QEEG Measures in Co-Occurring Major Depressive Disorder and Early-Stage Alzheimer's Disease: A Pilot Study.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {8919887251366637}, doi = {10.1177/08919887251366637}, pmid = {40769959}, issn = {1552-5708}, abstract = {Major Depressive Disorder (MDD) and Alzheimer's disease (AD) represent two of the most prevalent diseases worldwide. Notably, it is estimated that 30%-50% of individuals with AD have co-occurring MDD and there are overlapping symptoms across numerous domains. In this pilot study, a Deep TMS protocol (targeting the left frontal and bilateral temporal regions) was delivered for 36 sessions to patients with co-occurring MDD and early-stage AD (N = 12). All participants received the treatment and there was no control condition. The treatment yielded a response rate of 83.33% (defined by a ≥50% reduction in depressive symptoms on the Patient Health Questionnaire-9 [PHQ-9]) and a remission rate of 50.00% (PHQ-9 score of 4 or less following treatment). Further, participants displayed reductions in left prefrontal and right temporal delta power using QEEG analysis pre- and -post treatment. Alpha coherence was also enhanced in key areas. The observed shift in neurophysiological measures suggested reduced cortical slowing and dysconnectivity, which are hallmark traits in MDD and AD. This proof-of-concept study suggests that further research on the application of Deep TMS (paired with QEEG) for early-stage AD is warranted.}, } @article {pmid40768640, year = {2025}, author = {Bentivegna, M and Pomilio, C and Bellotto, M and Pérez, NG and Rossi, SP and Gregosa, A and Vota, D and Merech, F and Bonaventura, MM and Presa, J and Vinuesa, Á and Lux-Lantos, V and Alcón, SP and Saravia, F and Beauquis, J}, title = {Amyloid Beta Regulates Astrocytic Glucose Metabolism and Insulin Signaling in Experimental Models of Alzheimer's Disease.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.0484}, pmid = {40768640}, issn = {2152-5250}, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by amyloid beta (Aβ) plaques, neuroinflammation and cognitive impairment. Metabolic disturbances, particularly brain insulin resistance, are increasingly recognized as central features of AD pathophysiology. Astrocytes, essential for brain energy metabolism, exhibit a loss of homeostatic functions in AD, possibly promoting neurodegeneration. Even though the main astrocytic glucose transporters are non-insulin dependent, insulin may regulate astroglial glucose metabolism. Our objective was to evaluate insulin signaling and astrocyte metabolism in the PDAPP-J20 transgenic mouse model of familial AD and in mouse primary astrocyte cultures exposed to Aβ. Adult PDAPP-J20 mice showed hyperinsulinemia, hippocampal insulin resistance and astrocytic proinflammatory activation. The reactive glial phenotype was accompanied by decreased insulin receptor levels in this chronic setting. Exposure of primary astrocytes to Aβ induced proinflammatory activation, oxidative stress and loss of glutamate transporter EAAT2, crucial for neuroprotection. Even though Aβ-exposed astrocytes showed increased insulin receptor levels in this acute setting, insulin-induced phosphorylation of the receptor was hampered. Amyloid-treated astrocytes also showed increased glucose uptake, lactate release and glycogen storage. Insulin treatment was associated with a recovery of mitochondrial membrane potential and increased amyloid uptake, highlighting a pro-homeostatic role for the hormone. Our results highlight the interplay between insulin signaling and astrocyte metabolism at different experimental and temporal settings of amyloid pathology. Understanding these mechanisms may help to design therapeutic strategies aimed at restoring metabolic balance and mitigating neurodegeneration.}, } @article {pmid40768115, year = {2025}, author = {Birmann, PT and Zugno, GP and Sinott, A and Rodrigues, RR and Conceição, FR and Sousa, FSS and Collares, T and Seixas, FK and Savegnago, L}, title = {Komagataella pastoris KM71H Attenuates Cognitive Deficits and Depressive-Like Behavior by the TLR4/NF-κB Signaling Pathway in an Aβ1-40-Induced AD-Like Mouse Model.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {16448-16459}, pmid = {40768115}, issn = {1559-1182}, mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; *Toll-Like Receptor 4/metabolism ; *Signal Transduction/drug effects ; *Alzheimer Disease/metabolism/complications/drug therapy/chemically induced ; *NF-kappa B/metabolism ; Disease Models, Animal ; *Depression/drug therapy/metabolism/complications ; *Peptide Fragments/toxicity ; Male ; Mice ; *Cognitive Dysfunction/metabolism/drug therapy ; Behavior, Animal/drug effects ; Hippocampus/metabolism ; }, abstract = {Komagataella pastoris is a promising probiotic for modulating the microbiota-gut-brain axis, and growing evidence has demonstrated the relevance of this axis in the pathophysiology of neurological and psychiatric disorders, such as Alzheimer's disease and major depressive disorder. This study investigated the ameliorated cognitive impairment and antidepressive-like effect of K. pastoris treatment on an AD-like mouse model induced by amyloid β1-40 peptide (Aβ1-40). Behavioral tests revealed that Aβ1-40 administration (400 pmol/mouse, icv) increased immobility time in the tail suspension test, decreased spatial and working memory, and increased the time animals took to reach the chocolate cookies, and these behavioral changes were attenuated by the K. pastoris KM71H treatment (8 log CFU[-1]/mouse, ig). Biochemical changes also occurred as the applied protocol decreased reactive species and lipid peroxidation in the hippocampi and small intestine and reduced NRLP3, TLR4, Nfҡb, and IL-1β expression in the small intestine of mice. We believe that the ameliorated cognitive impairment and antidepressant effects of K. pastoris KM71H are due to its antioxidant activity and the modulation of the TLR4/NF-κB pathway, and our findings led us to conclude that K. pastoris KM71H is a promising therapeutic strategy for treating Alzheimer's disease and major depressive disorder.}, } @article {pmid40766949, year = {2025}, author = {Warren, A and Wynia, Z}, title = {Dementia-related stigma in physicians: a scoping review of stigma-reduction interventions.}, journal = {Frontiers in dementia}, volume = {4}, number = {}, pages = {1601462}, pmid = {40766949}, issn = {2813-3919}, abstract = {INTRODUCTION: Despite progress in dementia diagnosis and treatment, physician-held stigma remains a significant barrier to early recognition and effective care. Stigmatizing attitudes among healthcare professionals can negatively impact diagnosis rates, clinical interactions, and care quality for people living with dementia. METHODS: This scoping review was conducted following Arksey and O'Malley's framework. Peer-reviewed literature from 2014 to 2024 was systematically reviewed to identify and evaluate interventions aimed at reducing dementia-related stigma among physicians. A total of 14 studies met inclusion criteria, examining educational, skill-building, and person-centered approaches. RESULTS: Interventions included brief workshops, online modular training, and interdisciplinary methods integrating person-centered frameworks and behavior management tools. Validated outcome measures used in the studies included the Alzheimer's Disease Knowledge Scale (ADKS), the Dementia Negative Stereotype Scale (DNS), and the General Practitioners Confidence and Attitude Scale for Dementia (GPACS-D). Across studies, interventions were found to improve clinical confidence, reduce negative stereotypes, and enhance care quality. DISCUSSION: Findings highlight the importance of culturally sensitive and interdisciplinary interventions to address stigma, improve clinical confidence, and enhance care quality, particularly in low-resource settings. Notable gaps remain in understanding the long-term impact and scalability of such interventions. This review aims to contribute a deeper understanding of the barriers and facilitators to implementing dementia care practices, offering a conceptualization for enhanced physician education and improved health outcomes for persons with dementia. We offer recommendations for future research to develop tailored strategies that support stigma reduction and improve care delivery.}, } @article {pmid40766301, year = {2025}, author = {Gribsholt, SB and Horváth-Puhó, E and Elser, H and Laugesen, K and Skajaa, N and Fuglsang, CH and Henderson, V and Sørensen, HT}, title = {Obstructive sleep apnoea and risk of dementia: a Danish population-based cohort study.}, journal = {BMJ neurology open}, volume = {7}, number = {2}, pages = {e001174}, pmid = {40766301}, issn = {2632-6140}, abstract = {BACKGROUND: Obstructive sleep apnoea (OSA) is associated with adverse health outcomes. However, the association with dementia remains uncertain. Thus, we examined the association of OSA with all-cause dementia and Alzheimer's disease. METHODS: We conducted a Danish nationwide population-based cohort study using health registries. Patients with OSA were identified from 1995 to 2017. Furthermore, a propensity score-matched comparison cohort was defined. Propensity scores were computed based on age, sex, comorbidities and education. With follow-up until 2018, we computed incidence rates (IRs) and HRs for all-cause dementia and Alzheimer's disease. Subgroup analyses were conducted by sex, age, overweight/obesity, hypertension and continuous positive airway pressure (CPAP) treatment. RESULTS: We identified 62 928 patients with OSA and 62 928 in the propensity score-matched comparison cohort (76% male, median age 52 years). The IR for all-cause dementia was 1.27 (95% CI 1.17 to 1.37) per 1000 person-years in patients with OSA and 1.15 (95% CI 1.05 to 1.25) in the propensity score-matched comparison cohort, yielding an HR of 1.10 (95% CI 0.98 to 1.24). The HR for Alzheimer's disease was 1.16 (95% CI 0.94 to 1.43). Among individuals with overweight/obesity, the HR for all-cause dementia was 0.71 (95% CI 0.51 to 0.99), while it was 1.17 (95% CI 1.03 to 1.33) in those without. CPAP treatment attenuated associations. CONCLUSION: Our findings support a modest association between OSA and dementia, including Alzheimer's disease, motivating early clinical detection of OSA as a potentially modifiable risk factor for subsequent dementia. The finding that the dementia hazard was not increased in the setting of overweight or obesity requires further study and points to the need for research on mechanisms underlying the association between OSA and dementia.}, } @article {pmid40765720, year = {2025}, author = {Hamilton, JL and Fuller, RLM and Modi, N and Sampaio, C}, title = {Utilizing MCID for evaluating clinical relevance of AD therapeutic interventions.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70138}, pmid = {40765720}, issn = {2352-8737}, abstract = {UNLABELLED: With the recent approval of disease-modifying treatments for mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) by the United States Food and Drug Administration (FDA), Medicines and Healthcare products Regulatory Agency (MHRA), European Medicine Agency's Committee for Medicinal Products for Human Use (EMA/CHMP) entities, there is a growing sense of urgency and renewed efforts to reassess and understand what constitutes a clinically meaningful benefit in the context of new treatments for AD care, despite the discordance between regulatory entities in regulatory decision-making. While the concept of minimal clinically important difference (MCID) was introduced many years ago, there remains an ongoing debate about how best to evaluate and define clinical benefit in the context of emerging and new therapies for dementia. In this perspective piece, we assess how MCID can be applied to common endpoints and identify areas where MCID application or generation could be useful to enable a better valuation of therapeutic innovation. We offer recommendations for greater consistency in measures used to define MCID, and encourage the prioritized use of patient-reported measures in early AD to build fieldwide consensus for MCID estimation methods and application in AD. HIGHLIGHTS: There is no gold standard or field-wide consensus on what constitutes a clinically meaningful change in Alzheimer's disease (AD) progression trajectories.Anchor-based minimal clinically important difference (MCID) may be used as a tool that can be leveraged for greater contextualization of the clinical relevance of a treatment effect.Patient-reported outcomes (PROs) should be used to define MCID, particularly within mild cognitive impairment (MCI), prodrome/mild AD groups.Greater consistency is needed in the outcome measures used to detect cognitive and functional change to define MCID. This will enable MCID comparisons and support replications of MCID estimates across AD populations.Observational data can augment the clinical characterization and impact of treatment effect and help establish a "ground truth" MCID.MCID estimates for AD outcomes may be used in regulatory submissions to help contextualize the importance of a statistically significant treatment effect.}, } @article {pmid40765614, year = {2025}, author = {Li, X and Lu, X and Ou, J and Lyu, H and Liu, Y and Zhang, J}, title = {Effect of acupuncture on episodic memory for amnestic mild cognitive impairment based on hippocampal subregion: study protocol of a randomized, controlled trial.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1536291}, pmid = {40765614}, issn = {1664-2295}, abstract = {BACKGROUND: The hippocampus is a key brain region for episodic memory, and impairment of episodic memory is the earliest feature of amnestic mild cognitive impairment (aMCI). Preserving the structure and function of the hippocampus plays a key role in preventing progression to Alzheimer's disease (AD). Therefore, early intervention is crucial, and acupuncture could significantly improve episodic memory in aMCI, but the mechanism is not clear. Accordingly, this experiment aims to explore the mechanism of acupuncture to improve episodic memory in aMCI based on the hippocampal subregion. METHODS: A randomized, controlled, blinded research will be performed. 150 aMCI participants will be assigned to the verum acupuncture group, sham acupuncture group, and waiting group; 50 healthy controls will also be recruited. Patients in the acupuncture group will receive real acupuncture treatment or placebo acupuncture three times per week, 36 sessions over 12 consecutive weeks in total. Patients in the waiting group will receive the same verum acupuncture treatment for compensation after the trials are finished. The primary outcome will be the auditory-verbal learning test. Secondary outcomes will include Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Hamilton Depression Scale (HAMD), and functional magnetic resonance imaging data. Outcomes will be measured at baseline and 12 weeks after randomization. Repeated measurement analysis of variance will be used to explore the intervention effect. DISCUSSION: This protocol will provide theoretical support for the neural mechanisms by which acupuncture improves episodic memory in aMCI. We hope that this study will provide objective evidence and offer alternative treatment options for the early treatment of aMCI. CLINICAL TRIAL REGISTRATION: ChiCTR2400084308.}, } @article {pmid40765028, year = {2025}, author = {Kudpaje, M and Joghee, S and Ram Kumar, RM}, title = {Exosomes as a Nanotheranostic Platform in Brain Diseases.}, journal = {The European journal of neuroscience}, volume = {62}, number = {3}, pages = {e70215}, doi = {10.1111/ejn.70215}, pmid = {40765028}, issn = {1460-9568}, support = {D.O. NO.BT/HRD/35/02/2006//Department of Biotechnology, Government of India/ ; }, mesh = {Humans ; *Exosomes/metabolism ; Animals ; *Theranostic Nanomedicine/methods ; *Drug Delivery Systems/methods ; *Brain Diseases/therapy/drug therapy ; Blood-Brain Barrier/metabolism ; }, abstract = {Exosomes, nanoscale extracellular vesicles (30-150 nm), play a critical role in intercellular communication by transporting bioactive molecules, including proteins, lipids, and nucleic acids. These vesicles have emerged as a transformative tool for drug delivery in brain diseases, particularly due to their ability to cross the blood-brain barrier (BBB), a major challenge in treating central nervous system (CNS) disorders. Recent studies have highlighted the potential of exosome-based therapies in treating neurodegenerative diseases such as Alzheimer's and Parkinson's, neuroinflammatory conditions, and brain tumors like glioblastoma. Exosomes can be engineered to enhance their targeting precision by modifying their surface to selectively deliver therapeutic agents to specific brain cells, including neurons, glial cells, and endothelial cells. This review explores the latest advancements in optimizing exosome-mediated drug delivery, focusing on surface modifications and other strategies to improve targeting efficiency and therapeutic outcomes. Additionally, exosomes are being investigated as diagnostic biomarkers for early disease detection and monitoring, offering a noninvasive alternative to traditional methods. Despite their promise, challenges such as large-scale production, cargo loading, safety concerns, and regulatory barriers remain. This review provides an overview of the current state of exosome-based therapies, critically evaluates the ongoing challenges, and explores future directions for optimizing their use in brain disease treatment, emphasizing enhancing targeted delivery and therapeutic efficacy.}, } @article {pmid40764790, year = {2025}, author = {Sepúlveda-Rivera, V and Olivieri-Henry, G and Morales-González, H and Ruiz-Adames, J and Herrero-Rivera, C and Rentas-Echeverria, A and Cardona-Berdecia, V and Soler-Llompart, C and Sala-Morales, AC and Pérez-Montero, G and Blanco-Ruiz, E and Godoy-Vitorino, F}, title = {Gut microbiota distinguishes aging hispanics with Alzheimer's disease: associations with cognitive impairment and severity.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {28505}, pmid = {40764790}, issn = {2045-2322}, support = {U54 MD007600/MD/NIMHD NIH HHS/United States ; S21MD001830/MD/NIMHD NIH HHS/United States ; P20GM103475//National Institute Of General Medical Sciences of the National Institutes of Health/ ; U54GM133807//National Institute Of General Medical Sciences of the National Institutes of Health/ ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Aging ; *Alzheimer Disease/microbiology ; Case-Control Studies ; *Cognitive Dysfunction/microbiology ; Dysbiosis/microbiology ; *Gastrointestinal Microbiome ; Hispanic or Latino ; Puerto Rico ; Severity of Illness Index ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that begins with memory loss and can lead to death. In Puerto Rico, AD is the fourth leading cause of death, while in the United States, it ranks fifth. Research suggests the gut microbiome contributes to the pathophysiology of AD by promoting inflammation and amyloid buildup in the brain. This study examined the composition and diversity of the gut microbiota in Puerto Ricans with AD compared to controls and its relationship with cognitive impairment severity and APOE status. We recruited 100 participants (50 AD, 50 controls), who underwent clinical and cognitive assessments (MoCA/CDR). While overall microbial diversity and richness showed no significant differences, specific bacterial taxa exhibited subtle differential abundance. Faecalibacterium and Bacteroides were moderately significant and increased on controls compared to AD. Moreover, individuals carrying the APOE E4 allele exhibited lower abundances of butyrate-producing bacteria and an enrichment of potentially pro-inflammatory genera, including Eggerthella and Lachnoclostridium. These findings suggest that gut microbiota dysbiosis may contribute to cognitive decline and AD progression, highlighting the potential for microbiome-targeted therapeutic interventions in AD prevention and treatment.}, } @article {pmid40764372, year = {2025}, author = {Lin, CH and Lane, HY}, title = {Sodium benzoate treatment decreased amyloid beta peptides and improved cognitive function among patients with Alzheimer's disease: secondary analysis of a randomized clinical trial.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {264}, pmid = {40764372}, issn = {2158-3188}, support = {NHRI-EX113-11133NI//National Health Research Institutes (NHRI)/ ; DMR-114-188//China Medical University Hospital (CMUH)/ ; MOST 111-2314-B-182A-024-MY3//Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)/ ; CMRPG8M1311, CMRPG8M1361, CMRPG8N1201, CMRPG8N1121, CMRPG8N1212//Chang Gung Memorial Hospital (CGMH)/ ; CMRPG8M1311, CMRPG8M1361, CMRPG8N1201, CMRPG8N1121, CMRPG8N1212//Chang Gung Memorial Hospital (CGMH)/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/psychology ; *Amyloid beta-Peptides/blood/drug effects ; Male ; Female ; *Sodium Benzoate/administration & dosage/pharmacology/therapeutic use ; Aged ; Double-Blind Method ; *Cognition/drug effects ; *Peptide Fragments/blood/drug effects ; Middle Aged ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {With the recent approval of anti-amyloid beta (Aβ) monoclonal antibody infusion therapies for Alzheimer's disease (AD), more feasible and safter Aβ-reducing approaches are anticipated. Previous studies showed that 750-mg/day or 1000-mg/day (but not 500-mg/day) sodium benzoate treatment improved cognitive function in AD patients with excellent safety and that benzoate decreased Aβ burden in an animal AD model. The current study aimed to explore whether oral sodium benzoate was able to reduce Aβ peptides in AD patients and whether Aβ before treatment was correlated with cognitive improvement after treatment. This secondary analysis used data from a double-blind trial, in which 149 patients with mild AD were randomized to receive oral placebo or one of three benzoate doses (500, 750, or 1000 mg/day). Cognitive function and plasma Aβ 1-40 and Aβ 1-42 levels were measured before and after treatment. When compared to placebo, benzoate therapy at effective doses (750 and 1000 mg/day) reduced Aβ 1-40 and the sum of both Aβ peptides (Aβ 1-40 plus Aβ 1-42) in AD patients. Moreover, higher Aβ 1-42 levels at baseline were associated with better cognitive improvements after benzoate treatment at effective doses in the patients. The findings suggest that sodium benzoate therapy can reduce Aβ 1-40 and the total Aβ in AD patients and higher Aβ 1-42 levels before treatment predict better cognitive improvements. Due to its superior safety and convenient administration, sodium benzoate has the potential to be a novel Aβ-reducing therapy for AD treatment. TRIAL REGISTRATION: Name of trial registry: NMDA Enhancer for the Treatment of Mild Alzheimer's Disease. Identifying number: ClinicalTrials.gov Identifier: NCT03752463 (https://clinicaltrials.gov/ct2/show/NCT03752463). Registration date: 2018-11-21.}, } @article {pmid40764129, year = {2025}, author = {Zhang, B and Lu, H and Li, WP and Liu, DM and Zhang, X and Zhan, SH and Li, KC and Wang, Y and Yang, QX and Gu, XS and Xu, TS}, title = {[The application value of olfactory brain imaging combined with olfactory-stimulating and brain-invigorating acupuncture in the early diagnosis and treatment of Alzheimer's disease].}, journal = {Zhonghua nei ke za zhi}, volume = {64}, number = {8}, pages = {801-806}, doi = {10.3760/cma.j.cn112138-20240918-00587}, pmid = {40764129}, issn = {0578-1426}, mesh = {*Alzheimer Disease/therapy/diagnosis ; Humans ; *Acupuncture Therapy ; Early Diagnosis ; Brain ; }, } @article {pmid40764088, year = {2025}, author = {Liu, H and Chen, Y and Zhang, J and Chen, X}, title = {Adaptive immunity in the neuroinflammation of Alzheimer's disease.}, journal = {Chinese medical journal}, volume = {138}, number = {17}, pages = {2116-2129}, pmid = {40764088}, issn = {2542-5641}, mesh = {*Alzheimer Disease/immunology/metabolism ; Humans ; *Adaptive Immunity/immunology/physiology ; Immunity, Innate/immunology ; Animals ; *Neuroinflammatory Diseases/immunology ; *Inflammation/immunology ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia and is a growing public health challenge. Neuroinflammation has been proposed as a prominent pathological feature of AD and has traditionally been attributed to the innate immune system. However, emerging evidence highlights the involvement of adaptive immunity, particularly T and B lymphocytes, in the neuroinflammatory processes of AD. It remains unclear how adaptive immune responses, originally intended to protect the body, contribute to chronic inflammation and neuronal dysfunction in AD. Here, we review the roles of adaptive immunity, cellular composition, and niches and their contribution to AD development and progression. Notably, we synthesize the crosstalk between adaptive immunity and the innate immune system of the central nervous system (CNS), which is mainly mediated by glial cells and myeloid cells, and their interrelationships with amyloid-β (Aβ)/Tau pathology. We hypothesized that the alterations observed in innate immunity in AD mirror age-related immune alterations, whereas the dysregulation of adaptive immunity contributes more accurately to disease-specific immune responses. Targeting adaptive immunity in the context of neuroinflammation may provide new insights into potential therapeutic strategies designed to modulate immune responses, thereby facilitating the diagnosis, intervention, and treatment of AD.}, } @article {pmid40763898, year = {2025}, author = {Porel, P and Hunjan, G and Singh, S and Aran, KR}, title = {Is the renin-angiotensin system a friend or foe in neurological diseases? Unveiling its role and therapeutic potential.}, journal = {Ageing research reviews}, volume = {112}, number = {}, pages = {102854}, doi = {10.1016/j.arr.2025.102854}, pmid = {40763898}, issn = {1872-9649}, mesh = {Humans ; *Renin-Angiotensin System/physiology/drug effects ; Animals ; *Nervous System Diseases/drug therapy/metabolism/physiopathology ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use/pharmacology ; Angiotensin Receptor Antagonists/therapeutic use/pharmacology ; Neurodegenerative Diseases/drug therapy ; }, abstract = {The renin-angiotensin system (RAS), an important regulator of body fluid and cardiovascular homeostasis, is gradually implicated in the pathogenesis of neurological diseases due to its dysregulation. In addition to their traditional functions, components of the RAS, especially angiotensin-II (Ang-II), enhance neuroinflammation, oxidative stress, and neuronal injury. Ang-II exacerbates blood-brain barrier (BBB) disruption, promotes glial activation, and contributes to neurodegeneration via the Angiotensin type 1 (AT1) receptor (AT1R) and causes neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), epilepsy, depression, and anxiety. The angiotensin (1-7) axis mediated by the Mas receptor appears to be neuroprotective, however, as it reverses the negative effects of Ang-II. In experimental models and clinical trials, blocking RAS specifically by angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) has demonstrated promise in reducing neuroinflammation and neuronal damage, especially in stroke and neurodegenerative diseases. In the current era of research, neuropharmacologists have new optimism due to emerging evidence of the promising potential of RAS-modulating drugs, such as ARBs and ACEIs, in the treatment of various neurological diseases. Since RAS imbalance causes neuroinflammation, neuronal damage, and cognitive decline in conditions including AD, PD, and MS, these drugs may offer a new treatment approach. In the current era of neuropharmacology, this technique is novel since it enables more targeted therapies to address the root causes of neurodegeneration. This review explores the molecular pathways of RAS dysregulation in various neurological diseases, highlighting its therapeutic potential and paving the way for future treatment strategies.}, } @article {pmid40763881, year = {2025}, author = {Garbo, S and Raucci, A and Zwergel, C and Handzlik, J and Battistelli, C}, title = {Beyond Antibodies: Reinventing Alzheimer's Treatment for the Next Decade.}, journal = {Drug discovery today}, volume = {30}, number = {9}, pages = {104445}, doi = {10.1016/j.drudis.2025.104445}, pmid = {40763881}, issn = {1878-5832}, } @article {pmid40763582, year = {2026}, author = {Zuo, Z and Xiao, Z and Zhang, L and Deng, S and He, X and Mu, Y and Wang, P and Feng, Y and Wang, Z and Li, S and Yang, X and Xu, J and Guo, K and Guo, W and Shuai, X and Hu, X and Zheng, H}, title = {Engineered peripheral CD4 T cells delivery across the BBB promote intracerebral Treg conversion unleashes microglial phagocytotic activity for Alzheimer's disease treatment.}, journal = {Biomaterials}, volume = {325}, number = {}, pages = {123574}, doi = {10.1016/j.biomaterials.2025.123574}, pmid = {40763582}, issn = {1878-5905}, mesh = {Animals ; *Alzheimer Disease/therapy/immunology/pathology ; *T-Lymphocytes, Regulatory/immunology/cytology ; *Microglia/immunology ; *Blood-Brain Barrier/metabolism ; Mice ; *CD4-Positive T-Lymphocytes/immunology/transplantation ; *Phagocytosis ; Amyloid beta-Peptides/metabolism/immunology ; Mice, Transgenic ; Disease Models, Animal ; Mice, Inbred C57BL ; Peptide Fragments ; Brain/pathology ; }, abstract = {Alzheimer's disease (AD) affects thirty million individuals worldwide, but a viable treatment has yet to be identified. During disease progression, peripheral immune cells, including peripheral T cells, infiltrate the brain. Although CD4[+] regulatory T cells have been demonstrated to exhibit neuroprotective efficacy in AD, the precise roles of these cells in the brain remain elusive. Here, we report that β-amyloid (Aβ) 1-42 antigen-specific CD4[+] T cells spontaneously cross the blood-brain barrier (BBB) into the brain in an APP/PS1 mouse model. To promote parenchymal Treg conversion from infiltrated CD4[+] T cells and minimize the perturbations of the brain microenvironment, we engineered an Aβ1-42 antigen-specific CD4[+] T cell-based nanodelivery system to release the compound AS2863619, a CDK8/19 inhibitor (eTc-AS), which can bypass the BBB and selectively induce the conversion of CD4[+] T cells into Treg cells within the brain region. These cells demonstrated notable pathological amelioration in APP/PS1 mice, in part by interacting with microglia or recruited macrophage via PD-L1/PD-1 signaling. Our study reveals valuable engineered T cell therapies and suggests an immune checkpoint mechanism underlying the neuroprotective function of the Treg-microglia like cell interplay in AD.}, } @article {pmid40763193, year = {2025}, author = {Lv, L and Fazio-Eynullayeva, E and Mystkowski, P and McKay, C and Al-Zubeidi, T and Miller, J and McKee, S and Bottomley, C and Floegel, C and Hyde, R and Aly, A}, title = {Experiences of patient and care partner dyads in early Alzheimer's disease: a mixed-method study in the United States.}, journal = {Neurodegenerative disease management}, volume = {15}, number = {5}, pages = {223-234}, pmid = {40763193}, issn = {1758-2032}, mesh = {Humans ; *Alzheimer Disease/psychology/economics/therapy ; Male ; Female ; Aged ; United States ; *Caregivers/psychology ; Aged, 80 and over ; Middle Aged ; Surveys and Questionnaires ; }, abstract = {AIMS: Understanding the holistic experience of patients with early Alzheimer's disease (AD) and their care partners is important to identify unmet needs. This study aimed to describe and compare patient-care partner dyad experiences and perspectives in early AD. PATIENTS & METHODS: Experiences of patients and their care partners (dyads) were explored using a survey, qualitative interviews, and social media listening. Each dyad completed a 25-minute quantitative online survey exploring their perceptions of symptoms, comorbidity impact, financial burden, and preferred treatment characteristics. Data were analyzed descriptively and comparatively. RESULTS: 150 patient-care partner dyads completed the survey. Patients and care partners frequently reported memory-related issues and cognitive challenges (68% and 77%, respectively); approximately 19% of responses were discordant, with patients often under-reporting symptoms. Managing comorbidities worsened overall well-being of patients (41%) and care partners (40%). Treatments slowing AD progression (patients: 99%; care partners: 96%) and improving symptoms (patients: 95%; care partners: 93%) were important. Approximately 26% of respondents experienced significant negative financial impacts. CONCLUSIONS: Patients and care partners perceived early AD impacts similarly whereas some symptoms were perceived differently. There was a shared desire for disease-modifying treatments. Limited financial impact may reflect preserved functionality and limited use of disease-modifying treatments.}, } @article {pmid40762111, year = {2025}, author = {Cao, F and Zhang, P and Zheng, Z and Wang, P and Wang, Y and Shi, Q and Zhang, D and Xu, L}, title = {Celastrol treatment attenuates the inflammatory response in Alzheimer's disease model mice.}, journal = {Neurological research}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/01616412.2025.2534077}, pmid = {40762111}, issn = {1743-1328}, abstract = {OBJECTIVE: Alzheimer's disease (AD) is the most common neurodegenerative disease. Unfortunately, current effective therapeutics for AD are limited, and thus, the discovery of novel anti-AD agents is urgently needed. Celastrol, a plant-derived triterpene, has both antioxidant and anti-inflammatory activities. METHODS AND RESULTS: Here, we found that celastrol treatment promoted microglial M2 polarization and inhibited inflammatory factor expression in both in vivo and in vitro experiments. Celastrol treatment significantly improved cognitive function in AD mice by regulation the TLR4/NFκB pathway, overexpression TLR4 reversed the protective effect of CEL to cognitive function in AD model mice. Suggesting that TLR4/NFκB plays a crucial role in regulating the inflammatory response. CONCLUSION: Taken together, the results indicate that celastrol treatment attenuated the inflammatory response in AD mice by promoting microglial M2 polarization via the TLR4/NFκB pathway.}, } @article {pmid40762089, year = {2025}, author = {Chatanaka, MK and Pascual Lorén, M and Diamandis, EP}, title = {Is screening for Alzheimer's disease ready for prime time? Ask Wilson and Jungner.}, journal = {Critical reviews in clinical laboratory sciences}, volume = {62}, number = {8}, pages = {631-645}, doi = {10.1080/10408363.2025.2533860}, pmid = {40762089}, issn = {1549-781X}, mesh = {Humans ; *Alzheimer Disease/diagnosis/epidemiology ; *Mass Screening/methods ; Early Diagnosis ; }, abstract = {Population screening is an effective strategy for disease prevention, early diagnosis and treatment; however, the benefits and harms of disease screening need to be carefully evaluated before clinical implementation. Various national and international bodies, including the U.S. Preventive Services Task Force (USPSTF), periodically develop recommendations for screening after reviewing the available published evidence and, in some instances, expert opinions. In 1968, Wilson and Jungner formulated a set of 10 rules that must be considered and fulfilled before introducing screening for any disease into clinical practice. Alzheimer's disease (AD), a devastating chronic disease that affects millions of people worldwide and is the most common cause of dementia, has recently been reviewed in the context of population screening. Data and predictions show that the prevalence of AD is steadily increasing and will likely become one of the most common causes of death by 2060. Currently, there are no effective curative therapeutic options for this disease, but new developments have allowed earlier detection at asymptomatic and early symptomatic stages. New classes of disease-modifying therapeutics show promise of slowing the progression of the disease. These new developments prompted us to examine the near-future feasibility of screening for presymptomatic or early symptomatic AD by considering the general screening principles of Wilson and Jungner. In 2020, USPSTF published a guideline regarding screening for cognitive impairment, an AD symptom, and concluded that the current evidence is insufficient to assess the balance of benefits and harms and did not recommend screening for cognitive impairment in older adults. This was recapitulated in 2024 by the Canadian Task Force on Preventive Health Care (CTFPHC). After careful consideration, and despite the recent significant biological, diagnostic and therapeutic advances for AD, screening does not seem to be justified at present, due to numerous reasons, such as lack of trained professionals and specialized clinics to handle the anticipated highly increased workload, the huge cost, the ineffectiveness and side effects of current therapy, the lack of long-term therapy studies, and the disagreement among experts as to whom to test and treat and when (at either asymptomatic or early symptomatic stages).}, } @article {pmid40762084, year = {2025}, author = {Wang, X and Xia, Y and Guo, MS and Wu, J and Dilidaer, A and Gao, J and Dong, TT and Zhu, Y and Tsim, KWK}, title = {The Tacrine-Induced Endoplasmic Reticulum Stress in AChE-Expressed Cells Leads to Improper Assembly and Transport of the Oligomeric Enzyme: Reversal by Trehalose.}, journal = {Journal of neurochemistry}, volume = {169}, number = {8}, pages = {e70178}, pmid = {40762084}, issn = {1471-4159}, support = {ZDSYS201707281432317//Shenzhen Science and Technology Innovation Committee/ ; HMRF18SC06//Health and Medical Research Fund, Food and Health Bureau of Hong Kong/ ; HMRF20SC07//Health and Medical Research Fund, Food and Health Bureau of Hong Kong/ ; 16100921//Hong Kong GRF/ ; T13-605/18-W//Hong Kong GRF Theme-based Research Scheme/ ; ITCPD/17-9//Hong Kong Innovation and Technology Fund/ ; }, mesh = {*Trehalose/pharmacology ; *Tacrine/toxicity/pharmacology ; *Endoplasmic Reticulum Stress/drug effects/physiology ; Animals ; *Acetylcholinesterase/metabolism/biosynthesis/genetics ; *Cholinesterase Inhibitors/pharmacology/toxicity ; Mice ; Cell Line, Tumor ; Humans ; Protein Transport/drug effects ; Neurons/drug effects ; }, abstract = {Alzheimer's disease (AD) is the most common dementia with progressive loss of cognitive functions. Acetylcholinesterase (AChE) inhibitors have been approved as conventional pharmacotherapies for AD. Tacrine was the first AChE inhibitor introduced into clinics for AD; however, it was withdrawn from use in 2013 because of safety concerns. In cultured neurons, as well as in mice, tacrine was found to induce endoplasmic reticulum (ER) stress and finally lead to cell apoptosis: the event was triggered by binding the inhibitor to the intracellular enzyme serving as a pharmacological chaperone. Trehalose, a known ER stress reducer, was shown here to ameliorate the ER stress induced by tacrine in AChE-overexpressed NG108-15 cells, with the increased level of C/EBP homologous protein (CHOP) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α). In tetrameric G4 AChE overexpressed cells, the tacrine-exposed cultures revealed considerable G1/G2 forms of AChE accumulated in the ER fraction, whereas the treatment of trehalose decreased the accumulation of G1/G2 AChE. Meanwhile, trehalose reduced the ER stress induced by other AChE inhibitors, for example, lycobetaine, bis(3)-cognitin, daurisoline, and dauricine, in the cultured neuronal cells. Besides, this tacrine-induced ER stress was identified in all AChE isoforms, as well as in butyrylcholinesterase (BChE) expressing cells. Thus, we proposed that the AChE inhibitors, particularly tacrine, could act as 'chemical/pharmacological chaperones' during AChE biosynthesis in the ER, disrupting the proper folding of AChE in neurons as a result of ER stress. Trehalose possesses the ability to relieve ER stress by promoting the proper assembly of AChE. The results provide guidance for the drug design and discovery of AChE inhibitors for AD treatment.}, } @article {pmid40761983, year = {2025}, author = {DiGiovanni, A and Shehaj, A and Millar, D and Tse, C and Rizk, E}, title = {Utility of Pharmacological Agents for Diabetes Mellitus in the Prevention of Alzheimer's Disease: Comparison of Metformin, Glucagon-Like Peptide-1 (GLP-1) Agonists, Insulin, and Sulfonylureas.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e87350}, pmid = {40761983}, issn = {2168-8184}, abstract = {BACKGROUND: Metformin is a drug primarily used for the treatment of diabetes mellitus (DM), but it also offers clinical benefits that extend beyond glycemic control. Existing literature provides an unclear conclusion as to whether metformin's benefits extend to preventing neurodegeneration, such as in Alzheimer's disease (AD). METHODS: A retrospective database study was conducted to evaluate the likelihood of developing AD in DM patients taking metformin compared to those taking glucagon-like peptide (GLP-1) analogs, sulfonylureas, and short-acting insulin variants. An analysis was also run to assess whether metformin has a protective benefit for AD and mortality when used in those with DM compared to those without DM. RESULTS: In analyses totaling greater than 2.5 million patients, those on metformin had lower A1C percentages and a decreased mortality risk when compared to sulfonylureas (HR = 0.519, (CI: (0.493,0.546)), and short-acting insulins (HR = 0.372, (CI: (0.364,0.380)). Metformin use for DM was associated with a statistically significant increased likelihood of AD diagnosis compared to GLP-1 use (HR = 2.228, CI: (1.036,4.794)) but an insignificant difference compared to both sulfonylureas and insulins. Those with DM were at a significantly higher risk of being diagnosed with Alzheimer's compared to those without DM (HR = 1.826, (CI: 1.579, 2.111)). CONCLUSIONS: Metformin, previously thought to have significant benefits in preventing neurodegeneration, may not be the optimal pharmacologic agent of choice, particularly in patients with DM, if neurodegeneration is a primary concern in treatment decision-making based on other risk factors.}, } @article {pmid40761698, year = {2025}, author = {Zhou, B and Li, J and Wu, A and Wang, X and Cheng, L and Yang, G and Gao, D and Zhu, C}, title = {Insights into targeted ferroptosis in mechanisms, biology, and role of Alzheimer's disease: an update.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1587986}, pmid = {40761698}, issn = {1663-4365}, abstract = {Ferroptosis is a newly discovered form of programmed cell death, primarily caused by an imbalance between iron-dependent oxidative damage and antioxidant defense mechanisms within the cell. It differs from previously reported forms of cell death, such as apoptosis, necrosis, and autophagy, in terms of morphology, biochemistry, and genetics. Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by pathological features including neurofibrillary tangles (NFTs), senile plaques (SPs), and abnormal iron deposition, suggesting that ferroptosis may be involved in its disease progression. Although recent studies have made significant progress, the mechanisms underlying neuronal ferroptosis in AD remain incompletely understood. This review, based on elucidating the process and regulatory mechanisms of cellular ferroptosis, explores, and supplements the correlation between iron overload and redox imbalance with the main pathological mechanisms of AD, providing new insights for the treatment of AD and the development of new drugs.}, } @article {pmid40761545, year = {2025}, author = {Zhu, H and Yang, W and Suo, Y and Liu, Y and Zhan, X and Zhou, J and Chen, Z and Wu, X and Yin, X and Bao, B}, title = {Nanomaterials engineered for photothermal therapy in neural tumors and neurodegenerative diseases: biomaterial design, clinical mechanisms and applications.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {13}, number = {}, pages = {1631627}, pmid = {40761545}, issn = {2296-4185}, abstract = {The rising incidence of neural tumors and neurodegenerative diseases cause significant health, emotional, and financial burdens. Conventional treatments like surgery and chemotherapy often lack effectiveness. However, advancements in nanotechnology, particularly photothermal therapy (PTT), offer new hope. PTT is widely studied for neural tumors and neurodegenerative diseases due to its simplicity, rapid recovery, combined therapeutic potential, and compatibility with imaging techniques. This innovative approach could revolutionize the diagnosis and treatment of neural tumors and neurodegenerative diseases, addressing current limitations and improving outcomes. In this article, we offer a comprehensive overview of the rational design and engineering of various nanomaterials designed specifically for PTT applications in neural tumors and neurodegenerative diseases, including organic platforms such as liposomes, dopamine, etc. and inorganic platforms such as gold nanomaterials, carbon nanomaterials, etc. A comparative analysis of these platforms examines their biocompatibility and potential for biodegradation. It also assesses their manufacturing scalability, cost-effectiveness, regulatory challenges, and ultimate potential for clinical translation. We also update the therapeutic advances of PTT in neural tumors (Glioma, Peripheral nerve sheath tumors, Spinal metastases from in situ tumors and brain metastases) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), and systematically summarize the mechanisms of PTT application in neural tumors and neurodegenerative diseases. In the end, we provide an in-depth discussion of the advantages and disadvantages of PTT and the perspectives for its application in the above neurological disorders.}, } @article {pmid40761402, year = {2025}, author = {Zampatti, S and Peconi, C and Farro, J and Piras, F and Pellicano, C and Caltagirone, C and Giardina, E}, title = {Pharmacogenetics or predictive genetics? APOE testing blurs the lines.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1627239}, pmid = {40761402}, issn = {1663-9812}, abstract = {The integration of pharmacogenetics into personalized medicine enables the optimization of drug selection and dosage, maximizing therapeutic benefits while minimizing the risk of adverse drug reactions. The association between APOE alleles and ARIA, a known adverse reaction in Alzheimer's disease patients treated with anti-amyloid monoclonal antibodies, has led to the inclusion of APOE genotyping among conventional pharmacogenetic tests. Given the dual role of APOE alleles, the widespread implementation of this genetic test requires caution and should be accompanied by appropriate genetic counselling. APOE genotyping is uniquely positioned at the intersection of pharmacogenetics and germline testing: it provides insight not only into drug safety (specifically the risk of Amyloid-Related Imaging Abnormalities) but also into familial risk for developing Alzheimer's disease. Carriers of risk alleles, especially homozygotes, face the highest risk and require close monitoring. While APOE genotyping can inform treatment decisions, it also raises ethical concerns due to the broader implications of disclosing genetic risk information for neurodegenerative diseases. Identifying a high-risk APOE genotype in a patient substantially impacts family members. Therefore, patients considered for treatment with anti-amyloid monoclonal antibodies should receive comprehensive pre- and post-test genetic counseling that goes beyond traditional standards, as currently provided for other peculiar tests. Such counseling ensures that patients are adequately informed about potential outcomes, psychological impacts, and familial implications. It also supports ethical decision-making and facilitates truly informed consent, helping to prevent deterministic or overly simplistic interpretations of genetic risk.}, } @article {pmid40760852, year = {2025}, author = {Duchesne, S and Potvin, O and Hudon, C and Bocti, C}, title = {A brain health framework with application to the study of neurodegeneration.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {3}, pages = {960-972}, pmid = {40760852}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/pathology ; *Brain/pathology/physiopathology ; Models, Neurological ; *Neurodegenerative Diseases/pathology ; }, abstract = {An all-encompassing framework seems necessary for understanding brain health in the context of neurodegeneration, particularly due to Alzheimer's disease (AD). We argue that current views, dominated by the amyloid-beta hypothesis, oversimplify the complexity of brain degeneration. We propose a multi-scale, multi-entity approach, treating the brain as a complex system composed of interacting subsystems across various scales, from the nanoscale (genes and proteins) to the macroscale (cognition) and beyond. By redefining brain health through mathematical complexity, we emphasize the importance of integrating diverse biological, environmental, and lifestyle factors to account for the heterogeneity in AD presentations. This framework suggests that failures at different levels of brain function can lead to cascading effects that influence neurodegenerative trajectories. Additionally, it calls for a shift toward personalized treatment approaches that target multiple yet specific pathological mechanisms affecting an individual. We propose computational models as essential tools for simulating and testing these complex interactions. Through this framework, we aim to provide a deeper understanding of neurodegeneration, and advocate for more comprehensive and multi-factorial approaches in both research and clinical practice to advance the treatment of brain health disorders such as AD.}, } @article {pmid40760799, year = {2025}, author = {Li, Z and Kang, Y and Li, S and Guo, S and Zheng, H}, title = {Unveiling the Relationship Between Oral Microbiota and Alzheimer's Disease: A Genetic Instrumental Variable Analysis via Mendelian Randomization.}, journal = {Brain and behavior}, volume = {15}, number = {8}, pages = {e70753}, pmid = {40760799}, issn = {2162-3279}, mesh = {Mendelian Randomization Analysis ; *Alzheimer Disease/genetics/microbiology ; *Microbiota ; *Tongue/microbiology ; *Saliva/microbiology ; Humans ; }, abstract = {BACKGROUND: The potential relationship between oral microbiota (OM) and Alzheimer's disease (AD) is increasingly recognized, but the exact causal relationship between them remains uncertain. This study aims to reveal the causal relationship between OM and AD. METHODS: A two-sample Mendelian randomization (MR) approach was employed to examine the association between 594 OM exposures and AD outcomes. Effect estimates were derived from external genome-wide association study (GWAS) summary statistics, primarily utilizing inverse-variance weighted (IVW) analysis. Sensitivity analyses were conducted to assess the robustness of the findings. In addition, we genetically mapped SNPs corresponding to OM in the MR analysis to identify genes that may link OM to AD. RESULTS: A total of 48 OM exposures exhibited statistically significant associations with AD outcomes (p ≤ 0.05). Of these, 30 were identified at the genus level, 12 at the species level, and six at the family level. Genetic function analyses indicated that OM-related genes are closely linked to the regulation of neurobiological functions, supporting a potential role for OM in the pathogenesis of AD. CONCLUSION: The findings presented here provide genetic evidence for a causal relationship between OM and AD, offering insights that may guide the future development of prevention and treatment strategies targeting OM in the context of AD.}, } @article {pmid40760788, year = {2025}, author = {Ke, S and Yan, J and Li, B and Feng, X}, title = {Causal Association Between Immune Cell Traits and Risk of Multiple Malignant and Nonmalignant CNS Diseases: A Mendelian Randomization and Single-Cell Transcriptomic Analysis.}, journal = {Brain and behavior}, volume = {15}, number = {8}, pages = {e70632}, pmid = {40760788}, issn = {2162-3279}, mesh = {Humans ; Mendelian Randomization Analysis ; Single-Cell Analysis ; Quantitative Trait Loci/genetics ; Glioblastoma/genetics/immunology ; *Central Nervous System Diseases/genetics/immunology ; Transcriptome ; Gene Expression Profiling ; Brain Neoplasms/genetics/immunology ; }, abstract = {BACKGROUND: The influence of immune cell traits (ICTs) on the onset of multiple brain diseases has been previously investigated; however, it is limited by the sample size or colocalization evidence. Besides, the impact remains inconclusive. METHODS: We performed a Mendelian randomization (MR) study to elucidate the causal correlation between significant ICTs and diverse brain disorders and explored the biomarkers linked to glioblastoma (GBM), a form of solid tumor, by integrating expression quantitative trait locus (eQTL) and single-cell RNA sequencing (scRNA-seq) analyses. The nonnegative matrix factorization (NMF) method was utilized to reclassify malignant cells into distinct cell states. Related functional analyses at the scRNA-seq level were also performed. RESULTS: We examined 731 ICTs across 13 brain disorders; impacts from these ICTs varied a lot across different brain diseases. Such ICTs mainly involved T/natural killer (NK) cell activation, B cell differentiation, and myeloid cell suppression or activation. Pleiotropy or heterogeneity in current results has been checked and excluded via sensitivity analyses. Specifically, colocalization analyses demonstrated protective roles of distinct ICTs in T/B/NK cell panels for amyotrophic lateral sclerosis (ALS) and GBM, while myeloid and human leukocyte antigen (HLA)-associated traits were associated with increased risk of Alzheimer's disease (AD), and then two memory cell traits were linked to the increased risk of major depressive disease (MDD). By NMF, we identified six distinct cell states within GBM cells. Furthermore, we established an eight-marker glioblastoma risk signature (GBRS) using scRNA-seq and eQTL data, with higher GBRS scores observed in the NFkB cluster and EGFR cluster, indicating their highlighted aggression among malignant cells. Epigallocatechin gallate could be an effective treatment candidate targeting the EGFR cluster via markers of SQLE and VCP. CONCLUSION: Our findings identified causal effects of distinct ICTs on both malignant and nonmalignant brain diseases and underscored the pivotal role of neuroinflammation in their etiology. With combined evidence from eQTL and scRNA-seq, GBM could be better characterized and managed.}, } @article {pmid40760693, year = {2025}, author = {Iwatsubo, T and Sperling, RA and Algeciras-Schimnich, A and Arai, H and Barron, AM and Benzinger, TLS and Carrillo, MC and Chen, C and Choi, SH and Fontana, IC and Graff-Radford, J and Grill, JD and Heidebrink, J and Hu, CJ and Ihara, R and Ikeuchi, T and Iwata, A and Ip, FCF and Fitri, FI and Jack, CR and Jeong, JH and Jia, J and Kandiah, N and Kim, S and Kowa, H and La Joie, R and Niimi, Y and Noritake, R and Okonkwo, OC and Palmqvist, S and Rafii, MS and Raman, R and Shen, Y and Simuni, T and Snyder, HM and Sriwannopas, O and Stoeckel, LE and van der Flier, WM and Wang, H and Wilcock, DM and Zetterberg, H and Zhou, J and Mahinrad, S and Sexton, CE}, title = {Modernizing diagnosis of Alzheimer's disease: A review of global trends and Asia-specific perspectives.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70536}, pmid = {40760693}, issn = {1552-5279}, support = {//Gates Ventures/ ; R01AG070028/NH/NIH HHS/United States ; //Eisai/ ; //European Union's Horizon 2020 research and innovation programme/ ; //Roche Nederland/ ; R01 AG066203/AG/NIA NIH HHS/United States ; R01 AG070028/AG/NIA NIH HHS/United States ; //Combinostics/ ; #ADSF-21-831377-C/ALZ/Alzheimer's Association/United States ; U19 AG073153/AG/NIA NIH HHS/United States ; //Pasman stichting/ ; //Health∼Holland/ ; //anonymous donor/ ; R01AG077507/NH/NIH HHS/United States ; //Alzheimer Nederland/ ; //Biogen/ ; U19AG078109/NH/NIH HHS/United States ; //Alexander family professorship/ ; MRP/042/18X//Innovation and Technology Commission - Hong Kong/ ; R01 AG077507/AG/NIA NIH HHS/United States ; #ADSF-21-831376-C/ALZ/Alzheimer's Association/United States ; //Familjen Rönströms Stiftelse/ ; //Edwin Bouw fonds/ ; #2022-01018//Vetenskapsrådet/ ; R01 AG085592/AG/NIA NIH HHS/United States ; U19AG032438/NH/NIH HHS/United States ; //Alzheimer's Drug Discovery Foundation/ ; 2021ZD0201805//The Science and Technology Innovation 2030-Major Project/ ; #2019-02397//Vetenskapsrådet/ ; JP20dk0207048h002//Japan Agency for Medical Research and Development/ ; R01AG027161/NH/NIH HHS/United States ; JP24K10653//Japan Society for the Promotion of Science/ ; JP19dk0207048h001//Japan Agency for Medical Research and Development/ ; //Fujifilm/ ; JP24dk0207060//Japan Agency for Medical Research and Development/ ; R01 AG062167/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; //Eli Lilly-NL/ ; JP23dk0207054h0003//Japan Agency for Medical Research and Development/ ; #2023-00356//Vetenskapsrådet/ ; //Innovative Health Initiative/ ; JP24dk0207054h0004//Japan Agency for Medical Research and Development/ ; //UK Dementia Research Institute at UCL/ ; P30AG072931/NH/NIH HHS/United States ; //Novarti-NL/ ; R01 AG027161/AG/NIA NIH HHS/United States ; 2021ZD0201802//The Science and Technology Innovation 2030-Major Project/ ; //Erling-Persson Family Foundation/ ; R01AG066203/NH/NIH HHS/United States ; //GHR Foundation/ ; U19 AG024904/AG/NIA NIH HHS/United States ; Z201100005520017//Beijing Municipal Science and Technology Commission, Adminitrative Commission of Zhongguancun Science Park/ ; R61AG066543/NH/NIH HHS/United States ; JP21dk0207054h0001//Japan Agency for Medical Research and Development/ ; 23re0122003//Japan Agency for Medical Research and Development/ ; //Philips/ ; MRP/097/20X//Innovation and Technology Commission - Hong Kong/ ; //Swedish State Support for Clinical Research/ ; JP24dk0207069h0001//Japan Agency for Medical Research and Development/ ; 25dk0207068h0003//Japan Agency for Medical Research and Development/ ; //Hersenstichting/ ; R01AG062167/NH/NIH HHS/United States ; //Stichting Equilibrio/ ; JPND2021-00694//EU Joint Programme - Neurodegenerative Disease Research/ ; JP23dk0207048h005//Japan Agency for Medical Research and Development/ ; //Life-MI/ ; #ADSF-21-831381-C/ALZ/Alzheimer's Association/United States ; //Topsector Life Sciences & Health/ ; //Avid Radiopharmaceuticals/ ; //Davis Alzheimer's Prevention Project/ ; //GIESKES-STRIJBIS FONDS/ ; //Stichting Dioraphte/ ; JP21dk0207048h0003//Japan Agency for Medical Research and Development/ ; U19 AG078109/AG/NIA NIH HHS/United States ; P01AG003991/NH/NIH HHS/United States ; //Stiftelsen för Gamla Tjänarinnor/ ; //Cure Alzheimer's Fund/ ; Z201100005520016//Beijing Municipal Science and Technology Commission, Adminitrative Commission of Zhongguancun Science Park/ ; //European Union's Horizon Europe research and innovation programme/ ; //European Partnership on Metrology/ ; R01AG085592/NH/NIH HHS/United States ; U19AG073153/NH/NIH HHS/United States ; U19AG024904/NH/NIH HHS/United States ; RF1 AG052324/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; //Olav Thon Stiftelsen/ ; /ZONMW_/ZonMw/Netherlands ; RF1AG052324/NH/NIH HHS/United States ; //Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; FO2022-0270//Hjärnfonden/ ; JP22dk0207054h0002//Japan Agency for Medical Research and Development/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; R61 AG066543/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; JP22dk0207048h004//Japan Agency for Medical Research and Development/ ; #ADSF-24-1284328-C/ALZ/Alzheimer's Association/United States ; }, mesh = {*Alzheimer Disease/diagnosis/therapy ; Humans ; Biomarkers ; Asia ; Early Diagnosis ; }, abstract = {The landscape of Alzheimer's disease (AD) and related dementias (ADRD) diagnosis is evolving rapidly, driven by advances in disease understanding, biomarker tools, and disease-modifying therapies. Modern diagnostic approaches emphasize biological precision, early detection, and dynamic frameworks that adapt to treatment-induced changes in disease biology. These frameworks enable opportunities for personalized interventions-encompassing pharmacological and non-pharmacological strategies-and for enhanced clinical trial design. However, implementing these advancements globally is influenced by diverse cultural, infrastructural, and regulatory factors. The 2024 Alzheimer's Association International Conference Advancements: Modernizing Diagnosis, held in Japan, provided a unique platform to explore these global dynamics, particularly from an Asian perspective. This article highlights key discussions from the conference, exploring the role of biomarker-based diagnostic frameworks in shaping the future of AD/ADRD research, diagnosis, and treatment. We highlight regional challenges and successes and emphasize ethical considerations and practical strategies needed to ensure equitable access to diagnostic and therapeutic innovations. HIGHLIGHTS: Advances in biomarkers are reshaping Alzheimer's disease diagnosis and treatment. Modern diagnostic frameworks highlight biological precision, early detection, and dynamic frameworks. The 2024 Alzheimer's Association International Conference Advancements: Modernizing Diagnosis explored challenges and opportunities in global biomarker implementation. The conference explored geographic-specific impacts, focusing on Asia.}, } @article {pmid40760649, year = {2025}, author = {Chen, W and Chen, Y and Tang, Q and Kong, D and Xu, M and Yang, Y and Li, Q and Yang, M}, title = {Analysis of risk-factors associated with hospital-acquired pneumonia in patients with alzheimer's disease based on gender differences.}, journal = {BMC geriatrics}, volume = {25}, number = {1}, pages = {587}, pmid = {40760649}, issn = {1471-2318}, support = {2022172//Health Commission of Chengdu/ ; 2024141//Health Commission of Chengdu/ ; S23012//Sichuan medical association/ ; 2022-YF05-01867-SN//Chengdu Science and Technology Bureau/ ; 24CXTD11//Health Commission of Sichuan Province/ ; 62373079//The National Natural Science Foundation of China/ ; 2024ZYD0039//Science and Technology Department of Sichuan Province/ ; SYYXHPT202420//Sichuan Medical Association/ ; }, mesh = {Humans ; Male ; Female ; *Alzheimer Disease/epidemiology/diagnosis/complications ; Aged ; Risk Factors ; Sex Factors ; Aged, 80 and over ; *Healthcare-Associated Pneumonia/epidemiology/diagnosis ; *Cross Infection/epidemiology/diagnosis ; }, abstract = {BACKGROUND: Pneumonia is an important cause of death in patients with Alzheimer's disease (AD), and understanding the factors associated with hospital-acquired pneumonia (HAP) is essential for preventing the development of HAP in AD patients. This study aimed to elucidate the specific risk factors related to HAP in AD patients based on gender differences. METHODS: A total of 1066 patients with Alzheimer's disease (483 males, 583 females), who were admitted to a large psychiatric hospital for the first time between 2013 and 2023, were included in the study. The association between HAP and patients' personal characteristics, medication use and blood test results among genders was analysed. Finally, binary logistic regression was used to identify the independent risk factors for men and women. RESULTS: The infection rate of HAP in male AD patients was significantly higher than that in females, at 41.8% and 23.3%, respectively (χ[2] = 41.726, P < 0.001). Regression results showed that in male patients, HAP was independently correlated with age, apolipoprotein A1 level and lymphocyte count, whereas in female patients, HAP was independently correlated with age, albumin, low-density lipoprotein cholesterol and neutrophil count. CONCLUSION: This study suggests that older AD patients are more susceptible to HAP; the infection rate of HAP in male patients with Alzheimer's disease is higher than that in females, and there are differences in the factors associated with the occurrence of HAP between male and female patients. It is suggested that prevention and treatment strategies for hospital-acquired pneumonia in individuals with Alzheimer's disease could consider age and gender differences.}, } @article {pmid40760501, year = {2025}, author = {Yu, L and Wang, X and Doan, TH and Fan, Y and Bussiere, T and Bacskai, BJ and Kastanenka, KV}, title = {Aducanumab binds high molecular weight soluble Aβ oligomers and restores intracellular calcium levels.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {180}, pmid = {40760501}, issn = {1758-9193}, support = {R01 AG066171/AG/NIA NIH HHS/United States ; PYJH2024314//Advanced Program of The Affiliated Hospital of Xuzhou Medical University/ ; }, mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Calcium/metabolism ; Mice, Transgenic ; Humans ; *Antibodies, Monoclonal, Humanized/pharmacology ; Neurons/drug effects/metabolism ; Mice ; Astrocytes/drug effects/metabolism ; Molecular Weight ; Cells, Cultured ; *Peptide Fragments/metabolism ; Alzheimer Disease/metabolism ; Coculture Techniques ; Brain/metabolism/drug effects ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) accumulation, leading to the formation of neurotoxic soluble oligomers (AβOs) that impair calcium homeostasis in neurons and astrocytes. Aducanumab, a fully human monoclonal antibody targeting aggregated Aβ, has been approved for AD treatment due to its ability to reduce amyloid plaque burden. However, its specificity toward different AβO species and its functional impact on calcium homeostasis remain unclear. METHODS: We investigated aducanumab's ability to recognize and immunodeplete low-molecular-weight (LMW) and high-molecular-weight (HMW) AβOs using three Aβ preparations: (1) transgenic conditioned media (TgCM) from cultured Tg2576 neurons, (2) synthetic Aβ42-derived diffusible ligands (ADDLs), and (3) TBS-soluble fractions from aged Tg2576 mouse brain. Size exclusion chromatography and ELISA were used to characterize AβO species. Multiphoton calcium imaging of neuron-astrocyte co-cultures was performed to assess the impact of aducanumab on AβO-induced calcium overload. RESULTS: Aducanumab preferentially bound and immunodepleted HMW AβOs in ADDLs and the TBS-soluble fraction of Tg2576 mouse brain extracts but did not recognize LMW AβOs in TgCM. In calcium imaging experiments, all three AβO preparations induced calcium overload in neuron-astrocyte co-cultures. Immunodepletion with aducanumab prevented calcium overload in cultures exposed to ADDLs and Tg2576 brain extracts but not in those treated with immunodepleted TgCM, indicating that aducanumab selectively neutralizes HMW AβOs. CONCLUSIONS: Our findings demonstrate that aducanumab specifically targets HMW AβOs, mitigating their neurotoxic effects by restoring intracellular calcium homeostasis. These results provide mechanistic insight into aducanumab's therapeutic action and support its potential role in modifying AD pathology by selectively neutralizing Aβ species.}, } @article {pmid40760500, year = {2025}, author = {Hamadelseed, O and Skutella, T}, title = {Stem cell-based therapeutic strategies for down syndrome and Alzheimer's disease.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {420}, pmid = {40760500}, issn = {1757-6512}, mesh = {Humans ; *Down Syndrome/therapy/pathology ; *Alzheimer Disease/therapy/pathology ; *Stem Cell Transplantation/methods ; Animals ; }, abstract = {BACKGROUND: Down syndrome (DS) and Alzheimer's disease (AD) are two distinct yet interconnected neurological conditions that share overlapping pathological features, including amyloid-beta plaque accumulation, neuroinflammation, and progressive neurodegeneration. Individuals with DS are at increased risk of developing AD-like dementia owing to the overexpression of the amyloid precursor protein-encoding gene on chromosome 21. Despite significant research efforts, effective disease-modifying treatments remain unavailable for both conditions, necessitating the exploration of novel therapeutic approaches. METHODS: We analyzed and synthesized the existing literature on stem cell therapy as a treatment for DS and AD. We conducted a comprehensive search of PubMed, Google Scholar, and Web of Science databases, focusing on recent, high-quality, and peer-reviewed studies on stem cell therapy in DS and AD. RESULTS: The findings indicate that stem cell therapy represents a promising therapeutic approach for both conditions. Preclinical trials using neural, mesenchymal, and induced pluripotent stem cells have shown their potential to mitigate disease pathology, restore neuronal function, modulate neuroinflammation, enhance neurogenesis, and improve cognitive performance in DS and AD models; these findings suggest the viability of stem cell-based interventions as a disease-modifying strategy. However, despite promising findings, the efficacy and safety of these approaches require further validation through well-designed human clinical trials before clinical translation. Furthermore, AD research in stem cell therapy is currently more advanced than DS research, with a greater number of preclinical and early clinical investigations. In fact, people with DS have been previously excluded from clinical trials. CONCLUSIONS: While both DS and AD share common neurodegenerative mechanisms and are potential candidates for stem cell therapeutic approaches, the therapeutic focus varies. This study underscores the potential of stem cell therapy as a novel disease-modifying approach for both conditions while emphasizing the need for further research to refine therapeutic protocols, address ethical and safety concerns, and evaluate the feasibility of translating these therapies into clinical practice.}, } @article {pmid40759310, year = {2025}, author = {Mao, YF and Chen, L and Liu, JY and Guo, ZY and Lu, PL and Chen, YX}, title = {Intranasal insulin administration shows limited tau-targeted effects in early-stage APP/PS1 Alzheimer's mice.}, journal = {Neuroscience letters}, volume = {865}, number = {}, pages = {138337}, doi = {10.1016/j.neulet.2025.138337}, pmid = {40759310}, issn = {1872-7972}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology/genetics ; Administration, Intranasal ; *tau Proteins/metabolism ; *Insulin/administration & dosage/pharmacology ; Mice ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Brain/metabolism/drug effects ; Disease Models, Animal ; Phosphorylation ; Male ; }, abstract = {Brain insulin signaling deficits contribute to multiple pathologicalfeatures of Alzheimer's disease (AD).Intranasal insulin has demonstrated therapeutic potential, but its underlying mechanisms remain unclear. This study investigated whether intranasal insulinmodulates tau pathology in early-stage APPswe/PS1dE9 (APP/PS1) mice.After six weeks of treatment, no significant changes in total or phosphorylated tau levels were observed. However, there was a trend toward improvement in dysregulated signaling pathways associated with tau kinases. These findings suggest that the protective effect of nasal insulin in early AD may not primarily be against tau-related neurotoxicity.}, } @article {pmid40759295, year = {2025}, author = {Song, ZY and Yu, WJ and Jin, YJ and Zhou, MF and He, CX and Li, Z and He, JW and Chen, Q and Li, P and Yi, Y and Cheng, SW}, title = {Baicalin alleviates pathological changes in Alzheimer's disease comorbid with type 2 diabetes: Targeting metabolic dysregulation and neuroinflammation.}, journal = {Journal of ethnopharmacology}, volume = {353}, number = {Pt A}, pages = {120352}, doi = {10.1016/j.jep.2025.120352}, pmid = {40759295}, issn = {1872-7573}, mesh = {Animals ; *Flavonoids/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Diabetes Mellitus, Type 2/drug therapy/metabolism/complications/pathology ; Male ; Rats ; Rats, Sprague-Dawley ; Molecular Docking Simulation ; *Diabetes Mellitus, Experimental/drug therapy/metabolism/complications ; Streptozocin ; *Neuroinflammatory Diseases/drug therapy ; Lipid Metabolism/drug effects ; Disease Models, Animal ; }, abstract = {Derived from the plant Scutellaria baicalensis Georgi, baicalin is a naturally occurring flavonoid, has demonstrated anti-inflammatory, neuroprotective, hypoglycemic, and lipid-lowering properties. While its effects on Alzheimer's disease (AD) or type 2 diabetes mellitus (T2DM) have been studied individually, its therapeutic role in AD comorbid with T2DM remains unclear. AIM OF THE STUDY: This study aims to explore the potential therapeutic mechanisms associated with baicalin through a rat model featuring AD combined with T2DM. MATERIALS AND METHODS: A dual-pathology rat model was developed using a streptozotocin (STZ) and a high-fat dietary regimen injections to induce T2DM, followed by intracerebroventricular STZ to induce AD pathology. Behavioral tests, biochemical assays, histological analyses, qPCR, and Western blotting were used to evaluate baicalin's effects. Untargeted metabolomics was applied to profile metabolic alterations, while network pharmacology and molecular docking were integrated to predict key targets and pathways. Finally, cellular thermal shift assay (CETSA) was conducted to validate the direct binding of baicalin to core proteins. RESULTS: Baicalin significantly improved cognitive performance, ameliorated glucose and lipid metabolism, and suppressed neuroinflammation in AD-T2DM rats. Metabolomics identified disruptions in energy metabolism, amino acid metabolism, and purine metabolism pathways. Network pharmacology analysis revealed ALDH2, NOS2, GOT1, GPT, and XDH as key targets associated with these metabolic disturbances. Molecular docking demonstrated strong binding affinities between baicalin and the identified targets. qPCR confirmed the regulation of ALDH2 and NOS2 gene expression by baicalin, and CETSA experiments further validated the thermal stabilization of these proteins, supporting direct interactions in vivo. CONCLUSIONS: Baicalin exerts therapeutic effects by targeting ALDH2 and NOS2 to modulate arginine and proline metabolism and regulate key metabolites such as GABA and L-arginine. This mechanism improves neuronal function and insulin sensitivity, highlighting baicalin as a promising multi-target treatment for AD with T2DM.}, } @article {pmid40759059, year = {2025}, author = {Xie, Y and Li, C and Zhang, Y and Liu, X and Wang, W and Zheng, L and Gu, X}, title = {Fisetin alleviates Aβ-induced neuronal cell ferroptosis by regulating Sirt6-mediated deacetylation modification.}, journal = {Journal of neuroimmunology}, volume = {407}, number = {}, pages = {578699}, doi = {10.1016/j.jneuroim.2025.578699}, pmid = {40759059}, issn = {1872-8421}, mesh = {Animals ; *Ferroptosis/drug effects/physiology ; Mice ; *Sirtuins/metabolism ; *Flavonols/pharmacology ; *Amyloid beta-Peptides/toxicity ; *Neurons/drug effects/metabolism ; Acetylation/drug effects ; *Neuroprotective Agents/pharmacology ; NF-E2-Related Factor 2/metabolism ; Cell Line ; Kelch-Like ECH-Associated Protein 1/metabolism ; *Flavonoids/pharmacology ; Cell Survival/drug effects ; Hippocampus/drug effects/metabolism ; *Peptide Fragments/toxicity ; }, abstract = {BACKGROUND: Ferroptosis contributes to Alzheimer's disease (AD) pathology. Fisetin, a flavonoid with neuroprotective properties, has shown potential in reducing oxidative stress and inflammation. This study investigates the protective effects and underlying molecular pathways of fisetin against amyloid-β (Aβ)-induced ferroptosis in neuronal cells. METHODS: HT22 mouse hippocampal neuronal cells were pre-incubated with fisetin before exposure to amyloid-β (Aβ). Cell viability was evaluated by Cell Counting Kit-8 (CCK-8) assay, and lipid peroxidation was measured with the C11-BODIPY probe. Protein expression patterns were determined via Western blot analysis. Co-immunoprecipitation (CoIP) and ubiquitination assays were used to explore the interactions between Sirtuin 6 (Sirt6), nuclear factor erythroid 2-related factor 2 (Nrf2), and kelch-like ECH-associated protein 1 (Keap1). RESULTS: Fisetin pre-treatment significantly alleviated Aβ-induced ferroptosis in HT22 cells. Sirt6 upregulation was observed following fisetin treatment, and silencing Sirt6 reversed its protective effects on Aβ-induced neuronal cell ferroptosis. Mechanistically, Sirt6 deacetylated Nrf2 and enhanced its stability by preventing its degradation through Keap1-mediated ubiquitination. As expected, fisetin alleviated Aβ-induced ferroptosis in neuronal cells through activation of the Sirt6/Nrf2 axis. CONCLUSION: Fisetin alleviated Aβ-induced neuronal cell ferroptosis by activating the Sirt6/Nrf2 axis. These results underscore fisetin's therapeutic potential for AD by targeting ferroptosis, providing a new strategy for disease intervention.}, } @article {pmid40758321, year = {2025}, author = {Hoidy, WH and Essa, SM and Al-Saadi, MH}, title = {Pro-inflammatory/Anti-Inflammatory Interleukin Imbalance in Iraqi Alzheimer's Patients: Implications for Post-Conflict Environmental Exposures.}, journal = {The European journal of neuroscience}, volume = {62}, number = {3}, pages = {e70214}, doi = {10.1111/ejn.70214}, pmid = {40758321}, issn = {1460-9568}, mesh = {Humans ; *Alzheimer Disease/blood/immunology/metabolism ; Male ; Female ; Aged ; Iraq ; Middle Aged ; *Environmental Exposure/adverse effects ; Interleukin-1beta/blood ; *Interleukins/blood ; Interleukin-10/blood ; Iraq War, 2003-2011 ; Inflammation ; Aged, 80 and over ; Interleukin-6/blood ; Amyloid beta-Peptides/metabolism ; Interleukin-4/blood ; }, abstract = {The role of inflammatory processes has been increasingly recognized in the pathology of Alzheimer's disease (AD), especially in populations with particular environmental exposures. This study examined the profiles of pro-inflammatory (IL-1β, IL-6) and anti-inflammatory (IL-4, IL-10) interleukins in a cohort of 112 Iraqi AD patients and a control group of 240 age-matched subjects. Peripheral blood samples were obtained and analyzed using quantitative real-time PCR and ELISA methods, with correlations made to cognitive performance and degree of amyloid burden. AD patients showed significant upregulation of IL-1β (2.8-fold, p < 0.001) and IL-6 (3.2-fold, p < 0.001) as well as downregulation of IL-10 (0.6-fold, p < 0.01). Interleukin 4 expression was unchanged. Striking correlations were found between pro-inflammatory cytokine expression and cognitive decline measured by the MMSE scores. Increased expression of IL-1β was associated with higher PET imaging-derived amyloid-β deposition. Carriers of the APOE ε4 allele showed a greater degree of inflammatory marker dysregulation compared to non-carriers. A combined model with multiple interleukins achieved superb distinguishing capacity (AUC = 0.94) between AD patients and healthy controls. This study suggests that dysregulation of inflammation likely plays a considerable role in the pathogenesis of AD in the Iraqi population, possibly modified by specific environmental exposures due to decades of conflict. The connection made between peripheral inflammatory markers and central AD pathology underscores the potential value of interleukin expression profiles as accessible biomarkers for prognosis and monitoring. Thus, the connection made between peripheral inflammatory markers and central AD pathology underscores the potential value of interleukin expression profiles as easily obtainable biomarkers for diagnosis and monitoring, which may inform future development of targeted treatment strategies aimed at modulating inflammation in specific populations.}, } @article {pmid40757693, year = {2025}, author = {Chen, WX and Huang, QY and Sun, JH and Yang, XY and Pei, H and Cao, Y and Li, H and Ma, LN}, title = {The mechanism of Yizhi Qingxin formula to improve neuroinflammation in Alzheimer's disease by regulating the TLR4/NF‑κB/NLRP3 pathway.}, journal = {Journal of Asian natural products research}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/10286020.2025.2539987}, pmid = {40757693}, issn = {1477-2213}, abstract = {Yizhi Qingxin formula (YQF) is a traditional Chinese medicine for the treatment of Alzheimer's disease (AD). This study explored the mechanism of YQF to improve AD-related neuroinflammation in vivo and in vitro. The behavioral tests, immunohistochemical analysis and Western blot were performed. The present results showed that YQF ameliorated cognitive deficits, reduced hippocampal Aβ deposition, and decreased the number of GFAP and Iba1-positive cells. The results also indicated that YQF suppressed neuroinflammatory cytokines (TNF-α, IL-1β, IL-6) by inhibiting TLR4/NF-κB/NLRP3 pathway. In summary, YQF provides a multi-targeted strategy for AD-related neuroinflammation, which may address limitations of single-pathway therapies.}, } @article {pmid40757649, year = {2025}, author = {Siguier, PLM and Planton, M and Pages, B and Gérard, F and Rafiq, M and Wolfrum, M and Archambault, O and Damour, A and Guidolin, V and Pefferkorn, P and Danet, L and Virchien, L and Magnin, E and Richard-Mornas, A and Sauvée, M and Thomas-Antérion, C and Mouton, S and Jucla, M and Pariente, J}, title = {Neurodevelopmental Vulnerability in Alzheimer's Disease and Frontotemporal Dementia.}, journal = {European journal of neurology}, volume = {32}, number = {8}, pages = {e70322}, pmid = {40757649}, issn = {1468-1331}, support = {ANR-21-CE28-0020-01//Agence Nationale de la Recherche/ ; }, mesh = {Humans ; *Alzheimer Disease/epidemiology/complications/physiopathology/diagnosis ; *Frontotemporal Dementia/epidemiology/diagnosis/physiopathology ; Female ; Male ; Aged ; Middle Aged ; *Neurodevelopmental Disorders/epidemiology/complications ; Prospective Studies ; Age of Onset ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Neurodevelopmental disorders (NDDs) may influence the course of Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, prior studies have focused on specific pairs of NDDs and variants of AD/FTD. Adopting a dimensional approach to NDDs and considering the heterogeneity of AD/FTD, we investigated the association between a neurodevelopmental vulnerability (DV) and the clinical presentation and age at onset of AD/FTD. METHODS: We prospectively and consecutively recruited 84 AD/FTD participants and 41 matched controls. AD/FTD participants were classified into typical (amnestic AD, behavioral FTD) and atypical (primary progressive aphasia, frontal and posterior variants of AD, right temporal variant of FTD, amnestic FTD) presentations. Participants underwent a neuropsychological assessment and answered a novel questionnaire on NDDs symptoms. Using k-means clustering based on the questionnaire, participants were assigned to a DV+ (with neurodevelopmental vulnerability) or a DV- (without) cluster. This data-driven approach enabled an unbiased classification of individuals with a DV, beyond traditional diagnostic labels. RESULTS: DV frequencies did not differ between the AD/FTD (18%) and control (15%) χ[2] = 0.205; p = 0.651); and between typical (21%) and atypical (11%) subgroups (Fisher's test, p = 0.184). However, in DV+ patients, symptom onset occurred 8.0 years earlier than in DV- patients (95% CI [-14, -3.0]; p = 0.005), with a median onset age of 58 years (IQR: 15). CONCLUSIONS: A DV could favor early-onset AD/FTD, but may not affect susceptibility to typical and atypical variants of AD/FTD. The underlying neurophysiological processes involved require future investigation, with implications for precision medicine and individualized treatment strategies. STUDY REGISTRATION NUMBERS: RnIPH 2023-71 and Research Ethics Committee file No. 2023_765.}, } @article {pmid40757035, year = {2025}, author = {Gooding, DC and Carter, FP and Zuelsdorff, M and Gee, A and Anthony, RL and Boustead, B and Russell, T and Chin, NA and Clark, L and Cornelius, K and Asthana, S and Johnson, SC and Gleason, CE}, title = {Guided by the community: Insights on recruitment science from the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) Project.}, journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging}, volume = {1}, number = {2}, pages = {}, pmid = {40757035}, issn = {2997-3805}, support = {P30 AG062715/AG/NIA NIH HHS/United States ; R01 AG027161/AG/NIA NIH HHS/United States ; R01 AG054059/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Although Alzheimer's disease and related dementias (ADRDs) are disproportionately high in Black/African American (AA) individuals, this population is under-included in biomarker studies and clinical trials. This underrepresentation contributes to health disparities in treatment and disease outcomes. The Wisconsin Alzheimer's Disease Research Center (ADRC) and the Wisconsin Registry for Alzheimer's Prevention (WRAP) at the University of Wisconsin-Madison have been successfully conducting the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) Project since 2016. The AA-FAIM Project aims to promote the timely, valid detection of ADRD for Black/AA groups and to increase their inclusion in ADRD research. METHOD: We describe the infrastructure and engagement strategies of AA-FAIM, a longitudinal research program focused on examining and reducing the health disparities observed in Black/AA individuals facing risk for ADRD. We describe practical, sustainable methods used to meet our recruitment, enrollment, participation, and retention goals. RESULTS: We report enrollment numbers as evidence of the effectiveness of this work. We attribute our success to several strengths. First, AA-FAIM incorporates the principles of community-based participatory research (CBPR), including strong community partnerships and an active, engaged advisory board. Second, the program is guided by the Participant and Relationship-Centered Research Engagement (PRCRE) and the STEPS models. Third, AA-FAIM uses creative, culturally respectful programs. Fourth, a key element is the partnership between the Academy and the people embedded within the community. DISCUSSION: We discuss our experiences establishing and maintaining the AA-FAIM Project and offer insights to increase the representation and inclusion of Black/AA individuals in ADRD studies.}, } @article {pmid40756364, year = {2025}, author = {Xie, J and Cao, K and Liu, L and Zhang, L and Yang, Y and Gong, H and Luo, H}, title = {Mn3O4 nanozyme-based anti-inflammatory therapy modulates microglial phenotype by downregulating TLR4/NOX2 expression and further alleviates Alzheimer's disease pathology.}, journal = {Theranostics}, volume = {15}, number = {15}, pages = {7467-7488}, pmid = {40756364}, issn = {1838-7640}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Microglia/drug effects/metabolism ; *Toll-Like Receptor 4/metabolism ; Mice ; *Manganese Compounds/pharmacology/administration & dosage ; *Oxides/pharmacology/administration & dosage ; Mice, Transgenic ; *Anti-Inflammatory Agents/pharmacology/administration & dosage ; *NADPH Oxidase 2/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Lipopolysaccharides ; Down-Regulation/drug effects ; Humans ; Phenotype ; }, abstract = {Rationale: Evidence shows that neuroinflammation mediated by microglial activation plays an important role in Alzheimer's disease (AD) pathogenesis. However, the relationship between microglial phenotype and fibrillar β-amyloid (fAβ) pathology in anti-inflammatory treatment of AD remains unclear. Methods: We designed a water-soluble Mn3O4 nanozymes and demonstrated its ability to reverse lipopolysaccharide (LPS)-induced microglial transition from M1 to M2 phenotype by clearing reactive oxygen species (ROS). Results: In 5×FAD transgenic mice, intranasal (IN) instillation of Mn3O4 nanozymes initially promoted M2 microglial polarization and significantly reduced neuroinflammation after 4 weeks of treatment. After 8 weeks of continuous treatment, they further alleviate fAβ pathology and improved learning and memory deficits in 5×FAD mice. The excellent anti-inflammatory effect of Mn3O4 nanozymes is achieved by inhibiting the Toll-like receptor 4 (TLR4)/nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase isoform 2 (NOX2) pathway to clear ROS. Conclusions: This study reveals the molecular mechanism of Mn3O4 nanozymes modulating microglia phenotype to attenuate neuroinflammation primarily through inhibition of the TLR4/NOX2 pathway and highlights the temporal sequence of anti-inflammatory treatment in regulating microglial phenotype and improving fAβ pathology, providing new insights for the anti-inflammatory treatment of AD and other neurological diseases.}, } @article {pmid40756032, year = {2025}, author = {Demirhan, I and Necip, A and Oner, E and Gumuscu, N and Demirci, O and Gok, Y and Doni, NY and Işık, M and Rudrapal, M and Khan, J and Ibrahim, RM}, title = {Imidazolium salts carrying two positive charges: design, synthesis, characterization, molecular docking, antibacterial and enzyme inhibitory activities.}, journal = {Frontiers in cellular and infection microbiology}, volume = {15}, number = {}, pages = {1579916}, pmid = {40756032}, issn = {2235-2988}, mesh = {*Imidazoles/pharmacology/chemical synthesis/chemistry ; Molecular Docking Simulation ; *Anti-Bacterial Agents/pharmacology/chemical synthesis/chemistry ; Microbial Sensitivity Tests ; Drug Design ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Bacteria/drug effects ; *Enzyme Inhibitors/pharmacology/chemical synthesis/chemistry ; Salts/pharmacology/chemical synthesis/chemistry ; Acetylcholinesterase/metabolism ; Structure-Activity Relationship ; }, abstract = {INTRODUCTION: The discovery of alternative drugs has gained importance due to the many side effects of these drugs used for treatment. METHODS: Herein, the synthesis of a series of unsymmetrical imidazolium salts containing 4-acetylphenyl/4-formylphenyl and bioactive heterocyclic groups such as morpholine, piperidine, pyrrole or pyridine was reported. 4-(1-H-imidazol-1-yl)acetophenone and 4-(1-H-imidazol-1-yl)benzaldehyde were used as salt precursors. Alkyl halides containing heterocyclic groups such as 2-morpholinoethyl hydrochloride, 2-pyrrolidinoethyl hydrochloride, 2-piperidinoethyl hydrochloride and pyridin-2-ylmethyl bromide hydrobromide were used. Thus, there are two positively charged nitrogens in the structure of these salts synthesized by the quaternization method. The structures of all salts were fully characterized by [1]H, [13]C NMR, FTIR spectroscopic and elemental analysis methods. the a series of imidazolium salts (1a-d and 2a-d) were designed, synthesized and fully characterized by spectroscopic methods. RESULTS: The inhibitory effect against AChE of the series compounds was evaluated as in vitro and in silico studies. The results indicated that the compounds showed remarkably potent inhibitory effects on AChE with K I values ranging from 0.63 ± 0.04 μM to 11.23 ± 1.05 μM and IC50 values spanning from 0.82 ± 0.06 μM to 14.75 ± 0.82 μM. The antimicrobial activities of the synthesized compounds were measured by inhibition of bacterial growth expressed as minimum inhibitory concentration (MIC) values. It was observed that the synthesized compounds exhibited antimicrobial activity especially against Gram negative bacteria. In addition, the results of molecular docking studies of bacteria supported our antimicrobial results. CONCLUSIONS: The results suggested that the synthesized compounds showed the potential to be antimicrobial and acetylcholinesterase inhibitors.}, } @article {pmid40756022, year = {2025}, author = {Hirose, S and Kobayashi, R and Hatakeyama, S and Kawakatsu, S and Suzuki, A and Kawanishi, C and Utsumi, K}, title = {Corticobasal degeneration preceded by cognitive impairment and apathy: An autopsy case report.}, journal = {PCN reports : psychiatry and clinical neurosciences}, volume = {4}, number = {3}, pages = {e70174}, pmid = {40756022}, issn = {2769-2558}, abstract = {BACKGROUND: Corticobasal degeneration (CBD) presents with a range of clinical phenotypes, making diagnosis challenging. We report the clinical course of a patient with autopsy-confirmed CBD who initially presented with cognitive impairment and apathy, without motor symptoms. CASE PRESENTATION: A 51-year-old man presented to our hospital with decreased motivation, amnesia, and executive dysfunction. Memory disturbance and frontal lobe dysfunction were evident on examination. No motor symptoms such as Parkinsonism, apraxia, or oculomotor abnormalities were apparent. Magnetic resonance imaging and brain perfusion imaging revealed mild atrophy and hypoperfusion in the left frontal lobe. Based on these findings, he was initially diagnosed with behavioral variant frontotemporal dementia. However, due to the presence of memory impairment, Alzheimer's disease was also considered in the differential diagnosis. At the age of 53 years, he began experiencing frequent falls, followed by rapid progression of extrapyramidal symptoms. Dopamine-transporter (DAT) imaging revealed a marked reduction in DAT availability in the striatum. The patient died of aspiration pneumonia at the age of 55 years. Neuropathological examination confirmed the diagnosis of CBD, showing abundant tau pathology in the frontal lobes and basal ganglia. CONCLUSION: In this case, abundant tau pathology in the frontal lobe corresponded with early cognitive impairment, including frontal lobe dysfunction, whereas abundant tau pathology in the basal ganglia corresponded with rapid exacerbation of extrapyramidal symptoms and marked reduction in DAT availability. Clinicians should be aware that patients with CBD without motor symptoms may seek treatment at outpatient clinics specializing in dementia.}, } @article {pmid40756017, year = {2025}, author = {Feng, Q and Chen, F and Liu, R and Li, D and Feng, H and Yang, J}, title = {Mesenchymal stem cell application in Alzheimer's disease.}, journal = {Regenerative therapy}, volume = {30}, number = {}, pages = {439-445}, pmid = {40756017}, issn = {2352-3204}, abstract = {Alzheimer's disease (AD) is a type of degenerative disease that primarily affects in the central nervous system of elderly or pre-elderly individuals. The symptoms of Alzheimer's disease include memory impairment, aphasia, loss of function, dementia, and impairment of visual spatial ability, which in turn affects the physical health of patients. Mesenchymal stem cell therapy is a branch of regenerative medicine that primarily utilizes stem cells or their derivatives to stimulate the body's own healing process and repair damaged, diseased, or injured tissues. Its utilization in the treatment of autoimmune diseases and neurological disorders has been extensively documented. This review summarizes the preclinical and clinical applications of mesenchymal stem cells in AD, their underlying mechanisms and the application limitations of their application and potential solutions. It is hoped that researchers in this field will find it a useful foundation for further study of mesenchymal stem cell therapy.}, } @article {pmid40756009, year = {2025}, author = {Huang, H and Xuan, Y and Ma, ZC}, title = {Safety Profile of Intravenous Ferulic Acid Nanoparticles: Acute Toxicity and Neurological Effects in Sprague-Dawley Rats.}, journal = {Nanotechnology, science and applications}, volume = {18}, number = {}, pages = {319-358}, pmid = {40756009}, issn = {1177-8903}, abstract = {BACKGROUND: Ferulic acid (FA) exhibits therapeutic potential for various disorders, but its clinical application is hindered by poor bioavailability and solubility. This study aimed to develop and evaluate FA-loaded lipid nanoparticles (FA-LNPs) as a safe and efficient drug delivery system. METHODS: FA-LNPs were prepared via an optimized active loading method. The Morris water maze test was conducted to evaluate FA efficacy against LPS-induced cognitive impairment in rats. Comprehensive neurotoxicity assessment was performed in three brain regions (striatum, hippocampus, and cerebellum-brain stem) using multiple staining techniques (LFB, GFAP, IBA-1, and Fluoro-Jade) to evaluate myelin integrity, glial activation, and neuronal degeneration. Acute toxicity, pharmacokinetics, and network pharmacology analysis were conducted to assess safety profiles and potential mechanisms. RESULTS: FA-LNPs were successfully prepared using an optimized active loading method, achieving high drug loading (≥4 mg/mL), superior encapsulation efficiency (EE%) ≥80%, and uniform particle size distribution (<200 nm, PDI=0.053), zeta potential of +5.97 mV (Quality Factor = 1.701), excellent storage stability over two weeks, and was scaled up for batch production. The Morris water maze test revealed an effective FA concentration of 50 mg/kg, with FA-LNPs achieving 46.5 mg/kg through active loading method. Toxicological studies demonstrated favorable safety profiles. Pharmacokinetic analysis showed a prolonged elimination half-life (12.8 ± 1.88 hours) and moderate systemic clearance (0.535 ± 0.0851 L/h/kg). Short-term administration did not elicit significant neuroprotection. Network pharmacology analysis identified 141 potential therapeutic targets and five key proteins (EGFR, ESR1, PTGS2, CTNNB1, and STAT3), with molecular docking confirming favorable binding energies (-7.6 to -5.2 kcal/mol). CONCLUSION: FA-LNPs enhanced FA's bioavailability without apparent systemic toxicity or neurotoxicity. While safe for short-term use, longer treatment durations may be necessary to observe potential neuroprotective benefits and toxicity. This study provides a foundation for further investigation of FA-LNPs as a promising drug delivery system for neurological disorders.}, } @article {pmid40756002, year = {2025}, author = {Dastgheib, ZA and Lithgow, BJ and Moussavi, ZK}, title = {Differential Impact of Repetitive Transcranial Magnetic Stimulation on Alzheimer's Disease Symptomology: Evidence from Electrovestibulography Does repetitive transcranial magnetic stimulation treatment alter Alzheimer's disease symptomology? a clue to show who will benefit.}, journal = {Cognitive neurodynamics}, volume = {19}, number = {1}, pages = {120}, pmid = {40756002}, issn = {1871-4080}, abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has shown promise in enhancing cognitive function through neuroplasticity. This study investigates the impact of rTMS on Alzheimer's disease (AD) and AD with cerebrovascular disease (AD-CVD) symptomologies, using Electrovestibulography (EVestG). METHODOLOGY: Participants were recruited from a randomized, double-blind, placebo-controlled clinical trial on rTMS efficacy for mild to moderate AD. Thirty-five individuals who volunteered for the EVestG study (28 received active rTMS and 7 the sham treatment) were recorded at baseline, post-treatment, and two months' follow-up. EVestG recordings were analyzed to calculate normalized probability (NP) values for AD and AD-CVD symptomologies and compare with standard cognitive outcome. RESULTS: Changes in NP values from pre to post active treatment showed improved participants exhibited opposite trends in AD and AD-CVD symptomologies compared to non-improved participants with a decrease in NPAD-CVD and a slight increase in NPAD value. Significant associations were found between changes in cognitive score and NP values, even after adjusting for age, sex, and multiple comparisons, indicating that patients with higher certainty of AD diagnosis (versus AD-CVD) were more likely to benefit from rTMS. CONCLUSION: These findings suggest rTMS cognitive improvement may result from reduced AD-CVD symptomatology, especially in patients with higher certainty of AD diagnoses, potentially due to increased cerebral blood flow (CBF). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11571-025-10310-5.}, } @article {pmid40755499, year = {2025}, author = {Wang, X and Hou, R and Chen, Z and Wang, X and Malek, M and Wang, H}, title = {The Beneficial Effects of Berberine on Brain Functions in Age-Related Neurological Disorders: From Molecular Signaling to Treatment.}, journal = {Food science & nutrition}, volume = {13}, number = {8}, pages = {e70563}, pmid = {40755499}, issn = {2048-7177}, abstract = {Berberine (BBR), a naturally occurring compound with diverse medicinal properties, is emerging as a compelling candidate for managing age-related central nervous system conditions. Preclinical studies have extensively explored its impact on neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease, revealing its capacity to modulate key pathological processes. Mechanistically, BBR is shown to mitigate neuroinflammation, oxidative stress, and endoplasmic reticulum stress, thereby reducing neuronal damage and apoptosis. While these mechanistic insights and preclinical data are robust, clinical evidence remains nascent, necessitating further rigorous investigation to fully understand BBR's therapeutic efficacy and translate its promise into clinical practice. This narrative review provides a comprehensive examination of BBR's application in treating neurological conditions, emphasizing its molecular signaling pathways and critically evaluating the current translational landscape. It also identifies promising directions for future research into BBR's neuroprotective roles.}, } @article {pmid40755338, year = {2025}, author = {Liu, C and Xie, Q and Xu, JP and Hua, KY and Zhao, WJ}, title = {Neuregulin 2 reversed astrocytosis in the spinal cord in a mouse model of Alzheimer's disease.}, journal = {Folia neuropathologica}, volume = {63}, number = {2}, pages = {138-147}, doi = {10.5114/fn.2025.151824}, pmid = {40755338}, issn = {1509-572X}, mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism ; Disease Models, Animal ; Mice ; *Spinal Cord/pathology/drug effects/metabolism ; Mice, Transgenic ; *Gliosis/pathology/drug therapy/metabolism ; *Astrocytes/drug effects/pathology/metabolism ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is classified as a neurodegenerative disorder without efficacious therapeutic interventions. Accumulating evidence has demonstrated the deposition of b-amyloid peptide (Ab) in the spinal cord in several mouse AD models. Neuregulin 2 (Nrg2), structurally homologous to neuregulin 1 (Nrg1), exerts a regulatory influence over various biological processes within the nervous system. However, the neuroprotective role of Nrg2 in the spinal cord in AD remains unclear. MATERIAL AND METHODS: Reverse transcription PCR (RT-PCR) was employed to confirm the expression of mutated amyloid precursor protein (APP) in APPswe mice. Immunohistochemical staining was used to compare the differences between wild-type and APPswe mice in APP and GFAP expression. We applied western blot to test the changes of ErbB4, Akt1, and Erk1/2 activation, as well as that of GFAP in response to recombinant Nrg2 (rNrg2) treatment in the spinal cord in APPswe mice. RESULTS: In the current study, we observed that mutated APP mRNA level was upregulated, and astrocytes were activated in the spinal cord of APPswe transgenic mice. rNrg2 treatment down-regulated astrocyte activation, as indicated by the reduced level of GFAP. Meanwhile, Nrg2 treatment enhanced the phosphorylation-mediated activation of ErbB4, Akt1, and Erk1/2 in most of the spinal cord segments. CONCLUSIONS: These combined results suggest the involvement of astrocytosis in the spinal cord of APPswe transgenic mice. Neuregulin 2, when administered exogenously, may represent a potential strategy for preventing and treating AD-induced astrocytosis in the spinal cord.}, } @article {pmid40755109, year = {2025}, author = {Poszwa, J and Słowikowski, B and Owecki, W and Szymanowicz, O and Jagodziński, PP and Kozubski, W and Dorszewska, J}, title = {Integration of Neuroimaging and Molecular Biomarkers in the Diagnosis of Alzheimer's Disease and Frontotemporal Dementia: The Promise of fMRI.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050390340250716061313}, pmid = {40755109}, issn = {1875-5828}, abstract = {INTRODUCTION: Dementia is a set of acquired and progressive neuropsychiatric disorders. The most common types of dementia include Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD). Early intravital diagnosis of both types of dementia is difficult. Both molecular and neuroimaging markers are important for the diagnosis of different types of dementia. METHODS: This review employed freely accessible databases, including PubMed, Google Scholar, and ScienceDirect, using keywords such as molecular parameters, neuroimaging factors, dementia, FTD, Alzheimer's disease, and fMRI. RESULTS: Among the molecular markers of dementia, there are parameters common to its various types and enabling their differentiation. These parameters include both genetic and biochemical factors. Markers include genetic factors that help differentiate AD (APP, PSEN1, PSEN2) from FTD (e.g., TARDBP, FUS, MAPT). Simultaneously, there are important biochemical parameters differentiating AD (amyloid-beta (Aβ), neurofibrillary tangles) from FTD (TDP-43, FUS, and different forms of tau protein aggregates). Currently, there is growing interest in neuroimaging studies in the differential diagnosis of dementia. Positron Emission Tomography (PET) imaging enables the quantification and localization of Aβ deposits in the brain through the selective binding of the Pittsburgh Compound-B (PiB) ligand. This method has become the standard in AD diagnostics. In the context of magnetic resonance imaging studies, it is worth noting the search for structural differences between AD (mainly affecting the temporal lobe, including the hippocampus and entorhinal cortex, and the parietal lobe) and FTD (primarily involving the prefrontal cortex, anterior temporal lobes, and subcortical structures, as well as exhibiting an anteroposterior gradient of atrophy). However, the method of the future appears to be functional Magnetic Resonance Imaging (fMRI), especially since functional changes precede structural changes in the development of dementia. DISCUSSION: The review encompasses the basic diagnostic criteria for AD and FTD dementia, as well as molecular and neuroimaging parameters important for the intravital diagnosis of these dementias. It seems that the use of fMRI can contribute to both early diagnosis and early introduction of targeted treatment in developing dementia. Although it is not yet widely used clinically, its diagnostic value is increasingly recognized. CONCLUSION: The benefits of fMRI studies complementing molecular markers in the diagnosis of dementia were highlighted.}, } @article {pmid40755106, year = {2025}, author = {Saini, M and Rohilla, S and Kumar, R}, title = {Revolutionizing Therapeutic Approaches Against Pathophysiology of Alzheimer's Disease: A Therapeutic Review.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098376646250715094707}, pmid = {40755106}, issn = {1874-6128}, abstract = {Alzheimer's disease (AD) is a multifactorial neuron-degenerative old age illness, which deteriorates the neuronal cells of the brain ultimately leading to dementia, decreased thinking ability and intricacy in performing daily routine activities. In most of the cases, AD is suspected to be caused by a combination of numerous factors, like environmental, genetic and lifestyle affecting the brain functioning. The present permitted treatments include N-methyl-Daspartate (NMDA) receptor antagonists, cholinesterase inhibitors, and their combinations, which provide only momentary and symptomatic relief. Nowadays, clinical research is interested, in the pathology of Alzheimer's disease to target the metabolism of abnormal tau protein, removal of beta-amyloid inflammatory response, the cholinergic neuron, and free radical damage, and treatments that can either stop or modify the course, of AD. Globally, efforts are continued to search new targets to invent new options for the treatment of AD. The present review critically discusses about various treatment strategies for the patients presented with AD. Moreover, herbal drug and new drug candidates, along with nanoformulations for the treatments of AD and the role of AI-based technology in searching therapy for AD have been delineated in the present article. We concluded that preventing amyloid-β (Aβ) synthesis, enhancing the removal of Aβ deposition, or preventing Aβ aggregation can suppress AD. Moreover, herbal medicines have become an attractive alternative to cure this disease with numerous beneficial effects with little side effects. Novel approaches using AI are therefore required to create treatments with novel targets that may not only cure symptoms but also prevent disease development at an early stage to improve the quality of patients' lives.}, } @article {pmid40755103, year = {2025}, author = {Beigh, S and Alsahag, M and Alisaac, A and Dar, SA and Alyami, MH and Ajlan, SE and Malak, HA and Alshehri, AA}, title = {Ginkgolide as a Promising Multi-Target Therapeutic for Alzheimer's Disease: Targeting ApoE4 and Beyond.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128386836250723134001}, pmid = {40755103}, issn = {1873-4286}, abstract = {INTRODUCTION: The progressive neurodegenerative disease known as Alzheimer's disease (AD) is typified by neuroinflammation, amyloid-beta buildup, and cognitive impairment. Current pharmacological treatments merely alleviate symptoms, despite extensive research, which underscores the need for innovative, multi-target medicines. Since apolipoprotein E4 (ApoE4) is a significant genetic risk factor linked to the development of AD, it is a potentially effective treatment target. With their neuroprotective qualities, natural substances like ginkgolide may help treat some diseases. This study investigates ginkgolide's potential as a multi-target treatment for AD, with a particular emphasis on how it interacts with the ApoE4 N-terminal domain. METHODS: The interaction between Ginkgolide and ApoE4 (PDB ID: 8AX8) was assessed using pharmacokinetic profiling, molecular docking, and molecular dynamics (MD) simulations. MD simulations were used to determine stability, and AutoDock Vina was used to obtain the binding affinity. To predict pharmacokinetics and toxicity, SwissADME and PkCSM were employed. The effectiveness of ginkgolide was contextualized using comparative docking with curcumin and resveratrol. RESULTS: Ginkgolide formed sustained hydrophobic contacts with important sites and demonstrated a substantial binding affinity (-7.1 kcal/mol) to ApoE4. MD simulations verified negligible fluctuations and complex stability over 100 ns. Pharmacokinetics showed no significant toxicity risks, good gastrointestinal absorption, and favorable blood-brain barrier permeability. In terms of binding affinity and stability, ginkgolide fared better than curcumin and resveratrol, indicating its greater therapeutic potential. DISCUSSION: The results indicate that ginkgolide effectively binds and stabilizes the ApoE4 N-terminal domain, supporting its potential role in modulating a key pathological factor in Alzheimer's disease. Its superior pharmacokinetic profile and interaction dynamics compared to curcumin and resveratrol suggest a broader therapeutic relevance. These in silico insights provide a mechanistic basis for further investigation into ginkgolide's neuroprotective effects. CONCLUSION: The results demonstrated ginkgolide as a potentially effective multi-target treatment for AD through ApoE4 regulation. It is a better option than other natural chemicals because of its potent binding affinity, stability, and pharmacokinetics. These findings highlight the value of in silico methods in the early stages of drug discovery and the need for additional experimental support before they can be used in clinical settings.}, } @article {pmid40754996, year = {2025}, author = {Stam, R}, title = {Low frequency magnetic field exposure and neurodegenerative disease: systematic review of animal studies.}, journal = {Electromagnetic biology and medicine}, volume = {44}, number = {4}, pages = {566-580}, doi = {10.1080/15368378.2025.2540435}, pmid = {40754996}, issn = {1536-8386}, mesh = {Animals ; *Magnetic Fields/adverse effects ; *Neurodegenerative Diseases/etiology/pathology/therapy ; Humans ; Disease Models, Animal ; }, abstract = {Epidemiological studies have found an association between occupational exposure to low frequency magnetic fields and the occurrence of motor neuron disease and Alzheimer's disease. No association has been found for Parkinson's disease and the evidence for multiple sclerosis is insufficient. Animal models studying the effects of low frequency magnetic fields on neurodegenerative disease induction or progression could provide more evidence on causation and the underlying mechanisms. A systematic search and review was conducted of peer-reviewed research articles involving animal experiments on the effects of low frequency magnetic field exposure on behavioural and neuroanatomical outcomes relevant for neurodegenerative diseases in humans. Firstly, experimental studies in naive animals do not support a causal relationship between exposure to low frequency magnetic fields and the induction of neuropathology relevant for Alzheimer's disease, but the number of studies relevant for motor neuron disease, multiple sclerosis and Parkinson's disease is too limited to draw conclusions. Secondly, experimental studies in existing animal models for neurodegenerative disease support a therapeutic (beneficial) effect of low frequency magnetic field treatment on behavioural and neuroanatomical abnormalities relevant for dementia (including Alzheimer's disease), multiple sclerosis and Parkinson's disease and no effect on disease progression in models relevant for motor neuron disease.}, } @article {pmid40754917, year = {2025}, author = {Zhang, Y and Li, L and Zhu, A and Xiao, W and Wang, Q}, title = {[Protective effects of escin and dextromethorphan on Alzheimer disease in Caenorhabditis elegans models].}, journal = {Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences}, volume = {57}, number = {4}, pages = {764-771}, pmid = {40754917}, issn = {1671-167X}, mesh = {Animals ; *Caenorhabditis elegans/genetics/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Disease Models, Animal ; *Dextromethorphan/pharmacology ; Amyloid beta-Peptides/metabolism/genetics ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Animals, Genetically Modified ; Memantine/pharmacology ; }, abstract = {OBJECTIVE: To investigate whether escin (ESC) and dextromethorphan (DEX) have the protective effects on the progression and symptoms of Alzheimer disease (AD). METHODS: The AD model of Caenorhabditis elegans (C. elegans) was established by transgenic amyloid β-protein (Aβ protein). Different concentrations of ESC or DEX or 50 μmol/L memantine (MEM) were used to treat the AD model worms, and their lifespan was detected. The movement ability of AD model C. elegans was evaluated by body bending frequency and head swinging frequency. The changes in cognitive functions of AD model C. elegans before and after treatment were detected by chemotaxis experiments. The changes in Aβ protein and reactive oxygen species (ROS) content in C. elegans were detected. The changes in gene pathways related to oxidative stress were detected by Real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: At high dose 1 000 μmol/L, ESC or DEX treatment showed no significant effects on the activity of C. elegans. Compared with untreated worms, the survival time of AD model C. elegans in the 20 μmol/L ESC and 60 μmol/L DEX intervention groups was significantly extended. In the middle stage of AD progression, the body bending frequency and head swinging frequency of AD model worms after ESC or DEX treatment was significantly increased compared with the untreated control group with DEX being more effective in the recovery of head swinging frequency. For the early cognitive function tests, the chemotaxis index of ESC or DEX treated worms was significantly higher than that of the untreated worms, which correlated with marked reductions in the Aβ protein levels. The reactive oxygen species content in the drug intervention group was also lower than that in the control group. RT-qPCR results showed that ESC could inhibit oxidative stress in the AD model C. elegans by a 2-fold upregulation of skn1 expression. CONCLUSION: ESC and DEX could improve the reductions of movement ability and cognitive function in the AD model worms and delay the aggravation of AD-related symptoms. ESC delays the progression of AD possibly by activating the SKN-1/Nrf2 pathway to protect against oxidative injury in the AD model.}, } @article {pmid40754800, year = {2025}, author = {Barbour, AJ}, title = {Screening antiseizure medications to break the cycle between neuronal hyperexcitability and Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {3}, pages = {994-996}, pmid = {40754800}, issn = {1875-8908}, support = {R01 AG077692/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/drug therapy/complications/genetics ; Animals ; *Anticonvulsants/therapeutic use/pharmacology ; Mice ; Disease Models, Animal ; Humans ; *Seizures/drug therapy ; *Neurons/drug effects ; Male ; Female ; }, abstract = {Epilepsy is commonly comorbid with Alzheimer's disease and is now well established to accelerate disease course. In the present study, Knox and colleagues evaluated the efficacy of several antiseizure medications (ASMs) in mitigating seizure induction in two aged Alzheimer's disease mouse models with distinct etiologies. They found differential responses to seizure induction and ASM treatment across sexes and models. These results reveal a complex interplay between sex, Alzheimer's disease risk genes, and neuronal hyperexcitability that suggest a tailored approach to seizure control may maximize therapeutic benefit in Alzheimer's disease.}, } @article {pmid40754079, year = {2025}, author = {Shao, X and Cao, X and Fan, T and Yan, C and Wang, C and Wang, J and Bai, M and Cui, C and Wang, X and Guan, P and Fan, L and Hu, X}, title = {Tannic acid-derived carbon dots: Dual-function inhibitors against β-amyloid fibrosis and bacterial infections.}, journal = {International journal of biological macromolecules}, volume = {322}, number = {Pt 1}, pages = {146516}, doi = {10.1016/j.ijbiomac.2025.146516}, pmid = {40754079}, issn = {1879-0003}, mesh = {*Tannins/chemistry/pharmacology ; *Carbon/chemistry/pharmacology ; *Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors ; *Anti-Bacterial Agents/pharmacology/chemistry ; Humans ; *Quantum Dots/chemistry ; Blood-Brain Barrier/metabolism/drug effects ; *Bacterial Infections/drug therapy ; Animals ; Alzheimer Disease/drug therapy/metabolism ; Peptide Fragments ; Polyphenols ; }, abstract = {Alzheimer's disease is a puzzle that has been plaguing mankind for a long time, and amyloid plaque cascade and microbial infection are now widely accepted hypotheses of pathogenicity. In this work, we prepared carbon dots TACDs by solvothermal carbonization using tannic acid and o-Phenylenediamine as precursors. TACDs have abundant functional groups and large conjugated structures, and binds to Aβ42 through hydrophobic interactions, hydrogen bonding, electrostatic interaction and π-π stacking to efficiently inhibit the self-assembly and mis-folding of Aβ42. The existence of a good binding and co-localization capacity between TACDs and the Aβ42 species. TACDs have good biocompatibility and TACDs can rapidly enter the cells within 0.5 h. In an in vitro blood-brain barrier model, TACDs show good BBB penetration ability. Moreover, TACDs have good antibacterial ability and can achieve a dual function. The above results will provide the foundation for the application of polyphenol-derived carbon dots in AD diagnosis and treatment.}, } @article {pmid40753965, year = {2025}, author = {Jia, L and Hao, L and Zhang, HL}, title = {Cognitive performance correlated with hemoglobin level in patients with chronic kidney disease: a data analysis from the National Health and Nutrition Examination Survey (NHANES) 2011- 2014.}, journal = {Kidney & blood pressure research}, volume = {50}, number = {1}, pages = {1-26}, pmid = {40753965}, issn = {1423-0143}, abstract = {INTRODUCTION: Given the increased incidence of renal anemia and cognitive dysfunction in patients with chronic kidney disease (CKD), the association between hemoglobin levels and cognitive function in these patients remains elucidated. An optimal level of hemoglobin for the best cognitive performance in CKD has yet to be determined. METHODS: A retrospective cross-sectional study was conducted using data from 2011-2014 of the National Health and Nutrition Examination Survey (NHANES). Enrolled subjects for analysis were divided into the CKD and the non-CKD groups. The Animal Fluency Test (AF), Digit Symbol Substitution Test (DSST), Consortium to Establish a Registry for Alzheimer's Disease Word Learning Test (CERAD-WL) and Word List Recall Test (CERAD-DR) were used to evaluate cognitive performances. We quantified the association between hemoglobin levels and cognitive function in patients with CKD and non-CKD subjects by using the logistic regression analysis. Plotted curves and inflection points were calculated by a recursive algorithm. RESULTS: The ratio of cognitive impairment was higher in the CKD group than in the non-CKD group. Hemoglobin levels were correlated with CERAD-DR and DSST in patients with CKD. For non-CKD subjects, the hemoglobin level was not correlated with any test results. The potential range of the hemoglobin level was 11.0 - 12.7 mg/dL for keeping better cognitive performance of patients with CKD. CONCLUSION: Hemoglobin levels are associated with cognitive performance in patients with CKD. The treatment of renal anemia would be meaningful to reduce cognitive impairment in CKD.}, } @article {pmid40753124, year = {2025}, author = {Peng, W and Li, C and Ma, Y and Dai, W and Fu, D and Liu, L and Liu, L and Yu, N and Liu, J}, title = {Integrating Time and Frequency Domain Features of fMRI Time Series for Alzheimer's Disease Classification Using Graph Neural Networks.}, journal = {Interdisciplinary sciences, computational life sciences}, volume = {}, number = {}, pages = {}, pmid = {40753124}, issn = {1867-1462}, support = {62472202//National Natural Science Foundation of China/ ; 61972185//National Natural Science Foundation of China/ ; 62172444//Natural Science Foundation of Jilin Province/ ; 62472450//Natural Science Foundation of Jilin Province/ ; }, abstract = {Accurate and early diagnosis of Alzheimer's Disease (AD) is crucial for timely interventions and treatment advancement. Functional Magnetic Resonance Imaging (fMRI), measuring brain blood-oxygen level changes over time, is a powerful AD-diagnosis tool. However, current fMRI-based AD diagnosis methods rely on noise-susceptible time-domain features and focus only on synchronous brain-region interactions in the same time phase, neglecting asynchronous ones. To overcome these issues, we propose Frequency-Time Fusion Graph Neural Network (FTF-GNN). It integrates frequency- and time-domain features for robust AD classification, considering both asynchronous and synchronous brain-region interactions. First, we construct a fully connected hypervariate graph, where nodes represent brain regions and their Blood Oxygen Level-Dependent (BOLD) values at a time series point. A Discrete Fourier Transform (DFT) transforms these BOLD values from the spatial to the frequency domain for frequency-component analysis. Second, a Fourier-based Graph Neural Network (FourierGNN) processes the frequency features to capture asynchronous brain region connectivity patterns. Third, these features are converted back to the time domain and reshaped into a matrix where rows represent brain regions and columns represent their frequency-domain features at each time point. Each brain region then fuses its frequency-domain features with position encoding along the time series, preserving temporal and spatial information. Next, we build a brain-region network based on synchronous BOLD value associations and input the brain-region network and the fused features into a Graph Convolutional Network (GCN) to capture synchronous brain region connectivity patterns. Finally, a fully connected network classifies the brain-region features. Experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate the method's effectiveness: Our model achieves 91.26% accuracy and 96.79% AUC in AD versus Normal Control (NC) classification, showing promising performance. For early-stage detection, it attains state-of-the-art performance in distinguishing NC from Late Mild Cognitive Impairment (LMCI) with 87.16% accuracy and 93.22% AUC. Notably, in the challenging task of differentiating LMCI from AD, FTF-GNN achieves optimal performance (85.30% accuracy, 94.56% AUC), while also delivering competitive results (77.40% accuracy, 91.17% AUC) in distinguishing Early MCI (EMCI) from LMCI-the most clinically complex subtype classification. These results indicate that leveraging complementary frequency- and time-domain information, along with considering asynchronous and synchronous brain-region interactions, can address existing approach limitations, offering a robust neuroimaging-based diagnostic solution.}, } @article {pmid40752775, year = {2025}, author = {Meshram, HK and Gupta, SK and Gupta, A and Nagori, K and Ajazuddin, }, title = {Next-generation CRISPR gene editing tools in the precision treatment of Alzheimer's and Parkinson's disease.}, journal = {Ageing research reviews}, volume = {111}, number = {}, pages = {102851}, doi = {10.1016/j.arr.2025.102851}, pmid = {40752775}, issn = {1872-9649}, mesh = {Humans ; *Gene Editing/methods ; *Parkinson Disease/therapy/genetics ; *Alzheimer Disease/therapy/genetics ; *CRISPR-Cas Systems/genetics ; Animals ; *Genetic Therapy/methods ; *Precision Medicine/methods ; }, abstract = {Emerging gene-editing technologies, such as the CRISPR system, represent a potential pathway for precision medicine targeting the genetic and molecular causes of diseases. Second-generation CRISPR technologies, including base editing, prime editing, and engineered Cas variants, have improved fidelity and offer alternative strategies for precise gene correction, transcriptional repression or activation, and modulation of pathological pathways in neurodegeneration. These tools can correct single-nucleotide mutations, reduce pathological protein accumulation, and modulate neuroinflammatory responses, all integral to the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD), both chronic, progressive neurodegenerative disorders. Unfortunately, currently available treatments are limited and primarily palliative. Preclinical studies have shown promising results, with improvements in cognitive and motor deficits in animal models. However, significant challenges must be addressed to ensure safe and effective delivery to the CNS, minimize off-target effects, and address ethical concerns. Current clinical investigations aim to translate these findings into available therapeutic options. This review also identifies the biological mechanisms, therapeutic use cases, and current limitations of next-generation CRISPR systems as tools in the context of AD and PD, providing both therapeutic and research capabilities through their unique strengths. Ultimately, the future of transactional neurogenomics will determine the clinical possibilities of CRISPR-based strategies for advancing neurodegenerative disease management beyond palliative and symptomatic treatment, toward a feasible mechanistic form of disease modification.}, } @article {pmid40752028, year = {2025}, author = {Liew, KY and Aumeeruddy, MSUIZ and Goh, NY and Kong, BH and Tang, YQ and Ng, ST and Tan, CS and Fung, SY}, title = {Antioxidant Activity and Total Terpenoid Content of Tropicoporus linteus Cultivar (Agaricomycetes) Cold Water Extract and In Silico Assessment of Potential Neuroprotective Compounds.}, journal = {International journal of medicinal mushrooms}, volume = {27}, number = {11}, pages = {51-61}, doi = {10.1615/IntJMedMushrooms.2025059827}, pmid = {40752028}, issn = {1940-4344}, mesh = {*Antioxidants/pharmacology/chemistry/isolation & purification ; Molecular Docking Simulation ; *Terpenes/chemistry/pharmacology/isolation & purification ; *Neuroprotective Agents/chemistry/pharmacology/isolation & purification/pharmacokinetics ; Alzheimer Disease/drug therapy ; *Basidiomycota/chemistry ; Humans ; Amyloid Precursor Protein Secretases/metabolism ; Computer Simulation ; }, abstract = {Tropicoporus linteus (formerly Phellinus linteus) is a medicinal fungus used in China, Korea and Japan for its therapeutic properties. This study assessed the antioxidant capabilities of cold-water extract (xSHTM) from a T. linteus cultivar (SH02), and its terpenoid content. The potential of bioactive compounds in T. linteus as treatment against Alzheimer's disease (AD) was also explored with pharmacokinetic prediction via SwissADME and molecular docking. xSHTM is found to have high superoxide anion scavenging capability (expressed as trolox equivalents (35.10 ± 2.58) mmol/g), and its terpenoid content is expressed as 490.12 ± 31.51 mg LE/g of extract. SwissADME was used to screen all 68 of the compounds contained in T. linteus according to PubChem to identify their pharmacokinetic properties. Nine bioactive compounds are selected based on their gastrointestinal absorption, lipophilicity, water solubility, violation of Lipinski's rule, and the ability to cross the blood-brain barrier (BBB) to proceed with molecular docking against common AD treatment targets, acetylcholinesterase (AChE) and β-secretase (BACE1), which revealed 4 compounds with high binding affinity (expressed as Kcal/mol). Phellilin B and phellilane L showed binding affinities of -8.8 and -8.0, respectively, when docked against AChE, while phellinulin L, phellinulin K and phellilin B showed binding affinities of -7.4, -7.3 and -7.1 respectively when docked against BACE1.}, } @article {pmid40751793, year = {2025}, author = {Santana, RA and McWhirt, JM and Brewer, GJ}, title = {Treatment of age-related decreases in GTP levels restores endocytosis and autophagy.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {40751793}, issn = {2509-2723}, support = {RF1 AG058218/DK/NIDDK NIH HHS/United States ; }, abstract = {Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimer's model mice and a novel genetically encoded fluorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free GTP colocalized in the mitochondria decreased with age accompanied by the accumulation of free GTP-labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while bafilomycin inhibition of autophagy raised GTP levels. Twenty-four-hour supplementation of aged neurons with the NAD precursor nicotinamide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endocytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal Aβ aggregates, improved viability, and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy deficits that impair autophagy and endocytosis. GTP deficits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path.}, } @article {pmid40751388, year = {2025}, author = {Saberi, Z and Rostamkhani, N and Saghatchi Zanjani, M and Salimi, M and Andalib, S and Rashidzadeh, H and Jafari Anarkooli, I and Karami, Z}, title = {Neuroprotective effect of rosuvastatin-loaded nanoemulsions against lipopolysaccharide-induced neuroinflammation and oxidative stress.}, journal = {Journal of drug targeting}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/1061186X.2025.2538037}, pmid = {40751388}, issn = {1029-2330}, abstract = {Neuroinflammation is a pathophysiological feature of several neurological disorders, including Parkinson's disease, Alzheimer's disease and traumatic brain injury, resulting from various intrinsic and environmental triggers. However, effective treatments are hindered by challenges in drug delivery to the central nervous system, primarily due to the blood-brain barrier. In this study, we investigated the potential of rosuvastatin-loaded nanoemulsions for neuroinflammation treatment. The mean diameter and zeta potential of developed RSV-NEs were 124.8 ± 1.23 nm and -40.5 ± 3.2 mV, respectively. TEM analysis revealed the spherical morphology and uniformity of nano-droplets. A cell viability study on the PC12 cell line confirmed the safety of RSV-NEs up to the concentration of 300 µg/mL. The protective efficacy of orally administrated RSV-NEs against LPS-induced neuroinflammation and oxidative stress was assessed in SD rats. According to histopathological assessments, LPS-induced damage was prevented by RSV-NEs through a neuroprotective effect linked to a reduction in GFAP[+] cells. Moreover, TBARS levels in the rat brain cortex decreased by 3.9 times, and the cerebellum's SH increased by 1.7 times in the RSV-NEs-treated group compared to the LPS group. These findings suggest that utilising nanoemulsion delivery systems may offer improved efficacy for CNS disorders, addressing significant challenges in the management of neuroinflammatory diseases.}, } @article {pmid40751333, year = {2025}, author = {Cimen, YA and Elibol, B and Korkmaz, ND and Yuzgulec, M and Kinsiz, B and Kutlu, S and Ustunova, S}, title = {The Impact of Ketogenic Diet Consumption on the Sporadic Alzheimer's Model Through MT1/MT2 Regulation.}, journal = {Journal of neuroscience research}, volume = {103}, number = {8}, pages = {e70070}, doi = {10.1002/jnr.70070}, pmid = {40751333}, issn = {1097-4547}, support = {20220409//Bezmialem Vakıf Üniversitesi/ ; }, mesh = {Animals ; *Diet, Ketogenic/methods ; Male ; *Alzheimer Disease/metabolism/diet therapy ; Rats, Sprague-Dawley ; Rats ; *Receptor, Melatonin, MT2/metabolism ; *Receptor, Melatonin, MT1/metabolism ; Melatonin/metabolism ; Disease Models, Animal ; Hippocampus/metabolism ; Corpus Striatum/metabolism ; }, abstract = {Melatonin and its receptors play a primary role in regulating circadian rhythms, which are frequently disrupted in patients with Alzheimer's disease (AD). Furthermore, there is increasing evidence that the use of a ketogenic diet (KD) delays the onset of AD. Therefore, we aimed to investigate whether KD has an ameliorative effect on AD through the regulation of melatonin receptors. In this study, male Sprague-Dawley rats were divided into three groups: sham, AD, and KD. At the end of KD supplementation, behavioral parameters were determined by the Morris Water Maze. Melatonin levels, protein expression levels, and immunoreactivity of MT1-MT2 in thehippocampus and striatum were determined by ELISA, Western blotting, and immunofluorescence staining, respectively. As a result, KD improved memory decline in AD rats. Also, KD increased melatonin levels in the hippocampus but did not affect striatum melatonin levels. MT1 expression tended to increase in the hippocampus of the AD group, while MT2 expression decreased. On the contrary, KD treatment increased both MT1 and MT2 expressions. In the striatum, there was no change in MT1 expression in the AD and KD groups, but MT2 expression increased in the AD group compared with the sham group and was suppressed in the KD group. In addition, KD treatment reduced streptozotocin-induced apoptosis and neuroinflammation in the hippocampus and striatum. Our results suggest that KD may improve AD-associated inflammation and apoptosis by altering melatonin levels and the expression of MT2 receptors in the hippocampus and striatum. Therefore, KD may be a promising preventive and therapeutic option for AD.}, } @article {pmid40750068, year = {2025}, author = {Košak, U and Knez, D and Pišlar, A and Horvat, S and Žakelj, S and Igert, A and Dias, J and Nachon, F and Brazzolotto, X and Gobec, S}, title = {N-Propargylpyrrolidine-based butyrylcholinesterase and monoamine oxidase inhibitors.}, journal = {Chemico-biological interactions}, volume = {420}, number = {}, pages = {111681}, doi = {10.1016/j.cbi.2025.111681}, pmid = {40750068}, issn = {1872-7786}, mesh = {*Butyrylcholinesterase/metabolism/chemistry ; *Pyrrolidines/chemistry/pharmacology/metabolism ; Humans ; *Cholinesterase Inhibitors/chemistry/pharmacology/metabolism/chemical synthesis ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology/metabolism ; Animals ; *Monoamine Oxidase/metabolism/chemistry ; Crystallography, X-Ray ; Molecular Docking Simulation ; Amyloid beta-Peptides/toxicity ; Structure-Activity Relationship ; Peptide Fragments/toxicity ; }, abstract = {Butyrylcholinesterase (BChE) inhibitors are or could be used for the treatment of Alzheimer's disease, canine cognitive dysfunction, depression, multiple sclerosis, heroin abuse and metabolic disorders. Monoamine oxidase (MAO) inhibitors are or could be used for the treatment of depression, anxiety, Alzheimer's disease, Parkinson's disease, cancer, cardiovascular disease and chronic inflammatory diseases. We have designed, synthesized, and evaluated ten new N-propargylpyrrolidine-based inhibitors of these enzymes. Sulfonamide 10 is the most potent human (h)BChE (IC50 = 0.203 μM) of the series, and secondary carboxamide 1 is a time-dependent and irreversible inhibitor of hMAO-A (IC50 = 6.42 μM) and hMAO-B (IC50 = 7.83 μM). The X-ray crystal structures of carboxamide 4 [IC50(hBChE) = 3.89 μM] and sulfonamide 10 with hBChE confirmed our previous observation that carboxamides and sulfonamides have distinct binding poses in the active site of hBChE. The X-ray crystal structure of the complex of pyrrolidine 4 with hBChE also revealed a distinct binding pose compared to its direct piperidine analogue (PDB code 5LKR). Furthermore, compounds 1 and 10 should be able to cross the blood-brain barrier, exhibit low cytotoxicity (>50 μM) in two cell lines and protect against amyloid β1-42-induced neuronal cell death.}, } @article {pmid40749808, year = {2025}, author = {Wang, M and Zhang, L and Huang, W and Huang, J and Luo, Y and Huang, N}, title = {The potential of acupuncture in the treatment of Alzheimer's disease: An exploration from traditional Chinese medicine to modern technology.}, journal = {Complementary therapies in medicine}, volume = {93}, number = {}, pages = {103222}, doi = {10.1016/j.ctim.2025.103222}, pmid = {40749808}, issn = {1873-6963}, mesh = {*Alzheimer Disease/therapy ; Humans ; *Acupuncture Therapy/methods ; *Medicine, Chinese Traditional/methods ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with the highest prevalence worldwide, and it places considerable life and economic burdens on patients and their families. Currently, treatments for AD only delay symptoms, fail to reverse disease progression, and are often accompanied by significant side effects. Acupuncture, a nonpharmacological therapeutic method originating from China, has a history of thousands of years and is characterized by safety and economy. In recent years, the potential of acupuncture use in AD treatment has received widespread attention. With the rapid development of modern science and technology, the mechanism of action of acupuncture in the treatment of AD has gradually become increasingly clear. Therefore, we searched the databases of China National Knowledge Infrastructure (CNKI), PubMed and Web of Science for relevant studies on acupuncture for AD in recent years. According to the literature, acupuncture can improve cognitive function in AD patients through various mechanisms, such as reducing β-amyloid deposition, inhibiting Tau protein hyperphosphorylation, and attenuating neuroinflammation, and shows good therapeutic potential. Future studies should further explore in depth the mechanisms of acupuncture in treating AD through the rational use of modern science and technology techniques, with the aim of providing new strategies for the treatment of AD.}, } @article {pmid40749181, year = {2025}, author = {Galić, M and Ćilerdžić, J and Stajic, M}, title = {Mushrooms: Potential Agents for the Prevention and Slowdown of Alzheimer's Disease: A Review.}, journal = {International journal of medicinal mushrooms}, volume = {27}, number = {10}, pages = {7-19}, doi = {10.1615/IntJMedMushrooms.2025059428}, pmid = {40749181}, issn = {1940-4344}, mesh = {*Alzheimer Disease/prevention & control/drug therapy ; *Agaricales/chemistry ; Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Biological Products ; Dietary Supplements ; }, abstract = {Alzheimer's disease as a neurodegenerative disorder is characterized by a decline in cognitive abilities that makes it difficult or impossible to perform ordinary tasks. It is the most common form of dementia and its exact causes are still unknown. Approximately 45.0 million people are affected by this disease, which is the leading cause of death worldwide. Although numerous commercial drugs are available on the world market, many of them have mutagenic, toxic, carcinogenic and other side effects. Therefore, today the world's trend is use of natural products without any harmful effects. Edible and medicinal mushrooms as producers of numerous biologically active compounds, such as polysaccharides, proteins, sterols, terpenoids, etc., could be a safe and effective neuroprotective agents and a promising therapy for patients with Alzheimer's disease. Mushrooms are highly valued functional foods and diet supplementation with them could significantly reduce the risk of apparence of Alzheimer's disease or slow down its development. The results of numerous studies have shown that the addition of mushrooms to the diet not only increases the effectiveness of conventional drugs but also reduces their harmful effects. However, despite numerous studies on mushrooms' medicinal properties, much more in vivo research and clinical trials are still needed to fully understand the potential of mushrooms for the prevention and treatment of Alzheimer's disease, as well as to determine their optimal administration. Reviewing all the results so far and considering future necessary studies were the main aims of this review article.}, } @article {pmid40748474, year = {2025}, author = {Suhaili, INA and Yow, HY and Mah, SH and Zaman Huri, H and Tan, SLJ}, title = {Alzheimer's disease: unraveling role of xanthone derivatives and nanocarriers.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40748474}, issn = {1432-1912}, support = {FP010-2024//Ministry of Higher Education Malaysia under the Fundamental Research Grant Scheme (FRGS 2024-1)/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and neuronal loss. Xanthones, a class of polyphenolic compounds, have shown potential neuroprotective effects in AD due to their antioxidant, anti-inflammatory, and acetylcholinesterase inhibitory properties. However, their therapeutic use is limited by low bioavailability and restricted blood-brain barrier (BBB) penetration. This review highlights the novelty of bridging the therapeutic findings of xanthone derivatives with brain-targeted nano-based delivery systems, while identifying gaps for pre-clinical development. A literature review was conducted focusing on the pathophysiology of AD, current therapeutic strategies, the pharmacological properties of xanthone derivatives and recent advancements in nano-based drug delivery systems for xanthone delivery to the brain. The literature search was performed across the PubMed database to identify relevant articles published until January 2025. Evidence from preclinical studies suggests that xanthone derivatives possess multiple neuroprotective properties that can weaken the AD pathophysiology. These compounds can reduce oxidative stress, suppress neuroinflammatory responses, and improve neurotransmission. Besides improving the solubility, recent nanoformulations of α-mangostin, particularly polymer nanoparticles, have demonstrated the potential to overcome the BBB through the enhancement of low-density lipoprotein receptor expression in microglia. Animal studies show improved cognitive outcomes and neuroprotection when xanthones are delivered via nanocarriers, highlighting their disease-modifying potential. Xanthone-loaded nanocarriers represent a promising disease-modifying strategy for AD as they enhance bioavailability and therapeutic outcomes. Future validation of nanoformulations through clinical trials and development of multi-targeted approaches paves the way for innovative and patient-centered neurotherapies, holding significant promise for AD treatment.}, } @article {pmid40747637, year = {2025}, author = {Zimmer, AR and Bourourou, M and Lesage, F and Hamel, E}, title = {Neurovascular coupling and functional connectivity changes through the Alzheimer's disease spectrum: Effects of simvastatin treatment.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70402}, pmid = {40747637}, issn = {1552-5279}, support = {MOP-126001//Canadian Institutes of Health Research (CIHR)/ ; 436352//Canadian Institutes of Health Research (CIHR)/ ; //Canadian Consortium on Neurodegeneration in Aging/ ; //McGill Healthy Brains Healthy Lives/ ; //Canada First Research Excellence Fund/ ; //Quebec's Ministère de l'Économie et de l'Innovation/ ; //Fonds de recherche du Québec-Santé/ ; 88887.363553/2019-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PRINT)/ ; RGPIN-2017-06140//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {*Simvastatin/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/physiopathology ; Animals ; Mice, Transgenic ; *Neurovascular Coupling/drug effects ; Mice ; Disease Models, Animal ; *Brain/drug effects/physiopathology ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Male ; Humans ; *Nerve Net/drug effects/physiopathology ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a leading cause of dementia, with vascular dysfunction being an early pathogenic event. Cardiovascular interventions show therapeutic promise, hence may improve neurovascular coupling (NVC) and resting-state functional connectivity (RSFC) hemodynamic responses. METHODS: NVC and RSFC were recorded longitudinally in control and AD transgenic mice treated or not with simvastatin (SV) using optical imaging of intrinsic signals (OIS), together with memory testing. RESULTS: AD mice showed early decreases in NVC and bilateral connectivity (BC) in motor and cingulate cortex, and hypoconnectivity within the sensory-motor network. Early default-mode network (DMN) hyperconnectivity was followed by hypoconnectivity, together with a decreased BC in somatosensory (S) cortex. SV restored NVC, prevented aberrant DMN hyperconnectivity, improved BC of S, and preserved memory. DISCUSSION: Our results indicate that OIS can detect early AD-related changes in NVC and RSFC, and that a preventive cardiovascular strategy may bear therapeutic promise in at-risk individuals. HIGHLIGHTS: Optical imaging of intrinsic signals captures Alzheimer's disease (AD) progression and response to therapy. Neurovascular coupling (NVC) and resting-state functional connectivity (RSFC) disruptions precede memory decline in AD transgenic mice. Simvastatin prevented NVC and AD-specific RSFC disruptions and protected memory. This study supports translational value of hemodynamic signal in early AD detection.}, } @article {pmid40747287, year = {2025}, author = {Kwon, D and Kim, D}, title = {Effects of cognitive stimulation group programs in patients with mild Alzheimer's disease.}, journal = {The British journal of occupational therapy}, volume = {88}, number = {8}, pages = {467-478}, pmid = {40747287}, issn = {1477-6006}, abstract = {OBJECTIVES: This study examined the effects of a cognitive stimulation group program on cognitive functions, depression, activities of daily living (ADL), and quality of life in patients with mild Alzheimer's disease (AD). METHODS: Sixty patients with mild AD were randomized into the experimental or control groups (30 in each). Both groups underwent conventional occupational therapy for 30 minutes, followed by a 50-minute session of a cognitive stimulation group program for the experimental group and a cognitive workbook group program for the control group. Interventions for both groups were carried out for 4 weeks, five times a week, and once a day. RESULTS: After the interventions, both groups showed significant differences in cognitive functions, depression, ADL, and quality of life (p < 0.01, p < 0.001), with the experimental group demonstrating slightly higher scores in all assessment items. Significant intergroup differences were found in the scores for memory, the shortened Korean version of the Boston Naming Test, the Elderly Seoul Verbal Learning Test, the Korean version of the Trail Making Test Part A (depression), the Korean version of the Instrumental ADL scale, and quality of life (p < 0.05, p < 0.01, p < 0.001). CONCLUSION: It has been shown that the cognitive simulation group program can be an effective intervention method to reduce the depression of mild AD patients and improve cognitive function, ADL, and quality of life. In addition, it is significant that various enjoyable activities were organized for each cognitive domain to induce active participation and motivation of the subjects. It is expected that this study can be usefully used as a guideline for the treatment of AD patients in the future.}, } @article {pmid40746342, year = {2025}, author = {Kwon, HS and Park, KH and Lee, JS and Choi, H and Lee, CN and Lim, JS and Jang, JW and Shim, Y and Choi, SH and Yang, DW}, title = {Nationwide Survey on the Awareness of Mild Cognitive Impairment.}, journal = {Dementia and neurocognitive disorders}, volume = {24}, number = {3}, pages = {198-207}, pmid = {40746342}, issn = {2384-0757}, abstract = {BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI), particularly due to Alzheimer's disease (AD), is an important stage for early intervention. We aim to assess awareness among the general population of MCI and AD, and evaluate their willingness to pay for treatment that delays the progression to dementia. METHODS: A nationwide cross-sectional telephone survey was conducted from August 29 to 31, 2022, targeting adults aged ≥18 years in the Republic of Korea. In toto, 1,006 respondents were randomly selected via a proportional allocation based on age, sex, and region. The survey consisted of 11 questions covering demographic information, awareness of MCI and AD, understanding of diagnostic procedures, such as amyloid positron emission tomography (PET), and willingness to pay for disease-modifying treatment. RESULTS: Among the respondents, 41.3% had heard of MCI, but only 12.0% were well informed. Some 77.0% stated that if they experienced cognitive decline, they would visit a hospital. Only 12.4% of respondents knew the important role of amyloid PET in diagnosing MCI due to AD. Regarding the treatment costs of disease-modifying drugs, 42.1% were willing to pay <600,000 KRW (approximately 420 USD) per month, while 18.4% were unwilling to pay. Older age and lower socioeconomic status were significantly associated with decreased willingness to pay (p<0.001). CONCLUSIONS: Public awareness of MCI is limited, and willingness to pay decreases with older age and lower socioeconomic status. Targeted education and strategies are therefore required to increase awareness and reduce disparities.}, } @article {pmid40745950, year = {2026}, author = {Jeong, YJ and Lee, HJ and Kim, JS and Kim, SJ and Jo, U and Park, JY and Jun, SJ and Lee, WS and Song, M and Kim, D and Cho, G and Song, JH and Hoe, HS}, title = {Digital Therapeutics for Alzheimer's and Parkinson's Diseases: Current Trends and Future Perspectives.}, journal = {Medicinal research reviews}, volume = {46}, number = {1}, pages = {316-327}, pmid = {40745950}, issn = {1098-1128}, mesh = {*Alzheimer Disease/physiopathology/therapy ; *Parkinson Disease/physiopathology/therapy ; Humans ; *Software/trends ; *Digital Health/trends ; Executive Function/physiology ; Cognition/physiology ; Motor Activity/physiology ; Machine Learning/trends ; Virtual Reality Exposure Therapy/trends ; Clinical Trials as Topic ; }, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD), which are characterized by the accumulation of misfolded protein aggregates and cognitive/motor dysfunction, are the most prevalent neurodegenerative diseases (NDDs). Despite strategic investigations aimed at augmenting the pharmaceutical pipeline, available drugs for AD and PD merely slow disease progression without curing or treating the underlying pathology. Recent technological advances have given rise to digital therapeutics (DTx): software systems that aim to prevent, cure, and manage specific diseases, including NDDs. For AD and PD, the majority of DTx focus on enhancing cognitive/executive function and motor-related functions, respectively. In this review, we describe the status of therapeutic development for AD and PD, as well as the characteristics and status of DTx targeting these NDDs. In addition, we address the limitations and challenges of DTx and their implications for the treatment of AD and PD. Ultimately, this review provides insights into the potential of DTx as a therapeutic modality and future directions for the development of DTx targeting AD and PD.}, } @article {pmid40745641, year = {2025}, author = {Bao, S and Zheng, F and Jiang, L and Wang, Q and Lyu, Y}, title = {TA-SSM net: tri-directional attention and structured state-space model for enhanced MRI-Based diagnosis of Alzheimer's disease and mild cognitive impairment.}, journal = {BMC medical imaging}, volume = {25}, number = {1}, pages = {309}, pmid = {40745641}, issn = {1471-2342}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Aged ; *Deep Learning ; Male ; Female ; Imaging, Three-Dimensional ; *Image Interpretation, Computer-Assisted/methods ; Neuroimaging/methods ; Brain/diagnostic imaging ; Aged, 80 and over ; }, abstract = {Early diagnosis of Alzheimer's disease (AD) and its precursor, mild cognitive impairment (MCI), is critical for effective prevention and treatment. Computer-aided diagnosis using magnetic resonance imaging (MRI) provides a cost-effective and objective approach. However, existing methods often segment 3D MRI images into 2D slices, leading to spatial information loss and reduced diagnostic accuracy. To overcome this limitation, we propose TA-SSM Net, a deep learning model that leverages tri-directional attention and structured state-space model (SSM) for improved MRI-based diagnosis of AD and MCI. The tri-directional attention mechanism captures spatial and contextual information from forward, backward, and vertical directions in 3D MRI images, enabling effective feature fusion. Additionally, gradient checkpointing is applied within the SSM to enhance processing efficiency, allowing the model to handle whole-brain scans while preserving spatial correlations. To evaluate our method, we construct a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), consisting of 300 AD patients, 400 MCI patients, and 400 normal controls. TA-SSM Net achieved an accuracy of 90.24% for MCI detection and 95.83% for AD detection. The results demonstrate that our approach not only improves classification accuracy but also enhances processing efficiency and maintains spatial correlations, offering a promising solution for the diagnosis of Alzheimer's disease.}, } @article {pmid40745201, year = {2025}, author = {Xiaoying, M and Zhiming, H and Mingwen, S and Hong, W and Tao, Y and Jun, X and Na, G}, title = {Uncovering active ingredients and mechanisms of Pholiota adiposa in the treatment of Alzheimer's disease based on network pharmacology and bioinformatics.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {27981}, pmid = {40745201}, issn = {2045-2322}, support = {2024MS0604//the Presidential Foundation of the Liaoning Academy of Agricultural Sciences/ ; 2022JH2/101300160//Applied Basic Research Program of Liaoning Province/ ; 2024XTCX0403//the Fundamental Research Funds of Liaoning Academy of Agricultural Sciences/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Network Pharmacology/methods ; *Computational Biology/methods ; Molecular Docking Simulation ; *Drugs, Chinese Herbal/pharmacology/chemistry/therapeutic use ; Machine Learning ; Molecular Dynamics Simulation ; }, abstract = {Pholiota adiposa is recognized for its health benefits, particularly in Alzheimer's disease (AD), but its molecular mechanism remains elusive. Our study employs network pharmacology and machine learning to uncover its therapeutic potential. We constructed a network of AD-relevant target proteins using databases like TCMSP, CTD, and GeneCards, and performed gene enrichment and functional analysis with DAVID, GO, and KEGG via Hiplot. Targets were identified through Cytoscape's degree analysis and the Aging Atlas database for aging-related genes. Clinical targets were confirmed with GEO, and molecular docking was executed using AutoDock Vina. LASSO regression and random forest algorithms were applied for target model selection, and molecular dynamics simulations were run with Gromacs2022.3. Our findings suggest Pholiota adiposa modulates key proteins involved in AD, including STAT3, PRKCA, NF-κB1, and CDK1, potentially inhibiting protein phosphorylation and influencing neuronal membrane synthesis and RNA polymerase II activity. KEGG analysis revealed its impact on cancer pathways, indicating a multifaceted role. High-degree targets like STAT3 and NF-κB1 were identified as effective, with TERT showing a significant role in aging. Machine learning confirmed the diagnostic importance of STAT3 and NFKB1 in AD. Molecular docking highlighted the affinity of Pholiota adiposa for these targets, with carnosol, carnosic acid, and clovane diol as key components. Carnosol, in particular, induced a conformational change in STAT3, enhancing its efficacy. Pholiota adiposa shows promise as a therapeutic agent in AD treatment by modulating various pathways and signaling mechanisms, as demonstrated through network pharmacology and machine learning analyses. This study underscores its potential in managing neurodegenerative diseases.}, } @article {pmid40744715, year = {2025}, author = {Ying, C and He, Y and Guo, Y and Fan, F and Wang, B and Gao, J and Li, Y and Zhang, Y}, title = {Application of Traditional Chinese Medicine in Alzheimer's Disease Treatment: A Focus on the Wnt/[Formula: see text]-Catenin Pathway.}, journal = {The American journal of Chinese medicine}, volume = {53}, number = {6}, pages = {1641-1683}, doi = {10.1142/S0192415X25500624}, pmid = {40744715}, issn = {1793-6853}, mesh = {*Alzheimer Disease/drug therapy/metabolism/genetics/etiology ; Humans ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Wnt Signaling Pathway/drug effects/genetics ; *Medicine, Chinese Traditional/methods ; Animals ; Amyloid beta-Peptides/metabolism ; *Neuroprotective Agents/therapeutic use ; *Phytotherapy ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by cognitive decline. Its etiology and pathogenesis are complex and multifactorial, with neurotoxicity induced by the abnormal aggregation of amyloid-beta (A[Formula: see text]) protein widely recognized as a central pathological hallmark. Current pharmacological treatments provide only limited symptomatic relief and are often associated with dose-dependent adverse effects. In contrast, Traditional Chinese Medicine (TCM) has garnered growing attention due to its distinctive therapeutic profile, and in particular, its multi-target and multi-pathway synergistic mechanisms. The Wnt/[Formula: see text]-catenin signaling pathway plays a crucial role in intracellular signal transduction and is closely associated with several key pathological processes involved in AD. This review provides a comprehensive analysis of the molecular interplay between the Wnt/[Formula: see text]-catenin signaling pathway and the pathogenesis of AD, as well as a specific focus on how natural compounds, herbal monomers, and classical TCM formulations modulate this pathway. Accumulating evidence suggests that TCM exerts neuroprotective effects by regulating Wnt/[Formula: see text]-catenin signaling to thereby suppress A[Formula: see text] deposition, preserve synaptic structure and tissue homeostasis, modulate cell proliferation and apoptosis, and maintain metabolic and redox homeostasis. Additionally, the review discusses key challenges, such as improving blood-brain barrier permeability and enhancing bioavailability, and outlines future directions involving advanced delivery systems and optimized administration routes. These insights provide a robust scientific foundation for the development of Wnt/[Formula: see text]-catenin-targeted therapies and highlight the potential of TCM in the clinical treatment of AD.}, } @article {pmid40744389, year = {2025}, author = {Nelson, VK and Begum, MY and Suryadevara, PR and Madhuri Kallam, SD and Panda, SP and Bodapati, A and Sanga, V and Bishoyi, AK and Ballal, S and Monsi, M and Walia, C and Prasad, GVS and Abomughaid, MM and Shukla, S and Chauhan, P and Jha, NK}, title = {Natural bioactive compounds as modulators of autophagy: A herbal approach to the management of neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {1005}, number = {}, pages = {178003}, doi = {10.1016/j.ejphar.2025.178003}, pmid = {40744389}, issn = {1879-0712}, mesh = {Humans ; *Autophagy/drug effects ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism ; Animals ; *Biological Products/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Polyglutamine (polyQ), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) disease are a significant health concern that affects millions of people every year worldwide. The main pathological hallmark of various NDs is the formation of misfolded protein aggregation and accumulation of inclusion bodies. These protein aggregates are mainly responsible for producing toxic effects and initiating neuronal cell death, ultimately promoting various NDs. On the other hand, the patients suffering from these kinds of diseases live in impaired conditions, imposing a substantial financial burden on the family. However, the current treatment strategies can only offer temporary relief from the disease symptoms and can't reverse the disease completely. Hence, there is an urgent need for specific and novel drug treatment that can significantly eradicate NDs. Ubiquitin proteasome system (UPS) and autophagy are the two essential intracellular defensive mechanisms that are involved in clearing the protein aggregates, pathogens, and damaged organelles from the cytoplasm and maintaining protein homeostasis. Nevertheless, UPS is inefficient in removing some kinds of organelles and aggregating-prone proteins, specifically in neuronal and glial cells. Under this kind of circumstance, the autophagy mechanism plays a vital role in eliminating the accumulated protein aggregates and other toxic elements from the cytoplasm of the neuronal cells that initiate oxidative stress. However, in NDs, the autophagy function is impaired, and the protein aggregates can't be eliminated effectively. Hence, forced up-regulation of autophagy function by applying various external agents could be a potential therapeutic strategy to control NDs like AD, PD, HD, and ALS. In this review, we focused on different kinds of plant-derived compounds that induce autophagy. We also discussed the role of these plant-derived autophagy modulators in various NDs. In this way, the current review will be a standalone reference to the researchers working in this area.}, } @article {pmid40743720, year = {2025}, author = {Ali, A and Ganeshpurkar, A and Ganeshpurkar, A and Dubey, N}, title = {In Silico Investigation of Ganoderic Acid A Targeting Amyloid-Beta and Tau Protein Aggregation in Alzheimer's Disease.}, journal = {International journal of medicinal mushrooms}, volume = {27}, number = {9}, pages = {85-92}, doi = {10.1615/IntJMedMushrooms.2025059137}, pmid = {40743720}, issn = {1940-4344}, mesh = {*tau Proteins/metabolism/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism/chemistry ; *Lanosterol/analogs & derivatives/pharmacology/chemistry ; Molecular Docking Simulation ; Humans ; Computer Simulation ; Protein Aggregates/drug effects ; Protein Binding ; *Reishi/chemistry ; Heptanoic Acids ; }, abstract = {Alzheimer's disease (AD) represents a significant challenge in neurodegenerative disorders, characterized by the accumulation of amyloid-beta (Aβ) plaques and tau protein tangles in the brain. Current treatments provide symptomatic relief but do not halt disease progression. ganoderic acid A, derived from Ganoderma lucidum, has shown to act as a dual inhibitor of Aβ and tau protein aggregation through in vitro and animal model studies. This study aims to explore the therapeutic potential of ganoderic acid A using in silico methods to predict its binding affinity and mode of interaction with Aβ and tau proteins. Analysis included molecular docking simulations using computational models to evaluate the binding of ganoderic acid A to Aβ and tau proteins. Various tools were employed to predict the binding energy, interaction sites (Autodock), and MD (CABSflex 2.0) of these complexes. Ganoderic acid A demonstrated favorable binding energies and interactions with both Aβ and tau proteins. The compound exhibited potential dual inhibition capabilities by forming stable complexes with critical residues involved in Aβ aggregation and tau protein hyperphosphorylation. The findings suggest that ganoderic acid A holds promise as a dual inhibitor of Aβ and tau protein aggregation in AD. By targeting these key pathological processes, ganoderic acid A may offer therapeutic benefits in halting or slowing disease progression. Confirming these predictions and advancing ganoderic acid A as a possible AD treatment will require additional experimental validation, including in vitro and in vivo research.}, } @article {pmid40742404, year = {2025}, author = {Chen, X and Zhou, XY and Lan, C and Fu, HJ and Li, ZC and Chen, MY and Wen, YP and Yu, L and Qin, DL and Wu, AG and Wu, JM and Zhou, XG}, title = {Araloside A Induces Raf/MEK/ERK-Dependent Autophagy to Mitigate Alzheimer's and Parkinson's Pathology in Cellular and C. elegans Models.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {16061-16080}, pmid = {40742404}, issn = {1559-1182}, support = {2024YFHZ0361//The Department of Science and Technology of Sichuan Province/ ; SKL-KF202311//The Open Project Program of State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China/ ; 81801398//the National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/drug effects ; *Autophagy/drug effects ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *Parkinson Disease/pathology/drug therapy/metabolism ; Humans ; *MAP Kinase Signaling System/drug effects ; *raf Kinases/metabolism ; *Oleanolic Acid/pharmacology/analogs & derivatives/therapeutic use ; Disease Models, Animal ; Animals, Genetically Modified ; Neurons/drug effects/metabolism/pathology ; alpha-Synuclein/metabolism ; }, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by pathological protein aggregation and oxidative stress, leading to progressive neurodegeneration. Enhancing autophagy, the primary intracellular pathway for clearing misfolded proteins, represents a promising therapeutic strategy. In this study, we identify Araloside A (ARA), a triterpenoid saponin derived from Aralia elata, as a potent autophagy inducer that alleviates AD- and PD-related pathology. In neuronal cell models, ARA promotes autophagosome formation, increases LC3-II and Beclin-1 levels, and decreases P62, indicating enhanced autophagic activity. Mechanistic investigations reveal that ARA directly binds to Raf, MEK, and ERK proteins and activates autophagy in a Raf/MEK/ERK-dependent manner. This activation facilitates the clearance of APP, total Tau, phosphorylated Tau, and α-synuclein, thereby reducing cytotoxicity. Furthermore, in transgenic Caenorhabditis elegans models of AD and PD, ARA treatment alleviates protein aggregation and behavioral deficits via ERK-dependent autophagy. Together, these findings identify ARA as a natural compound that enhances autophagic clearance of neurotoxic aggregates via Raf/MEK/ERK pathway activation, offering promising therapeutic insights for neurodegenerative proteinopathies.}, } @article {pmid40742252, year = {2026}, author = {Morgan, TM and Snyder, B}, title = {Pharmacokinetics and Bioavailability of a Novel Rivastigmine Nasal Spray Compared to Rivastigmine Oral Capsule in Healthy Men.}, journal = {Journal of clinical pharmacology}, volume = {66}, number = {1}, pages = {e70086}, doi = {10.1002/jcph.70086}, pmid = {40742252}, issn = {1552-4604}, support = {AC76937//Lachesis Biosciences and AusIndustry/ ; ACTRN12619001513101//Australian New Zealand Clinical Trials Registry/ ; }, mesh = {Humans ; Male ; Rivastigmine ; Adult ; Cross-Over Studies ; Biological Availability ; Administration, Oral ; Young Adult ; Middle Aged ; Nasal Sprays ; Adolescent ; *Phenylcarbamates/pharmacokinetics/administration & dosage/adverse effects/blood ; Capsules ; Administration, Intranasal ; Area Under Curve ; *Cholinesterase Inhibitors/pharmacokinetics/administration & dosage/adverse effects/blood ; }, abstract = {To compare the pharmacokinetics, bioavailability, tolerability, and safety of a novel 4 mg rivastigmine nasal spray to 3 mg rivastigmine oral capsule, a single-dose, open-label, randomized, crossover study was conducted in 16 fasted healthy young men (18 to 55 years). Mean (SD) rivastigmine Cmax was 8.39 (6.8) and 13.77 (10.7) ng/mL for oral and nasal, respectively. Rivastigmine AUC0-inf was 19.6 (14.9) and 40.6 (24.4) ng h/mL for oral and nasal, respectively. The ratio of LS means (nasal test / oral reference; 90% C.I.) for rivastigmine Cmax was 185.83% (134.22, 257.28) and for rivastigmine AUC0-inf was 257.35% (197.26, 335.73). Rivastigmine tmax for nasal (0.7 h) was significantly lower than oral (1.2 h, P < .05), however, NAP226-90 tmax for nasal (1.9 h) and oral (1.8 h) were similar. NAP226-90 Cmax was 3.93 (1.1) and 3.01 (0.8) ng/mL for oral and nasal, respectively. NAP226-90 AUC0-inf was 22.9 (5.3) and 23.2 (5.1) ng h/mL for oral and nasal, respectively. Median NAP226-90 to rivastigmine AUC0-inf ratio for nasal (0.55) was significantly lower than oral (1.38, P < .05) because nasal bypassed first-pass metabolism. Both single-dose treatments were safe and well tolerated. Nasal and throat irritation were mostly perceived as mild and transient following nasal administration. The 4 mg rivastigmine nasal spray had 1.5- and 2.0-fold higher dose normalized rivastigmine Cmax and AUC0-inf, respectively, and 2.5-fold lower NAP226-90 to rivastigmine AUC0-inf ratio compared to 3 mg oral capsule. This nasal spray has good potential to improve the local and gastrointestinal tolerability of rivastigmine treatment in Alzheimer's and Parkinson's disease dementia patients.}, } @article {pmid40741047, year = {2025}, author = {Yang, Y and Chen, H and Liu, Q and Niu, Y and Mao, C and Wang, R}, title = {Elucidating molecular pathogenesis and developing targeted therapeutic interventions for cerebrovascular endothelial cell-mediated vascular dementia.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1623050}, pmid = {40741047}, issn = {1663-4365}, abstract = {Vascular dementia (VaD) ranks as the second most prevalent subtype of dementia, surpassed only by Alzheimer's disease (AD). The maintenance of neurological function and cerebral homeostasis critically depends on precisely regulated blood flow within the intricately organized cerebrovascular network. Disruptions in cerebral hemodynamics may impair neurovascular homeostasis, thereby inducing pathophysiological cascades characterized by oxidative stress, neuroinflammation, and neuronal degeneration. Emerging evidence identifies cerebrovascular dysregulation and impaired neurovascular coupling (NVC) as primary pathogenic mechanisms underlying VaD, emphasizing the necessity to elucidate their complex interplay. Cerebrovascular endothelial cells exhibit remarkable heterogeneity, serving dual roles as both architectural components of the blood-brain barrier (BBB) and functional regulators of NVC. Furthermore, pericytes residing abluminal on capillary endothelia demonstrate critical involvement in hemodynamic modulation through contractile regulation of microvascular tone, while concurrently maintaining BBB integrity through dynamic paracrine signaling. This study examines cerebrovascular endothelial-neuronal interactions within the neurovascular unit (NVU) framework, analyzing their bidirectional regulatory mechanisms and therapeutic potential in cognitive dysfunction remediation. The pathophysiological progression of VaD manifests through multiple interdependent pathways, including cerebral hypoperfusion, oxidative stress cascades, neuroinflammatory responses, mitochondrial dysregulation, and electrolyte homeostasis perturbations. Through three interventional axes: (1) BBB fortification strategies; (2) cerebral hemodynamic optimization and NVC enhancement; (3) nanotherapeutic platforms integrating endothelial-specific molecular targets we systematically evaluate endothelial-centric therapeutic paradigms. This multi-modal approach proposes novel mechanistic insights and clinical translation frameworks for VaD management.}, } @article {pmid40740995, year = {2025}, author = {Zhang, Y and Zhang, T and Zhao, M and Li, P and Liu, T and Xie, J}, title = {Pharmacological mechanisms and potential clinical applications of Dihydromyricetin in neurological disorders.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1618623}, pmid = {40740995}, issn = {1663-9812}, abstract = {Neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, and stroke) have complex pathogenesis and affect a substantial proportion of the population; yet, available treatments have poor or limited efficacy, and the patients have a poor prognosis, with high morbidity and mortality. Dihydromyricetin (DHM), a flavonoid compound extracted from plants, has received widespread attention in recent years because of its diverse pharmacological effects. In vitro and in vivo studies have revealed its substantial antioxidant, anti-inflammatory, and neuroprotective properties, making it a promising candidate for the treatment of central nervous system disorders through multiple mechanisms and pleiotropic effects. Therefore, there is an urgent need to develop novel therapeutic strategies. DHM is an attractive candidate for the management of neurological disorders, but there is a lack of a systematic summary of the knowledge status and gaps. Therefore, to address this challenge, we systematically reviewed the pharmacological mechanisms of DHM in central nervous system disorders and its potential applications in related conditions. We analyzed the therapeutic potential and current challenges of DHM to provide a reference for its development and application as a novel therapeutic agent. The review suggests that DHM possesses significant potential for the management of neurological disorders.}, } @article {pmid40740514, year = {2025}, author = {Wang, J and Mao, Y and Liu, X and Hao, W and , }, title = {Learning Patient-Specific Spatial Biomarker Dynamics via Operator Learning for Alzheimer's Disease Progression.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {40740514}, issn = {2331-8422}, support = {R35 GM146894/GM/NIGMS NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with substantial heterogeneity in progression and treatment response. Despite recent therapeutic advances, predictive models capable of accurately forecasting individualized disease trajectories remain limited. Here, we present a machine learning-based operator learning framework for personalized modeling of AD progression, integrating longitudinal multimodal imaging, biomarker, and clinical data. Unlike conventional models with prespecified dynamics, our approach directly learns patient-specific disease operators governing the spatiotemporal evolution of amyloid, tau, and neurodegeneration biomarkers. Using Laplacian eigenfunction bases, we construct geometry-aware neural operators capable of capturing complex brain dynamics. Embedded within a digital twin paradigm, the framework enables individualized predictions, simulation of therapeutic interventions, and in silico clinical trials. Applied to AD clinical data, our method achieves high prediction accuracy exceeding 90% across multiple biomarkers, substantially outperforming existing approaches. This work offers a scalable, interpretable platform for precision modeling and personalized therapeutic optimization in neurodegenerative diseases.}, } @article {pmid40740460, year = {2025}, author = {Fu, HX}, title = {Effects of repetitive transcranial magnetic stimulation on electroencephalogram and memory function in patients with mild cognitive impairment.}, journal = {World journal of psychiatry}, volume = {15}, number = {7}, pages = {106761}, pmid = {40740460}, issn = {2220-3206}, abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a high-risk precursor to Alzheimer's disease characterized by declining memory or other progressive cognitive functions without compromising daily living abilities. AIM: To investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with MCI. METHODS: This retrospective analysis involved 180 patients with MCI who were admitted to The First Hospital of Shanxi Medical University from January 2021 to June 2023. Participants were allocated into the research (n = 98, receiving rTMS) and control groups (n = 82, receiving sham stimulation). Memory tests, cognitive function assessments, event-related potential-P300 tests, and electroencephalogram (EEG) examinations were conducted pre-treatment and post-treatment. Further, memory quotient (MQ), cognitive function scores, and EEG grading results were compared, along with adverse reaction incidences. RESULTS: Pre-treatment MQ scores, long-term and short-term memory, as well as immediate memory scores, demonstrated no notable differences between the groups. Post-treatment, the research group exhibited significant increases in MQ scores, long-term memory, and short-term memory compared to baseline (P < 0.05), with these improvements being statistically superior to those in the control group. However, immediate memory scores exhibited no significant change (P > 0.05). Further, the research group demonstrated statistically better post-treatment scores on the Revised Wechsler Memory Scale than the control group. Furthermore, post-treatment P300 latency and amplitude improved significantly in the research group, surpassing the control group. EEG grading in the research group improved, and the incidence of adverse reactions was significantly lower than in the control group. CONCLUSION: Patients with MCI receiving rTMS therapy demonstrated improved memory and cognitive functions and EEG grading and exhibited high safety with fewer adverse reactions.}, } @article {pmid40740038, year = {2025}, author = {Zheng, M and Yang, M and Li, X and Tian, L and Zhou, S and Wang, G and Gao, W}, title = {Attenuation of Tacrine Combined With Rosmarinic Acid.}, journal = {Phytochemical analysis : PCA}, volume = {36}, number = {7}, pages = {2022-2038}, doi = {10.1002/pca.70009}, pmid = {40740038}, issn = {1099-1565}, support = {2060302//Key Project at the Central Government Level/ ; ZYYCXTD-D-202005//Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine/ ; 81872956//National Natural Science Foundation of China/ ; 82173929//National Natural Science Foundation of China/ ; }, mesh = {Rosmarinic Acid ; *Depsides/pharmacology/administration & dosage ; *Cinnamates/pharmacology/administration & dosage ; Animals ; *Tacrine/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Mice ; Male ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Microglia/drug effects/metabolism ; Galactose ; Brain/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of dementia among the elderly in the world. With the increase of human life expectancy, its incidence is also increasing year by year. Tacrine (TAC) is the first acetylcholine inhibitor approved for the treatment of AD. Although TAC has obvious anti-AD activity, it was eventually delisted due to acute liver injury caused by its strong hepatotoxicity. Rosmarinic acid (RA) has shown good activity in both neuroprotection and hepatoprotection. PURPOSE AND STUDY DESIGN: In this study, the combination of RA and TAC was explored, and a high dose of d-galactose was used to build an AD mouse model, which was given at the same time for 4 weeks in order to alleviate TAC hepatotoxicity and enhance the intervention of AD in mice through RA. In particular, we pay attention to the key role of Aβ and microglia in the pathogenesis of AD, so we evaluate the ability of RA combined with TAC in alleviating chronic neuroinflammation induced by Aβ plaque in the brain of AD mice and enhancing the ability of microglia to clear Aβ plaque. RESULTS: The results show that the combination of RA and TAC has the best intervention effect on AD compared with the single use of the two drugs, and it is basically positively correlated with RA dose. RA + TAC significantly improved body weight, organ index, and behavioral state of AD mice. Further analysis showed that RA + TAC enhanced the antioxidant level of hippocampus and serum of AD mice, alleviated the pathological damage of hippocampus, significantly improved cholinergic system, reduced the expression levels of AB plaque and neurotoxic Aβ1-41 and Aβ1-42 in the brain, and significantly increased the level of neuroprotective protein trigger receptor expressed on myeloid cells 2 (TREM2), which mediated the phagocytosis of microglia. More importantly, the combination therapy of RA and TAC decreased the expression of M1 microglia marker (ionized calcium-binding adapter molecule 1 [Iba-1]), increased the expression of M2 microglia marker Arg-1, and promoted the release of anti-inflammatory compounds. In addition, RA + TAC also inhibited the mRNA expression of TLR4 and NF-κB related to neuroinflammation. In the aspect of liver function, RA reduced cell death mediated by Caspase-3 by regulating the expression of bcl-2/bax, alleviated TAC-induced liver injury in mice, and made the serum indexes of ALT, AST, ALP, TBIL, and γ-GT reflecting liver function closer to the normal range. CONCLUSION: The combination of RA and TAC shows the potential to reduce the hepatotoxicity of TAC and is expected to enhance its therapeutic effect on AD.}, } @article {pmid40739944, year = {2025}, author = {Hardy, J}, title = {Alzheimer's Disease: Treatment Challenges for the Future.}, journal = {Journal of neurochemistry}, volume = {169}, number = {8}, pages = {e70176}, pmid = {40739944}, issn = {1471-4159}, mesh = {*Alzheimer Disease/drug therapy/therapy/metabolism ; Humans ; Animals ; Amyloid beta-Peptides/metabolism/immunology/antagonists & inhibitors ; }, abstract = {The approvals of the first anti-amyloid antibodies for the treatment of Alzheimer's disease have changed both the clinical and research landscape for the disease. These antibodies, lecanemab and donanemab, mark a turning point for our understanding of the disease pathogenesis and for the treatment of this prevalent disorder. This review discusses what they imply for disease pathogenesis and what is needed to progress from the current imperfect therapies toward safe and better, disease halting therapies. The research over the next period will involve drug development, largely aimed at reducing the side effects of the anti-amyloid therapies, biomarker and genetic research to try and identify patients earlier in the disease process, and neuropathological research in individuals who have received treatment to try and understand the pathological substrates of the continuing clinical decline in the disease.}, } @article {pmid40739673, year = {2025}, author = {Zheng, X and Yuan, W and Li, L and Ma, H and Zhu, M and Li, X and Feng, X}, title = {Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to tackle central nervous system diseases: role as a promising approach.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {690}, pmid = {40739673}, issn = {2047-783X}, mesh = {Humans ; *Proprotein Convertase 9/metabolism/genetics ; *PCSK9 Inhibitors/therapeutic use ; *Central Nervous System Diseases/drug therapy/metabolism ; Animals ; }, abstract = {Atherosclerosis-associated disease (ASD) represents a complex pathological condition, characterized by the formation of atherosclerotic plaques within the arterial walls, encompassing cholesterol depositions, which is primarily attributed to elevated levels of low-density lipoprotein-cholesterol (LDL-C). A log-linear association between the absolute magnitude of LDL-C exposure and ASD risk has been widely studied. High levels of LDL-C have been acknowledged as the predominant culprit. The previous research findings have demonstrated that PCSK9 inhibitors (PCSK9i) can remarkably diminish the risk of ASD. The current research has primarily focused on the relevance of PCSK9 to the cardiovascular system and lipid metabolism; however, an increasing body of evidence shows that PCSK9 is pivotal in pathogenic processes in other organ systems. Yet, PCSK9's impact on the brain is complex and not fully clarified, although several recent studies emphasize a putative role of its impact on various neurodegenerative disorders. Among neurological disorders, not only stroke but neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, alcohol use disorder (AUD), amyotrophic lateral sclerosis(ALS), and Alzheimer's Disease (AD) are related to PCSK9. PCSK9 expression in brain is low but greatly upregulated in neurological disorders. Therefore, PCSK9 is a promising pathway for the treatment of central nervous diseases. This review comprehensively describes evidence from the previous research on the effects of PCSK9i on the central nervous system, with a focus on the clinical potential of PCSK9i. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop treatments for the neurological diseases based on PCSK9i.}, } @article {pmid40737743, year = {2025}, author = {Liu, J and Liu, K and Cui, X and Ji, Y and Ding, Z and Chang, Z and Zhang, J and Wang, X and Liu, Y}, title = {From gut to brain: donepezil and nimodipine combination therapy improves cognitive deficits in Alzheimer's disease via gut microbiota and metabolites.}, journal = {Biochemical and biophysical research communications}, volume = {778}, number = {}, pages = {152418}, doi = {10.1016/j.bbrc.2025.152418}, pmid = {40737743}, issn = {1090-2104}, mesh = {*Gastrointestinal Microbiome/drug effects ; *Donepezil/pharmacology/therapeutic use/administration & dosage ; Animals ; *Alzheimer Disease/drug therapy/metabolism/microbiology ; Male ; Drug Therapy, Combination ; Rats ; *Brain/drug effects/metabolism ; Rats, Sprague-Dawley ; *Cognitive Dysfunction/drug therapy/metabolism ; Feces/microbiology ; Hippocampus/drug effects/pathology/metabolism ; }, abstract = {Donepezil (DNP) is often combined with nimodipine (NMD) for the treatment of Alzheimer's disease (AD). However, its underlying mechanisms remain poorly understood. This study integrated pharmacodynamics, microbiomics, and fecal metabolomics analysis to explore the therapeutic potential and mechanism of DNP + NMD in AD. The results showed that DNP + NMD significantly reduced the contents of serum inflammatory cytokines interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) as well as the contents of nitric oxide synthase (NOS), glycogen synthase kinase-3β (GSK-3β) and acetylcholinesterase (AChE) in the hippocampus, alleviated neuronal damage in hippocampal tissues and effectively improved cognitive deficits of AD rats. Furthermore, DNP + NMD greatly increased the relative abundance of beneficial bacteria (Lactobacillus and Prevotellaceae_Prevotella) and decreased the relative abundance of harmful bacteria (Ruminococcus and Akkermansia). Fecal metabolomic analyses indicated that DNP + NMD regulated 28 fecal differential metabolite levels mainly through six key pathways, including linoleic acid metabolism, arachidonic acid metabolism, unsaturated fatty acid biosynthesis, steroid hormone biosynthesis, saturated fatty acid biosynthesis, primary bile acid biosynthesis, pantothenic acid biosynthesis, and coenzyme A biosynthesis pathway. Moreover, Spearman's correlation analysis revealed significant associations between affected metabolites and specific gut microbes. In general, our research sheds light that DNP + NMD exerts a neuroprotective effect against AD by ameliorating the gut microbiota and fecal metabolic disorders, uncovering novel mechanistic insights and therapeutic targets for AD intervention.}, } @article {pmid40737409, year = {2025}, author = {Zou, F and Liu, Y and Luo, Y and Xu, T}, title = {A wearable spatiotemporal controllable ultrasonic device with amyloid-β disaggregation for continuous Alzheimer's disease therapy.}, journal = {Science advances}, volume = {11}, number = {31}, pages = {eadw1732}, pmid = {40737409}, issn = {2375-2548}, mesh = {*Alzheimer Disease/therapy/metabolism/pathology ; Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; Mice ; Disease Models, Animal ; *Wearable Electronic Devices ; Microglia/metabolism ; Humans ; Brain/metabolism/pathology ; Plaque, Amyloid/metabolism ; *Ultrasonic Therapy/instrumentation ; Mice, Transgenic ; *Protein Aggregates ; }, abstract = {The rising prevalence of Alzheimer's disease (AD) due to an aging population has made the search for effective treatments more urgent than ever. Previous studies have demonstrated that continuous ultrasound can depolymerize amyloid proteins, offering potential relief from AD. In this study, we present a portable, fully integrated wearable ultrasound system designed to promote amyloid protein depolymerization. The system comprises a flexible honeycomb ultrasonic array patch, a flexible printed circuit, and an interactive terminal control system to facilitate the treatment process. Our results demonstrate that the system effectively reduces amyloid proteins in the brain, improves cognitive function in a familial Alzheimer's disease (FAD) mouse model, enhances microglial phagocytosis of amyloid-β plaques, and shifts microglia polarization from M1 to M2. These changes contribute to a mitigated inflammatory environment in the brain. This innovative approach may pave the way for noninvasive, personalized treatments for AD, potentially transforming therapeutic strategies in neurodegenerative disorders.}, } @article {pmid40736488, year = {2025}, author = {Johnston, EM and Lounsbery, JL}, title = {Benzgalantamine (Zunveyl) for the Treatment of Mild to Moderate Alzheimer Disease.}, journal = {American family physician}, volume = {112}, number = {1}, pages = {22-23}, pmid = {40736488}, issn = {1532-0650}, } @article {pmid40735986, year = {2025}, author = {Akocak, S and Lolak, N and Ammara, A and Güler, ÖÖ and Supuran, CT}, title = {Exploring the Carbonic Anhydrase Activation Properties of 4-arylazo-3,5- diamino-1H-pyrazoles against hCA I, II, IV, and VII isoenzymes.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266373008250723064558}, pmid = {40735986}, issn = {1873-4294}, abstract = {INTRODUCTION: CAs serve as crucial enzymes involved in a variety of physiological processes, including brain metabolism and cognitive function. hCA VII, a brain-associated isoform, plays an important role in modulating cerebral metabolism. Activating hCA VII may provide therapeutic benefits in Alzheimer's disease and other neurodegenerative or age-related illnesses. This study proposes to add to the growing interest in CAAs by developing innovative drugs with selective activation characteristics that target brain-associated CA isoforms. METHOD: A series of 4-arylazo-3,5-diamino-1H-pyrazoles have been produced by reacting aniline and aniline derivatives with a malononitrile solution at 0-5 °C, resulting in compounds 1(a-m). Then, arylazo malononitrile compounds were added with hydrazine monohydrate to obtain 4- arylazo-3,5-diamino-1H-pyrazole derivatives 2(a-m). The activity of the synthesized compounds was examined on human CA isoforms I, II, IV, and VII to determine activation potency and selectivity. RESULTS: The synthesized compounds demonstrated a wide spectrum of strong micromolar activation on human CA isoforms, with particularly encouraging results for hCA VII. The discovered activators showed a high selectivity profile for the brain-associated hCA VII isoform, indicating their potential use in neurological methods of therapy. DISCUSSION: Among the most compelling findings of this study is the unprecedented potency of several synthesized derivatives, particularly 2i and 2m, in selectively activating hCA VII far beyond the benchmark histamine, positioning them as promising pharmacological candidates for addressing CA-related neurological disorders. CONCLUSION: The research successfully discovered potent and selective CAAs with specific activity against hCA VII, a key enzyme in brain metabolism. These outcomes offer novel possibilities for developing medicinal products for neurological disorders and provide critical molecules for further study into CAAs. Furthermore, the study advances our understanding of enzyme activation kinetics and gives significant insights into the future of enzyme-based treatment research.}, } @article {pmid40735980, year = {2025}, author = {Agarwal, U and Tonk, RK and Verma, S}, title = {Pathogens Association with Alzheimer Disease: Emerging Concepts and New Perspectives.}, journal = {Current gene therapy}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115665232389348250722073721}, pmid = {40735980}, issn = {1875-5631}, abstract = {Alzheimer's Disease (AD) represents a significant global health challenge, distinguished by a complex pathology that involves the accumulation of abnormal proteins in the brain, leading to neuronal loss and brain atrophy. Recent research has indicated a potential association between various pathogens and the development of AD, suggesting that infectious pathogens may play a role in its pathology. The study focuses on the exploration of pathogens linked to AD. It aims to enhance the understanding of the disease's etiopathogenesis, which refers to the causes and development of the condition. The findings from this analysis have the potential to contribute to improved diagnostic methods and treatment strategies for AD. Overall, the manuscript highlights the importance of exploring infectious pathogens relating to neurodegenerative disorders. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to March 2025. Articles were searched based on keywords related to reviews and research exploring the association/link between different pathogens and AD, emerging interventions, preventive strategies, and limitations in study design. This study indicates that various viruses, bacteria, and fungi are significant contributors to the condition, while parasites and prions play a lesser role. Notably, the variability in pathogen species among patients could provide insights into the evolution and severity of clinical symptoms associated with the disease. Additionally, some studies propose that after modification, certain fungi may actually reduce the amyloid burden in Alzheimer's patients. However, it is crucial to emphasize that there is currently no definitive evidence supporting the notion that treating infections alone can prevent or cure AD. The prevention and treatment of pathogens, including viruses, bacteria, and fungi, as well as infectious prions, may play a significant role in reducing the risk of AD. Effective management of these pathogens can help to control and prevent further damage in individuals who have already been diagnosed with AD. There is a pressing need for additional pre-clinical and clinical research to deepen the understanding of the pathophysiological connections between pathogens and AD.}, } @article {pmid40735445, year = {2025}, author = {Khan, W and Khan, MS and Qasem, SN and Ghaban, W and Saeed, F and Hanif, M and Ahmad, J}, title = {An explainable and efficient deep learning framework for EEG-based diagnosis of Alzheimer's disease and frontotemporal dementia.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1590201}, pmid = {40735445}, issn = {2296-858X}, abstract = {The early and accurate diagnosis of Alzheimer's Disease and Frontotemporal Dementia remains a critical challenge, particularly with traditional machine learning models which often fail to provide transparency in their predictions, reducing user confidence and treatment effectiveness. To address these limitations, this paper introduces an explainable and lightweight deep learning framework comprising temporal convolutional networks and long short-term memory networks that efficiently classifies Frontotemporal dementia (FTD), Alzheimer's Disease (AD), and healthy controls using electroencephalogram (EEG) data. Feature engineering has been conducted using modified Relative Band Power (RBP) analysis, leveraging six EEG frequency bands extracted through power spectrum density (PSD) calculations. The model achieves high classification accuracies of 99.7% for binary tasks and 80.34% for multi-class classification. Furthermore, to enhance the transparency and interpretability of the framework, SHAP (SHapley Additive exPlanations) has been utilized as an explainable artificial intelligence technique that provides insights into feature contributions.}, } @article {pmid40735383, year = {2025}, author = {Luca, A and Luca, M and Ferri, R and Barbanti, M and Malaguarnera, R and Pecorino, B and Scollo, P and Serretti, A}, title = {Medical Comorbidities in Alzheimer's Disease: An Autopsy Confirmed Study with a Focus on Sex-Differences?.}, journal = {Clinical neuropsychiatry}, volume = {22}, number = {3}, pages = {207-214}, pmid = {40735383}, issn = {2385-0787}, abstract = {OBJECTIVE: Systemic comorbidities are common in Alzheimer's disease (AD) and may influence disease progression, severity, and management. Aim of the study was to assess the prevalence of comorbid medical conditions in a large cohort of AD patients, focusing on sex differences. METHOD: AD patients from the NIMH Alzheimer Disease Genetics Initiative were enrolled. Data on multimorbidity, demographics, disease characteristics, and clinical assessments were collected from interviews, medical records, and examinations. Univariate and multivariate logistic regression models were performed to identify possible associations between comorbidities and sex. Subgroup analysis was performed for patients with autopsy-confirmed AD. RESULTS: Four hundred and twenty-four AD patients (295 women; mean age: 78.4±8.3 years) were included. Men had a higher prevalence of heart disease, diabetes, chronic obstructive pulmonary disease and smoking, whereas thyroid disease, hypertension and depression were more common in women (all p<0.05). Except for hypertension, all associations found in the univariate analysis were confirmed in the multivariate analysis after adjustment for age. Subgroup analysis of autopsy-confirmed cases confirmed these findings. CONCLUSIONS: Our findings support the importance of considering sex-specific comorbidities in AD for precision medicine and emphasize the need for comprehensive assessment of comorbidities to improve clinical outcomes, treatment strategies and health equity.nt.}, } @article {pmid40734951, year = {2025}, author = {Yang, JC and Kuo, PJ and Chang, C and Wang, YM and Ou, YC and Cheng, YC and Wu, SC and Chien, PC and Hsieh, CH and Lin, WC}, title = {Linking Lymphedema, Chronic Inflammation, Oxidative Stress, Alzheimer Disease, and Potential Role of Lymphaticovenous Anastomosis.}, journal = {Plastic and reconstructive surgery. Global open}, volume = {13}, number = {7}, pages = {e6955}, pmid = {40734951}, issn = {2169-7574}, abstract = {BACKGROUND: Lymphedema and Alzheimer disease (AD) share common mechanisms involving oxidative stress and chronic inflammation. However, the link between these 2 conditions and the impact of lymphaticovenous anastomosis (LVA) has not been fully explored. This study aimed to evaluate their association by examining changes in AD biomarkers, inflammatory cytokines, and oxidative stress markers before and after LVA. METHODS: Twenty-four patients with unilateral lower limb lymphedema who underwent LVA as primary treatment and 18 healthy controls were recruited. Exclusion criteria included previous LVA, liposuction, or excisional surgery. Venous blood samples were obtained before and 1 month after LVA. RESULTS: After matching, 15 patients remained in each group. The lymphedema group had significantly elevated levels of t-tau (p < 0.001), amyloid beta (Aβ)1-40 (P = 0.033), Aβ1-42 (P = 0.033), Aβ1-42 × t-tau (P < 0.001), and Aβ1-42/Aβ1-40 ratio (P = 0.021) compared with controls. One month post-LVA, there were significant reductions in t-tau (P = 0.007) and Aβ1-42 × t-tau (P = 0.002), and a notable increase in brain-derived neurotrophic factor (P = 0.006). Post-LVA samples also showed significant improvements in antioxidative enzymes, antioxidant capacity, and reductions in lipid peroxidation. Inflammatory cytokine levels were also significantly reduced, indicating decreased oxidative stress and inflammation. The median follow-up period was 6.3 months. CONCLUSIONS: Findings suggest a possible association between lymphedema and increased AD risk possibly linked to elevated oxidative stress and inflammation. LVA may modulate this risk by reducing AD biomarkers and systemic inflammation/oxidative stress, supporting further investigation into its neuroprotective potential.}, } @article {pmid40734473, year = {2025}, author = {Prajapat, M and Sarma, P and Kaur, G and Choudhary, G and Jain, S and Kamal, R and Bains, O and Sangwan, N and Prakash, A and Medhi, B}, title = {Therapeutic potential of 6BIO and DKK1-LRP6 inhibitor in Wnt/β-catenin pathway modulation for amyloid-β-induced Alzheimer's disease model.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {857-878}, doi = {10.1177/13872877251362787}, pmid = {40734473}, issn = {1875-8908}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; Amyloid beta-Peptides/toxicity ; Humans ; *Low Density Lipoprotein Receptor-Related Protein-6/antagonists & inhibitors/metabolism ; Male ; Rats, Wistar ; *Wnt Signaling Pathway/drug effects/physiology ; Rats ; Peptide Fragments/toxicity ; Disease Models, Animal ; Cell Line, Tumor ; *Intercellular Signaling Peptides and Proteins/metabolism ; }, abstract = {BackgroundThe Wnt/β-catenin signaling pathway plays a crucial role in central nervous system development, with emerging evidence linking its dysregulation to the progression of Alzheimer's disease (AD).ObjectiveThis study investigates the activation of Wnt signaling by targeting GSK3β and the DKK1/LRP6 interaction using a combination of 6BIO (6Bromoindirubin-3-oxime) and a novel gallocyanine derivative (8e) modulator.MethodsWe identified the interaction energy scores of both modulators with target proteins through an in-silico approach. Furthermore, the effects of 6BIO (10 µM) and 8e (20 µM) were assessed in SH-SY5Y cells treated with Aβ1-42 (20 µM). The efficacy of these modulators was also evaluated in male Wistar rats through dose-ranging studies. An Alzheimer's disease model was established via intracerebroventricular injection of Aβ1-42, followed by treatment with 6BIO (23.8 µg/kg/day, i.p.) and 8e (4.2 mg/kg/day, i.p.).ResultsBoth modulators demonstrated favorable binding energy scores and dynamic simulation results against the targeted proteins. In Aβ1-42-treated SHSY5Y cells, the combination of 6BIO and 8e significantly reduced reactive oxygen species production and apoptotic activity while modulating protein expression. In vivo study, rats treated with combination of 6BIO and 8e modulators exhibited improved neurobehavioral activity compared to AD model rats, along with altered expression of DKK1, β-catenin, p-tau, and pGSK3β. Additionally, decreased oxidative stress and apoptosis markers.ConclusionsThese findings suggest that the combined targeting of GSK3β and LRP6 represents a promising therapeutic strategy for AD. The combination of 6BIO and 8e shows potential as a novel modulator and warrants further investigation in clinical trials to assess its therapeutic efficacy.}, } @article {pmid40734451, year = {2025}, author = {Wang, H and Yang, Q and Ge, C and Liu, J and Mistry, H and Jia, YF and He, G}, title = {Integrated transcriptomic and proteomic analysis identifies FBXW7 as a key regulator of tau homeostasis in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {542-560}, doi = {10.1177/13872877251361042}, pmid = {40734451}, issn = {1875-8908}, mesh = {*F-Box-WD Repeat-Containing Protein 7/genetics/metabolism ; *Alzheimer Disease/metabolism/genetics ; Humans ; *tau Proteins/metabolism/genetics ; Proteomics/methods ; Homeostasis/physiology ; *Transcriptome ; Male ; Animals ; Mice ; Female ; }, abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder driven by complex, incompletely understood genetic and pathogenic factors. E3 ubiquitin ligases (E3s), crucial for protein degradation, are implicated in AD, but their specific contributions to its progression remain to be elucidated.ObjectiveThis study aimed to identify dysregulated E3s in AD and elucidate the role of a hub E3, FBXW7, in its pathogenesis and tau protein regulation.MethodsWe integrated four datasets to identify differentially expressed E3s (DE-E3s) in AD and performed functional enrichment and PPI network analyses. Machine learning identified hub E3s and stratified AD patients into molecular subtypes. Furthermore, we validated the expression and functional role of FBXW7 using western blot, immunoprecipitation-mass spectrometry (IP-MS), and co-immunoprecipitation (Co-IP).ResultsWe identified 42 DE-E3s primarily enriched in protein ubiquitination and Notch signaling pathways. FBXW7 and ENC1 emerged as hub E3s, stratifying patients into two subtypes. Subtype I exhibited enrichment of inflammatory pathways, suggesting immune dysregulation. Conversely, subtype II displayed activation of pathways associated with synaptic dysfunction and neuronal loss, potentially representing distinct primary pathological features. Furthermore, we observed decreased FBXW7 expression in AD models compared to controls. Notably, FBXW7 interacted with Tau protein. Overexpression of FBXW7 reduced the levels of both total Tau and p-Tau Ser262, and this reduction in Tau levels was reversed by MG132 treatment.ConclusionsThis study comprehensively identified E3s associated with AD, with our findings highlighting FBXW7 as a potential key regulator of AD pathogenesis through its modulation of tau protein levels.}, } @article {pmid40734422, year = {2025}, author = {Miles, LA and Masters, CL}, title = {The structural foundations of anti-amyloid-β immunotherapies: Unravelling antibody-antigen interactions in Alzheimer's disease treatment.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {393-408}, doi = {10.1177/13872877251361049}, pmid = {40734422}, issn = {1875-8908}, mesh = {*Alzheimer Disease/immunology/drug therapy/therapy ; Humans ; *Amyloid beta-Peptides/immunology/metabolism/antagonists & inhibitors ; *Immunotherapy/methods ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Antibodies, Monoclonal/therapeutic use ; Structure-Activity Relationship ; }, abstract = {BackgroundAnti-amyloid-β (Aβ) immunotherapies are emerging as treatments for Alzheimer's disease (AD).ObjectiveThis review examines the structure-activity relationships of anti-Aβ therapeutics tested in phase 3 trials.MethodsWe analyzed crystallographic data and molecular models to elucidate the Aβ binding mechanisms of donanemab, lecanemab, aducanumab, bapineuzumab, gantenerumab, solanezumab, and crenezumab.ResultsLecanemab recognizes minimally degraded Aβ missing 1-2 residues, avoiding common Aβ in circulation and further degraded material sequestered in plaques. Bapineuzumab buries the N-terminus of Aβ requiring Asp1 and is reactive with benign, common Aβ. Donanemab buries the truncated N-Glu3 terminus with strong contacts engaging the cyclized pyro-Glu3 modification. Gantenerumab shows lecanemab-like properties but also binds common Aβ. Aducanumab likely needs mAb-mAb cooperation to scavenge a spectrum of Aβ oligomers explaining higher doses. Solanezumab and crenezumab target a pre-amyloid epitope resulting in off-target engagement, including monomers and likely excluding Aβ-ApoE complexes.ConclusionsPreventing primary Aβ nucleation failed due to limitations imposed by the blood-brain barrier, intracellular aggregation routes, and the natural abundance of Aβ. Anti-Aβ monoclonal antibody therapies in clinical use capture Aβ at various stages of decay where post translational modifications have been used effectively as proxies for time spent in vivo. By targeting a relatively labile epitope of aging Aβ, lecanemab selects more biologically active species of Aβ avoiding both benign monomers and old fortified species. This focal point may account for the significant cognitive effects of lecanemab. The structure of aducanumab suggests a broadly neutralizing role has evolved for natural immunity to AD.}, } @article {pmid40734174, year = {2025}, author = {Zare, A and Salehi, S and Bader, JM and Wiessler, AL and Prokesch, M and Albrecht, V and Villmann, C and Mann, M and Briese, M and Sendtner, M}, title = {Axonal tau reduction ameliorates tau and amyloid pathology in a mouse model of Alzheimer's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {39}, pmid = {40734174}, issn = {2047-9158}, support = {BR4910/2-2//Deutsche Forschungsgemeinschaft/ ; SE697/5-2//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Animals ; *tau Proteins/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology/genetics ; Disease Models, Animal ; *Axons/metabolism/pathology ; Mice ; Mice, Knockout ; Humans ; *Plaque, Amyloid/pathology/metabolism ; Brain/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Cells, Cultured ; Neurons/metabolism ; Mice, Transgenic ; }, abstract = {BACKGROUND: Pathological deposition of hyperphosphorylated tau in the brain closely correlates with the course of Alzheimer's disease (AD). Tau pathology occurs in axons of affected neurons and tau removal from axons might thus be an early intervention strategy. METHODS: We investigated the role of the RNA-binding protein hnRNP R in axonal localization and local translation of Mapt mRNA in neurons cultured from hnRNP R knockout mice. hnRNP R knockout mice were crossed with 5×FAD mice, an AD mouse model, and the effects of hnRNP R loss on the deposition of phospho-tau and amyloid-β plaques were evaluated. We designed antisense oligonucleotides (MAPT-ASOs) to block the binding of hnRNP R to Mapt mRNA. Cultured mouse and human neurons were treated with MAPT-ASOs and axonal Mapt mRNA and tau protein levels were quantified. MAPT-ASO was injected intracerebroventricularly into 5×FAD mice followed by quantification of phospho-tau aggregates and amyloid-β plaques in their brains. Protein changes in brains of 5×FAD mice treated with the MAPT-ASO were measured by mass spectrometry. RESULTS: Mapt mRNA and tau protein were reduced in axons but not cell bodies of primary neurons cultured from hnRNP R knockout mice. Brains of 5×FAD mice deficient for hnRNP R contained less phospho-tau aggregates and amyloid-β plaques in the cortex and hippocampus. Treatment of neurons with MAPT-ASOs to block hnRNP R binding to Mapt similarly reduced axonal tau levels. Intracerebroventricular injection of a MAPT-ASO reduced the phospho-tau and plaque load and prevented neurodegeneration in the brains of 5×FAD mice, accompanied by rescue of proteome alterations. CONCLUSION: Lowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.}, } @article {pmid40733241, year = {2025}, author = {Asim, A and Jastrzębski, MK and Kaczor, AA}, title = {Dual Inhibitors of Acetylcholinesterase and Monoamine Oxidase-B for the Treatment of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {14}, pages = {}, pmid = {40733241}, issn = {1420-3049}, support = {2021/43/B/NZ7/01732//National Science Center/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism/enzymology ; *Monoamine Oxidase Inhibitors/chemistry/therapeutic use/pharmacology ; Humans ; *Cholinesterase Inhibitors/chemistry/therapeutic use/pharmacology ; *Monoamine Oxidase/metabolism/chemistry ; *Acetylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Animals ; Molecular Structure ; }, abstract = {Alzheimer's disease (AD) is a multi-factorial neurodegenerative disease with a complex pathomechanism that can be best treated with multi-target medications. Among the possible molecular targets involved in AD, acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) are well recognized because they control the neurotransmitters responsible for memory processes. This review discusses the current understanding of AD pathology, recent advances in AD treatment, and recent reports in the field of dual AChE/MAO-B inhibitors for treating AD. We provide a classification of dual inhibitors based on their chemical structure and describe active compounds belonging to, i.a., chalcones, coumarins, chromones, imines, and hydrazones. Special emphasis is given to the computer-aided strategies of dual inhibitors design, their structure-activity relationships, and their interactions with the molecular targets at the molecular level.}, } @article {pmid40732328, year = {2025}, author = {Alghamdi, MA}, title = {From Molecules to Medicines: The Role of AI-Driven Drug Discovery Against Alzheimer's Disease and Other Neurological Disorders.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {7}, pages = {}, pmid = {40732328}, issn = {1424-8247}, support = {IMSIU-DDRSP2501//Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University/ ; }, abstract = {The discovery of effective therapeutics against Alzheimer's disease (AD) and other neurological disorders remains a significant challenge. Artificial intelligence (AI) tools are of considerable interest in modern drug discovery processes and, by exploiting machine learning (ML) algorithms and deep learning (DL) tools, as well as data analytics, can expedite the identification of new drug targets and potential lead molecules. The current study was aimed at assessing the role of AI-based tools in the discovery of new drug targets against AD and other related neurodegenerative diseases and their efficacy in the discovery of new drugs against these diseases. AD represents a multifactorial neurological disease with limited therapeutics available for management and limited efficacy. The discovery of more effective medications is limited by the complicated pathophysiology of the disease, involving amyloid beta (Aβ), neurofibrillary tangles (NFTs), oxidative stress, and inflammation-induced damage in the brain. The integration of AI tools into the traditional drug discovery process against AD can help to find more effective, safe, highly potent compounds, identify new targets of the disease, and help in the optimization of lead molecules. A detailed literature review was performed to gather evidence regarding the most recent AI tools for drug discovery against AD, Parkinson's disease (PD), multiple sclerosis (MLS), and epilepsy, focusing on biological markers, early diagnoses, and drug discovery using various databases like PubMed, Web of Science, Google Scholar, Scopus, and ScienceDirect to collect relevant literature. We evaluated the role of AI in analyzing multifaceted biological data and the properties of potential drug candidates and in streamlining the design of clinical trials. By exploring the intersection of AI and neuroscience, this review focused on providing insights into the future of AD treatment and the potential of AI to revolutionize the field of drug discovery. Our findings conclude that AI-based tools are not only cost-effective, but the success rate is extremely high compared to traditional drug discovery methods in identifying new therapeutic targets and in the screening of the majority of molecules for clinical trial purposes.}, } @article {pmid40732267, year = {2025}, author = {Liu, C and Wang, X and Xu, W and Yu, S and Zhang, Y and Xu, Q and Tan, X}, title = {Study on the Pharmacological Efficacy and Mechanism of Dual-Target Liposome Complex AD808 Against Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {7}, pages = {}, pmid = {40732267}, issn = {1424-8247}, support = {32471351//National Science Foundation of China/ ; }, abstract = {Background/Objectives: To study the efficacy and pharmacological mechanism of the dual-target liposome complex AD808 in the treatment of Alzheimer's disease. Methods: Using APP/PS1 mouse models, the therapeutic efficacy and pharmacological mechanism of AD808 on Alzheimer's disease were studied through water maze tests, brain tissue staining, immunofluorescence, and ELISA for inflammatory and neurotrophic factors. Results: AD808 exhibited significant pharmacodynamic effects in improving behavioral and cognitive abilities (70% reduction in escape latency) and repairing damaged nerve cells (90% reduction in Aβ plaque) in Alzheimer's disease mice. The efficacy of the liposome complex AD808 was significantly better than that of ST707 or gh625-Zn7MT3 alone. AD808 significantly reduced brain inflammation (57.3% and 61.5% reductions in TNF-α and IL-1β, respectively) in AD (Alzheimer's disease) mouse models and promoted the upregulation of neurotrophic factors and nerve growth factors (142.8% increase in BDNF, 275.9% in GDNF, and 111.3% in NGF-1) in brain homogenates. By activating the PI3K/AKT signaling pathway in brain microglia, AD808 upregulated TREM2 protein expression and removed Aβ amyloid plaques in the brain. Additionally, it promoted the transition of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, regulated the M1/M2 balance, released anti-inflammatory and neurotrophic factors, reduced chronic inflammation, and enhanced neurological repair. Based on these results, the potential pharmacological mechanism of AD808 against Alzheimer's disease was proposed. Conclusions: As a dual-target liposome complex, AD808 has shown promising therapeutic potential in the treatment of Alzheimer's disease, providing a new strategy for innovative drug development.}, } @article {pmid40732244, year = {2025}, author = {Wiśniewski, K and Zglejc-Waszak, K and Antonowski, T and Szablinska-Piernik, J and Juskiewicz, J and Lahuta, L and Jozwik, M and Wojtkiewicz, J}, title = {Analysis of Scyllo-Inositol in a Wistar Rat Animal Model-A Preliminary Study.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {7}, pages = {}, pmid = {40732244}, issn = {1424-8247}, support = {RID/SP/0025/2024/01//the Minister of Science under "the Regional Initiative of Excellence Program/ ; }, abstract = {Background: Scyllo-inositol (SCI) is a naturally occurring carbocyclic sugar implicated in many biological processes. Studies have highlighted the potential of using SCI in Alzheimer's therapy. However, in order to fully use this compound in the treatment of neurovegetative diseases, its pharmacokinetics must be thoroughly understood. Objectives: We undertook the task of analyzing SCI in a Wistar rat animal model. The aim of this study was to observe the changes in SCI concentration after oral administration. Methods: All rats received 10 mg/kg of SCI as a solution in distilled water by oral gavage. Estimated parameters were based on the serum concentration of SCI observed in six individual rats with regard to time. Results: The first peak concentration appeared at 30 min for SCI. Thereafter, the serum SCI concentration increased rapidly and reached its highest level after approximately 1.5 h. There was no second peak in SCI concentration. The elimination half-life was determined to be 10.07 h and the mean residence time was 14.52 h. There were no side effects of SCI supplementation noticed during the study. Conclusions: Although our results present an analysis of SCI immediately after oral administration up to 48 h, further studies are necessary.}, } @article {pmid40731203, year = {2025}, author = {Gao, H and Jensen, K and Nesbitt, J and Ostroot, M and Cary, GA and Wiley, J and Trushin, S and Watzlawik, JO and Springer, W and Galkin, A and Baloni, P and Funk, C and Trushina, E}, title = {Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70519}, pmid = {40731203}, issn = {1552-5279}, support = {RF1AG55549/NH/NIH HHS/United States ; //Michael J. Fox Foundation for Parkinson's Research/ ; W81XWH-17-1-0248//Department of Defense Congressionally Directed Medical Research Programs/ ; R01 NS131322/NS/NINDS NIH HHS/United States ; RF1 AG062135/AG/NIA NIH HHS/United States ; R01NS112381/NH/NIH HHS/United States ; R56 AG062556/AG/NIA NIH HHS/United States ; //Ted Nash Long Life Foundation/ ; R01NS110085/NH/NIH HHS/United States ; RO1AG062135/NH/NIH HHS/United States ; U54 AG065187/AG/NIA NIH HHS/United States ; RO1AG59093/NH/NIH HHS/United States ; R01NS131322/NH/NIH HHS/United States ; U54NS110435/NH/NIH HHS/United States ; R56AG062556/NH/NIH HHS/United States ; RF1NS085070/NH/NIH HHS/United States ; Emory-Sage-SGC-JAX U54AG065187//National Institute of Health Target Enablement to Accelerate Therapy Development for Alzheimer's Disease Consortia/ ; R01 NS110085/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/drug therapy ; *Electron Transport Complex I/deficiency/genetics ; Mice ; Disease Models, Animal ; Female ; Humans ; Male ; Mice, Knockout ; *Mitochondrial Diseases/genetics/metabolism/complications ; Mitochondria/metabolism ; Brain/metabolism ; Transcriptome ; }, abstract = {INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4[-/-] mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2. METHODS: Cortico-hippocampal tissue from Ndufs4[-/-] and wild-type mice was subjected to transcriptomic analysis, followed by cross-species comparisons to human late-onset AD and familial AD mouse datasets. RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4[-/-] mice showing greater compensatory adaptations and treatment responses. DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest important considerations for personalized therapeutics. HIGHLIGHTS: Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks. A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late-onset Alsheimer's disease (AD) patients and familial mouse models of AD. Pharmacological targeting of mtCI mediates neuroprotective signaling. Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria-targeted therapeutics. Mitochondria play a key role in AD development and treatment.}, } @article {pmid40731005, year = {2025}, author = {Ghaderi Yazdi, B and Razlighi, QR}, title = {Translation of task-evoked negative BOLD response into aging and Alzheimer's disease: a systematic review of the current literature.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {850}, pmid = {40731005}, issn = {1479-5876}, support = {R01AG085972/AG/NIA NIH HHS/United States ; R01AG057962/AG/NIA NIH HHS/United States ; K01AG044467/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging/blood ; *Magnetic Resonance Imaging ; *Aging/physiology ; *Oxygen/blood ; Cognitive Dysfunction/physiopathology ; }, abstract = {BACKGROUND: Aging, mild cognitive impairment (MCI), Alzheimer's disease (AD), and individuals at risk for AD are associated with impaired negative blood-oxygen-level-dependent (BOLD) response (NBR) in task-evoked functional magnetic resonance imaging (fMRI) studies. In addition, autosomal dominant AD patients have exhibited NBR alterations in the default mode network (DMN) regions nearly a decade before any accumulation of amyloid-β (Aβ) or tau and subsequent memory decline. Studies examining exclusively the NBR are rare in clinical settings, but some existing studies using task-evoked fMRI also report alterations in the NBR. However, in many studies, NBR is often disregarded, left lingering in the shadows, or, more generally, masked out as a bothersome noise. METHODS: We reviewed the Embase, Scopus, and PubMed databases, and forward and backward citation tracking for studies published up to 6/11/2024. Included articles detailed the use of task-evoked fMRI (tb-fMRI) to investigate aging, AD, mild cognitive impairment (MCI), and early tau or Aβ deposition, with all results reported on NBR. FINDINGS: From 319 records identified for aging, 154 records for tau or Aβ, and 159 records for AD and MCI, 42, 14, and 9 papers were included, respectively. Forward and backward citation tracking added 44, 3, and 55 papers, respectively resulting in 167 studies with 11310 individuals. A significantly reduced magnitude of NBR in some regions of the DMN in healthy aging compared with young participants and individuals with elevated Aβ levels, MCI, and AD compared to healthy aging was found in 57, 12, 17, and 14 studies, respectively. INTERPRETATION: This review highlights the DMN NBR's importance in the AD continuum and underscores its potential as an early diagnostic biomarker when pharmacological treatment options can still alter the disease course.}, } @article {pmid40730714, year = {2025}, author = {Xia, X and Aye, S and Frisell, O and Aho, E and Handels, R and Li, Y and Wimo, A and Winblad, B and Eriksdotter, M and Skillbäck, TB and Kern, S and Zetterberg, H and Jönsson, L}, title = {The Cost-Effective Price of Lecanemab for Patients with Early Alzheimer's Disease in Sweden.}, journal = {PharmacoEconomics}, volume = {43}, number = {10}, pages = {1251-1266}, pmid = {40730714}, issn = {1179-2027}, support = {101112145//The Innovative Health Initiative Joint Undertaking/ ; 2021-02680//VINNOVA/ ; 2024-03573//Vetenskapsrådet/ ; 2023-00356//Vetenskapsrådet/ ; 2022-01018//Vetenskapsrådet/ ; 2019-02397//Vetenskapsrådet/ ; 2019-02075//Vetenskapsrådet/ ; 2019-02075_15//Vetenskapsrådet/ ; FO2024-0287//Swedish Brain Foundation/ ; FO2024-0097//Swedish Brain Foundation/ ; FO2024-0339//Swedish Brain Foundation/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; ALFGBG-81392//Swedish State Support for Clinical Research/ ; ALFGBG-771071//Swedish State Support for Clinical Research/ ; ALFGBG-1005471//Swedish State Support for Clinical Research/ ; ALFGBG-965923//Swedish State Support for Clinical Research/ ; AF-842471//Alzheimerfonden/ ; AF-737641//Alzheimerfonden/ ; AF-929959//Alzheimerfonden/ ; AF-939825//Alzheimerfonden/ ; 2024-03599//Swedish Research Council/ ; }, mesh = {Humans ; Sweden ; *Alzheimer Disease/drug therapy/economics ; *Antibodies, Monoclonal, Humanized/economics/therapeutic use ; Cost-Effectiveness Analysis ; Markov Chains ; Quality-Adjusted Life Years ; *Drug Costs ; Models, Economic ; Quality of Life ; Male ; Female ; Age Factors ; Sex Factors ; }, abstract = {INTRODUCTION: We sought to estimate the cost-effective price for lecanemab for treating early Alzheimer's disease in Sweden from the perspective of formal care payers. METHODS: We developed a Markov model with states defined by disease severity and care setting. The model was populated by integrated clinical and economic data from Swedish registers. We included patients with biomarker-confirmed Alzheimer's disease and fitted survival models for transitions between model states. Costs in 2023 Swedish kronor (SEK), life-years (LYs), and quality-adjusted LYs (QALYs) over a 10-year time horizon were estimated for standard of care and for lecanemab in addition to standard of care, assuming a maximum treatment duration of 3 years with lecanemab and no treatment effect after treatment stops. We also explored the impact of different assumptions regarding treatment efficacy and duration. RESULTS: Treatment with lecanemab over 3 years resulted in 0.13 LYs gained, 0.17 QALYs gained, and a net cost increase of 87,146 SEK (€1 = 11.5 SEK, $US1 = 10.6 SEK) due to administration and monitoring, before considering the cost of drug. The cost-effective price of lecanemab at a willingness-to-pay level of 1 million SEK per QALY was 33,886 SEK per year of treatment. The health gain, net costs, and cost-effective price of lecanemab varied significantly by treatment duration, potential residual effects, and patient characteristics. CONCLUSIONS: The future price of lecanemab in European countries is unknown. However, treatment with lecanemab is unlikely to be cost effective in Sweden at the levels of current list prices in the USA.}, } @article {pmid40730660, year = {2025}, author = {Kumar, S and Song, K and Wang, J and Baghel, MS and Zeng, Y and Shen, K and Zheng, J and Crane, J and Demehri, S and Gao, P and Jain, A and Skolasky, RL and Wong, P and Cao, X and Wan, M}, title = {Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis.}, journal = {Nature aging}, volume = {5}, number = {9}, pages = {1771-1789}, pmid = {40730660}, issn = {2662-8465}, support = {P01AG066603//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P01 AG066603/AG/NIA NIH HHS/United States ; R01AG068226//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG072090/AG/NIA NIH HHS/United States ; R01AG072090//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG068226/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Serum Amyloid P-Component/metabolism ; *Amyloidosis/metabolism/pathology ; *Adipocytes/metabolism/pathology ; Mice ; Mice, Transgenic ; *Aging/pathology/metabolism ; Alzheimer Disease/metabolism/pathology ; C-Reactive Protein/metabolism ; Amyloid beta-Peptides/metabolism ; *Bone Marrow Cells/metabolism ; Humans ; Mice, Inbred C57BL ; Male ; }, abstract = {The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on organ aging. Here, we demonstrate that both transgenic Alzheimer's disease (AD) mice and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits. Senescent BMAds acquire a secretory phenotype, markedly increasing secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAds in vivo and promotes insoluble amyloid formation from soluble amyloid-β (Aβ) peptides in in vitro and ex vivo three-dimensional (3D) BMAd-based cultures. Combined SAP/PTX2 and Aβ treatment promotes osteoclastogenesis but inhibits osteoblastogenesis. Transplanting senescent BMAds into the bone marrow cavity of young mice induces bone loss, which is reversed by senolytic treatment. Finally, depleting SAP/PTX2 in aged mice abolishes marrow amyloid deposition and rescues low bone mass. Thus, senescent BMAds drive age-related skeletal amyloidosis and bone deficits via SAP/PTX2.}, } @article {pmid40730291, year = {2025}, author = {Magdalena, R and Ferrada, L and Ramírez, E and Smith-Ghigliotto, JF and Salazar, K and Nualart, F}, title = {Dehydroascorbic acid impairs neurite growth through RIPK1-associated caspase activation.}, journal = {Free radical biology & medicine}, volume = {239}, number = {}, pages = {406-416}, doi = {10.1016/j.freeradbiomed.2025.07.036}, pmid = {40730291}, issn = {1873-4596}, mesh = {*Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics ; *Neurites/drug effects/metabolism/pathology ; Animals ; *Dehydroascorbic Acid/pharmacology ; Enzyme Activation/drug effects ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Imidazoles/pharmacology ; Indoles/pharmacology ; *Caspases/metabolism ; Mice ; Amino Acid Chloromethyl Ketones/pharmacology ; Ascorbic Acid ; Antioxidants/pharmacology ; Humans ; }, abstract = {Axonal and neurite loss is a common event in neurodegenerative diseases, such as Alzheimer's disease or amyotrophic lateral sclerosis, which are enhanced by oxidative damage and reactive oxygen species (ROS) production. In the central nervous system, vitamin C can be found as ascorbic acid (AA), its reduced form, or dehydroascorbic acid (DHA), its oxidized form. Vitamin C mainly acts as an antioxidant agent, and homeostasis in the brain is maintained through its recycling between neurons and astrocytes. However, DHA accumulation under pathophysiological conditions has been associated with changes in neuronal metabolism and necroptotic cell death through RIPK1 activation. Furthermore, recent studies show that DHA accumulation induces significant neurite loss; however, it is unknown whether this effect is associated with RIPK1 activation. Here, we show that DHA treatment on neurospheres (NE) in vitro induces significant neurite shortening and reduced branching, effects associated with early RIPK1 activation and inhibited through Necrostatin-1s and zVAD-FMK treatment, suggesting the activation of apoptotic mechanisms. Finally, we propose DHA, the oxidized form of vitamin C, impairs neurite growth through ripk1-associated caspase activation.}, } @article {pmid40729740, year = {2025}, author = {Hu, L and Li, J and Guo, H and Su, L and Dong, P and Huang, J and Liu, Y and Liu, X and Luo, Z and Xiong, W and Ju, Z and Zhou, Q and Wang, H and Wang, W}, title = {SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {40}, pages = {e03408}, pmid = {40729740}, issn = {2198-3844}, support = {2021YFA08049000//National Key Research and Development Program of China/ ; 32430049//National Natural Science Foundation of China/ ; 82370576//National Natural Science Foundation of China/ ; 82370596//National Natural Science Foundation of China/ ; 32170772//National Natural Science Foundation of China/ ; 32270810//National Natural Science Foundation of China/ ; 92049304//National Natural Science Foundation of China/ ; 82030039//National Natural Science Foundation of China/ ; 82071340//National Natural Science Foundation of China/ ; 82401526//National Natural Science Foundation of China/ ; 2022A1515140040//Guangdong Basic and Applied Basic Research Foundation/ ; 2023B1515120089//Guangdong Basic and Applied Basic Research Foundation/ ; 2021A1515011227//Guangdong Basic and Applied Basic Research Foundation/ ; 2022A0505050041//Guangdong Basic and Applied Basic Research Foundation/ ; }, mesh = {*Mitochondria/metabolism/genetics ; Animals ; Mice ; Homeostasis ; Sumoylation ; Humans ; Mitochondrial Precursor Protein Import Complex Proteins/metabolism ; Alzheimer Disease/metabolism/genetics ; *Cysteine Endopeptidases/metabolism/genetics ; *Mitochondrial Proteins/metabolism ; Protein Transport ; Mice, Transgenic ; Proteostasis ; }, abstract = {SUMOylation, a reversible post-translational modification, regulates various mitochondrial processes, including biogenesis, dynamics, mitophagy, and the mitochondrial unfolded protein response. Although SUMOylation is shown to be triggered by mitochondrial protein import failure in yeast, its impact on mammalian mitochondrial protein import remains unclear. Here, it is demonstrated that SENP6 knockdown-induced SUMOylation causes loss of mitochondrial proteostasis, which impairs mitochondrial morphology and function. Mechanistically, SENP6 knockdown dampens TOM complex assembly by SUMOylating TOM40, thereby hindering the mitochondrial protein import process, including TOM40 precursor, and ultimately disrupts mitochondrial homeostasis. Additionally, it is observed that CCCP treatment resulted in a decrease of SENP6 within mitochondria fraction, accompanied by increased TOM40 SUMOylation in the brains of 3×Tg-Alzheimer's disease (AD) mice or Aβ1-42 peptide-stimulated cells. Collectively, the results suggest that Aβ1-42 accumulation may enhance TOM40 SUMOylation by suppressing SENP6, thereby impairing mitochondrial homeostasis through protein import failure and potentially contributing to the pathological process of AD. This study elucidates the role of TOM40 SUMOylation/deSUMOylation in regulating the mitochondrial import process during mitochondrial stress.}, } @article {pmid40728824, year = {2025}, author = {Helal, MM and Almosilhy, NA and Hamam, NG and Abdelbaset, MAA and Shelbaya, AN and Musse, HAY and Prasad, A}, title = {Sacubitril/Valsartan Reduces the Risk of All-Cause Dementia in Patients with Heart Failure: A Systematic Review and Meta-Analysis.}, journal = {Drugs & aging}, volume = {42}, number = {10}, pages = {907-920}, pmid = {40728824}, issn = {1179-1969}, mesh = {Humans ; *Heart Failure/drug therapy/complications ; *Biphenyl Compounds/therapeutic use/adverse effects ; Drug Combinations ; *Aminobutyrates/therapeutic use/adverse effects ; *Valsartan/therapeutic use/adverse effects ; *Dementia/prevention & control ; *Angiotensin Receptor Antagonists/therapeutic use/adverse effects ; Neprilysin/antagonists & inhibitors ; }, abstract = {BACKGROUND: Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), has become a cornerstone therapy for heart failure (HF) since its approval over a decade ago. However, concerns have emerged about potential cognitive risks, as neprilysin inhibition may contribute to the accumulation of amyloid-beta (Aβ) in the brain-a hallmark of Alzheimer's disease, the most common form of dementia. OBJECTIVE: Given the already elevated risk of dementia in patients with HF and the widespread use of sacubitril/valsartan, this meta-analysis aimed to evaluate whether its use is associated with an increased risk of all-cause dementia in HF populations. METHODS: A systematic literature search was conducted on 23 March 2025, to identify eligible studies comparing the risk of dementia in patients receiving sacubitril/valsartan versus those receiving placebo, no treatment, or other HF medications. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model. RESULTS: Six studies, comprising 101,074 participants and published between 2017 and 2024, were included in the meta-analysis. Treatment with sacubitril/valsartan was associated with a significant 15% reduction in the risk of all-cause dementia (RR = 0.85; 95% CI: 0.74-0.98; p = 0.02). Leave-one-out sensitivity and subgroup analyses confirmed the robustness of the findings. CONCLUSIONS: This meta-analysis suggests that sacubitril/valsartan is associated with a reduced risk of dementia in patients with HF, helping to alleviate previous concerns about potential cognitive adverse effects. These findings support the continued use of sacubitril/valsartan as a foundational therapy in this high-risk population.}, } @article {pmid40728549, year = {2025}, author = {Al Saihati, HA and Alazabi, NI and Bakeer, RM and Abol-Fetouh, GM and Ahmed-Farid, OA and Alshedi, AF and Alsabeelah, NF}, title = {Optimizing predictive biomarkers for alzheimer's disease: muscarinic M1 antagonist-induced synaptic signaling disruptions and bee venom intervention through cholinergic modulation and multiregression dose selection.}, journal = {Metabolic brain disease}, volume = {40}, number = {6}, pages = {244}, pmid = {40728549}, issn = {1573-7365}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/chemically induced ; Rats ; *Bee Venoms/pharmacology/therapeutic use ; Biomarkers/metabolism ; Male ; Oxidative Stress/drug effects ; Rats, Wistar ; *Receptor, Muscarinic M1/antagonists & inhibitors/metabolism ; Scopolamine ; Dose-Response Relationship, Drug ; *Muscarinic Antagonists/pharmacology ; Neuroprotective Agents/pharmacology ; Memantine/pharmacology ; Disease Models, Animal ; Brain/metabolism/drug effects ; Maze Learning/drug effects ; }, abstract = {Alzheimer's (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neurochemical imbalances. The present study aims to ensure the correct dosage of scopolamine (SC) for inducing AD using Quality by Design to optimize the predictive biomarker acetylcholine esterase. Further, neuroprotective effects will be assessed with variable doses of bee venom (BV) by analyzing its effect on cognitive function, neurochemical markers, and oxidative stress. The goal of this study is to improve models of AD and learn more about how BV can protect neurons in a dose-dependent way during treatment. Methods: The rats were randomly divided into six groups (n = 6): Control, SC -induced AD, SC + Memantine (1 mg/kg bwt p.o.), and three BV doses (5, 10, 15 µl/kg, i.p, every other day) to study dose-dependent effects combined with SC. Memantine and BV were given to the animals two months before they developed AD, which happened on its own 14 days after treatment. After four days of behavioral assessment using the Morris Water Maze to evaluate cognitive function, the animals were humanely sacrificed. Blood and brain samples were collected for the measurement of serum liver and kidney function markers, oxidative and nitrosative stress parameters, cellular energy metabolites, amino acid profiles, neurotransmitters, and inflammatory markers in brain tissue. Results and Conclusion: The most remarkable neuroprotective effect was found in the group treated with BV medium and high dose showed a plateau, beyond which no more improvement was shown. These findings point toward a promising therapeutic approach for BV in the cognitive decline of AD.}, } @article {pmid40727792, year = {2025}, author = {Wang, N and Liu, W and Zhou, L and Liu, W and Liang, X and Liu, X and Xu, Z and Zhong, T and Wu, Q and Jiao, X and Chen, J and Ning, X and Jiang, X and Zhao, Q}, title = {Retraction of "Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3β for the Treatment of Alzheimer's Disease".}, journal = {ACS omega}, volume = {10}, number = {28}, pages = {31208}, doi = {10.1021/acsomega.5c06137}, pmid = {40727792}, issn = {2470-1343}, abstract = {[This retracts the article DOI: 10.1021/acsomega.2c03368.].}, } @article {pmid40727583, year = {2025}, author = {Matuszewska, M and Wilkaniec, A and Gąssowska-Dobrowolska, M and Cieślik, M and Olech-Kochańczyk, G and Pałasz, E and Gawinek, E and Strawski, M and Czapski, GA}, title = {Inhibition of BET proteins modulates amyloid-beta accumulation and cognitive performance in middle-aged mice prenatally exposed to maternal immune activation.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1619583}, pmid = {40727583}, issn = {1662-5099}, abstract = {INTRODUCTION: Given the complex etiological basis of Alzheimer's disease (AD), it is reasonable to hypothesize that neuronal dysfunction and death result from the interplay of numerous factors, both genetic and environmental. Accumulating evidence implicates the immune system and inflammation as key components of the pathomechanism of AD. In the present study, we analyzed the effect of maternal immune activation (MIA) on AD-related pathological changes in middle-aged 12-month-old offspring mice. Additionally, we investigated whether the inhibition of bromodomain and extraterminal domain (BET) proteins, which are readers of the histone acetylation code, could influence these changes. METHODS: In our study, we administered a viral mimetic, polyinosinic-polycytidylic acid (PIC), on gestation day 17 to induce MIA in wild-type C57BL/6J mice. The BET protein inhibitor, OTX-015 (Birabresib), was administered orally to 12-month-old male offspring for 14 days. Subsequently, behavioral, genetic, and immunochemical analyses were conducted. RESULTS: Our results demonstrated several MIA-evoked molecular alterations in the brains of middle-aged offspring. We observed an increase in App gene expression (qPCR) and amyloid-β (Aβ) levels (ELISA), while the levels and phosphorylation of Tau protein remained unchanged (WB). The mRNA levels of selected microglial markers were also elevated in the MIA group. Treatment with OTX-015 improved memory, as observed in the novel object recognition test, and reduced Aβ levels, but did not alter the expression of inflammatory genes or amyloidogenesis-related genes. DISCUSSION: Our findings suggest that inhibition of BET proteins may effectively attenuate neuropathological alterations in the aged brain.}, } @article {pmid40727259, year = {2025}, author = {Sun, W and Zhu, A and Chang, H and Xia, J and Gao, J and Zhang, Z and Chi, F and Zhu, Y and Bao, X}, title = {Causal associations and shared genetic etiology between neurodegenerative diseases and constipation.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251362469}, pmid = {40727259}, issn = {2542-4823}, abstract = {BACKGROUND: There is increasing evidence suggesting a correlation between neurodegenerative diseases (NDDs) and constipation; however, their genetic relationship and causal mechanisms remain inadequately elucidated. OBJECTIVE: We aim to investigate the causal link and shared genetic basis between NDDs and constipation. METHODS: We obtained summary statistics from large-scale genome-wide association studies, encompassing five NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), as well as constipation. The primary analysis employed five Mendelian randomization methods to evaluate causal effects, while linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) were utilized to investigate genetic correlations. Additionally, significant pleiotropic SNPs were identified using pleiotropic analysis under the composite null hypothesis (PLACO) and functional mapping and annotation (FUMA). Finally, enrichment analysis was conducted to explore the biological pathways associated with the identified pleiotropic genes. RESULTS: MR analysis revealed a significant causal relationship between AD and an enhanced risk of constipation was demonstrated (OR = 1.043, 95% CI: 1.015-1.073, p = 0.003), while no causality was found between PD, MS, ALS, LBD, and the risk of constipation (p > 0.05). LDSC and HDL analysis revealed a significant positive genetic correlation between AD and constipation. Using PLACO combined with FUMA, we identified 30 overlapping pleiotropic loci, with pathway enrichment analysis revealing important biological pathways related to Aβ metabolism and processing, tau protein process, and the complement and coagulation cascades. CONCLUSIONS: Our study indicates that AD is a contributing factor to constipation and uncovers the complex genetic mechanisms linking AD and constipation, which holds significant implications for diagnosis and treatment of both conditions.}, } @article {pmid40727044, year = {2025}, author = {Jiang, Q and Liu, Y and Wei, Y and Kuan, G and Ma, L and Wang, H and Wang, Y and Lou, H}, title = {The underlying mechanism of physical exercise on neurodegenerative diseases: the mediating role of psychological stress and resilience: a systematic review.}, journal = {Frontiers in psychology}, volume = {16}, number = {}, pages = {1474579}, pmid = {40727044}, issn = {1664-1078}, abstract = {Theories and experiments have shown that physical exercise can improve mental resilience and resist the negative effects of psychological stress. Neurodegenerative diseases are a collection of diseases in which progressive changes in the structure and function of neurons result in progressive disorders of cognitive and motor function, greatly reducing the quality of life of the patient. The latest research suggests that psychological factors such as psychological stress and resilience also have an impact on the onset, symptoms, and course of Neurodegenerative diseases. However, the specific mechanisms in the above pathways are unclear, so this study introduced psychological factors such as psychological stress and resilience and explore the mechanism of physical exercise in improving NDDs by influencing psychological factors such as psychological stress and resilience. This review examined four electronic databases (PubMed, Web of Science, Cochrane Library, and CNKI) up to May 2024, selecting a total of 95 articles. A logical analysis approach was employed to evaluate the literature. The findings revealed that: (1) Exercise can enhance resilience by reducing negative emotions or fulfilling individual needs, thereby diminishing the harmful effects of stress, a key risk factor for NDDs. (2) Exercise alleviates NDDs through neurobiological pathways such as improving immune function, regulating endocrine and neurotransmitter levels, and modifying neuronal structure. (3) Long-term, regular high-intensity exercise effectively enhances resilience and helps prevent and treat NDDs. Exercise has a positive impact on the prevention and treatment of NDDs. Clarifying the mechanisms by which exercise improves NDDs is crucial for providing new theoretical insights into the diagnosis, prevention, and treatment of psychologically induced NDDs, as well as offering practical guidance and feasible strategies for using exercise to prevent and mitigate NDDs.}, } @article {pmid40726797, year = {2025}, author = {Mondal, S and An, J and Bera, T and Banerjee, M and Debnath, S and Mandal, D and Sikder, A and Guha, S and Kim, JS and Singh, NDP}, title = {Engineering a Green Fluorescent Protein-Core-Inspired NIR-Photocage: Exploring meso-GFP-PRPG toward Alzheimer's Disease Therapeutics.}, journal = {ACS central science}, volume = {11}, number = {7}, pages = {1062-1070}, pmid = {40726797}, issn = {2374-7943}, abstract = {NIR light-activated photocage with inherent protein tagging ability is unprecedented in contemporary photochemistry. Herein, we introduce a series of protein-taggable NIR-photocages derived from green fluorescent protein (GFP) chromophore analogs with spatiotemporal control for releasing the caged bioactive molecules. Through molecular engineering of the GFP chromophoric scaffold, a series of meso-substituted oxazolone-photocages (meso-GFP-PRPG) were judiciously designed and synthesized. These photocages, anchored with electron-donating groups (EDG) and electron-withdrawing groups (EWG), accommodate diverse payloads, including aliphatic carboxylic acids, expanding the possibilities for tailoring their properties and applications. Notably, under anaerobic conditions, irradiation of meso-GFP-PRPG leads to fast and efficient release of caged molecules. Insightful experimental and theoretical investigations revealed that photorelease is predominantly driven by the triplet state photochemistry in anaerobic conditions. The concept's theranostic potential was demonstrated by the conditional release of valproic acid, a neuroprotective agent for Alzheimer's disease (AD) treatment. meso-GFP-PRPG (15E) showed enhanced NIR emission with Aβ oligomers and fibrils (30-37 fold vs ThT) and effectively degraded amyloid fibrils under 640 nm light, offering a promising targeted treatment approach for neurodegenerative disorders.}, } @article {pmid40726790, year = {2025}, author = {Ma, M and Zhao, Y}, title = {Protein-Taggable Near-Infrared Photocages for Theranostics of Alzheimer's Disease.}, journal = {ACS central science}, volume = {11}, number = {7}, pages = {1024-1025}, pmid = {40726790}, issn = {2374-7943}, abstract = {Protein-tagged near-infrared-activatable photocages have been developed for the simultaneous diagnosis and treatment of Alzheimer's disease.}, } @article {pmid40726727, year = {2025}, author = {Rao, SP and Imam-Fulani, AO and Xie, W and Phillip, S and Chennavajula, K and Bhilare, KD and Lind, EB and Zhang, Y and Vince, R and Lee, MK and More, SS}, title = {Oral Prodrug of a Novel Glutathione Surrogate Reverses Metabolic Dysregulation and Attenuates Neurodegenerative Process in Transgenic Alzheimer's Mice.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {8}, pages = {2448-2464}, pmid = {40726727}, issn = {2575-9108}, support = {R01 AG062469/AG/NIA NIH HHS/United States ; R01 AG077743/AG/NIA NIH HHS/United States ; RF1 AG062135/AG/NIA NIH HHS/United States ; }, abstract = {Glycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer's disease (AD). Reduced glutathione levels in AD lead to increased oxidative stress, including glycation-induced pathology. Previously, we showed that the accumulation of reactive 1,2-dicarbonyls such as methylglyoxal, the major precursor of nonenzymatic glycation products, was reduced by the increased function of GSH-dependent glyoxalase-1 enzyme in the brain. In this two-pronged study, we evaluate the therapeutic efficacy of an orally bioavailable prodrug of our lead glyoxalase substrate, pro-ψ-GSH, for the first time in a transgenic Alzheimer's disease mouse model. This prodrug delivers pharmacodynamically relevant brain concentrations of ψ-GSH upon oral delivery. Chronic oral dosing of pro-ψ-GSH effectively reversed the cognitive decline observed in the APP/PS1 mouse model. The prodrug successfully mirrors the robust effects of the parent drug, i.e., reducing amyloid pathology, glycation stress, neuroinflammation, and the resultant neurodegeneration, in these mice. We also report the first metabolomics study of such a treatment that yields key biomarkers linked to the reversal of AD-related metabolic dysregulation. Collectively, this study demonstrates the neuroprotective effect of pro-ψ-GSH in a symptomatic preclinical model of AD and paves the way for further preclinical advancement of such therapeutics. Metabolomic signatures identified could prove beneficial in the development of treatment-specific, clinically translatable biomarkers.}, } @article {pmid40726442, year = {2025}, author = {Ehtezazi, T and Sarker, SD}, title = {Phytochemical Nanoparticles for the Treatment of Neurological Disorders.}, journal = {Phytochemical analysis : PCA}, volume = {36}, number = {7}, pages = {1918-1935}, pmid = {40726442}, issn = {1099-1565}, mesh = {Humans ; *Phytochemicals/therapeutic use/chemistry ; *Nanoparticles/chemistry ; *Nervous System Diseases/drug therapy ; Animals ; *Neurodegenerative Diseases/drug therapy ; Alzheimer Disease/drug therapy ; Curcumin/therapeutic use ; }, abstract = {Neurological disorders impose a significant burden on the healthcare systems. The latest published data by WHO indicated that stroke was the second leading cause of death globally in 2020, with Alzheimer's disease (AD) and other dementias in the seventh position. The treatment of neurological disorders is challenging because of the complex nature of the disease, as well as limited accessibility to this target organ due to several biological barriers. There is a wide range of treatment options for neurological disorders. Small drug molecules, antibodies, and stem cells have been employed for the treatment of neurodegenerative diseases such as AD, but currently, there is no effective treatment for AD. As conventional drugs have not been successful in achieving therapeutic outcomes, natural products such as curcumin, stemming from traditional medicines, have been tested for the treatment of neurodegenerative diseases such as AD. However, this compound has not shown significant therapeutic effects for the treatment of brain diseases, mainly due to rapid clearance from the body. Therefore, phytochemical nanoparticles have been developed. In this review article, the rationale has been provided for the use of nanoparticles for the treatment of neurodegenerative diseases with emphasis on phytochemical nanoparticles.}, } @article {pmid40726148, year = {2025}, author = {Rahman, AU and Esa, M and Panichayupakaranant, P}, title = {The therapeutic potential of pomegranate in the prevention and management of noncommunicable diseases.}, journal = {Food & function}, volume = {16}, number = {16}, pages = {6313-6345}, doi = {10.1039/d5fo01999k}, pmid = {40726148}, issn = {2042-650X}, mesh = {*Pomegranate/chemistry ; Humans ; *Noncommunicable Diseases/prevention & control ; *Plant Extracts/pharmacology/chemistry ; Fruit/chemistry ; Animals ; Neoplasms/prevention & control ; }, abstract = {Noncommunicable diseases (NCDs), including cardiovascular diseases, cancer, respiratory conditions, and metabolic and central nervous system disorders, are the leading causes of morbidity and mortality worldwide. These diseases are primarily driven by unhealthy diets and sedentary lifestyles. Pomegranate (Punica granatum L.), a fruit rich in diverse functional phytoconstituents, has emerged as a promising natural therapeutic agent for the prevention and management of NCDs. Every part of the fruit harbors distinct bioactive compounds that contribute to its health-promoting properties. The peels are particularly rich in punicalagins, the arils are abundant in anthocyanins and ellagic acid, and the seeds contain significant amounts of punicic acid, ellagic acid, and quercetin. Pomegranate peel extracts and juice demonstrate cardioprotective effects through inhibition of angiotensin-converting enzyme (ACE) activity, reduction of inflammatory cytokines, e.g., interleukins and TNF-α, and improvements in lipid profiles. Additionally, their anticancer properties are associated with the upregulation of pro-apoptotic markers (Bax, cytochrome c, caspases 3 and 9, and p53) and the downregulation of tumor-promoting and inflammatory markers (Bcl-2, MMP-2, MMP-9, GOLPH-3, and N-cadherin), as well as the attenuation of reactive oxygen species (ROS) generation. Moreover, pomegranate extracts have exhibited hypoglycemic, nephroprotective, hepatoprotective, antidepressant, anti-Alzheimer's, and anti-Parkinson's properties, as demonstrated in in vitro and in vivo studies, and clinical trials. Recent investigations have identified key bioactive constituents, including punicalagin, ellagic acid, gallic acid, and urolithin A, as major contributors to these therapeutic effects. This review provides an overview of the metabolomic profile of pomegranate, its therapeutic potential, safety, and quality control assessments, and strategies to enhance the stability and bioavailability of its active constituents, thus underscoring its potential as a natural intervention for the prevention and treatment of NCDs.}, } @article {pmid40725913, year = {2025}, author = {Ugwu, OP and Okon, MB and Alum, EU and Ugwu, CN and Anyanwu, EG and Mariam, B and Ogenyi, FC and Eze, VHU and Anyanwu, CN and Ezeonwumelu, JOC and Egba, SI and Uti, DE and Onohuean, H and Aja, PM and Ugwu, MN}, title = {Unveiling the therapeutic potential of the gut microbiota-brain axis: Novel insights and clinical applications in neurological disorders.}, journal = {Medicine}, volume = {104}, number = {30}, pages = {e43542}, pmid = {40725913}, issn = {1536-5964}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; Probiotics/therapeutic use ; *Nervous System Diseases/therapy/microbiology ; *Dysbiosis/therapy/complications ; *Brain ; Fecal Microbiota Transplantation/methods ; Prebiotics/administration & dosage ; *Brain-Gut Axis/physiology ; }, abstract = {Over the last several years, the gut microbiota-brain axis has been the focus of medical study, demonstrating the bidirectional nature of gut and brain communication and the resulting influence on neurological and mental health. Trillions of microorganisms, particularly those found in the gastrointestinal tract, contribute the most to the pathophysiology recovery of organs that are critical to human health, such as digestive processes and metabolism, immune responses, and even cognitive function. Dysbiosis (a disturbance in the microbiome balance) has been identified as one of the risk factors for neuropsychiatric illnesses such as depression, anxiety, autism spectrum disorder, Parkinson's disease, and Alzheimer's disease. Therapeutic strategies aimed at the gut microbiota, such as probiotics, dietary modifications, prebiotics, and fecal microbiota transplantation, will eventually offer ways to alleviate symptoms associated with these disorders by restoring microbial balance, modulating the immune response, and influencing the production of major neurotransmitters. Innovative drug carriers, such as microbially-derived nanoparticles and probiotics that target particular parts of the gut or microbial communities, may improve pharmaceutical treatment efficacy and specificity. The resolution of difficulties such as ethical concerns, unexpected repercussions, and peak performance optimization in a clinical setting is critical for the advancement of this subject.}, } @article {pmid40725728, year = {2025}, author = {Riachi, R and Khalife, E and Kędzia, A and Niechciał, E}, title = {Understanding Insulin Actions Beyond Glycemic Control: A Narrative Review.}, journal = {Journal of clinical medicine}, volume = {14}, number = {14}, pages = {}, pmid = {40725728}, issn = {2077-0383}, abstract = {Insulin, traditionally recognized for its pivotal role in glycemic regulation, exerts extensive effects beyond glucose homeostasis, influencing multiple physiological systems. This narrative review explores the multifaceted actions of insulin, emphasizing its impact on skeletal muscle remodeling, protein and lipid metabolism, growth, reproductive health, and the central nervous system. Methods: An in-depth review of articles with evidence-based research discussing insulin actions beyond glycemic control was conducted in this review paper. Results: Insulin directly influences lipid and protein metabolism as well as growth hormone levels. This hormone provides a protective effect on the skeletal and central nervous systems, helping to maintain homeostasis and potentially reducing the risk of certain disorders such as Alzheimer's disease. The significance of insulin balance in the reproductive system is also crucial, with recent research indicating that insulin plays a role in worsening symptoms and complications associated with polycystic ovary syndrome. This review underscores the importance of maintaining proper insulin levels to lower the risk of insulin resistance. Ongoing research aims to deepen our understanding of insulin's functions, which are essential for preventing specific diseases and developing new treatment strategies. Conclusions: Insulin's action extends far beyond glucose metabolism, affecting many systems and preventing pathological changes in some.}, } @article {pmid40725270, year = {2025}, author = {Tahri, A and Niccolai, E and Amedei, A}, title = {Neurosteroids, Microbiota, and Neuroinflammation: Mechanistic Insights and Therapeutic Perspectives.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40725270}, issn = {1422-0067}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Neuroinflammatory Diseases/metabolism/microbiology/therapy ; Animals ; *Neurosteroids/metabolism ; *Neurodegenerative Diseases/metabolism/microbiology ; Brain/metabolism ; Inflammation ; }, abstract = {The gut-brain axis (GBA) represents a complex bidirectional communication network that links the gut microbiota (GM) and the central nervous system (CNS). Recent research has revealed that neurosteroids (NSs) play crucial roles in modulating neuroinflammatory responses and promoting neuroprotection. Meanwhile, GM alterations have been associated with various neuroinflammatory and neurodegenerative conditions, such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. This review aims to provide a comprehensive overview of the intricate interactions between NS, GM, and neuroinflammation. We discuss how NS and metabolites can influence neuroinflammatory pathways through immune, metabolic, and neuronal mechanisms. Additionally, we explore how GM modulation can impact neurosteroidogenesis, highlighting potential therapeutic strategies that include probiotics, neuroactive metabolites, and targeted interventions. Understanding these interactions may pave the way for innovative treatment approaches for neuroinflammatory and neurodegenerative diseases, promoting a more integrated view of brain health and disease management.}, } @article {pmid40725224, year = {2025}, author = {Scarano, N and Musumeci, F and Casini, B and Brullo, C and D'Ursi, P and Fossa, P and Schenone, S and Cichero, E}, title = {Alzheimer's Disease Etiology Hypotheses and Therapeutic Strategies: A Perspective.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40725224}, issn = {1422-0067}, support = {FRA2023//University of Genoa/ ; }, mesh = {*Alzheimer Disease/etiology/therapy/metabolism/drug therapy/pathology ; Humans ; Animals ; Neuroprotective Agents/therapeutic use ; Neurotransmitter Agents/metabolism ; Risk Factors ; Cholinesterase Inhibitors/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is a progressive, complex, multifactorial, neurodegenerative disease and accounts for most cases of dementia. The currently approved therapy includes cholinesterase inhibitors, NMDA-receptor antagonists and monoclonal antibodies. However, these medications were gradually discovered to be ineffective in removing the root of AD pathogenesis, having only symptomatic effects. Thus, the priority remains prevention and clarifying AD etiology. A better understanding of the neuroprotective mechanisms undertaken by specific genes is crucial to guide the design of novel therapeutic agents via selective ligands and precision medicine. In this review, we present a perspective of the physiological phase of the AD spectrum, of risk factors in AD with a focus on therapeutic approaches in three categories: neurotransmitters/ion modulations, peptide deposit control and aspecific treatments, followed by a discussion of treatment limitations. An overview of innovative strategies and non-pharmaceutical ancillary support is given.}, } @article {pmid40725167, year = {2025}, author = {Abdul-Nasir, S and Chau, CT and Nguyen, TT and Bajgai, J and Rahman, MH and Hwang-Un, K and You, IS and Kim, CS and Seo, BA and Lee, KJ}, title = {Hydrogen Gas Attenuates Toxic Metabolites and Oxidative Stress-Mediated Signaling to Inhibit Neurodegeneration and Enhance Memory in Alzheimer's Disease Models.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40725167}, issn = {1422-0067}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy ; *Oxidative Stress/drug effects ; *Hydrogen/pharmacology ; Mice ; Disease Models, Animal ; Astrocytes/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; Hippocampus/metabolism/drug effects ; Mice, Transgenic ; Signal Transduction/drug effects ; Male ; *Memory/drug effects ; Hydrogen Peroxide/metabolism ; Memory Disorders/drug therapy ; Maze Learning/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition in which amyloid-beta (Aβ) plaques trigger oxidative stress (OS) and neuroinflammation, causing memory loss. OS and neurodegeneration can also be caused by reactive astrocytes, thereby promoting AD via toxic metabolite accumulation in the astrocytic urea cycle. However, the effect of molecular hydrogen (H2) on this cycle remains unknown. Therefore, we investigated whether H2 treatment could reduce OS-induced neurodegeneration and memory loss. 5xFAD (n = 14) and wild-type (n = 15) mice were randomized into four groups and treated with either 3% hydrogen gas (H2) or vehicle for 60 days. Cognitive behaviors were evaluated using the Morris water maze and Y-maze tests. In addition, we used biochemical assays to measure ammonia and hydrogen peroxide (H2O2) levels in the hippocampi of the mice and AβO-treated primary mouse astrocytes. Aβ, γ-aminobutyric acid (GABA), and the expression of inflammatory markers were evaluated using immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). We observed that H2 treatment significantly prevented cognitive deficits, oxidative stress, the accumulation of toxic metabolites, and the increase in inflammatory markers in 5xFAD mice. These results suggest that H2 therapy can mitigate toxic metabolites in the astrocytic urea cycle, thereby reducing neurodegeneration and memory loss in AD.}, } @article {pmid40725005, year = {2025}, author = {Heller, E and McGurran, L and Brown, JK and Love, K and Hobbs, M and Kim-Han, JS and Han, BH}, title = {Aβ40 Improves Cerebrovascular Endothelial Function via NOX4-Dependent Hydrogen Peroxide Release.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40725005}, issn = {1422-0067}, support = {851-075//A.T. Still University/ ; }, mesh = {*NADPH Oxidase 4/metabolism ; Animals ; *Hydrogen Peroxide/metabolism ; *Amyloid beta-Peptides/pharmacology/metabolism ; Mice ; *Endothelial Cells/metabolism/drug effects ; *Peptide Fragments/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Cell Line ; Nitric Oxide/metabolism ; Brain/metabolism/blood supply ; Alzheimer Disease/metabolism ; Cell Survival/drug effects ; }, abstract = {Alzheimer's disease (AD) is associated with an abnormal accumulation of amyloid β (Aβ) fibrils in the brain parenchyma and cerebrovasculature, which leads to cognitive impairment and cerebrovascular dysfunction. Cerebrovascular endothelial cells play a crucial role in regulating cerebral blood flow, vascular permeability, and neurovascular function. Reactive oxygen species (ROS), particularly those generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), contribute to vascular dysfunction and amyloid deposition in the Alzheimer's disease (AD) brain. However, the role of the NOX4 isoform in AD pathogenesis remains to be examined. In the present study, we found that NOX4 among the NOX isoforms is predominantly expressed in bEnd.3 mouse brain endothelial cells. Treatment with Aβ40 significantly enhanced the release of H2O2 and NO, and increased the endothelial cell viability. To test the involvement of NOX4 in Aβ40-induced H2O2 production, we utilized pharmacological inhibitors of NOX isoforms. Aβ40-induced H2O2 production was attenuated in the presence of the pan-NOX inhibitor, apocynin, or the NOX1/4-selective inhibitors, setanaxib and GKT136901. Since only the NOX4 isoform is expressed in bEnd.3 cells, these results indicate that NOX4 is responsible for the release of H2O2 stimulated by Aβ40. Taken together, the present study demonstrated that Aβ40 peptide exerts beneficial effects in bEnd.3 endothelial cells via the NOX4-dependent mechanism.}, } @article {pmid40724974, year = {2025}, author = {Gagliardi, S and Hotchkin, T and Hillmer, G and Engelbride, M and Diggs, A and Tibebe, H and Izumi, C and Sullivan, C and Cropp, C and Lantz, O and Marquez, D and Chang, J and Ezaki, J and Zestos, AG and Riley, AL and Izumi, T}, title = {Oxidative Stress in HIV-Associated Neurodegeneration: Mechanisms of Pathogenesis and Therapeutic Targets.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40724974}, issn = {1422-0067}, support = {R41 NS113702/NS/NINDS NIH HHS/United States ; R41 MH139088/MH/NIMH NIH HHS/United States ; 7R15AI172610-02/NH/NIH HHS/United States ; R15 AI172610/AI/NIAID NIH HHS/United States ; P30AI117970//DC CFAR/ ; }, mesh = {Humans ; *Oxidative Stress/drug effects ; *HIV Infections/complications/metabolism/drug therapy/virology ; Reactive Oxygen Species/metabolism ; *Neurodegenerative Diseases/metabolism/etiology/drug therapy ; Animals ; *AIDS Dementia Complex/metabolism/drug therapy ; Antioxidants/therapeutic use ; }, abstract = {Treatment for HIV infection has become more manageable due to advances in combination antiretroviral therapy (cART). However, HIV still significantly affects the central nervous system (CNS) in infected individuals, even with effective plasma viral suppression, due to persistent viral reservoirs and chronic neuroinflammation. This ongoing inflammation contributes to the development of HIV-associated neurocognitive disorders (HANDs), including dementia and Alzheimer's disease-like pathology. These complications are particularly prevalent among the aging population with HIV. This review aims to provide a comprehensive overview of HAND, with a focus on the contribution of oxidative stress induced by HIV-mediated reactive oxygen species (ROS) production through viral proteins such as gp120, Tat, Nef, Vpr, and reverse transcriptase. In addition, we discuss current and emerging therapeutic interventions targeting HAND, including antioxidant strategies and poly (ADP-ribose) polymerase (PARP) inhibitors. These are potential adjunctive approaches to mitigate neuroinflammation and oxidative damage in the CNS.}, } @article {pmid40724820, year = {2025}, author = {Tomaszewska-Zaremba, D and Gajewska, A and Misztal, T}, title = {Anti-Inflammatory Effects of Cannabinoids in Therapy of Neurodegenerative Disorders and Inflammatory Diseases of the CNS.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40724820}, issn = {1422-0067}, mesh = {Humans ; *Cannabinoids/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Animals ; *Inflammation/drug therapy ; Central Nervous System/drug effects ; *Central Nervous System Diseases/drug therapy ; }, abstract = {Many neurodegenerative diseases are associated with immune system disorders, while neurodegenerative processes often occur in inflammatory conditions of the Central Nervous System (CNS). Cannabinoids exhibit significant therapeutic potential due to their dual ability to modulate both neural and immune functions. These compounds have a broad spectrum of action, allowing them to target multiple pathological mechanisms underlying neurodegenerative and inflammatory CNS diseases. The present review outlines the therapeutic potential of cannabinoids, with a focus on their anti-inflammatory properties, in the treatment of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, as well as inflammatory CNS disorders like multiple sclerosis and HIV-associated dementia.}, } @article {pmid40724803, year = {2025}, author = {Ivanova, P and Kortenska, L and Angelova, VT and Tchekalarova, J}, title = {The Novel Melatonin Analog Containing Donepezil Fragment Prevents Cognitive Impairments and Associated Oxidative Stress in a Hybrid Rat Model of Melatonin Deficiency and icvAβ1-42.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40724803}, issn = {1422-0067}, support = {grant number KP-06-N63/11; 14.12.2022 and IC-SK/03/2025-2026.//the Bulgarian National Science Fund, Bulgarian Academy of Sciences/ ; }, mesh = {Animals ; *Melatonin/analogs & derivatives/pharmacology ; *Donepezil/chemistry/pharmacology ; *Oxidative Stress/drug effects ; Rats ; *Amyloid beta-Peptides/toxicity ; *Cognitive Dysfunction/drug therapy/metabolism/prevention & control ; *Peptide Fragments ; Male ; Disease Models, Animal ; Alzheimer Disease/drug therapy/metabolism ; Hippocampus/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia in older adults and is becoming a major public health crisis as life expectancy increases worldwide. A major contributor to this disease is a deficiency in melatonin signaling. We have recently synthesised a series of melatonin analogs containing donepezil fragments. These compounds have been tested both in silico and in vitro. In this study, a particularly potent compound, 3a, was evaluated in a hybrid rat model of melatonin deficiency and AD. Rats underwent pinealectomy followed one week later by bilateral intracerebroventricular infusion of Aβ1-42 (1 µg/µL). A 14-day subchronic treatment with compound 3a was started simultaneously with the neurotoxin infusion. Melatonin was used as a reference drug, while a matched sham group received vehicle treatment. One week after the Aβ1-42 infusion, the rats' cognitive functions were assessed using two Y-maze protocols, object recognition and object location tests. Markers of oxidative stress, including hippocampal glutathione, superoxide dismutase, and malondialdehyde, were assessed by ELISA. Compound 3a effectively prevented cognitive impairment induced by the AD model, and its effects were comparable to those of melatonin. In addition, this melatonin analogue with a donepezil fragment reduced AD-associated oxidative stress and suppressed model-associated increased Aβ1-42 levels in the hippocampus. Our findings suggest that melatonin analogs containing donepezil fragments are promising therapeutic options for targeting oxidative stress associated with AD.}, } @article {pmid40723783, year = {2025}, author = {Muñoz de León-López, CA and Navarro-Lobato, I and Khan, ZU}, title = {The Role of Astrocytes in Synaptic Dysfunction and Memory Deficits in Alzheimer's Disease.}, journal = {Biomolecules}, volume = {15}, number = {7}, pages = {}, pmid = {40723783}, issn = {2218-273X}, support = {PID2022-136954OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PROYEXCEL-00422//Junta de Andalucía/ ; CTS-586-G-FEDER//Fondo Europeo de Desarrollo Regional/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology/physiopathology ; *Astrocytes/metabolism/pathology ; Humans ; *Synapses/metabolism/pathology ; Animals ; *Memory Disorders/metabolism/pathology ; Neuronal Plasticity ; Synaptic Transmission ; Amyloid beta-Peptides/metabolism ; }, abstract = {Astrocytes are the most abundant glial cells in the brain. They play critical roles in synapse formation and function, neurotransmitter release and uptake, the production of trophic factors, and energy supply for neuronal survival. In addition to producing proteases for amyloid-β degradation, astrocytes express various receptors, transporters, gliotransmitters, and other molecules that enable them to sense and respond to external signals. They are also implicated in amyloid-β clearance. In Alzheimer's disease, excessive accumulation of amyloid-β induces the polarization of astrocytes into the A1 phenotype, promoting the release of inflammatory cytokines and mitochondrial reactive oxygen species, leading to alterations in astrocytic functions. Under such conditions, gliotransmitter release, glutamate neurotransmission, AMPA receptor trafficking, and both Hebbian and non-Hebbian forms of synaptic plasticity-biological activities essential for synaptic functions-are compromised. Moreover, astrocytes are essential for learning, memory, and synaptic plasticity, and alterations in their function are associated with memory deficits in Alzheimer's disease. This review provides an overview of the current understanding of the defects in astrocytes that lead to altered synaptic functions, neuronal structural plasticity, and memory deficits in Alzheimer's disease.}, } @article {pmid40722053, year = {2025}, author = {Rajan, R and Singh, M and Suzuki, K and Matsumura, K}, title = {Design of Zwitterionic Conjugated Polymers as Protein Aggregation Inhibitors.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {41}, number = {31}, pages = {20623-20630}, doi = {10.1021/acs.langmuir.5c02043}, pmid = {40722053}, issn = {1520-5827}, mesh = {*Protein Aggregates/drug effects ; *Amyloid beta-Peptides/chemistry/antagonists & inhibitors/metabolism ; *Polyethylene Glycols/chemistry/pharmacology ; *Peptide Fragments/chemistry/antagonists & inhibitors ; *Polymers/chemistry/pharmacology ; Humans ; Betaine/analogs & derivatives ; }, abstract = {Protein aggregation and misfolding is the root cause of several neurodegenerative diseases, including Alzheimer's disease, and can be mitigated using small molecules, peptides, and conjugated or zwitterionic polymers. However, polymers that are both conjugated and zwitterionic have not been evaluated as protein aggregation/misfolding inhibitors. Herein, to bridge this gap, we prepare polymers with a conjugated backbone bearing zwitterionic sulfobetaine moieties and poly(ethylene glycol) chains and examine their abilities to inhibit protein aggregation. These polymers not only strongly inhibit the aggregation of amyloid β peptide (Aβ42) and other proteins but also actively disrupt and solubilize pre-established amyloid fibrils. This dual functionality enables almost complete fibril disaggregation at concentrations lower than those required for existing alternatives and results in protective capability extension across a broad spectrum of proteins. The results open new avenues for advancing neurodegenerative disease treatment strategies and represent considerable progress in the development of biomedical materials.}, } @article {pmid40722027, year = {2025}, author = {Hua, Z and Zhou, N and Zhou, Z and Fu, Z and Guo, R and Akogo, HY and Yang, J and Yu, M and Jiang, Y and Lan, S and Chang, H and Ma, J and Cui, H}, title = {Intranasal administration of stem cell derivatives for the treatment of AD animal models: a systematic review and meta-analysis.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {409}, pmid = {40722027}, issn = {1757-6512}, support = {H2021206321//Natural Science Foundation of Hebei Province/ ; }, abstract = {BACKGROUND: Alzheimer’s disease (AD) is a neurodegenerative disorder with increasing prevalence and limited efficacy of current therapies. Stem cell-derived therapies have attracted attention for their potential neurodegenerative and reparative effects. Intranasal administration provides a non-invasive route that bypasses the blood-brain barrier and delivers stem cell derivatives directly to the brain. Although studies have shown that the intranasal administration of stem cell derivatives alleviates symptoms in animal models of AD, a comprehensive meta-analysis evaluating their therapeutic efficacy is yet to be conducted. This study aims to evaluate the efficacy of intranasal stem cell derivatives therapies in AD animal models and provide a foundation for clinical translation. METHODS: We conducted a systematic literature search across four databases (Pubmed, Embase, Web of Science and Cochrane Library) using subject terms and complementary keywords. After applying inclusion and exclusion criteria, data were extracted using Origin 2024 software and analysed using Review Mange 5.4. The SYRCLE tool was applied to assess study quality and evaluate the potential risk of bias systematically. RESULTS: This meta-analysis of 14 studies investigated the efficacy of intranasal stem cell-derived therapies in animal models of Alzheimer’s disease (AD). Using predominantly mouse and rat models from diverse geographical locations and employing various stem cell types (bone marrow, umbilical cord blood, adipose tissue, hiPSCs), the analysis revealed a significant reduction in amyloid-beta (Aβ) deposition (SMD = -2.69, p < 0.0001). Subgroup analyses indicated that stem cell source, stem cell derivative types and Aβ detection method were not primary drivers of heterogeneity. Furthermore, treatment significantly reduced inflammatory markers IL-1β (SMD = -0.92, p = 0.008) and IBA-1 (SMD = -1.68, p = 0.006), suggesting an anti-inflammatory effect. Auxiliary outcomes CD68 and GFAP also exhibited decreased expression levels. Improved cognitive function was evident, as measured by increased target quadrant dwell time (MD = 10.17, p < 0.00001) and decreased escape latency (MD = -15.74, p = 0.003) in behavioral experiments, and enhanced recognition in the Novel Object Recognition Test (NORT) (SMD = 1.10, p = 0.006). Nissl staining demonstrated a significant reduction in neuronal cell death (SMD=-3.33,p < 0.00001),suggesting a role in neuronal repair.Together, these findings support the potential of intranasal stem cell-derived therapies to improve Alzheimer’s disease pathology, neuronal repair, and cognition in animal models. CONCLUSION: Intranasal administration of stem cell derivatives has demonstrated efficacy in Alzheimer’s disease (AD) animal models, leading to reductions in amyloid-beta (Aβ) deposition, cognitive improvement, repair neurons and attenuation of inflammatory responses. However, limitations such as potential publication bias and heterogeneity among existing studies are noted. Due to insufficient data and study limitations, additional preclinical and clinical trials are required to confirm these results and explore the therapy’s long-term safety and efficacy. GRAPHICAL ABSTRACT: [Image: see text]}, } @article {pmid40716511, year = {2025}, author = {Feng, NN and Li, L and Liu, LZ and He, RB and Xian, XH and Liu, LR and Hu, YY and Li, WB}, title = {Ceftriaxone ameliorates tau phosphorylation and mislocalization in APP/PS1 AD mice by inhibiting endoplasmic reticulum stress.}, journal = {Neuropharmacology}, volume = {279}, number = {}, pages = {110600}, doi = {10.1016/j.neuropharm.2025.110600}, pmid = {40716511}, issn = {1873-7064}, mesh = {Animals ; *tau Proteins/metabolism ; *Endoplasmic Reticulum Stress/drug effects ; Phosphorylation/drug effects ; Mice ; Hippocampus/drug effects/metabolism ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; *Alzheimer Disease/metabolism/drug therapy ; *Ceftriaxone/pharmacology ; Mice, Inbred C57BL ; Presenilin-1/genetics ; Male ; Disease Models, Animal ; Glycogen Synthase Kinase 3 beta/metabolism ; *Neuroprotective Agents/pharmacology ; Synaptosomes/drug effects/metabolism ; }, abstract = {Tau phosphorylation and mislocalization are hallmark pathological features of Alzheimer's disease (AD), with endoplasmic reticulum stress (ERS) contributing to tauopathy. We previously showed that ceftriaxone (Cef) improves cognition in APP/PS1 AD mice through regulating GLT-1-mediated glutamate homeostasis. Here, we examined Cef's neuroprotection against ERS-related tauopathy. C57BL/6J and APP/PS1 AD mice were used. Cognitive functions were assessed by new object recognition (NOR), new location recognition (NLR) and Morris water maze (MWM) tests. Hippocampal synaptosomes were isolated using the Syn-PER™ Synaptic Protein Extraction Kit. Western blot analysis evaluates the protein levels of ERS markers, total and phosphorylated tau (Ser396/Ser262/Thr181), and Gsk3β. Transmission electron microscopy examined the endoplasmic reticulum ultrastructural changes of the hippocampus. Confocal 3D-reconstructed imaging assessed the phosphorylated tau (Ser396) distribution on the dendrites in the hippocampal region. The results showed that Cef treatment effectively reduced protein levels of ERS markers and restored endoplasmic reticulum ultrastructural integrity of hippocampus. Simultaneously, Cef treatment significantly alleviated tau phosphorylation levels, decreased accumulation of total and phosphorylated tau in synaptosomes, reduced phosphorylated tau (Ser396) distribution in dendritic compartments and inhibited Gsk3β activity in the hippocampus of APP/PS1 AD mice. Tunicamycin, a promoter of ERS, exacerbated cognitive impairments, tau phosphorylation levels and mislocalization, and Gsk3β activity, and notably, this exacerbation was inhibited by Cef treatment. Simultaneously, the ERS activation significantly inhibited Cef's above benefits on APP/PS1 AD mice. In conclusion, Cef improves cognitive impairment by alleviating ERS, decreasing Gsk3β activity, and reducing tau phosphorylation and mislocalization in the hippocampus of APP/PS1 AD mice.}, } @article {pmid40715899, year = {2025}, author = {Suk-In, N and Promphet, N and Rodthongkum, N and Ummartyotin, S}, title = {Cellulose nanocrystals from waste cotton fabric and polyvinyl alcohol composite hydrogel for non-invasive colorimetric sensing of cysteine.}, journal = {Mikrochimica acta}, volume = {192}, number = {8}, pages = {526}, pmid = {40715899}, issn = {1436-5073}, mesh = {*Cysteine/urine/analysis ; *Colorimetry/methods ; *Cellulose/chemistry ; *Polyvinyl Alcohol/chemistry ; *Cotton Fiber ; *Nanoparticles/chemistry ; Humans ; Limit of Detection ; *Hydrogels/chemistry ; Copper/chemistry ; }, abstract = {Cellulose nanocrystals (CNCs) were successfully extracted and purified from cotton fabric waste via alkali treatment and acid hydrolysis. The resulting nanostructure was characterized using transmission electron microscopy (TEM) and X-ray diffraction spectroscopy (XRD), confirming the successful isolation of CNCs. A PV/Cu[2+]-CNCs/CNFs/PVA hydrogel was then synthesized through chemical crosslinking of polyvinyl alcohol (PVA), cellulose nanofibrils (CNFs), cellulose nanocrystals (CNCs), and borax. The incorporation of CNCs as a reinforcing agent significantly enhanced the hydrogel's surface area and water absorption capacity, leading to a substantial improvement in the colorimetric sensitivity of the sensor. This hydrogel was employed as a non-invasive colorimetric sensor for urinary cysteine detection, utilizing an indicator-displacement assay (IDA) with pyrocatechol violet/copper ion (PV/Cu[2+]) as the indicator. Upon exposure to cysteine, the sensor exhibited a distinct color change from greenish-blue to orange-red. The sensor demonstrated a linear detection range of 0-0.6 g/L and a limit of detection (LOD) of 0.017 g/L, effectively encompassing the clinical cut-off level for cysteine in human urine (0.25 g/L), relevant for Alzheimer's disease indication. Eventually, this sensor was validated for cysteine determination in artificial urine samples, confirming its practical applicability.}, } @article {pmid40720733, year = {2025}, author = {Li, W and Zha, X and Zhang, X and Dai, H and Pu, S and Yao, X and Hui, W and Xu, R and Bao, J and Yu, J and Wei, Y and Huang, J and Guo, N and Xu, M and Zhao, J and Cheng, B and Luo, Z}, title = {Enhanced Positron Emission Tomography Imaging of β-Amyloid through Focused Ultrasound-Mediated Gallium-68 Radiotracer Delivery across the Blood-Brain Barrier.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {15}, pages = {3070-3081}, doi = {10.1021/acschemneuro.5c00476}, pmid = {40720733}, issn = {1948-7193}, mesh = {Animals ; *Blood-Brain Barrier/metabolism/diagnostic imaging ; *Positron-Emission Tomography/methods ; *Gallium Radioisotopes ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Hippocampus/metabolism/diagnostic imaging ; Brain/metabolism/diagnostic imaging ; Radiopharmaceuticals ; }, abstract = {Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is an innovative approach for enhancing the delivery of central nervous system drugs. [68]Ga radiotracers are advantageous for imaging due to their ideal half-life and imaging properties; however, their limited ability to traverse the BBB constrains their application in brain imaging. This study investigates the application of FUS to selectively deliver the [68]Ga radiotracer, [[68]Ga]STZL4110, into the hippocampus for β-amyloid positron emission tomography (PET) imaging in an Alzheimer's disease (AD) mouse model. The synthesis and radiolabeling of [[68]Ga]STZL4110 were accomplished, demonstrating robust binding to β-amyloid, as validated by Thioflavin T assays and in vitro autoradiography with both wild-type (WT) and APP/PS1 AD mouse brain sections. Cavitation activity measurements confirmed effective and consistent BBB opening post-FUS treatment, ensuring targeted delivery without vascular damage, as supported by histological analysis. Quantitative PET imaging revealed the successful detection of β-amyloid deposition following FUS treatment. Initially, [[68]Ga]STZL4110 showed a low volume of distribution in the right hippocampus of AD mice. FUS application significantly enhanced BBB permeability, leading to a 74% increase in [[68]Ga]STZL4110 uptake in the targeted right hippocampus of APP/PS1 mice compared with the left hippocampus, whereas no significant change was observed in WT mice. These findings suggest that combining FUS with [[68]Ga]STZL4110 could significantly enhance the sensitivity and specificity of [68]Ga PET imaging for β-amyloid. FUS-mediated PET imaging may potentially address the challenge of effective brain imaging with radiotracers that traditionally exhibit a low penetration of the BBB.}, } @article {pmid40720390, year = {2025}, author = {Hwang, J and Choi, J and Cha, SY and Lee, IS and Yoon, JH and Jung, DJ and Lee, CW and Kim, SR and Lee, JH and Jeon, B and Park, JH and Maeng, S and Park, H}, title = {Memory improving effect of silkworm larva on insulin resistance related cognitive impairment model.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0328847}, pmid = {40720390}, issn = {1932-6203}, mesh = {Animals ; *Bombyx/chemistry ; *Insulin Resistance ; Larva/chemistry ; *Cognitive Dysfunction/drug therapy/physiopathology ; Disease Models, Animal ; Male ; Hippocampus/drug effects/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; *Memory/drug effects ; Rats ; Blood Glucose/metabolism ; Diet, High-Fat/adverse effects ; }, abstract = {Hongjam (HJ) is the steamed and freeze-dried powder of larva-stage silkworm (Bombyx mori) rich in protein, unsaturated fatty acids, and minerals. Silkworm products have traditionally been used for medical purposes, and their effectiveness in diabetic and neurodegenerative diseases has been studied. In particular, the anti-inflammatory-antioxidant, blood sugar-lowering, and neuroprotective effects are expected to be useful for the prevention and treatment of dementia, especially in a model of dementia related to insulin resistance. Most animal models of Alzheimer's disease (AD) are based on genetic factors and research based on these models does not explain the pathophysiology of sporadic AD. Therefore, no drug can effectively delay the progression of AD. We hypothesized that HJ may improve cognitive function in an insulin resistance model which is considered one of the causes of sporadic AD. Insulin resistance was induced by a high-fat diet and streptozotocin injection. Additionally, the effect of HJ was tested in in vitro cultured hippocampal slices treated with an N-methyl-D-aspartate antagonist. At the given dose, HJ did not affect on the body weight but lowered blood glucose concentration, improved spatial memory in the Morris water maze and avoidance memory in the passive avoidance tests which was related to hippocampal brain-derived neurotrophic factor. In hippocampal slices, HJ strengthened long-term potentiation, which was suppressed by AP5. Thus, HJ improved cognitive functions in an insulin-resistance related dementia model and may be useful in treating sporadic AD.}, } @article {pmid40720331, year = {2025}, author = {Royall, DR and Palmer, RF}, title = {Affliction class moderates the dementing impact of amyloidopathy.}, journal = {Neuropsychology}, volume = {39}, number = {7}, pages = {587-598}, pmid = {40720331}, issn = {1931-1559}, support = {R01 AG080548/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; //Julia and Van Buren Parr Endowment/ ; //National Institutes of Health; National Institute on Aging/ ; }, mesh = {Humans ; Positron-Emission Tomography ; Male ; Female ; Aged ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aged, 80 and over ; Severity of Illness Index ; Biomarkers ; Disease Progression ; Neuroimaging ; }, abstract = {OBJECTIVE: The treatment of dementia is increasingly likely to focus on dementia-related biomarkers. Unfortunately, there is variability with regard to biomarker-related effects. This analysis tests an algorithm capable of identifying persons adversely impacted by any dementia-related biomarker in this case, amyloidopathy as estimated by positron emission tomography (PET). METHOD: N = 1,737 subjects of the Alzheimer's disease neuroimaging initiative were assigned to amyloidopathy-affliction classes. Moderation effects were tested by chi-square difference. RESULTS: 39.3% of subjects with (+) PET results were assigned to the afflicted class. The afflicted subjects had greater dementia severity and higher amyloid burdens. These effects persisted at 36 months. Furthermore, the association between amyloid burden and dementia severity was moderated by affliction class. Afflicted nondemented cases with positive PET findings were more likely to convert to clinical "Alzheimer's disease" over 48 months, by Cox's F: F(312, 154) = 1.27, p = .05. PET assessed amyloid burden was not related to dementia severity in resilient PET (+) cases. CONCLUSION: Our approach could allow for more accurate prediction of biomarker effects and guide precision interventions against specific biomarkers. (PsycInfo Database Record (c) 2025 APA, all rights reserved).}, } @article {pmid40720180, year = {2025}, author = {Mehta, NV and Kapadia, A and Khambete, M and Abhyankar, A}, title = {The Evolution of AChE Inhibitors in Alzheimer's Disease: From Single-Target to Multi-Target Ligands.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {26}, number = {17}, pages = {e202500053}, doi = {10.1002/cbic.202500053}, pmid = {40720180}, issn = {1439-7633}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Ligands ; *Acetylcholinesterase/metabolism ; Blood-Brain Barrier/metabolism ; Animals ; }, abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disease marked by cognitive decline, neuronal degeneration, and the accumulation of intracellular neurofibrillary tangles, extracellular amyloid plaques, and neuroinflammation. Current treatment strategies, such as acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate receptor antagonists, offer symptomatic relief but fail to stop disease progression. The development of multi-target-directed ligands (MTDLs) has gained attention as a method to address the complex pathology of AD. This review provides a detailed account of the journey of AChE inhibitors from single-target ligands to MTDLs, emphasizing the structural changes that improve target specificity, blood-brain barrier penetration, and therapeutic impact. By exploring these advancements, the review highlights the potential of MTDLs to overcome the limitations of traditional single-target approaches and contribute to the discovery of more effective anti-Alzheimer therapies along with discussing potential pitfalls.}, } @article {pmid40720133, year = {2025}, author = {Zeltzer, E and Schonhaut, DR and Mundada, NS and Blazhenets, G and Soleimani-Meigooni, DN and Cho, H and Ranasinghe, KG and Windon, C and Yadollahikhales, G and Apgar, C and Gatsonis, C and Carrillo, MC and Hanna, L and Romanoff, J and Hillner, BE and Koeppe, RA and March, A and Siegel, BA and Smith, K and Whitmer, RA and Iaccarino, L and Rabinovici, GD and La Joie, R}, title = {Concordance Between Amyloid-PET Quantification and Real-World Visual Reads.}, journal = {JAMA neurology}, volume = {82}, number = {9}, pages = {952-962}, pmid = {40720133}, issn = {2168-6157}, support = {P30 AG062422/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Cross-Sectional Studies ; *Positron-Emission Tomography/methods/standards ; Female ; Aged ; Male ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; Aged, 80 and over ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aniline Compounds ; Radiopharmaceuticals ; *Brain/diagnostic imaging/metabolism ; }, abstract = {IMPORTANCE: With increased payer coverage and the advent of antiamyloid therapies, clinical use of amyloid positron emission tomography (PET) is likely to increase to help guide the diagnosis and treatment of patients with cognitive impairment. However, unlike most previous research studies, in clinical practice, scan acquisition is less standardized, interpretation typically relies purely on visual reads rather than scan quantification, and patients have more frequent comorbidities, all of which might compromise test accuracy. OBJECTIVE: To compare visual interpretation of amyloid-PET in real-world clinical settings to scan interpretation based on central quantification, in order to assess the accuracy of clinical reads. This cross-sectional quality improvement study used data from the Imaging Dementia-Evidence for Amyloid Scanning study, collected between February 2016 and January 2018 and analyzed between December 2021 and April 2023. The setting included 294 imaging facilities in the US. Medicare beneficiaries 65 years or older with cognitive decline for whom Alzheimer disease was a diagnostic consideration were recruited by dementia specialists from their clinical practices. EXPOSURES: Amyloid-PET with [18F]florbetapir, [18F]florbetaben, or [18F]flutemetamol. MAIN OUTCOMES AND MEASURES: PET scans were visually interpreted as positive or negative by local radiologists or nuclear medicine physicians following approved guidelines. Independently, scans were centrally processed and quantified using the standardized Centiloid (CL) scale. We applied an a priori autopsy-based threshold of 24.4 CL to quantitatively define scan positivity. RESULTS: Of 18 293 participants included in the parent study, scan images were available for 10 774 (59%), of which Centiloids were successfully calculated for 10 361 (96%). Median (IQR) patient age was 75 (71-80) years; 5245 patients (51%) were female, 6500 (63%) had mild cognitive impairment, and 3861 (37%) had dementia). Participants self-reported the following races and ethnicities: 1 Alaska Native (0%), 23 American Indian (0.2%), 188 Asian (1.8%), 316 Black (3.1%), 449 Hispanic or Latino (4.3%), 8 Native Hawaiian or Other Pacific Islander (0.1%), and 9125 White (88.2%). A total of 6332 scans (61%) were visually read as positive, and 6121 (59%) were quantitatively positive. Agreement between visual reads and quantitative classification was 86.3% (95% CI, 85.7%-87.0%; Cohen κ = 0.72; 95% CI, 0.70-0.73). A total of 5519 (53%) scans were positive visually and quantitatively (V+/Q+), 3416 (33%) were negative by both (V-/Q-), 813 (8%) were V+/Q-, and 602 (6%) were V-/Q+. Female sex (female: 4581/5241 [87.4%]; male: 4354/5109 [85.2%]; P =.001), White race (White race: 7900/9125 [86.6%]; non-White race: 1035/1225 [84.5%]; P =.046), and use of [18F]flutemetamol and [18F]florbetaben ([18F]flutemetamol: 559/628 [89.0%]; [18F]florbetaben: 2664/3032 [87.9%]; [18F]florbetapir: 5712/6690 [85.4%]; P <.001), compared with [18F]florbetapir, were associated with higher visual-quantitative concordance. Scans within a 10- to 40-CL borderline positivity zone were more likely to be discordant. CONCLUSIONS AND RELEVANCE: This cross-sectional study found high concordance between local visual reads and central quantification of clinical amyloid-PET scans, supporting the validity of amyloid-PET visual reads in real-world clinical practice.}, } @article {pmid40719892, year = {2025}, author = {Yu, Q and Li, L and Yu, S and Han, J and Cheng, Q and Cui, Z and Chen, H and Li, M and Lu, Z}, title = {Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.}, journal = {Neurochemical research}, volume = {50}, number = {4}, pages = {251}, pmid = {40719892}, issn = {1573-6903}, support = {tsqnz20240852//Taishan Scholars Program of Shandong Province/ ; 2022CXGC010507//Key Technology Research and Development Program of Shandong Province/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology/drug therapy ; Humans ; *Mitochondria/metabolism/pathology/drug effects ; *Autophagy/physiology/drug effects ; Animals ; Mitophagy/physiology/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive neurodegeneration and a variety of cognitive deficits. Of note, mitochondrial malfunctions occur early in the disease's development. Mitophagy impairment leads to the build-up of damaged mitochondria inside the cells, causing malfunction and eventual death of the cells. This review summarizes the mechanisms linking mitochondrial damage and autophagy dysregulation to AD and highlights potential therapeutic opportunities. We summarize how mitochondrial dysfunction contributes to AD, including defects in mitochondrial biogenesis, impaired dynamics, the impact of AD-related protein aggregates on mitochondrial integrity, and defective axonal transport. We also explore the roles of mitophagy in AD, including its function in the removal of harmed proteins and organelles. Finally, we highlight the therapeutic strategies for the treatment of AD, targeting molecular components involved in mitochondrial damage and autophagy dysregulation in AD, i.e., antioxidants, mitochondrial modulators, and mitophagy enhancers.}, } @article {pmid40719827, year = {2025}, author = {Yde Ohki, CM and Walter, NM and Smigielski, L and Bender, A and Rickli, M and Walitza, S and Grünblatt, E}, title = {Assessing the effects of methylphenidate in proliferation and Wnt activity of neuronal stem cells from attention deficit/hyperactivity disorder patients.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {40719827}, issn = {1435-1463}, abstract = {As the most common neurodevelopmental and mental disorder around the world, attention-deficit/hyperactivity disorder (ADHD) affects primarily children and adolescents. Both genetic (polygenicity) and environmental variables interplay in the etiology of this disorder. The Wnt signaling pathway, which regulates proliferation and differentiation during neurodevelopment, has been implicated in ADHD. Clinically, individuals with ADHD may exhibit delays in structural and functional brain development. Available evidence suggests that methylphenidate (MPH) treatment can potentially improve these delays. However, the molecular and cellular mechanisms underlying ADHD and the therapeutic targets of MPH are not yet completely elucidated. In a pilot investigation, the proliferation of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) was significantly lowered in ADHD male patients. Yet, we did not observe any variations in proliferation rates during the iPSC stage. To extend the earlier results, we increased the sample size to include females, explored whether MPH may improve NSC proliferation in ADHD and clarified the role of the Wnt pathway. To do so, iPSC and NSC proliferation from five ADHD patients and five controls was assessed. The results corroborated our previous findings of decreased proliferation in ADHD NSCs. Conversely, ADHD NSC proliferation was modestly regulated by MPH treatment at 10 nM, which also showed modulatory effects on Wnt signaling in this group. Interestingly, no increase in proliferation was seen when DKK1 blocked Wnt signaling before MPH treatment. These findings suggest MPH regulates the canonical Wnt pathway and may partially explain ADHD-related neurodevelopmental abnormalities and MPH-specific benefits.}, } @article {pmid40718958, year = {2025}, author = {Plantera, L and Immig, K and Fritsche, AK and Reinicke, M and Zemer, A and Monsonego, A and Ceglarek, U and Bechmann, I}, title = {Exploring the Impact of a High-Fat Diet on Brain Homeostasis: A Comprehensive Analysis of the Absence of Inflammation.}, journal = {Molecular nutrition & food research}, volume = {69}, number = {20}, pages = {e70168}, pmid = {40718958}, issn = {1613-4133}, mesh = {Animals ; *Diet, High-Fat/adverse effects ; Male ; Mice, Inbred C57BL ; Microglia/drug effects/metabolism ; *Brain/metabolism/drug effects ; Female ; *Homeostasis ; *Phytosterols/pharmacology ; Mice ; Inflammation ; Cytokines/metabolism ; Neuroinflammatory Diseases ; Weight Gain/drug effects ; Membrane Glycoproteins/metabolism ; Receptors, Immunologic ; }, abstract = {Excessive fat consumption increases the risk of Alzheimer's disease (AD), potentially through diet-induced neuroinflammation. Microglia, the brain's immune cells, are affected by obesity and diet. Phytosterols (PS), plant-derived cholesterol-like compounds, accumulate in the brain with age, and their content correlates with dietary intake. We hypothesize that the accumulation of PS modulates microglial activation and exerts anti-inflammatory effects. We investigated the effects of a normal diet (ND), high-fat diet (HFD), HFD with 2% PS (HFD+2% PS), and HFD with 4% PS (HFD+4% PS) on neuroinflammation in female and male C57BL/6J mice. Flow cytometry (FC) of microglia showed no significant regulation of pro- (IFN-γ, IL-1β, TNF-α) and anti-inflammatory (IL-10) cytokines due to diet, but sex- and age-dependent differences were observed. Immunofluorescence staining showed no TREM2 upregulation, indicating a lack of microglial activation in response to HFD. PS supplementation significantly reduced HFD-induced weight gain, suggesting metabolic effects. Contrary to existing research, we found no evidence of HFD-induced neuroinflammation or microglial activation. However, the reduction in weight gain with PS supplementation suggests potential metabolic benefits, which could have implications for the treatment of obesity. The potential effects on neuroinflammation remain unclear.}, } @article {pmid40718314, year = {2025}, author = {Auti, ST and Kulkarni, YA}, title = {Beneficial Effects of Caraway Oil in Aluminium Chloride-Induced Neurotoxicity.}, journal = {Cureus}, volume = {17}, number = {6}, pages = {e86783}, pmid = {40718314}, issn = {2168-8184}, abstract = {PURPOSE: Alzheimer's disease (AD) is characterized by cognitive decline and memory impairment, amyloid plaques, and neurofibrillary tangles (NFT). Current therapies provide symptomatic treatment but do not address the exact cause of the disease. Caraway oil, derived from Carum carvi, is rich in carvone and limonene with reported anticholinesterase, antioxidant, and neuroprotective properties. This study aimed to evaluate the neuroprotective effect of caraway oil in an aluminum chloride-induced rat model of neurotoxicity. METHODS: Albino Wistar rats were randomized into five groups: normal control, disease control (aluminum chloride, 100 mg/kg), standard (donepezil, 1 mg/kg), and caraway oil treatment groups (100 and 200 mg/kg). Treatments were administered orally for 42 days. Behavioral assessments included locomotor activity, the Morris water maze, the elevated plus maze, and passive avoidance tests. Acetylcholinesterase (AChE) activity and oxidative stress markers were assessed in the hippocampus and cortex. RESULTS: Caraway oil administration significantly improved locomotor activity and spatial memory in rats at 100 mg/kg and 200 mg/kg. The oil showed a significant effect on oxidative stress parameters in the hippocampus and cortex. AChE activity was also improved significantly (p<0.001) after caraway oil treatment. CONCLUSION: Caraway oil demonstrated significant neuroprotective effects in aluminum chloride-induced neurotoxicity, improving cognitive and behavioral functions and reducing oxidative stress. These findings suggest that caraway oil may have therapeutic potential in the management of AD.}, } @article {pmid40717971, year = {2025}, author = {Rong, Y and Li, Q and Du, Y and Wang, W and Su, W and Zhang, J and He, W}, title = {Preclinical evidence and potential mechanisms of tanshinone ⅡA on cognitive function in animal models of Alzheimer's disease: a systematic review and meta-analysis.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1603861}, pmid = {40717971}, issn = {1663-9812}, abstract = {BACKGROUND: Tanshinone ⅡA (Tan ⅡA) is a monomer extracted from Salvia miltiorrhiza Bunge. Animal studies have demonstrated its potential in providing cognitive protection in Alzheimer's disease (AD), but the overall effects remain inconclusive, and its multiple mechanisms have not been systematically summarized. OBJECTIVE: This systematic review and meta-analysis (SR/MA) aimed to evaluate the overall effects of Tan ⅡA on cognitive function in AD animal models and to summarize the mechanisms. METHODS: Seven databases (PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Chinese Biological Medical Disc, Chongqing VIP, and Wanfang databases) and grey literature were retrieved. Risk of bias was evaluated following the Systematic Review Center for Laboratory Animal Experiments. The mean difference (MD) or standard mean difference (SMD) with 95% confidence intervals (CIs) were used to evaluate the effect of Tan ⅡA on cognitive function, neuropathology, neuroinflammation, oxidative stress, apoptosis, and neural/synaptic plasticity, with P < 0.05 considered a significant difference. The effect and potential mechanisms of Tan ⅡA were demonstrated by performing multiple subgroup analyses. RESULTS: Nineteen studies involving 581 AD animals were identified. The included studies showed satisfactory reporting quality but had certain risks of bias in methodology. Tan ⅡA ameliorated cognitive deficits, evidenced by reducing escape latency (MD = -17.94 s; 95% CI: -22.92 to -12.96) and increasing time spent in the target quadrant (MD = 10.69 s; 95% CI: 7.32-14.07). It attenuated neuropathological damage by reducing amyloid-β (Aβ) plaques in thioflavine S staining (SMD = -3.46; 95% CI: -5.65 to -1.26) and increasing neuronal density in Nissl staining (SMD = 2.82; 95% CI: 2.11-3.52) and NeuN staining (SMD = 2.89; 95% CI: 1.71-4.08). Tan ⅡA also demonstrated anti-inflammatory effects through downregulation of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6)] and antioxidant stress properties by increasing superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels while reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Additionally, it exhibited antiapoptotic effects by increasing the B-cell lymphoma-2/Bcl-2-associated X protein (Bcl-2/Bax) ratio and decreasing Caspase-3 expression. Moreover, treatment improved neuronal/synaptic plasticity by upregulating postsynaptic density-95 (PSD-95) and brain-derived neurotrophic factor (BDNF) levels. CONCLUSION: Tan ⅡA could improve cognitive function and neuropathology through multiple mechanisms. This suggests that Tan IIA may serve as a viable candidate for the development of therapeutic strategies for AD. https://www.crd.york.ac.uk/PROSPERO/view/CRD42024588415.}, } @article {pmid40717894, year = {2025}, author = {Yu, M and Ma, H and Lai, X and Wu, J and Shen, M and Yan, J}, title = {Stem cell extracellular vesicles: a new dawn for anti-inflammatory treatment of neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1592578}, pmid = {40717894}, issn = {1663-4365}, abstract = {Mesenchymal stem cell-derived extracellular vesicles, as carriers for intercellular communication, are rich in bioactive substances such as proteins and nucleic acids, and show unique potential in the treatment of neurodegenerative diseases. Their vesicular structure, with a diameter of 30-150 nm, can penetrate the blood-brain barrier and modulate the activity of microglia and astrocytes by delivering functional molecules. This process inhibits the release of pro-inflammatory factors and enhances the expression of anti-inflammatory mediators, thereby alleviating neuroinflammation in the pathological process of neurodegenerative diseases. As natural drug carriers, extracellular vesicles can improve the targeted delivery efficiency of therapeutic molecules. However, their specific anti-inflammatory mechanisms remain not fully understood and require further exploration. This article discusses the anti-inflammatory effects in the context of neurodegenerative diseases and provides a summary and outlook on the anti-inflammatory actions associated with extracellular vesicles from past research.}, } @article {pmid40717814, year = {2025}, author = {Righes, G and Semenzato, L and Koutsikos, K and Zanato, V and Pinton, P and Giorgi, C and Patergnani, S}, title = {The role of autophagy in the pathogenesis and treatment of multiple sclerosis.}, journal = {Autophagy reports}, volume = {4}, number = {1}, pages = {2529196}, pmid = {40717814}, issn = {2769-4127}, abstract = {Autophagy is a crucial cellular process responsible for the degradation and recycling of damaged or unnecessary components, maintaining cellular homeostasis and protecting against stress. Dysregulation of autophagy has been implicated in a variety of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Various types of autophagy exist, each with distinct mechanisms, such as macroautophagy, mitophagy, lipophagy, and chaperone-mediated autophagy. These processes are essential for the removal of toxic substrates like protein aggregates and dysfunctional mitochondria, which are vital for neuronal health. In neurodegenerative diseases, the impairment of these clearance mechanisms leads to the accumulation of harmful substances, which accelerate disease progression. Modulating autophagy has emerged as a promising therapeutic strategy, with ongoing studies investigating molecules that can either stimulate or regulate this process. However, despite its potential, significant challenges remain in translating preclinical findings into clinically effective treatments. In this review, we will explore the different types of autophagy, their roles in neurodegenerative diseases, and the therapeutic potential associated with modulating these processes.}, } @article {pmid40717739, year = {2025}, author = {Kenaan, N and Alshehabi, Z}, title = {A review on recent advances in Alzheimer's disease: The role of synaptic plasticity.}, journal = {AIMS neuroscience}, volume = {12}, number = {2}, pages = {75-94}, pmid = {40717739}, issn = {2373-7972}, abstract = {Alzheimer's Disease (AD) remains a significant global health challenge, characterized by progressive neurodegeneration and a decline in cognitive abilities such as memory and learning. Despite being the main cause of dementia worldwide, the precise mechanisms that underlie neuronal dysfunction and synaptic plasticity impairment in AD remain elusive. However, while genetic mutations, dietary factors, and immune dysregulation are implicated in AD pathogenesis, the current therapeutic approaches are largely centered around acetylcholinesterase inhibitors (AChEIs). Nevertheless, this cholinergic hypothesis of AD is no longer satisfactory in describing this disease and has demonstrated a limited efficacy. Hence, new treatment approaches should be developed, and that requires us to view AD from a new perspective. Herein, in our review, we present the latest studies that discussed possible AD pathologies and pharmacotherapies. Additionally, we highlight that the emerging treatments that precisely targets brain regions associated with enhancing neuroplasticity have delivered promising results and seem to be more effective than older treatments. Finally, by viewing AD as a complex interplay of various factors that ultimately cause synaptic dysfunction and cognitive decline, we can develop more effective therapeutic interventions and ultimately alleviate the significant burden of this debilitating disease for both patients and their families.}, } @article {pmid40717666, year = {2025}, author = {Nakamura, Y and Adachi, J and Hirota, N and Iba, K and Sasajima, C and Shimizu, K and Nakai, M and Takahashi, K}, title = {Brexpiprazole's impacts on patients and caregivers in agitation in Alzheimer's dementia.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70522}, pmid = {40717666}, issn = {1552-5279}, support = {//Otsuka Pharmaceutical Co., Ltd/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/complications/psychology ; *Caregivers/psychology ; Male ; Female ; Double-Blind Method ; *Psychomotor Agitation/drug therapy/etiology ; Aged ; *Thiophenes/therapeutic use ; *Quinolones/therapeutic use ; Aged, 80 and over ; Treatment Outcome ; Middle Aged ; Neuropsychological Tests ; Japan ; }, abstract = {INTRODUCTION: We evaluated the impacts of brexpiprazole treatment on patient neuropsychiatric symptoms and caregiver distress in Japanese patients with agitation in Alzheimer's dementia (AAD). METHODS: In a phase 2/3 multicenter, double-blind study, patients were randomized to receive brexpiprazole 1 or 2 mg/day, or placebo (3:4:4) for 10 weeks. The Neuropsychiatric Inventory (NPI) was used for evaluation. The areas of patient symptoms and caregiver distress were defined as NPI and NPI-Distress, respectively. RESULTS: At Week 10, the differences of brexpiprazole 1 and 2 mg versus placebo for NPI total score were -1.2 (p = 0.5891) and -8.4 (p < 0.0001), and those for NPI-Distress total score were -1.1 (p = 0.2292) and -3.9 (p < 0.0001), respectively. In brexpiprazole 2 mg versus placebo, NPI and NPI-Distress agitation/aggression score showed ≥ 2 and ≥ 1 point improvement, respectively. DISCUSSION: Brexpiprazole is suggested to improve patient symptoms and to reduce caregiver distress in the treatment of AAD in Japanese patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03620981 HIGHLIGHTS: Brexpiprazole improved symptoms of patients with agitation in Alzheimer's dementia. The improvements included not only agitation, but also various behavioral and psychological symptoms of dementia scores. The improvements of patient symptoms led to the reduction of caregiver distress. Our study suggests that brexpiprazole is beneficial for both patients and caregivers.}, } @article {pmid40717576, year = {2026}, author = {Liu, Y and Sun, Y and Zhao, P and Liu, Z and Wang, Y and Wang, Y and Zhao, R and Wang, C and Wang, S}, title = {Near-Infrared Fluorescent Probe for the Early Diagnosis of Alzheimer's Disease.}, journal = {Medicinal research reviews}, volume = {46}, number = {1}, pages = {5-39}, doi = {10.1002/med.70000}, pmid = {40717576}, issn = {1098-1128}, support = {//We sincerely thank the Key R&D Program of Gansu Province, under Grant No.24YFWA010; the Talent Innovation and Entrepreneurship Project of Lanzhou City, under Grant No. 2020-RC-43; the Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital, under Grant No. CY2024-MS-A15 and No. CY2024-MS-B17; the Inner Mongolia Science and Technology Plan Project, under Grant No. 2021GG0339./ ; }, mesh = {*Alzheimer Disease/diagnosis/metabolism/diagnostic imaging ; Humans ; *Fluorescent Dyes/chemistry ; Early Diagnosis ; Animals ; Biomarkers/metabolism ; Spectroscopy, Near-Infrared/methods ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a common progressive neurodegenerative disease characterized by abnormal deposition of amyloid-β protein (Aβ) and the formation of neurofibrillary tangles (NFT). Although there are drugs available for clinical treatment, they do not fundamentally cure AD, so early diagnosis and intervention for AD are essential. In recent years, near-infrared fluorescent (NIRF) probes have been widely used in diagnosing AD due to their advantages of high tissue penetration, low autofluorescence interference, and non-invasiveness. This paper reviewed the recent progress of NIRF probes in AD. We described the effects of NIRF probes on AD biomarkers, including Aβ protein, Tau tangles, mitochondrial viscosity, reactive oxygen species, copper ions, zinc ions, and so on. In detail, we also described the optical properties, in vitro detection, and in vivo imaging of NIRF probes based on different dyes and their derivatives, such as curcumin, Boron dipyrromethene, Quinoline, and Donor-Acceptor. Despite significant progress, NIRF probes remain challenging in imaging and treating AD in vivo. Their selectivity and sensitivity need to be improved due to the complex structure of brain tissue and interfering factors. In conclusion, studying NIRF probes provides us with new ideas. Through further optimization, these probes may be used for early diagnosis and treatment detection of AD to better cope with the challenges brought by AD.}, } @article {pmid40717475, year = {2025}, author = {Hsiao, CH and Wu, CE and Wang, CM and Lin, TY and Wu, RY and Wu, MJ and Lin, SH and Sung, PS}, title = {Intracerebral hemorrhage risk in Alzheimer's disease patients on anticoagulants: A nationwide cohort study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {769-777}, doi = {10.1177/13872877251362362}, pmid = {40717475}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/epidemiology/drug therapy/complications ; Female ; Male ; *Cerebral Hemorrhage/epidemiology/chemically induced ; Aged ; Taiwan/epidemiology ; *Anticoagulants/adverse effects/therapeutic use ; Cohort Studies ; Aged, 80 and over ; Risk Factors ; Incidence ; Middle Aged ; Databases, Factual ; }, abstract = {BackgroundThe risk of intracerebral hemorrhage (ICH) in Alzheimer's disease (AD) patients undergoing anticoagulation (AC) remains unclear.ObjectiveThis nationwide cohort study assessed ICH risk in AC-treated AD patients.MethodsUsing Taiwan's National Health Insurance Research Database, we identified 1638 AC-treated AD patients and established four matched cohorts: AD with AC, AD without AC, non-AD with AC, and non-AD without AC. We applied inverse probability of treatment weighting (IPTW) and competing risks regression (CRR) to adjust for confounders and mortality risk. Cox proportional hazards regression estimated ICH risk.ResultsThe ICH incidence per 100 person-years was 2.21 in AD patients with AC, 1.03 without AC, 1.71 in non-AD with AC, and 0.28 in non-AD without AC. After IPTW adjustment, compared to non-AD without AC, AD patients with AC had the highest ICH risk (aHR 1.94, 95% CI: 1.44-2.61), followed by non-AD with AC (aHR 1.84, 95% CI: 1.51-2.23) and AD without AC (aHR 1.74, 95% CI: 1.42-2.11). ICH risk in AC-treated AD patients was comparable to non-AD with AC. Subgroup analysis showed higher ICH risk in females and those with hyperlipidemia, diabetes, heart failure, chronic kidney disease, or cancer.ConclusionsAD is associated with increased ICH risk, which is further elevated by AC use. These findings highlight the need for individualized risk-benefit evaluation, particularly in high-risk populations.}, } @article {pmid40717228, year = {2025}, author = {Gertz, MA and Aras, MA and Bart, N and Brannagan, TH and Griffin, JM and Kontorovich, AR and Rosen, AM}, title = {Unravelling the myriad physiologic roles of transthyretin: critical considerations for treating transthyretin amyloidosis.}, journal = {Annals of medicine}, volume = {57}, number = {1}, pages = {2536755}, pmid = {40717228}, issn = {1365-2060}, mesh = {Humans ; *Prealbumin/genetics/metabolism/physiology ; *Amyloid Neuropathies, Familial/therapy/genetics/physiopathology/drug therapy/metabolism ; Animals ; }, abstract = {BACKGROUND: Transthyretin (TTR) is a highly conserved protein with crucial and broadly protective physiologic roles across organ systems and diseases. Evidence shows that TTR contributes to neuroprotection, cognition, glucose regulation, pregnancy, muscle development, and bone mineralization. In several disease states, including diabetes, Alzheimer's disease, Lewy body dementia, cerebrovascular disease, and osteoporosis, higher TTR levels may be protective. Numerous studies have shown that low levels of TTR are associated with increased mortality overall and in relation to cardiovascular disease and several malignancies. PURPOSE: There is a growing portfolio of approved and investigational transthyretin amyloidosis (ATTR) treatments that differ in their mechanisms and effects on circulating TTR. When selecting an ATTR therapy, clinicians must decide whether to stabilize and preserve TTR and its functions or knockdown and drastically reduce TTR. This review summarizes the vital physiologic roles of TTR in health and disease. We consider the potential effects on normal biologic pathways that may occur while therapeutically suppressing TTR and discuss clinical decisions concerning ATTR therapies in the context of the summarized literature. DISCUSSION: TTR is essential for a broad range of physiologic processes and may confer clinically protective effects in neurologic and other organ systems. While a link between low TTR and severe disease and mortality is well established, it remains unclear whether long-term TTR suppression via ATTR therapies increases risk of disease. Clinical decisions in ATTR, however, should reflect the current understanding of the roles of TTR and the patient's clinical history. CONCLUSION: TTR serves vital physiologic roles across organ systems. Given its clinically protective properties, continued investigation into the potential long-term impact of TTR suppression via knockdown or gene editing therapies is prudent. ATTR treatment selection should reflect an awareness of the physiologic importance of TTR, as well as consideration of the potential long-term impact of chronic TTR suppression.}, } @article {pmid40715349, year = {2025}, author = {Ebrahimifar, A and Ahmadi, S and Rostamzadeh, J and Rahimi, K}, title = {Vanadyl sulfate restores memory impairment in streptozotocin-induced rat model of sporadic alzheimer's disease by repressing FoxO1 gene expression.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {27293}, pmid = {40715349}, issn = {2045-2322}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/genetics/metabolism ; Male ; Rats ; Streptozocin ; *Forkhead Box Protein O1/genetics/metabolism ; Rats, Wistar ; Disease Models, Animal ; Hippocampus/metabolism/drug effects ; *Memory Disorders/drug therapy ; *Gene Expression Regulation/drug effects ; HMGA1a Protein/genetics/metabolism ; Maze Learning/drug effects ; }, abstract = {Impaired brain insulin signaling is a risk factor for the pathogenesis of Alzheimer's disease (AD). FoxO1 and HMGA1 transcription factors are involved in the pathogenesis of both type 2 diabetes (T2D) and Alzheimer's disease (AD). This study aimed to assess the effect of vanadyl sulfate (VS) on impaired memory and hippocampal FoxO1 and HMGA1 RNA expression in sporadic AD (sAD) model in rats. Thirty-two male Wistar rats (250 ± 10 g) were divided into sham, AD, and VS 0.5 and 0.75 treated groups. The animals were subjected to two bilateral intracerebroventricular (icv) injections of either citrate buffer or streptozotocin (STZ) at 72-hour intervals. The VS-treated groups were treated with either 0.5 or 0.75 mg/ml oral VS for 3 weeks. The target quadrant entry latency, path length, and time and distance traveled in the target quadrants were assessed with the Morris water maze (MWM). Hippocampal tissues were analyzed for FoxO1 and HMGA1 RNA expressions. Group differences and group‒time interactions were analyzed via mixed two-way repeated-measures ANOVA. VS treatment in icv STZ rats restored impaired spatial memory. Hippocampal FOXO1 and HMGA1 RNA expressions were significantly lower in VS-treated and sham groups compared to AD control. VS can restore impaired spatial memory in sAD rats, possibly via the repression of FoxO1 and HMGA1 RNA expression in hippocampus.}, } @article {pmid40713860, year = {2025}, author = {Lancaster, TM and Murphy, K and Chandler, H}, title = {Reductions in brainstem volume as a key macrostructural indicator in at-risk populations for Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {177}, pmid = {40713860}, issn = {1758-9193}, support = {PNU-80762-CU-14//European Regional Development Fund/ ; 104943/Z/14/Z//Wellcome Trust/United Kingdom ; 104943/Z/14/Z//Wellcome Trust/United Kingdom ; WT224267//Wellcome/ ; WT224267//Wellcome/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/genetics ; *Brain Stem/pathology/diagnostic imaging ; Aged ; Male ; Female ; Magnetic Resonance Imaging ; Middle Aged ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Organ Size ; }, abstract = {BACKGROUND: Alterations to brain macrostructure, assessed via T1-weighted magnetic resonance imaging are observed in preclinical models of Alzheimer's disease (AD), reflecting susceptibility, prodromal stages of AD or correlates of early AD pathophysiology. While changes in cingulate and medial temporal lobe structures may be functionally implicated in cognitive decline, little is known about the viability of brain-based biomarkers that support autonomic functions implicated in preclinical AD risk such as the brainstem. METHODS: In a series of multiple linear regressions, we assess the volume of the brainstem in two asymptomatic at-AD-risk samples, assessed via the presence of either mild cognitive impairment (MCI, N = 148), or extremely high polygenic risk (N = 13) with matched demographics (mean age = 67 [range 58-76], in both cases). We further determine the strength of the association, compared to 150 other structural MRI features. RESULTS: We observed brainstem volume reductions (MCI: b = -0.29, P = 0.018; Genetic risk: b = -1.29, P = 0.002) in both samples. The magnitude of each preclinical AD marker (MCI / AD-polygenic risk)- brainstem association was empirically larger (Z > 2.3, P < 0.05, in both cases) than 150 frequently segmented MRI features. We further replicate the negative AD-polygenic risk score- brainstem association in UK Biobank (N = 31968; b = -0.002, P = 0.03), with weaker evidence that the association was larger than all other MRI features (Z = 1.622; P = 0.052). CONCLUSIONS: These observations suggest that AD risk, assessed via the presence of MCI or extremely high AD-polygenic risk score is linked to reduced brainstem volume before most typically observed morphological brain alterations. This conforms with evidence implicating the brainstem as one of the earliest sites of morphological neurodegeneration and provides a plausible biological mechanism linking prodromal autonomic symptoms to AD risk in later life. These observations warrant future investigation into the molecular correlates of AD-linked brainstem dysfunction, assessment as a candidate biomarker, and the exploration of brainstem mediated treatment strategies in AD prevention.}, } @article {pmid40713733, year = {2025}, author = {Li, H and Bai, L}, title = {Advances in mesenchymal stem cell and exosome-based therapies for aging and age-related diseases.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {401}, pmid = {40713733}, issn = {1757-6512}, support = {No. 2022YFA1103803//National Key Research and Development Project/ ; 2021-I2M-1-035//Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ ; }, mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Mesenchymal Stem Cells/metabolism/cytology ; *Aging ; *Mesenchymal Stem Cell Transplantation/methods ; Animals ; *Osteoporosis/therapy ; Primary Ovarian Insufficiency/therapy ; Atherosclerosis/therapy ; *Alzheimer Disease/therapy ; }, abstract = {Mesenchymal stem/stromal cells (MSCs) and their exosomes (MSC-Exos) have great potential for tissue repair and regenerative medicine, which can improve the symptoms and prognosis of aging-related diseases and potentially slow the aging process through multiple pathways. This comprehensive review summarizes the characterization of MSCs and MSC-Exos from various tissue sources and their applications in treating diseases associated with aging, such as premature ovarian failure (POF), Alzheimer's disease (AD), atherosclerosis (AS), and osteoporosis (OP). MSCs exert therapeutic effects through multiple mechanisms, including differentiation into various cell types, secretion of bioactive molecules, and immune response regulation. MSC-Exos, which contain a diverse array of proteins, miRNAs, and other biomolecules, can deliver MSC-derived bioinformatics to target cells and demonstrate comparable therapeutic benefits to MSCs. This review highlights the signaling pathways and molecular mechanisms underlying the therapeutic efficacy of MSCs and MSC-Exos in age-related diseases, and further discusses the importance of MSC and MSC-Exo tissue source selection for specific disease applications and the potential of combination therapies and preconditioning strategies to enhance their therapeutic outcomes. Despite promising preclinical and clinical results, challenges such as uneven distribution, in vivo environmental maladaptation, apoptosis, and immune responses need to be addressed before widespread clinical application. Future research requires multidisciplinary collaboration to further elucidate the mechanisms of action and develop optimized therapeutic strategies for the prevention and treatment of age-related pathologies using MSCs and MSC-Exos.}, } @article {pmid40713730, year = {2025}, author = {Budda, B and Mitra, A and Park, L and Long, H and Kurnellas, M and Bien-Ly, N and Estacio, W and Burgess, B and Chao, G and Schwabe, T and Paul, R and Kenkare-Mitra, S and Rosenthal, A}, title = {Development of AL101 (GSK4527226), a progranulin-elevating monoclonal antibody, as a potential treatment for Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {174}, pmid = {40713730}, issn = {1758-9193}, support = {R44AG050363//National Institutes of Health/ ; R44AG050363//National Institutes of Health/ ; }, mesh = {*Progranulins/metabolism/blood ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Male ; Rats ; Female ; *Antibodies, Monoclonal/pharmacology/therapeutic use/pharmacokinetics ; Adaptor Proteins, Vesicular Transport/metabolism ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid plaques, tau tangles, and neuronal loss. Progranulin (PGRN) is a secreted immune regulator, lysosomal chaperone, and neuronal survival factor. Genetic polymorphisms that reduce PGRN levels are associated with an increased risk for AD and other neurodegenerative disorders. The receptor sortilin binds and targets PGRN for lysosomal degradation, resulting in a reduction of extracellular PGRN. AL101 (GSK4527226) is a monoclonal antibody that binds to the sortilin receptor and is being developed as a potential PGRN-elevating therapy for AD. METHODS: Cell-based in vitro studies examined the interaction of AL101 with sortilin and its effect on PGRN levels. In vivo studies evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of AL101 in rats and nonhuman primates. A phase 1 study in healthy volunteers assessed PK, safety, tolerability, and PD biomarkers after intravenous or subcutaneous dosing of AL101. RESULTS: Cell-based assays showed that AL101 increased PGRN levels by decreasing cell surface sortilin levels and partially blocking the sortilin-PGRN interaction. Preclinical studies in rats and monkeys demonstrated that AL101 decreased cell surface sortilin levels on white blood cells and increased PGRN levels by up to 2-fold in cerebrospinal fluid (CSF) and up to 4-fold in blood. In the phase 1 study in healthy volunteers, both single and multiple doses of AL101 led to significant increases in plasma and CSF PGRN levels, providing additional support for its potential as a PGRN-elevating therapy. LIMITATIONS: The first-in-human dose-finding study was aimed at investigating the safety and tolerability of AL101 and was not sufficiently powered to detect changes in exploratory outcomes, such as neurodegeneration biomarkers. Clinical studies are needed to evaluate AL101 in AD patients. CONCLUSIONS: AL101 was shown to bind sortilin and decrease cell surface sortilin levels, leading to consistent elevations of PGRN across in vitro, preclinical, and human studies. These results support continued development of AL101 and its investigation as a potential treatment for AD and other neurodegenerative conditions where PGRN could play a role. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04111666. Registered on October 1, 2019. https://clinicaltrials.gov/ct2/show/NCT04111666 .}, } @article {pmid40712813, year = {2025}, author = {Tan, Q and Liu, Z and Zheng, J and Wang, Y and Wu, H and Wang, Q and Liang, Y}, title = {Experimental validation, molecular docking, proteomic analysis and network pharmacology reveal Morroniside promoting neurogenesis and improving cognitive impairment via Notch1/Hes1 pathway in intracerebroventricular-streptozotocin mice.}, journal = {Journal of ethnopharmacology}, volume = {353}, number = {Pt A}, pages = {120322}, doi = {10.1016/j.jep.2025.120322}, pmid = {40712813}, issn = {1872-7573}, mesh = {Animals ; *Transcription Factor HES-1/metabolism/genetics ; *Neurogenesis/drug effects ; Molecular Docking Simulation ; *Receptor, Notch1/metabolism ; Mice, Inbred C57BL ; Proteomics ; Network Pharmacology ; Mice ; Male ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Disease Models, Animal ; Streptozocin ; Neuroprotective Agents/pharmacology ; Signal Transduction/drug effects ; Hippocampus/drug effects/metabolism ; *Alzheimer Disease/drug therapy ; Cognition/drug effects ; Cornus/chemistry ; Glycosides ; }, abstract = {ETHNOPHARMACOLOGY RELEVANCE: Alzheimer's disease (AD) is a widely occurred neurodegenerative disease and Notch1/Hes1 pathway based neural stem cell (NSC) proliferation and neurogenesis are very crucial to restore cognitive ability. Cornus officinalis Sieb. et Zucc, a famous traditional Chinese herb remedy was widely used to tonify kidney and essence to ameliorate AD symptoms. Morroniside (MOR), a prominent bioactive component of Cornus officinalis Sieb. et Zucc has demonstrated promising neuroprotective properties, while its function of neurogenesis to improve cognitive ability largely remains unclear. AIM OF THE STUDY: This study aimed to reveal the role of MOR promoting neurogenesis and improving cognitive function via Notch1/Hes1 pathway thus to discover more neuropharmacological merit of MOR for AD treatment. MATERIALS AND METHODS: An AD model was induced in C57BL/6 mice by bilateral intracerebroventricular injection of streptozotocin (ICV-STZ). The mice were divided into control, model, low-dose, high-dose, DAPT + MOR, and donepezil groups. Cognitive functions were assessed using open field test, novel object recognition test, and Morris water maze (MWM). Histopathological changes were evaluated by Nissl and hematoxylin-eosin (HE) staining. Immunofluorescence double-labeling was performed to detect the expression of neurogenesis biomarkers in dentate gyrus. qRT-PCR and Western blotting were employed to measure the mRNA levels and Notch1, Hes1 expression. Molecular docking and dynamics simulations were performed to assess the binding affinity and stability between MOR and Notch1/Hes1 proteins. Proteomic analysis combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were integrated to verify the effects of MOR on including Notch1/Hes1 pathway for neurogenesis. RESULTS: MOR (20 and 40 mg/kg) significantly improved cognitive function of ICV-STZ mice from the behavioral tests. Histological analysis showed that MOR enhanced neuronal survival in the hippocampus, improved cellular arrangement and structure, and reduced oxidative stress. Immunofluorescence results indicated that MOR promoted NSC proliferation and neurogenesis, as evidenced by the elevated number of BrdU/Nestin and DCX/Ki67 double-positive cells. Mechanistically, MOR upregulated the mRNA and protein expression of Notch1 and Hes1 in the hippocampus and increased the expression of downstream Cyclin D1 and CDK4. Molecular docking and dynamics simulations further supported stable binding of MOR to Notch1 and Hes1. Proteomics combined with GO and KEGG enrichment further confirmed MOR (40 mg/kg, ∗P < 0.05) could significantly regulated multiple signaling pathways including Notch1 to ameliorate AD symptoms. CONCLUSION: This work demonstrated MOR could promote neural stem cell proliferation and neurogenesis by activating Notch1/Hes1 pathway, thereby enhancing learning and memory abilities in ICV-STZ mice. Such findings will further promote the clinical application of MOR for AD treatment.}, } @article {pmid40712769, year = {2025}, author = {Košak, U and Knez, D and Benetik, SF and Sokolov, PM and Pišlar, A and Horvat, S and Stojan, J and Lv, B and Zhang, W and Wang, Y and Wang, Q and Igert, A and Dias, J and Nachon, F and Brazzolotto, X and Sun, H and Gobec, S}, title = {Chiral switch of a butyrylcholinesterase inhibitor for the treatment of Alzheimer's disease.}, journal = {Chemico-biological interactions}, volume = {420}, number = {}, pages = {111670}, doi = {10.1016/j.cbi.2025.111670}, pmid = {40712769}, issn = {1872-7786}, mesh = {*Alzheimer Disease/drug therapy ; *Butyrylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/therapeutic use/pharmacology/metabolism ; Animals ; Humans ; Stereoisomerism ; Mice ; Acetylcholinesterase/metabolism/chemistry ; *Sulfonamides/chemistry/therapeutic use/pharmacology ; Male ; Crystallography, X-Ray ; }, abstract = {Butyrylcholinesterase (BChE) is a viable drug target to alleviate the symptoms of Alzheimer's disease (AD). We recently developed and biologically evaluated racemic N-benzylpiperidine-based naphthalene-2-sulfonamide 2, a nanomolar BChE inhibitor with procognitive effects. To optimize it, we performed a chiral switch. Using semi-preparative chiral HPLC, we isolated the pure enantiomers (R)-(-)-2 and (S)-(+)-2 and confirmed that (R)-(-)-2 is the eutomer and (S)-(+)-2 is the distomer with respect to human (h)BChE inhibition. Notably, (R)-(-)-2 is a less potent inhibitor of human acetylcholinesterase (hAChE) than both racemate 2 and (S)-(+)-2, which is advantageous, since AChE inhibition is associated with undesirable peripheral parasympathomimetic adverse effects. The crystal structures of hBChE in complexes with each enantiomer revealed distinct binding poses. The crystal structure of hBChE in complex with (R)-(-)-2 confirmed our previous hypothesis that only the (R)-(-)-2 is bound in the active site of hBChE when the racemate is crystallized. The synthesis of (R)-2 hydrochloride has a higher overall yield (73 %) than the synthesis of racemate 2 hydrochloride (64 %) and is safer as it avoids the use of LiAlH4. (R)-(-)-2 has in vivo efficacy in mice with scopolamine-induced AD-like symptoms, and (R)-(-)-2 is less toxic in mice (LD50 = 169 mg/kg) than racemate 2 (LD50 = 112 mg/kg). These results support the chiral switch from racemate 2 to (R)-(-)-2 as a safer and more selective lead compound in the anti-AD drug development pipeline.}, } @article {pmid40711709, year = {2025}, author = {Chen, R and Gao, H and Zhu, T and Zheng, N and Jin, Y and Li, M and Lu, Z}, title = {Syringaldehyde Ameliorates Cognitive Dysfunction in APP/PS1 Mice by Stabilizing the NLRP3 Pathway.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {15844-15858}, pmid = {40711709}, issn = {1559-1182}, support = {202134029//Jinan Clinical Medical Science and Technology Innovation Plan/ ; tsqnz20240852//Taishan Scholars Program of Shandong Province/ ; 82272414//the National Natural Science Foundation of China/ ; 2022CXGC010507//the Key Research and Development Program of Shandong Province, China/ ; }, mesh = {Animals ; *Cognitive Dysfunction/drug therapy/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Mice, Transgenic ; Mice ; *Benzaldehydes/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Hippocampus/drug effects/pathology/metabolism ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Presenilin-1/metabolism ; Plaque, Amyloid/pathology/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Male ; Oxidative Stress/drug effects ; Neurons/drug effects/metabolism/pathology ; Maze Learning/drug effects ; Mice, Inbred C57BL ; }, abstract = {This study aimed to assess the therapeutic efficacy of syringaldehyde (SYD) in Alzheimer's disease (AD) and to investigate its potential underlying molecular mechanisms. The potential of SYD for AD treatment was first explored through a network pharmacology approach. APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with SYD via intraperitoneal injection for 9 weeks, and cognitive and behavioral functions were evaluated using the Y-maze, Morris water maze, and novel object recognition tests. Histopathological analysis was conducted to assess neuronal changes and amyloid plaque deposition in the hippocampus using immunofluorescence, hematoxylin and eosin staining, Nissl staining, and Congo red staining. RNA sequencing and transcription factor prediction analyses were utilized to identify the potential molecular mechanisms underlying SYD's therapeutic effects. In addition, in vitro experiments were performed on HT22 hippocampal neuronal cells, including ROS assay, TUNEL assay, and quantitative reverse transcription PCR, to validate the mechanisms suggested by the in vivo results. The results demonstrated that SYD treatment significantly reduced amyloid plaque deposition in the hippocampus of APP/PS1 mice, promoted neuronal repair, and improved cognitive performance. Further analysis indicated that these therapeutic effects were mediated by SYD's ability to enhance resistance to oxidative stress, alleviate neuronal damage, and inhibit the NF-κB/IL-1β/NLRP3 inflammatory pathway, thereby counteracting neuroinflammation induced by neuronal activation. In conclusion, this study provides strong evidence for the potential of SYD to ameliorate cognitive impairment and reduce amyloid plaque deposition in AD, highlighting its promising role as a therapeutic agent in the treatment of Alzheimer's disease.}, } @article {pmid40710322, year = {2025}, author = {Koch-Paszkowski, J and Sennett, C and Pula, G}, title = {Alzheimer's Disease-Thrombosis Comorbidity: A Growing Body of Evidence from Patients and Animal Models.}, journal = {Cells}, volume = {14}, number = {14}, pages = {}, pmid = {40710322}, issn = {2073-4409}, mesh = {*Alzheimer Disease/complications/epidemiology/pathology ; Humans ; Animals ; Disease Models, Animal ; *Thrombosis/complications/epidemiology/pathology ; Comorbidity ; Brain/pathology/blood supply ; }, abstract = {BACKGROUND/OBJECTIVES: A growing body of evidence is amassing in the literature suggesting a correlation between Alzheimer's disease (AD) and thrombotic vascular complications, which led to the suggestive hypothesis that thrombosis may contribute to AD onset and progression by damaging the neurovasculature and reducing the cerebral blood flow. In turn, low cerebral blood flow is likely to contribute to neurodegeneration by reducing nutrient and oxygen supply and impairing toxic metabolite removal from the brain tissue. METHODS: We searched the literature for studies in animal models of AD or patients diagnosed with the disease that reported circulating markers of platelet hyperactivity or hypercoagulation, or histological evidence of brain vascular thrombosis. RESULTS: Platelet hyperactivity and hypercoagulability have been described in multiple animal models of AD, and histological evidence of neurovascular thrombosis has also been reported. Similarly, clinical studies on patients with AD showed circulating markers of platelet hyperactivity and hypercoagulation, or histological evidence of neurovascular thrombosis collected from post-mortem brain tissue samples. CONCLUSIONS: Taken together, a convincing picture is emerging that suggests a strong correlation between systemic or neurovascular thrombosis and AD. Nonetheless, a mechanistic role for haemostasis dysregulation and neurovascular damage in the onset or the progression of AD remains to be proven. Future research should focus on this important question in order to clarify the mechanisms underlying AD and identify a treatment for this disease.}, } @article {pmid40710114, year = {2025}, author = {Nazir, S and Dogan, M and Wei, Y and Pan, G}, title = {Electrochemical Immunosensor Using COOH-Functionalized 3D Graphene Electrodes for Sensitive Detection of Tau-441 Protein.}, journal = {Biosensors}, volume = {15}, number = {7}, pages = {}, pmid = {40710114}, issn = {2079-6374}, mesh = {*Graphite/chemistry ; *Biosensing Techniques ; *tau Proteins/analysis ; Humans ; Electrodes ; *Electrochemical Techniques ; Immunoassay ; Alzheimer Disease/diagnosis ; Limit of Detection ; Amyloid beta-Peptides ; }, abstract = {Early diagnosis of Alzheimer's disease (AD) is essential for effective treatment; however current diagnostic methods are often complex, costly, and unsuitable for point-of-care testing. Graphene-based biosensors offer an alternative due to their affordability, versatility, and high conductivity. However, graphene's conductivity can be compromised when its carbon lattice is oxidized to introduce functional groups for biomolecule immobilization. This study addresses this challenge by developing an electrochemical immunosensor using carboxyl-modified commercial graphene foam (COOH-GF) electrodes. The conductivity of graphene is preserved by enabling efficient COOH modification through π-π non-covalent interactions, while antibody immobilization is optimized via EDC-NHS carbodiimide chemistry. The immunosensor detects tau-441, an AD biomarker, using differential pulse voltammetry (DPV), achieving a detection range of 1 fM-1 nM, with a limit of detection (LOD) of 0.14 fM both in PBS and human serum. It demonstrates high selectivity against other AD-related proteins, including tau-217, tau-181, amyloid beta (Aβ1-40 and Aβ1-42), and 1% BSA. These findings underscore its potential as a highly sensitive, cost-effective tool for early AD diagnosis.}, } @article {pmid40709649, year = {2025}, author = {Radanovic, M and Passos Neto, CEB and Monteiro, LH and Forlenza, OV}, title = {Transactive response DNA-binding protein 43 (TDP-43) proteinopathy: the complex biological and clinical findings in limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathological changes, limbic-predominant amnestic neurodegenerative syndrome, and other mixed age-related major neurocognitive disorders.}, journal = {Current opinion in psychiatry}, volume = {38}, number = {5}, pages = {341-347}, doi = {10.1097/YCO.0000000000001025}, pmid = {40709649}, issn = {1473-6578}, mesh = {Humans ; *TDP-43 Proteinopathies/pathology/diagnosis/genetics ; *Neurodegenerative Diseases/pathology ; *DNA-Binding Proteins/metabolism ; *Limbic System/pathology ; *Aging ; Dementia ; }, abstract = {PURPOSE OF REVIEW: As the term limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE) was coined in 2019, more than 200 articles addressing the subject were published. This review aims to provide an updated synthesis of knowledge regarding LATE-NC as a cause of age-related neurodegeneration and cognitive decline while addressing the challenges posed by overlapping neuropathologies in aging populations. RECENT FINDINGS: LATE-NC is marked by TDP-43 deposition in limbic structures, such as the amygdala and hippocampus, and is often associated with cognitive decline resembling Alzheimer's disease, though with a slower progression in isolated cases. The frequent coexistence of LATE-NC with other neuropathologies, particularly Alzheimer's disease neuropathologic changes (ADNC) and Lewy body dementia (LBD), exacerbates dementia severity and complicates diagnosis and treatment. Recent efforts have established clinical criteria for in-vivo diagnosis, including neuroimaging markers like hippocampal atrophy and limbic hypometabolism. Genetic studies have identified key risk genes, including GRN, TMEM106B, SORL1, and APOE, while biomarker development in cerebrospinal fluid (CSF) and blood remains in its early stages. SUMMARY: The review highlights the importance of multidisciplinary research and clinical approaches in addressing the complexities of neurodegenerative diseases involving TDP-43 proteinopathy, enhancing diagnostic accuracy, and developing effective treatments tailored to individual patient profiles.}, } @article {pmid40709644, year = {2025}, author = {Radanovic, M and Passos Neto, CEB and Monteiro, LH and Forlenza, OV}, title = {TDP-43 proteinopathy: the complex biological and clinical findings in LATE-NC, LANS, and other mixed age-related major neurocognitive disorders.}, journal = {Current opinion in psychiatry}, volume = {38}, number = {5}, pages = {361-367}, doi = {10.1097/YCO.0000000000001027}, pmid = {40709644}, issn = {1473-6578}, mesh = {Humans ; *TDP-43 Proteinopathies/diagnosis/pathology/physiopathology/genetics ; DNA-Binding Proteins/metabolism ; *Aging ; *Cognitive Dysfunction ; Dementia ; }, abstract = {PURPOSE OF REVIEW: Since the term limbic-predominant age-related TDP-43 encephalopathy (LATE) was coined in 2019, more than 200 articles addressing the subject were published. This review aims to provide an updated synthesis of knowledge regarding LATE-NC as a cause of age-related neurodegeneration and cognitive decline while addressing the challenges posed by overlapping neuropathologies in aging populations. RECENT FINDINGS: LATE-NC is marked by TDP-43 deposition in limbic structures, such as the amygdala and hippocampus, and is often associated with cognitive decline resembling Alzheimer's disease, though with a slower progression in isolated cases. The frequent coexistence of LATE-NC with other neuropathologies, particularly Alzheimer's disease neuropathologic changes (ADNC) and Lewy body dementia (LBD), exacerbates dementia severity and complicates diagnosis and treatment. Recent efforts have established clinical criteria for in-vivo diagnosis, including neuroimaging markers like hippocampal atrophy and limbic hypometabolism. Genetic studies have identified key risk genes, including GRN , TMEM106B , SORL1 , and APOE , while biomarker development in cerebrospinal fluid (CSF) and blood remains in its early stages. SUMMARY: The review underscores the need for multidisciplinary research and clinical approaches to address the complexities of neurodegenerative diseases involving TDP-43 proteinopathy, improve diagnostic accuracy, and develop effective treatments tailored to individual patient profiles.}, } @article {pmid40709598, year = {2025}, author = {Kaur, G and Mankoo, OK and Kaur, A and Mann, S and Priyadarshi, N and Singh, PP and Goyal, B and Singhal, NK and Goyal, D}, title = {The Synergistic Potential of Rationally Designed Phenol-Triazole Derivatives to Attenuate Aβ/Cu[2+]-Aβ Aggregation and Reactive Oxygen Species.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {15}, pages = {3020-3037}, doi = {10.1021/acschemneuro.5c00386}, pmid = {40709598}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism ; *Reactive Oxygen Species/metabolism ; Animals ; *Copper/metabolism ; Rats ; PC12 Cells ; *Peptide Fragments/metabolism ; *Triazoles/pharmacology/chemistry ; Chelating Agents/pharmacology ; Clioquinol/pharmacology/chemistry ; Protein Aggregates/drug effects ; Phenols/pharmacology/chemistry ; Protein Aggregation, Pathological/metabolism/drug therapy ; }, abstract = {Alzheimer's disease (AD) is a neurological disorder characterized by a spectrum of symptoms such as memory loss and cognitive decline. AD is a multifaceted disease, and designing multipotent ligands is an effective strategy for AD treatment. In this regard, the pharmacophore moiety of clioquinol (CQ, metal chelator) was employed to design the multifunctional phenol-triazole derivatives 4(a-p). In particular, 4k with an o-I group on the phenyl ring displayed a noteworthy higher inhibition (inhibition efficiency 4k = 90.5%, IC50 = 6.51 ± 0.01 μM) against Aβ42 aggregation as compared to 38.1% noted for CQ. Furthermore, 4k significantly disassembled the preformed Aβ42 fibrils (Aβf, 92.5%), chelated Cu[2+] ions, and inhibited Cu[2+]-mediated Aβ42 aggregation. Compound 4k ceases the production of reactive oxygen species (ROS) as it acts as an antioxidant due to the presence of a phenolic hydroxyl group. Compound 4k has a sufficient safety-efficacy profile and alleviates the cytotoxicity by Aβ42 aggregates in PC-12 cells. For studying the modulation in the fibrillary architecture, hydrodynamic size, and structural transition of Aβ42 in the presence of 4k, we resorted to transmission electron microscopy (TEM), dynamic light scattering (DLS), and circular dichroism (CD), respectively. The molecular dynamics (MD) simulations depicted a notable reduction in the conformational transformations in the Aβ42 monomer (Aβm) and Aβf on the incorporation of 4k. Compound 4k modulates Aβ42 fibrillation by maintaining a helix conformation and simultaneously reduces the sampling of β-sheet structures in Aβm, consistent with the CD results. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis depicted a favorable binding of 4k to Aβm (-42.12 ± 7.14 kcal/mol) and Aβf (-74.42 ± 4.98 kcal/mol) with a significant contribution of van der Waals interactions to the binding free energy. The 4k-induced deformation in Aβf chains noted in the conformational snapshots depicts its destabilization potential against Aβf. Finally, our results uncovered the potential of phenol-triazole derivatives as a promiscuous ligand for targeting various pathological conditions in AD. The key insights into the prevention of conformational transitions in Aβm and destabilization of Aβf by 4k illuminated by experimental and computational studies are central to unraveling the molecular understanding of amyloid aggregation as well as designing future therapeutic candidates against multifaceted AD.}, } @article {pmid40709526, year = {2025}, author = {Sharma, N and Kim, D and Sharma, H and Kim, MI and Lee, H and Kim, M and Ryoo, N and Kang, MJ and Pyun, JM and Park, YH and Ryu, J and Oh, HJ and Yang, HS and Kim, HR and Kim, GH and Han, S and Yang, Y and Youn, YC and Teunissen, C and Zetterberg, H and Scheltens, P and An, SSA and Kim, YB and Kim, S and , }, title = {Unveiling blood biomarkers for neuronal hyperplasticity: Insights from AD molecular subtyping, a comprehensive review.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70475}, pmid = {40709526}, issn = {1552-5279}, support = {RS-2023-00251396//National Research Foundation of Korea/ ; RS-2021-NR060117//Ministry of Education/ ; 2021R1A6A1A03038996//Ministry of Education/ ; RS-2025-02292973//Korea Institute of Marine Science & Technology Promotion (KIMST)/ ; }, mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood/pathology/classification/diagnosis ; *Neurons/pathology ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, predominantly affecting the aging population. Early detection through biomarkers is essential for early intervention. Recent sub-classification of AD through extensive cerebrospinal fluid (CSF) proteomic analyses revealed distinct characteristics of each subtype, necessitating tailored therapeutic strategies. While CSF proteomics has identified potential biomarkers, the need for non-invasive and cost-effective substitutions highlights the importance of blood-based biomarkers (BBMs). This review is a comprehensive review that categorizes potential BBMs based on neuronal hyperplasticity (subtype 1), underlining their role in refining subtype classification and enabling precision medicine. Early AD is often marked by cortical and hippocampal hyperactivity, followed by hypoactivity during later stages of neurodegeneration. While the exact mechanisms remain unclear, factors like Ca[2+], glutamate, amyloid beta, tau, genetic factors, and impaired glial function play a role. Advancements in blood-based diagnostics would improve detection, individual treatment strategies, and evaluation of therapeutic response, eventually reducing the burden of AD on health-care systems. HIGHLIGHTS: Alzheimer's disease (AD; subtype 1) exhibits neuronal hyperplasticity, mild cortical atrophy, and moderate microglial activation. The neuronal hyperplasticity subtype of AD is characterized by an upregulation of synaptic and plasticity-related proteins, distinguishing it from other AD subtypes. Identifying biomarkers specific to neuronal hyperplasticity would enable real-time monitoring of therapeutic responses, allowing for individualized therapy as opposed to a "one-size-fits-all" strategy. The treatments based on neuronal hyperactivity reduction, restoration of synaptic plasticity, and anti-inflammation/metabolic dysfunction would be useful in this AD subtype. Blood-based biomarkers offer a cost-effective and accessible alternative to cerebrospinal fluid and neuroimaging methods.}, } @article {pmid40709497, year = {2025}, author = {Liu, W and Guo, J and Dong, Y and Li, J and Wang, Y}, title = {Efficacy of probiotic supplementation in influencing cognitive function in Alzheimer's disease: A systematic review and meta-analysis.}, journal = {Journal of food science}, volume = {90}, number = {7}, pages = {e70037}, doi = {10.1111/1750-3841.70037}, pmid = {40709497}, issn = {1750-3841}, mesh = {*Probiotics/administration & dosage ; Humans ; *Alzheimer Disease/psychology/drug therapy/microbiology ; *Cognition/drug effects ; Aged ; Gastrointestinal Microbiome/drug effects ; Randomized Controlled Trials as Topic ; *Dietary Supplements ; Male ; Female ; Aged, 80 and over ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral changes. Emerging evidence suggests that the gut microbiota influences central nervous system function. Probiotic interventions may offer a promising therapeutic approach by modulating the gut microbiota composition and potentially improving cognitive outcomes in AD patients. This meta-analysis aimed to assess the effects of probiotic supplementation on cognitive function in AD patients by analyzing randomized controlled trials (RCTs). Following PRISMA 2020 guidelines and registered with PROSPERO (CRD42024508725), we conducted a comprehensive search across PubMed, Embase, Cochrane Library, and ClinicalTrials.gov through April 9th, 2024. Only double-blind RCTs comparing probiotic supplementation to placebo in patients aged 65 or older with clinically diagnosed AD were included. Primary outcomes were cognitive function scores from validated tools like MMSE and TYM. Our stringent inclusion criteria identified four double-blind RCTs with 251 participants aged 65 or older with clinically diagnosed AD. Statistical analysis using a random-effects model revealed significant cognitive improvement in probiotic-treated groups compared to placebo controls (Standardized Mean Difference [SMD] = 0.67; 95% CI [0.14, 1.19]; P < 0.05), though substantial heterogeneity was observed (I[2] = 79.16%). Subgroup analyses indicated that probiotic formulation type, dosage, and baseline AD severity may influence cognitive outcomes. While these findings suggest probiotics may offer cognitive benefits for AD patients, the high heterogeneity and limited study number necessitate additional well-designed clinical trials to confirm these promising results and establish optimal treatment protocols for clinical implementation.}, } @article {pmid40709486, year = {2025}, author = {Munn, EE and Montelongo, A and Patel, VK and Fodstad, JC and Ciccarelli, MR and Ptomey, LT and Pangelinan, MM}, title = {A meta-analysis and systematic review of interventions to prevent or treat cognitive decline related to Alzheimer's disease in adults with Down syndrome.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70471}, pmid = {40709486}, issn = {1552-5279}, mesh = {Humans ; *Down Syndrome/complications ; *Alzheimer Disease/complications/therapy ; *Cognitive Dysfunction/therapy/prevention & control/etiology ; Adult ; Cognitive Behavioral Therapy ; }, abstract = {Down syndrome (DS) is a leading genetic risk factor for Alzheimer's disease (AD). Although prevention and treatment of AD are well documented for those without DS, less is known about individuals with DS. This review evaluates the efficacy of AD and dementia interventions in people with DS. It includes 26 articles with 1417 participants ages 18-69 in the qualitative synthesis and 17 articles with 1118 participants in the meta-analysis. Four types of interventions demonstrated small-to-moderate effects: pharmacological (n = 19), exercise (n = 5), environmental (n = 1), and cognitive training (n = 1). Significant treatment effects were observed across interventions (t(66) = 4.67, p < 0.0001, d = 0.29, 95% confidence interval [CI]: 0.16-0.40); however, high heterogeneity (I[2] = 93.8% CI = 92.8-94.7) was noted, which was not explained by intervention type or outcome. The meta-analysis indicates that interventions enhance AD-related cognitive and behavioral outcomes, emphasizing the need for further research to address heterogeneity. This review was registered with PROSPERO: CRD42024567026. HIGHLIGHTS: This study is the first to comprehensively review both pharmacological and non-pharmacological interventions for Alzheimer's disease (AD) in individuals with Down syndrome (DS), extending previous reviews by including a meta-analysis and examining key mediating variables. Donepezil, the most studied pharmacological treatment, showed significant cognitive and behavioral improvements in individuals with DS, especially with longer treatment periods. However, further trials are needed to explore its efficacy in combination with non-pharmacological interventions. All seven non-pharmacological studies reported significant improvement, suggesting that even small doses of exercise and cognitive training can be effective and feasible for individuals with DS. Online formats may enhance scalability and reduce barriers to participation. Significant heterogeneity in cognitive assessments across studies highlights the need for standardized, sensitive assessments to enable meaningful comparisons of intervention effects. Additional studies are required to determine the long-term efficacy of pharmacological interventions like Donepezil and to assess the sustained impact of non-pharmacological interventions on key AD-related cognitive domains such as memory, language, and executive function.}, } @article {pmid40709360, year = {2025}, author = {Zhang, Y and Wang, Y and Xu, K and Zhang, C and Lv, P and Bai, Y and Wang, S}, title = {Repetitive transcranial magnetic stimulation across neurodegenerative diseases: a systematic review and dose-response meta-analysis.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1615734}, pmid = {40709360}, issn = {1663-4365}, abstract = {OBJECTIVE: We summarized the existing clinical evidence of repetitive transcranial magnetic stimulation (rTMS) for Parkinson's Disease (PD) and Alzheimer's Disease (AD) and conducted a series of dose-response meta-analyses to determine the curve relationship between the number of pulses and the effect size of the treatment. METHODS: Existing evidence was retrieved from five databases, and relevant outcome data on rTMS treatment for motor and non-motor symptoms of PD and AD were collected. Data were analyzed using R software to assess effect size using standardized mean differences (SMD) and 95% confidence intervals (CI). Heterogeneity testing was performed to assess differences in efficacy among the evidence, and restricted cubic spline (RCS) was used to fit the dose-response curves. RESULTS: A total of 51 publications were included, involving 1,938 subjects. We found that for PD patients, the total number of rTMS pulses showed significant bell-shaped curves in TUG (χ[2] = 6.87, df = 2, p = 0.03), FOGQ (χ[2] = 15.17, df = 2, p = 0.001), BDI (χ[2] = 14.33, df = 2, p = 0.001), HAMD (χ[2] = 12.63, df = 2, p = 0.001), and HAMA (χ[2] = 6.06, df = 2, p = 0.04). For AD patients, the total number of rTMS pulses demonstrated significant bell-shaped curves for MMSE (χ[2] = 8.76, df = 2, p = 0.01) and MoCA (χ[2] = 6.79, df = 2, p = 0.03). CONCLUSION: Our dose-response meta-analysis results show that rTMS demonstrates significant efficacy in certain motor and non-motor symptoms of PD and AD. The number of rTMS pulses presents a typical bell-shaped curve for these symptoms, indicating that more number of rTMS pulses is not always better; beyond a certain threshold, increasing the number of rTMS pulses correlates negatively with therapeutic efficacy.}, } @article {pmid40709087, year = {2025}, author = {Wang, G and Zhou, X and Pang, X and Ma, K and Li, L and Song, Y and Hou, D and Wang, X}, title = {Pharmacological effects, molecular mechanisms and strategies to improve bioavailability of curcumin in the treatment of neurodegenerative diseases.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1625821}, pmid = {40709087}, issn = {1663-9812}, abstract = {With the global population aging, the incidence of neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, has been progressively increasing. However, effective therapeutic strategies and clinical drugs for these disorders remain scarce. Curcumin, a natural polyphenolic compound primarily derived from the herbaceous plant Curcuma longa L., has been proposed as a promising candidate for ND treatment based on the excellent antioxidant, anti-inflammatory and neuroprotective properties. Its pharmacological activities encompass scavenging reactive oxygen species, mitigating toxic protein aggregation and cytotoxicity, repairing mitochondrial dysfunction, and inhibiting excessive neuronal apoptosis. Compared with synthetic drugs, curcumin demonstrates a more favorable safety profile with fewer side effects. Nevertheless, its clinical application is substantially hindered by poor bioavailability, which stems from low aqueous solubility, inefficient intestinal absorption, and rapid metabolism and systemic elimination. Conventional administration methods often fail to achieve effective concentrations in vivo. Further clinical trials are also required to validate the therapeutic efficacy and potential adverse effects in human subjects. This article systematically reviews the pathogenesis of NDs and the knowledge on curcumin including pharmacological effects, neuroprotective mechanisms, functions across specific NDs and advanced strategies to enhance the bioavailability, with the aim of promoting the development and clinical translation of curcumin-based therapeutics for NDs.}, } @article {pmid40708863, year = {2025}, author = {Nagarajan, R and Lyu, J and Kambali, M and Wang, M and Pearce, RA and Rudolph, U}, title = {Noncanonical sustained actions of propofol reverse surgery-induced microglial activation and cognitive impairment in aged mice.}, journal = {PNAS nexus}, volume = {4}, number = {7}, pages = {pgaf213}, pmid = {40708863}, issn = {2752-6542}, abstract = {Perioperative neurocognitive disorder is a major concern in aged individuals, and currently, treatment options are limited. Chronic intermittent propofol (CIP) has been shown to have neuroprotective effects in aged mice and in a mouse model of Alzheimer's disease. Here, we investigated whether CIP could reverse surgery-induced cognitive deficits and propose a mechanism of action. Male and female mice (21-24 months old) underwent exploratory laparotomy under isoflurane anesthesia. Animals were administered either CIP (75 mg/kg i.p.) or vehicle every fifth day throughout the experiment. Cognitive function was assessed using a battery of behavioral tests: the Y-maze test (spatial working memory), the novel object recognition test (recognition memory), the Morris water maze (spatial learning and memory), and trace and contextual fear conditioning (nondeclarative associative memory). Expression of α5-GABAA receptors, markers of apoptosis, and a microglial activation marker were assessed in the hippocampus using western blotting. The amount of α5-GABAA receptor subunits in cell-surface membranes was determined by biotinylation followed by western blotting. CIP induced a sustained redistribution of α5-GABAA receptors to the cell-surface membranes. Laparotomy led to an increased expression of the microglial activation marker Iba-1 and of proapoptotic markers, and impaired cognitive functions. CIP prevented these molecular and cognitive changes. Perioperative CIP redistributes α5-GABAA receptors to cell-surface membranes and thus prevents or reverses surgery-induced increases in markers of microglial activation, apoptosis, and cognitive dysfunction. Increasing the number or activity of α5-GABAA receptors on cell-surface membranes may be an effective therapeutic strategy to reduce postoperative morbidity in elderly patients.}, } @article {pmid40708572, year = {2025}, author = {Pan, Y and Ji, N and Jiang, L and Zhou, Y and Feng, X and Li, J and Zeng, X and Wang, J and Shen, YQ and Chen, Q}, title = {GPCRs identified on mitochondrial membranes: New therapeutic targets for diseases.}, journal = {Journal of pharmaceutical analysis}, volume = {15}, number = {7}, pages = {101178}, pmid = {40708572}, issn = {2214-0883}, abstract = {G protein-coupled receptors (GPCRs) are the largest family of membrane proteins in eukaryotes, with nearly 800 genes coding for these proteins. They are involved in many physiological processes, such as light perception, taste and smell, neurotransmitter, metabolism, endocrine and exocrine, cell growth and migration. Importantly, GPCRs and their ligands are the targets of approximately one third of all marketed drugs. GPCRs are traditionally known for their role in transmitting signals from the extracellular environment to the cell's interior via the plasma membrane. However, emerging evidence suggests that GPCRs are also localized on mitochondria, where they play critical roles in modulating mitochondrial functions. These mitochondrial GPCRs (mGPCRs) can influence processes such as mitochondrial respiration, apoptosis, and reactive oxygen species (ROS) production. By interacting with mitochondrial signaling pathways, mGPCRs contribute to the regulation of energy metabolism and cell survival. Their presence on mitochondria adds a new layer of complexity to the understanding of cellular signaling, highlighting the organelle's role as not just an energy powerhouse but also a crucial hub for signal transduction. This expanding understanding of mGPCR function on mitochondria opens new avenues for research, particularly in the context of diseases where mitochondrial dysfunction plays a key role. Abnormalities in the phase conductance pathway of GPCRs located on mitochondria are closely associated with the development of systemic diseases such as cardiovascular disease, diabetes, obesity and Alzheimer's disease. In this review, we examined the various types of GPCRs identified on mitochondrial membranes and analyzed the complex relationships between mGPCRs and the pathogenesis of various diseases. We aim to provide a clearer understanding of the emerging significance of mGPCRs in health and disease, and to underscore their potential as therapeutic targets in the treatment of these conditions.}, } @article {pmid40708508, year = {2025}, author = {Rana, A and Malviya, R and Rajput, S and Sridhar, SB and Wadhwa, T}, title = {Trends in Nanoparticle-based Strategies for the Management of Neuroinflammation.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273373041250707012835}, pmid = {40708508}, issn = {1996-3181}, abstract = {Neuroinflammation, characterised by an overactive immune system in the brain and spinal cord, has now been tied to several neurodegenerative diseases. Here, immune cells invade into the brain, activating astrocytes and microglia. Neuroinflammation is a common symptom of many neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This inflammatory reaction occurs within the central nervous system (CNS). Neurological dysfunction results from the inflammatory response, which arises in reaction to any kind of brain injury. Regulating neuroinflammation can be useful for controlling brain disorders associated with neuroinflammation. Several targeted drug delivery systems attempt to treat neuroinflammation caused by neurodegenerative illnesses or brain tumours by targeting the microglia and other immune cells in the central nervous system. Therefore, biodegradable and biocompatible NPs (nanoparticles) could be developed as a treatment for neurodegenerative diseases caused by neuroinflammation or as a less invasive means of transporting other drugs across the blood-brain barrier. Numerous applications of gold nanoparticles (AuNPs) in the treatment of neurological diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are studied in this article. To prevent neuroinflammation and microglia over-activation, some NPs have recently been found to be effective anti-inflammatory medication carriers that cross the blood-brain barrier.}, } @article {pmid40707875, year = {2025}, author = {Wang, C and Bu, X and Cao, M and Lian, Y and Ling, H and You, M and Yi, J and Gao, X and Wu, D and Li, Y}, title = {Mir-199a-3p aggravates neuroinflammation in an Alzheimer's disease transgenic mouse model by promoting M1-polarization microgliaMir-199a-3p M1.}, journal = {BMC neuroscience}, volume = {26}, number = {1}, pages = {45}, pmid = {40707875}, issn = {1471-2202}, support = {yzjj2023qn15//President Foundation of Zhujiang Hospital, Southern Medical University/ ; 2018A0303130216//Natural Science Foundation of Guangdong Province/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *MicroRNAs/metabolism/genetics ; *Microglia/metabolism ; Mice, Transgenic ; Mice ; *Neuroinflammatory Diseases/metabolism/genetics/pathology ; Disease Models, Animal ; Hippocampus/metabolism ; Male ; Cytokines/metabolism ; }, abstract = {Chronic neuroinflammation, driven by M1-polarized microglia, is a core pathological mechanism of Alzheimer's disease (AD). Elevated expression levels of miR-199a-3p and pro-inflammatory cytokines were detected in the hippocampi of AD transgenic mice and in LPS-stimulated BV2 microglial cells. We hypothesized that miR-199a-3p exacerbates neuroinflammation by promoting M1 microglial polarization in AD progression. M1 （AD）。 AD LPS BV2 miR-199a-3p 。 miR-199a-3p AD M1 。 OBJECTIVE: To explore the role of miR-199a-3p in AD-associated neuroinflammation. miR-199a-3p AD 。 METHODS: AD transgenic (APPswe/PSEN1dE9) mice and LPS-treated BV2 cells were used to assess miR-199a-3p effects in vivo and in vitro. Inflammatory cytokines and markers for microglial cell typing were detected. Transcriptome sequencing was performed on miR-199a-3p-modulated BV2 cells, and the sequencing data were cross-analyzed with public databases to predict miR-199a-3p-mediated pathways.AD （APPswe/PSEN1dE9） LPS BV2 miR-199a-3p 。。 miR-199a-3p BV2 ，， miR-199a-3p 。 RESULTS: Intracerebroventricular administration of miR-199a-3p agomir exacerbated amyloid deposition and impaired cognitive function in AD mice, and promoted microglial polarization toward the M1 phenotype. Conversely, treatment with miR-199a-3p antagomir attenuated AD pathology and suppressed M1 polarization. In LPS treated BV2 cells, miR-199a-3p mimics promoted M1 polarization, while inhibitors reversed this effect. Transcriptome analysis revealed that miR-199a-3p downregulated WDR76, subsequently suppressing cell cycle-associated pathways, IL-17 signaling, and FOXO pathways, resulting in an increase in the proportion of M1 type microglia. miR-199a-3p agomir AD ， M1 。， miR-199a-3p AD M1 。 LPS BV2 ，miR-199a-3p M1 ，。，miR-199a-3p WDR76，、 IL-17 FOXO ， M1 。 CONCLUSION: MiR-199a-3p aggravates neuroinflammation of AD by promoting M1-polarization microglia. These findings highlight miR-199a-3p as a potential therapeutic target for AD.}, } @article {pmid40707826, year = {2025}, author = {Chun, MY and Jeon, J and Chung, SJ and Kim, J}, title = {Association between osteoporosis and risk of dementia: a Korean women nationwide population-based cohort study.}, journal = {Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA}, volume = {36}, number = {10}, pages = {1987-1997}, pmid = {40707826}, issn = {1433-2965}, support = {RS-2024-00345524//National Research Foundation of Korea/ ; }, mesh = {Humans ; Female ; Aged ; Republic of Korea/epidemiology ; *Dementia/epidemiology/etiology/physiopathology ; Retrospective Studies ; Bone Density/physiology ; *Osteoporosis, Postmenopausal/epidemiology/physiopathology/complications ; Risk Factors ; Risk Assessment/methods ; Incidence ; Bone Diseases, Metabolic/epidemiology/physiopathology/complications ; Aged, 80 and over ; Mass Screening/methods ; Follow-Up Studies ; }, abstract = {UNLABELLED: Brief rationale: dementia and osteoporosis share risk factors and are rising in aging populations. MAIN RESULTS: osteoporosis significantly increases the risk of all-cause dementia, Alzheimer's disease dementia, and vascular dementia in Korean older women. Significance of the paper: early detection and treatment of osteoporosis may reduce dementia risk. PURPOSE: Dementia and osteoporosis share common risk factors and are increasing in prevalence in the aging population. This study aimed to investigate the impact of osteoporosis on dementia and its subtypes in women using data from a population-based, health-screening cohort, with a follow-up period of more than 10 years. METHODS: This retrospective study included 66-year-old Korean women who participated in the "National Screening Program for Transitional Ages" from 2010 to 2011. Participants were categorized based on spine bone mineral density T-scores into three groups: normal (T-score ≥ - 1.0 standard deviation [SD]; 18.7%), osteopenia (- 2.5 SD < T-score < - 1.0 SD; 42.5%), and osteoporosis (T-score ≤ - 2.5 SD; 38.8%). Incident dementia cases were evaluated until 2021 using national healthcare claims databases. Fine-Gray subdistribution hazard models were used to assess the risks of all-cause dementia including Alzheimer's disease (AD) dementia and vascular dementia (VaD), accounting for death as a competing risk. RESULTS: The study included 131,872 dementia-free women aged 66 years. Over an average follow-up of 10.4 ± 1.8 years, 9399 individuals developed all-cause dementia (7.1%). Osteoporosis was associated with increased risks for all-cause dementia (adjusted subdistribution hazard ratio [asHR] 1.14; 95% confidence interval [CI] 1.08-1.21; p < 0.001), AD dementia (asHR 1.14; 95% CI 1.08-1.22; p < 0.001), and VaD (asHR 1.42; 95% CI 1.08-1.87; p = 0.013), compared to normal. CONCLUSION: Our findings highlight an association between osteoporosis and increased risks of developing all-cause dementia, AD dementia, and VaD. Further research is needed to explore the effects of early identification and treatment of osteoporosis in preventing dementia.}, } @article {pmid40706971, year = {2025}, author = {Alshehri, GH and Al-Kuraishy, HM and Al-Gareeb, AI and Fawzy, MN and Waheed, HJ and Papadakis, M and Alexiou, A and El-Saber Batiha, G}, title = {A novel therapeutic prospect: a dual-acting tirzepatide for Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1003}, number = {}, pages = {177979}, doi = {10.1016/j.ejphar.2025.177979}, pmid = {40706971}, issn = {1879-0712}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Animals ; *Glucagon-Like Peptide 1/metabolism/therapeutic use/analogs & derivatives ; *Neuroprotective Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Brain/drug effects/metabolism ; Cognition/drug effects ; Insulin/metabolism ; Insulin Resistance ; Tirzepatide ; }, abstract = {Alzheimer's disease (AD), the leading cause of dementia, involves microglial activation, pro-inflammatory cytokine release, and impaired insulin signaling via insulin receptor substrate 1 (IRS-1) inhibition. Brain insulin resistance (BIR) is a key factor in AD progression, disrupting synaptic plasticity and neuronal function. Additionally, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) signaling, which regulate insulin pathways, are compromised in AD. GLP-1/GIP receptor activation or their analogs, such as tirzepatide, show potential in mitigating AD neuropathology. However, the precise neuroprotective mechanisms of tirzepatide remain unclear. This mini-review explores tirzepatide's potential therapeutic effects in AD, focusing on its role in restoring insulin signaling, reducing neuroinflammation, and improving cognitive function. Understanding these mechanisms could offer new insights into AD treatment strategies.}, } @article {pmid40706880, year = {2025}, author = {Duan, K and Qin, C and Zhang, Y and Li, D and Zhang, J and Li, F}, title = {Scorpion venom heat-resistant synthetic peptide regulates Nrf-2 to alleviate neuronal pyroptosis in an AD model induced by endoplasmic reticulum stress under PM2.5 exposure.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {265}, number = {}, pages = {108504}, doi = {10.1016/j.toxicon.2025.108504}, pmid = {40706880}, issn = {1879-3150}, mesh = {Animals ; *Particulate Matter/toxicity ; *Pyroptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; Mice ; *Endoplasmic Reticulum Stress/drug effects ; *Alzheimer Disease/drug therapy ; *Scorpion Venoms/pharmacology ; Neurons/drug effects ; Rats ; Disease Models, Animal ; PC12 Cells ; *Peptides/pharmacology ; Amyloid beta-Peptides ; Male ; Oxidative Stress/drug effects ; Peptide Fragments ; }, abstract = {In recent years, the impact of fine particulate matter (PM2.5) on the nervous system, particularly on neurodegenerative diseases, has garnered widespread attention. Epidemiological studies have shown that exposure to PM2.5 is closely associated with the development and progression of Alzheimer's disease (AD). However, the mechanisms through which PM2.5 exacerbates AD remain unclear. Scorpion venom heat-resistant synthetic peptide (SVHRSP) is a pharmacologically active product synthesised from the amino acid sequence of scorpion venom heat-resistant peptide. In this study, we investigated the mechanism through which PM2.5 exposure aggravates neuronal pyroptosis and validated the protective effects of SVHRSP against AD. PC12 and HT22 neuronal cells were used to construct in vitro models of AD. Mice were stereotactically injected with Aβ25-35 protein to induce AD. Subsequently, PM2.5 exposure-induced changes in ER stress, pyroptosis, and oxidative stress in AD models, were detected through in vivo and in vitro experiments. The results indicated that PM2.5 exposure aggravated cognitive impairment, ER stress, and pyroptosis in mice with AD. Conversely, treatment with SVHRSP counteracted the damage induced by PM2.5 exposure. At a mechanistic level, PM2.5 might enhance oxidative stress and trigger pyroptosis by suppressing the expression of Nrf-2. These findings offer novel insights into the mechanisms through which PM2.5 exposure hastens the progression of AD and propose a promising strategy for the pharmacological treatment of AD.}, } @article {pmid40706761, year = {2025}, author = {Ohno, M}, title = {BACE1 as an early biomarker and its relevance to risk factors for Alzheimer's disease.}, journal = {Brain research bulletin}, volume = {230}, number = {}, pages = {111475}, doi = {10.1016/j.brainresbull.2025.111475}, pmid = {40706761}, issn = {1873-2747}, mesh = {Humans ; *Alzheimer Disease/metabolism/diagnosis ; *Amyloid Precursor Protein Secretases/metabolism ; *Aspartic Acid Endopeptidases/metabolism ; Biomarkers/metabolism ; Animals ; Risk Factors ; Amyloid beta-Peptides/metabolism ; }, abstract = {While the β-secretase BACE1 is responsible for the rate-limiting initial step to generate amyloid-β (Aβ) peptides, BACE1 inhibitor clinical trials have been halted due to a lack of efficacy and/or safety concerns at symptomatic/prodromal stages of Alzheimer's disease (AD). These trials were often targeted at high levels of BACE1 inhibition (>70 %) and ended up with signs of mild cognitive worsening instead of expected improvement. BACE1 concentration and activity are elevated in the cerebrospinal fluid and plasma/serum as well as brains of patients with mild cognitive impairment and AD dementia. Interestingly, recent evidence suggests that these fluid-based biomarkers reflective of BACE1 elevation may be associated with yet asymptomatic pathological changes in preclinical AD populations who are at high-risk for developing AD. Consistent with these findings, it has been demonstrated that exposures to major environmental and genetic risks such as diabetes, sleep disturbances, seizure, vascular disorders, stress, apolipoprotein E4, etc. converge on BACE1 elevation in humans and animal models, which may contribute to triggering sporadic AD. Moreover, vicious cycles exist between BACE1/Aβ elevations and certain prognostic conditions, further accelerating disease progression. Conversely, protective factors for AD are associated with reduced BACE1 level/activity. This review provides an overview of BACE1 alterations as common responses to a broad battery of AD risk and protective factors. The findings validate BACE1 as a biomarker for preclinical AD status that may be useful for earlier diagnosis and identifying subpopulations of individuals under AD risks who would benefit from preventive low-dose BACE1 inhibitor treatment with a higher probability.}, } @article {pmid40705095, year = {2025}, author = {Wang, C and Wang, L and Liu, X and Wang, J and Chen, M and Li, J}, title = {Ponicidin attenuates Aβ1-42-induced hippocampal cell injury through SIRT1 and PI3K/Akt pathways.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {752}, pmid = {40705095}, issn = {1573-4978}, support = {PW2022B-04//The Scientific Research Program of Shanghai Pudong New Area Health Commission (the Youth Program)/ ; ZQZR202427//the scientific research project of Shanghai Zhongqiao Vocational and Technical University/ ; }, mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; *Sirtuin 1/metabolism ; *Hippocampus/drug effects/metabolism/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Animals ; Signal Transduction/drug effects ; *Peptide Fragments/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Mice ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Neuroprotective Agents/pharmacology ; Cell Line ; Cell Survival/drug effects ; Neurons/drug effects/metabolism ; Alzheimer Disease/metabolism/drug therapy ; *Diterpenes/pharmacology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) accumulation that leads to synaptic dysfunction and neuronal death. Ponicidin, a natural diterpenoid, possesses anti-inflammatory and neuroprotective properties. However, its potential effects on Aβ-induced neurotoxicity remain unclear. This study investigated whether ponicidin ameliorates Aβ1-42-induced hippocampal neuronal injury by modulating SIRT1 and PI3K/Akt signaling pathways. METHODS: HT22 cells were exposed to Aβ1-42 to establish an in vitro AD model, followed by treatment with ponicidin. Cell viability, apoptosis, oxidative stress, and inflammatory responses were assessed using MTT assay, flow cytometry, ROS detection, and ELISA. Western blotting and qRT-PCR were performed to evaluate the expression of SIRT1, the components of the PI3K/Akt pathway, and neuroinflammation. RESULTS: Ponicidin significantly attenuated Aβ1-42-induced cytotoxicity, reduced oxidative stress, and suppressed apoptosis and inflammatory cytokine release. Mechanistically, ponicidin upregulated SIRT1 expression and activated PI3K/Akt pathway. The protective effects of ponicidin were reversed by the PI3K/Akt inhibitor EX-527, confirming the involvement of this pathway. CONCLUSION: These findings suggest that ponicidin exerts neuroprotective effects against Aβ1-42-induced hippocampal injury by enhancing SIRT1 and activating PI3K/Akt signaling, highlighting its potential as a therapeutic candidate for AD.}, } @article {pmid40703204, year = {2025}, author = {Ramanan, VK and Heckman, MG and Hofrenning, EI and Przybelski, SA and Graff-Radford, J and Lowe, VJ and Machulda, MM and Murray, ME and Algeciras-Schimnich, A and Figdore, DJ and Bennett, DA and Knopman, DS and Jack, CR and Petersen, RC and Ross, OA and Vemuri, P and , }, title = {Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition: Beyond APOE.}, journal = {Neurology. Genetics}, volume = {11}, number = {4}, pages = {e200266}, pmid = {40703204}, issn = {2376-7839}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: The APOE (apolipoprotein E) ε4 allele is the strongest known genetic risk factor for sporadic Alzheimer disease (AD) and for brain amyloidosis, an early marker of disease pathophysiology. However, APOE ε4 is present in only 25% of the general population and is by itself inadequate for explaining susceptibility to amyloid accumulation or AD diagnosis. Existing studies have been limited by potential confounding due to inclusion of individuals carrying APOE ε4 or ε2 (which has a modest protective association). We hypothesized that genome-wide association study (GWAS) and genetic risk score (GRS) analyses in APOE ε3/ε3 individuals would uniquely identify novel predictors of β-amyloid pathology in older adults. METHODS: We analyzed data from the Mayo Clinic Study of Aging (MCSA), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Rush Religious Orders Study and Memory and Aging Project. Frequency of APOE ε3/ε3 in those samples ranged from 48% to 61%. A GWAS was performed across 1,496 individuals with amyloid PET to identify candidate variants for GRS generation. Postmortem neuropathologic data (N = 710) were used to refine the variant list to capture high-likelihood true associations. An independent sample (N = 641) with plasma p-tau181 data was used for validation. RESULTS: The GWAS identified previously implicated (e.g., PICALM and RBFOX1) and novel potential associations with amyloid PET burden. A non-APOE GRS of top variants was strongly associated with amyloid PET levels in the MCSA (p = 4.34 × 10[-9], β = 5.88) and ADNI (p = 1.87 × 10[-8], β = 12.1) cohorts. In both cohorts, this non-APOE amyloid GRS outperformed a comparator GRS (based on variants associated with clinically diagnosed AD dementia risk) in explaining phenotypic variation. The non-APOE amyloid GRS was also associated with postmortem neuropathologic β-amyloid and neurofibrillary tangle burden and in an independent sample was associated with plasma p-tau181 concentrations (a robust indicator of cerebral amyloidosis). DISCUSSION: Our non-APOE amyloid GRS, which appropriately includes variants associated with amyloid deposition in APOE ɛ4/ɛ2 noncarriers, may advance personalized prediction of genetic susceptibility to β-amyloid accumulation within the large segment of the population that is APOE ε3/ε3. This may have future implications for risk modification, trial enrollment, and treatment selection.}, } @article {pmid40702815, year = {2025}, author = {Huo, Z and Yip, BH and Lee, AT and Cheng, ST and Chan, WC and Fung, AW and Ma, SL and Cheng, CP and Lai, FH and Wong, SY and Lam, LC}, title = {Healthcare utilization and economic costs of neurocognitive disorders in community-dwelling older Chinese adults: A comparison with 9 Asian economies.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {515-528}, doi = {10.1177/13872877251361057}, pmid = {40702815}, issn = {1875-8908}, mesh = {Humans ; Aged ; Male ; Female ; *Independent Living/economics ; *Health Care Costs/statistics & numerical data ; Hong Kong/epidemiology ; Cross-Sectional Studies ; Middle Aged ; *Neurocognitive Disorders/economics/epidemiology/therapy ; *Patient Acceptance of Health Care/statistics & numerical data ; Aged, 80 and over ; China/epidemiology ; *Cost of Illness ; East Asian People ; }, abstract = {BackgroundIt is increasing recognized that care for people with neurocognitive disorders (NCDs) is costly, and cost of NCDs can be highly context dependent.ObjectiveTo evaluate the healthcare utilization and economic costs of NCDs in Hong Kong, cross referencing with other Asian metropolitan cities.Methods461 older adults aged ≥60 (major NCD: 68, mild NCD: 264, normal cognition: 129) were recruited from a population-based cross-sectional survey, Hong Kong Mental Morbidity Survey for Older People. Healthcare utilization was collected by Resource Utilization of Dementia. Per person cost was estimated from a societal perspective and expressed in 2022 US dollars. Cost-associative factors were explored. Our findings were compared to cost-of-illness evidence in major Asian metropolitan cities by a systematic review.ResultsAnnual costs per community-living adult with mild and major NCD were US$5677 (95%CI: 4985-6465) and US$12,841 (9940-16,590) in Hong Kong. For those with major NCD, costs doubled in severer stages, and diagnosed cases incurred nearly 30% more costs than hidden cases. Dementia cost in Hong Kong was lower than other high-income Asian economies and mainland China, mainly due to methodological heterogeneities and lower utilization of social care services.ConclusionsThe great economic burden of NCDs in Hong Kong reflects a striking social and care needs, particularly in moderate and severe stages. Care planning should prepare for the blowout needs being revealed by hidden cases and the diversified needs by different stages and family caregivers. Region- and population-specific studies with rigor design are warranted to estimate cost-effectiveness of upcoming treatment strategies.}, } @article {pmid40702688, year = {2025}, author = {Song, X and Wang, Y and Zheng, K}, title = {Taurine ameliorates viral encephalitis by restoring PRKN-mediated mitophagy.}, journal = {Autophagy}, volume = {21}, number = {11}, pages = {2523-2525}, pmid = {40702688}, issn = {1554-8635}, mesh = {Animals ; *Mitophagy/drug effects ; Mice ; Humans ; *Encephalitis, Viral/drug therapy/metabolism/pathology ; Mitochondria/metabolism/drug effects ; Activating Transcription Factor 4/metabolism ; Herpesvirus 1, Human ; }, abstract = {Mitophagy is a selective type of autophagy that removes damaged mitochondria to maintain mitochondrial homeostasis and regulate the antiviral immune response. Despite increasing evidence that herpes simplex virus type 1 (HSV-1) infection causes mitochondrial damage, the regulatory mechanisms governing mitochondrial homeostasis and its biological implications in the context of HSV-1 infection and viral encephalitis remain unclear. In our recent work, we find that HSV-1 infection causes the accumulation of damaged mitochondria via defective mitophagy in vitro and in brain tissue of mice. The viral proteins ICP34.5 and US11 inhibit the EIF2S (eukaryotic translation initiation factor 2 subunit alpha)-ATF4 (activating transcription factor 4) axis to transcriptionally suppress PRKN/Parkin expression and subsequently impede PRKN-dependent mitophagy. Consequently, modulation of mitophagy significantly affects HSV-1 infection and NFKB/NF-κB-mediated neuroinflammation, as well as the severity of viral encephalitis in mice. Moreover, taurine, a metabolite differentially regulated by HSV-1 infection, transcriptionally promotes PRKN-mediated mitophagy, thereby limiting HSV-1 infection both in vitro and in vivo. This work reveals a protective function of mitophagy in restricting viral encephalitis and highlights the ATF4-PRKN axis as a potential therapeutic approach for the treatment of neurotropic virus-related diseases.Abbreviations: Aβ: amyloid β protein; AD: Alzheimer disease; ATF4: activating transcription factor 4; EIF2AK2/PKR: eukaryotic translation initiation factor 2 alpha kinase 2; EIF2S1: eukaryotic translation initiation factor 2 subunit alpha; HSE: herpes simplex encephalitis; HSV-1: herpes simplex virus type 1.}, } @article {pmid40702549, year = {2025}, author = {Zhang, P and Song, C and Shi, J and Wei, Z and Wang, J and Huang, W and Zhang, R and Wang, J and Yang, X and Wang, G and Gao, X and Zhang, Y and Chen, H and Wang, H}, title = {Endothelium-specific endoglin triggers astrocyte reactivity via extracellular vesicles in a mouse model of Alzheimer's disease.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {84}, pmid = {40702549}, issn = {1750-1326}, support = {82204374//National Natural Science Foundation of China/ ; 2022M722140//China Postdoctoral Science Foundation/ ; zyyzdxk-2023070//NATCM's Project of High-level Construction of Key TCM Disciplines/ ; STAR project 20230101//Shanghai Jiao Tong University Trans-med Awards Research/ ; QKHZYD-[2025]030//Central Government Guidance Funds for Local Scientific and Technological Development/ ; KFKT2024-02//Open Funds of Shanghai Jiao Tong University School of Medicine and Affiliated Hospital of Hebei University of Engineering/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Astrocytes/metabolism ; *Extracellular Vesicles/metabolism ; Mice ; Disease Models, Animal ; Humans ; *Endoglin/metabolism ; *Endothelial Cells/metabolism ; Mice, Transgenic ; Brain/metabolism ; Male ; Female ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder with a complex etiology that extends beyond the well-documented amyloid-β and tau pathologies. Growing evidence implicates cerebrovascular dysfunction, particularly brain microvascular endothelial cells (BMECs) dysfunction, as an early contributor to AD pathogenesis. However, how BMECs influence on neighboring astrocytes needs to be further explored. METHODS: We employed a multi-omics approach integrating bulk RNA sequencing of human BMECs with proteomic analysis of cerebrospinal fluid (CSF) from AD patients and cerebrovascular endothelial extracellular vesicles (CEEVs). The role of identified candidate proteins was investigated in vitro and in vivo utilizing CEEVs transplantation and BMEC-astrocyte co-cultures. Endothelial cell-specific knockdown or treatment with a monoclonal antibody was used to assess the functional consequences on cognitive impairment and AD pathology via two-photon imaging and behavioral experiments on APP/PS1 mice. RESULTS: The elevated endothelium-specific protein Endoglin (ENG) was identified in the brain and serum of AD individuals and APP/PS1 mice, and the supernatant of injured BMECs. ENG was released and delivered to adjacent astrocytes via CEEVs, and subsequently upregulated TGFBRI/Smad3 pathway in astrocytes, leading to astrocyte reactivity and the release of pro-inflammatory cytokines. Endothelial cell-specific ENG knockdown or treating with ENG monoclonal antibody Carotuximab significantly suppressed reactive astrocytes, reduced neuroinflammation, and improved cognitive performance of APP/PS1 mice. CONCLUSIONS: This study reveals a novel mechanism by which BMECs-derived ENG, delivered via CEEVs, drives astrocyte reactivity. These findings redefine the role of cerebrovascular dysfunction in AD pathogenesis and identify ENG as both a potential biomarker and a promising therapeutic target for AD.}, } @article {pmid40702219, year = {2025}, author = {Jamshidiha, S and Rezaee, A and Hajati, F and Golzan, M and Chiong, R}, title = {An explainable transformer model for Alzheimer's disease detection using retinal imaging.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {26773}, pmid = {40702219}, issn = {2045-2322}, support = {A24/2676//University of New England, Australia/ ; A24/2676//University of New England, Australia/ ; }, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Retina/diagnostic imaging/pathology ; Algorithms ; Aged ; Male ; Female ; Artificial Intelligence ; Image Processing, Computer-Assisted/methods ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions worldwide. In the absence of effective treatment options, early diagnosis is crucial for initiating management strategies to delay disease onset and slow down its progression. In this study, we propose Retformer, a novel transformer-based architecture for detecting AD using retinal imaging modalities, leveraging the power of transformers and explainable artificial intelligence. The Retformer model is trained on datasets of different modalities of retinal images from patients with AD and age-matched healthy controls, enabling it to learn complex patterns and relationships between image features and disease diagnosis. To provide insights into the decision-making process of our model, we employ the Gradient-weighted Class Activation Mapping algorithm to visualise the feature importance maps, highlighting the regions of the retinal images that contribute most significantly to the classification outcome. These findings are compared to existing clinical studies on detecting AD using retinal biomarkers, allowing us to identify the most important features for AD detection in each imaging modality. The Retformer model outperforms a variety of benchmark algorithms across different performance metrics by margins of up to 11%.}, } @article {pmid40701934, year = {2025}, author = {Ataman Sadık, D and Cansız, CS and Turğut, M and Dağ, Ç and Duman, M}, title = {Investigation of Methylsulfonamide's Capability to Prevent Zn[2+]-Induced Aβ Peptide Aggregation Based on Zn[2+] Coordination within the Zinc Binding Region of Aβ for Treatment of Alzheimer's Disease (AD).}, journal = {ACS chemical neuroscience}, volume = {16}, number = {15}, pages = {2945-2957}, doi = {10.1021/acschemneuro.5c00238}, pmid = {40701934}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism ; *Zinc/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Sulfonamides/pharmacology ; *Peptide Fragments/metabolism ; Humans ; Protein Aggregates/drug effects ; Protein Aggregation, Pathological/metabolism ; }, abstract = {There is no cure for Alzheimer's disease (AD) with the currently suggested therapies. Thus, designing and synthesis of new drugs for the treatment of Alzheimer's disease for safe and effective therapy have become an important task. Metal ions such as Zn[2+], Cu[2+], and Fe[3+] are known to increase the rate of Aβ aggregation and exist in amyloid plaques at high concentrations. Aβ oligomers, whether formed on the way to amyloid fibril formation or formed off-pathway due to the interaction of Aβ monomers with Zn[2+], are considered to be the most neurotoxic aggregates. Using NMR and SPR, this study reports the methylsulfonamide inhibition of Zn[2+]-induced Aβ1-16 dimer formation via methylsulfonamide coordination of Zn[2+] within the Zn[2+] binding region of Aβ, (11EVHH14) and inhibit the H14-Zn[2+] coordination between the 11EVHH14 regions of two Aβ peptides, preventing their interactions and hence the Aβ dimer formation. According to the results of this study, methylsulfonamide has the potential to be used as a drug in Alzheimer's disease for the prevention of the formation of the Zn[2+]-induced toxic Aβ oligomers formed during Aβ aggregation.}, } @article {pmid40701789, year = {2025}, author = {Mukherjee, S and Reddy, A and Dutta, N and Vaiphei, KK and Vivek, and Kumar, A and Gulbake, A}, title = {Exploring the potential of repurposed deferoxamine: bridging challenges and novel formulation opportunities.}, journal = {Nanomedicine (London, England)}, volume = {20}, number = {16}, pages = {2117-2141}, pmid = {40701789}, issn = {1748-6963}, mesh = {Humans ; *Deferoxamine/therapeutic use/chemistry/pharmacokinetics/pharmacology ; *Drug Repositioning ; Neoplasms/drug therapy ; Nanoparticles/chemistry ; Animals ; Drug Carriers/chemistry ; Drug Compounding ; Drug Delivery Systems ; }, abstract = {Since the FDA approval of deferoxamine mesylate (Desferal) in 1968, the characteristic low plasma half-life, low plasma protein binding (PB), constrained volume of distribution (Vd), and variety of adverse effects made the dosing, bioavailability, and patient compliance as the main hurdle for clinical application of Deferoxamine (DFO). Nevertheless, these pharmacokinetic and pharmacodynamic constraints have been lessened by recent developments in novel drug carrier systems, which has resulted in an increased acceptance of DFO. The effective use of this drug in the treatment of Alzheimer, Parkinson, cancer, wound healing, and ferroptosis has further increased its clinical importance. According to our literature search on various reputed databases such as ScienceDirect, Nature, Wiley, ACS, etc. accumulating results of last 18 years, there has been a significant increase in the overall number of studies conducted on various novel formulations and strategies regarding DFO e.g. polymeric nanoparticles, micelles, nanofibers, conjugates, photothermal therapy, etc. Clinical trial applications found on clinicaltrials.gov have doubled since 2020, and patent applications found on Google Patent have climbed by 320% since 2011. These results demonstrate DFO's versatility and its potential for usage not just in traditional applications but also as a repurposed therapeutic agent.}, } @article {pmid40701551, year = {2025}, author = {Shukla, S and Shukla, S and Sharma, S and Vasudeva, N and Khatri, R and Lather, A and Hooda, T}, title = {Neuroprotective Role of Eupalitin in Streptozotocin-Induced Diabetic Rats: In Silico and In Vivo Studies.}, journal = {Planta medica}, volume = {91}, number = {12}, pages = {664-675}, doi = {10.1055/a-2654-7657}, pmid = {40701551}, issn = {1439-0221}, mesh = {Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; *Diabetes Mellitus, Experimental/drug therapy ; Molecular Docking Simulation ; Male ; Rats ; Acetylcholinesterase/metabolism ; Streptozocin ; Rats, Wistar ; Oxidative Stress/drug effects ; Lipid Peroxidation/drug effects ; Brain/drug effects/metabolism ; Glutathione/metabolism ; Donepezil ; Memory/drug effects ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition with marked cognitive loss and impaired thinking abilities as well as spatial memory, working memory, and communication skills. Numerous studies have found that both type 1 and type 2 diabetes lead to neuropathological and neurobehavioral problems, which lead to notable cognitive dysfunction and deterioration in memory. The aims of this study are to find out the neuroprotective potential of eupalitin on memory in streptozotocin-induced diabetic rats and to evaluate its in silico binding affinity on acetylcholinesterase by using molecular docking studies. Eupalitin (dose 1 mg/kg/day) was used to study the behavior model and other biochemical parameters measurement in acute as well as chronic streptozotocin (STZ)-induced diabetic rats. Eupalitin treatment increased the level of acetylcholinesterase (AChE) and lipid peroxidation and decreased glutathione in STZ-infused diabetic rat's brain tissue, suggesting that this substance may modulate cognitive function that is altered by oxidative stress. Results were comparable to standard drugs metformin and donepezil. Docking score and molecular mechanics generalized born surface area (MMGBSA) study results of eupalitin in comparison with donepezil possess superior predicted binding affinity toward AChE. The level of Aβ (1 - 42) was considerably lower in the eupalitin-treated group than in the STZ-treated group during both the acute and chronic phases of treatment, but results were more prominent in the case of chronic-level treatment. In silico studies showed the binding affinity toward AChE. This result concluded that eupalitin antioxidant potential may be utilized as a therapy for diabetes mellitus (DM)-related cognitive impairment.}, } @article {pmid40701395, year = {2025}, author = {Yang, FG and Liang, YL and Wang, X and Wang, JT and Gao, W and Ye, QY and Li, XY and Yang, Y and Li, HL}, title = {The evolution of Alzheimer's disease: From mitochondria to microglia.}, journal = {Ageing research reviews}, volume = {111}, number = {}, pages = {102838}, doi = {10.1016/j.arr.2025.102838}, pmid = {40701395}, issn = {1872-9649}, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Microglia/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Oxidative Stress/physiology ; }, abstract = {Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide. Recent studies highlights that mitochondrial dysfunction drives alterations in microglial function, serving as a pivotal mechanism in the pathogenesis and progression of AD. Increasingly, there is evidence that mitochondrial dysfunction encompasses energy metabolism deficits, heightened oxidative stress, impaired mitochondrial dynamics, disrupted autophagy, and calcium homeostasis imbalances. These impairments modulate microglial activation states, precipitating exacerbated neuroinflammation, altered phagocytic capacity, and increased cellular apoptosis, collectively contributing to microglial dysfunction. This paper presents a narrative review on the relationship between mitochondrial dysfunction and AD, elucidating the impact of mitochondrial impairment on microglia. It summarizes therapeutic strategies that target mitochondria to modulate microglial function, aiming to prevent and treat AD. The goal is to provide new perspectives and insights for AD research and treatment, contributing to improving patients' quality of life and prognosis.}, } @article {pmid40701259, year = {2025}, author = {Dai, H and Huang, Y and Liu, Y and He, X and Guo, J and Prosperi, M and Bian, J}, title = {Variational temporal deconfounder network for individualized treatment effect estimation with longitudinal observational data.}, journal = {Journal of biomedical informatics}, volume = {169}, number = {}, pages = {104880}, pmid = {40701259}, issn = {1532-0480}, support = {RF1 AG084178/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; U01 AG088076/AG/NIA NIH HHS/United States ; R01 AG080991/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG084236/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; R01 AG080624/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; R01 AG083039/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; R01 AI172875/AI/NIAID NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; RF1 AG077820/AG/NIA NIH HHS/United States ; R01 AG076234/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; R01 AG089445/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Precision Medicine/methods ; *Electronic Health Records ; Longitudinal Studies ; Treatment Outcome ; Alzheimer Disease/therapy ; Algorithms ; }, abstract = {OBJECTIVE: By leveraging real-world electronic health record (EHR) data, this study set out to estimate individualized treatment effects (ITE) in longitudinal observational settings to advance personalized medicine, addressing key challenges that are often observed in real-world clinical scenarios and pose statistical challenges, including hidden confounding and dynamic treatment regimens. METHODS: We propose the Variational Temporal Deconfounder Network (VTDNet), a novel framework designed to account for time-varying hidden confounding using a variational recurrent transformer-based autoencoder. Specifically, VTDNet comprises three critical components: a temporal Encoder-Decoder structure to capture hidden representation, a Treatment Block that captures interdependencies among multiple treatments, and a Potential Outcome Block that predicts both factual and counterfactual outcomes. We assess the effectiveness of the proposed framework using a synthetic dataset and two real-world datasets: MIMIC-III, an EHR dataset focusing on intensive care settings, and NACC, emphasizing neurodegenerative disease, collected using a standardized protocol from participants enrolled in Alzheimer's Disease Research Center (ADRC) clinical cores. RESULTS: Experimental results on the synthetic dataset demonstrate superior accuracy under varying levels of confounding. On real-world EHR datasets, VTDNet achieves lower root mean squared error, mean absolute error, and influence function precision in the estimation of heterogeneous effects compared to existing state-of-the-art methods. CONCLUSION: The proposed VTDNet offers a robust framework for estimating individualized treatment effects in longitudinal settings, effectively accommodating irregular time points and high-dimensional data while addressing hidden confounders through a deep generative approach. It holds significant potential to advance personalized medicine and support real-world evidence generation. Future work will aim to extend VTDNet to continuous treatment scenarios, such as dose-response analysis, to further broaden its applicability in clinical practice.}, } @article {pmid40701134, year = {2025}, author = {Wu, N and Shao, Y and Wu, Z and Zhu, S and Wang, P and Zhu, Z and Zhang, C and Wu, C and Huo, X and Lin, H and Zhang, G}, title = {Electric field variations across DLPFC targeting methods in TMS therapy for Alzheimer's disease.}, journal = {NeuroImage. Clinical}, volume = {48}, number = {}, pages = {103847}, pmid = {40701134}, issn = {2213-1582}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology/diagnostic imaging ; *Transcranial Magnetic Stimulation/methods ; Male ; Female ; Aged ; Magnetic Resonance Imaging/methods ; *Dorsolateral Prefrontal Cortex/diagnostic imaging/physiopathology ; Middle Aged ; Aged, 80 and over ; }, abstract = {BACKGROUND: The dorsolateral prefrontal cortex (DLPFC) is crucial for cognitive control and a primary target for transcranial magnetic stimulation (TMS) in Alzheimer's disease (AD). However, understanding the distribution of TMS-induced electric field (E-field) across different targeting methods remains limited, as does its relationship to therapeutic outcomes. OBJECTIVE: This study assesses differences in TMS-induced E-field using functional versus anatomical targeting methods for DLPFC stimulation. METHODS: Functional and anatomical targets were identified in 30 (11 M/19F) AD patients and 30 (13 M/17F) age-matched healthy controls (HCs) using T1 and fMRI data. E-field characteristics, including magnitude (EROI) and normal component (E⊥), were calculated via SimNIBS software for comparisons across stimulation targets. RESULTS: Functional targeting showed greater spatial dispersion compared to anatomical targeting in both groups. Significant E-field differences were observed between the functional target and adjacent anatomical regions when the coil was positioned over the functional target in both groups. Optimal coil orientation exhibited directional specificity: parallel alignment with the LOI E-field produced higher field intensity in the functional target compared to the anatomical target (AD patients: P < 0.001; HCs: P = 0.052), while perpendicular orientation maintained functional stability with reduced anatomical interference (both groups: P < 0.001). And significant variations in E-field ratios were observed across coil orientations. CONCLUSION: This study reveals key E-field disparities across DLPFC targeting approaches and establishes coil orientation optimization as a critical strategy to improve TMS precision, offering actionable insights for developing personalized protocols in AD therapy that may enhance treatment efficacy while minimizing adverse effects.}, } @article {pmid40700403, year = {2025}, author = {Hook, V and Podvin, S and Yoon, MC and Phan, VV and Florio, J and Spencer, B and Mosier, C and Cheng, A and Ahuett, S and Almaliti, J and Gerwick, WH and Rissman, RA and O'Donoghue, AJ}, title = {Neutral pH-Selective Inhibition of Cytosolic Cathepsin B: A Novel Drug Targeting Strategy for Traumatic Brain Injury and Alzheimer's Disease.}, journal = {ACS chemical biology}, volume = {20}, number = {8}, pages = {1841-1848}, pmid = {40700403}, issn = {1554-8937}, support = {R01 NS109075/NS/NINDS NIH HHS/United States ; R21 AT013004/AT/NCCIH NIH HHS/United States ; }, mesh = {*Cathepsin B/antagonists & inhibitors/metabolism ; Hydrogen-Ion Concentration ; *Brain Injuries, Traumatic/drug therapy/metabolism/enzymology ; Animals ; *Alzheimer Disease/drug therapy/metabolism/enzymology ; Humans ; *Cytosol/metabolism/enzymology/drug effects ; Mice ; Lysosomes ; }, abstract = {Cathepsin B contributes to the behavioral deficits and neuropathology that occur in traumatic brain injury (TBI) and Alzheimer's disease (AD). TBI and AD patients display elevated levels of cathepsin B that correlate with the severity of injury or cognitive deficits, respectively. In animal models of TBI and AD, cathepsin B gene knockout ameliorates behavioral deficits and improves neuropathology. While cathepsin B is normally located in acidic lysosomes, during TBI and AD, lysosomal leakage results in the translocation of cathepsin B to the neutral pH environment of the cytosol, thereby initiating neurodegeneration. Neutral pH-selective inhibitors are hypothesized to specifically target the pathogenic cytosolic cathepsin B without affecting its normal lysosomal form. Therefore, this review focuses on a novel strategy to utilize pH-dependent substrate cleavage properties of cathepsin B for the design of a neutral pH-selective inhibitor. Investigation of the enzymatic properties of cathepsin B at different pH conditions led to the development of Z-Arg-Lys-AOMK, a neutral pH-selective inhibitor that does not affect the enzyme's activity at normal lysosomal acidic pH. Z-Arg-Lys-AOMK potently inhibits cathepsin B at nM concentrations and effectively inhibits cellular cathepsin B in neuronal cell cultures at similar levels. In mice subjected to controlled cortical impact (CCI) brain injury, a model of TBI, cytosolic cathepsin B activity was significantly elevated in the brain. Treatment of the CCI-TBI mice with Z-Arg-Lys-AOMK reduced cytosolic cathepsin B activity and resulted in less motor dysfunction. These findings show that pH-dependent cleavage properties of cathepsin B can be utilized for the development of selective inhibitors to target the neutral cytosolic form of cathepsin B. The new concept of pH-selective inhibitors of cathepsin B reveals novel opportunities for targeting pathogenic, cytosolic cathepsin B involved in brain disorders.}, } @article {pmid40700397, year = {2025}, author = {Jamal, QMS and Alharbi, AH and Ahmad, V and Ahmad, K}, title = {Integrated in silico identification of cholinesterase inhibitors from Nyctanthes arbor-tristis.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0328457}, pmid = {40700397}, issn = {1932-6203}, mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology ; Butyrylcholinesterase/metabolism/chemistry ; Molecular Dynamics Simulation ; Humans ; Acetylcholinesterase/metabolism/chemistry ; Molecular Docking Simulation ; Computer Simulation ; Alzheimer Disease/drug therapy ; *Plant Extracts/chemistry/pharmacology ; }, abstract = {Alzheimer's disease (AD) remains a major neurodegenerative disorder, characterized by cognitive decline alongside functional impairments that affect daily living. Natural therapeutic alternatives have spurred the search for novel inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two well-established targets in AD therapy. This study utilizes an in silico methodology to investigate new cholinesterase inhibitors sourced from Nyctanthes arbor-tristis, a plant known for its abundant bioactive phytochemicals. Through virtual screening, molecular dynamics simulations (MDS), free energy landscape analysis, and ADMET predictions, eight compounds have been identified as potential inhibitors of AChE and/or BChE. These compounds include Apigenin, Arborside-B, Arbortristoside-D, Arbortristoside-E, Nicotiflorin, Arborside-A, Beta-amyrin, and Nyctanthic acid. These compounds exhibited robust binding affinities compared to the control, advantageous ADMET profiles, and sustained stability throughout 200 ns of MDS and energy assessments, highlighting their potential as viable drug candidates for further exploration. Further experimental studies are required to validate their therapeutic efficacies, thereby confirming their potential as neurological therapeutics for the treatment of AD and related disabilities.}, } @article {pmid40699791, year = {2025}, author = {Klein, BY and Gofrit, ON and Greenblatt, CL}, title = {Testing Protein Stress Signals in Peripheral Immunocytes Under the Same Treatment Capable of Decreasing the Incidence of Alzheimer's Disease in Bladder Cancer Patients.}, journal = {Current issues in molecular biology}, volume = {47}, number = {6}, pages = {}, pmid = {40699791}, issn = {1467-3045}, abstract = {Several studies showed that the incidence of Alzheimer's disease (AD) is significantly lower in patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical bacillus Calmette-Guérin (BCG) instillations compared to treatment by alternative methods. Hypothetically, failure to clear misfolded and aggregated proteins (i.e., beta-amyloid) in AD brains and peripheral blood mononuclear cells (PBMCs) implicates BCG in upgrading the unfolded protein response (UPR). To test this hypothesis, pre- versus post-BCG PBMC proteins of the UPR pathway were compared in six NMIBC patients by capillary immunoelectrophoresis on an Abby instrument. PERK, the endoplasmic reticulum (ER) resident kinase, a stress-activated sensor, and its substrate alpha component of the eIF2 translation factor (eIF2a) complex inactivation were considered as potentially proapoptotic via a downstream proapoptotic transcription factor only if persistently high. GAPDH, a glycolytic marker of innate immunocyte training by BCG, and eight other UPR proteins were considered antiapoptotic. Summation of antiapoptotic %change scores per patient showed that the older the age, the lower the antiapoptotic %change. Higher antiapoptotic scores were observed upon a longer time from BCG treatment (with the exception of the patient in her ninth decade of life). Studies with more individuals could substantiate that BCG enhances the antiapoptotic aggregate-clearance effect of the UPR in PBMCs of NMIBC patients, which hypothetically protects brain cells against AD.}, } @article {pmid40698680, year = {2025}, author = {Rohilla, S and Goyal, G}, title = {Computer-aided Drug Design for Alzheimer's Disease: Recent Advancements and Future Perspectives.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266343814250713100224}, pmid = {40698680}, issn = {1873-4294}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by a decline in cognitive function and memory loss, primarily resulting from cholinergic dysfunction, the accumulation of amyloid plaques, the formation of tau tangles, and the progressive degeneration of neurons. While existing treatments offer limited symptomatic relief, they do not effectively halt or reverse the underlying progression of the disease, presenting a major global challenge in Alzheimer's research. Developing therapeutic strategies for AD remains complex, largely due to the inability of current medications to significantly slow neurodegeneration. Traditional drug discovery processes are often lengthy, costly, and inefficient, further complicating the search for effective treatments. To overcome these obstacles, researchers have turned to a combination of computational approaches alongside conventional drug design techniques. These integrated methodologies help accelerate the discovery process by significantly reducing both time and costs. This review delves into the underlying physiological and pathological mechanisms of Alzheimer's disease, while identifying potential drug targets such as acetylcholinesterase, butyrylcholinesterase, β-Secretase (BACE-1), A2A adenosine receptor, Dickkopf-1 protein, glycogen synthase kinase-3β, indoleamine 2,3-dioxygenase, monoamine oxidase-B, NMDA receptor, Wnt inhibitory factor, cyclindependent kinase-5, glutaminyl cyclase, and cathepsin-B. Furthermore, the review examines various computer-aided drug design (CADD) methodologies, including structure-based and ligandbased approaches, virtual screening, pharmacophore modeling, molecular modelling, and simulation techniques. These computational strategies are playing an increasingly important role in Alzheimer's research, particularly in drug discovery. By investigating promising drug candidates and lead molecules that target key proteins involved in Alzheimer's pathogenesis, the review highlights their binding modes with these targets and assesses the chemical properties essential for the development of effective clinical candidates. The aim is to provide researchers with critical insights and tools to design novel compounds with the necessary chemical and physical characteristics required for the successful treatment of Alzheimer's disease.}, } @article {pmid40698455, year = {2025}, author = {Topalis, V and Voros, C and Ziaka, M}, title = {Targeting Inflammation in Alzheimer's Disease: Insights Into Pathophysiology and Therapeutic Avenues-A Comprehensive Review.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {8919887251361578}, doi = {10.1177/08919887251361578}, pmid = {40698455}, issn = {1552-5708}, abstract = {Alzheimer's Disease (AD) is the most common dementia, affecting mainly older adults, particularly over 65. Characterized by progressive cognitive decline-including deficits in memory, executive functions, and language, alongside behavioral disturbances-AD arises from complex pathophysiological mechanisms. These include neurotransmitter imbalances, cholinergic deficits, amyloid-beta (Aβ) toxicity, tau protein hyperphosphorylation, oxidative stress, synaptic dysfunction, and neuroinflammatory processes. Growing evidence highlights the protective role of microglia in AD pathology through their immune functions, phagocytic clearance of Aβ proteins, and trophic support to promote tissue repair and maintain cerebral homeostasis, as alterations in their response to Aβ are linked to an increased risk of AD. However, disruptions in homeostasis or tissue alterations may trigger microglial activation, leading to detrimental effects such as increased inflammatory activity, impaired microglial-mediated clearance, synapse loss, and neuronal damage. Astrocytes, a distinct type of glial cell with homeostatic functions, also exhibit neuroprotective effects. However, the presence of Aβ may result in astrocyte reactivity, leading to neurotoxic effects associated with disturbances of calcium levels, activation of proinflammatory pathways, gliotransmission, altered tau metabolism, and impaired clearance of Aβ. Despite substantial research, AD remains challenging to diagnose early and lacks effective treatments. Given its multifactorial nature, therapeutic approaches primarily aim to slow progression and remain limited in achieving a definitive cure. While most current strategies focus on mitigating the toxic effects of Aβ and tau proteins, growing interest has emerged in addressing neuroinflammation as a potential means to delay or prevent neurodegeneration. Targeting neuroinflammation could open new therapeutic avenues for the treatment of AD.}, } @article {pmid40698100, year = {2025}, author = {Singh, D and Singhal, S and Kanaujiya, V and Ranjan, A and Mani, VE and Paliwal, VK and Jain, V and Aishwarya, A and Agarwal, R}, title = {Ganglion Cell Layer Thickness as a Biomarker for Amyotrophic Lateral Sclerosis Functional Outcome: An OCT study.}, journal = {Romanian journal of ophthalmology}, volume = {69}, number = {2}, pages = {200-207}, pmid = {40698100}, issn = {2501-2533}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; *Retinal Ganglion Cells/pathology ; *Visual Acuity/physiology ; *Nerve Fibers/pathology ; Adult ; *Optic Disk/pathology ; Aged ; Intraocular Pressure/physiology ; Biomarkers ; }, abstract = {AIM: This study aims to evaluate various optical coherence tomography (OCT) parameters in patients diagnosed with amyotrophic lateral sclerosis (ALS). METHODS: Assessment of BCVA was done using Snellen charts, and subjective refraction was done to achieve a BCVA for distance and near. Measurement of intraocular pressure (IOP) was done with Goldman applanation tonometry. Stereoscopic fundus examination was performed using a 90D lens to assess the status of the optic nerve and retina, ruling out any ocular pathology. The patients were then subjected to OCT scanning to measure optic nerve head and macular parameters. Optical coherence tomography was performed using CIRRUS™ HD OCT (500-21822) (version 8.0.0.518) (Carl Zeiss Meditec, Dublin, CA, USA). The analyzed area was centered manually, and the absence of segmentation errors was confirmed for each scan. RESULTS: RE Avg RNFL and LE Avg RNFL showed weak correlations with ALSFRS, indicated by Pearson Correlation coefficients of 0.073 and -0.026, respectively. The p-values (0.637 and 0.86) suggested that these correlations were not statistically significant. RE Avg GCL and LE Avg GCL, on the other hand, exhibited moderate positive correlations with ALSFRS scores, with correlation coefficients of 0.337 (RE) and 0.389 (LE). These correlations were statistically significant, as indicated by p-values of 0.021 and 0.006, respectively, suggesting a substantial association between GCL thickness and ALS functional outcomes. DISCUSSION: All patients in our study were clinically diagnosed cases of ALS, as per the El Escorial criteria. Age group-wise analysis showed statistically significant thinning overall as well as quadrant-wise RNFL parameters in patients less than 50 years compared to age-matched controls, indicating that the pathological process occurring in larger motor neurons in ALS might also be happening in smaller sensory neurons of the retina, causing thinning, which was not due to age-related process. Although GCIPL thinning was occurring in our cases, though statistically not significant compared to control, the significant positive correlation observed between GCIPL and ALS functional outcome and between RNFL and GCIPL measurements highlighted the fact that though the axonal degeneration in retinal neurons might not be translating to the same extent in ganglion cells in ALS, the subtle thinning of GCIPL correlated strongly with functional disability in patients with ALS, implying better functional scores with higher values of GCIPL parameters. CONCLUSION: In summary, GCL measurements in both eyes showed a notable relationship with ALSFRS, whereas RNFL did not appear to correlate significantly.}, } @article {pmid40697975, year = {2025}, author = {Gogu, P and Bharti, J and Yadav, JP and Grishina, M and Verma, A and Kumar, V and Singh, AK and Verma, A and Kumar, P and Khalilullah, H and Jaremko, M and Emwas, AH and Dwivedi, AR and Pathak, P}, title = {Exploring GPR120/FFAR4 pharmacology: Unveiling novel therapeutic avenues through molecular signaling pathways for Alzheimer's disease intervention.}, journal = {Brain, behavior, & immunity - health}, volume = {48}, number = {}, pages = {101061}, pmid = {40697975}, issn = {2666-3546}, abstract = {G-protein-coupled receptors (GPCRs) are a major class of membrane proteins involved in numerous physiological and pathological processes. Among them, free fatty acid receptor 4 (FFAR4/GPR120), activated by long-chain free fatty acids, has shown anti-inflammatory effects and is expressed in the brain-implicating its role in neurodegenerative diseases like Alzheimer's disease (AD). AD is characterized by brain atrophy, cognitive decline, and neuroinflammation, involving complex signaling networks. This review explores the pharmacological relevance of GPR120/FFAR4 in AD, focusing on its involvement in neuroinflammatory, amyloidogenic, and intracellular signaling cascades. Targeting GPR120 may help modulate chronic inflammation and amyloid-β accumulation. Additionally, activation of nuclear receptors and regulation of pathways such as MAPK, NLRP3, PPARs, and cAMP have shown promise in mitigating AD pathology. Despite the complexity of brain signaling, GPR120 emerges as a compelling multitarget therapeutic receptor. These insights provide a foundation for developing novel anti-inflammatory strategies in AD treatment.}, } @article {pmid40697447, year = {2025}, author = {Senanayake, D and Yapa, P and Dabare, S and Munaweera, I}, title = {Precision targeting of the CNS: recent progress in brain-directed nanodrug delivery.}, journal = {RSC advances}, volume = {15}, number = {32}, pages = {25910-25928}, pmid = {40697447}, issn = {2046-2069}, abstract = {The therapeutic drug penetration into brain tissues meets limitations through the restrictive function of the blood-brain barrier (BBB) within the central nervous system (CNS). The advancement of nanocarrier engineering techniques allows scientists to develop nanoscale delivery vehicles that successfully cross the BBB. This review analyses modern brain-delivery nanodrug delivery platforms by examining the properties and distribution of liposomes and polymeric nanoparticles, dendrimers, solid lipid nanoparticles, and exosomes. Organizations use specific physicochemical approaches designed for each platform to boost brain penetration and enhance therapeutic drug distribution for improving drug effectiveness. An analysis is presented of the various procedures to cross or bypass the BBB where receptor-mediated transcytosis joins focused ultrasound, as well as magnetic targeting and chemical modifications. The article presents therapeutic developments regarding neurological treatment of Alzheimer's disease, alongside Parkinson's disease and glioblastoma. Early laboratory success has produced promising results, yet challenges persist during the translation of these findings for clinical use because of safety issues as well as compatibility problems and difficulties with scaling up manufacturing processes. Finally, it discusses regulatory advancements and describes active market trends in nanomedicine that focus on precise delivery techniques and combination treatment methods, and brain-targeted delivery systems. The innovations combined present an optimistic future for CNS drug development because they create substantial opportunities to reshape neurological disorder treatments.}, } @article {pmid40697193, year = {2025}, author = {Zhang, L and Wu, Y and Jin, Q and Wang, C}, title = {Association between genetically proxied PPARG activation and early onset Alzheimer's disease: A drug target Mendelian randomization study.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251359579}, pmid = {40697193}, issn = {2542-4823}, abstract = {BACKGROUND: Early-onset Alzheimer's disease (EOAD), which has an onset before the age of 65, is overshadowed by the more prevalent late-onset Alzheimer's disease (LOAD). Nevertheless, rather than being merely a form of LOAD that occurs at a prematurely defined younger age, EOAD differs from LOAD in multiple ways. Given these disparities, understanding the potential treatment options for EOAD becomes crucial. OBJECTIVE: We aim to assess anti-diabetic drugs' potential utility in treating EOAD and LOAD from a novel perspective via drug-targeted Mendelian randomization (MR) analysis. METHODS: Through Summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) analysis, we assessed the associations between anti-diabetic drug targets (including DPP-4 inhibitor, Thiazolidinedione, GLP1R agonist, Sulfonylureas, SLC5A2 inhibitor, and Insulin/Insulin analog) and AD outcomes (EOAD and LOAD). We utilized two types of genetic instruments to represent the exposure to anti-diabetic drugs: eQTLs of genes encoding drug target proteins and genetic variants within or near genes encoding these target proteins associated with HbA1c from genome-wide association studies. RESULTS: SMR analysis showed that enhanced PPARG gene expression in the blood was a protective factor for EOAD (OR = 0.733, 95%CI = 0.548-0.979, p = 0.035). Additionally, an IVW-MR association was found between HbA1c mediated by PPARG and EOAD (OR = 0.295, 95%CI = 0.092-0.949, p = 0.041). CONCLUSIONS: This study suggests that Thiazolidinedione therapy could help suppress the development of EOAD, supporting further exploration of PPARG-targeted anti-diabetic drug development.}, } @article {pmid40696527, year = {2025}, author = {Jeon, SY and Wang, SM and Roh, HW and Kim, KY and Chang, YY and Kim, E and Bae, JN and Ryu, SH}, title = {Practical Guide of the Korean Association for Geriatric Psychiatry to Anti-Amyloid Monoclonal Antibody Therapy for Alzheimer's Disease: Focused on Lecanemab.}, journal = {Journal of Korean medical science}, volume = {40}, number = {28}, pages = {e215}, pmid = {40696527}, issn = {1598-6357}, support = {//Korean Association for Geriatric Psychiatry/Korea ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology ; Republic of Korea ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Amyloid beta-Peptides/antagonists & inhibitors/immunology ; Aged ; Antibodies, Monoclonal/therapeutic use ; }, abstract = {The advent of anti-amyloid monoclonal antibody (mAb) therapies represents a paradigm shift in the treatment of Alzheimer's disease (AD), from symptomatic relief to disease modification. Lecanemab, a humanized mAb targeting soluble Aβ protofibrils and plaque, received regulatory approval in Korea in July 2024, following global randomized controlled trial data demonstrating its efficacy to reduce amyloid burden and slow cognitive decline. However, the introduction of such therapies into routine clinical realm presents several practical and systemic challenges, particularly in the context of Korea's unique healthcare infrastructure and reimbursement environment. In response, the Korean Association for Geriatric Psychiatry has developed the first comprehensive domestic guidance to facilitate the safe, evidence-based, and patient-centered use of anti-amyloid mAb therapies, first focused on lecanemab. This practical guide goes beyond simple eligibility criteria. It provides detailed recommendations on clinical and imaging-based candidate selection, amyloid-related imaging abnormalities (ARIA) risk stratification and monitoring protocols, infusion workflows, adverse event management strategies, and multidisciplinary coordination within hospital systems. It also emphasizes shared decision-making and outlines how to navigate situations where treatment is not appropriate, such as in patients with advanced dementia, high-risk magnetic resonance imaging findings, or poor treatment adherence, reinforcing that non-treatment can also represent a legitimate, evidence-based clinical decision. The guidance further highlights the urgent need to generate real-world data that reflect the treatment experiences of Korean patients. Multicenter collaboration will be essential for collecting data on adherence rates, ARIA incidence, cognitive outcomes, and functional trajectories, which in turn can inform policy decisions, insurance reimbursement models, and future updates to clinical guidelines. This publication represents the first nationwide roadmap in Korea to support clinicians in the appropriate integration of monoclonal antibody therapies for AD. By combining scientific rigor, operational feasibility, and ethical sensitivity, it aims to promote safe and responsible adoption of disease-modifying treatment across various clinical settings.}, } @article {pmid40696469, year = {2025}, author = {Oosthoek, M and Vijverberg, EGB and Blujdea, ER and Veld, SGJGI and Avilés, MP and Zsadanyi, SE and Hok-A-Hin, YS and Visser, A and van der Flier, WM and Barkhof, F and Del Campo, M and Schut, MC and Bejanin, A and Alcolea, D and Teunissen, CE and Vermunt, L}, title = {CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer's disease patients.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {169}, pmid = {40696469}, issn = {1758-9193}, support = {WE.03-2018-05//Alzheimer Nederland/ ; WE.03-2018-05//Alzheimer Nederland/ ; NR170065//Selfridges Group Foundation/ ; NR170065//Selfridges Group Foundation/ ; PI21/00791, PI14/01126, PI17/01019, PI20/01473, PI13/01532, PI16/01825, PI18/00335, PI19/00882, PI18/00435, PI22/00611, INT19/00016, INT23/00048, PI17/01896 and AC19/00103//Fondo de Investigaciones Sanitario/ ; PI21/00791, PI14/01126, PI17/01019, PI20/01473, PI13/01532, PI16/01825, PI18/00335, PI19/00882, PI18/00435, PI22/00611, INT19/00016, INT23/00048, PI17/01896 and AC19/00103//Fondo de Investigaciones Sanitario/ ; Program 1, Alzheimer Disease//CIBERNED program/ ; Program 1, Alzheimer Disease//CIBERNED program/ ; NIA grants 1R01AG056850-01A1; R21AG056974; and R01AG061566),//Office of Dietary Supplements/ ; NIA grants 1R01AG056850-01A1; R21AG056974; and R01AG061566),//Office of Dietary Supplements/ ; 2017-SGR-547, SLT006/17/125, SLT006/17/119, SLT002/16/408//Generalitat de Catalunya/ ; 2017-SGR-547, SLT006/17/125, SLT006/17/119, SLT002/16/408//Generalitat de Catalunya/ ; 20141210, 044412 and 20142610//Fundació la Marató de TV3/ ; 20141210, 044412 and 20142610//Fundació la Marató de TV3/ ; }, mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/genetics ; Male ; Female ; Aged ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; *Hexosaminidases/cerebrospinal fluid ; Cohort Studies ; Proteomics ; Peptide Fragments/cerebrospinal fluid ; Chitinase-3-Like Protein 1 ; }, abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) are a common and potentially dangerous side effect in anti-amyloid therapies, creating a need for tools to assess ARIA risk. Several patient factors have been linked to ARIA; namely the presence of microbleeds (MBL[+]), APOE E4 carriership (APOE4[+]), and extremely low CSF Aβ42 concentrations (A[L]). We hypothesize that studying the CSF proteome of Alzheimer's disease (AD) dementia patients from a high-risk group (MBL[+]APOE4[+]A[L]) can inform on the biological underpinnings of ARIA risk and aid the progress of ARIA risk biomarkers. METHODS: We utilized CSF proteomic data of AD (n = 156) and cognitively unimpaired individuals (CU n = 100) of the Amsterdam Dementia Cohort. The proteome of the defined high-risk (n = 13) was compared to low-risk AD group (n = 23), using age and sex corrected linear regressions followed by gene ontology analysis. For biomarker prioritization, we selected proteins that were abnormal in the high-risk group versus low-risk and CU patients. The biomarkers were validated in an independent cohort (high risk n = 14, low risk n = 9) analyzed using customized multiplex panels. Lastly, we assessed biomarker lead co-expression. RESULTS: Ninety-four proteins differentiated in the high-risk group compared to low-risk (p < 0.05), none surviving FDR correction. These proteins were enriched for synapse-related proteins and axonogenesis. CHIT1 (vs. low-risk AD: FC = 1.0, p = 0.014, vs. CU: FC = 2.4, p < 0.001) and DDAH1 (vs. low-risk AD: FC=-0.31, p = 0.046, vs. CU: FC = 0.5, p < 0.001) were prioritized as biomarker. DDAH1 protein changes replicated in an independent cohort (FC=-0.37, p = 0.010), and CHIT1 replicated on a trend level (FC = 0.70, p = 0.104). DDAH1 levels had the highest co-expression with synaptic process, energy utilization and RNA-binding cell signaling related proteins (R > 0.8). CONCLUSIONS: The findings suggest that in the high risk group, there is a lack of upregulation in synapse and axonogenesis related proteins. High CSF CHIT1 and less increased CSF DDAH1 levels within AD relate to ARIA risk. From the literature, the link to ARIA risk for CHIT1 could be its contribution to innate immunity or vascular amyloid deposition, and for DDAH1 to blood-brain barrier integrity. Biomarker assays are available to assess the potential of CHIT1 and DDAH1 in trials and treatment studies in the clinical setting.}, } @article {pmid40695613, year = {2025}, author = {Sun, M and Wang, X and Lu, Z and Yang, Y and Lv, S and Miao, M and Chen, WM and Wu, SY and Zhang, J}, title = {Evaluating GLP-1 receptor agonists versus metformin as first-line therapy for reducing dementia risk in type 2 diabetes.}, journal = {BMJ open diabetes research & care}, volume = {13}, number = {4}, pages = {}, pmid = {40695613}, issn = {2052-4897}, mesh = {Humans ; *Metformin/therapeutic use ; *Diabetes Mellitus, Type 2/drug therapy/complications ; Male ; Female ; *Dementia/prevention & control/epidemiology/etiology ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Hypoglycemic Agents/therapeutic use ; Retrospective Studies ; Aged ; Middle Aged ; Risk Factors ; Follow-Up Studies ; Incidence ; Aged, 80 and over ; }, abstract = {INTRODUCTION: No direct comparisons have evaluated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus metformin as first-line antidiabetic therapy for preventing dementia in patients with type 2 diabetes mellitus (T2DM). This study aimed to assess the comparative effectiveness of GLP-1 RAs and metformin in reducing dementia risk. RESEARCH DESIGN AND METHODS: This retrospective cohort study used data from a global health research network between 2004 and 2024. Patients with T2DM initiating GLP-1 RAs or metformin as first-line monotherapy were included. Propensity score matching was employed to balance baseline characteristics. Dementia incidence was analyzed using Cox proportional hazards models, with sensitivity analyses to confirm robustness. RESULTS: Among 87,229 matched patients per cohort, GLP-1 RA use was associated with a significantly lower risk of overall dementia (adjusted HR (AHR) 0.90; 95% CI 0.85 to 0.95), Alzheimer's disease (AD) (AHR 0.88; 95% CI 0.83 to 0.94), and non-vascular dementias (non-VaDs) (AHR 0.75; 95% CI 0.70 to 0.81) compared with metformin. No significant difference was observed for VaD. Subgroup analyses showed consistent benefit across age and sex, with the strongest effect among older adults and females. CONCLUSIONS: GLP-1 RAs were more effective than metformin in reducing the risk of dementia-especially AD and non-vascular types-highlighting their potential as a preferred first-line treatment in T2DM. Further randomized trials are warranted to validate these findings.}, } @article {pmid40695276, year = {2025}, author = {Li, Y and Pereda Serras, C and Blumenfeld, J and Xie, M and Hao, Y and Deng, E and Chun, YY and Holtzman, J and An, A and Yoon, SY and Tang, X and Rao, A and Woldemariam, S and Tang, A and Zhang, A and Simms, J and Lo, I and Oskotsky, T and Keiser, MJ and Huang, Y and Sirota, M}, title = {Cell-type-directed network-correcting combination therapy for Alzheimer's disease.}, journal = {Cell}, volume = {188}, number = {20}, pages = {5516-5534.e18}, pmid = {40695276}, issn = {1097-4172}, support = {R01 AG060393/AG/NIA NIH HHS/United States ; R01 AG078164/AG/NIA NIH HHS/United States ; P01 AG073082/AG/NIA NIH HHS/United States ; R01 AG057683/AG/NIA NIH HHS/United States ; RF1 AG076647/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/drug therapy/genetics/pathology/metabolism ; Animals ; Mice ; Humans ; Disease Models, Animal ; Drug Therapy, Combination ; Irinotecan/therapeutic use/pharmacology ; Neurons/metabolism/drug effects ; Transcriptome/drug effects ; Gene Regulatory Networks/drug effects ; Neuroglia/metabolism/drug effects ; Nitriles/therapeutic use/pharmacology ; Triazoles/therapeutic use/pharmacology ; Single-Cell Analysis ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Mice, Transgenic ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were identified as a potential combination therapy, each targeting AD-related gene expression changes in neurons and glial cells, respectively. In an AD mouse model with both Aβ and tau deposits, this combination therapy significantly improved memory performance and reduced AD-related pathologies compared with vehicle and single-drug treatments. Single-nucleus transcriptomic analysis confirmed that the therapy reversed disease-associated gene networks in a cell-type-specific manner. These results highlight the promise of cell-type-directed combination therapies in addressing multifactorial diseases like AD and lay the groundwork for precision medicine tailored to patient-specific transcriptomic and clinical profiles.}, } @article {pmid40695043, year = {2025}, author = {Kritika, and Sanjay, and Lee, HJ}, title = {Eriocitrin and its derivatives against Alzheimer's disease: Cumulative accounts of in vitro and in vivo studies.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {190}, number = {}, pages = {118362}, doi = {10.1016/j.biopha.2025.118362}, pmid = {40695043}, issn = {1950-6007}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Flavanones/therapeutic use/pharmacology/chemistry ; *Brain/drug effects/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease (ND), and its adversities are not limited to the brain. Due to complex and interconnected pathologies with other NDs, an effective treatment for multidimensional AD-related adversities has yet to be reported. Several phytoconstituents have been reported and are currently being studied for their bioactive potential in AD. Eriocitrin, a dihydroflavonoid compound present in citrus fruits, such as lemons, limes, lemon peels, grapefruit, and vegetables, and processed items, such as beverages and wine, along with its derivatives hesperetin, hesperidin, eriodictyol, and homoeriodictyol, has been reported to possess various neuroprotective bioactivities, including anti-inflammatory, anti-oxidative, anti-amyloidogenic, anti-tau phosphorylation, and anti-apoptotic properties, in several in vitro and in vivo models. However, a comprehensive review summarizing and correlating the multidimensional bioactive potentials of eriocitrin and its derivatives against AD has yet to be compiled. This review extensively discusses the in-depth role of eriocitrin and its derivatives in ameliorating different AD-related signaling pathways both in vitro and in vivo, and summarizes the incorporation of eriocitrin like different plant-based flavonoids in long-term dietary practice to combat AD and other similar NDs. Additionally, this review suggests examining various nano-formulations of eriocitrin and its derivatives for their anti-AD effects in comparison to the parent compound. Furthermore, in-depth in vitro and in vivo studies, along with different clinical trials, should be conducted to fully elucidate the true potential of eriocitrin and its derivatives in AD pathology.}, } @article {pmid40694204, year = {2025}, author = {Goleij, P and Khazeei Tabari, MA and Poudineh, M and Sanaye, PM and Khan, H and Kumar, AP and Larsen, DS and Daglia, M}, title = {Therapeutic potential of melatonin-induced mitophagy in the pathogenesis of Alzheimer's disease.}, journal = {Inflammopharmacology}, volume = {33}, number = {8}, pages = {4553-4575}, pmid = {40694204}, issn = {1568-5608}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; *Melatonin/pharmacology/therapeutic use ; *Mitophagy/drug effects/physiology ; Humans ; Animals ; Mitochondria/drug effects/metabolism ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Neuroprotective Agents/pharmacology ; Mice ; Neurons/metabolism/drug effects ; }, abstract = {Neurons rely heavily on functional mitochondria for energy production. Mitochondrial dysfunction is a key player in age-related neurodegenerative diseases like Alzheimer's disease (AD). In AD, damaged mitochondria accumulate early, worsening the disease. This dysfunction disrupts cellular balance in neurons, leading to energy deficiencies, calcium imbalances, and oxidative stress. These issues further aggravate the harmful effects of amyloid beta (Aβ) plaques and tau tangles, ultimately leading to synaptic dysfunction, memory loss, and cognitive decline. While a complex link exists between mitochondrial dysfunction and AD hallmarks like Aβ plaques and tau tangles, the exact cause-and-effect relationship remains unclear. Additionally, recent evidence suggests impaired mechanisms for mitophagy in AD. Mitophagy is crucial for neuronal health, and studies have found changes to proteins involved in this process, mitochondrial dynamics, and mitochondrial production in AD. Impaired mitophagy might also be linked to problems with how cells fuse waste disposal compartments (autophagosomes) with lysosomes, and issues with maintaining proper acidity within lysosomes. Interestingly, melatonin, a hormone known for regulating sleep, has recently emerged as a potential neuroprotective agent. Studies using a mouse model of AD showed that melatonin treatment improved cognitive function by enhancing mitophagy. These findings suggest that melatonin's ability to improve mitophagy may be a promising avenue for future AD therapies. Therefore, in this review, we discuss the therapeutic effect of melatonin on mitochondrial dysfunction, especially mitophagy, in AD.}, } @article {pmid40694170, year = {2025}, author = {Shah, Z and Iqbal, A and Badshah, SL and Mir, MA and Sohni, S and Ullah, H and Shah, SA and Bashir, N and Ayaz, M and Daglia, M}, title = {Macroalgae Polysaccharides Enhance Brain Health by Mitigating Scopolamine-induced Oxidative Stress and Inflammation Via Nrf-2/TLR4/NF-kB Pathways.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {20}, number = {1}, pages = {74}, pmid = {40694170}, issn = {1557-1904}, mesh = {Animals ; *Polysaccharides/pharmacology/isolation & purification ; *Oxidative Stress/drug effects/physiology ; Scopolamine/toxicity ; Mice ; NF-kappa B/metabolism ; Male ; NF-E2-Related Factor 2/metabolism ; Toll-Like Receptor 4/metabolism ; *Seaweed/chemistry ; *Neuroprotective Agents/pharmacology/isolation & purification ; *Brain/drug effects/metabolism ; Signal Transduction/drug effects ; Inflammation/chemically induced/metabolism/drug therapy ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder commonly associated with memory loss and difficulties in performing daily activities, particularly in the aging brain. PURPOSE OF THE STUDY: This study aimed to evaluate the neuroprotective effects of macroalgae-derived polysaccharides from seaweed against scopolamine-induced amnesia, oxidative stress, and amyloid plaque (Aβ) production in rodents, following standard experimental protocols. METHODS: Three novel polysaccharides were extracted from Chara vulgaris, Cladophora glomerata, and Spirogyra crassa, namely: methylated pectin-type polysaccharides (PS1), methylated pectin-type polysaccharides (homo galacturonan and rhamno galacturonan, PS2), Ulvan-type polysaccharide, and xyloglucan polysaccharides (PS3). These polysaccharides were characterized using a variety of analytical techniques, including SEM, FTIR, XRD, [1]H-NMR, and [13]C-NMR. The polysaccharides were administered at a dose of 30 mg/kg to male albino mice exposed to scopolamine (1 mg/kg) for three weeks. To assess their neuroprotective effects, Morris Water Maze (MWM) and Y-maze tests, antioxidant enzyme assays (Catalase, GSH, LPO), and western blotting were performed. RESULTS: The results showed that all three polysaccharides significantly (p ≤ 0.001) mitigated redox imbalance and reduced (p ≤ 0.001) microglial activation, thereby decreasing scopolamine-induced neuroinflammation and amyloid beta (Aβ) accumulation. Additionally, these polysaccharides improved neuronal synapses and cognitive function by modulating the NRf-2/TLR4/NF-kB signaling pathway. DATA ANALYSIS: The data analysis and graph generation were performed using GraphPad Prism software, version 5.0, with a significance level set at a p-value of < 0.05. CONCLUSION: The findings highlighted the potential of these three novel natural polysaccharides as promising candidates for the treatment of scopolamine-induced oxidative stress-mediated neurodegenerative disorders, such as Alzheimer's disease.}, } @article {pmid40693114, year = {2025}, author = {Xiao, S and Wei, X and Han, B and Shi, X and Wei, C and Liang, R and Sun, J and Zhang, Z and Han, Z and Shen, L}, title = {Quantitative analysis of targeted lipidomics in the hippocampus of APP/PS1 mice employing the UHPLC-MS/MS method.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1561831}, pmid = {40693114}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is marked by the pathological features of amyloid-β plaque accumulation, as well as intracellular neurofibrillary tangles formation in the patients' brain. Aberrant lipid metabolism is increasingly recognized as one of the important contributors to AD. PURPOSE: The main goal of this research was to conduct quantitative detection of targeted lipidomics in hippocampal tissue of APPSwe/PS1dE9 mice in order to identify lipid metabolic biomarkers of early-onset AD mice. METHODS: Our approach departs from conventional lipid detection methods, employing a highly accurate quantificational Ultra High Performance Liquid Chromatography Tandem Mass Spectrometry (UHPLC-MS/MS) technique to analyze targeted lipid biomarkers. The innovative method was utilized to detect targeted lipids in the hippocampus of AD and wild-type mice. Statistical method was performed by Student's t-test and multivariate analysis. Differential metabolites were identified through fulfilling the standard of Variable Importance in Projection surpassing one and the significance probability lower than 0.05 thresholds. RESULTS: Both groups utilized identical methodologies and adhered strictly to standardized treatment protocols. Sphingolipids (SPs), Glycerophospholipids (GPs), Glycolipids, Glycerides (GLs), Sterol Lipids (STs), and Free Fatty Acid (FA) were identified as prominent lipids exhibiting alterations in the hippocampus of AD models. Regarding glycolipid and glycerolipid composition, monogalactosyldiacylglycerols (MGDGs) and Triacylglycerols (TGs) constituted a significant proportion (p < 0.05, VIP > 1). Among glycerophospholipids, phosphatidylethanolamines (PEs) and phosphatidylcholines (PCs) emerged as significant constituents (p < 0.05, VIP > 1). Furthermore, hexosylceramides (HexCers) and ceramides (Cers) in the AD model's hippocampus, the prominent sphingolipids in the hippocampus of AD mice, existed as the two primary changed lipid metabolites. The levels of some TGs in GLs and CEs in STs showed a significant elevation (p < 0.05, VIP > 1). In contrast, most kinds of MGDGs, HexCers, Cers, PEs and FA (18:2) demonstrated a notable decrease in the hippocampus of AD group (p < 0.05, VIP > 1). CONCLUSION: The present research represents the important quantitative identification of distinct lipid biomarker profiles within the hippocampal portion of 7.5-month-aged AD mice. It encompasses glycolipid, GLs, GPs, SPs, STs, and FAs using a targeted HPLC-MS method for quantification. These findings suggest potential diagnostic lipid biomarkers in hippocampus of early-onset AD mice related to cellular membrane integrity, atherosclerosis, oxidative stress damage, and inflammation.}, } @article {pmid40692324, year = {2025}, author = {Pereira da Silva, AM and Falcão, L and Virgilio, F and Rodrigues Menezes, I and Leite, M and Farias, E and Nascimento, M and Lee Han, M and Mota Telles, JP and de Souza Franco, E and de Sousa Maia, MB}, title = {Efficacy and APOE ε4-stratified risk of donanemab in Alzheimer's disease: A systematic review and meta-analysis of randomized clinical trials.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {477-493}, doi = {10.1177/13872877251361044}, pmid = {40692324}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; Randomized Controlled Trials as Topic ; *Apolipoprotein E4/genetics ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Treatment Outcome ; }, abstract = {BackgroundDonanemab, a monoclonal antibody targeting amyloid-β (Aβ) plaques, has shown the ability to reduce cerebral amyloid burden in early Alzheimer's disease (AD). However, uncertainties remain regarding its clinical relevance, particularly in relation to tau pathology, APOE ε4 genotype, and methodological limitations in existing trials.ObjectiveTo conduct a systematic review and exploratory meta-analysis to evaluate the efficacy, safety, and tolerability of donanemab in patients with mild to moderate AD.MethodsWe conducted a systematic review and exploratory meta-analysis following PRISMA guidelines. Randomized controlled trials comparing donanemab to placebo in individuals aged ≥65 years with biomarker-confirmed mild to moderate AD were included. Outcomes included cognitive measures (ADAS-Cog13, MMSE, CDR-SB, iADRS, ADCS-iADL) and adverse events (ARIA-E, ARIA-H, infusion reactions, discontinuations). Random-effects models were used to estimate pooled mean difference (MD) or risk ratio (RR) with 95% confidence intervals. Subgroup analyses were performed by baseline tau burden and APOE ε4 genotype.ResultsThree trials (n = 2054) were included. Donanemab modestly reduced cognitive decline compared to placebo: ADAS-Cog13 (MD, -1.86), CDR-SB (MD, -0.36), MMSE (MD, 0.64), and iADRS (MD, 3.19), with similar effects across tau subgroups. The risk of ARIA-E was markedly increased (RR, 12.39), especially among APOE ε4 homozygotes. Infusion reactions (RR, 11.90) and discontinuations (RR, 3.22) were also more frequent.ConclusionsDonanemab demonstrated modest cognitive benefits, the clinical significance of which remains uncertain. Independent, longer-term trials with rigorous methodology and active comparators are warranted to more clearly define its therapeutic value in the treatment of AD.}, } @article {pmid40692317, year = {2025}, author = {Yin, M and Ding, S and Zhao, M and Liu, J and Su, W and Fu, M and Wu, M and Ma, C and Sun, X and Kong, Y}, title = {The global, regional, and national burden and attributable risk factors of Alzheimer's disease and other dementias, 1990-2021: A systematic analysis for the Global Burden of Disease Study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {1}, pages = {192-206}, doi = {10.1177/13872877251360221}, pmid = {40692317}, issn = {1875-8908}, mesh = {Humans ; Risk Factors ; *Alzheimer Disease/epidemiology ; *Global Burden of Disease/trends ; Female ; Male ; Cross-Sectional Studies ; Aged ; *Dementia/epidemiology ; Middle Aged ; Incidence ; Aged, 80 and over ; Disability-Adjusted Life Years ; Global Health ; Adult ; }, abstract = {BackgroundDementia is a syndrome characterized by a decline in cognitive function, with Alzheimer's disease (AD) being the most common type. Updated global statistics on the burden of AD and other dementias provide critical insights for guiding prevention and treatment strategies.ObjectiveTo estimate the global, regional, and national burden and attributable risk factors of AD and other dementias from 1990 to 2021.MethodsThis cross-sectional study utilized the 2021 Global Burden of Disease (GBD) dataset from 204 countries and territories. The analysis focused on individuals aged 40 years and older with AD and other dementias and included data on incidence, all-cause and cause-specific mortality, disability-adjusted life years (DALYs), and estimated annual percentage changes (EAPCs). These trends were stratified by region, country, age, sex, and Socio-Demographic Index (SDI).ResultsFrom 1990 to 2021, global DALYs attributable to AD and other dementias rose from 3.83 million to 9.84 million. Age-standardized rates (ASRs) of incidence and DALYs increased for both sexes, with a more pronounced rise in males. ASRs for incidence, prevalence, and DALYs were positively correlated with SDI. Smoking was identified as the primary risk factor for dementia burden among males, whereas obesity was the leading risk factor for females.ConclusionsThe global burden of AD and other dementias has significantly increased from 1990 to 2021, especially in high-SDI regions. While females have a higher overall risk, the burden has grown more rapidly in males. These findings highlight the need for targeted interventions to address aging populations and reduce dementia risk factors.}, } @article {pmid40691719, year = {2025}, author = {Rafii, MS and Aisen, PS}, title = {Amyloid-lowering immunotherapies for Alzheimer disease: current status and future directions.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {9}, pages = {490-498}, pmid = {40691719}, issn = {1759-4766}, mesh = {Humans ; *Alzheimer Disease/therapy/immunology/drug therapy/metabolism ; *Immunotherapy/methods/trends ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Animals ; }, abstract = {The treatment of Alzheimer disease (AD) has crossed a pivotal threshold, marked by the landmark approvals of the first-ever disease-modifying therapies. These immunotherapies, specifically monoclonal antibodies (mAbs) that target various amyloid-β (Aβ) species including proto-fibrillar and fibrillar forms, substantially lower levels of Aβ in the brain. The therapies have collectively demonstrated the ability to slow cognitive and clinical decline in large placebo-controlled trials, ushering a new era in the management of AD. Here, we review recent progress made in bringing amyloid-lowering mAb therapies to the clinic and explore future directions in this rapidly evolving field. We also delve into the current understanding of AD as a biological continuum, from its asymptomatic preclinical stage to its clinically overt dementia stage. We explore how this conceptualization provides a regulatory framework to evaluate amyloid-lowering mAbs across the entire spectrum of the disease. Additionally, we review key factors that affect the integration of these treatments into clinical practice.}, } @article {pmid40691577, year = {2025}, author = {Kim, HB and Yoo, S and Kwak, H and Ma, SX and Kim, R and Lee, M and Ha, N and Pyo, S and Kwon, SG and Cho, EH and Lee, SM and Jang, J and Kim, WK and Park, HC and Baek, M and Park, Y and Park, JY and Park, JW and Hwang, SW and Hwang, JI and Seong, JY}, title = {Inhibition of FAM19A5 reverses synaptic loss and cognitive decline in mouse models of Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {168}, pmid = {40691577}, issn = {1758-9193}, mesh = {Animals ; Humans ; Male ; Mice ; Rats ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Cognitive Dysfunction/metabolism/drug therapy ; Disease Models, Animal ; Excitatory Postsynaptic Potentials/drug effects ; Hippocampus/metabolism/drug effects/pathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurons/metabolism/drug effects ; *Synapses/drug effects/pathology/metabolism ; }, abstract = {BACKGROUND: FAM19A5 is a secretory protein primarily expressed in neurons. Although its role in synaptic function has been suggested, the precise molecular mechanisms underlying its effects at the synapse remain unclear. Given that synaptic loss is a critical hallmark of Alzheimer's disease (AD), elucidating the mechanisms involving FAM19A5 could provide valuable insights into reversing synaptic loss in AD. METHODS: The binding partner of FAM19A5 was identified through co-immunoprecipitation experiments of mouse brain tissue. The effect of FAM19A5 on spine density in hippocampal neurons was evaluated using immunocytochemistry by overexpressing FAM19A5, treating neurons with FAM19A5 protein, and/or an anti-FAM19A5 antibody NS101. Target engagement of NS101 was determined by measuring FAM19A5 levels in mouse, rat, and human plasma at specific time points post NS101 injection using ELISA. Changes in spine density and dynamics in P301S tauopathy mice were assessed via Golgi staining and two-photon microscopy after NS101 administration. The synaptic strengthening of hippocampal neurons in APP/PS1 amyloidopathy mice after NS101 treatment was assessed by measuring miniature excitatory postsynaptic currents (mEPSCs) and field excitatory postsynaptic potentials (fEPSPs). Cognitive performance in AD mice after NS101 treatment was measured using the Y-maze and Morris water maze tests. RESULTS: FAM19A5 binds to LRRC4B, a postsynaptic adhesion molecule, leading to reductions in spine density in mouse hippocampal neurons. Inhibiting FAM19A5 function with NS101 increased spine density. Intravenous administration of NS101 increased spine density in the prefrontal cortex of P301S mice, which initially showed reduced spine density compared to wild-type (WT) mice. NS101 normalized the spine elimination rate in P301S mice, restoring the net spine count to levels comparable to WT mice. NS101 treatment enhanced the frequency of mEPSCs and fEPSPs in the hippocampal synapses of APP/PS1 mice, leading to improved cognitive function. The increases in plasma FAM19A5 levels upon systemic NS101 administration suggest that the antibody effectively engages its target and facilitates the transport of FAM19A5 from the brain. CONCLUSIONS: This study demonstrated that inhibiting FAM19A5 function with an anti-FAM19A5 antibody restores synaptic integrity and enhances cognitive function in AD, suggesting a novel therapeutic strategy for AD. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT05143463 , Identifier: NCT05143463, Release date: 3 December 2021.}, } @article {pmid40690192, year = {2025}, author = {Jiang, S and Arnold, SE and Betensky, RA}, title = {Design and Analysis of N-Of-1 Trials That Incorporate Sequential Monitoring.}, journal = {Statistics in medicine}, volume = {44}, number = {15-17}, pages = {e70177}, doi = {10.1002/sim.70177}, pmid = {40690192}, issn = {1097-0258}, support = {P30AG066512/NH/NIH HHS/United States ; UL1 TR002345/NH/NIH HHS/United States ; R01NS094610/NH/NIH HHS/United States ; P01AG036694/NH/NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Sample Size ; *Research Design ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Computer Simulation ; Cross-Over Studies ; Alzheimer Disease/drug therapy ; }, abstract = {For many diseases and disorders, such as Alzheimer's disease, patients demonstrate considerable heterogeneity in their responses to treatment interventions. One treatment may be most effective for some patients, while another may be most effective for others, and neither may be effective for another subset of patients. This potentially renders the conventional parallel group design highly inefficient. An attractive alternative is the N-of-1 design, also called the multi-crossover randomized controlled trial. In this design, each participant serves as their own control in a series of randomized blocks of treatment assignments. We propose novel designs for both the single-person and multi-person N-of-1 trials that employ sequential monitoring. In particular, we allow for early stopping for a single participant as soon as there is sufficient evidence of a preferred treatment for them, and early stopping for the group of participants as soon as there is sufficient evidence of a preferred treatment for the population of patients. We provide sample size calculations and decision rules for terminating the trial early and illustrate their properties in simulation studies. We apply our proposed methods to N-of-1 studies of brain tumor excisions and of methylphenidate in mild cognitive impairment.}, } @article {pmid40690160, year = {2025}, author = {Sompol, P and Jicha, GA and Hinman, JD and Brickman, AM and Greenberg, SM and Arfanakis, K and Buckwalter, MS and Llorente, IL and Williamson, JD and Wolf, MS and Smith, EE and Gupta, A and Flanagan, ME and Vazquez, MA and Burns, JM and Carmichael, ST and Barone, FC}, title = {Advancing clinical trial readiness in white matter disease and related dementias: key steps for future research progress.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {40690160}, issn = {2509-2723}, support = {K23 AG055666/AG/NIA NIH HHS/United States ; R33 AG068483/AG/NIA NIH HHS/United States ; R21AG074146/AG/NIA NIH HHS/United States ; }, abstract = {White matter disease, a broad-spectrum term that covers various types of white matter lesions and degeneration, is strongly related to age-related neurodegenerative disorders including Alzheimer's disease (AD), and vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's related dementias (ADRD). There is no specific treatment for white matter disease. Therefore, basic research and clinical studies are essential for future outcomes. Since its formation in 2020, the Albert Research Institute for White Matter and Cognition (ARIWMC) mission has been to support white matter research by providing a forum for communication where basic and clinical scientists meet to discuss and debate new knowledge and guidelines for studying white matter in dementia. The 4th annual ARIWMC workshop was held on May 31-June 2, 2023, where researchers met to set strategies for clinical trial readiness. Significant discussion by participants advocated research on multiple levels, including molecular, cellular, metabolic, behavioral, and risk factors that contribute to disease etiology and regeneration processes. Moreover, participants also addressed identifying and validating biomarkers and functional studies in animal models and human trials that are key steps for treatment development. Other areas that were discussed included epidemiological studies and pragmatic clinical trials where health care researchers and everyday medical practice support risk factor management or healthy lifestyle, and prevention trials could mitigate the incident of the disease. In summary, this workshop fostered a better understanding of how white matter lesions contribute to cognitive impairment from bench-to-biomarker-to-bedside-to-translational approaches which will facilitate and support the discovery and development of therapies and prevention strategies that facilitate a healthy brain and reduce white matter-related pathologies associated with and contributing to VCID and ADRD.}, } @article {pmid40689211, year = {2025}, author = {Yang, Z and Zhang, FR and Ren, L and Bai, JM and Wang, SC and Li, XY and Yang, HJ and Xiao, HH}, title = {Multi-omics reveal the neuroprotective mechanisms of Xinshubao tablet against scopolamine-induced cognitive dysfunction in mice.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1596728}, pmid = {40689211}, issn = {1663-9812}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatments. Xinshubao tablet (XSB), a traditional Chinese medicine, contains several bioactive compounds with notable neuroprotective effects. Our previous studies have demonstrated that XSB can alleviate cognitive deficits in vascular dementia (VaD) models, suggesting its potential as a therapeutic candidate for AD. METHODS: In this study, scopolamine-induced AD-like mice were orally administered with varying doses of XSB (0.13 g/kg, 0.26 g/kg and 0.52 g/kg) for 28 days. Behavior tests, H&E, Nissl, immunofluorescence staining, and Western blot assays were performed to evaluate the neuroprotection of XSB on AD-like mice. Then, fecal 16S rDNA sequencing, serum metabolomics, and hippocampal mRNA sequencing (mRNA-seq) analysis were performed to investigate the underlying mechanisms. RESULTS AND DISCUSSION: The results revealed that oral administration of XSB improved cognitive function, mitigated neuropathological damage, and alleviated dysfunction in the cholinergic system in AD-like mice. XSB treatment also enhanced gut microbiota diversity, increased the abundance of Enterococcus, Actinobacteriota, Coriobacteriales, and Eggerthellaceae, but reduced the abundance of Helicobacter rodentium and Lachnospiraceae. Integrating mRNA-seq and metabolomics data highlighted key regulatory pathways including the biosynthesis of unsaturated fatty acids, tyrosine metabolism, and glycerophospholipid metabolism. Furthermore, XSB treatment reduced the expression of TNF-α, IL-1β, MPO, enhanced SOD, GSH activities, reduced malondialdehyde (MDA) levels, upregulated the expression of BDNF, SYN, PSD95, and improved synaptic density. Transformation of XSB derived fecal microbiota (XSB-FM) effectively alleviated cognitive dysfunction and intestinal barrier injures. In conclusion, XSB may exert its neuroprotective effects via the microbiota-metabolite-brain axis, thereby improving neuroinflammation, neurotransmission, and synaptic integrity. These findings support the potential of XSB as a multifactorial therapeutic strategy for cognitive deficits in AD.}, } @article {pmid40689203, year = {2025}, author = {Mi, X and Ruan, X and Lin, R and Huang, S and Cai, P and Chen, X and Liao, J and Dai, X}, title = {Intranasal administration of Ganoderma lucidum-derived exosome-like nanovesicles ameliorates cognitive impairment by reducing inflammation in a mouse model of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1572771}, pmid = {40689203}, issn = {1663-9812}, abstract = {BACKGROUND/OBJECTIVES: Although Alzheimer's disease (AD) is the most prevalent dementia in late life, with amyloid beta (Aβ) deposition and neuroinflammation are recognized among its primary pathological features. Currently, there is currently still a lack of effective therapeutic drugs for AD. Ganoderma lucidum (G. lucidum) is abundant in active ingredients that harbor anti-inflammatory properties in both central nervous system and the periphery. We attempted to determine whether G. lucidum contained exosome-like nanovesicles (GLENVs) and whether these GLENVs can alleviate cognitive impairment. METHODS: We extracted GLENVs by the differential ultracentrifugation method and identified the components by liquid chromatography-mass spectrometry (LC-MS). The 5×FAD mice underwent a 3-month intranasal administration of GLENVs and their behavioral and pathological changes were evaluated. RESULTS: GLENVs were successfully extracted and identified to contain multiple ganoderic acids; intranasal administration allowed GLENVs to penetrate the blood-brain barrier to exert their effects directly. The 3-month GLENVs treatment effectively ameliorated the impairment in the memory and learning of the 5×FAD mice. The GLENVs treatment also reduced Aβ deposition in the cortex and hippocampus of 5×FAD mice, overactivated microglia, reactive astrocytes, and pro-inflammatory factors, and inhibited the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway. Moreover, GLENVs exerted no adverse effects on liver and kidney function. CONCLUSION: GLENVs may be a promising candidate for AD treatment.}, } @article {pmid40688757, year = {2025}, author = {Sur, TK and Mondal, T and Noreen, Z and Johnson, J and Nunlee-Bland, G and Loffredo, CA and Korba, BE and Chandra, V and Jana, SS and Kwabi-Addo, B and Sarkar, S and Ghosh, S}, title = {Developing non-invasive molecular markers for early risk assessment of Alzheimer's disease.}, journal = {Biomarkers in neuropsychiatry}, volume = {12}, number = {}, pages = {}, pmid = {40688757}, issn = {2666-1446}, support = {U54 MD007597/MD/NIMHD NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease, with no standard biomarker(s) to detect or confirm its risk at an early stage. The prevalence of AD increases exponentially worldwide in people of ages over 65 and older. Current improvements have unveiled the disease's pathophysiology and clinical diagnostic tests, targeting the neurological changes (neurodegeneration, amyloid precursor protein metabolism and tangle pathology) with precise PET/MRI imaging and xMAP/SIMOA (Multiplex simultaneous detection/single molecule array) to identify and quantify β-amyloids (Aβ40, Aβ42), total tau (T-tau) and phosphorylated tau (P-tau) proteins in the brain and cerebrospinal fluid (CSF) of patients. However, their utility for diagnosis in routine clinical practice is still challenging because of cost, accessibility, standardization, procedural limitation, and regulatory approval. Further research is needed to establish affordable, patient-friendly, easy, quick, and robust biomarkers for early AD detection, progression, and therapeutic management. Research on blood-based preclinical diagnosis and clinical practice for AD has advanced significantly in the last decade. Emerging literature supports the importance of new molecular biomarkers and signature genes from blood to detect and predict AD in advance. This review examines the potential applications of these blood-based target biomarkers for early disease detection, co-morbid condition risk prediction, and treatment management of AD.}, } @article {pmid40708156, year = {2024}, author = {Ghosh, P and Iyer, PK}, title = {Conjugated Polyelectrolytes: Illuminating the Path to Neurodegenerative Disorders Detection and Treatment.}, journal = {ACS applied materials & interfaces}, volume = {16}, number = {16}, pages = {20034-20054}, doi = {10.1021/acsami.3c17890}, pmid = {40708156}, issn = {1944-8252}, mesh = {Humans ; *Polyelectrolytes/chemistry/therapeutic use ; Amyloid beta-Peptides/metabolism/chemistry ; *Neurodegenerative Diseases/diagnosis/drug therapy/metabolism ; Alzheimer Disease/diagnosis/drug therapy/metabolism ; Animals ; }, abstract = {Conjugated polyelectrolytes (CPEs) have gained extensive attention for their potential efficacy in protein misfolding disease (PMD) studies. This comprehensive review article explores the importance of CPEs in PMD research and treatment strategies. CPEs have unique features and capabilities, such as selective binding to disease-specific biomarkers like amyloid-beta (Aβ) aggregates which allows for noninvasive imaging methods to detect and identify early pathological alterations. They also induce unique fluorescence responses upon interaction with Aβ aggregates, enabling real-time monitoring of aggregation kinetics. The exceptional selectivity of CPEs has been demonstrated by their strategic chemical modification, by conjugating them with certain specific ligands, enhancing their diagnostic precision. Thus, CPEs hold immense potential to serve in the diagnosis and treatment of neurodegenerative diseases such as Alzheimer's due to their versatility.}, } @article {pmid40703689, year = {2024}, author = {Kim, H and Lee, H}, title = {Current status and significance of research on sex differences in neuroscience: a narrative review and bibliometric analysis.}, journal = {Ewha medical journal}, volume = {47}, number = {2}, pages = {e16}, pmid = {40703689}, issn = {2234-2591}, abstract = {This review aims to highlight the importance of research on structural, functional, molecular-biological, and disease-specific sex differences in the brain, and to examine current bibliometric indicators related to research on sex differences. The Web of Science Core Collection was searched for related articles from 2010 to 2023. Structural and functional brain differences according to sex, including variations in communication patterns between hemispheres, may play a role in mental disorders. Sex differences in neurotransmitters such as serotonin, dopamine, and γ-aminobutyric acid contribute to disparities in mental health, addiction, and neurodevelopmental conditions. Neurodevelopmental disorders such as autism spectrum disorder and schizophrenia exhibit sex-based differences in prevalence, symptoms, brain changes, and neurotransmitter disruptions under hormonal influence. There is a growing body of research on depression, adolescence, the hippocampus, the amygdala, and cognition, highlighting the importance of considering sex/gender factors. Recent studies on sex differences in brain diseases have identified variations in brain structure, function, and neurophysiological substances, as well as in hormones and genes between the sexes. The incidence of psychiatric disorders such as autism spectrum disorder, depression, anxiety, and Alzheimer's disease is increasingly being linked to sex differences, and the need for research into the mechanisms underlying these differences is gaining recognition. However, there remains a significant gap in sex-specific neuroscience research related to the diagnosis, treatment, prevention, and management of these conditions. Advancing inclusive research will require comprehensive training, a consensus on methodology, diverse perspectives through collaborative frameworks, governmental/institutional support, and dedicated funding to create suitable research environments and implementation strategies.}, } @article {pmid40969174, year = {2024}, author = {Matz, LM and Shah, NS and Porterfield, L and Stuyck, OM and Jochum, MD and Kayed, R and Taglialatela, G and Urban, RJ and Buffington, SA}, title = {Gut pathobiont enrichment observed in a population predisposed to dementia, type 2 diabetics of Mexican descent living in South Texas.}, journal = {Frontiers in microbiomes}, volume = {3}, number = {}, pages = {}, pmid = {40969174}, issn = {2813-4338}, support = {P30 ES030285/ES/NIEHS NIH HHS/United States ; R01 HD109095/HD/NICHD NIH HHS/United States ; T32 AG067952/AG/NIA NIH HHS/United States ; UL1 TR001439/TR/NCATS NIH HHS/United States ; }, abstract = {Type 2 diabetes (T2D) is a common forerunner of neurodegeneration and accompanying dementia, including Alzheimer's Disease (AD), yet the mechanisms underlying this comorbidity remain unresolved. Individuals of Mexican descent living in South Texas have increased prevalence of comorbid T2D and early onset AD, despite low incidence of the APOE-ε4 risk variant among the population and an absence of a similar predisposition among relatives residing in Mexico - suggesting a role for environmental factors in coincident T2D and AD susceptibility. We therefore sought to test if differences in gut community structure could be observed in this population prior to any AD diagnosis. Here, in a small clinical trial (ClinicalTrials.gov Identifier NCT04602650), we report evidence for altered gut microbial ecology among subjects of Mexican descent living in South Texas with T2D (sT2D) compared to healthy controls without T2D (HC), despite no differences in expressed dietary preferences. We performed metataxonomic 16S rRNA gene amplicon sequencing of study participant stool samples. Although no significant decrease in microbial alpha diversity was observed between sT2D gut communities versus those of HC, body mass index was identified as a driver of gut community structure. Intriguingly, we observed a significant negative association of Faecalibacterium with T2D and an increase in the abundance of pathobionts Escherichia-Shigella, Enterobacter, and the erysipelotrichial species Clostridia innocuum among sT2D gut microbiota, as well as differentially abundant gene and metabolic pathways. Future large-scale, longitudinal sequencing efforts of the gut microbiome of individuals with T2D who go onto develop AD might identify key actors among "disease state" microbiota that contribute to increased susceptibility to comorbid dementia among type 2 diabetics. Finally, we identified candidate microbiome-targeted approaches for the treatment of T2D.}, } @article {pmid40766919, year = {2024}, author = {Tucker, M and Liao, GY and Keely, A and Park, JY and Rosenfeld, M and Wezeman, J and Mangalindan, R and Ratner, D and Darvas, M and Ladiges, W}, title = {Behavioral and neuropathological features of Alzheimer's disease are attenuated in 5xFAD mice treated with intranasal GHK peptide.}, journal = {Aging pathobiology and therapeutics}, volume = {6}, number = {3}, pages = {102-108}, pmid = {40766919}, issn = {2690-1803}, support = {R01 AG057381/AG/NIA NIH HHS/United States ; R01 AG067193/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease and a leading cause of morbidity and mortality. Efforts to find disease modifying treatments have met with limited success. The naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine), in its Cu-bound form, supports angiogenesis, remodeling, and tissue repair, has anti-inflammatory and antioxidant properties, and has been shown to improve cognitive performance in aging mice. These features raised the question of whether GHK-Cu could alleviate neurodegeneration observed in AD. Male and female 5xFAD transgenic mice on the C57BL/6J background at 4 months of age were given 15 mg/kg GHK-Cu intranasally 3 times per week for 3 months until 7 months of age. Results showed that intranasal GHK-Cu treatment delayed cognitive impairment, reduced amyloid plaques, and lowered MCP1-mediated inflammation levels in the frontal cortex and hippocampus. These observations provide the rationale for conducting additional studies to investigate the potential of GHK-Cu peptide as a promising treatment for AD.}, } @article {pmid40703952, year = {2023}, author = {Rezakhani, L and Salimi, Z and Zarei, F and Moradpour, F and Khazaei, MR and Khazaei, M and Pourjalili, M}, title = {Protective Effects of Statins against Alzheimer Disease.}, journal = {Ewha medical journal}, volume = {46}, number = {4}, pages = {e17}, pmid = {40703952}, issn = {2234-2591}, abstract = {Alzheimer disease (AD) is a common neurodegenerative disorder, characterized by memory impairment, dementia, and diminished cognitive function. This disease affects more than 20 million people worldwide. Amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) are important pathological markers of AD. Multiple studies have indicated a potential association between elevated cholesterol levels and increased risk of AD, suggesting that lowering the cholesterol level could be a viable strategy for AD treatment or prevention. Statins, potent inhibitors of cholesterol synthesis, are widely used in clinical practice to decrease the plasma levels of LDL cholesterol in patients with hyperlipidemia. Statins are known to play a neuroprotective role in limiting Aβ pathology through cholesterol-lowering therapies. In addition to Aβ plaques and neurofibrillary tangles, the brains of AD patients exhibit signs of oxidative stress, neuroinflammatory responses, and synaptic disruption. Consequently, compounds with antioxidant, anti-inflammatory, and/or neuroprotective properties could be beneficial components of AD treatment strategies. In addition to lowering LDL cholesterol, statins have demonstrated therapeutic efficacy in various forms, including antioxidant, anti-inflammatory, and neuroprotective effects. These properties of statins are potential mechanisms underlying their beneficial effects in treating neurodegenerative diseases. Therefore, this review was conducted to provide an overview of the protective effects of statins against AD.}, } @article {pmid40688669, year = {2025}, author = {Zhu, RK and Shi, J and Zhou, HJ and Ge, L and Yin, WH and Zeng, H and Wang, XW}, title = {Biological applications of graphene-based nanomaterials in neurodegenerative diseases.}, journal = {Materials today. Bio}, volume = {33}, number = {}, pages = {102064}, pmid = {40688669}, issn = {2590-0064}, abstract = {Neurodegenerative diseases (NDDs) have become a major challenge in global public health due to neurotoxicity caused by progressive neuronal degeneration and abnormal protein aggregation, which has attracted widespread attention. Graphene-based nanomaterials provide innovative solutions for the early diagnosis and precise treatment of NDDs by virtue of their ultra-high conductivity, large specific surface area and multifunctional properties. In this paper, we systematically discuss the key applications of these materials in the diagnosis and treatment of NDDs, and deeply analyze the technological breakthroughs and clinical translation challenges. The core of this paper is to illustrate that graphene-based nanomaterials are expected to reshape the paradigm of NDDs diagnosis and treatment through cross-scale technological innovations, promoting the synergistic development of early diagnosis, personalized treatment and real-time monitoring, and providing a transformative strategy for overcoming NDDs.}, } @article {pmid40688579, year = {2025}, author = {Zhang, G and Zhao, W and Lv, S and Wang, Z and Yi, Y and Ma, H and Lu, Y and Yan, W and Teng, J}, title = {Emerging trends in Alzheimer's disease diagnosis and prediction using artificial intelligence: A bibliometric analysis of the top cited 100 articles.}, journal = {Digital health}, volume = {11}, number = {}, pages = {20552076251362098}, pmid = {40688579}, issn = {2055-2076}, abstract = {BACKGROUND: AD is a significant public health challenge, and AI technologies, including deep learning and machine learning, offer the potential to dramatically improve diagnostic and predictive accuracy. These technologies are widely applied in AD research. However, comprehensive literature summaries of this field remain limited. This study uses bibliometric analysis to examine research hotspots, trends, future development potential, and limitations in AI-based AD diagnosis and prediction. METHODS: We conducted a bibliometric analysis of 100 top cited studies on AI-based diagnosis and prediction of AD, using data from the WoSCC. We performed the analysis using CiteSpace 6.3.R2, VOSviewer 1.6.19, Scimago Graphica 1.0.39, Microsoft Excel 2021, and R package Bibliometrix running in RStudio, visualizing the results through graphical representations. RESULTS: It was found that the top cited 100 articles came from 51 journals and 31 countries. The journal with both the highest number of published articles and the greatest citation frequency was NEUROIMAGE, while PROTEIN ENGINEERING DESIGN & SELECTION boasted the highest average citation rate. The country with the largest volume of published articles was the United States, followed by China and the United Kingdom. In terms of institutions, the University of North Carolina had produced the most publications. The keywords identified fall into 9 categories. The most frequently occurring keywords are "Alzheimers disease", "mild cognitive impairment", "classification", "MRI", "deep learning", "diagnosis", "dementia", "biomarkers", "brain atrophy", "machine learning", "voxel based morphometry", "prediction", and "patterns". CONCLUSION: AI-based technologies for AD diagnosis and prediction are becoming indispensable clinical tools. Future research should leverage AI to identify novel AD biomarkers, enabling precision diagnosis and treatment. However, our bibliometric analysis has limitations: language and citation biases may skew interpretation of emerging AI-AD trends.}, } @article {pmid40688402, year = {2025}, author = {Espinoza, C and Salinas, M and Morocho, A and Morales, A and Verdezoto, B}, title = {Mortality from Alzheimer's Disease and Other Dementias in Ecuador during the Period 2012-2022.}, journal = {Clinical practice and epidemiology in mental health : CP & EMH}, volume = {21}, number = {}, pages = {e17450179376076}, pmid = {40688402}, issn = {1745-0179}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a growing concern worldwide in healthcare. In Ecuador, the increasing life expectancy has raised the prevalence of age-related diseases, including dementias. The main objective of this study was to analyze the mortality from AD and other dementias in Ecuador from 2012 to 2022. METHODOLOGY: A retrospective, descriptive time series analysis was conducted on adult subjects with AD and other dementias across various geographic regions of Ecuador during the 2012-2022 period. A sample of 855,122 individuals registered in the databases of the National Institute of Statistics and Censuses (INEC) was analyzed. RESULTS: Out of the total evaluated subjects, 4,836 deaths were due to AD (0.56%) and 1,317 deaths from other types of dementia (0.15%). For AD, the distribution of deaths by sex showed a predominant trend in women (n=3,008) within the group aged 65 years or older (n=4,749). For other dementias, women were also the main group (n=766), along with those aged 65 years and older (n=1,294). The national mortality rate showed an upward trend during this decade, increasing from 2.2 per 100,000 inhabitants in 2012 to 4.86 per 100,000 inhabitants in 2022. DISCUSSION: This study reveals a worrying increase in mortality from Alzheimer's disease (AD) and other dementias in Ecuador between 2012 and 2022, especially among women, adults over 65 years of age, and residents of the Sierra region. Several factors that could negatively influence cognitive function were observed. These findings are consistent with global trends and suggest that biological, environmental, and social variables, such as aging, postmenopausal hormonal changes, chronic exposure to hypoxic altitude conditions, and unequal access to health services, could play a key role in this disease. CONCLUSION: Mortality from Alzheimer's disease and other dementias in Ecuador showed a sustained increase between 2012 and 2022, reflecting a growing burden of these pathologies in the population and the urgent need to strengthen prevention, early diagnosis, and comprehensive treatment strategies. The disproportionate impact on women, adults over 65 years of age, and residents of the Sierra region suggests the involvement of various biological, environmental, and social determinants of health, which requires more rigorous surveillance and a differentiated approach for these particularly vulnerable populations.}, } @article {pmid40687177, year = {2025}, author = {Zhang, Y and Lv, Y and Yang, T and Liu, Q and Guo, Q}, title = {Insulin resistance and Alzheimer's disease: Exploring research hotspots and frontiers from a bibliometric and visual analysis (2005-2024).}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251361056}, pmid = {40687177}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease (AD) and insulin resistance (IR) share intersecting pathological pathways, with IR increasingly implicated in AD pathogenesis. Systematic bibliometric analyses mapping the evolution of this interdisciplinary field remain limited. OBJECTIVE: To quantify global research trends, collaboration networks, knowledge structures, and emerging frontiers in IR-AD research from 2005-2024. METHODS: We analyzed 2676 publications from the Web of Science Core Collection. Using VOSviewer, CiteSpace, and bibliometrix R package, we conducted quantitative analyses and visualized multiple dimensions including annual publications/citations, countries/regions, institutions, journals, authors, references, and keywords. RESULTS: Annual publications grew steadily, peaking at 267 in 2022. The United States dominated productivity (942 papers, 35.2%) and citations (88,170). The University of Kentucky was the top institution (53 papers), while the Journal of Alzheimer's Disease led in output (214 papers) and co-citations (8046). Keyword analysis revealed three clusters: metabolic dysregulation, molecular pathology, and neuroimmune responses. Emerging frontiers highlight neuroimmune mechanisms, with current hotspots focusing on NLRP3 inflammasome activation, gut-brain axis dysregulation, glucose transporter impairment, and therapeutic repurposing of GLP-1 agonists. CONCLUSIONS: These findings underscore IR-AD as a critical intersection of metabolic and neurodegenerative pathways, advocating for targeted therapies addressing neuroinflammation and cerebral metabolism. By delineating global trends, this study provides a roadmap for future research to bridge translational gaps in AD pathogenesis and treatment.}, } @article {pmid40686359, year = {2025}, author = {Ashwin, JV and Shahi, MK and Singh, A and Kumar, ST}, title = {Efficacy and safety of dextromethorphan-bupropion combination (AXS-05) in the treatment of depression: A systematic review and network meta-analysis.}, journal = {Indian journal of pharmacology}, volume = {57}, number = {4}, pages = {262-268}, pmid = {40686359}, issn = {1998-3751}, mesh = {Adult ; Humans ; *Bupropion/adverse effects/therapeutic use/administration & dosage ; *Depressive Disorder, Major/drug therapy ; *Dextromethorphan/adverse effects/therapeutic use/administration & dosage ; Drug Combinations ; Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {This network meta-analysis evaluated the efficacy and safety of the dextromethorphan-bupropion combination (AXS-05) in treating major depressive disorder (MDD). Data were retrieved from multiple databases, including PubMed, Embase, Scopus, Google Scholar, and ClinicalKey, yielding 60 records. After removing duplicates and excluding irrelevant studies, such as reviews, case reports, posters, and studies focusing on unrelated populations (e.g., Alzheimer's dementia), two randomized controlled trials (RCTs) - Tabuteau et al. (2022) and Iosifescu et al. (2022) - were selected for final analysis. The inclusion criteria focused on RCTs published between 2014 and 2024, involving adult participants (18-65 years) diagnosed with MDD, and reporting on the efficacy and safety of the dextromethorphan-bupropion combination. Studies that did not focus on MDD, were not in English, or lacked control groups were excluded. The findings indicate superior efficacy of the dextromethorphan-bupropion combination, with remission rates of 46.5% and 39.5%, compared to 16.2% for Bupropion alone and 17.3% for placebo. Despite a higher incidence of mild to moderate adverse events (72.9% vs. 64.6% for Bupropion), the combination's safety profile remained comparable, with no significant increase in treatment discontinuation. These results suggest that AXS-05 is a promising treatment for MDD, warranting further investigation in larger, diverse populations to confirm its long-term efficacy and safety.}, } @article {pmid40686118, year = {2025}, author = {Chen, SL and Wang, ZC and Chen, GZ and Zheng, HB and Huang, SE}, title = {[Causal effects of chronic kidney disease on Alzheimer's disease and its prevention based on "kidney-brain interaction" theory].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {12}, pages = {3431-3440}, doi = {10.19540/j.cnki.cjcmm.20250306.501}, pmid = {40686118}, issn = {1001-5302}, mesh = {Humans ; *Alzheimer Disease/prevention & control/etiology/genetics ; *Renal Insufficiency, Chronic/complications/genetics ; *Kidney/physiopathology/metabolism ; *Brain/metabolism/physiopathology ; Genome-Wide Association Study ; Medicine, Chinese Traditional ; Mendelian Randomization Analysis ; }, abstract = {Based on the traditional Chinese medicine(TCM) theory of "kidney-brain interaction", a two-sample Mendelian randomization(MR) analysis was conducted to investigate the causal effects of chronic kidney disease(CKD) on Alzheimer's disease(AD) and analyze the potential mechanisms of kidney-tonifying and essence-replenishing TCM to improve AD. From the perspective that CKD is closely related to the core pathogenesis of AD, namely "kidney deficiency, essence loss, and marrow reduction", genome-wide association study(GWAS) data was used, with the inverse variance weighting(IVW) method as the main approach to reveal the causal association between CKD and AD. Sensitivity analysis was conducted to evaluate the robustness of the results. To further investigate the causal effects of CKD on AD, two different AD datasets were used as outcomes, and the urinary albumin-to-creatinine ratio(UACR) data was used as the exposure for a supplementary analysis. On this basis, the modern scientific mechanism of the kidney-tonifying and essence-replenishing method for improving AD was further explored. The IVW analysis show that CKD(ieu-b-2: OR=1.084, 95%CI[1.011, 1.163], P=0.024; ieu-b-5067: OR=1.001, 95%CI[1.000, 1.001], P=0.002) and UACR(ieu-b-2: OR=1.247, 95%CI[1.021, 1.522], P=0.031; ieu-b-5067: OR=1.001, 95%CI[1.000, 1.003], P=0.015) both have significant causal effects on AD in different datasets, with CKD increasing the risk of AD. The sensitivity analysis further confirmed the reliability of the results. Genetic studies have shown that CKD has a significant causal effect on AD, suggesting that controlling CKD is an important intervention measure for preventing and treating AD. Therefore, further research on CKD's role in AD is crucial in clinical practice. The research enriches the theoretical implication of "kidney-brain interaction", deepens the understanding of AD' etiology, and provides further insights and directions for the prevention and treatment of AD with TCM, specifically from a kidney-based perspective.}, } @article {pmid40685770, year = {2025}, author = {Farooq, U and Islam, M and Batool, Z and Mali, SN and Jawarkar, RD and Gurav, SS and Alharthy, RD and Şenol, H and Sadeghian, N and Taslimi, P and Shafiq, Z and Schenone, S}, title = {Design, Synthesis, In Vitro, and In Silico Studies of 5-(Diethylamino)-2-Formylphenyl Naphthalene-2-Sulfonate Based Thiosemicarbazones as Potent Anti-Alzheimer Agents.}, journal = {Archiv der Pharmazie}, volume = {358}, number = {7}, pages = {e70050}, pmid = {40685770}, issn = {1521-4184}, support = {//This Project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under grant no. GPIP: 46-665-2024./ ; }, mesh = {*Alzheimer Disease/drug therapy/enzymology ; *Cholinesterase Inhibitors/chemical synthesis/pharmacokinetics ; Monoamine Oxidase Inhibitors/chemical synthesis/pharmacokinetics ; *Thiosemicarbazones/chemical synthesis/pharmacokinetics ; Molecular Docking Simulation ; *Nootropic Agents/chemical synthesis/pharmacokinetics ; Humans ; *Drug Design ; }, abstract = {Alzheimer's disease (AD) is known as one of the more devastating neurodegenerative diseases diagnosed in older people. Cholinesterase inhibitors (ChEI) can be used as an effective palliative treatment for AD. An extensive range of new biologically active 4-(diethylamino) salicylaldehyde-based thiosemicarbazone derivatives 5(a-u) was synthesized and evaluated as inhibitors of cholinesterase (ChE) and monoamine oxidase (MAO) enzymes. 2,3-Dichloro-substituted compound 5u was the most potent inhibitor of AChE and MAO-A with IC50 values of 12.89 and 96.25 nM, respectively. In contrast, the 2,3-dichlorophenyl-substituted compound 5a was the most powerful inhibitor of BChE, with an IC50 value of 124.72 nM. Structure-activity analysis revealed that the electron-withdrawing substituents on the phenyl ring play a crucial role in the inhibition potential of synthesized compounds. Compound 5a showed the strongest binding with 4BDS (-11.3 kcal/mol) via hydrogen bonds and π-interactions. Compound 5u exhibited high affinity with 1B41 (-8.2 kcal/mol), 2Z5X (-8.6 kcal/mol), and 2V5Z (-7.8 kcal/mol), forming key hydrogen bonds, salt bridges, and π-interactions, highlighting its multi-target potential. In silico ADME, pharmacokinetics, and drug-likeness studies were conducted and compared with the standard drugs galantamine and clorgyline.}, } @article {pmid40685632, year = {2025}, author = {Huang, Y and Xu, T and Wang, L and Xiang, R and Zhou, M and Yu, H and Liu, D and Chen, Z}, title = {Application of machine learning reveals diagnostic biomarkers related to pyroptosis in Alzheimer's disease and analysis of immune infiltration.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {1}, pages = {361-373}, doi = {10.1177/13872877251360033}, pmid = {40685632}, issn = {1875-8908}, mesh = {*Alzheimer Disease/genetics/diagnosis/immunology/metabolism ; Humans ; *Pyroptosis/genetics ; *Machine Learning ; Biomarkers/metabolism ; Molecular Docking Simulation ; Brain/metabolism/pathology ; Gene Expression Profiling ; }, abstract = {BackgroundAlzheimer's disease (AD) is characterized by complex pathological mechanisms, with pyroptosis potentially contributing to neuroinflammation.ObjectiveTo identify pyroptosis-related genes (PRGs) in AD and explore their role in neuroinflammation, aiming to provide potential biomarkers and therapeutic targets for precision medicine in AD treatment.MethodsTranscriptomic data from AD brain tissues (GEO database) were analyzed using multi-omics integration and machine learning. Key PRGs were screened via weighted gene co-expression network analysis (WGCNA), LASSO regression, random forest, and SVM-RFE algorithms. Molecular subtypes and therapeutic potential were assessed through unsupervised clustering and molecular docking.ResultsAnalysis identified 609 differentially expressed genes (DEGs), with upregulated genes enriched in DNA transcription and mitosis-related pathways. Six core PRGs (MIB1, TUG1, GATA1, CA1, CFH, IL17A) demonstrated strong diagnostic accuracy (AUC > 0.85). Unsupervised clustering revealed two AD subtypes: a high-risk subtype with activated pyroptosis-inflammatory pathways and distinct immune microenvironment features (p < 0.05). Molecular docking confirmed stable binding between CFH and the anti-AD drug candidate fludrocortisone (binding energy < -7 kcal/mol).ConclusionsPyroptosis modulates neuroinflammation to drive AD progression. CFH and other PRGs serve as promising biomarkers and therapeutic targets, advancing precision strategies for AD subtyping and intervention.}, } @article {pmid40685475, year = {2025}, author = {Shin, S and Kim, M and Hong, SH}, title = {Economic Evaluation of Lecanemab for Early Symptomatic Alzheimer's Disease in South Korea.}, journal = {PharmacoEconomics - open}, volume = {9}, number = {5}, pages = {793-804}, pmid = {40685475}, issn = {2509-4254}, support = {2023//Health Fellowship Foundation/ ; }, abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) exerts a considerable economic burden on South Korea's aging population. Lecanemab, an amyloid-targeting therapy, has demonstrated efficacy in mitigating cognitive decline in early-stage AD but remains non-reimbursed in South Korea due to concerns over its economic feasibility. This study aimed to examine the cost-effectiveness of lecanemab using nationwide claims data for cost estimation within the South Korean healthcare system. Considering the substantial societal burden of AD, we also evaluated the cost-effectiveness of lecanemab from a limited societal perspective. METHODS: A Markov state transition cohort model was developed to compare costs and outcomes of lecanemab combined with standard of care (SoC) versus SoC alone. The model simulated five stages of AD progression: mild cognitive impairment, mild AD, moderate AD, severe AD, and death. Transition probabilities between health states were derived from data provided by the National Alzheimer's Coordinating Center. Formal medical costs and long-term care costs were obtained from the national claims database, while drug cost and other medical expenses were derived from previous studies. Additional cost components such as opportunity cost of caregiver time, out-of-pocket expenses, and time and travel costs for hospital visits were included in the limited societal perspective. Korean-specific utilities for patients and caregivers differentiated by states of AD progression and care settings were obtained from the published literature. Effectiveness was measured in quality-adjusted life years (QALYs) over a lifetime horizon. Scenario analyses were conducted by varying compositions of the cohort, age of onset, and drug pricing. RESULTS: The incremental cost-effectiveness ratio (ICER) of lecanemab combined with SoC was 198,171,820 Korean Won (KRW)/QALY from the healthcare payer perspective and 181,185,820 KRW/QALY from the limited societal perspective, which significantly exceeded South Korea's willingness-to-pay (WTP) threshold of 30 million KRW/QALY. Sensitivity analyses revealed that the ICER was highly influenced by variations in treatment effect and discount rates. The result of scenario analyses suggested that targeting lecanemab to patients with mild AD or implementing price reductions could substantially improve its cost-effectiveness. CONCLUSIONS: Lecanemab's high cost poses a challenge to its inclusion in the National Health Insurance formulary under South Korea's current WTP thresholds. Strategic price adjustments and patient targeting are essential to enhance its economic viability. These findings provide valuable insights for policymakers and stakeholders in balancing treatment outcomes and resource allocation for AD management.}, } @article {pmid40685330, year = {2025}, author = {Far, BF and Akbari, M and Habibi, MA and Katavand, M and Nasseri, S}, title = {CRISPR Technology in Disease Management: An Updated Review of Clinical Translation and Therapeutic Potential.}, journal = {Cell proliferation}, volume = {58}, number = {11}, pages = {e70099}, pmid = {40685330}, issn = {1365-2184}, mesh = {Humans ; *CRISPR-Cas Systems/genetics ; *Gene Editing/methods ; *Genetic Therapy/methods ; Neoplasms/therapy/genetics ; Disease Management ; COVID-19/therapy ; SARS-CoV-2 ; *Translational Research, Biomedical ; Nervous System Diseases/therapy/genetics ; Animals ; Immunotherapy/methods ; }, abstract = {CRISPR-Cas9 technology has rapidly advanced as a transformative genome-editing platform, facilitating precise genetic modifications and expanding therapeutic opportunities across various diseases. This review explores recent developments and clinical translations of CRISPR applications in oncology, genetic and neurological disorders, infectious diseases, immunotherapy, diagnostics, and epigenome editing. CRISPR has notably progressed in oncology, where it enables the identification of novel cancer drivers, elucidation of resistance mechanisms, and improvement of immunotherapies through engineered T cells, including PD-1 knockout CAR-T cells. Clinical trials employing CRISPR-edited cells are demonstrating promising results in hematologic malignancies and solid tumours. In genetic disorders, such as hemoglobinopathies and muscular dystrophies, CRISPR-Cas9 alongside advanced editors like base and prime editors show significant potential for correcting pathogenic mutations. This potential was affirmed with the FDA's first approval of a CRISPR-based therapy, Casgevy, for sickle cell disease in 2023. Neurological disorders, including Alzheimer's, ALS, and Huntington's disease, are increasingly targeted by CRISPR approaches for disease modelling and potential therapeutic intervention. In infectious diseases, CRISPR-based diagnostics such as SHERLOCK and DETECTR provide rapid, sensitive nucleic acid detection, particularly valuable in pathogen outbreaks like SARS-CoV-2. Therapeutically, CRISPR systems target viral and bacterial genomes, offering novel treatment modalities. Additionally, CRISPR-mediated epigenome editing enables precise regulation of gene expression, expanding therapeutic possibilities. Despite these advances, significant challenges remain, including off-target effects, delivery methodologies, immune responses, and long-term genomic safety concerns. Future improvements in editor precision, innovative delivery platforms, and enhanced safety assessments will be essential to fully integrate CRISPR-based interventions into standard clinical practice, significantly advancing personalised medicine.}, } @article {pmid40685037, year = {2025}, author = {Wang, T and Gao, C and Dong, X and Li, L}, title = {Therapeutic potential of traditional chinese medicine polysaccharides in alzheimer's disease via modulation of gut microbiota: A review.}, journal = {International journal of biological macromolecules}, volume = {321}, number = {Pt 2}, pages = {146160}, doi = {10.1016/j.ijbiomac.2025.146160}, pmid = {40685037}, issn = {1879-0003}, mesh = {Animals ; Humans ; *Alzheimer Disease/drug therapy/microbiology ; *Drugs, Chinese Herbal/therapeutic use/pharmacology/chemistry ; *Gastrointestinal Microbiome/drug effects ; *Medicine, Chinese Traditional ; *Polysaccharides/therapeutic use/pharmacology/chemistry ; }, abstract = {Alzheimer's disease (AD) is a chronic and progressively deteriorating neurodegenerative condition characterized by a strong association with gut microbiome imbalances. It is estimated that by 2025, there will be 35 million patients worldwide, imposing a substantial burden on society. Currently, AD treatments predominantly rely on single-target approaches aimed at alleviating symptoms, which exhibit limited efficacy and fail to influence disease progression. Consequently, there is an urgent need to investigate novel therapeutic strategies to enhance treatment outcomes. Polysaccharides derived from traditional Chinese medicine (TCMPs) are renowned for their capacity to target multiple pathways and function as potent natural immune regulators, delivering comprehensive treatment effects. TCMPs possess prebiotic properties and can be fermented by the intestinal flora, promoting the proliferation of beneficial bacteria, inhibiting pathogens, and exerting anti-inflammatory, antioxidant, and Aβ-deposition inhibitory effects within the intestine. This article provides a systematic review of the interplay between gut microbiota, AD, and TCMPs, showcasing specific TCMP examples that demonstrate significant anti-AD effects mediated through gut flora modulation. The aim is to deepen understanding of TCMPs' role in AD therapy involving gut microbiota and to propose innovative strategies for optimizing AD treatment.}, } @article {pmid40684900, year = {2026}, author = {Liu, Q and Siadat, SD}, title = {MicroRNA-155 in neurodegeneration.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {578}, number = {}, pages = {120506}, doi = {10.1016/j.cca.2025.120506}, pmid = {40684900}, issn = {1873-3492}, mesh = {Humans ; *MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/diagnosis ; Exosomes/metabolism ; Animals ; Biomarkers/metabolism ; }, abstract = {MicroRNA-155 (miR-155) is recognized for its multifaceted roles in neuroinflammation and neurodegeneration. This abstract explores the emerging significance of miR-155, both as an intracellular regulator and encapsulated within exosomes, as a biomarker and therapeutic target in neurodegenerative disorders. Dysregulation of miR-155 is implicated in various conditions, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, where it modulates key pathways involved in neuronal survival, synaptic plasticity, and immune cell activation. Specifically, miR-155 has been shown to influence microglial activation, cytokine production, and the clearance of protein aggregates, all critical processes in neurodegenerative pathogenesis. Exosomal miR-155, released by various cell types including immune cells and neurons, offers a particularly exciting avenue. These nanovesicles facilitate intercellular communication, delivering their cargo, including miR-155, to recipient cells and influencing their function. As such, exosomal miR-155 levels in biofluids like cerebrospinal fluid and blood are being investigated as potential non-invasive diagnostic and prognostic biomarkers for neurodegenerative diseases. Furthermore, the ability of exosomes to cross the blood-brain barrier makes them attractive vehicles for targeted delivery of therapeutic agents. This review highlights the dual promise of miR-155 and exosomal miR-155: first, as readily measurable indicators of disease progression and response to treatment, and second, as actionable targets for novel therapeutic strategies aimed at modulating neuroinflammation and protecting neuronal integrity.}, } @article {pmid40684705, year = {2025}, author = {Yu, J and Ma, D and Li, S and Yang, S and Li, T and Kong, L and Liu, Y and Zang, J and Yu, Y and Li, X}, title = {Construction of ROS-responsive cascade-targeted liposomes and investigation of their anti-AD effects.}, journal = {International immunopharmacology}, volume = {163}, number = {}, pages = {115234}, doi = {10.1016/j.intimp.2025.115234}, pmid = {40684705}, issn = {1878-1705}, mesh = {*Reactive Oxygen Species/metabolism ; Liposomes ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Microglia/drug effects/metabolism ; *Resveratrol/pharmacology/administration & dosage/therapeutic use/pharmacokinetics ; Blood-Brain Barrier/metabolism/drug effects ; Mice ; Polyethylene Glycols/chemistry ; *Antioxidants/pharmacology/administration & dosage ; *Anti-Inflammatory Agents/pharmacology ; Humans ; *Neuroprotective Agents/pharmacology/administration & dosage ; Male ; Oxidative Stress/drug effects ; Brain/metabolism/drug effects ; }, abstract = {Oxidative stress is considered a critical factor in the pathogenesis of Alzheimer's disease (AD). The interaction between oxidative stress and neuroinflammation is closely associated with the production of beta-amyloid (Aβ). Although many drugs exhibit potent anti-inflammatory and antioxidant properties, their poor water solubility and limited ability to penetrate the blood-brain barrier (BBB) often result in reduced efficacy, making accurate AD treatment challenging. Previous studies have shown that borneol (Bor) can enhance BBB permeability, while the MG1 peptide can specifically target M1-type microglial cells. In this study, we constructed reactive oxygen species (ROS)-responsive cascade-targeting liposomes (ROS@Res-Lip) using DSPE-PEG2000-MG1 and DSPE-TK-PEG2000-Bor co-modification. This design aimed to reduce ROS accumulation and enhance BBB penetration by incorporating ROS-responsive thioketal (TK) bonds and Bor, while leveraging the MG1 peptide to improve the targeting of resveratrol (Res) to M1-type microglia. As a result, the drug concentration in the brain was significantly increased, thereby improving therapeutic efficacy. Our findings demonstrate that ROS@Res-Lip can achieve anti-inflammatory, antioxidant, and neuroprotective effects by targeting M1-type microglia and promoting the conversion of M1-type microglia to M2-type microglia.}, } @article {pmid40684632, year = {2025}, author = {Li, M and Li, C and He, M and Chen, L and Wang, Q}, title = {Neurotoxic effects of Cis-bifenthrin on microbe-gut-brain axis: Disruption of neurolipid balance in Xenopus laevis.}, journal = {Ecotoxicology and environmental safety}, volume = {302}, number = {}, pages = {118675}, doi = {10.1016/j.ecoenv.2025.118675}, pmid = {40684632}, issn = {1090-2414}, mesh = {Animals ; *Xenopus laevis ; *Gastrointestinal Microbiome/drug effects ; *Brain/drug effects/metabolism ; *Pyrethrins/toxicity ; Female ; *Water Pollutants, Chemical/toxicity ; Bile Acids and Salts/metabolism ; Lipopolysaccharides/metabolism ; }, abstract = {The neurotoxic effects of cis-bifenthrin (cis-BF) on amphibians and its molecular mechanisms are unclear despite its common presence in aquatic environments. In present study, female Xenopus laevis were subjected to a three-month treatment with environmentally relevant concentrations of 60 and 300 ng/L cis-BF. Metabolomic analysis of brain tissue revealed differential metabolites enriching bile acid (BA) synthesis, impacting β-amyloid protein deposition. Reduced polyunsaturated fatty acids (PUFAs), essential for membrane integrity, were observed. Elevated amyloid β-protein and lipopolysaccharide (LPS) levels suggested potential Alzheimer's-like symptoms induced by cis-BF. Given PUFAs and BAs are processed via enterohepatic circulation, a notable decrease in the abundance of genera linked to PUFAs and BAs metabolism was observed. Gut metabolomics revealed decreased concentrations of PUFAs and secondary BAs across cis-BF treatment groups, attributed to changes in associated microbial communities. Cis-BF exposure raised intestinal LPS levels and plasma proinflammatory cytokines, resulting in intestinal damage. This facilitated the entry of LPS into the bloodstream and brain tissue, indicating a cytokine-LPS interaction that promotes LPS transit to the brain through the bloodstream. Our study suggests that cis-BF-induced alterations in gut microbiota and metabolism may trigger Alzheimer's-related neurological disorders in Xenopus laevis via the gut-brain axis by inducing neurolipid disorder and inflammation.}, } @article {pmid40684252, year = {2025}, author = {Idris, M and Saini, F and Ivain, P and Baksh, RA and Bianchi, LA and Pape, SE and Zetterberg, H and Wijeratne, PA and Strydom, A}, title = {Staging of Alzheimer's disease progression in Down syndrome using mixed clinical and plasma biomarker measures with machine learning.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70446}, pmid = {40684252}, issn = {1552-5279}, support = {MR/S011277/1/MRC_/Medical Research Council/United Kingdom ; MR/S005145/1/MRC_/Medical Research Council/United Kingdom ; MR/R024901/1/MRC_/Medical Research Council/United Kingdom ; 098330/Z/12/Z//Wellcome Trust Strategic Award/ ; //Baily Thomas Charitable Fund/ ; //Fondation Jérôme Lejeune/ ; AS-CP-18-0020//Alzheimer's Society/ ; 2023-00356//Swedish Research Council/ ; 101053962//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//Alzheimer's Drug Discovery Foundation/ ; //AD Strategic Fund/ ; ADSF-21-831376-C/ALZ/Alzheimer's Association/United States ; ADSF-21-831381-C/ALZ/Alzheimer's Association/United States ; ADSF-21-831377-C/ALZ/Alzheimer's Association/United States ; ADSF-24-1284328-C/ALZ/Alzheimer's Association/United States ; //European Partnership on Metrology/ ; 22HLT07//European Union's Horizon Europe Research and Innovation Programme/ ; //The Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Erling-Persson Family Foundation, Familjen Rönströms Stiftelse/ ; //Stiftelsen för Gamla Tjänarinnor/ ; FO2022-0270//Hjärnfonden/ ; 860197//Marie Skłodowska-Curie/ ; UKDRI-1003//UK Dementia Research Institute/ ; //Olav Thon Stiftelsen/ ; //UCLH Biomedical Research Centre/ ; JPND2021-00694//EU Joint Programme - Neurodegenerative Disease Research/ ; //H2020 Marie Skłodowska-Curie/ ; 101053962//HORIZON EUROPE European Research Council/ ; 2023-00356//Vetenskapsrådet/ ; 101053962//Vetenskapsrådet/ ; 2023-00356//Vetenskapsrådet/ ; 2022-01018//Vetenskapsrådet/ ; 2019-02397//Vetenskapsrådet/ ; //The Alzheimer's Society/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; }, mesh = {Humans ; *Down Syndrome/blood/complications ; *Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; Female ; *Disease Progression ; Male ; Middle Aged ; *Machine Learning ; Amyloid beta-Peptides/blood ; Adult ; tau Proteins/blood ; Neurofilament Proteins/blood ; Peptide Fragments/blood ; Neuropsychological Tests ; Aged ; Cross-Sectional Studies ; }, abstract = {INTRODUCTION: Adults with Down syndrome (DS) have a high risk for Alzheimer's disease (AD). Although the sequence of plasma biomarker and cognitive changes in AD in DS is well studied, their related trajectories are not fully characterized. Data-driven methods can estimate disease progression from cross-sectional data. METHODS: In 57 adults with DS and no AD, we used the event-based model to sequence plasma biomarker and cognitive changes in preclinical AD. Generalized additive models assessed the relationship between age and plasma biomarkers. RESULTS: The earliest changes occurred in the amyloid beta 42/40 ratio, followed by memory changes. Later alterations in neurofilament light and tau concentrations preceded executive and visuomotor function changes, with glial fibrillary acidic protein levels changing last. The highest rate of plasma biomarker changes occurred between ages 39 and 52. CONCLUSION: Changes in DS follow a pattern similar to that of sporadic and familial AD. Event-based modeling offers individual-level staging, potentially optimizing diagnosis and clinical trial patient selection. HIGHLIGHTS: The pre-clinical stages of Alzheimer's disease (AD) development in Down syndrome (DS) are not well defined, despite the extremely high prevalence of AD. Better understanding of early AD progression would aid in diagnostics and treatment. Data-driven methods, such as the event-based model, can aid in clarifying the sequence of cognitive and plasma biomarker changes in the early stages of AD while accounting for baseline variability. We find that plasma amyloid beta 42/40 ratio and memory changes precede changes in plasma biomarker levels of neurodegeneration, with changes in executive and visuomotor functions occurring later, before neuroinflammatory marker changes. Combining plasma biomarkers could be a useful measure of preclinical AD for trials, particularly in individuals between 39 and52 years of age.}, } @article {pmid40684196, year = {2025}, author = {Choi, Y and Kim, PW and Jung, IC and Kim, AR and Park, HJ and Kwon, O and Lee, JH and Kim, JH}, title = {Acupuncture for patients with mild cognitive impairment: a randomized, patient-assessor-blinded, sham-controlled pilot study.}, journal = {BMC complementary medicine and therapies}, volume = {25}, number = {1}, pages = {277}, pmid = {40684196}, issn = {2662-7671}, support = {K16122 and KSN2122211//Korea Institute of Oriental Medicine/ ; K16122 and KSN2122211//Korea Institute of Oriental Medicine/ ; }, mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods ; Pilot Projects ; Male ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; Neuropsychological Tests ; Treatment Outcome ; }, abstract = {BACKGROUND: Mild cognitive impairment (MCI) is the transitional stage between normal aging and early dementia. Although acupuncture is a promising non-pharmacological treatment, higher-quality evidence is needed to confirm its effectiveness. METHODS: A randomized, patient- and assessor-blinded, sham-controlled, pilot clinical trial was conducted to evaluate the feasibility of acupuncture for treating MCI. In total, 30 participants were randomized into acupuncture and sham acupuncture groups. The participants underwent 24 treatment sessions over 12 weeks. The primary outcome was a change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) score over 12 weeks, whereas the secondary outcomes included the Seoul Neuropsychological Screening Battery (SNSB-II) score. Adverse events and the success of blinding were also assessed. RESULTS: Of the 30 participants, 28 completed the study. Participants in the acupuncture and sham acupuncture groups exhibited a decrease in ADAS-cog scores from 10.27 ± 4.03 and 11.47 ± 3.85 at baseline to 5.78 ± 3.04 and 6.27 ± 2.83 at week 12, respectively. Both groups exhibited clinically meaningful improvements, with no significant difference between groups (P = 0.6590). The SNSB-II memory domain exhibited a moderate effect size favoring acupuncture (Cohen's d = 0.57, P = 0.1317). No intervention-related adverse events were reported, and participant blinding was adequate throughout the trial. CONCLUSIONS: The 12-week acupuncture treatment is feasible for patients with MCI and may improve memory. Although the primary outcomes did not reach statistical significance, the secondary outcomes suggested potential benefits. Larger confirmatory trials are warranted to investigate the effectiveness of acupuncture in patients with MCI. TRIAL REGISTRATION: Clinical Research Information Service (cris.nih.go.kr) KCT0001938 (Registered on June 3, 2016).}, } @article {pmid40682852, year = {2025}, author = {Guan, X and Zha, L and Zhu, X and Rao, X and Huang, X and Xiong, Y and Guo, Y and Zhang, M and Zhou, D and Tu, Q and Wu, J and Wang, X and Hua, F and Xu, J}, title = {Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review).}, journal = {International journal of molecular medicine}, volume = {56}, number = {4}, pages = {}, pmid = {40682852}, issn = {1791-244X}, mesh = {Humans ; *Calgranulin B/metabolism ; *Calgranulin A/metabolism ; *Cognitive Dysfunction/metabolism/drug therapy ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Animals ; Biomarkers/metabolism ; Molecular Targeted Therapy ; }, abstract = {The complex of proteins S100A8/A9 has been recognized as a major initiator of cognitive disorder onset, including, but not restricted to, neuroinflammation. Cognitive impairment or decline in memory, attention and executive function has been on the rise and is a major public health priority. Several neurological conditions that affect the brain and cognitive processes, including central nervous system diseases such as Alzheimer's disease and stroke, and systemic diseases, such as sepsis and systemic lupus erythematosus, are associated with S100A8/A9. Experiments have progressively demonstrated that S100A8/A9 plays a role in cognitive decline, as it regulates cognitive domains, including sleep, learning, memory, and emotion control, via several mechanisms. In this review, a critical overview of the role of S100A8/A9 in the treatment of neurocognitive diseases is provided, including the regulation of brain function and the pathogenesis of diseases, and potential novel therapies are suggested. It is necessary to study S100A8/A9 alone as an alternative marker for the diagnosis and treatment of neurocognitive diseases, and in line with the requirements of therapy for cognitive impairment. As S100A8/A9 research continues, the understanding and treatment of neurocognitive diseases may improve.}, } @article {pmid40682719, year = {2025}, author = {Ryu, HS and Sanjay, and Choi, SK and Lee, KH and Jang, SS and Yang, SY and Kwon, YS and Ku, SK and Lee, HJ}, title = {Golden Oyster Mushroom Extract Ameliorates Oxidative Stress-Induced Cell Death in Neurons and Scopolamine-Induced Cholinergic System Impairment in Mice.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {15494-15508}, pmid = {40682719}, issn = {1559-1182}, support = {(RS-2023-00236592)//This research was supported by Korea Institute of Marine Science & Technology Promotion (KIMST) funded by the Ministry of Oceans and Fisheries/ ; }, mesh = {Animals ; *Oxidative Stress/drug effects ; *Scopolamine/toxicity ; Cell Death/drug effects ; *Neurons/drug effects/pathology/metabolism ; Mice ; Neuroprotective Agents/pharmacology ; Male ; Hydrogen Peroxide/toxicity ; Acetylcholine/metabolism ; Cell Line ; Cholinergic Neurons/drug effects/pathology ; Acetylcholinesterase/metabolism ; }, abstract = {Impaired cholinergic system is an important therapeutic target to develop drugs against Alzheimer's disease (AD), as cholinergic signal transduction is associated with the memory, learning, and behavior of an individual. Acetylcholine (ACh) is an important neurotransmitter and is degraded by an enzyme, acetylcholinesterase (AChE), blocking neuronal signal transmission, which leads to amnesia or memory loss. Oxidative stress (OS) also worsens AD pathology by damaging lipids, proteins and DNA of the neuronal cells, leading to neuronal cell death. Golden oyster mushroom (GOM), an edible mushroom native to the regions of Japan, Korea, Russia, and China, has been reported to possess several bioactivities. However, there is no study reported till date, studying the anti-amnesic properties of GOM. The objectives of this study were to assimilate the in vitro neuroprotective and in vivo anti-amnesic properties of GOM. The GOM at 0.1, 0.5, 1, 5, and 10 mg/ml was nontoxic and was able to prevent H2O2 (500 µM) and glutamate (5 mM)-induced OS-mediated cell death in HT-22 cells. In addition, all the selected concentrations of GOM extract (50, 100, and 200 mg/kg, 28 days) were able to prevent scopolamine (ACh receptor antagonist, 1 mg/kg, 1 h post-treatment after the 7[th], 14[th], and 28[th] administrations)-induced cholinergic system impairment, memory loss, histopathological alteration, antioxidant defense system disruption, and reduced memory susceptibility markers in C57BL mice compared to the positive control tacrine (10 mg/kg, 28 days). In conclusion, GOM extract emerged as a natural AChE inhibitor and could be seen as a potential therapeutic AD agent.}, } @article {pmid40682580, year = {2025}, author = {Degan, S and Feng, Y and Colton, C and Schmidt, S and Peterchev, AV and Turner, DA}, title = {Cerebral Blood Flow Responses to Extracranial Alternating Current Brain Stimulation in CVN Mouse Model of Alzheimer's Disease: A Pilot Study Determining Optimal Dose.}, journal = {Neuromodulation : journal of the International Neuromodulation Society}, volume = {}, number = {}, pages = {}, pmid = {40682580}, issn = {1525-1403}, support = {R01 AG074999/AG/NIA NIH HHS/United States ; R01 AG081774/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Insufficient metabolic supply in response to neural demand is a key mechanism of degeneration in Alzheimer's disease [AD]. However, extracranial alternating current [AC] stimulation can increase cerebral blood flow [CBF] and metabolic substrate supply to the brain. In this work, we investigate in an initial, pilot study the optimal dosage of extracranial AC brain stimulation appropriate for long-term treatment to retard degeneration in a mouse AD model [CVN]. MATERIALS AND METHODS: We applied extracranial AC (0.5-2.0 mA; 10 Hz; 20-second bursts) to CVN and control C57Bl/6 mice while measuring CBF and intracerebral electric field in vivo in anesthetized animals, and behavioral responses in awake animals. RESULTS: We found a significant, diffuse increase in cortical CBF (2.6% increase at 0.75 mA) and intracerebral electric field (6.36mV/mm gradient at 0.75 mA) in response to extracranial AC brain stimulation in both CVN and control mice. In awake, behaving mice, the optimal dose of stimulation was 0.75 mA (in 30-second bursts), causing no adverse behavioral effects. CONCLUSION: Scheduled (at fixed times) or demand-triggered (during dynamic metabolic need) bursts of extracranial brain stimulation could enhance CBF to improve brain metabolic supply. The goal of this potential AD treatment is to alleviate mismatches between neural metabolic demand and brain substrate supply, to prevent AD phenotypic disease progression. Based on these pilot data, 0.75 mA is an optimal stimulation treatment dose leading to an appreciable net change in CBF, at a moderate intracranial electrical field, while also indicating behavioral tolerability, now being implemented in a long-term treatment trial.}, } @article {pmid40681915, year = {2025}, author = {Shah, A and Estilo, A and Sheridan, PL and Kalu, U and Chen, D and Chang, D and Slomkowski, M and Lee, D and Hefting, N and Hobart, M and Behl, S and Such, P and Brubaker, M and Grossberg, GT}, title = {Safety and Tolerability of Brexpiprazole in Participants with Agitation Associated with Dementia due to Alzheimer's Disease: Pooled Analysis of Three Randomized Trials and an Extension Trial.}, journal = {CNS drugs}, volume = {39}, number = {10}, pages = {1011-1023}, pmid = {40681915}, issn = {1179-1934}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/complications/drug therapy ; *Antipsychotic Agents/adverse effects/therapeutic use/administration & dosage ; Clinical Trials, Phase III as Topic ; *Dementia/drug therapy/etiology ; Double-Blind Method ; *Psychomotor Agitation/drug therapy/etiology ; *Quinolones/adverse effects/therapeutic use/administration & dosage ; Randomized Controlled Trials as Topic ; *Thiophenes/adverse effects/therapeutic use/administration & dosage ; }, abstract = {BACKGROUND AND OBJECTIVE: Older adults with dementia are particularly vulnerable to antipsychotic side effects. Brexpiprazole, an atypical antipsychotic, is approved in a number of countries for the treatment of agitation associated with dementia due to Alzheimer's disease. This pooled analysis aimed to evaluate the safety and tolerability of brexpiprazole in this patient population. METHODS: Data were included from three Phase 3, 12-week, randomized, double-blind, placebo-controlled trials and a Phase 3, 12-week, active-treatment extension trial in participants with agitation associated with dementia due to Alzheimer's disease. Safety outcomes included treatment-emergent adverse events (TEAEs), weight change, suicidality, extrapyramidal symptoms, and cognitive dysfunction. Two datasets were considered: a 12-week dataset that pooled data from the three randomized trials for brexpiprazole 0.5-3 mg/day and placebo, and a 24-week dataset that combined data from the parent randomized trial and the extension trial for brexpiprazole 2-3 mg/day. RESULTS: Over 12 weeks, 335/655 (51.1%) participants on brexpiprazole and 178/388 (45.9%) participants on placebo reported ≥ 1 TEAE, which led to discontinuation in 41 (6.3%) and 13 (3.4%) participants, respectively. Headache was the only TEAE with incidence ≥ 5% (brexpiprazole, 50 [7.6%] participants; placebo, 36 [9.3%] participants). The incidences of cerebrovascular TEAEs (brexpiprazole, 0.5%; placebo, 0.3%), cardiovascular TEAEs (3.7%; 2.3%), extrapyramidal symptom-related TEAEs (5.3%; 3.1%), and somnolence/sedation TEAEs (3.7%; 1.8%) were generally similar between treatment groups. Six (0.9%) participants on brexpiprazole and 1 (0.3%) participant on placebo died; causes of death were not considered related to brexpiprazole and were generally in line with those expected in Alzheimer's disease. Over 24 weeks, 110/226 (48.7%) participants on brexpiprazole reported ≥ 1 TEAE, which led to discontinuation in 19 (8.4%) participants. Headache was the only TEAE with incidence ≥ 5% (18 [8.0%] participants). No participants died during the extension trial. Over 12 and 24 weeks, mean changes in weight, suicidality, and extrapyramidal symptoms were minimal, with no worsening of cognition. CONCLUSIONS: Considering pooled data from > 1000 participants on brexpiprazole or placebo, brexpiprazole appears to be generally well tolerated for up to 24 weeks in participants with agitation associated with dementia due to Alzheimer's disease. STUDY REGISTRATION: ClinicalTrials.gov identifiers: NCT01862640, NCT01922258, NCT03548584, NCT03594123.}, } @article {pmid40680978, year = {2025}, author = {Zhang, Y and Liu, M and Wang, Y and Hu, D and Wu, S and Zhao, B and Zhou, B and Yang, L}, title = {Nasal nanotherapeutics for central nervous system disorders: Bridging the translational gap in central nervous system drug delivery.}, journal = {European journal of pharmacology}, volume = {1003}, number = {}, pages = {177958}, doi = {10.1016/j.ejphar.2025.177958}, pmid = {40680978}, issn = {1879-0712}, mesh = {Humans ; Administration, Intranasal ; *Central Nervous System Diseases/drug therapy/metabolism ; Animals ; *Drug Delivery Systems ; *Central Nervous System Agents/administration & dosage/pharmacokinetics ; *Nanoparticles ; }, abstract = {Neurological disorders such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), cerebrovascular accidents, brain tumors, and functional impairments are becoming an increasingly urgent global health concern, particularly as aging populations expand worldwide. The blood-brain barrier significantly limits current treatment strategies, such as pharmacological therapies (oral or systemic), neurosurgical procedures, and neuromodulation. This highly selective barrier prevents most small-molecule drugs and virtually all biologics from reaching effective concentrations within the central nervous system (CNS), thereby restricting their therapeutic potential. Therefore, traditional drug delivery methods face challenges in effectively delivering therapeutic agents to the CNS. Intranasal delivery circumvents this limitation through direct nose-to-brain transport via olfactory/trigeminal pathways, achieving higher cerebrospinal fluid drug bioavailability compared to intravenous routes. In this review, we present a comprehensive elucidation of the pathophysiology of CNS disorders and the intricate mechanisms governing drug transport from the nasal cavity. Significantly advancing the field, we provide an exhaustive overview of cutting-edge nanocarriers and inhalation devices specifically designed for inhalable formulations, highlighting their unique advantages and limitations. This review combines clinical and engineering insights to evaluate innovative treatment methods through intranasal delivery, while identifying critical research pathways for improving central nervous system therapies.}, } @article {pmid40680673, year = {2025}, author = {Meng, D and Luo, G and Liu, P}, title = {Copper metabolism and cuproptosis in Alzheimer's disease: mechanisms and therapeutic potential.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {190}, number = {}, pages = {118354}, doi = {10.1016/j.biopha.2025.118354}, pmid = {40680673}, issn = {1950-6007}, mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; *Copper/metabolism ; Humans ; Animals ; *Brain/metabolism/pathology/drug effects ; Oxidative Stress ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with an increasing incidence rate year by year. The pathogenesis of AD is complex and closely related to protein misfolding and aggregation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and other factors. Cuproptosis is a newly discovered form of programmed cell death caused by excessive intracellular copper. Unlike other known forms of cell death, it shows significant potential in the treatment of neurodegenerative diseases. Copper binds to the acylated components of the tricarboxylic acid cycle, causing protein toxicity stress, which ultimately leads to cell cuproptosis. AD is characterized by pathological features such as β-amyloid plaque formation and excessive phosphorylation of tau protein, which are closely linked to the cuproptosis mechanism. However, the specific relationship between the pathogenesis of AD and copper metabolism remains unclear. This article summarizes the metabolism of copper in the brain, the mechanisms of cuproptosis, and the pathogenesis of cuproptosis in AD, and also discusses the regulation of cuproptosis in the treatment of AD. This article provides a basis for targeted research on cuproptosis in AD.}, } @article {pmid40680380, year = {2025}, author = {Wang, B and Li, W and Hong, C and Jin, F and Xu, B and Guo, Z and Chen, S and Zhang, Q}, title = {Amyloid β (Aβ) inhibits retinal angiogenesis in Alzheimer's disease via LncRNA-XIST/miRNA-126-5p/VEGF axis.}, journal = {Immunobiology}, volume = {230}, number = {4}, pages = {153097}, doi = {10.1016/j.imbio.2025.153097}, pmid = {40680380}, issn = {1878-3279}, mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; *MicroRNAs/genetics/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism/genetics ; *Vascular Endothelial Growth Factor A/genetics/metabolism ; Mice ; Disease Models, Animal ; Humans ; Retina/pathology/metabolism ; Signal Transduction ; *Retinal Neovascularization/metabolism/genetics ; Gene Expression Regulation ; *Neovascularization, Pathologic ; Angiogenesis ; }, abstract = {Alzheimer's disease (AD) is often accompanied by retinal lesions, in which Amyloid β (Aβ) is a key mediator. Vascular dysfunction is always associated with the malignant progression of AD, but the precise mechanisms remain poorly understood. The aim of this study is to investigate how Aβ regulates retinal angiogenesis in AD models through the LncRNA-XIST/miR-126-5p/VEGF axis. The research results showed that in the retina of AD model mice, the expression of Aβ and miR-126-5p increased, while the expression of LncRNA-XIST and VEGF decreased. In vitro experiments demonstrated that Aβ treatment downregulated LncRNA-XIST and VEGF expression in RF/6 A cells, while upregulating miR-126-5p and significantly suppressing angiogenesis. Overexpression of LncRNA-XIST can reverse the inhibitory effect of Aβ on angiogenesis, while further overexpression of miR-126-5p can counteract the pro-angiogenic effect of LncRNA-XIST. The dual-luciferase reporter assay results showed that Aβ repressed the transcriptional activity of the LncRNA-XIST promoter by targeting the -800 to -600 fragment. Mechanism studies have revealed that LncRNA-XIST competitively binds to miR-126-5p, preventing its binding to VEGF mRNA and upregulating VEGF expression. In vivo experiments demonstrated that miR-126-5p inhibitor resulted in elevated expression of LncRNA-XIST and VEGF in the mouse retina. This study reveals the molecular mechanism by which Aβ regulates retinal angiogenesis in AD models through the LncRNA-XIST/miR-126-5p/VEGF axis, providing a potential new strategy for targeted therapy of AD-related retinal lesions.}, } @article {pmid40680313, year = {2025}, author = {Hamuľaková, S and Gucký, A and Mezencev, R and Kožurková, M and Bednáriková, Z and Marek, J and Soukup, O and Janoušek, J and Gažová, Z}, title = {Inhibition of amyloid fibrillization of amyloid β peptide by 4,7-disubstituted coumarin derivatives.}, journal = {Bioorganic & medicinal chemistry}, volume = {129}, number = {}, pages = {118302}, doi = {10.1016/j.bmc.2025.118302}, pmid = {40680313}, issn = {1464-3391}, mesh = {*Coumarins/pharmacology/chemistry/chemical synthesis ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Humans ; Structure-Activity Relationship ; Cell Line, Tumor ; Blood-Brain Barrier/metabolism ; *Antioxidants/pharmacology/chemistry/chemical synthesis ; Molecular Structure ; Cell Survival/drug effects ; *Peptide Fragments/metabolism/antagonists & inhibitors ; Dose-Response Relationship, Drug ; Protein Aggregates/drug effects ; }, abstract = {Coumarins are well-known for their unique chemical structure and a wide range of biological effects. Various substituted coumarin-based compounds have emerged as promising candidates for the development of novel therapeutic agents against numerous diseases. This study was focused on the synthesis of new 4,7-disubstituted coumarin derivatives and investigation of their ability to inhibit the aggregation of Aβ40 peptide, their cytotoxic effect on SH-SY5Y cells, their antioxidant properties, and their ability to penetrate the blood-brain barrier (BBB). The results revealed that the trihydroxy derivatives 5a-c had been the most effective inhibitors of Aβ aggregation, promoting the formation of non-toxic, amorphous aggregates instead. Importantly, no significant decrease in the viability of SH-SY5Y neuroblastoma cells was observed after treatment with the studied coumarins. Among them, coumarin 5a demonstrated the strongest antioxidant activity, while compound 5b also exhibited good antioxidant properties, along with the best inhibition of Aβ aggregation (IC50 = 13.5 μM), and adequate permeability across the blood-brain barrier. These findings suggest that compound 5b is a promising candidate for further investigation in Alzheimer's disease pharmacotherapy.}, } @article {pmid40679987, year = {2025}, author = {Li, B and Golovynska, I and Stepanov, YV and Golovynskyi, S and Golovynskyi, A and Kolesnik, D and Stepanova, LI and Lai, P and Lin, F and Qu, J}, title = {Transcranial photobiomodulation therapy with 808 nm light changes expression of genes and proteins associated with neuroprotection, neuroinflammation, oxidative stress, and Alzheimer's disease: Whole RNA sequencing of mouse cortex and hippocampus.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0326881}, pmid = {40679987}, issn = {1932-6203}, mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/therapy ; *Hippocampus/metabolism/radiation effects ; *Oxidative Stress/radiation effects/genetics ; Mice ; *Low-Level Light Therapy/methods ; *Neuroprotection/genetics/radiation effects ; *Neuroinflammatory Diseases/genetics ; *Cerebral Cortex/metabolism/radiation effects ; Mice, Inbred BALB C ; Sequence Analysis, RNA ; Male ; Gene Expression Regulation/radiation effects ; Gene Regulatory Networks ; }, abstract = {Light therapy, using red and near-infrared (NIR) irradiation, is currently applied for the treatment of various neurodegenerative diseases, such as Alzheimer's disease (AD). Transcranial photobiomodulation therapy (tPBMT) can alleviate neurodegeneration, neuronal loss, and β-amyloid peptide plaque burden. Alternatively, potential early inhibition of oxidative stress, neuroinflammation, apoptosis, and amyloidogenic cellular pathways may constrain pathological changes with aging. In this research, we conduct an 808-nm tPBMT with a 30-day course of daily 1-hour sessions for mice and assess its influence on molecular mechanisms related to the potential onset of neurodegeneration. To comprehensively identify molecular mechanisms of tPBMT on the brain cells, the next-generation whole RNA sequencing of over 30,000 mRNA of the cortex and hippocampus of BALB/c mice is performed. After tPBMT, transcriptional alterations are found in 1,005 genes in the hippocampus and 1,482 genes in the cortex. Pathway-gene enrichment network analysis identifies genes associated with about 20 pathways of neurodegeneration, and a disease-gene network is constructed. Particularly, tPBMT alters the transcription and expression of the essential genes associated with oxidative stress (NF-κBIα, JUN, JUND, and PKC genes), inflammation (DOCK4/6, IL-1RAPL1, and TNFαIP6), and apoptosis (CASP3, TNFαIP6, AKT3, CDKN1A, CYP51, RASA2, and RESTAT). Additionally, 808-nm light modulates the main risk genes for AD (BACE1, BACE2, PSEN2, APH1B, GATA2, YY2, RELA, STAT3, JUN, JUND, ARNTL, CREB3L1, CELF2, E2F4, ELK3, and CEBPD), involved in APP processing supporting AD development. Moreover, the APP concentration is reduced after tPBMT. Hence, PBMT may help inhibit the development of different neurodegeneration types and maintain normal brain conditions.}, } @article {pmid40679583, year = {2025}, author = {Sun, X and Zhong, G and Zeng, Y and Xu, T and Liu, Y}, title = {Fully Integrated Wearable Biosensor for Multiple In Situ Phosphorylated Tau Protein Detection.}, journal = {Analytical chemistry}, volume = {97}, number = {29}, pages = {15941-15948}, doi = {10.1021/acs.analchem.5c02541}, pmid = {40679583}, issn = {1520-6882}, mesh = {*Biosensing Techniques/instrumentation ; *tau Proteins/analysis/metabolism ; *Wearable Electronic Devices ; Humans ; *Alzheimer Disease/diagnosis ; Phosphorylation ; *Electrochemical Techniques/instrumentation ; Limit of Detection ; }, abstract = {Early diagnosis is critical for the prevention and treatment of Alzheimer's disease (AD), as it allows for timely detection and intervention. Here, we developed a fully integrated wearable electrochemical sensing patch for early screening of AD, which combines sample collection and detection within a device. This wearable patch integrates a custom-developed microneedle sampling system with a wearable multimodal electrochemical biosensor. Such a microneedle sampling system can deliver interstitial fluid (ISF) to the detection area through a microneedle array, where the electrochemical sensing system can directly detect AD-related biomarkers P-tau181 and P-tau217 in situ with detection limits of 0.058 and 0.079 pg/mL. Additionally, the sensing patch includes a Bluetooth module, enabling the transmission of detection results to a mobile phone APP for display and further detection control. This fully integrated wearable electrochemical sensing patch provides a promising strategy for early multiple in situ diagnosis of AD.}, } @article {pmid40678834, year = {2025}, author = {Islam, MR and Rauf, A and Akter, S and Akter, H and Al-Imran, MIK and Fakir, MNH and Thufa, GK and Islam, MT and Hemeg, HA and Abdulmonem, WA and Aljohani, ASM and Iriti, M}, title = {Neuroprotective Potential of Curcumin in Neurodegenerative Diseases: Clinical Insights Into Cellular and Molecular Signaling Pathways.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {8}, pages = {e70369}, pmid = {40678834}, issn = {1099-0461}, mesh = {*Curcumin/therapeutic use/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Signal Transduction/drug effects ; Animals ; Oxidative Stress/drug effects ; }, abstract = {Progressive neuronal loss and dysfunction characterize neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, and Huntington's diseases, spinal cord injury, and stroke, making them difficult to treat. Curcumin, a bioactive substance derived from the turmeric plant (Curcuma longa), is interesting due to its potential neuroprotective properties. This review thoroughly shows the cellular and molecular signaling mechanisms that curcumin utilizes to provide neuroprotective effects in NDs. Curcumin regulates several signaling pathways linked to neuroprotection, such as those that reduce oxidative stress, prevent Aβ formation, and decrease neuroinflammation. NF-κB suppression reduces inflammatory responses, while Nrf2 activation boosts antioxidant response element expression. Furthermore, curcumin enhances autophagy and neurotrophic factor expression, facilitating the removal of harmful protein aggregates. The function of curcumin as a metal chelator is emphasized particularly to iron and other metal dysregulations linked to neurodegenerative processes. Curcumin's capacity to regulate metal ion homeostasis is essential since the pathophysiology of NDs is significantly influenced by metal-induced oxidative stress and toxic buildup. It shows potential therapeutic effects by reducing oxidative damage and chelating excess metals. Clinical research indicates that curcumin can penetrate the blood-brain barrier, making it an effective treatment option. The regulation of these pathways reduces neuronal damage and improves neurons' survival and functionality. In addition, curcumin's anti-inflammatory properties and low toxicity make it a promising long-term treatment option for NDs. Therefore, this review emphasizes the potential of curcumin as a targeted neuroprotective compound, presenting recent clinical insights and experimental data. Future studies should optimize curcumin formulations and delivery systems to enhance its bioavailability and therapeutic efficacy.}, } @article {pmid40678772, year = {2025}, author = {Choi, SH and Shim, Y and Kim, S and Yang, DW and Park, KH and Kim, J and Youn, YC}, title = {The Care Pathway for Patients with Mild Cognitive Impairment in Korea: A Survey of Dementia Specialists.}, journal = {Dementia and geriatric cognitive disorders extra}, volume = {15}, number = {1}, pages = {99-107}, pmid = {40678772}, issn = {1664-5464}, abstract = {INTRODUCTION: Mild cognitive impairment (MCI) represents a loss of memory or other cognitive function while maintaining the ability to independently perform most activities of daily living. This study assessed how Korean specialists in dementia care diagnosed and treated patients with MCI symptoms. METHODS: A questionnaire on the current management of MCI was developed by 6 experts in MCI care. Specialists in MCI care (n = 24: 14 neurologists/10 psychiatrists) verbally answered questions relating to their experience/views in caring for MCI patients. RESULTS: Respondents diagnosed MCI using the Seoul Neuropsychological Screening Battery (79%) and the Consortium to Establish a Registry for Alzheimer's Disease - Korea (21%) neuropsychological battery tests. All or nearly all respondents also assessed patients with Mini-Mental State Examination, Geriatric Depression Scale, Clinical Dementia Rating, Activities of Daily Living (ADL), and Instrumental ADL tests. All respondents used MRI or CT for differential diagnosis of diseases causing MCI, about one-third used amyloid PET. Most respondents (96%) treated patients with MCI due to Alzheimer's disease (AD) with medication, commonly choline alfoscerate (71%) and donepezil (53%), mainly as combination therapy. Unmet needs included patient/caregiver education (63%) and time constraints for consulting patients (54%). Most respondents considered that increased amyloid-β testing for patients with MCI due to AD or subjective cognitive decline is likely to increase. CONCLUSIONS: This survey described the current management of MCI due to AD, identified unmet needs and considered possible future developments in the changing landscape of early AD treatment. Early detection and diagnosis and continued development of emerging preventative or therapeutic interventions are critical for MCI outcomes.}, } @article {pmid40678242, year = {2025}, author = {Batista, AF and Presumey, J and Singh, B and Schroeder, MK and Khan, K and Spooner, E and Li, S and Carroll, MC and Lemere, CA}, title = {Global C3 lowering in adulthood protects against hippocampal dysfunction and cognitive impairment in aged mice.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40678242}, issn = {2693-5015}, support = {R01 NS136122/NS/NINDS NIH HHS/United States ; RF1 AG060057/AG/NIA NIH HHS/United States ; R01 AR074105/AR/NIAMS NIH HHS/United States ; R21 AG044713/AG/NIA NIH HHS/United States ; R01 AI130307/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Complement component 3 (C3) is increasingly recognized for its role in neurodegenerative processes; however, its specific impact on age-related hippocampal dysfunction remains poorly understood. This study investigates the effects of inducible C3 knockdown in adulthood on hippocampal function using a novel mouse model. METHODS: We developed a chimeric floxed C3 mouse line (C3[fl/fl]) and crossed it with Rosa-26-Cre-ERT2+/- mice, resulting in C3[fl/fl] ; Rosa-26-Cre-ERT2[+/-] (C3iKO) mice that allow for global C3 knockdown via Tamoxifen (TAM) administration at any age. Young adult female and male C3iKO mice were treated with TAM or corn oil (CO) as a control, to induce global C3 lowering in 4 cohorts of mice. Serum C3 levels were monitored throughout the lifespan for all cohorts. Other outcome measures varied by cohort and included behavior, C3 mRNA and protein levels in brain, C1q levels, immune gene expression in brain, gliosis, synaptic changes in hippocampus. RESULTS: TAM treatment led to a sustained reduction in C3 levels in serum, liver, and brain tissues of C3iKO mice. Global C3 lowering was associated with reduced expression of C1q, C4b, IFNa, IFNb,and APOE, and increase expression of homeostatic genes Tgfb1 and Tgfbr1 in mouse brain one-year following TAM treatment. Notably, C3 lowering in adulthood conferred significant neuroprotection against age-related cognitive decline, which corresponded to increased hippocampal synaptic density and dendritic spine formation and increased pre-synaptic proteins in hippocampal synaptosomes. Moreover, long-term potentiation (LTP) impairments induced by Aβ-oligomers were rescued following C3 knockdown, highlighting potential therapeutic implications. CONCLUSION: Our C3iKO mouse model was consistently effective in lowering C3 levels in the brain and periphery in mice. The findings reported here demonstrate that global C3 lowering in adulthood, after brain development, protected the brain against age-associated hippocampal dysfunction and cognitive decline, suggesting that complement modulation may provide a neuroprotective strategy against brain aging. The C3iKO model provides a valuable platform for understanding the role of complement C3 in age-related neurodegenerative conditions, including Alzheimer's disease. Further studies are needed to better understand these neuroprotective effects in models of neurodegeneration and to assess the therapeutic potential of complement modulation in the brain.}, } @article {pmid40677108, year = {2025}, author = {Hakim, MA and Sanni, A and Osman, ST and Hamdy, NA and Purba, WT and Bhuiyan, MMAA and Onigbinde, S and El-Khordagui, LK and El-Yazbi, A and Mechref, Y}, title = {Serum Proteome Profiling of Diabetic Patients Treated With DPP4 and SGLT2 Inhibitors Shows Improved Cognitive and Cardiovascular Functions.}, journal = {Proteomics}, volume = {25}, number = {14}, pages = {e70000}, doi = {10.1002/pmic.70000}, pmid = {40677108}, issn = {1615-9861}, support = {D-0005//Robert A. Welch Foundation/ ; //The CH Foundation/ ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/blood ; Male ; Female ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/pharmacology ; Middle Aged ; *Proteome/analysis/metabolism ; Metformin/therapeutic use ; *Cognition/drug effects ; Aged ; Hypoglycemic Agents/therapeutic use/pharmacology ; Proteomics/methods ; Cardiovascular Diseases/drug therapy ; Dipeptidyl Peptidase 4 ; }, abstract = {Type 2 diabetes (T2D) is a complex metabolic disorder with rising global prevalence, leading to major complications such as cognitive decline, cardiovascular disease, and systemic inflammation. Although advances in T2D pharmacotherapy have shown promise in addressing these complications, the underlying protective mechanisms remain unclear, especially as they appear to be independent of glycemic control. In this study, we performed a comprehensive proteomic analysis using LC-MS/MS to explore the molecular effects of newer antidiabetic drugs, specifically dipeptidyl peptidase 4 (DPP4) and sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is), when combined with metformin, the first-line treatment for T2D. Serum samples from 76 individuals were analyzed, including 16 healthy subjects, 32 T2D patients on metformin monotherapy, and 28 T2D patients receiving combination therapy. We identified and quantified 505 low-abundance proteins, followed by statistical analysis and ingenuity pathway analysis. Our findings revealed significant changes in key biological pathways related to synaptogenesis, insulin-like growth factor transport, and neurovascular coupling signaling. These results were further validated using parallel reaction monitoring. Notably, pathways associated with cognitive function and cardiovascular health were adversely affected in T2D patients on metformin monotherapy but showed improvement with combination therapy. These results suggest that the combination of DPP4 and SGLT2is offers a therapeutic advantage, underscoring the importance of personalized treatment strategies in managing T2D complications. Summary: Type 2 diabetes (T2D) is a chronic metabolic disorder that contributes to the progression of cognitive impairment, cardiovascular diseases, and renal dysfunction. Cognitive decline in T2D patients can also increase the risk of developing neurological conditions like Alzheimer's disease. Recently developed antidiabetic drugs have shown promising cardiovascular and renal health effects, such as dipeptidyl peptidase 4 (DPP4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is). However, the precise mechanisms by which these drugs influence biological pathways related to cognitive function and central nervous system (CNS) development remain unclear. In this study, we explored the impact of these newer antidiabetic drugs in combination with metformin, compared to metformin monotherapy and healthy controls, by investigating differentially expressed proteins and their role in cognitive processes. Our findings reveal that DPP4 and SGLT2is activate key biological pathways-such as synaptogenesis, insulin-like growth factor regulation, and neurovascular coupling-that are either suppressed or not enriched in the metformin-only group. These pathways are critical for maintaining and regulating CNS function and cognitive health.}, } @article {pmid40676911, year = {2025}, author = {Chhipa, RR and Kurien, BT and Scofield, RH and Wolf, RF and Huang, H and Sundaram, P}, title = {Amytrapper Catheter: A Prototype Extracorporeal Device That Traps Blood Amyloid-β in a Rat Model of Alzheimer's Disease.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {40}, number = {}, pages = {15333175251361265}, pmid = {40676911}, issn = {1938-2731}, support = {R44 AG057327/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/blood/therapy ; *Amyloid beta-Peptides/blood ; Disease Models, Animal ; Rats ; Male ; *Catheters ; }, abstract = {Alzheimer's disease (AD) presents a pressing global health challenge, with amyloid-β (Aβ) accumulation in the brain being a hallmark feature. While monoclonal antibodies targeting Aβ have shown cognitive benefits, safety concerns remain. Here, we introduce the Amytrapper catheter, a novel extracorporeal device developed by Recombinant Technologies to trap circulating Aβ using a retro-inverso peptide conjugated to polyethylene glycol. Through in vivo experiments using a rat model of AD, we demonstrate significant reductions in blood Aβ levels and behavioral improvements following Amytrapper catheter treatment. This innovative approach holds promise as a disease-modifying therapy for AD, offering a complementary strategy to existing treatments and advocating for further clinical development.}, } @article {pmid40676897, year = {2025}, author = {Sánchez-Soblechero, A and Gil, M and Rojo, JM and Muñiz, R and Hoyos-Alonso, MC and Olazarán, J}, title = {Trends of antipsychotic prescribing for people with dementia in Spain.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {1}, pages = {104-111}, doi = {10.1177/13872877251359682}, pmid = {40676897}, issn = {1875-8908}, mesh = {Humans ; *Antipsychotic Agents/therapeutic use ; Spain/epidemiology ; *Dementia/drug therapy/epidemiology ; Male ; Female ; Retrospective Studies ; Aged ; Aged, 80 and over ; *Practice Patterns, Physicians'/trends ; *Drug Prescriptions/statistics & numerical data ; Middle Aged ; }, abstract = {BackgroundAntipsychotic medications are frequently prescribed in people with dementia (PwD), despite concern regarding risk-benefit balance.ObjectiveTo describe the evolution of antipsychotic prescribing for PwD in Spain, with special interest in the effect of administration regulatory warnings (2004 and 2008).MethodsLongitudinal retrospective study using the national Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP). We included patients with incident dementia during the study period (January 1, 2002 to December 31, 2018) and excluded those with major psychiatric conditions, mental retardation, or previous use of antipsychotics. Paper-based and electronic prescriptions of antipsychotics were collected. Annual prevalence of prescribing was obtained for single medications and antipsychotic group. All calculations were conducted for the total sample and stratified by sex. The results were compared with those of other countries.ResultsAntipsychotic prescribing doubled during the study period, raising from 12.6% (2002) to 23.8% (2018). A mild decrease of prescribing was observed from 2004 to 2007, followed by steady increase from 2007 on. This increase was due to atypical antipsychotic use, specifically quetiapine, which grew from 0.2% (2002) to 16.4% (2018) and was more frequently utilized in men. Spain prevalence of antipsychotics doubled the UK's.ConclusionsBetter designed warnings appear as a key means to rationalize use of antipsychotics in Spain and other countries, ideally as part of national dementia strategies. Dearly needed non-pharmacological approaches for comprehensive treatment of neuropsychiatric symptoms could be generalized as a first step through nursing home and day care networks. Quetiapine requires the agencies' urgent attention.}, } @article {pmid40676867, year = {2025}, author = {Chen, G and McKay, NS and Gordon, BA and Joseph-Mathurin, N and Liu, J and Schindler, SE and Hassenstab, J and Doering, S and Aschenbrenner, AJ and Wang, Q and LaMontagne, PJ and Keefe, SJ and Massoumzadeh, P and Cruchaga, C and Xiong, C and Morris, JC and Benzinger, TL}, title = {Baseline and longitudinal changes in cortical thickness and hippocampal volume predict cognitive decline.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {106}, number = {4}, pages = {1452-1462}, pmid = {40676867}, issn = {1875-8908}, support = {R01 AG043434/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; S10 RR022984/RR/NCRR NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; R01 AG021910/AG/NIA NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; P50 MH071616/MH/NIMH NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; U24 RR021382/RR/NCRR NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Hippocampus/pathology/diagnostic imaging ; Male ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Female ; Aged ; Magnetic Resonance Imaging ; Longitudinal Studies ; Middle Aged ; Aged, 80 and over ; *Cerebral Cortex/pathology/diagnostic imaging ; *Brain Cortical Thickness ; Organ Size ; Neuropsychological Tests ; Disease Progression ; }, abstract = {BackgroundAs we transition to disease-modifying treatment for Alzheimer's disease (AD), identifying individuals most at risk for future cognitive decline is crucial. Amyloid PET, cerebrospinal fluid and more recently blood-based biomarkers can identify the first stage of AD. However, changes detectable by PiB-PET may precede the onset of the dementia by 20-30 years. MRI is a widely available tool for detecting longitudinal changes in brain structure, such as cortical thickness and hippocampal volume and may provide additional insight into which patients are at greatest risk to develop cognitive decline.ObjectiveTo determine how well the hippocampal volume and cortical thickness, without specific AD biomarkers, can predict cognitive decline.MethodsMRI data from 344 participants (cognitively unimpaired or mild cognitive impairment, age 50-86) were used to evaluate if changes in cortical thickness and hippocampal volume predict cognitive decline, measured by a global cognitive composite score. A random coefficient model was employed to calculate longitudinal changes in cortical thickness and hippocampal volume and assess their ability to predict cognitive decline.ResultsBaseline cortical thickness as well as hippocampal volume predicted cognitive decline, regardless of baseline cognitive status. In individuals unimpaired at baseline, decreases in cortical thickness and hippocampal volume independently predicted cognitive decline. For participants with baseline mild impairment, decreases in hippocampal volume predicted further cognitive decline.ConclusionsThese findings indicate that MRI could serve as an effective tool for identifying individuals at elevated risk of cognitive decline, a growing public health concern as global populations continue to age.}, } @article {pmid40676669, year = {2025}, author = {Li, B and Wang, L and Xiao, Y and Tang, Z and Wang, Y and Sun, T and Qi, X}, title = {Modulation of neuronal α1-adrenergic receptor reduces tauopathy and neuroinflammation by inhibiting the STING/NF-κB/NLRP3 signaling pathway in Alzheimer's disease mice.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {187}, pmid = {40676669}, issn = {1742-2094}, support = {Qiankehe Basic-[2024] Youth 228//the Guizhou Provincial Science and Technology Program Project/ ; Qiankehe Platform Talents-GCC[2023]035//the Guizhou Provincial Science and Technology Program Project/ ; QianJiaoji [2024]92//the Guizhou Provincial Department of Education Youth Science and Technology Talent Project/ ; 82260263//This research was funded by the Chinese National Natural Science Foundation/ ; }, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Mice ; *Alzheimer Disease/metabolism/pathology/genetics ; *Signal Transduction/physiology/drug effects ; NF-kappa B/metabolism ; Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism/pathology ; *Tauopathies/metabolism/pathology/genetics ; *Receptors, Adrenergic, alpha-1/metabolism/genetics/biosynthesis ; *Neurons/metabolism/pathology ; Humans ; Mice, Inbred C57BL ; Membrane Proteins/metabolism ; Male ; Disease Models, Animal ; }, abstract = {BACKGROUND: Neuroinflammation is closely associated with the pathological progression of Alzheimer's disease (AD). The α1-adrenergic receptor (ADRA1), a G protein-coupled receptor, has been identified as a critical therapeutic target in inflammatory disorders. However, its precise mechanistic role in AD pathogenesis remains unclear. METHODS: To investigate ADRA1's role in AD, we employed 3xTg-AD and wild-type (WT) mice, modulating neuronal ADRA1 expression via intracerebroventricular delivery of adeno-associated viruses. Cognitive function, tau pathology, neuronal morphology, and activation of the STING/NF-κB/NLRP3 signaling pathway were evaluated using behavioral tests, Western blot, Golgi-Cox staining, immunohistochemistry, and immunofluorescence. In vitro AD models were established using Aβ42 oligomer-stimulated SH-SY5Y cells and primary murine neurons, along with SH-SY5Y cells transfected with full-length human tau (SH-SY5Y/htau). Pharmacological antagonists, inhibitors, lentiviral transduction, co-immunoprecipitation, and calcium flux assays were utilized to dissect ADRA1-mediated molecular mechanisms in tauopathy and neuroinflammation. RESULTS: Hippocampal ADRA1 expression was significantly elevated in 10-month-old 3xTg-AD mice. Neuronal ADRA1 knockdown suppressed STING/NF-κB/NLRP3 pathway activation, ameliorated tauopathy and neuroinflammation, restored neuronal structure/function, and improved cognitive deficits in 3xTg-AD mice. Conversely, ADRA1 overexpression in C57/BL6 mice induced tauopathy, neuroinflammation, and cognitive impairment. Mechanistically, ADRA1 interacts with CXCR4 to form heterodimers, triggering cytoplasmic Ca[2]⁺ overload and subsequent STING/NF-κB/NLRP3 pathway activation. CONCLUSIONS: ADRA1 critically mediates tauopathy and neuroinflammation through STING/NF-κB/NLRP3 signaling. These results identify ADRA1 as a promising therapeutic target for AD prevention and treatment.}, } @article {pmid40676541, year = {2025}, author = {Zhang, Y and Xu, K and Wang, Y and Shen, Y and Liu, Z and Zhang, C and Zhou, Y and Lv, P and Bai, Y and Wang, S}, title = {Efficacy of repetitive transcranial magnetic stimulation in cognitive impairment of neurodegenerative diseases: a systematic review and meta-analysis.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {295}, pmid = {40676541}, issn = {1471-2377}, mesh = {Humans ; *Transcranial Magnetic Stimulation/methods ; *Cognitive Dysfunction/therapy/etiology ; *Neurodegenerative Diseases/therapy/complications/psychology ; Randomized Controlled Trials as Topic/methods ; Treatment Outcome ; *Alzheimer Disease/therapy/psychology ; *Parkinson Disease/therapy/complications/psychology ; }, abstract = {OBJECTIVE: Currently, there is a lack of reliable evidence to prove the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the cognitive and emotional domains of neurodegenerative diseases (ND), leading to the absence of a unified and effective rTMS treatment protocol or stimulation targets. This systematic review and meta-analysis summarizes existing evidence to evaluate the efficacy of rTMS targeting the dorsolateral prefrontal cortex (DLPFC) and non-DLPFC in the cognitive and emotional aspects of ND. METHODS: For two common types of ND Alzheimer's disease (AD) and Parkinson's disease (PD), we included 17 relevant randomized controlled trials (RCTs) from five databases. Search terms included rTMS, Parkinson's disease, Alzheimer's disease, cognitive impairment, and randomized controlled studies. Two independent reviewers assessed the risk of bias in the included literature, performed data extraction, and evaluated the evidence. Treatment effects were assessed using the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Hamilton Depression Rating Scale (HAMD), the Hamilton Anxiety Rating Scale (HAMA), and Activities of Daily Living (ADL). Data were analyzed using R software to evaluate effect sizes and 95% confidence interval (CI). Heterogeneity tests were conducted to assess differences in treatment effects between DLPFC and non-DLPFC. RESULTS: We screened 3,467 articles and identified 17 studies that met the inclusion criteria. The pooled results showed significant effects: MoCA (MD: 2.13, 95% CI [0.75, 3.52], p < 0.001); MMSE (MD: 1.16, 95% CI [0.91, 1.41], p = 0.0075); HAMD (MD: -2.63, 95% CI [-6.45, -1.20], p = 0.14); HAMA (SMD: -0.62, 95% CI [-0.91, -0.33], p < 0.001); ADL (MD: -0.56, 95% CI [-1.10, 2.22], p = 0.48). CONCLUSION: rTMS has a positive effect on cognitive impairment and emotional abnormalities associated with ND. There is a significant difference in MoCA scores between rTMS applied to DLPFC and non-DLPFC. DLPFC may serve as a reliable stimulation target for treating non-motor symptoms related to ND (such as cognitive and emotional issues), which is beneficial for developing an rTMS treatment protocol with broad applicability for ND. However, due to the small number of included studies and the indirect nature of the comparison methods, we should interpret these results with caution.}, } @article {pmid40676466, year = {2025}, author = {Hu, H and Brys, M and Ruberg, SJ and Qu, Y}, title = {Estimand Endpoints for Longitudinal Measures of Continuous Disease Progression with an Alzheimer's Disease Example.}, journal = {Therapeutic innovation & regulatory science}, volume = {59}, number = {6}, pages = {1413-1420}, pmid = {40676466}, issn = {2168-4804}, mesh = {*Alzheimer Disease/drug therapy/physiopathology ; Humans ; *Disease Progression ; Longitudinal Studies ; Quality of Life ; *Endpoint Determination/methods ; }, abstract = {The ICH E9 (R1) Addendum provides a framework to define an estimand and perform sensitivity analysis. The clinical endpoint (i.e., variable, response, outcome) is one of the important estimand attributes. In our opinion, the selection of the endpoint in Alzheimer's disease requires more exploration beyond what is used currently. The change in a cognitive and functional assessment scale from baseline to a specific time point of interest is often used as a primary or key secondary endpoint in clinical trials. However, such a change from baseline to the time point of interest may not reflect the benefit of the treatment over the course of treatment duration and may be difficult to intuitively understand by patients and clinicians. For two patients with the same change from baseline, the patient with rapid disease progression in the beginning is considered to have overall worse quality of life compared to the other patient with slow disease progression in the beginning but rapid progression toward the end. We explore time-averaged measurement (TAM) as a new endpoint and propose using the relative change to quantify the treatment difference. Estimands under the ICH E9 (R1) Addendum were considered by using various strategies in handling intercurrent events and used corresponding methods for handling missing data. We illustrate the use of TAM and compare the results with other commonly used estimand endpoints (the change from baseline, the relative disease progression model, and the slope of disease progression) for different estimands and imputation methods from retrospective analyses of a historical study.}, } @article {pmid40675957, year = {2025}, author = {Vaghari, D and Mohankumar, G and Tan, K and Lowe, A and Shering, C and Tino, P and Kourtzi, Z}, title = {AI-guided patient stratification improves outcomes and efficiency in the AMARANTH Alzheimer's Disease clinical trial.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {6244}, pmid = {40675957}, issn = {2041-1723}, support = {/WT_/Wellcome Trust/United Kingdom ; U19 AG024904/AG/NIA NIH HHS/United States ; 221633/Z/20/Z//Wellcome Trust (Wellcome)/ ; INF\R2\202107//Royal Society/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/diagnosis ; Male ; Female ; Aged ; Amyloid beta-Peptides/metabolism ; Treatment Outcome ; Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Aspartic Acid Endopeptidases/antagonists & inhibitors ; Aged, 80 and over ; Prognosis ; Cognitive Dysfunction/drug therapy ; Patient Selection ; Cognition/drug effects ; }, abstract = {Alzheimer's Disease (AD) drug discovery has been hampered by patient heterogeneity, and the lack of sensitive tools for precise stratification. Here, we demonstrate that our robust and interpretable AI-guided tool (predictive prognostic model, PPM) enhances precision in patient stratification, improving outcomes and decreasing sample size for a AD clinical trial. The AMARANTH trial of lanabecestat, a BACE1 inhibitor, was deemed futile, as treatment did not change cognitive outcomes, despite reducing β-amyloid. Employing the PPM, we re-stratify patients precisely using baseline data and demonstrate significant treatment effects; that is, 46% slowing of cognitive decline for slow progressive patients at earlier stages of neurodegeneration. In contrast, rapid progressive patients did not show significant change in cognitive outcomes. Our results provide evidence for AI-guided patient stratification that is more precise than standard patient selection approaches (e.g. β-amyloid positivity) and has strong potential to enhance efficiency and efficacy of future AD trials.}, } @article {pmid40675659, year = {2025}, author = {Singla, P and Argoff, CE}, title = {How Common Is Pain in Neurologic Disorders and Why Should Neurologists Care?.}, journal = {Neurologic clinics}, volume = {43}, number = {3}, pages = {457-465}, doi = {10.1016/j.ncl.2025.04.001}, pmid = {40675659}, issn = {1557-9875}, mesh = {Humans ; *Neurologists ; *Nervous System Diseases/complications/therapy ; *Pain Management/methods ; *Pain/etiology ; *Chronic Pain/therapy/etiology ; }, abstract = {This article explores the link between chronic pain and neurologic disorders, focusing on how pain affects conditions like Alzheimer's disease, Parkinson's disease, multiple sclerosis, and post-stroke pain. The article highlights the need to recognize pain as an important symptom in these conditions and encourages neurologists to take an active role in managing pain. By understanding how pain works and using a team approach, health care providers can improve the quality of life for patients and create better treatment plans for chronic pain related to neurologic disorders.}, } @article {pmid40675338, year = {2025}, author = {Shtilbans, A}, title = {Combination Supplement Therapy: A New Frontier in Treatment of Neurodegenerative Diseases.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tjnut.2025.07.004}, pmid = {40675338}, issn = {1541-6100}, abstract = {This review highlights the importance and potential beneficial effects of dietary supplements, including taurine, tauroursodeoxycholic acid (TUDCA), curcumin, coenzyme Q10, creatine, and N-acetylcysteine, in the management of neurodegenerative diseases. Studies in preclinical models have consistently shown significant potential of these supplements in mitigating neurodegenerative pathology. Through a range of mechanisms targeting different molecular pathways, these supplements demonstrate therapeutic outcomes in preclinical models of conditions such as Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, and Huntington disease. This review discusses published data on each of these supplements in the context of neurodegenerative diseases. It also discusses a combination therapy concept and proposes a strategy to formulate an optimal blend of these supplements. This combination approach will target key processes, including mitochondrial dysfunction, protein misfolding, neuroinflammation, and oxidative stress responsible for neurodegenerative conditions. Additionally, this review examines various models used for both the initial screening and subsequent assessment of candidate supplement combinations.}, } @article {pmid40674898, year = {2025}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {Artificial intelligence in medicine}, volume = {168}, number = {}, pages = {103218}, doi = {10.1016/j.artmed.2025.103218}, pmid = {40674898}, issn = {1873-2860}, support = {R01 DA054992/DA/NIDA NIH HHS/United States ; }, mesh = {*Drug Repositioning/methods ; *Data Mining/methods ; Humans ; *Dementia/drug therapy/genetics ; *Artificial Intelligence ; Discriminant Analysis ; }, abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, and HIV-associated neurocognitive disorder severely impact patients and healthcare systems. While effective treatments remain limited, researchers are actively developing ways to slow progression and improve patient outcomes, requiring innovative approaches to handle huge volumes of new scientific data. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20,889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. We focused on repurposing drugs for dementia by identifying dementia-associated genes highly ranked in other disease classes. The method was developed for detection of genes that shared across multiple conditions and classified them based on their roles in biological pathways. This led to the selection of six primary drugs for further study.}, } @article {pmid40672883, year = {2025}, author = {Zammit, AR and Capuano, AW and Barnes, LL and Schneider, JA and Sperling, RA and Bennett, DA and Grodstein, F}, title = {Cognitive decline across five cognitive batteries: Sample size implications for clinical trials.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70137}, pmid = {40672883}, issn = {2352-8737}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG022018/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; K01 AG054700/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: We evaluated the statistical power for a theoretical randomized trial of anti-amyloid treatment in preclinical Alzheimer's Disease across five cognitive composites in preclinical Alzheimer's Disease across five cognitive composites: Alzheimer's Prevention Initiative Preclinical Composite Cognitive Test (APCC); Preclinical Alzheimer's Composite with Semantic Processing (PACC5); Preclinical Alzheimer's Cognitive Composite (PACC); and global and episodic memory composites. METHODS: We utilized annual cognitive assessments from 517 decedents (78.2 ± 4.7years; 72% female) with post mortem pathologic Alzheimer's disease (AD) to represent amyloid positivity. We calculated sample sizes to detect 30% reduction in 5-year slopes of cognitive decline for equal size treatment versus placebo groups across composites. RESULTS: Estimated sample sizes for APCC (n = 1633, 95% confidence interval [CI] 1400-1823), PACC (n = 1822, 95% CI 1612-2122), and episodic memory (n = 3141 95%CI 2563-3732) were larger than for PACC5 (n = 1424, 95% CI 1249-1575). Sample size estimates were similar between PACC5 and the global composite (n = 1267, 95%CI 1336-1407). DISCUSSION: Small changes in composites, such as addition of semantic fluency in PACC5, could be considered as part of approaches to improve statistical power. HIGHLIGHTS: We evaluated statistical power of a theoretical 5-year randomized trial testing anti-amyloid treatments in early Alzheimer's across five cognitive composite endpoints.We leveraged annual cognitive assessment in Rush Alzheimer's Disease Center cohorts and used post mortem pathologic AD to represent amyloid positivity.Preclinical Alzheimer's Composite with Semantic Processing (PACC5) required significantly lower sample size to achieve power for a 30% reduction in cognitive slope than Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (PACC).PACC5 had better statistical power than Alzheimer's Prevention Initiative Preclinical Composite Cognitive Test (APCC) and an episodic memory composite.Small changes in cognitive composites can improve detection of cognitive decline.}, } @article {pmid40672873, year = {2025}, author = {Xu, Q and An, L and Yang, H and Hong, KS}, title = {A multi-graph convolutional network method for Alzheimer's disease diagnosis based on multi-frequency EEG data with dual-mode connectivity.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1555657}, pmid = {40672873}, issn = {1662-4548}, abstract = {OBJECTIVE: Alzheimer's disease (AD) is mainly identified by cognitive function deterioration. Diagnosing AD at early stages poses significant challenges for both researchers and healthcare professionals due to the subtle nature of early brain changes. Currently, electroencephalography (EEG) is widely used in the study of neurodegenerative diseases. However, most existing research relies solely on functional connectivity methods to infer inter-regional brain connectivity, overlooking the importance of spatial connections. Moreover, many existing approaches fail to fully integrate multi-frequency EEG features, limiting the comprehensive understanding of dynamic brain activity across different frequency bands. This study aims to address these limitations by developing a novel graph-based deep learning model that fully utilizes both functional and structural information from multi-frequency EEG data. METHODS: This paper introduces a Multi-Frequency EEG data-based Multi-Graph Convolutional Network (MF-MGCN) model for AD diagnosis. This method integrates both functional and structural connectivity to more thoroughly capture the relationships among brain regions. By extracting differential entropy (DE) features from five distinct frequency bands of EEG signals for each segment and using graph convolutional networks (GCNs) to aggregate these features, the model effectively distinguishes between AD and healthy controls (HC). RESULTS: The outcomes show that the developed model outperforms existing methods, achieving 96.15% accuracy and 98.74% AUC in AD and HC classification. CONCLUSION: These findings highlight the potential of the MF-MGCN model as a clinical tool for Alzheimer's disease diagnosis. This approach could help clinicians detect Alzheimer's at earlier stages, enabling timely intervention and personalized treatment plans.}, } @article {pmid40672508, year = {2025}, author = {, and Cao, H and Song, Z and Duggan, MR and Erus, G and Srinivasan, D and Tian, YE and Bai, W and Rafii, MS and Aisen, P and Belsky, DW and Walker, KA and Zalesky, A and Ferrucci, L and Davatzikos, C and Wen, J}, title = {Multi-organ MRI digitizes biological aging clocks across proteomics, metabolomics, and genetics.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40672508}, support = {RF1 AG054409/AG/NIA NIH HHS/United States ; }, abstract = {Leveraging clinical phenotypes[1,2], neuroimaging[3], proteomics[4], metabolomics[5], and epigenetics[6], biological aging clocks across organ systems and tissues have advanced our understanding of human aging and disease. In this study, we expand this biological aging clock framework to multi-organ magnetic resonance imaging (MRI) by developing 7 organ-specific MRI-based biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney, and pancreas. Leveraging imaging, genetic, proteomic, and metabolomic data from 313,645 individuals curated by the MULTI consortium, we link the 7 MRIBAGs to 2,923 plasma proteins, 327 metabolites, and 6,477,810 common genetic variants. These associations reveal organ-specific and cross-organ interconnection landscapes, identifying distinct molecular signatures related to organ aging. Genome-wide associations identify 53 MRIBAG-locus pairs (P<5×10[-8]). Genetic correlation and Mendelian randomization analyses further support organ-specific and cross-organ interconnections with 9 phenotype-based[1,2], 11 proteome-based[7], and 5 metabolome-based aging clocks[5], as well as 525 disease endpoints. Through functional gene mapping and Bayesian colocalization analysis linking evidence from genetics, proteomics, and metabolomics, we prioritize 9 druggable genes as targets for future anti-aging treatments. Finally, we demonstrate the clinical relevance of the 7 MRIBAGs in predicting disease endpoints (e.g., diabetes mellitus), all-cause mortality, and capturing differential and heterogeneous cognitive decline trajectories over 240 weeks of treatment with the Alzheimer's disease drug (Solanezumab). Sex differences are evident across multiple organ systems, manifesting at structural, molecular, and genetic levels. In summary, we developed 7 MRI-based aging clocks that enhance the existing multi-organ biological aging framework, offer multi-scale insights into aging biology, and demonstrate clinical potential to advance future aging research.}, } @article {pmid40672452, year = {2025}, author = {Mei, X and Zhao, Z and Wang, J and Qiu, C and Li, L and Xiong, C and Zhu, S and Zheng, C}, title = {Synergistic effects of surface-enhanced Raman spectroscopy and enzyme-linked immunoassays in diagnosis of Alzheimer's disease, mild cognitive impairment, and late-life depression.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1615457}, pmid = {40672452}, issn = {1664-2295}, abstract = {BACKGROUND: Objective tests that can be used to identify neurodegenerative diseases and neuropsychiatric disorders are urgently needed. The primary objective of this study is to evaluate the diagnostic accuracy of surface-enhanced Raman spectroscopy (SERS), a novel blood-based detection method, in differentiating neurodegenerative diseases and neuropsychiatric disorders. Additionally, we aim to assess the synergistic diagnostic performance of combining SERS with enzyme-linked immunosorbent assay (ELISA) technology for Alzheimer's disease (AD), mild cognitive impairment (MCI), and late-life depression (LLD). METHODS: In total, 23 patients with AD, 24 with MCI, 20 with LLD, and 20 cognitively normal (control) individuals were enrolled. ELISA and SERS were used to test various biomarkers in the AD, MCI, LLD, and control groups. RESULTS: Amyloid-β, tau, brain-derived neurotrophic factor, proinflammatory cytokine IL-1β, and growth differentiation factor-15 levels as measured using ELISA significantly differed among the four groups (P < 0.05). SERS peaks at 592 (P = 0.038), 725 (P = 0.001), 1,003 (P = 0.010), 1,331 (P = 0.000), and 165 cm[-1] (P = 0.000) likewise significantly differed among the four groups. The area under the curve was significantly higher after combining multiple blood indicators than that with single-blood indicators. CONCLUSIONS: Combining SERS and ELISA can significantly increase diagnostic accuracy for AD, MCI, and LLD. The findings are expected to provide potential therapeutic targets for precise intervention in these diseases, thereby contributing to improved clinical stratification and personalized treatment strategies. ChiCTR2300076307 (30/09/2023).}, } @article {pmid40672178, year = {2025}, author = {Labra, SR and Compher, J and Prabhavalkar, A and Almaraz, M and Kwong, CC and Baal, C and Talantova, M and Dolatabadi, N and Piña-Sanz, J and Wang, Y and Yoon, L and Ghatak, S and Gao, Z and Zhang, Y and Trudler, D and Massey, L and Lin, W and Balistreri, A and Bula, M and Schork, NJ and Mondala, TS and Head, SR and Kelly, JW and Lipton, SA}, title = {Autophagy activators normalize aberrant Tau proteostasis and rescue synapses in human familial Alzheimer's disease iPSC-derived cortical organoids.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40672178}, issn = {2692-8205}, support = {R35 AG071734/AG/NIA NIH HHS/United States ; R01 AG056259/AG/NIA NIH HHS/United States ; R01 AG073418/AG/NIA NIH HHS/United States ; U01 AG088679/AG/NIA NIH HHS/United States ; TL1 TR002551/TR/NCATS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. To illuminate the earliest changes in hereditary (familial) Alzheimer's disease, we developed an isogenic AD cerebrocortical organoid (CO) model. Our refined methodology produces COs containing excitatory and inhibitory neurons alongside glial cells, utilizing established isogenic wild-type and diseased human induced pluripotent stem cells (hiPSCs) carrying heterozygous familial AD mutations, namely PSEN1[ΔE9/WT], PSEN1[M146V/WT], or APP[swe/WT]. Our CO model reveals time-progressive accumulation of amyloid beta (Aβ) species, loss of monomeric Tau, and accumulation of aggregated high-molecular-weight (HMW) phospho(p)-Tau species. This is accompanied by neuronal hyperexcitability, as observed in early human AD cases on electroencephalography (EEG), and synapse loss. Single-cell RNA-sequencing analyses reveal significant differences in molecular abnormalities in excitatory vs. inhibitory neurons, helping explain AD clinical phenotypes. Finally, we show that chronic dosing with autophagy activators, including a novel CNS-penetrant mTOR inhibitor-independent drug candidate, normalizes pathologic accumulation of Aβ and HMW p-Tau, normalizes hyperexcitability, and rescues synaptic loss in COs. Collectively, our results demonstrate these COs are a useful human AD model suitable for assessing early features of familial AD etiology and for testing drug candidates that ameliorate or prevent molecular AD phenotypes.}, } @article {pmid40671844, year = {2025}, author = {Mohammed, O and Kelemu, T}, title = {Incretin-Based Therapies in Alzheimer's and Parkinson's Disease: Advancing Neuroprotection With Dual and Triple Agonists-A Review.}, journal = {Health science reports}, volume = {8}, number = {7}, pages = {e71065}, pmid = {40671844}, issn = {2398-8835}, abstract = {BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD) are progressive neurodegenerative disorders with significant cognitive and motor impairments, affecting millions globally. Current treatments offer limited efficacy, prompting the exploration of new therapeutic approaches. AIM: To discuss the intricate relationship between incretin and insulin signaling pathways and their relevance to the pathogenesis and treatment of Alzheimer's and Parkinson's diseases. METHODS: A comprehensive literature review was conducted using a variety of search engines, including Google Scholar, PubMed Central, Scopus, Web of Science, and others. RESULTS: Emerging evidence highlights disrupted insulin signaling in AD and, to a lesser extent, in PD, suggesting that insulin plays a key neuroprotective role. Incretins, such as GLP-1 and GIP, which enhance insulin signaling, have shown potential in preclinical and clinical studies. Incretin-based therapies, particularly GLP-1/GIP receptor agonists, have demonstrated promising effects by addressing several pathological processes, including oxidative stress, inflammation, misfolded protein aggregation, and insulin resistance. Dual agonists like DA-CH3, DA5-CH, and DA4-JC have proven superior in crossing the blood-brain barrier and offering improved neuroprotection in comparison with conventional GLP-1 agonists. Triple agonists provide even greater neuroprotective benefits, highlighting their potential as disease-modifying therapies for AD and PD. CONCLUSION: While GLP-1 and GIP analogs hold promise in modulating early neurodegenerative processes, their efficacy likely depends on timely intervention before permanent neuronal damage occurs.}, } @article {pmid40671308, year = {2025}, author = {Creeden, JF and Machiraju, SN and Amin, JB and Stahl, SM}, title = {From betel nuts to Cobenfy: how an ancient recreational drug gave rise to a new class of schizophrenia medications.}, journal = {CNS spectrums}, volume = {30}, number = {1}, pages = {e55}, doi = {10.1017/S1092852925100424}, pmid = {40671308}, issn = {1092-8529}, mesh = {Humans ; *Areca ; *Schizophrenia/drug therapy/history ; *Antipsychotic Agents/therapeutic use/history ; *Arecoline/therapeutic use/pharmacology ; *Illicit Drugs/history ; }, abstract = {The term "betel" most accurately refers to the betel pepper (Piper betle). Confusingly, this term is also frequently used to refer to a street drug that often-but not always-includes the betel leaf as a constituent. This linguistic misdirection only intensifies with terms such as "betel nut," which, in common usage, may refer to this same composite street drug or to a single isolated constituent of that street drug: the nut of the areca palm (Areca catechu), which is otherwise wholly unrelated to the betel pepper. This composite street drug, colloquially referred to as "betel" or "betel nut" or "betel quid," is one of the most frequently used psychoactive substances in the world. It carries a cultural legacy spanning over 10,000 years and a current user base numbering in the hundreds of millions. Its primary psychoactive constituent is arecoline, a well-established parasympathomimetic agent. Early studies exploring arecoline's ability to modulate cholinergic signaling pathways and exert therapeutic psychiatric effects on conditions such as Alzheimer's disease were initially mired by intolerable parasympathetic side effects. Indeed, over the course of its long history, various hints regarding the therapeutic utility of arecoline have been obfuscated by a variety of challenges which have only recently been overcome. Now, developments in psychopharmacology and our growing understanding of neurochemical brain circuitry have unlocked a new mechanism of action by which arecoline-derived medications interact with dopaminergic processes to improve outcomes for schizophrenia patients. One such medication, xanomeline-trospium (Cobenfy), has emerged as the first such agent to receive U.S. Food and Drug Administration (FDA) approval for the treatment of schizophrenia and represents an entirely new class of pro-cholinergic medication within the field of psychiatry. Many in the field believe that this heralds the beginning of a new era of psychopharmacology: the era of muscarinic agonism. This article briefly described the fascinating journey from ancient betel nuts to modern muscarinic therapeutics.}, } @article {pmid40671224, year = {2025}, author = {Wen, J and Hu, J and Yang, X and Luo, F and Zou, G}, title = {Effective Analysis of Alzheimer's Disease and Mechanisms of Methyl-4- Hydroxybenzoate using Network Toxicology, Molecular Docking, and Machine Learning Strategies.}, journal = {Current Alzheimer research}, volume = {22}, number = {6}, pages = {456-475}, pmid = {40671224}, issn = {1875-5828}, support = {20243BCE51028, 310201384304//Science and Technology Department of Jiangxi Province/ ; 81760811, 81960854, 82260911//National Natural Science Foundation of China/ ; S202410412112//Innovation and Entrepreneurship Training Program for College Students/ ; zyyzdxk-2023113//State Administration of Traditional Chinese Medicine has built a high-level key discipline of traditional Chinese medicine/ ; 20192B AB205099, 20202BA206070//Natural Science Foundation of Jiangxi Province/ ; 20204420, SKJP-220210188, 2022B516//Science and Technology Program of Jiangxi Provincial Health Commission/ ; }, mesh = {*Alzheimer Disease/chemically induced/genetics/metabolism ; *Molecular Docking Simulation ; Humans ; *Machine Learning ; *Environmental Pollutants/toxicity ; Gene Regulatory Networks/drug effects ; }, abstract = {INTRODUCTION: Nowadays, the large increase in environmental pollutants has led to the occurrence and development of an increasing number of diseases. Studies have shown that exposure to environmental pollutants, such as methyl-4-hydroxybenzoate (MEP) may lead to Alzheimer's disease (AD). Therefore, the purpose of this study was to elucidate the complex effects and potential molecular mechanisms of environmental pollutants MEP on AD. METHODS: Through exhaustive exploration of databases, such as ChEMBL, STITCH, SwissTarget- Prediction, and Gene Expression Omnibus DataSets (GEO DataSets), we have identified a comprehensive list of 46 potential targets closely related to MEP and AD. After rigorous screening using the STRING platform and Cytoscape software, we narrowed the list to nine candidate targets and ultimately identified six hub targets using three proven machine learning methods (LASSO, RF, and SVM): CREBBP, BCL6, CXCR4, GRIN1, GOT2, and ITGA5. The "clusterProfiler" R package was used to conduct GO and KEGG enrichment analysis. At the same time, we also constructed disease prediction models for core genes. At last, six hub targets were executed molecular docking. RESULTS: We derived 46 key target genes related to MEP and AD and conducted gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. MEP might play a role in AD by affecting the pathways of neuroactive ligand-receptor interaction. Nine genes were screened as pivotal targets, followed by machine learning methods to identify six hub targets. Molecular docking analysis showed a good binding ability between MEP and CREBBP, BCL6, CXCR4, GRIN1, GOT2 and ITGA5. In addition, changes in the immune microenvironment revealed a significant impact of immune status on AD. DISCUSSIONS: This study revealed that MEP may induce AD through multiple mechanisms, such as oxidative stress, neurotoxicity, and immune regulation, and identified six core targets (CREBBP, BCL6, etc.) and found that they are related to changes in the immune microenvironment, such as T cells and B cells, providing new molecular targets for AD intervention. CONCLUSION: Overall, CREBBP, BCL6, CXCR4, GRIN1, GOT2, and ITGA5 have been identified as the crucial targets correlating with AD. Our findings provide a theoretical framework for understanding the complex molecular mechanisms underlying the effects of MEP on AD and provide insights for the development of prevention and treatment of AD caused by exposure to MEP.}, } @article {pmid40671162, year = {2025}, author = {Rodríguez, A and Calero, O and Veiga, S and Menacho-Román, M and Arribas, I and Cano, L and García-Ribas, G and Calero, M}, title = {A novel biochemical analysis for ApoE4 quantification in plasma and discrimination of homozygous and heterozygous APOE ε4 carriers.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {163}, pmid = {40671162}, issn = {1758-9193}, support = {AB-SER1-19-025//Servicio Gallego de Salud (SERGAS) and Fondo Europeo de Desarrollo Regional (FEDER)/ ; CB06/05/0085//CIBER - Consorcio Centro de Investigación Biomédica en Red/ ; }, mesh = {Humans ; *Apolipoprotein E4/blood/genetics ; *Heterozygote ; Homozygote ; Male ; Female ; Aged ; Alzheimer Disease/genetics/blood ; Middle Aged ; ROC Curve ; Genotype ; Aged, 80 and over ; }, abstract = {BACKGROUND: The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with increased risk of amyloid-related imaging abnormalities (ARIA) during anti-amyloid therapy. Accurate identification of ε4 carriers, particularly APOE ε4/ε4 individuals, is clinically relevant. This study outlines the development and validation of e4Quant, a novel turbidimetric assay for quantifying plasma ApoE4 as a non-genetic alternative to APOE genotyping. METHODS: The e4Quant test utilizes a proprietary particle-enhanced immunoturbidimetry method, employing an isoform-specific anti-ApoE4 antibody on standard chemistry analyzers. Plasma samples from 160 individuals of known APOE genotype (35 APOE ε4/ε4 homozygotes, 115 APOE ε4 heterozygotes, and 10 APOE ε4 non-carriers) were analyzed for ApoE4 and total ApoE levels. The test's discriminatory performance was assessed by ROC analysis and two-threshold classification algorithms. RESULTS: ApoE4 levels ascertained by the e4Quant test exhibited clear genotype-dependent stratification. ROC analysis indicated 100% sensitivity and specificity in distinguishing APOE ε4 carriers from non-carriers, and 88.6% sensitivity and 90.4% specificity for discriminating homozygous from heterozygous carriers. Normalizing ApoE4 to total ApoE improved classification (sensitivity 94.3%, specificity 93.9%). A combined ratio-plus-concentration approach further enhanced discrimination (sensitivity 91.4%, specificity 100%). Three ε4 homozygous samples with low ApoE4/total ApoE ratios were misclassified. DISCUSSION: The e4Quant assay offers a rapid, cost-effective, and highly accurate biochemical alternative to APOE genotyping, suitable for clinical and research settings, particularly in assessing AD risk and optimizing anti-amyloid therapeutic strategies. One subgroup of APOE ε4/ε4 subjects had unexpectedly low ApoE4 levels, raising questions about potential biological heterogeneity and its impact on Alzheimer's disease biology. CONCLUSION: The e4Quant assay is a novel alternative for genotyping to determine APOE ε4 carrier status, while also providing quantitative measurements of ApoE4 levels. Its high diagnostic accuracy, ease of use in standard clinical laboratories, and potential utility for personalized medicine in AD treatment highlight its translational value. Further studies are warranted to investigate the clinical significance of APOE ε4 expression variability and its impact on disease progression and treatment response.}, } @article {pmid40670451, year = {2025}, author = {Ali, ZH and Hassan, E and Elgamal, S and El-Rashidy, N}, title = {Developing an explainable machine learning and fog computing-based visual rating scale for the prediction of dementia progression.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {25872}, pmid = {40670451}, issn = {2045-2322}, mesh = {Humans ; *Machine Learning ; Aged ; Male ; Female ; *Dementia/diagnosis ; Disease Progression ; Cognitive Dysfunction/diagnosis ; Magnetic Resonance Imaging ; Mental Status and Dementia Tests ; Aged, 80 and over ; Neuropsychological Tests ; Middle Aged ; }, abstract = {Recently, dementia research has primarily concentrated on using Magnetic Resonance Imaging (MRI) to develop learning models in processing and analyzing brain data. However, these models often cannot provide early detection of affected brain regions. Alternatively, mental test scores such as the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) offer valuable insights into the likelihood of dementia and cognitive impairments. The main objective of this study is to introduce an innovative and dependable context-aware health monitoring system based on fog computing to measure mental impairment in the elderly population. The framework provides screening tests utilizing MMSE and MoCA to achieve accurate and real-time monitoring of cognitive function, allowing for early detection and treatment of mental disorders. To assess the effectiveness of our screening test, we evaluated a dataset comprising 450 subjects with Mild Cognitive Impairment (MCI) from Kaferelshikh University. The aggregated dataset is categorized into three classes: (1) 150 patients with MCI, (2) 150 subjects with subcortical diseases, Parkinson's Disease (PD), and (3) 150 subjects with cortical diseases, Alzheimer's Disease (AD). To accurately determine health risks, we employ an ensemble AdaBoost model, providing superior performance in accuracy, precision, recall, F-score, and Area Under the Curve (AUC). To validate the effectiveness of our Machine Learning (ML) model on unseen data, we evaluate an additional 18 subjects using the proposed scoring test, with six subjects from each class. The results indicate that our proposed ML model achieves an impressive accuracy of 0.93, outperforming the MoCA score (0.90) and MMSE score (0.83). Through our research, we demonstrate the potential of our context-aware fog computing approach in significantly enhancing early diagnosis of dementia, leveraging mental test scores as valuable indicators.}, } @article {pmid40668823, year = {2025}, author = {Castelli, V and Cesare, P and Bej, E and d'Angelo, M and Volpe, AR}, title = {Mechanistic insights into the anti-aging effects of Crocus sativus in a D-Gal-induced in vitro neural senescence model.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0320572}, pmid = {40668823}, issn = {1932-6203}, mesh = {*Crocus/chemistry ; *Galactose/pharmacology ; *Cellular Senescence/drug effects ; Animals ; *Plant Extracts/pharmacology ; Reactive Oxygen Species/metabolism ; *Aging/drug effects ; Lipid Peroxidation/drug effects ; Cell Proliferation/drug effects ; Endoplasmic Reticulum Stress/drug effects ; *Neurons/drug effects/metabolism/cytology ; beta-Galactosidase/metabolism ; Glycation End Products, Advanced/metabolism ; Malondialdehyde/metabolism ; Cell Cycle/drug effects ; Humans ; Oxidative Stress/drug effects ; Rats ; }, abstract = {BACKGROUND: The increasing number of elderly individuals has made age-related disorders a significant health concern. Aging is a natural, progressive and gradual phenomenon that leads to irreversible modifications in all molecules, cells, tissues and organs of an organism. Brain senescence is associated with increased risk of developing various neurological diseases, such as Alzheimer's disease, Parkinson's disease, and stroke. Therefore, finding effective strategies to counteract or delay brain senescence is of great importance for improving the quality of life and health span of the elderly population. Previous studies demonstrated that D-galactose is an appropriate agent to induce aging effects in in vivo and in vitro models. PURPOSE: In the present study, we evaluated anti-aging effects of a local Saffron extract (SE from Central Italy) on D-GAL-induced aging model in vitro. Based on promising preliminary results, future studies will focus on testing this specific Crocus sativus stigma preparation in animal models of aging. METHODS: The potential anti-aging effect was evaluated using assessment of cell proliferation, live-cell cytotoxicity, Beta-Galactosidase (β-GAL), lipid peroxidation, intracellular reactive oxygen species (ROS), advanced glycation end products (AGEs) and malondialdehyde (MDA) levels. Additionally, the effects of SE pretreatment were examined on cell cycle and endoplasmic reticulum stress. Additionally, we employed a novel approach to analyze deeper changes upon saffron extract treatment, which is label-free holotomography. RESULTS: Overall, our findings suggested that pretreatment with SE was protective against D-GAL-induced senescence, by counteracting oxidative and endoplasmic reticulum stress and proteins that regulate cell death. CONCLUSION: We obtained interesting results since pre-treatment with SE ameliorated overall condition, and for the first time we observed the strong anti-aging effect of SE not only in term of morphology, but also dynamics and total dry mass of cells. Overall, our work introduces a novel and promising approach to counteract or delay brain senescence, potentially improving the quality of life and health span of the elderly population.}, } @article {pmid40668694, year = {2025}, author = {Padliya, T}, title = {Breaking Barriers With Sound: Focused Ultrasound in the Brain.}, journal = {IEEE pulse}, volume = {16}, number = {3}, pages = {30-35}, doi = {10.1109/MPULS.2025.3572600}, pmid = {40668694}, issn = {2154-2317}, mesh = {Humans ; *Brain/diagnostic imaging ; Magnetic Resonance Imaging ; *Ultrasonic Therapy/methods ; }, abstract = {Focused ultrasound (FUS) is rapidly redefining the landscape of brain therapy, offering a noninvasive, highly precise alternative to traditional neurosurgical techniques. Enabled by advances in phased-array transducer technology, MRI-guided targeting and thermometry, and sophisticated treatment planning software, FUS delivers sub-millimeter accuracy through the skull while sparing surrounding tissue. This article provides a comprehensive yet accessible overview of the core technologies that make FUS possible, including phase correction for skull variability and real-time imaging for safety. We survey the broadening spectrum of clinical applications, from FDA-approved treatments for essential tremor and Parkinson's disease to investigational uses in Alzheimer's, glioblastoma, obsessive-compulsive disorder, and targeted drug delivery. Pioneering trials have demonstrated not only durable tremor control and motor improvement, but also the unique ability to deliver drugs directly to the brain and noninvasively target deep neuropsychiatric circuits.}, } @article {pmid40668687, year = {2025}, author = {Kern, R}, title = {Restoring the Brain's Rhythm: A Physics-Driven Approach to Treating Alzheimer's Disease.}, journal = {IEEE pulse}, volume = {16}, number = {3}, pages = {56-59}, doi = {10.1109/MPULS.2025.3572591}, pmid = {40668687}, issn = {2154-2317}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology ; *Brain/physiopathology ; *Gamma Rhythm/physiology ; }, abstract = {Alzheimer's disease (AD) has traditionally been addressed through biochemical interventions targeting amyloid and tau pathologies. However, these approaches are constrained by high costs, limited accessibility, and suboptimal efficacy. This article introduces a novel, physics-based therapeutic modality: noninvasive neuromodulation via synchronized visual and auditory stimulation to restore gamma frequency brain rhythms. The Spectris AD device, developed by Cognito Therapeutics, leverages principles of signal processing and systems engineering to drive gamma oscillations in patients with mild to moderate AD. Early clinical studies, including the OVERTURE and FLICKER trials, demonstrate promising results, such as a 77% reduction in functional decline [Alzheimer's disease co-operative study ADL (ADCS-ADL)], a 76% slowing of cognitive decline [mini mental-state exam (MMSE)], and structural brain preservation without the safety risks associated with monoclonal antibodies. The ongoing HOPE pivotal trial aims to validate these findings in a diverse U.S. population. Spectris AD exemplifies a shift from molecular to network-level interventions, offering a scalable, home-based solution that reimagines neurodegenerative treatment as a systems-engineering challenge. This article presents the engineering, clinical data, and broader implications of this pioneering approach to neurotherapeutics.}, } @article {pmid40667684, year = {2025}, author = {Gueorguieva, I and Chow, K and Chua, L and Shcherbinin, S and Zimmer, JA and Evans, CD and Wang, H and Nery, ESM and Brooks, DA and Sims, JR}, title = {Donanemab exposure-response in early symptomatic Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70491}, pmid = {40667684}, issn = {1552-5279}, support = {//Eli Lilly and Company/ ; }, mesh = {Aged ; Female ; Humans ; Male ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacokinetics ; Disease Progression ; Dose-Response Relationship, Drug ; *Plaque, Amyloid/drug therapy ; Treatment Outcome ; }, abstract = {INTRODUCTION: These analyses aimed to identify factors impacting donanemab exposure, amyloid plaque, and clinical efficacy in early symptomatic Alzheimer's disease using a population pharmacokinetic/pharmacodynamic (PK/PD) approach. METHODS: Analyses included donanemab trial participants (NCT02624778; NCT03367403; NCT04640077; NCT04437511). Dose- and exposure-response relationships were characterized relative to amyloid plaque lowering using indirect response PK/PD and disease progression models. RESULTS: Donanemab population PK was described by a biphasic distribution with an estimated terminal elimination half-life of approximately 12.1 days for a typical participant (72 kg body weight, 1:2560 maximum antidrug antibody [ADA] titer). Amyloid reduction was associated with maintaining median serum donanemab concentrations over 15 µg/mL (95% confidence interval: 8.54, 18.0). After completing active treatment, simulations showed an estimated plaque reaccumulation rate (median, 95% confidence interval) of 2.8 (2.16, 3.11) Centiloids/year. The donanemab disease progression model showed a clear treatment effect. DISCUSSION: These donanemab models can inform dosing strategies in future clinical trials. HIGHLIGHTS: Weight-based and flat dosing had similar exposure metrics; flat dosing was adopted. Donanemab exposure was influenced by weight and titer (not clinically relevant). 2.8 Centiloids/year amyloid reaccumulation rate observed upon donanemab treatment completion. Around 30% reduction in disease progression rate on treatment for integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB).}, } @article {pmid40667349, year = {2025}, author = {Young, JI and Varma, A and Gomez, L and Schmidt, MA and Kunkle, B and Wang, L and Martin, ER}, title = {Sex-Stratified Transcriptomic Meta-Analysis of Alzheimer's Disease Reveal Brain Region and Sex Specific Dysregulation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.25.661596}, pmid = {40667349}, issn = {2692-8205}, abstract = {OBJECTIVE: Alzheimer disease (AD) is a neurodegenerative disorder leading to cognitive decline. Despite growing recognition of sex differences in epidemiology, symptomatology, and clinical outcomes of AD, the molecular mechanisms underlying these variations remain poorly defined. We performed transcriptome association studies of AD aiming to identify sex-specific and sex-dependent transcriptomic profiles that could provide insights into the molecular mechanisms underlying sex differences in AD pathogenesis. METHODS: We conducted a meta-analysis of bulk-RNAseq data derived from human postmortem brain studies. Specifically, we analyzed gene expression differences between individuals diagnosed with AD and non-cognitively impaired (NCI) individuals across two key brain regions: the prefrontal cortex and the temporal lobe. We performed stratified differential expression analyses separately in males and females, alongside combined analyses across sexes. Additionally, we assessed the data in relation to known AD genes, proteomic studies, and drug repurposing opportunities. RESULTS: Beyond the genes commonly dysregulated across both sexes, our meta-analyses identified multiple differentially expressed genes (DEGs) between AD and NCI that are either altered in only one sex or show different effects between sexes. Some genes are known AD genes from genetic studies, but others are novel. Correlation with proteomic data suggests that these transcriptional differences have functional significance, potentially contributing to the biological mechanisms underlying sex differences observed in AD. Finally, we identify drug compounds that are potential candidates for treatment. INTERPRETATION: Our findings enhance our understanding of sex-related differences in disease etiology and progression, and underscore the importance of incorporating sex as a critical variable in transcriptomic studies of AD. These insights help pave the way for more precise, personalized medicine approaches that account for sex-specific molecular mechanisms.}, } @article {pmid40666518, year = {2025}, author = {Liao, Y and Xu, F and Yan, Y and Zhou, S and Liu, N and Dou, B and Srinivasan, N and Wang, W and Zhu, X and Ye, J and Xu, Y}, title = {Chronic ethanol administration exacerbates memory loss by altering N6-methyladenosine-mediated epigenetic signaling.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1455994}, pmid = {40666518}, issn = {1664-3224}, support = {RF1 AG083811/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Adenosine/analogs & derivatives/metabolism ; *Ethanol/administration & dosage/adverse effects/toxicity ; *Epigenesis, Genetic/drug effects ; Mice ; *Memory Disorders/genetics/metabolism/etiology/chemically induced ; Mice, Transgenic ; Signal Transduction/drug effects ; Disease Models, Animal ; Male ; Alzheimer Disease/genetics/metabolism ; }, abstract = {BACKGROUND: Chronic alcohol use disorder (AUD) is recognized as one of the most critical risk factors for the progression of Alzheimer's disease (AD). Epigenetic and neuroimmune alterations are closely associated with the development of memory impairment related to AUD and AD. METHODS: Adult APP/PS1 transgenic mice received intermittently intraperitoneal injections of ethanol (EtOH, 2.5 g/kg, i.p.) or vehicle with two "drug" treatment days, and one and two "drug-free" days every 7 days for 10 weeks. The novel object recognition (NOR) and Y-maze tests were performed to determine whether chronic ethanol treatment exacerbated memory impairment in these mice. The brain tissues were collected for pathological changes through MeRIP/RNA-sequence analyses and molecular biological assays. RESULTS: The results suggested that chronic intermittent ethanol (CIE) treatment for 10 weeks exacerbated sporadic and spatial memory deficits in NOR and Y-maze tests in the APP/PS1 mice. The pathological assays revealed that CIE procedure increased Aβ plaque burden in the brain of the AD mice, which were consistent with memory behavioral deficits. The subsequent MeRIP/RNA sequence analyses showed that two genes, e.g. Rbm15b and Hnrnpa2b1, were related to N6-methyladenosine (m[6]A) methylation that plays an important role in the development of memory loss. These results were further supported by molecular biological and mRNA-microRNA-lncRNA ceRNA network analyses that demonstrated that the increased Rbm15b and decreased Hnrnpa2b1 were involved in synaptic dysfunction and neuroinflammation in CIE-induced memory impairment in these AD mice. CONCLUSIONS: The conclusion is drawn that m[6]A mediated epigenetic dysfunction and immune cells infiltration participate in chronic alcohol use disorder related memory loss in AD mice.}, } @article {pmid40666174, year = {2025}, author = {Arya, P and Sharma, V and Singh, P and Thapliyal, S and Sharma, M}, title = {Bacterial endotoxin-lipopolysaccharide role in inflammatory diseases: An overview.}, journal = {Iranian journal of basic medical sciences}, volume = {28}, number = {5}, pages = {553-564}, pmid = {40666174}, issn = {2008-3866}, abstract = {Despite advancements in antimicrobial and anti-inflammatory treatments, inflammation and its repercussions continue to pose a considerable challenge in medicine. Acute inflammation may cause life-threatening conditions like septic shock, while chronic inflammation leads to tissue degeneration and impaired function. Lipopolysaccharides (LPS), a well-known pathogenic trigger contributing to several dysfunctions, is a crucial part of the outer membrane of gr-negative bacteria. LPS are well-known for eliciting acute inflammatory responses by activating a pathogen-associated molecular pattern (PAMP), which stimulates the innate immune system and triggers local or systemic inflammatory responses. LPS also activate numerous intracellular molecules that modulate the expression of a wide range of inflammatory mediators. These mediators subsequently initiate or exacerbate various inflammatory processes. Beyond immune cells, LPS can also activate non-immune cells, leading to inflammatory reactions. These excessive inflammatory responses are often detrimental and typically result in chronic and progressive inflammatory diseases, including neurodegenerative, cardiovascular diseases, and cancer. This review delves into the mechanisms by which the bacterial endotoxin LPS contribute to multiple inflammatory diseases. These insights into LPS signaling pathways could inform the design of new treatment strategies such as TLR4, NLRP3, HMGA1, MAPK, and NF-kB inhibitors. This enables precise targeting of inflammation-related processes in disease management.}, } @article {pmid40665449, year = {2025}, author = {Chen, BK and Hunsberger, HC and Whye, A and Matthews, LC and Yook, A and Willner, MJ and Logan, RW and Johns, S and Weisblum, E and Denny, CA}, title = {Combinatorial targeting of NMDARs and 5-HT4Rs exerts beneficial effects in a mouse model of Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {160}, pmid = {40665449}, issn = {1758-9193}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Mice ; Male ; Disease Models, Animal ; Female ; *Receptors, Serotonin, 5-HT4/metabolism ; Mice, Transgenic ; *Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; *Serotonin 5-HT4 Receptor Agonists/pharmacology/administration & dosage ; *Benzofurans/pharmacology/administration & dosage ; *Excitatory Amino Acid Antagonists/pharmacology ; Amyloid beta-Protein Precursor/genetics ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia. There are limited approved medications that delay cognitive decline or lessen neuropsychiatric symptoms. Numerous clinical trials for AD using a single drug administration have failed to meet therapeutic endpoints, which is most likely due to the complexity of AD. A multimodal therapeutic intervention is more likely to improve symptoms by targeting multiple targets implicated in AD. Here, we investigated if targeting both N-Methyl-D-aspartic acid receptors (NMDARs) and serotonin type 4 receptors (5-HT4R) may have beneficial effects in a mouse model of AD, as they have separately been shown to improve cognition and/or mood. METHODS: Male and female control (Ctrl) or APP/PS1 mice were administered single, intermittent, or chronic administration of 1) saline; 2) (R,S)-ketamine, an NMDAR antagonist; 3) prucalopride, a 5-HT4R agonist; or 4) (R,S)-ketamine + prucalopride to simultaneously target co-morbid neuropsychiatric and cognitive deficits. Behavioral assays were then administered to measure cognition, perseverative behavior, hyponeophagia, and/or sleep. Brains were processed for glial fibrillary acidic protein (GFAP) immunohistochemistry. RESULTS: Single and chronic administration of (R,S)-ketamine + prucalopride administration improved cognitive decline by increasing memory retrieval in a contextual fear conditioning (CFC) paradigm in APP/PS1 mice. Drug efficacy was less effective in females than in males and was age dependent. Hippocampal GFAP immunoreactivity was decreased by chronic (R,S)-ketamine + prucalopride treatment in females. CONCLUSIONS: Our results indicate that combined administration of (R,S)-ketamine + prucalopride is a novel multimodal therapeutic strategy to treat cognitive decline in AD. Future work will further characterize these interactions with the goal of clinical development.}, } @article {pmid40665063, year = {2025}, author = {Yu, L and Yang, X and Lei, HP and Hu, YT and Wu, LN and Zhou, SY and Jin, F}, title = {Multiple Mechanisms and Therapeutic Strategies for the Involvement of AMPK in the Development of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {15390-15409}, pmid = {40665063}, issn = {1559-1182}, support = {ZK [2023]058//the Key Projects of Basic Research Program of the Science and Technology Department of Guizhou Province/ ; 82060727//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/enzymology/drug therapy/therapy/pathology/metabolism ; Humans ; *AMP-Activated Protein Kinases/metabolism ; Animals ; Signal Transduction ; Amyloid beta-Peptides/metabolism ; Oxidative Stress ; }, abstract = {Alzheimer's disease (AD) is a major cause of dementia, a life-threatening condition for which there is currently no cure. Currently, the treatment of AD focuses on reducing the accumulation of amyloid β-protein (Aβ) and the phosphorylation of Tau proteins (Tau). However, simply reducing pathological features does not completely improve AD. Therefore, there is an urgent need to explore a target that regulates AD-related pathologies and highlights its potential as a novel therapeutic target. Recent studies suggest that oxidative stress, neuroinflammation, autophagy dysfunction, and energy metabolism alterations are associated with the development of AD. Reviewing previous data, we found that AMP-activated protein kinase (AMPK) not only acts as a cellular energy sensor to influence the progression of AD, but also activation of AMPK affects the pathologic processes above. In this review, we provide an update on activating the AMPK pathway with targeting in AD therapy. Finally, research has shown that compounds can activate the AMPK pathway to affect a series of cellular processes and improve AD. We propose that AMPK activation represents a paradigm-shifting strategy for AD therapy by simultaneously targeting multiple pathological cascades, although challenges in isoform-specific activation and brain delivery warrant further investigation.}, } @article {pmid40665048, year = {2025}, author = {Imam, F and Saloner, R and Vogel, JW and Krish, V and Abdel-Azim, G and Ali, M and An, L and Anastasi, F and Bennett, D and Pichet Binette, A and Boxer, AL and Bringmann, M and Burns, JM and Cruchaga, C and Dage, JL and Farinas, A and Ferrucci, L and Finney, CA and Frasier, M and Hansson, O and Hohman, TJ and Johnson, ECB and Kivimaki, M and Korologou-Linden, R and Ruiz Laza, A and Levey, AI and Liepelt-Scarfone, I and Lu, L and Mattsson-Carlgren, N and Middleton, LT and Nho, K and Oh, HS and Petersen, RC and Reiman, EM and Robinson, O and Rothstein, JD and Saykin, AJ and Shvetcov, A and Slawson, C and Smets, B and Suárez-Calvet, M and Tijms, BM and Timmers, M and Vieira, F and Vilor-Tejedor, N and Visser, PJ and Walker, KA and Winchester, LM and Wyss-Coray, T and Yang, C and Bose, N and Lovestone, S and , }, title = {The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging.}, journal = {Nature medicine}, volume = {31}, number = {8}, pages = {2556-2566}, pmid = {40665048}, issn = {1546-170X}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; U01 AG079847/AG/NIA NIH HHS/United States ; RF1 AG053303/AG/NIA NIH HHS/United States ; R01 AG053960/AG/NIA NIH HHS/United States ; R01 AG057911/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; RF1 AG057471/AG/NIA NIH HHS/United States ; R01 AG061800/AG/NIA NIH HHS/United States ; R01 AG057339/AG/NIA NIH HHS/United States ; R01 AG069453/AG/NIA NIH HHS/United States ; U01 AG058922/AG/NIA NIH HHS/United States ; R01 AG044546/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; RF1 AG058501/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; RF1 AG062553/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; U01 AG045390/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; U54 NS092089/NS/NINDS NIH HHS/United States ; R01 AG064227/AG/NIA NIH HHS/United States ; RF1 AG057470/AG/NIA NIH HHS/United States ; R01 AG083740/AG/NIA NIH HHS/United States ; R01 AG056477/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Proteomics/methods ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Drug Discovery ; *Aging/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Parkinson Disease/metabolism ; Alzheimer Disease/metabolism ; Frontotemporal Dementia/metabolism ; }, abstract = {More than 57 million people globally suffer from neurodegenerative diseases, a figure expected to double every 20 years. Despite this growing burden, there are currently no cures, and treatment options remain limited due to disease heterogeneity, prolonged preclinical and prodromal phases, poor understanding of disease mechanisms, and diagnostic challenges. Identifying novel biomarkers is crucial for improving early detection, prognosis, staging and subtyping of these conditions. High-dimensional molecular studies in biofluids ('omics') offer promise for scalable biomarker discovery, but challenges in assembling large, diverse datasets hinder progress. To address this, the Global Neurodegeneration Proteomics Consortium (GNPC)-a public-private partnership-established one of the world's largest harmonized proteomic datasets. It includes approximately 250 million unique protein measurements from multiple platforms from more than 35,000 biofluid samples (plasma, serum and cerebrospinal fluid) contributed by 23 partners, alongside associated clinical data spanning Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This dataset is accessible to GNPC members via the Alzheimer's Disease Data Initiative's AD Workbench, a secure cloud-based environment, and will be available to the wider research community on 15 July 2025. Here we present summary analyses of the plasma proteome revealing disease-specific differential protein abundance and transdiagnostic proteomic signatures of clinical severity. Furthermore, we describe a robust plasma proteomic signature of APOE ε4 carriership, reproducible across AD, PD, FTD and ALS, as well as distinct patterns of organ aging across these conditions. This work demonstrates the power of international collaboration, data sharing and open science to accelerate discovery in neurodegeneration research.}, } @article {pmid40664126, year = {2025}, author = {Jangid, K and Devi, B and Kumar, N and Upadhayay, S and Kumar, V and Thareja, S and Kumar, V}, title = {ML-based prediction to experimental validation: Development of dihydroquinazoline based multi-potent ligands as anti-Alzheimer's agents.}, journal = {Computers in biology and medicine}, volume = {196}, number = {Pt A}, pages = {110762}, doi = {10.1016/j.compbiomed.2025.110762}, pmid = {40664126}, issn = {1879-0534}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Monoamine Oxidase/chemistry/metabolism ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology ; *Quinazolines/chemistry/pharmacology ; Molecular Docking Simulation ; Acetylcholinesterase/chemistry/metabolism ; Amyloid beta-Peptides/chemistry/metabolism/antagonists & inhibitors ; *Machine Learning ; Ligands ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurological disorder accounting for the cognitive decline in the patients. The disease is linked to numerous pathological factors including hyperactivation of acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B), accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain etc. The single-target medications already available in the market are found to be ineffective and the research focus is shifting towards the development of multitargeting agents. In order to find a multi-potent inhibitor against AChE, MAO-B and Aβ1-42, in the present study we employed a machine learning-based tool, PyRMD, to screen an in-house generated library of dihydroquinazoline derivatives. This screening process identified six promising compounds, KV-271, KV-832, KV-968, KV-1131, KV-1159, KV-1234 with dual inhibition potential against AChE and MAO-B enzymes. In the docking studies, these compounds showed good interactions at the active cavity of the AChE and MAO-B comparable to the standard inhibitors donepezil (AChE) and pargyline (MAO-B). To validate these predictions, the six identified compounds were synthesized and subjected to in vitro enzymatic assays. All the six compounds displayed significant inhibitory activity, with IC50 values below 5 μM for both AChE and MAO-B. Amongst these compounds, KV-1131 and KV-1234 were found to be the most potent inhibitors with IC50 values of 0.93 μM and 0.85 μM against AChE and IC50 values of 1.17 μM and 0.79 μM against MAO-B, respectively. In addition, KV-1131 and KV-1234 exhibited inhibitory activity against Aβ1-42 self-aggregation inhibition of 34.79 % and 45.70 %, respectively, after 48 h of incubation. Both KV-1131 and KV-1234 were found to be non-toxic up to 10 μM concentration and showed neuroprotective potential against 6-hydroxydopamine induced neurotoxicity in the SHSY-5Y cells. Thus, KV-1131 and KV-1234 were identified as potent leads that can be developed as drug candidates for the treatment of Alzheimer's disease.}, } @article {pmid40663501, year = {2025}, author = {Bian, Z and Liu, X and Li, J and Hu, S and Choo, YM and Zhao, Z and Hu, J and Ji, K and Hamann, MT and Wang, X and Wang, X}, title = {Bletistrosides M-X, Anti-Alzheimer's Disease Compounds from the Tubers of Bletilla striata.}, journal = {Journal of natural products}, volume = {88}, number = {7}, pages = {1752-1765}, pmid = {40663501}, issn = {1520-6025}, support = {R01 AT007318/AT/NCCIH NIH HHS/United States ; R01 GM145845/GM/NIGMS NIH HHS/United States ; }, mesh = {*Orchidaceae/chemistry ; *Alzheimer Disease/drug therapy ; Molecular Structure ; *Plant Tubers/chemistry ; Animals ; Amyloid beta-Peptides ; Humans ; Glycosides/pharmacology/chemistry/isolation & purification ; }, abstract = {Twelve new compounds, bletistrosides M-X (1-12), including five glucosyloxybenzyl 2-isobutylmalates (1-5), along with four neolignan glycosides (6-9), two phenanthrene derivatives (10-11), and one bibenzyl derivative (12), were isolated from the tubers of Bletilla striata (B. striata). The structures and absolute configurations of the undescribed compounds were elucidated on the basis of spectroscopic data analysis, experimental and calculated electronic circular dichroism data, chiroptical analysis, and chemical derivatizations. In silico, compounds 2, 3, and 12 bound well to Aβ1-42. Compounds 2, 3, and 12 significantly delayed the paralysis phenotype in CL4176 worms compared to controls. Higher nonparalysis rates were observed in these treatment groups (5 μM for compound 2; 25, 50 μM for compounds 2, 3 and 12), suggesting their potential role in anti-Alzheimer's disease.}, } @article {pmid40662861, year = {2025}, author = {Feng, J and Shi, H and Da, M and Beg, MF and Cao, J}, title = {A Latent-Class Model for Time-To-Event Outcomes and High-Dimensional Imaging Data.}, journal = {Statistics in medicine}, volume = {44}, number = {15-17}, pages = {e70186}, pmid = {40662861}, issn = {1097-0258}, support = {RGPIN-2021-02963//Natural Sciences and Engineering Research Council of Canada/ ; RGPIN-2023-04057//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Magnetic Resonance Imaging/statistics & numerical data/methods ; Neuroimaging/methods/statistics & numerical data ; Computer Simulation ; Algorithms ; *Latent Class Analysis ; Proportional Hazards Models ; Logistic Models ; Disease Progression ; Brain/diagnostic imaging ; *Models, Statistical ; }, abstract = {Structural magnetic resonance imaging (MRI) is one of the primary predictors of Alzheimer's disease risk, enabling the identification of patients with similar risk profiles for precision medicine treatment. Motivated by the need for flexible modeling in AD research, we propose a latent-class model that addresses the heterogeneity within study populations. This model allows for varying relationships between covariates and survival outcomes, accommodating the dynamics of AD progression. The imaging predictors are characterized by bivariate splines over triangulation to accommodate the irregular domain of the brain images. We develop a generalized expectation-maximization (EM) algorithm that combines the computational methods for logistic regression and penalized proportional hazards models to implement the proposed approach. We demonstrate the advantages of the proposed method through extensive simulation studies and provide an application to the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, which helps to reveal different subtypes or stages of the disease process in Alzheimer's Disease.}, } @article {pmid40662560, year = {2025}, author = {Talluri, S}, title = {Computational Design of Drugs for Epilepsy using a Novel Guided Evolutionary Algorithm for Enhanced Blood Brain Barrier Permeability.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249385792250709073502}, pmid = {40662560}, issn = {1875-6166}, abstract = {INTRODUCTION: Epilepsy is a common disorder of the Central Nervous System (CNS). The rational design of small-molecule drugs for disorders of the CNS is a difficult process because the majority of small molecules are unable to cross the Blood-Brain-Barrier. An efficient method for the design of inhibitors that have high permeability through the Blood-Brain-Barrier has the potential for application in drug design for CNS disorders such as Addiction, Alzheimer's disease, Bipolar disorder, Depression, Epilepsy, Gliomas, and Tuberculous meningitis. METHOD: Supervised learning was used to model the Blood-Brain-Barrier permeability of drugs like small organic molecules. This information was utilized to guide an evolutionary algorithm for the design of inhibitors with increased affinity for the target as well as higher Blood-Brain-Barrier permeability. RESULTS: The ligands designed with guided evolution were predicted to have higher binding affinity for the target as well as higher permeability across the Blood-Brain-Barrier compared to an evolutionary algorithm without the guidance. The guided evolutionary method was applied to design a set of drug-like ligands that were predicted to bind to GABA-T with high affinity, to be BBB permeable, and to be chemically synthesizable. DISCUSSION: Despite the availability of several drugs that are approved for the treatment of epilepsy, there are many cases that do not respond to available drugs or experience adverse effects. The novel ligands designed as part of this work have the potential to address the limitations of available drugs. CONCLUSION: Guided evolution is an efficient computational approach for the design of CNS drugs. The de novo design of drugs by application of the guided evolution algorithm, developed as part of this work, has resulted in the generation of ligands that are potential drugs for the cure of epilepsy. However, the effectiveness of these drugs for the cure of epilepsy has to be validated experimentally.}, } @article {pmid40662425, year = {2025}, author = {Shen, J and Isenberg, D and Linn, KA and Hubbard, RA}, title = {Integrating Misclassified EHR Outcomes With Validated Outcomes From a Non-Probability Sample.}, journal = {Statistics in medicine}, volume = {44}, number = {15-17}, pages = {e70127}, pmid = {40662425}, issn = {1097-0258}, support = {R21AG075574/AG/NIA NIH HHS/United States ; U19AG066567/AG/NIA NIH HHS/United States ; U01 AG006781/AG/NIA NIH HHS/United States ; U01AG006781/AG/NIA NIH HHS/United States ; R21 AG075574/AG/NIA NIH HHS/United States ; U19 AG066567/AG/NIA NIH HHS/United States ; }, mesh = {*Electronic Health Records/statistics & numerical data ; Humans ; Alzheimer Disease/pathology ; Longitudinal Studies ; Dementia ; Computer Simulation ; Bias ; Models, Statistical ; Selection Bias ; Washington ; *Outcome Assessment, Health Care/statistics & numerical data/methods ; }, abstract = {Although increasingly used for research, electronic health records (EHR) often lack a gold-standard assessment of key data elements. Linking EHRs to other data sources with higher-quality measurements can improve statistical inference, but such analyses must account for selection bias if the linked data source arises from a non-probability sample. We propose a set of novel estimators targeting the average treatment effect (ATE) that combine information from binary outcomes measured with error in a large, population-representative EHR database with gold-standard outcomes obtained from a smaller validation sample subject to selection bias. We evaluate our approach in extensive simulations and an analysis of data from the Adult Changes in Thought (ACT) study, a longitudinal study of incident dementia in a cohort of Kaiser Permanente Washington members with linked EHR data. For a subset of deceased ACT participants who consented to brain autopsy prior to death, gold-standard measures of Alzheimer's disease neuropathology are available. Our proposed estimators reduced bias and improved efficiency for the ATE, facilitating valid inference with EHR data when key data elements are ascertained with error.}, } @article {pmid40662084, year = {2025}, author = {Kunevičius, A and Vijaya, AK and Atzeni, A and Mingaila, J and Šimoliūnė, I and Jamontas, R and Keževičiūtė, E and Gueimonde, M and Meškys, R and Baltriukienė, D and Arboleya, S and Burokas, A}, title = {Intermittent supplementation with Akkermansia muciniphila and galactooligosaccharides modulates Alzheimer's disease progression, gut microbiota, and colon short-chain fatty acid profiles in mice.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1617980}, pmid = {40662084}, issn = {1663-4365}, abstract = {BACKGROUND: Bidirectional communication and mutual regulation between the gastrointestinal tract and the CNS is facilitated through the gut-brain axis. Recent studies have found reduced diversity of the gut microbiota in Alzheimer's disease (AD) patients, and animal models suggest microbial involvement in amyloid beta peptide (Aβ) accumulation. Modulation of the gut microbiota by new-generation probiotics represents a novel treatment strategy to alleviate the symptoms and slow the progression of AD. METHODS: In this study, the therapeutic effect of the probiotic Akkermansia muciniphila and the prebiotic galactooligosaccharides (GOS) was investigated in the APP/PS1 mouse model. After 7 months of triweekly administration, we evaluated physiological parameters, glucose metabolism, and behavioral outcomes. Additionally, we assessed gut microbiota diversity and composition, short-chain fatty acid (SCFA) concentrations in the cecum, Aβ load in the hippocampus and prefrontal cortex, and microglial abundance in the hippocampus. RESULTS: A. muciniphila and GOS administration normalized fasting glucose levels, glucose metabolism, and intestinal transit time to wild-type levels. Furthermore, supplementation reduced anxiety, improved long-and short-term memory, and partially restored activity levels. It also regulated SCFA concentrations in the cecum, improved the richness of the gut microbiota, and normalized abundance of microglia in the hippocampus, indicating reduced neuroinflammation. CONCLUSION: These findings suggest that long-term administration of A. muciniphila and GOS effectively improves metabolic health and modulates symptoms of AD in the APP/PS1 mouse model.}, } @article {pmid40661491, year = {2025}, author = {Santana, RA and McWhirt, JM and Brewer, GJ}, title = {Treatment of age-related decreases in GTP levels restores endocytosis and autophagy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.09.658689}, pmid = {40661491}, issn = {2692-8205}, abstract = {Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimer's model mice and a novel genetically encoded fluorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free-GTP co-localized in the mitochondria decreased with age accompanied by the accumulation of free-GTP labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while bafilomycin inhibition of autophagy raised GTP levels. 24 hr. supplementation of aged neurons with the NAD precursor nicotinamide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endocytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal Aβ aggregates and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy deficits that impair autophagy and endocytosis. GTP deficits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path.}, } @article {pmid40661469, year = {2025}, author = {Khajuria, P and Kour, D and Sharma, K and Singh, L and Banoo, R and Manhas, D and Ramajayan, P and Nandi, U and Bharate, S and Ahmed, Z and Kumar, A}, title = {Bisdemethoxycurcumin mitigates Alzheimer disease pathology through autophagy-mediated reduction of senescence and amyloid beta.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661469}, issn = {2692-8205}, abstract = {AD pathology is accompanied by increased senescence and reduced levels of autophagy in the brain. We investigated whether pharmacologically inducing autophagy could alter the senescent phenotype and help ameliorate AD pathology. We discovered that Bisdemethoxycurcumin (BDMC), a natural compound found in Curcuma longa, stimulates autophagy in primary astrocytes. We found that autophagy and senescence exhibit an inverse relationship in aging astrocytes, with increased expression of senescent proteins and downregulation of autophagic proteins. However, treatment of aged astrocytes with BDMC reversed the senescent phenotype by ameliorating the impaired autophagy. Interestingly, the senescent phenotype persisted when autophagy was downregulated by knockdown of AMPK. Additionally, BDMC-induced autophagy aided in the removal of amyloid beta that was administered externally to the astrocytes. Further, to validate these results in a mouse model of AD, we confirmed that BDMC can significantly penetrate the blood-brain barrier (BBB) in mice. Therefore, we administered 50 and 100 mg/kg b.w. of BDMC to transgenic 3xTg-AD mice for two months. In their hippocampus, the Control 3xTg-AD animals showed more senescent cells and lower autophagy levels. In contrast, autophagic proteins were significantly upregulated while senescence indicators, such as senescence-associated secretory phenotype (SASP) proteins, were sharply downregulated in the brain of treated animals. Additionally, we discovered that the treated mice's hippocampus had a significantly lower amyloid beta load. These molecular changes in the brain were ultimately reflected in the improved working memory and neuromuscular coordination behavior of mice treated with BDMC. This study warrants further evaluation of BDMC for the management of AD.}, } @article {pmid40661460, year = {2025}, author = {Falvey, A and Palandira, SP and Chaudhry, S and Tynan, A and Consolim-Colombo, FM and Metz, CN and Brines, M and Chang, EH and Chavan, SS and Tracey, KJ and Pavlov, VA}, title = {The cholinergic drug galantamine ameliorates acute and subacute peripheral and brain manifestations of acute respiratory distress syndrome in mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661460}, issn = {2692-8205}, support = {R01 GM121102/GM/NIGMS NIH HHS/United States ; R01 GM128008/GM/NIGMS NIH HHS/United States ; R35 GM118182/GM/NIGMS NIH HHS/United States ; }, abstract = {Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute lung injury (ALI), which is a common cause of respiratory failure and high mortality in critically ill patients. Long-term mortality and brain dysfunction have been documented in ARDS patients after hospital discharge. Inflammation plays a key role in ALI/ARDS pathogenesis. Neural cholinergic signaling regulates cytokine responses and inflammation. Here, we studied the effects of galantamine, an approved cholinergic drug (for Alzheimer's disease) on ALI/ARDS severity and inflammation in mice, using a clinically relevant mouse model induced by intratracheal administration of hydrochloric acid and lipopolysaccharide. Mice were treated 30 mins prior to each insult with vehicle or galantamine (4 mg/kg, i.p.). Galantamine treatment significantly decreased bronchoalveolar lavage (BAL) and serum TNF, IL-1β, and IL-6 levels, as well as BAL total protein and myeloperoxidase and lung histopathology in ALI/ARDS mice. In addition, galantamine improved the functional state of mice with ALI/ARDS during a 10-day monitoring and attenuated lung injury and indices of brain inflammation at 10 days. These findings support further studies utilizing this approved cholinergic drug in therapeutic strategies for ARDS and its subacute sequelae.}, } @article {pmid40661442, year = {2025}, author = {Jayarathne, H and Manchanayake, DH and Chimienti, N and Kadri, O and Gurdziel, K and Kim, S and Jang, H and Ginsburg, BC and Miller, RA and Yakar, S and Sadagurski, M}, title = {Canagliflozin reprograms the aging hippocampus in genetically diverse UM-HET3 mice and attenuates Alzheimer's-like pathology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.10.658747}, pmid = {40661442}, issn = {2692-8205}, abstract = {Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana's potential to combat brain aging and AD through sex-specific mechanisms.}, } @article {pmid40661313, year = {2025}, author = {Mervosh, N and Devi, G}, title = {Estrogen, menopause, and Alzheimer's disease: understanding the link to cognitive decline in women.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1634302}, pmid = {40661313}, issn = {2296-889X}, abstract = {BACKGROUND: Women face a significantly higher lifetime risk of developing Alzheimer's disease (AD) than men. This disparity is often attributed to longer female longevity, but growing evidence suggests a multifactorial origin, including hormonal, vascular, and immunologic contributions. Estrogen plays a critical neuroprotective role across multiple systems implicated in AD pathogenesis, including synaptic plasticity, mitochondrial function, and cerebrovascular integrity. However, clinical trials investigating hormone therapy (HT) for AD prevention have yielded mixed results, in part due to variability in study populations, timing of intervention, and formulation of hormones. AIMS/METHODS: This review examines the biological rationale for estrogen's role in cognitive aging, synthesizes clinical and translational data on hormone therapy and AD risk, and highlights the importance of vascular comorbidity, including cerebral small vessel disease, in mediating AD pathology. CONCLUSION: We propose that estrogen's neuroprotective potential may be best realized in personalized treatment frameworks that account for age, timing, APOE genotype, and vascular burden. Interpretation of estrogen's role in AD is further complicated by variability in diagnostic criteria, which may contribute to conflicting findings across studies. Recognition of menopause-related cognitive impairment as an early, hormonally modulated risk state may offer additional opportunity for timely intervention. Addressing this complexity is essential to refining AD prevention strategies in midlife women.}, } @article {pmid40661291, year = {2025}, author = {Seiger, R and Fierlinger, P}, title = {Predicting conversion from mild cognitive impairment to Alzheimer's disease using a Vision Transformer and hippocampal MRI slices.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40661291}, support = {U19 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Convolutional neural networks (CNNs) have been the standard for computer vision tasks and are frequently applied in medical conditions, such as in Alzheimer's disease (AD). Recently, Vision Transformers (ViTs) have been introduced, which provide a strong alternative to CNNs by discarding the convolution approach in favor of the attention mechanism. This allows modeling global and distant relationships within distinct parts of an image without relying on the strong inductive biases present in CNNs. A common precursor stage of AD is a syndrome called mild cognitive impairment (MCI). However, not all individuals diagnosed with MCI progress to AD. The establishment of reliable classification models that predict converters versus non-converters would be a valuable tool to support clinical decision-making, such as enabling early treatment. Hence, in this investigation a transfer learning approach was used by applying a pretrained ViT model, fine-tuned on the ADNI dataset comprising 575 subjects with MCI. We included baseline T1-weighted structural MRI data from 299 stable MCI and 276 progressive MCI individuals, who developed Alzheimer's disease within 36 months. Inputs to the model were three normalized axial slices covering areas of the hippocampal region, consisting of the combined gray and white matter segmentations. The final model was evaluated over multiple runs to obtain stable performance estimates, yielding an average area under the receiver operating characteristic curve (AUC-ROC) on the test set of 0.74 ± 0.02 (mean ± SD), an accuracy of 0.69 ± 0.03, a sensitivity of 0.65 ± 0.07, a specificity of 0.72 ± 0.06, and a F1-score for the pMCI class of 0.67 ± 0.04. By specifically focusing on axial slices covering the hippocampal region, we aimed to target the brain structure often reported as being the first affected by the disease, while our results indicate that a ViT approach achieves reasonable classification accuracy for predicting the conversion from MCI to AD.}, } @article {pmid40660741, year = {2025}, author = {McCullough, A and Chen, CD and Gordon, BA and Joseph-Mathurin, N and Jack, CR and Koeppe, R and Hornbeck, R and Koudelis, D and McKay, NS and Hobbs, DA and Flores, S and Keefe, SJ and Aggarwal, NT and Allegri, RF and Berman, SB and Bird, T and Black, SE and Brooks, WS and Chhatwal, JP and Day, GS and Farlow, MR and Fox, NC and Gauthier, S and Honig, LS and Hsiung, GY and Jucker, M and Levin, J and Masellis, M and Masters, C and Mendez, PC and Ringman, JM and Snider, BJ and Salloway, S and Schofield, PR and Shimada, H and Suzuki, K and van Dyck, CH and Klein, G and Clifford, DB and Cruchaga, C and Hassenstab, J and Li, Y and McDade, E and Mills, S and Morris, JC and Perrin, RJ and Supnet-Bell, C and Wang, G and Xiong, C and Bateman, RJ and Benzinger, TLS and , }, title = {Regional effects of gantenerumab on neuroimaging biomarkers in the DIAN-TU-001 trial.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70347}, pmid = {40660741}, issn = {1552-5279}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; //F. Hoffman-LaRoche Ltd/ ; T32AG078117-01/GF/NIH HHS/United States ; //F. Hoffman-LaRoche Ltd./ ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01 AG046179/AG/NIA NIH HHS/United States ; R01AG053267-S1/NH/NIH HHS/United States ; R01AG053267-S2/NH/NIH HHS/United States ; R01AG053267/NH/NIH HHS/United States ; A2022013F//BrightFocus Foundation/ ; AARFD-20-681815//N.J.M./ ; U01AG042791/GF/NIH HHS/United States ; //GHR Foundation/ ; AARF-21-722077/ALZ/Alzheimer's Association/United States ; K01 AG080123/AG/NIA NIH HHS/United States ; T32 AG078117/AG/NIA NIH HHS/United States ; 1K01AG080123//N.J.M./ ; R01 AG053267/AG/NIA NIH HHS/United States ; T32AG078117-01/NH/NIH HHS/United States ; //Avid Radiopharmaceuticals/ ; //Eli Lilly and Company/ ; U01AG042791-S1/NH/NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; R01AG046179/NH/NIH HHS/United States ; //Cerveau Technologies, Cogstate, and Signant/ ; U01AG042791/NH/NIH HHS/United States ; U01 AG042791/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/genetics/pathology ; Positron-Emission Tomography ; Male ; Female ; Magnetic Resonance Imaging ; *Brain/diagnostic imaging/drug effects/pathology/metabolism ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Neuroimaging ; Middle Aged ; Biomarkers/metabolism ; Thiazoles ; Fluorodeoxyglucose F18 ; Aniline Compounds ; Aged ; Amyloid beta-Peptides/metabolism ; }, abstract = {INTRODUCTION: Monoclonal anti-amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD). METHODS: In the DIAN-TU-001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [[11]C]-Pittsburgh compound-B (PiB) positron emission tomography (PET), [[18]F]-fluoro-2-deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI). RESULTS: Gantenerumab significantly reduced PiB-PET uptake overall and in most regions and showed no changes in FDG-PET or MRI measures. Drug effects were associated with baseline PiB-PET uptake, and the largest effects occurred in medial regions. DISCUSSION: Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB-PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design. HIGHLIGHTS: Gantenerumab unevenly decreased Aβ burden as measured by PiB-PET across brain regions. The strongest decrease in PiB-PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG-PET metabolism or MRI volumetrics after 4 years.}, } @article {pmid40660634, year = {2025}, author = {Zhang, Y and Wu, YX and Zhang, XG and Guo, SY and He, J and Hu, NN and Huang, YL and Kong, Y and Li, QF and Sui, AR and Zhu, BH and Piao, H and Zhao, J and Li, S}, title = {Scorpion venom heat-resistant synthetic peptide improves cognitive dysfunction of APP/PS1 mice through microglial retromer complex.}, journal = {British journal of pharmacology}, volume = {182}, number = {21}, pages = {5391-5408}, doi = {10.1111/bph.70124}, pmid = {40660634}, issn = {1476-5381}, support = {LJKQZ2021101//Department of Education of Liaoning Province/ ; LJ222510161002//Department of Education of Liaoning Province/ ; 82101275//National Natural Science Foundation of China/ ; 82471464//National Natural Science Foundation of China/ ; 82101661//National Natural Science Foundation of China/ ; U1908208//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Microglia/drug effects/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism ; Mice, Transgenic ; Mice ; *Scorpion Venoms/pharmacology/therapeutic use/chemistry ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; Mice, Inbred C57BL ; *Peptides/pharmacology/therapeutic use ; Cells, Cultured ; Disease Models, Animal ; *Alzheimer Disease/drug therapy ; }, abstract = {BACKGROUND AND PURPOSE: The abnormal accumulation of amyloid-β (Aβ) in the brain is a characteristic pathological change observed in patients with Alzheimer's disease (AD). Microglial phagocytosis, dependent on recycling through the retromer complex and cell membrane-bound receptors, plays a vital role in clearing Aβ from the brain. Previous studies have demonstrated the neurotrophic and neuroprotective effects of Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP); however, its impacts on cognitive function remain unclear. The present study aims to investigate the impact of SVHRSP on cognitive function in APP/PS1 transgenic mice and underlying mechanisms associated with microglial retromer complex. EXPERIMENTAL APPROACH: SVHRSP and 3-methyladenine (3-MA) were intraperitoneally injected at 7.5 months to investigate their effects on cognitive dysfunction in APP/PS1 mice. Following behavioural testing, brain samples were harvested 24 h later for electrophysiological recordings, analysis of protein and gene expression, and histological assessment. The role of microglial retromer complex was examined using primary microglia cultures. KEY RESULTS: SVHRSP treatment effectively improved AD-related pathological features, including cognitive impairment, neuronal loss, impaired synaptic plasticity, neuroinflammation, and Aβ deposition in APP/PS1 mice. Both in vivo and in vitro studies revealed that SVHRSP treatment increased expression of retromer complex protein VPS35. 3-MA, a specific class III phosphoinositide 3-kinase (PI3K) inhibitor that prevents autophagosome formation, reduced retromer complex protein expression and hindered the cognitive function improvements of SVHRSP. CONCLUSION AND IMPLICATIONS: Our findings suggest that SVHRSP may enhance microglial phagocytosis by modulating retromer complex activity, thereby alleviating Aβ accumulation and improving cognitive dysfunction in AD.}, } @article {pmid40660446, year = {2025}, author = {Singh, D}, title = {Mitochondrial Dysfunction in Neurodegenerative Disorders: Role of Prototype Targeted Drug Delivery Solutions.}, journal = {Current drug safety}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115748863375490250626163609}, pmid = {40660446}, issn = {2212-3911}, abstract = {Mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Targeted drug delivery to mitochondria represents a promising therapeutic strategy to mitigate neuronal degeneration and preserve mitochondrial function in these devastating conditions. This review provides a comprehensive overview of recent advances in targeted drug delivery solutions for mitochondrial dysfunction in neurodegenerative disorders. The mechanisms underlying mitochondrial dysfunction in AD, PD, HD, and ALS are explored, highlighting the specific challenges and opportunities for therapeutic intervention. Emerging drug delivery technologies are discussed, including mitochondriaresponsive systems, nanoparticles, peptides, and viral vectors, designed to deliver therapeutic agents directly to mitochondria along with suitable case studies. Furthermore, preclinical and clinical studies evaluating the efficacy and safety of mitochondria-targeted therapeutics are reviewed, and future directions and challenges in the field are outlined. By elucidating the intersection of mitochondrial biology and drug delivery, this review aims to inspire further research and innovation toward effective treatments for neurodegenerative diseases.}, } @article {pmid40660381, year = {2025}, author = {Zhang, J and Kong, G and Yang, J and Pang, L and Li, X}, title = {Pathological mechanisms and treatment progression of Alzheimer's disease.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {625}, pmid = {40660381}, issn = {2047-783X}, mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism ; Disease Progression ; Animals ; Biomarkers/metabolism ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder and leading cause of dementia worldwide, with its incidence rising dramatically in aging populations. This progressive disease is neuropathologically characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tau tangles, and chronic neuroinflammation, leading to synaptic dysfunction and neuronal loss. Despite extensive research efforts, the complex and multifactorial nature of AD pathogenesis has prevented the development of truly disease-modifying therapies. Current therapeutic approaches, including recently approved anti-amyloid immunotherapies, demonstrate limited clinical efficacy and significant adverse effects, highlighting the need for alternative treatment strategies. This comprehensive review systematically evaluates recent advances in understanding AD pathophysiology, emphasizing the interplay between genetic risk factors (particularly APOE ε4), proteostasis imbalance, metabolic dysfunction, and neurovascular contributions. We critically analyze emerging diagnostic biomarkers, including novel neuroimaging techniques and cerebrospinal fluid/blood-based biomarkers, that enable earlier and more accurate detection. The review provides an in-depth assessment of both pharmacological interventions (such as tau-targeting therapies, anti-inflammatory agents, and neurotransmitter modulators) and non-pharmacological approaches (including lifestyle modifications and cognitive training). Special attention is given to personalized medicine strategies that account for disease heterogeneity and individual risk profiles. By synthesizing evidence from molecular studies, animal models, and clinical trials, we identify key challenges in therapeutic translation and propose future research directions. Our analysis underscores the importance of multimodal interventions targeting multiple pathological processes simultaneously, combined with early detection methods, to effectively combat this devastating disease. This review aims to provide researchers and clinicians with an updated framework for understanding AD pathogenesis and developing more effective treatment paradigms.}, } @article {pmid40659845, year = {2025}, author = {Ardura-Fabregat, A and Bosch, LFP and Wogram, E and Mossad, O and Sankowski, R and Aktories, P and Kieger, L and Cook, J and Hasavci, D and Ulupinar, H and Brock, D and Wang, F and Iovino, N and Wald, S and Preissl, S and Yilmaz, B and Schnepf, D and Macpherson, AJ and Blank, T and Kierdorf, K and Prinz, M}, title = {Response of spatially defined microglia states with distinct chromatin accessibility in a mouse model of Alzheimer's disease.}, journal = {Nature neuroscience}, volume = {28}, number = {8}, pages = {1688-1703}, pmid = {40659845}, issn = {1546-1726}, mesh = {Animals ; *Microglia/metabolism/pathology ; *Alzheimer Disease/pathology/metabolism/genetics ; Disease Models, Animal ; Mice ; Female ; Plaque, Amyloid/pathology/metabolism ; Mice, Transgenic ; *Chromatin/metabolism ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; }, abstract = {Microglial spatial heterogeneity remains a crucial yet not fully answered question in the context of potential cell-directed therapies for Alzheimer's disease (AD). There is an unclear understanding of the dynamics of distinct microglia states adjacent to or far from amyloid-beta (Aβ) plaques and their contributions to neurodegenerative diseases. Here we combine multicolor fluorescence cell fate mapping, single-cell transcriptional analysis, epigenetic profiling, immunohistochemistry and computational modeling to comprehensively characterize the relation of plaque-associated microglia (PAM) and non-plaque-associated microglia (non-PAM) in a mouse model of AD. We show that non-PAM are a distinct and highly dynamic microglial state, transitioning to PAM after Aβ plaque deposition in female mice. Non-PAM modulate the cell population expansion in response to amyloid deposition and rapidly respond to environmental cues. Indeed, Csf1 signaling modulates non-PAM-to-PAM transition during disease progression. Our data suggest that microglia states and their dynamics between each other can have distinct contributions to disease, and they may be targeted for the treatment of AD.}, } @article {pmid40658838, year = {2025}, author = {Zhang, J and Zhang, HL and Xu, XR and Feng, YL and Zhu, QM and Morisseau, C and Qiu, F and Hammock, BD and Sun, CP}, title = {Targeting PBK with small-molecule 1-O-acetyl-4R,6S-britannilactone for the treatment of neuroinflammation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {29}, pages = {e2502593122}, pmid = {40658838}, issn = {1091-6490}, support = {P42 ES004699/ES/NIEHS NIH HHS/United States ; R35 ES030443/ES/NIEHS NIH HHS/United States ; 82274069//MOST | National Natural Science Foundation of China (NSFC)/ ; P42 ES04699//superfund basic research program of the national institutes of environmental health sciences/ ; }, mesh = {Animals ; Mice ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Lipopolysaccharides ; Microglia/drug effects/metabolism ; Autophagy/drug effects ; *Lactones/pharmacology ; Humans ; Mice, Inbred C57BL ; Inflammation/drug therapy ; Male ; AMP-Activated Protein Kinases/metabolism ; Epoxide Hydrolases/antagonists & inhibitors/metabolism ; }, abstract = {Neuroinflammation is a complex immunological phenomenon characterized by a dysregulated inflammatory response in the central nervous system (CNS) that can be triggered by various pathological injuries, such as toxins, which are involved in Parkinson's and Alzheimer's diseases (PD and AD), therefore, suppressing neuroinflammation serves as an effective treatment for CNS diseases. Herein, we found that natural soluble epoxide hydrolase (sEH) inhibitor 1-O-acetyl-4R,6S-britannilactone (AB) regulated mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways to suppress the microglial activation by regulating inflammation and autophagy in vitro and in vivo, contributing to the improvement of lipopolysaccharide (LPS)-mediated neuroinflammation. Protein microarray analysis indicated that AB could selectively target PDZ binding kinase (PBK) through covalently binding to C70, exhibiting a dissociation constant (Kd) of 0.62 μM, which was corroborated by subsequent chemical biology experiments. We gained a deeper understanding of the mechanistic by which AB interfered PBK function, specifically by disrupting its interaction with tumor necrosis factor alpha-induced protein-8 like-2 (TIPE2), blocking the serine 3 (S3) phosphorylation-mediated ubiquitylation and degradation of TIPE2. Additionally, our study revealed that PBK genetic deletion alleviated the course of LPS-mediated neuroinflammation in vitro and in vivo, and AB did not exhibit any extra effects in LPS-mediated PBK[-/-] mice. These findings first offered broader prospects for treating neuroinflammation by targeting PBK to repress inflammation and activate autophagy, suggesting that AB had the potential to serve as a direct inhibitor in the PBK-TIPE2 interaction.}, } @article {pmid40658710, year = {2025}, author = {Ji, H and Zhao, Z and Zhao, C}, title = {Unveiling Aducanumab's safety profile: A comprehensive pharmacovigilance analysis.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0328076}, pmid = {40658710}, issn = {1932-6203}, mesh = {Humans ; *Pharmacovigilance ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; *Alzheimer Disease/drug therapy ; Retrospective Studies ; Female ; Male ; Aged ; Adverse Drug Reaction Reporting Systems ; United States ; Middle Aged ; United States Food and Drug Administration ; Aged, 80 and over ; Bayes Theorem ; Adult ; }, abstract = {BACKGROUND: Aducanumab, a monoclonal antibody targeting amyloid-beta plaques, has been introduced as a pivotal therapeutic agent for Alzheimer's disease (AD). Although it offers promising benefits in the treatment of early-stage Alzheimer's disease, a thorough evaluation of its safety profile and potential adverse events (AEs) is essential to ensure patient safety. METHODS: This retrospective pharmacovigilance study analyzed data from the FDA Adverse Event Reporting System (FAERS) database to evaluate AEs associated with Aducanumab. Employing a case/non-case methodology, the study utilized signal detection algorithms, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS), to identify AEs signals related to Aducanumab use. RESULTS: The study encompassed a total of 11517459 reports, with 431 specifically citing Aducanumab. A substantial number of AEs were identified, particularly among the elderly population and those with pre-existing neurological conditions. The most frequently reported AEs were related to the nervous system, including "amyloid-related imaging abnormalities" such as edema/effusion and microhemorrhages. Other affected system organ classes (SOCs) included psychiatric disorders and general disorders and administration site conditions. Specific preferred terms (PTs) linked with Aducanumab included "confusional state," "disorientation," and "cerebral microhemorrhage." Unexpected AEs such as "subdural hematoma" and "head injury" were also noted, indicating a broader safety profile that requires further investigation. CONCLUSIONS: The study's findings underscore the necessity for close monitoring of Aducanumab use, especially in elderly patients with AD. The identification of both expected and unexpected AEs emphasizes the need for ongoing pharmacovigilance and additional research to fully understand the safety profile of Aducanumab in clinical practice. Strength: Utilized multiple signal detection algorithms (ROR, PRR, BCPNN, MGPS) to enhance robustness of pharmacovigilance findings. Limitation: Reliance on spontaneous FAERS reports, which are prone to underreporting, overreporting, and reporting bias.}, } @article {pmid40658276, year = {2025}, author = {Luo, J and Shang, P and Tan, Z and Huang, S and Liu, Y and Wang, Y and Chen, Q and Xie, H}, title = {Effects of accelerated intermittent theta-burst stimulation combined with cognitive training on brain function in amnestic mild cognitive impairment patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {10}, pages = {5379-5390}, pmid = {40658276}, issn = {1590-3478}, support = {2018YFC2001700//National Key R&D Program of China/ ; 2019A011//the Special Fund of the Foshan Summit Plan/ ; 20220319//the Medical Scientific Research Project of Foshan Municipal Health Bureau/ ; }, mesh = {Humans ; *Cognitive Dysfunction/therapy/physiopathology/diagnostic imaging ; Male ; Female ; Aged ; Double-Blind Method ; *Transcranial Magnetic Stimulation/methods ; Spectroscopy, Near-Infrared ; Middle Aged ; *Amnesia/therapy/physiopathology ; *Dorsolateral Prefrontal Cortex/physiopathology/diagnostic imaging ; *Theta Rhythm/physiology ; *Brain/physiopathology/diagnostic imaging ; Combined Modality Therapy ; Cognitive Training ; }, abstract = {OBJECTIVE: This double-blinded randomized trial investigated the effects of accelerated intermittent theta-burst stimulation (iTBS) and adaptive cognitive training on brain function in 24 patients with amnestic mild cognitive impairment (aMCI). METHODS: Participants received real (n=12) or sham (n=12) iTBS targeting the left dorsolateral prefrontal cortex (DLPFC) thrice daily alongside cognitive training for 14 days. The Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and functional near-infrared spectroscopy (fNIRS) during rest and N-back tasks, which measure cognitive function and brain activity respectively, were administered pre-and post-intervention. RESULTS: The active group demonstrated significant cognitive improvement. Compared to sham controls, postintervention fNIRS results revealed reduced global brain activation during the 1-back task in the active group, particularly in the left prefrontal cortex, and the brain activation correlated with reaction time. In the 2-back task after treatment, the active group exhibited decreased activation in the right motor cortex, while the sham group showed increased activation in the left motor cortex. The overall brain connectivity in the sham group enhanced following the intervention, with significant differences in the correlations between the left prefrontal cortex and left motor cortex between groups. CONCLUSION: These findings suggest that the combined intervention can effectively promote cognitive performance and brain function in aMCI patients. iTBS causes enhanced functional engagement of the left DLPFC, which further facilitates neural efficiency and restores the capacity to modulate the allocation of neural resources rather than relying on global compensatory hyperactivation. These may be the underlying neural mechanisms for memory improvement in aMCI patients (Chinese Clinical Trial Registry: ChiCTR2400087943).}, } @article {pmid40657643, year = {2025}, author = {Bi, S and Liu, S and Zhu, K and Gao, D and Chen, L and Yu, C and Liang, G}, title = {Preclinical and experimental evidence of salvianolic acid B in the treatment of neurological diseases.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1606146}, pmid = {40657643}, issn = {1663-9812}, abstract = {BACKGROUND: Neurological diseases such as stroke and Alzheimer's disease pose increasing challenges to global public health. Salvianolic Acid B (SalB), a major active component of Salvia miltiorrhiza, has garnered attention due to its anti-inflammatory, antioxidant, neuroprotective, and pro-angiogenic properties in neurological disease treatment. PURPOSE: This paper aims to review the mechanisms and effects of SalB in the treatment of neurological diseases, exploring its role in improving neurological function, mitigating neuroinflammation, and reducing oxidative stress. RESULTS: SalB demonstrates multifaceted mechanisms in neurological disease management. In animal models of cerebral ischemia/reperfusion injury, SalB reduces infarct size and enhances neurological recovery via anti-inflammatory, anti-oxidative stress, and angiogenic pathways. It protects the blood-brain barrier and inhibits neuronal apoptosis in stroke models. In spinal cord injury models, SalB alleviates edema and promotes motor function recovery. In Alzheimer's disease models, SalB suppresses amyloid-beta formation and neuroinflammation. Additionally, SalB exhibits antidepressant and analgesic effects in pain-depression comorbidity models. These effects are mediated through the regulation of signaling pathways, including NF-κB, AMPK, PI3K/Akt, and Nrf2, highlighting SalB's broad therapeutic potential in neurological diseases. CONCLUSION: SalB exhibits promising prospects in the treatment of neurological diseases. However, its clinical application faces challenges such as chemical stability and bioavailability. Further research on the mechanisms of SalB and innovative drug delivery strategies is needed to advance its application in neurological disease therapy.}, } @article {pmid40657533, year = {2025}, author = {Perez, F and Morisaki, J and Kanakri, H and Rizkalla, M and Abdalla, A}, title = {A Novel Design of a Portable Birdcage via Meander Line Antenna (MLA) to Lower Beta Amyloid (Aβ) in Alzheimer's Disease.}, journal = {IEEE journal of translational engineering in health and medicine}, volume = {13}, number = {}, pages = {158-173}, pmid = {40657533}, issn = {2168-2372}, mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; *Amyloid beta-Peptides/metabolism ; Brain/metabolism/radiation effects ; Electromagnetic Fields ; Cells, Cultured ; Equipment Design ; }, abstract = {Late Onset Alzheimer's Disease (LOAD) is the most common cause of dementia, characterized by the deposition of plaques primarily of neurotoxic amyloid-[Formula: see text] ([Formula: see text]) peptide and tau protein. Our objective is to develop a noninvasive therapy to decrease the toxic A[Formula: see text] levels, using repeated electromagnetic field stimulation (REMFS) in the brain of Alzheimer's disease patients. We previously examined the effects of REMFS on [Formula: see text] levels in primary human brain (PHB) cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro (DIV7) treated with 64 MHz with a SAR of 0.6 W/Kg, one hour daily for 14 days (DIV 21) had significantly reduced (p =0.001) levels of secreted [Formula: see text]-42 and [Formula: see text]-40 peptide without evidence of toxicity. The EMF frequency and power, and SAR levels used in our work is utilized in MRI's, thus suggesting REMFS can be further developed in clinical settings to lower ([Formula: see text]) levels and improve the memory in AD patients. These findings and numerous studies in rodent AD models prompted us to design a portable RF device, appropriate for human use, that will deliver a homogeneous RF power deposition with a SAR value of 0.4-0.9 W/kg to all human brain memory areas, lower ([Formula: see text]) levels, and potentially improve memory in human AD patients.The research took place at the Indiana University School of Medicine (IUSM) and Purdue University Indianapolis. The first phase was done in PHB cultures at the IUSM. Through this phase, we found that a 64 MHz frequency and an RF power deposition with a SAR of 0.4-0.6 W/kg reduced the (A[Formula: see text]) levels potentially impacting Alzheimer's disease. The second phase of the project was conducted at Purdue University, we used ANSYS HFSS (High Frequency Simulation System) to design the devices that produced an appropriate penetration depth, polarization, and power deposition with a SAR of 0.4-0.9 W/kg to all memory brain areas of several numerical models. In Phase II-B will validate the device in a physical phantom. Phase III will require the FDA approval and application in clinical trials.The research parameters were translated into a designed product that fits comfortably in human head and fed from an external RF source that generates an RF power deposition with a SAR of 0.4-0.9 W/kg to a realistic numerical brain. The engineering design is flexible by varying the leg capacitors of the Meander Line Antenna (MLA) devices. Thermal outcomes of the results guarantee less than 0.5 C temperature increase within one-hour time of exposure, which can be used in clinical trials for AD patients. Design parameters include dimension of the coil, the MLA structure, conducting material, and capacitance values with the produced EM fields. The flexible design was achieved by varying the additive capacitance between conductors, and via a hybrid approach integrating a birdcage with sixteen MLA. A coil antenna size within 16 cm radius and 13 cm length was achieved. A capacitance between 6.9 nF and 9.2 nF were observed when copper materials with 16 conductors were used to achieve the research parameters in focus.The medical project proposed here has three phases: The initial phase of determining the research parameters for reducing A[Formula: see text] levels in human brain cultures and animal studies was completed at the IUSM. The translational engineering design of the REMS device and the numerical head and Antenna devices was successfully completed and presented in this paper by Purdue University and IUSM. Future phases will require manufacture and experimental validation of the REMS device with FDA approval for human application. Clinical impact: Our biological studies in human brain cultures showed that an RF power with a SAR of 0.4-0.9 W/kg at 64 MHz, lowered A[Formula: see text] levels, which potentially will prevent the death of the brain neurons and improve memory in AD. The fact that we found a safe RF power deposition with a SAR value associated with the proposed biological effects in human neurons and that 64 MHz provides a penetration depth of 13.5 cm that reaches all memory areas in a human brain makes the design and manufacture of this device of high clinical impact in the study of these exposures on the treatment of Alzheimer's and other protein associate diseases. Also, 64 MHz and RF power deposition with similar SAR levels are administer routinely in routine MRI for more than 4 decades makes it a safe framework for these novel therapeutic strategy.Clinical and Translational Impact Statement: The basic science work presented previously is both mechanistic and translational, and would advance the field of neuroscience as well as AD. This prompted us to joint efforts between the Indiana University School of Medicine and the electrical and computer engineering at Purdue University to design and develop a suitable EMF device for human treatments. Recently, our engineering team designed a birdcage antenna that generate a homogeneous RF power deposition with the same SAR values of our biological experiments in a realistic numerical human brain. Here, the engineering research has been extended to investigate the design of a portable flexible birdcage antenna that will enable adjustments to fit physical patient's characteristics, such as geometry, head size, and tissue dimensions. This new device is expected to improve SAR uniformity and may reduce the likelihood of untreated regions in the brains of patients during treatments. Also, here we determined that the maximum temperature rise of these exposures was less than 0.5°C, which is a safe level per regulatory agencies. This study considers a portable device system that will achieve the research parameters and patient satisfaction regarding reliability and comfort.}, } @article {pmid40657407, year = {2025}, author = {Prabha, S and Choudhury, A and Jawaid, T and Saeed, MU and Thakur, SC and Hassan, MI}, title = {Multi-targeted approach via apigenin-7-O-glucoside for therapeutic intervention of Tau phosphorylating kinases in Alzheimer's disease.}, journal = {3 Biotech}, volume = {15}, number = {8}, pages = {252}, pmid = {40657407}, issn = {2190-572X}, abstract = {UNLABELLED: Alzheimer's disease (AD) is one of the leading tauopathies in which several kinases phosphorylate Tau in response to Aβ oligomers, inflammation, calcium dysregulation, oxidative stress, mitochondrial dysfunction, or disruption of the key signaling pathways. Tau is phosphorylated by Ser/Thr kinases such as GSK3β, CDK5, MAPK14, and MARK2, as well as Tyr kinases like Fyn. Given the large crosstalk among these kinases, targeting one of these kinases is ineffective in treating tauopathies such as AD, highlighting the need for a multi-targeted approach. In this study, we targeted key kinases involved in Tau hyperphosphorylation using compounds derived from the medicinal plant Berberis lycium (B.ly.), which is reported to have anti-inflammatory, autophagy, and antioxidant properties. We employed virtual screening, ADMET evaluation, PASS analysis, DFT, molecular dynamics (MD) simulation, and MM/PBSA studies to assess the interaction of B.ly. compounds with CDK5, Fyn, GSK3β, MARK2, and MAPK14. Apigenin-7-O-glucoside (A7OG) was selected for its strong binding affinity within the ATP-binding pockets of these kinases. MD simulations demonstrated that A7OG exhibited promising inhibitory effects on CDK5, Fyn, MARK2, and MAPK14, with minimal fluctuation in its interaction with GSK3β. MM/PBSA analyses indicated stable binding energies for all the kinase-A7OG complexes. Our multitargeted investigations revealed that A7OG could be a promising molecule implicated in modulating tau hyperphosphorylating kinases that could lead to the development of therapeutic interventions in AD treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04413-3.}, } @article {pmid40657310, year = {2025}, author = {Langhough, RE and Norton, DL and Cody, KA and Du, L and Jonaitis, EM and Wilson, R and Rea Reyes, RE and Hermann, BP and Zetterberg, H and Johnson, SC}, title = {Use of preclinical Alzheimer's disease trajectories for clinical trial design.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40657310}, support = {P30 AG062715/AG/NIA NIH HHS/United States ; R01 AG021155/AG/NIA NIH HHS/United States ; R01 AG027161/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: This study uses longitudinal amyloid biomarker and cognitive data to generate sample size estimates for two-armed, pre-clinical amyloid clearance clinical trials. METHODS: PET PiB DVR ranges defined three amyloid groups (positive, "A+"; sub threshold/low positive, "subA+"; and negative, "A-") in cognitively unimpaired Wisconsin Registry for Alzheimer's Prevention participants. Amyloid group trajectories estimated from mixed effects models informed per-treatment-arm sample size estimates to detect plausible treatment effects over 3-year (biomarker) or 6-year (cognition) study windows (80% power). RESULTS: To detect ≥60% slowing in PiB accumulation, ≤40 may be needed per arm for both SubA+ and A+; to detect the same effect sizes in plasma p-tau217 trajectories, ~50-1700 are needed, depending on assay and amyloid subgroup. Among cognitive outcomes, Digit Symbol Substitution and a 5-test Preclinical Alzheimer's Cognitive Composite consistently required fewest (<2000) per arm. DISCUSSION: Early intervention study planning will benefit from selection of outcomes that are most sensitive to AD biomarker-related preclinical change.}, } @article {pmid40655392, year = {2025}, author = {Le, TTM and Pham, HT and Trinh, HTT and Quach, NT and Do, TT and Phi, QT and Chu, HH}, title = {Huperzia javanica as a Novel Source of Huperzine Alkaloids and Huperzine-producing Fungi.}, journal = {Indian journal of microbiology}, volume = {65}, number = {2}, pages = {1201-1208}, pmid = {40655392}, issn = {0046-8991}, abstract = {Huperzine A (HupA) and huperzine B (HupB) are potent acetylcholinesterase inhibitor used widely for clinical treatment of Alzheimer's disease, which are mainly extracrted from natural populations of Huperzia species. This study aimed to the evaluate potential of producing Hup of native Huperzia javanica species collected in Vietnam as well as identify endophytic fungi that produce high Hup or simultaneously produce many types of Hup derived from this plant as a material source for natural Hup production. By HPLC-DAD-MS analysis, H. javanica collected from Ha Giang, Vietnam was found as a novel producer of HupA and HupB with a yield of 0.513 mg/g dry weight (wt) and 0.192 mg/g dry wt, respectively. Inspired by this discovery, a total of 63 endophytic fungi were isolated from healthy tissues of the collected H. javanica plants, including 52 fungal strains belonging to nine genera and 11 unidentified strains based on morphological characteristics. Using HPLC, 9 Hup-producing fungi were identified when compared to the standard HupA and HupB. Surprisingly, 7 fungal strains produced both HupA and HupB, among which strain TLC12 produced the highest HupA and HupB contents of 0.271 and 0.163 mg/g mycelium dry cell weight (gdcw), respectively. Fungal strains TLC19 and TLC22 only yielded a respective amount of 0.305 and 0.135 mg/ gdcw of HupA. Combining with Internal Transcribed Spacer sequence analysis, 9 potent fungi were identified as Neurospora calospora (TLC9, TLC10, TLC11), Schizophyllum commune TLC12, Epicoccum sorghinum TLC13, Alternaria tenuissima TLC14, Cephalotrichum sp. TLC20, Daldinia sp. TLC19, and Schizophyllum sp. TLC22. To the best of our knowledge, this is the first report demonstrating H. javanica as a prolific and novel source of endophytic fungi capable of yielding high HupA and HupB contents. The exploitation of 9 Hup-producing fungi is also valuable for both basic research and industrial Hup manufactures. These findings open new perspectives for industrial production of fungal HupA and HupB and conservation of Huperzia species.}, } @article {pmid40654912, year = {2025}, author = {Song, Z and Huang, X and Jannu, AJ and Johnson, TS and Zhang, J and Huang, K}, title = {Identify Alzheimer's disease subtypes and markers from multi-omic data of human brain and blood with a subspace merging algorithm.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40654912}, issn = {2692-8205}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; RF1 AG057440/AG/NIA NIH HHS/United States ; U54 AG065181/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; U01 AG061357/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; RC2 AG036547/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; R21 AG075541/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; R01 AG030146/AG/NIA NIH HHS/United States ; U01 AG046170/AG/NIA NIH HHS/United States ; U24 AG061340/AG/NIA NIH HHS/United States ; R01 AG036042/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; RF1 AG057473/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; U01 AG046161/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R01 AG048015/AG/NIA NIH HHS/United States ; P50 AG025711/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG036836/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, abstract = {Identifying Alzheimer's disease (AD) subtypes is essential for AD diagnosis and treatment. We integrated multiomics data from brain tissues of the ROSMAP and MSBB studies using a subspace merging algorithm and identified two AD patient clusters with notable cognitive and AD pathology differences. Analysis of differentially expressed genes (DEGs) in brain and blood samples pinpointed the LDLR gene as a potential blood biomarker linked to brain gene expression changes. Furthermore, we conducted PheWAS analysis on All of Us Project's EHR and WGS dataset for 105 eQTLs associated with the DEGs and revealed significant associations between these eQTLs and several phenotypes, shedding light on potential regulatory roles of these genes in diverse physiological processes. Our study successfully integrated multiomics data and proposes LDLR as a candidate blood biomarker for AD subtyping. The identified phenotypic signatures provide valuable insights on molecular mechanisms underlying AD heterogeneity, paving the way for personalized AD treatment.}, } @article {pmid40654760, year = {2025}, author = {Mekkittikul, M and Zhu, C and Danna, BT and Zuo, X and Rios, A and Yang, K and Villanueva, M and Agarwal, D and Castro, D and Gu, X and Strofs, AR and Shirihai, OS and Stiles, L and Frautschy, SA and Oscarsson, J and Esterline, RL and Cole, GM and Divakaruni, AS}, title = {13C tracing in synaptosomes reveals that SGLT2 inhibition with dapagliflozin prevents metabolic deficits in the 5X-FAD model of Alzheimer's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40654760}, issn = {2692-8205}, support = {R01 AG066212/AG/NIA NIH HHS/United States ; R35 GM138003/GM/NIGMS NIH HHS/United States ; T32 GM136614/GM/NIGMS NIH HHS/United States ; }, abstract = {Metabolic dysfunction is linked to several forms of age-related neurodegeneration including Alzheimer's Disease (AD), and targeting brain energy metabolism is an increasingly attractive mode of therapeutic intervention. However, commonly used in vitro methods to identify specific metabolic pathways of interest in preclinical models of neurodegenerative disease have considerable limitations. They are prone to subselection of sample material, unable to identify cell type-specific effects, or cannot identify metabolic defects upstream of mitochondria. Here we address these challenges by validating a method for stable isotope tracing with isolated synaptic nerve terminals, or 'synaptosomes'. We further applied this approach to study glucose metabolism in synaptosomes isolated from the 5X-FAD mouse model of AD treated with the antidiabetic sodium-glucose linked transporter-2 (SGLT-2) inhibitor Dapagliflozin. Treatment with Dapagliflozin preserved steady-state levels of synaptosomal metabolites and enrichment from labeled glucose into citrate that was reduced in the 5X-FAD model. These changes correlated with trends towards improved spatial working memory but not amyloid burden. The results highlight the utility of stable isotope tracing in synaptosomes to identify precise sites of metabolic dysfunction and mechanisms of action for metabolic drug candidates in preclinical models of neurodegeneration.}, } @article {pmid40654706, year = {2025}, author = {Meade, J and Mesa, H and Liu, L and Zhang, Q}, title = {Synaptic Toxicity of OGA Inhibitors and the Failure of Ceperognastat.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40654706}, issn = {2692-8205}, support = {R01 AG071865/AG/NIA NIH HHS/United States ; R15 AG085620/AG/NIA NIH HHS/United States ; RF1 AG079569/AG/NIA NIH HHS/United States ; }, abstract = {O-GlcNAcase inhibitors (OGAi) have been proposed as therapeutics for Alzheimer's disease due to their ability to increase O-GlcNAcylation of tau and reduce its aggregation. However, the recent failure of ceperognastat in a Phase II trial-marked by accelerated cognitive decline in the treatment arm-has raised concerns about the safety of this therapeutic class. Here, we evaluated the acute synaptic effects of three structurally distinct OGAi (ceperognastat, ASN90, and MK8719) in mouse hippocampal slices. Electrophysiological recordings revealed that all three compounds impaired both short- and long-term synaptic plasticity, as evidenced by reduced paired-pulse facilitation/depression and suppressed long-term potentiation. Immunohistochemistry showed altered synaptic protein levels, with increased PSD-95 and reduced Synaptophysin 1 in neurons, alongside a biphasic shift in Tau phosphorylation. These findings indicate that OGAi produce rapid and convergent synaptotoxic effects across pre- and postsynaptic compartments, likely reflecting a class-wide mechanism. We argue that electrophysiological screening should be standard in CNS drug development and caution against targeting essential synaptic processes in chronic neurodegenerative conditions.}, } @article {pmid40654371, year = {2025}, author = {Wang, Z and Zhang, K and Huang, M and Shang, D and He, X and Wu, Z and Yan, X and Zhang, X}, title = {Structures and functions of the MICOS: Pathogenesis and therapeutic implications in Alzheimer's disease.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {6}, pages = {2966-2984}, pmid = {40654371}, issn = {2211-3835}, abstract = {Mitochondrial dysfunction is a critical factor in the pathogenesis of Alzheimer's disease (AD). The mitochondrial contact site and cristae organizing system (MICOS) plays a pivotal role in shaping the inner mitochondrial membrane, forming cristae junctions and establishing interaction sites between the inner and outer mitochondrial membranes and thereby serving as a cornerstone of mitochondrial structure and function. In the past decade, MICOS abnormalities have been extensively linked to AD pathogenesis. In particular, dysregulated expression of MICOS subunits and mutations in MICOS-related genes have been identified in AD, often in association with hallmark pathological features such as amyloid-β plaque accumulation, neurofibrillary tangle formation, and neuronal apoptosis. Furthermore, MICOS subunits interact with several etiologically relevant proteins, significantly influencing AD progression. The intricate crosstalk between these proteins and MICOS subunits underscores the relevance of MICOS dysfunction in AD. Therapeutic strategies targeting MICOS subunits or their interacting proteins may offer novel approaches for AD treatment. In the present review, we introduce current understanding of MICOS structures and functions, highlight MICOS pathogenesis in AD, and summarize the available MICOS-targeting drugs potentially useful for AD.}, } @article {pmid40654362, year = {2025}, author = {Ren, L and Ma, X and Ye, J}, title = {Mechanism of Alzheimer's disease treatment by sound and light stimulation.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {6}, pages = {3346-3348}, pmid = {40654362}, issn = {2211-3835}, } @article {pmid40654342, year = {2025}, author = {Madamanchi, K and Zhang, J and Melkani, GC}, title = {Linkage of circadian rhythm disruptions with Alzheimer's disease and therapeutic interventions.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {6}, pages = {2945-2965}, pmid = {40654342}, issn = {2211-3835}, support = {R01 AG068550/AG/NIA NIH HHS/United States ; RF1 NS133378/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and pathological brain changes. While aging is the primary risk factor, circadian rhythm disruption (CRD) is increasingly recognized as a central driver of AD pathology. CRD exacerbates oxidative stress, systemic inflammation, and gut microbiome dysbiosis, impairing sleep-wake cycles, disrupting metabolic homeostasis, and promoting neuroinflammation, ultimately accelerating disease progression. Oxidative stress, a key factor in neuronal damage, is both a cause and consequence of circadian misalignment, while mitochondrial dysfunction further amplifies oxidative damage, impairing synaptic function and cognitive stability. Additionally, gut microbiome dysbiosis contributes to neuroinflammatory processes, worsening neurodegeneration. Given these complex interactions, this review aims to elucidate the role of CRD in AD pathology and explore potential therapeutic interventions targeting circadian dysfunction. Specifically, it examines the efficacy of time-restricted feeding (TRF), a dietary strategy that aligns food intake with circadian rhythms. TRF has shown promise in restoring circadian function, reducing oxidative stress, improving mitochondrial health, and promoting gut microbiome diversity. By addressing CRD, TRF may offer a novel approach to mitigating AD pathologies. This review also identifies current research gaps and future directions for developing circadian-based interventions in AD prevention and treatment.}, } @article {pmid40653764, year = {2025}, author = {Zhang, J and Wang, C and Chang, K and Peng, T and Liang, C and Cheng, J and Shi, Y and Wang, X and Wang, Z and Tan, Y and Hua, Q}, title = {A novel traditional Chinese medicine formula restores sleep and cognitive function in APP/PS1 mice by targeting glycolytic pathways and neuroinflammatory responses.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {617-627}, doi = {10.1177/13872877251355596}, pmid = {40653764}, issn = {1875-8908}, mesh = {Animals ; Mice ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Sleep/drug effects ; Mice, Transgenic ; *Glycolysis/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; *Cognition/drug effects ; Amyloid beta-Protein Precursor/genetics ; *Medicine, Chinese Traditional/methods ; Male ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Disease Models, Animal ; *Sleep Wake Disorders/drug therapy ; Presenilin-1/genetics ; Cognitive Dysfunction/drug therapy ; Mice, Inbred C57BL ; }, abstract = {BackgroundAlzheimer's disease (AD) is recognized as a multifactorial neurodegenerative disorder involving numerous cellular and molecular processes, such as sleep disturbance, imbalance in brain glucose metabolism and neuroinflammation; these dysregulations typically precede the onset of symptoms. Hence, the results of mono-target therapy after AD diagnosis are in many cases unsatisfactory.ObjectiveTraditional Chinese medicine (TCM) presents significant potential for treating AD. Sleep disorders are one of the early symptoms of AD; however, there is no effective solution to sleep disorders caused by AD. Some TCMs have been shown to treat sleep disorders by regulating energy metabolism or improving neuroinflammation. This study aims to investigate if XX-F administrated in advance could alleviate AD by improving sleep quality and neuroinflammation.MethodsMice were given Xiexintongfu formula (XX-F) intragastrically for three months. Morris water maze and pentobarbital-induced sleep test were performed to evaluate cognition and sleep. Determine changes in energy metabolism related to glycolysis through western blot and specific assay kits. Using immunofluorescence and western blot to detect neuroinflammation.ResultsShortened sleep duration and cognitive impairment were observed in 6-month-old APP/PS1 mice. XX-F significantly prolonged sleep duration and rescued cognition. In addition, XX-F reduced the number of amyloid-β (Aβ) plaques and ameliorated neuroinflammation, and inhibited glycolysis by reducing pyruvate kinase M2 (PKM2) and lactate levels while rescuing adenosine triphosphate (ATP) deficiency.ConclusionsWe demonstrate that XX-F can improve sleep and cognition of AD mice by regulating energy metabolism and reducing neuroinflammation. This is a potential treatment method for AD and requires further in-depth research.}, } @article {pmid40653095, year = {2025}, author = {Varga, K and Sikur, N and Paszternák, A and Friesenhahn, AL and Zymela, FE and Bagaméry, F and Tábi, T and Wölfl, S}, title = {Resveratrol restores insulin signaling and balances mitochondrial biogenesis and autophagy in streptozotocin-induced neurodegeneration in vitro.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {212}, number = {}, pages = {107202}, doi = {10.1016/j.ejps.2025.107202}, pmid = {40653095}, issn = {1879-0720}, mesh = {Resveratrol ; Animals ; *Autophagy/drug effects ; Signal Transduction/drug effects ; *Insulin/metabolism ; *Mitochondria/drug effects/metabolism ; Streptozocin ; Rats ; *Stilbenes/pharmacology ; Insulin Resistance ; Phosphorylation/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy/chemically induced ; Insulin Receptor Substrate Proteins/metabolism ; Organelle Biogenesis ; *Neuroprotective Agents/pharmacology ; }, abstract = {Resveratrol, a natural phytoalexin, has been suggested to have beneficial effects in age-related diseases, including Alzheimer's disease. Studies indicate that it may delay memory decline and exert neuroprotective properties in vitro and in vivo. However, the precise mechanisms underlying these effects remain unclear, and the impact of resveratrol on central insulin resistance-a key feature of neurodegenerative disorders-remains insufficiently explored. Given the potential therapeutic significance of targeting insulin sensitivity in neurodegeneration, further investigation into the role of resveratrol in modulating these pathways is warranted. Our aim was to investigate the effects of resveratrol on insulin signaling and mitochondrial function in a previously established streptozotocin-induced in vitro neurodegeneration model. The phosphorylation status of key insulin signaling proteins and regulators of insulin resistance and autophagy markers were analyzed via Western blot and an ELISA-based microarray technique. The effects of resveratrol on mitochondrial biogenesis were evaluated through Mitotracker staining and quantification of mitochondrial mRNA and protein expression. Resveratrol augmented the cytoprotective effect of insulin in a concentration-dependent manner. It reduced the Ser(312) phosphorylation of IRS1, which is commonly linked to insulin resistance, and lowered the IC50 value for Tyr(895) phosphorylation required for activation. Similar insulin-sensitizing effects were observed in downstream signaling components. Resveratrol treatment exerted a caloric restriction mimetic activity through activating the AMPK/PGC1α/SIRT1 pathway and upregulated the expression of mitochondrial transcription factor TFAM and ATP synthase subunit (ATP5B). Despite the activation of mitochondrial biogenesis, the number of mitochondria was not altered, because it simultaneously induced autophagy marked by ULK1 phoshorylation and LC3 lipidation. Our findings indicate that resveratrol can enhance insulin signaling, even at the initial step of IRS1 phosphorylation. Its insulin-sensitizing effects extend beyond metabolic regulation to include survival responses. Resveratrol as a caloric restriction mimetic exerted a balanced effect on mitochondrial biogenesis and autophagy therefore improving mitochondrial quality control.}, } @article {pmid40652712, year = {2025}, author = {Brüge, A and Ponimaskin, E and Labus, J}, title = {Targeting the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges.}, journal = {Pharmacological reviews}, volume = {77}, number = {5}, pages = {100071}, doi = {10.1016/j.pharmr.2025.100071}, pmid = {40652712}, issn = {1521-0081}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Serotonin/metabolism ; Receptors, Serotonin/metabolism ; *Serotonin Agents/therapeutic use/pharmacology ; Molecular Targeted Therapy ; }, abstract = {More than 65 million people worldwide experience neurodegenerative diseases, such as Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis. As the risk of developing these diseases increases with age, increasing life expectancy will further accelerate their prevalence. Despite major advances in the understanding of the molecular mechanisms of neurodegeneration, no curative therapy is available to date. Neurodegenerative diseases are known to be associated with alterations in serotonergic neurotransmission, which might critically contribute to the pathogenesis of these diseases. Therefore, targeting the serotonergic system appears to be a promising therapeutic approach. In this review, we provide a comprehensive overview of pathological changes in serotonergic neurotransmission in different neurodegenerative diseases and discuss novel treatment strategies based on targeted modulation of the serotonergic system. We primarily focus on the therapeutic approaches modulating serotonin homeostasis, its biosynthesis, and the modulation of defined serotonin receptors. SIGNIFICANCE STATEMENT: A common feature of multiple neurodegenerative diseases is dysregulation of the serotonergic system at the cellular, molecular, and genetic levels that strongly contributes to specific pathological phenotypes. Targeting these alterations represents a suitable therapeutic strategy to combat disease-relevant pathomechanisms, slow down disease progression, and overcome pathological consequences.}, } @article {pmid40652586, year = {2025}, author = {Li, X and Li, Z and Chen, H and Guo, H and Ge, Y and Dong, F and Zhang, F and Zhang, F}, title = {Unraveling APOE4: The dual role in CNS and peripheral inflammation in Alzheimer's disease.}, journal = {International immunopharmacology}, volume = {163}, number = {}, pages = {115199}, doi = {10.1016/j.intimp.2025.115199}, pmid = {40652586}, issn = {1878-1705}, mesh = {Humans ; *Alzheimer Disease/immunology/metabolism/genetics ; Animals ; *Apolipoprotein E4/metabolism/genetics/immunology ; *Inflammation/immunology ; *Central Nervous System/immunology ; Microglia/immunology ; T-Lymphocytes/immunology ; }, abstract = {Inflammation in both CNS and peripheral circulation system is known to have a significant impact in AD pathogenesis. In the CNS, AD-related inflammation involves the activation of various types of immune cells, such as microglia, astrocytes, and T cells. Meanwhile, one of the hallmarks of peripheral circulation inflammation in AD is activation of T cells. In addition, Apolipoprotein E4 (APOE4), as a key genetic risk factor for late-onset AD, significantly influences both CNS and peripheral circulation system inflammation in the pathogenesis of AD. Moreover, APOE4 play a key role in various pathological changes in AD, such as Aβ accumulation, tau phosphorylation, lipid metabolism disorders, and BBB dysfunction, resulting in microglia, astrocytes, and T cells activation, as well as the release of inflammatory factors. This comprehensive review aims to elucidate the specific mechanisms through which APOE4 triggers inflammation in both CNS and peripheral circulation system in the context of AD. Furthermore, we also summarize several therapeutic approaches that target APOE for the treatment of AD.}, } @article {pmid40651740, year = {2025}, author = {Zhang, Z and Xue, X and Liu, P and Zhang, C and Li, J and Liu, Y and Jiang, Y and Lv, S and Wang, L and Zhou, H and Shen, W and Yang, S and Wang, F}, title = {The role of photobiomodulation in modulating neural activity and brain function: A systematic bibliometric analysis.}, journal = {Photodiagnosis and photodynamic therapy}, volume = {55}, number = {}, pages = {104712}, doi = {10.1016/j.pdpdt.2025.104712}, pmid = {40651740}, issn = {1873-1597}, mesh = {*Low-Level Light Therapy/methods ; Humans ; Bibliometrics ; *Brain/radiation effects ; *Central Nervous System Diseases/therapy/radiotherapy ; }, abstract = {This systematic bibliometric analysis evaluates the scientific evidence, impact, and trends of photobiomodulation (PBM) for central nervous system (CNS) disorders. Analyzing 150 relevant PubMed-indexed studies (including 46 clinical trials) up to September 2024, we demonstrate PBM's positive effects on the CNS. Key mechanisms include enhanced ATP synthesis, modulated nitric oxide signaling, improved neuronal excitability, suppressed oxidative stress, anti-inflammatory effects, and ion channel modulation. PBM offers therapeutic flexibility: shorter-wavelength, high-irradiance power lasers effectively target deep brain structures, while both modalities suit superficial cortical applications where fine spatial control is nonessential.Crucially, PBM induces long-lasting biological effects, highlighting significant potential for chronic CNS conditions like Alzheimer's disease, Parkinson's disease, and stroke. However, critical challenges hinder translation: optimizing disease-specific wavelengths and light sources (laser vs. LED, continuous vs. pulsed), and establishing standardized, long-term treatment protocols based on robust dose-response relationships. Resolving heterogeneity in parameters (energy density, power, potential thermal effects) is paramount for PBM to become a reliable neuromodulation tool. This analysis provides critical insights for advancing targeted PBM therapies in CNS.}, } @article {pmid40651475, year = {2025}, author = {Bershteyn, M and Zhou, H and Fuentealba, L and Chen, C and Subramanyam, G and Cherkowsky, D and Sevilla, ES and Hampel, P and Salvatierra, J and Sezan, M and Maury, Y and Havlicek, S and Kriks, S and Lee, S and Au, W and Watson, M and Kuzmenko, O and Grimmett, ME and Vogel, A and Porkka, F and Qiu, Y and Nesterova, A and Anderson, D and Feld, BG and Hosford, V and Jung, JH and Kowal, T and Bulfone, A and Banik, G and Priest, C and Palop, JJ and Nicholas, CR}, title = {Human stem cell-derived GABAergic interneuron development reveals early emergence of subtype diversity and gradual electrochemical maturation.}, journal = {Neuron}, volume = {113}, number = {19}, pages = {3162-3184.e10}, doi = {10.1016/j.neuron.2025.06.010}, pmid = {40651475}, issn = {1097-4199}, mesh = {Humans ; Animals ; *Interneurons/physiology/metabolism/cytology ; Mice ; *GABAergic Neurons/physiology/cytology/metabolism ; *Pluripotent Stem Cells/physiology/cytology ; Somatostatin/metabolism ; Parvalbumins/metabolism ; Cell Differentiation/physiology ; Median Eminence/cytology ; }, abstract = {Medial ganglionic eminence-derived inhibitory γ-aminobutyric acid (GABAergic) pallial interneurons (MGE-pINs) are essential regulators of cortical circuits, and their dysfunction is associated with neurological disorders. We developed human MGE-pINs from pluripotent stem cells for the treatment of drug-resistant epilepsy. Here, we analyzed xenografted MGE-pINs from human pluripotent stem cells (hMGE-pINs) over the lifespan of host mice in healthy and epileptic environments using single-nuclei RNA sequencing. Comparative transcriptomics against endogenous human brain datasets revealed that 97% of grafted cells developed into somatostatin (SST) and parvalbumin (PVALB) subtypes, including populations that exhibit selective vulnerability in Alzheimer's disease. Transplanted hMGE-pINs demonstrated rapid emergence of subclass features, progressing through distinct transcriptional states sequentially involving neuronal migration, synapse organization, and membrane maturation. We present molecular, electrophysiological, and morphological data that collectively confirm the derivation of diverse bona fide human SST and PVALB subtypes, providing a high-fidelity model to study hMGE-pIN development as well as a compositional atlas for regenerative cell therapy applications.}, } @article {pmid40651201, year = {2025}, author = {D, C and M, M}, title = {Fusion of bio-inspired optimization and machine learning for Alzheimer's biomarker analysis.}, journal = {Computers in biology and medicine}, volume = {196}, number = {Pt A}, pages = {110746}, doi = {10.1016/j.compbiomed.2025.110746}, pmid = {40651201}, issn = {1879-0534}, mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; Humans ; Biomarkers/metabolism ; *Machine Learning ; *Deep Learning ; Male ; Female ; Magnetic Resonance Imaging ; Brain/diagnostic imaging ; *Image Processing, Computer-Assisted/methods ; }, abstract = {Identification of Alzheimer's Disease (AD), especially in its early phases, presents significant challenges due to the nonexistence of reliable biomarkers and effective treatments. Clinical trials for AD medications also suffer from high failure rates. Accurate diagnosis, prognosis determination, progression monitoring, and treatment effect assessment depend heavily on analysing various brain regions, including the Corpus Callosum (CC), Grey Matter (GM), Hippocampus (HC), Ventricle, and White Matter (WM). Among these, the Hippocampus plays a pivotal role in early detection. This study employs deep learning for classification and optimization techniques for segmenting the HC region to enable the AD diagnosis. The pre-processing of raw images involves histogram equalization and Otsu's thresholding methods. The research focuses on data collection and pre-processing as essential steps for advancing diagnostic methods. Segmentation and classification utilize Elephant Herding Optimization (EHO) and Crow Search Optimization (CSO) techniques in combination with the ResNet50 classifier. The results reveal that Crow Search Optimization achieves superior performance, with an accuracy of 92 %, surpassing Elephant Herding Optimization.}, } @article {pmid40651085, year = {2025}, author = {Aydemi̇r, M and Gacar, G and Halbutoğullari, ZS and Duruksu, G and Öztürk, A and Altuntaş, C and Yazir, Y}, title = {Adipose tissue-derived mesenchymal stem cell extracellular vesicles enhance amyloid-beta degradation in an in vitro Alzheimer's model.}, journal = {Tissue & cell}, volume = {96}, number = {}, pages = {103035}, doi = {10.1016/j.tice.2025.103035}, pmid = {40651085}, issn = {1532-3072}, mesh = {Humans ; *Mesenchymal Stem Cells/metabolism ; *Alzheimer Disease/pathology/metabolism ; *Extracellular Vesicles/metabolism/ultrastructure ; *Amyloid beta-Peptides/metabolism ; *Adipose Tissue/cytology/metabolism ; Cell Differentiation ; Hydrogen Peroxide/pharmacology ; Cell Line, Tumor ; *Models, Biological ; Cytokines ; }, abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder lacking effective treatment. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) have shown promise in degrading amyloid beta (Aβ) plaques due to their low immunogenicity and ability to mediate intercellular communication. This study investigates the therapeutic potential of EVs derived from human adipose tissue MSCs (hAT-MSCs) and preconditioned human adipose tissue MSCs in an in vitro AD model. METHODS: MSCs characterized by flow cytometry and differentiation assays. hAT-MSCs stimulated with hydrogen peroxide (H₂O₂) or a cytokine complex (CC; TNF-α, IL-1β, IFN-γ). EVs were isolated via ultracentrifugation and analyzed by electron microscopy and Zetasizer. An in vitro AD model was established using neural-differentiated SH-SY5Y cells treated with Aβ peptides. Differentiation and Aβ degradation were assessed using immunocytochemistry, qRT-PCR, and ELISA. RESULTS: EVs derived from cytokine complex stimulated hAT-MSCs significantly reduced Aβ plaque size and intensity compared to EVs from unstimulated or H₂O₂-stimulated cells. When immunocytochemistry images were analyzed using ImageJ, Aβ levels were found to be highest in the Alzheimer's group and lowest in the CC-EV group. According to ELISA analyses, no significant difference was observed between the Alzheimer's model (a1) and the hAT-MSC-EVs (a3) groups, whereas both the H₂O₂-EV (a4) and CC-EV (a5) groups showed a significant reduction compared to the control (**** P ≤ 0,0001) CONCLUSION: These findings suggest that cytokine-stimulated hAT-MSC-derived EVs effectively promote Aβ degradation and represent a promising cell-free therapeutic strategy for AD.}, } @article {pmid40650861, year = {2025}, author = {Sil, M and Mukherjee, N and Chatterjee, I and Ghosh, A and Goswami, A}, title = {Glial Cells in Alzheimer's Disease: Pathogenic Mechanisms and Therapeutic Frontiers.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {3}, pages = {87}, pmid = {40650861}, issn = {1559-1166}, mesh = {*Alzheimer Disease/therapy/metabolism/pathology/drug therapy ; Humans ; Animals ; *Neuroglia/metabolism ; Microglia/metabolism ; Receptors, Immunologic/metabolism ; Membrane Glycoproteins ; }, abstract = {The rising incidence of brain diseases parallels the global trend of an aging population, with Alzheimer's disease (AD) being a leading neurodegenerative disorder characterized by memory loss, dementia, and cognitive decline. Despite extensive research, current treatments for AD remain largely symptomatic and have had limited success in halting disease progression, thereby shifting attention toward glial cells as promising therapeutic targets due to their emerging roles in AD pathogenesis. Astrocytes are involved in both beneficial and pathological processes in AD, such as cytokine secretion, Aβ removal, metabolic support, and tau pathology, with deficiency resulting in neuroinflammation and excitotoxicity. Microglia have dual functions in AD by phagocytosing amyloid plaques and limiting tau spread in initial phases but may develop a pro-inflammatory, neurodegenerative phenotype with progression of the disease. Oligodendrocytes and their precursors are involved in Aβ generation and myelin homeostasis, and their disturbance is responsible for white matter lesions and cognitive impairment, though their exact mechanisms are less clear. This review also examines emerging therapeutic strategies targeting glial cells, including modulating TREM2 pathways and novel drug candidates. These methods highlight the therapeutic value of the glial cells and provide valuable leads for furthering the treatment of AD by elucidating their changing roles in the course of the disease.}, } @article {pmid40650773, year = {2025}, author = {Deepika, and Thakur, A and Panghal, A and Pundir, R and Singh, C and Goyal, M and Namdeo, AG and Kumar, J}, title = {Crosstalk between copper, Alzheimer's disease, and melatonin.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {38}, number = {5}, pages = {1381-1420}, pmid = {40650773}, issn = {1572-8773}, mesh = {*Melatonin/metabolism ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Copper/metabolism ; Humans ; Animals ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Antioxidants ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that causes cognitive impairment and loss of neurons. According to the Alzheimer's Association's 2022 US report, the USA saw a 145% increase in AD-related fatalities from 2000 to 2020, with an estimated financial burden of these disorders surpassing $1 trillion annually. Its pathological features include neurofibrillary tangles and amyloid-beta (Aβ) plaques. Although there is presently no treatment that may stop the growth of AD, new clinical trials have suggested that anti-amyloid disease-modifying drugs may reduce the progression of the illness. According to a recent study, Copper (Cu) dysregulation plays a crucial role in AD pathogenesis by causing oxidative stress and encouraging the aggregation of Aβ. Meanwhile, melatonin, a neurohormone with strong neuroprotective, antioxidant, and Cu chelation qualities, has drawn an interest due to its possible use for AD treatment. This review thoroughly summarizes the most recent research, including in vivo, in vitro, and human studies, and also examines the complex relationships among AD, melatonin, and Cu toxicity. We observe how an excess of Cu aggravates AD pathogenesis and how the special qualities of melatonin can counteract these effects. Melatonin is a promising molecule having a dual approach to address pathogenesis of AD by chelating excess Cu and lowering oxidative stress. Comprehending the interplay between Cu dysregulation and the protective mechanisms of melatonin may result in innovative therapies, providing promises for enhanced management of AD.}, } @article {pmid40650273, year = {2025}, author = {Merighi, S and Fernandez, M and Nigro, M and Travagli, A and Caldon, F and Salati, S and Borea, PA and Cadossi, R and Varani, K and Gessi, S}, title = {PEMFs Restore Mitochondrial and CREB/BDNF Signaling in Oxidatively Stressed PC12 Cells Targeting Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40650273}, issn = {1422-0067}, support = {R/IGEA/Gessi/01/21//Igea Clinical Biophysics/ ; }, mesh = {Animals ; PC12 Cells ; Rats ; *Brain-Derived Neurotrophic Factor/metabolism ; *Mitochondria/metabolism/radiation effects/drug effects ; *Oxidative Stress/drug effects ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Signal Transduction/radiation effects ; Amyloid beta-Peptides/toxicity ; Hydrogen Peroxide/toxicity/pharmacology ; *Electromagnetic Fields ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Cell Survival/drug effects ; Phosphorylation ; }, abstract = {Alzheimer's disease (AD), the most prevalent form of neurodegenerative dementia, is characterized by progressive cognitive decline and neuronal loss. Despite advances in pharmacological treatments, current therapies remain limited in efficacy and often induce adverse effects. Increasing evidence highlights oxidative stress, mitochondrial dysfunction, and disrupted neurotrophic signaling as key contributors to AD pathogenesis. Pulsed electromagnetic fields (PEMFs) are emerging as a non-invasive, multifactorial approach with promising biological effects. In this study, we investigated the neuroprotective potential of PEMFs in NGF-differentiated PC12 cells exposed to hydrogen peroxide (H2O2) or amyloid-β peptide (Aβ), both of which model pathological features of AD. PEMF treatment significantly counteracted H2O2- and Aβ-induced cytotoxicity by restoring cell viability, reducing reactive oxygen species production, and improving catalase activity. Furthermore, PEMFs preserved the mitochondrial membrane potential and decreased caspase-3 activation and chromatin condensation. Mechanistically, PEMFs inhibited ERK phosphorylation and enhanced cAMP levels, CREB phosphorylation, and BDNF expression, pathways known to support neuronal survival and plasticity. In conclusion, these findings suggest that PEMFs modulate multiple stress response systems, promoting neuroprotection under oxidative and amyloidogenic conditions.}, } @article {pmid40650049, year = {2025}, author = {Yang, HM}, title = {Recent Advances in Antibody Therapy for Alzheimer's Disease: Focus on Bispecific Antibodies.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40650049}, issn = {1422-0067}, support = {RS-2025-02263992//Patient-Centered Clinical Research Coordinating Center/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/drug therapy/immunology/metabolism ; *Antibodies, Bispecific/therapeutic use/immunology ; Animals ; Blood-Brain Barrier/metabolism ; *Immunotherapy/methods ; Amyloid beta-Peptides/immunology/metabolism ; tau Proteins/immunology/metabolism ; }, abstract = {Alzheimer's disease (AD) impacts more than half a million people worldwide, with no cure available. The regulatory approval of three anti-amyloid monoclonal antibodies (mAbs), including aducanumab, lecanemab, and donanemab, has established immunotherapy as a therapeutic approach to modify disease progression. Its multifactorial pathology, which involves amyloid-β (Aβ) plaques, tau neurofibrillary tangles, neuroinflammation, and cerebrovascular dysfunction, limits the efficacy of single-target therapies. The restricted blood-brain barrier (BBB) penetration and amyloid-related imaging abnormalities (ARIA), together with small treatment effects, demonstrate the necessity for advanced biologic therapies. Protein engineering advancements have created bispecific antibodies that bind to pathological proteins (e.g., Aβ, tau) and BBB shuttle receptors to boost brain delivery and dual therapeutic effects. This review combines existing information about antibody-based therapy in AD by focusing on bispecific antibody formats and their preclinical and clinical development, as well as biomarker-based patient selection and upcoming combination strategies. The combination of rationally designed bispecific antibodies with fluid and imaging biomarkers could show potential for overcoming existing therapeutic challenges and delivering significant clinical advantages.}, } @article {pmid40650013, year = {2025}, author = {Russo, AP and Pastorello, Y and Dénes, L and Brînzaniuc, K and Krupinski, J and Slevin, M}, title = {The Inflammatory Nexus: Unraveling Shared Pathways and Promising Treatments in Alzheimer's Disease and Schizophrenia.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40650013}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology/therapy ; *Schizophrenia/metabolism/drug therapy/pathology/therapy ; Signal Transduction ; Animals ; *Inflammation/metabolism/pathology ; Biomarkers/metabolism ; Blood-Brain Barrier/metabolism ; Autophagy ; Receptor for Advanced Glycation End Products/metabolism ; Antipsychotic Agents/therapeutic use ; }, abstract = {Alzheimer's disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, blood-brain barrier (BBB) disruption, and cognitive impairment. We examine key signaling pathways, particularly spleen tyrosine kinase (SYK), the mechanistic (or mammalian) target of rapamycin (mTOR), and the S100 calcium-binding protein B (S100B)/receptor for advanced glycation end-products (RAGE) axis, that link glial activation, excitatory/inhibitory neurotransmitter imbalances, and impaired proteostasis across both disorders. Specific biomarkers such as S100B, matrix metalloproteinase 9 (MMP9), and soluble RAGE show promise for stratifying disease subtypes and predicting treatment response. Moreover, psychiatric symptoms frequently precede cognitive decline in both AD and schizophrenia, suggesting that mood and behavioral disturbances may serve as early diagnostic indicators. The roles of autophagic failure, cellular senescence, and impaired glymphatic clearance are also explored as contributors to chronic inflammation and neurodegeneration. Current treatments, including cholinesterase inhibitors and antipsychotics, primarily offer symptomatic relief, while emerging therapeutic approaches target upstream molecular drivers, such as mTOR inhibition and RAGE antagonism. Finally, we discuss the future potential of personalized medicine guided by genetic, neuroimaging, and biomarker profiles to optimize diagnosis and treatment strategies in both AD and schizophrenia. A greater understanding of the pathophysiological convergence between these disorders may pave the way for cross-diagnostic interventions and improved clinical outcomes.}, } @article {pmid40649980, year = {2025}, author = {Mishra, P and Esfahani, EK and Fernyhough, P and Albensi, BC}, title = {Estradiol Prevents Amyloid Beta-Induced Mitochondrial Dysfunction and Neurotoxicity in Alzheimer's Disease via AMPK-Dependent Suppression of NF-κB Signaling.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40649980}, issn = {1422-0067}, support = {R16 NS134540/NS/NINDS NIH HHS/United States ; 1R16NS134540-01/GF/NIH HHS/United States ; PJT-162144//CIHR/ ; }, mesh = {*Alzheimer Disease/metabolism/prevention & control ; *Amyloid beta-Peptides/pharmacology ; Mice, Inbred C57BL ; Animals ; Mice ; Cells, Cultured ; *Estradiol/pharmacology ; *Mitochondria/drug effects/metabolism ; *AMP-Activated Protein Kinases/metabolism ; *Signal Transduction/drug effects ; NF-kappa B/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Enzyme Activation ; Cell Survival/drug effects ; Electron Transport/drug effects ; Neuroinflammatory Diseases/chemically induced/metabolism ; }, abstract = {Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. In addition to its two major pathological hallmarks, extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), recent evidence highlights the critical roles of mitochondrial dysfunction and neuroinflammation in disease progression. Aβ impairs mitochondrial function, which, in part, can subsequently trigger inflammatory cascades, creating a vicious cycle of neuronal damage. Estrogen receptors (ERs) are widely expressed throughout the brain, and the sex hormone 17β-estradiol (E2) exerts neuroprotection through both anti-inflammatory and mitochondrial mechanisms. While E2 exhibits neuroprotective properties, its mechanisms against Aβ toxicity remain incompletely understood. In this study, we investigated the neuroprotective effects of E2 against Aβ-induced mitochondrial dysfunction and neuroinflammation in primary cortical neurons, with a particular focus on the role of AMP-activated protein kinase (AMPK). We found that E2 treatment significantly increased phosphorylated AMPK and upregulated the expression of mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α), leading to improved mitochondrial respiration. In contrast, Aβ suppressed AMPK and PGC-1α signaling, impaired mitochondrial function, activated the pro-inflammatory nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and reduced neuronal viability. E2 pretreatment also rescued Aβ-induced mitochondrial dysfunction, suppressed NF-κB activation, and, importantly, prevented the decline in neuronal viability. However, the pharmacological inhibition of AMPK using Compound C (CC) abolished these protective effects, resulting in mitochondrial collapse, elevated inflammation, and cell death, highlighting AMPK's critical role in mediating E2's actions. Interestingly, while NF-κB inhibition using BAY 11-7082 partially restored mitochondrial respiration, it failed to prevent Aβ-induced cytotoxicity, suggesting that E2's full neuroprotective effects rely on broader AMPK-dependent mechanisms beyond NF-κB suppression alone. Together, these findings establish AMPK as a key mediator of E2's protective effects against Aβ-driven mitochondrial dysfunction and neuroinflammation, providing new insights into estrogen-based therapeutic strategies for AD.}, } @article {pmid40649809, year = {2025}, author = {Yoon, SM and Lee, YW and Kim, MJ and Shin, JJ and Bae, GW and Park, S}, title = {Neuroprotective Mechanisms of Porcine Brain Enzyme Hydrolysate in Memory Impairment: Multi-Target Strategy Against Amyloid-β-Induced Neurotoxicity.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40649809}, issn = {1422-0067}, support = {RS-2023-00208567//Korea National Research Foundation/ ; }, mesh = {Animals ; *Amyloid beta-Peptides/toxicity/metabolism ; *Neuroprotective Agents/pharmacology ; *Brain/enzymology/metabolism ; Swine ; Humans ; *Memory Disorders/drug therapy/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; *Protein Hydrolysates/pharmacology ; Neurons/drug effects/metabolism ; Cell Survival/drug effects ; Apoptosis/drug effects ; Brain-Derived Neurotrophic Factor/metabolism ; Cell Line, Tumor ; Peptide Fragments/toxicity ; }, abstract = {This study investigated the potential neuroprotective mechanisms of porcine brain enzyme hydrolysate (PBEH) against Alzheimer's disease pathology using differentiated SH-SY5Y cells. Differentiated neuronal cells were treated with 40 μM amyloid-β(1-42; Aβ) to induce neurotoxicity, followed by PBEH treatment (12.5-400 μg/mL), Com-A (peptide-based neuroprotective supplement; 200 μg/mL) treatment, and Com-B (herbal extract known for improving memory function; 100 μg/mL) treatment. Key assessments included cell viability, Aβ aggregation in adding 10 μM Aβ, amyloidogenic proteins (APP, BACE), synaptic markers (BDNF, ERK), apoptotic markers (BAX/BCL-2, caspase-3), oxidative stress (reactive oxygen species (ROS)), cholinergic function (ChAT, AChE), MAPK signaling (JNK, p38), and neuroinflammation (IL-1β). PBEH contained high concentrations of amino acids, including L-lysine (32.3 mg/g), L-leucine (42.4 mg/g), L-phenylalanine (30.0 mg/g) and the PSIS peptide (86.9 μg/g). Treatment up to 400 μg/mL showed no cytotoxicity and had cognitive protection effects up to 152% under Aβ stress (p < 0.05). PBEH significantly attenuated Aβ aggregation, decreased APP (28%) and BACE (51%) expression, enhanced synaptic function through increased BDNF, and restored ERK phosphorylation (p < 0.05). Anti-apoptotic effects included a 76% reduction in the BAX/BCL-2 ratio, a 47% decrease in caspase-3, and a 56% reduction in ROS levels. Cholinergic function showed restoration via increased ChAT activity (p < 0.01) and decreased AChE activity (p < 0.05). PBEH reduced IL-1β levels by 70% and suppressed JNK/p38 phosphorylation (p < 0.05). While Com-A enhanced BDNF and Com-B showed anti-inflammatory effects, PBEH demonstrated activity across multiple pathway markers. In conclusion, these findings suggest that PBEH may enable neuronal preservation through multi-pathway modulation, establishing foundational evidence for further mechanistic investigation in cognitive enhancement applications.}, } @article {pmid40649231, year = {2025}, author = {Calva, J and Cuenca, MB and León, A and Benítez, Á}, title = {Chemical Composition, Acetylcholinesterase-Inhibitory Potential and Antioxidant Activity of Essential Oils from Three Populations of Parthenium hysterophorus L. in Ecuador.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {13}, pages = {}, pmid = {40649231}, issn = {1420-3049}, support = {VIN-POA-56//Universidad Técnica Particular de Loja/ ; }, mesh = {*Oils, Volatile/chemistry/pharmacology ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Ecuador ; *Antioxidants/chemistry/pharmacology ; *Acetylcholinesterase/chemistry/metabolism ; Plant Leaves/chemistry ; Sesquiterpenes/chemistry ; Gas Chromatography-Mass Spectrometry ; *Asteraceae/chemistry ; Sesquiterpenes, Germacrane/chemistry ; Flowers/chemistry ; Alkenes/chemistry ; Parthenium hysterophorus ; }, abstract = {In this study, we analyzed the essential oils (EOs) extracted by steam distillation from the leaves and flowers of Parthenium hysterophorus L., grown in three different locations in southern Ecuador: Espíndola (ESP), Loja (LOJ) and Quilanga (QUI). Approximately 97.45%, 98.27% and 95.99% of the oil constituents were identified using gas chromatography-mass spectrometry (GC-MS) and gas chromatography-flame ionization detection (GC-FID). Sesquiterpene hydrocarbons were predominant in the EOs. The most representative constituents of the sample from ESP were germacrene D (35.08%), myrcene (11.32%), (E)-β-ocimene (10.21%), (E)-caryophyllene (7.90%), germacra-4(15),5,10(14)-trien-1-α-ol (5.18%) and (E, E)-α-farnesene (4.99%), with an AChE IC50 of 14.78 and with 16.38 and 93.16 µg/mL from ABTS and DPPH, respectively. The EOs from LOJ were characterized by the abundant presence of germacrene D (28.30%), myrcene (13.95%), (E)-β-ocimene (10.51%) and isolongifolan-7-α-ol (8.26%), with an AChE IC50 of 16.65 and with 36.18 and 158.43 µg/mL from ABTS and DPPH, respectively. Finally, the EOs from QUI contained germacrene D (32.20%), myrcene (13.36%), (E)-β-ocimene (8.54%), (E, E)-α-farnesene (6.77%), germacra-4(15),5,10(14)-trien-1-α-ol (5.69%) and (E)-caryophyllene (5.37%), with an AChE IC50 of 10.69 and with 14.50 and 92.98 µg/mL from ABTS and DPPH, respectively. This study identifies chemotypic variation in P. hysterophorus collected from different locations and, for the first time, the AChE inhibitor was evaluated. These findings provide a scientific basis for the clinical application of P. hysterophorus EOs in the future treatment of Alzheimer's disease.}, } @article {pmid40648018, year = {2025}, author = {Ferreira, FDS and de Mattos, JLA and da Silva, PHF and da Costa, CA and Ognibene, DT and Resende, AC and de Bem, GF}, title = {Antioxidant, Anti-Inflammatory, and Antiapoptotic Effects of Euterpe oleracea Mart. (Açaí) in Improving Cognition Deficits: Potential Therapeutic Implications for Alzheimer's Disease.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {13}, pages = {}, pmid = {40648018}, issn = {2223-7747}, abstract = {Euterpe oleracea Martius, also popularly known as açaí palm, is a palm tree of the Aracaceae family widely found in the Amazon region. Traditional plant use reports indicate the beneficial effects of açaí juice on fever, pain, and flu. Moreover, many studies have demonstrated the pharmacological potential of açaí, mainly the pulp and seed of the fruit, due to its chemical composition, which significantly consists of polyphenols. In recent years, there has been a growing interest in investigating the neuroprotective effects of açaí, with the potential for the prevention and treatment of neurodegenerative diseases, such as Alzheimer's disease, mainly due to the increasing aging of the population that has contributed to the increase in the number of individuals affected by this disease that has no cure. Therefore, this review aims to evaluate the potential role of açaí fruit in preventing or treating cognitive deficits, highlighting its potential in Alzheimer's disease therapy. Preclinical in vivo and in vitro pharmacological studies were utilized to investigate the learning and memory effects of the pulp and seed of the açaí fruit, focusing on antioxidant, anti-inflammatory, antiapoptotic, and autophagy restoration actions.}, } @article {pmid40647943, year = {2025}, author = {Lin, GD and Vishwakarma, P and Smith, PN and Li, RW}, title = {The Occurrence and Bioactivities of Amaryllidaceae Alkaloids from Plants: A Taxonomy-Guided Genera-Wide Review.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {13}, pages = {}, pmid = {40647943}, issn = {2223-7747}, abstract = {The distribution of Amaryllidaceae alkaloids, with a focus on their chemodiversity, has been reported previously, but not at a genera-wide diversity level. This review provides a comprehensive survey of the occurrence of Amaryllidaceae alkaloids across the genera of the Amaryllidaceae family. This survey is taxonomically guided by the National Center for Biotechnology Information (NCBI) Taxonomy Browser, with targeted keyword searches conducted in the Chemical Abstracts Service (CAS) SciFinder-n and PubMed. The family Amaryllidaceae comprises over 1214 species across three subfamilies: Agapanthoideae (1 genus, 5 species), Allioideae (3 genera plus 11 subgenera, 617 species), and Amaryllidoideae (58 genera plus 13 subgenera, 592 species). Amaryllidaceae alkaloids have been identified exclusively in 36 of the 58 genera and 6 of the 13 subgenera within the Amaryllidoideae subfamily. To date, more than 600 Amaryllidaceae alkaloids have been isolated, predominantly from this subfamily-hence the designation "Amaryllidaceae alkaloids". These alkaloids display a wide spectrum of biological activities, including acetylcholinesterase inhibition, anti-inflammatory, antioxidant, antimicrobial, antidiabetic, and anticancer effects. A notable example is galanthamine (also known as galantamine), an FDA-approved drug marketed under the brand names Reminyl™ (Janssen Research Foundation, Beerse, Belgium, 2001) and Razadyne™ (Johnson & Johnson Pharmaceutical Research, New Brunswick, NJ, USA, 2004) for the treatment of mild to moderate Alzheimer's disease, due to its potent acetylcholinesterase-inhibitory activity. Galanthamine has been isolated from species belonging to the genera Cyrtanthus, Galanthus, Leucojum, Lycoris, Narcissus, Ungernia, Chlidanthus, Crinum, Eucharis, Eustephia, Pancratium, and Phaedranassa. Lycorine is another widely distributed alkaloid found across multiple genera, and it has been extensively studied for its diverse bioactivities. Given the remarkable chemical diversity and bioactivity of Amaryllidaceae alkaloids, along with the many underexplored genera and species, further research into Amaryllidaceae species and their alkaloids is strongly warranted to support the discovery and development of novel therapeutic agents.}, } @article {pmid40647320, year = {2025}, author = {Varga, P and Lehoczki, A and Fekete, M and Jarecsny, T and Kryczyk-Poprawa, A and Zábó, V and Major, D and Fazekas-Pongor, V and Csípő, T and Varga, JT}, title = {The Role of Magnesium in Depression, Migraine, Alzheimer's Disease, and Cognitive Health: A Comprehensive Review.}, journal = {Nutrients}, volume = {17}, number = {13}, pages = {}, pmid = {40647320}, issn = {2072-6643}, support = {RRF-2.3.1-21-2022-00003//National Cardiovascular Laboratory Program/ ; TKP2021-NKTA-47//Ministry of Innovation and Technology of Hungary/ ; }, mesh = {Humans ; *Alzheimer Disease/physiopathology ; *Magnesium/therapeutic use ; *Migraine Disorders/physiopathology/drug therapy ; *Depression/etiology/drug therapy ; *Cognition/drug effects ; Magnesium Deficiency/complications ; Hypothalamo-Hypophyseal System ; }, abstract = {Magnesium is an essential mineral involved in hundreds of biochemical reactions, with particular relevance to maintaining neural homeostasis, modulating neurotransmitter systems, and regulating inflammatory and oxidative stress mechanisms. This comprehensive review aims to evaluate the potential role of magnesium in the pathophysiology and treatment of three prevalent neurological and psychiatric disorders-depression, migraine, and Alzheimer's disease-as well as its broader implications for cognitive health. Current research suggests that magnesium deficiency is associated with the development of depression, as magnesium influences glutamatergic and GABAergic neurotransmission, as well as the activity of the hypothalamic-pituitary-adrenal (HPA) axis, both of which play critical roles in stress responses and mood regulation. Additionally, magnesium's anti-inflammatory properties may contribute to the alleviation of depressive symptoms. In the context of migraine's pathophysiology, magnesium plays a role in regulating cerebral vascular tone, modulating the trigeminovascular system, and reducing neuronal hyperexcitability, which may explain the observed correlation between magnesium levels and the incidence of migraines. Regarding Alzheimer's disease, preclinical and epidemiological studies suggest that magnesium may contribute to modulating neurodegenerative processes and preserving cognitive function; however, due to the heterogeneity of the current findings, further longitudinal and interventional studies are necessary to determine its precise clinical relevance. This review aims to enhance the understanding of the relationship between magnesium and these disorders through a narrative review of relevant clinical studies. The findings may provide insights into the potential therapeutic applications of magnesium and guide the future directions of the research into the prevention and treatment of depression, migraine, and Alzheimer's disease and overall cognitive health.}, } @article {pmid40646945, year = {2025}, author = {Davì, F and Iaconis, A and Cordaro, M and Di Paola, R and Fusco, R}, title = {Nutraceutical Strategies for Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {14}, number = {13}, pages = {}, pmid = {40646945}, issn = {2304-8158}, abstract = {In neurons, mitochondria generate energy through ATP production, thereby sustaining the high energy demands of the central nervous system (CNS). Mitochondrial dysfunction within the CNS was implicated in the pathogenesis and progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, often involving altered mitochondrial dynamics like fragmentation and functional impairment. Accordingly, mitochondrial targeting represents an alternative therapeutic strategy for the treatment of these disorders. Current standard drug treatments present limitations due to adverse effects associated with their chronic use. Therefore, in recent years, nutraceuticals, natural compounds exhibiting diverse biological activities, have garnered significant attention for their potential to treat these diseases. It has been shown that these compounds represent safe and easily available sources for the development of innovative therapeutics, and by modulating mitochondrial function, nutraceuticals offer a promising approach to address neurodegenerative pathologies. We referred to approximately 200 articles published between 2020 and 2025, identified through a focused search across PubMed, Google Scholar, and Scopus using keywords such as "nutraceutical," "mitochondrial dysfunction," and "neurodegenerative diseases. The purpose of this review is to examine how mitochondrial dysfunction contributes to the genesis and progression of neurodegenerative diseases. Also, we discuss recent advances in mitochondrial targeting using nutraceuticals, focusing on their mechanisms of action related to mitochondrial biogenesis, fusion, fission, bioenergetics, oxidative stress, calcium homeostasis, membrane potential, and mitochondrial DNA stability.}, } @article {pmid40646316, year = {2025}, author = {Phan, DTA and Le, HP and Tran, TH and Van Le, U and Van Le, M and Ly, TH}, title = {Ameliorative role of Polyscias fruticosa leaf extract in aluminum chloride-induced neurotoxicity flies possibly mediated by N-methyl-D-aspartate receptor antagonistic and anticholinesterase active compounds.}, journal = {Journal of natural medicines}, volume = {79}, number = {5}, pages = {1167-1187}, pmid = {40646316}, issn = {1861-0293}, mesh = {Animals ; *Plant Extracts/pharmacology/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemistry ; Aluminum Chloride/toxicity ; Plant Leaves/chemistry ; Drosophila melanogaster/drug effects ; *Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; *Fabaceae/chemistry ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism ; Oxidative Stress/drug effects ; }, abstract = {Polyscias fruticosa leaves have been used in traditional medicine to aid in the therapy of brain and nerve-related disorders, including dementia. However, the evidences for the effects and mechanisms of P. fruticosa leaf extract (PFLE) and its constituents in improving dementia remain unclear. This study aims to evaluate the ameliorative effect of PFLE in aluminum chloride-induced neurotoxicity Drosophila melanogaster model. Simultaneously, the dementia-improving mechanisms of PFLE's compounds were explored by computational pharmacological analysis. Results showed that D. melanogaster exposed to 1.0, 2.0, and 4.0 mg/mL PFLE or 0.1 mg/mL donepezil hydrochloride had significant improvements in lifespan, memory, motor behavior, and oxidative stress markers, including decreased malondialdehyde level and increased glutathione level in flies' homogenates. Also, PFLE had acetylcholinesterase inhibitory ability with an IC50 value of 266.10 µg/mL. Applying the UHPLC-Q-TOF-MS/MS technique, 36 compounds were identified in the PFLE. Among these, 25 compounds, including acid amines, flavonoids, saponins, choline, piperine, and vitamin B1, have been demonstrated potential for supporting the treatment of Alzheimer's disease (AD). Interestingly, molecular docking study indicated that many of the compounds are agents of prominent targets in dementia treatment including N-methyl-D-aspartate (NMDA) receptor and cholinesterase, in which polyscioside A-E are the main components of the PFLE that may be responsible for the NMDA receptor antagonistic and anticholinesterase activities. These compounds have favorable physiochemical properties and drug-likeliness. This study suggested the potential of the PFLE and its compounds in the prophylactic and treatment of neurodegenerative pathologies, including AD, and laid the foundation for further studies.}, } @article {pmid40646278, year = {2025}, author = {Knezovic, A and Hosch, M and Hamann, CS and Popp, S and Ortega, G and Osmanovic-Barilar, J and Grünblatt, E and Monoranu, C and Riederer, P and Salkovic-Petrisic, M and Schmitt-Böhrer, A}, title = {Approaching therapy of Alzheimer's disease via the antidiabetic drug liraglutide-a study with streptozotocin intracerebroventricularly treated Wistar rats.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {10}, pages = {1587-1608}, pmid = {40646278}, issn = {1435-1463}, support = {A/00/200017//German Academic Exchange Service/ ; }, mesh = {Animals ; *Liraglutide/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; *Streptozocin/administration & dosage ; Rats, Wistar ; Male ; *Hypoglycemic Agents/pharmacology/administration & dosage ; Rats ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Maze Learning/drug effects ; Avoidance Learning/drug effects ; Injections, Intraventricular ; Neurogenesis/drug effects ; }, abstract = {Risk factors for developing dementia include type 2 diabetes and obesity. Streptozotocin (STZ) intracerebroventricularly (icv) treated rats are a well-accepted animal model for the sporadic Alzheimer`s disease (sAD). STZ-icv treatment results in an insulin-resistant brain state, cognitive deficits, and reduced hippocampal adult neurogenesis (AN). As the antidiabetic drug liraglutide (LIR) has been shown to improve AN, and spatial learning in an AD mouse model, we have investigated the effects of LIR treatment on spatial and fear-motivated learning, AN, and gene expression profiles in STZ-icv treated rats. Male Wistar rats were injected icv with STZ (f.c. 3 mg/kg) or vehicle. Two months later, four weeks of subcutaneous treatment with LIR (0.3 mg/kg) began. Cognitive abilities were assessed with the Morris water maze (MWM) and passive avoidance (PA) test. We performed quantitative immunohistochemistry to evaluate AN, and quantitative real-time PCR to determine the expression levels of genes involved in insulin signaling, glucose uptake, and neuroinflammation. STZ-icv rats showed significantly impaired spatial learning performance in the MWM and fear-motivated memory deficits in the PA test accompanied by reduced AN, downregulated insulin system- and glucose metabolism-related genes in the hippocampus and prefrontal cortex. LIR treatment did not reverse these cognitive deficits of STZ-icv rats in the MWM, and did even worsen PA performance. However, LIR partially restored dysregulated gene expression, however, additionally stimulated neuroinflammation. Refined experimental designs, e.g., refined dosing, should help to further clarify the therapeutic potential of LIR in the future.}, } @article {pmid40645537, year = {2025}, author = {Bashir, DJ and Bhat, KA and Bashir, M}, title = {Deciphering Alzheimer's disease: Molecular mechanisms, preclinical models and strategies to overcome Blood-Brain-Barrier.}, journal = {Brain research}, volume = {1863}, number = {}, pages = {149828}, doi = {10.1016/j.brainres.2025.149828}, pmid = {40645537}, issn = {1872-6240}, mesh = {*Alzheimer Disease/metabolism/physiopathology/pathology ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; Animals ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; }, abstract = {Neurodegenerative diseases involve a spectrum of diseases, with Alzheimer's being the most prevalent one. Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory loss, and synaptic dysfunction. Despite extensive research, effective therapeutic interventions remain limited, largely due to the complex molecular underpinnings of the disease and the challenge posed by the blood-brain barrier (BBB). This review explores the critical molecular mechanisms implicated in AD pathogenesis, i.e. disruption of cholinergic neurotransmission, aggregation of β-amyloid fragments, tau protein phosphorylation, and oxidative stress. As the establishment of effective treatments remains a major research goal, the present review further gives an insight into the various preclinical in vivo models like chemical, lesion-induced, beta-amyloid, streptozotocin infusion, and transgenic models that have been instrumental in advancing our understanding of disease progression and testing potential treatments. A significant focus is given to emerging strategies designed to circumvent or modulate the BBB, including nanoparticle-based delivery systems, receptor-mediated transport, and focused ultrasound techniques. By integrating insights from molecular biology, experimental modeling, and drug delivery science, this work aims to highlight current challenges and propose comprehensive strategies for improving the diagnosis and treatment of Alzheimer's disease.}, } @article {pmid40645230, year = {2025}, author = {Bayer, TA and DeVone, F and Singh, M and Leeder, C and Garbin, A and Halladay, C and McConeghy, K and Gravenstein, S and Rudolph, JL}, title = {Change in Distressed Behavior in Dementia During the COVID-19 Pandemic in Veterans Affairs Community Living Centers.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {9}, pages = {105752}, doi = {10.1016/j.jamda.2025.105752}, pmid = {40645230}, issn = {1538-9375}, mesh = {Humans ; *COVID-19/epidemiology/psychology ; Male ; Female ; Retrospective Studies ; United States/epidemiology ; Aged ; *Veterans/psychology ; *Dementia/psychology ; United States Department of Veterans Affairs ; Aged, 80 and over ; SARS-CoV-2 ; Pandemics ; }, abstract = {OBJECTIVES: To compare distressed behavior in Veterans with Alzheimer disease and related dementias (ADRD) residing in Veterans Affairs (VA) Community Living Centers (CLCs) during the COVID-19 pandemic to previous years. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Veterans with ADRD and without baseline distressed behavior residing in CLCs in March 2020 (Early-COVID) and March 2018 or March 2019 (Pre-COVID). METHODS: We measured distressed behavior with the Distressed Behaviors in Dementia Indicator. Using a Cox regression, we compared the 180-day hazard of distressed behavior in the Early-COVID group to that in the Pre-COVID group. RESULTS: Of 4383 sampled Veterans, 1190 (27%) had recently taken an antipsychotic medication. In the Pre-COVID (n = 2795) and Early-COVID groups (n = 1588), new distressed behavior occurred in 629 (22.5%) and 313 (19.7%) Veterans, respectively. The adjusted hazard ratio (HR) of new distressed behavior was 0.82 (95% CI 0.71-0.95) for Early-COVID compared with Pre-COVID. Antipsychotic medication was associated with new distressed behavior (HR 1.61, 95% CI 1.40-1.86). CONCLUSIONS AND IMPLICATIONS: New distressed behavior decreased during the first 6 months of the COVID-19 pandemic compared with the previous 2 years. The observed association between antipsychotic medication use and distressed behavior may reflect clinical recognition and treatment of a predisposition toward distressed behavior. Recorded changes in distressed behavior in Veterans with dementia residing in CLCs opposed the trend of decreased well-being in residents of non-VA nursing homes, but changes in resident assessment fidelity during the Early-COVID period could have confounded the study.}, } @article {pmid40644887, year = {2025}, author = {Ghorbian, M and Ghorbian, S}, title = {The potential of machine learning to personalized medicine in Neurogenetics: Current trends and future directions.}, journal = {Computers in biology and medicine}, volume = {196}, number = {Pt A}, pages = {110756}, doi = {10.1016/j.compbiomed.2025.110756}, pmid = {40644887}, issn = {1879-0534}, mesh = {Humans ; *Precision Medicine/methods/trends ; *Machine Learning ; *Nervous System Diseases/genetics/diagnosis ; }, abstract = {Neurogenetic disorders (NeD) are a group of neurological conditions resulting from inherited genetic defects. By affecting the normal functioning of the nervous system, these diseases lead to serious problems in movement, cognition, and other body functions. In recent years, machine learning (ML) approaches have proven highly effective, enabling the analysis and processing of vast amounts of medical data. By analyzing genetic data, medical imaging, and other clinical data, these techniques can contribute to early diagnosis and more effective treatment of NeD. However, using these approaches is challenged by issues including data variability, model explainability, and the requirement for interdisciplinary collaboration. This paper investigates the impact of ML on healthcare diagnosis and care of common NeD, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Multiple Sclerosis disease (MSD). The purpose of this research is to determine the opportunities and challenges of using these techniques in the field of neurogenetic medicine. Our findings show that using ML can increase the detection accuracy by 85 % and reduce the detection time by 60 %. Additionally, the use of these techniques in predicting patient prognosis has been 70 % more accurate than traditional methods. Ultimately, this research will enable medical professionals and researchers to leverage ML approaches in advancing the diagnostic and therapeutic processes of NeD by identifying the opportunities and challenges.}, } @article {pmid40644302, year = {2025}, author = {Stephenson, RA and Sepulveda, J and Johnson, KR and Lita, A and Gopalakrishnan, J and Acri, DJ and Beilina, A and Cheng, L and Yang, LG and Root, JT and Ward, ME and Combs, C and Skarnes, WC and Cookson, MR and Shih, HY and Larion, M and Rebeck, GW and Narayan, PS}, title = {Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4.}, journal = {Cell reports}, volume = {44}, number = {7}, pages = {115961}, pmid = {40644302}, issn = {2211-1247}, support = {F99 NS134164/NS/NINDS NIH HHS/United States ; R01 NS100704/NS/NINDS NIH HHS/United States ; ZIA DK075158/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Microglia/metabolism/pathology ; *Triglycerides/metabolism ; Animals ; Humans ; *Apolipoprotein E4/metabolism/genetics ; *Inflammation/metabolism/pathology ; Mice, Transgenic ; Mice ; Phenotype ; Lipid Droplets/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Phagocytosis ; Alzheimer Disease/metabolism/pathology/genetics ; Lipopolysaccharides/pharmacology ; Cytokines/metabolism ; }, abstract = {Changes to cellular lipids accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer's disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in the cell state. In fact, both triglyceride biosynthesis and catabolism are critical for the activation-induced transcription and secretion of inflammatory cytokines and chemokines, as well as changes in phagocytosis. In microglia harboring the Alzheimer's disease risk APOE4 genotype, inhibiting triglyceride biosynthesis attenuates disease-associated transcriptional states. Triglyceride biosynthesis inhibition also rescues microglial surveillance defects observed in slices from APOE4 humanized transgenic mice. Together, our findings establish that modulating triglyceride metabolism can tune microglial immune activity in response to extrinsic activation and in APOE4-associated disease.}, } @article {pmid40643478, year = {2025}, author = {Yadav, Y and Anwar, M and Sharma, H and Jain, S and Sharma, U and Haldar, P and Dey, AB and Dey, S}, title = {Anti-Inflammatory Peptide Prevents Aβ25-35-Induced Inflammation in Rats via Lipoxygenase Inhibition.}, journal = {Cells}, volume = {14}, number = {13}, pages = {}, pmid = {40643478}, issn = {2073-4409}, mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; *Peptide Fragments/toxicity ; Rats ; Male ; *Lipoxygenase Inhibitors/pharmacology/therapeutic use ; Alzheimer Disease/drug therapy/pathology ; Hippocampus/drug effects/pathology ; *Inflammation/drug therapy/pathology/chemically induced ; *Lipoxygenase/metabolism ; Rats, Sprague-Dawley ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Humans ; }, abstract = {Neuroinflammation, triggered by lipoxygenase (LOX), contributes to Alzheimer's disease (AD) progression. Overexpression of LOX-5 in patients with AD serum highlights its role. This study assessed the efficacy of the LOX-inhibitor-peptide YWCS in an AD rat model induced by Aβ25-35 injection. Cognitive tests, magnetic resonance imaging (MRI) scans, and molecular analyses were conducted. YWCS treatment significantly improved cognitive function, as evidenced by improved performance in the open field, novel object recognition, elevated plus maze, and Morris water maze tests. MRI scans revealed hippocampal shrinkage in AD rats and no changes were observed from YWCS treatment. Molecular analysis revealed altered expression of LOX-5, LOX-12, Aβ, γ-secretase components, p-Tau[181], Akt, p-Akt, and p53 in AD rats. Immunofluorescence staining confirmed increased expression of LOX, Aβ, and p-Tau[181] in the hippocampus of AD rats, which was reduced by YWCS treatment. Serum LOX levels were elevated in AD rats and significantly decreased after YWCS treatment, aligning with previous findings in human AD patients and AD cell models. YWCS offered improvements in behavioral and inflammatory marker regulation and also prevented progression of the disease, as shown by MRI results. These results suggest that YWCS, by targeting LOX, has the potential to be a promising therapeutic agent for AD.}, } @article {pmid40642909, year = {2025}, author = {Tan, Y and Yang, D and Ke, Z and Hu, Z and Song, W and Tang, L and Zhou, Z and Mo, Y and Huang, L and Xu, Y}, title = {The Effect of APOE ε4 Allele on Dynamic Local Spontaneous Brain Activity and Functional Integration in Alzheimer's Disease.}, journal = {Human brain mapping}, volume = {46}, number = {10}, pages = {e70269}, pmid = {40642909}, issn = {1097-0193}, support = {82130036//National Natural Science Foundation of China/ ; ZDXK202216//Jiangsu Province Key Medical Discipline/ ; 2022ZD0211800//STI 2030 - Major Projects/ ; }, mesh = {Humans ; *Alzheimer Disease/physiopathology/genetics/diagnostic imaging/blood ; *Apolipoprotein E4/genetics ; Male ; Female ; Aged ; Magnetic Resonance Imaging ; Middle Aged ; Amyloid beta-Peptides/blood ; Alleles ; Aged, 80 and over ; *Brain/physiopathology/diagnostic imaging ; }, abstract = {The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for sporadic Alzheimer's disease (AD), yet its mechanisms in AD pathology and cognitive decline remain unclear. Using a sliding-time window approach to directly quantify the instantaneous fluctuations of various local metrics based on continuous time series and calculate voxel-wise concordance of these metrics, we explored the impact of APOE ε4 on dynamic local brain activity and functional integration in AD, and its interrelations with plasma biomarkers and cognition. Results showed that APOE ε4 widely affected dALFF, dReHo, dGSCorr, and voxel-wise concordance. For AD patients, APOE ε4 carriers uniquely exhibited correlations between dALFF in the right angular gyrus/supramarginal gyrus and MoCA scores and orientation function, and between voxel-wise concordance in the right caudate nucleus (CAU) and general cognition, attention, language function, orientation function, plasma Aβ42. Critically, APOE ε4-related altered voxel-wise concordance in the right CAU mediated the relationship between plasma Aβ and language cognition in AD. Moreover, the combined model incorporating dynamic metrics, plasma AD biomarkers, and demographic data effectively distinguished AD from NC (AUC = 0.94, sensitivity = 87.69%, specificity = 86.84%). In conclusion, the APOE ε4 allele might play a pivotal role in modulating brain dynamic functional activities in AD, which may contribute to the association between Aβ pathology and cognitive decline. Our findings may provide imaging markers and targets for the diagnosis and treatment of AD.}, } @article {pmid40642529, year = {2025}, author = {Lizcano, F and Sanabria, D and Aviles, E}, title = {Hormonal modulation, mitochondria and Alzheimer's prevention: the role of GLP-1 agonists and estrogens.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1622186}, pmid = {40642529}, issn = {2296-889X}, abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide, disproportionately affecting women and lacking effective disease-modifying therapies. While traditional approaches have focused on amyloid β (Aβ) plaques and tau pathology, emerging evidence highlights the role of metabolic dysfunction, mitochondrial impairment, and hormonal signaling in the pathogenesis of AD. Estrogens exert neuroprotective effects by modulating synaptic plasticity, enhancing mitochondrial bioenergetics, and reducing oxidative stress and inflammation. Similarly, glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for the treatment of type 2 diabetes, have demonstrated promising cognitive benefits, potentially mediated through improved insulin signaling, neuronal survival, and reduced β-amyloid (Aβ) and tau burden. This review explores the converging mechanisms through which estrogens and GLP-1RAs may act synergistically to prevent or delay the onset of AD. We examine the influence of sex differences in mitochondrial dynamics, estrogen receptor distribution, and GLP-1 signaling pathways, particularly within central nervous system regions implicated in AD. Preclinical studies using GLP-1-estrogen conjugates have shown enhanced metabolic and neuroprotective outcomes, accompanied by reduced systemic hormonal exposure, suggesting a viable therapeutic strategy. As the global prevalence of AD continues to rise, especially among postmenopausal women, dual agonism targeting estrogen and GLP-1 receptors may represent a novel, physiologically informed approach to prevention and intervention. Ongoing clinical trials and future research must consider sex-specific factors, receptor polymorphisms, and brain-region selectivity to optimize the translational potential of this combined strategy.}, } @article {pmid40642320, year = {2025}, author = {}, title = {Correction to "The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non-carriers with mild cognitive impairment due to Alzheimer's disease".}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70131}, doi = {10.1002/trc2.70131}, pmid = {40642320}, issn = {2352-8737}, abstract = {[This corrects the article DOI: 10.1002/trc2.70004.].}, } @article {pmid40642087, year = {2025}, author = {Noor, F and Aslam, S and Piras, IS and Tremblay, C and Beach, TG and Serrano, GE}, title = {Integrative bioinformatics and machine learning approaches reveal oxidative stress and glucose metabolism related genes as therapeutic targets and drug candidates in Alzheimer's disease.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1572468}, pmid = {40642087}, issn = {1664-3224}, mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/drug therapy ; *Oxidative Stress/genetics ; *Machine Learning ; *Glucose/metabolism ; *Computational Biology/methods ; Molecular Docking Simulation ; Gene Regulatory Networks ; Gene Expression Profiling ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, has treatments that slow but do not stop cognitive decline. Additional treatments are based on its pathogenic mechanisms are needed. Evidence has long highlighted oxidative stress and impaired glucose metabolism as crucial factors in AD pathogenesis. Therefore, in this study we aimed to find key AD pathogenic pathways combining genes involved in oxidative stress and glucose metabolism as well as potential small-molecule therapeutic agents. METHODS: Using autopsy brain RNA sequencing data (GSE125583) derived from the Arizona Study of Aging and Brain and Body Donation Program, AD-related genes were identified via differential gene expression, pathway and coexpression analysis. Oxidative stress and glucose metabolism genes were correlated to pinpoint module genes. GSE173955 was used an independent dataset was used for validation, conducting molecular docking, assessing hub genes for AD, and integrating machine learning approaches. RESULTS: We identified 13,982 differentially expressed genes (DEGs) in AD patients. Through WGCNA coexpression analysis, 1,068 genes were linked to AD-specific modules. Pearson's correlation analysis highlighted 99 genes involved in oxidative stress and glucose metabolism. Overlap analysis of DEGs, module genes, and these metabolic genes revealed 21 key overlapping targets. PPI network and receiving operating curve (ROC) curve analyses then identified AKT1 and PPARGC1A as diagnostic hub genes for AD. Machine learning-based virtual screening of small molecules identified various inhibitors and enhancers with drug-like potential targeting AKT1 (upregulated) and PPARGC1A (downregulated), respectively. Among others, the Random Forest model was the most reliable for predicting molecular activity. Molecular docking further validated the binding affinities of these small molecules (inhibitors/enhancers) to AKT1 and PPARGC1A. CONCLUSION: This study identified AKT1 and PPARGC1A as potential therapeutic targets in AD. We discovered drug candidates with strong binding affinities, offering new avenues for effective AD treatment strategies.}, } @article {pmid40641595, year = {2025}, author = {Delvenne, A and Gobom, J and Reus, LM and Dobricic, V and Ten Kate, M and Schindler, SE and Ramakers, I and Tijms, BM and Vandenberghe, R and Schaeverbeke, J and Martinez-Lage, P and Tainta, M and Teunissen, CE and Popp, J and Peyratout, G and Tsolaki, M and Freund-Levi, Y and Lovestone, S and Streffer, J and Barkhof, F and Bertram, L and Blennow, K and Zetterberg, H and Visser, PJ and Vos, SJB}, title = {Cerebrospinal fluid proteomic profiling of cognitively unimpaired individuals with suspected non-Alzheimer's disease pathophysiology.}, journal = {Brain communications}, volume = {7}, number = {4}, pages = {fcaf253}, pmid = {40641595}, issn = {2632-1297}, support = {K23 AG053426/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; }, abstract = {Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker-based concept describing individuals with abnormal tau and/or neurodegeneration markers but normal amyloid levels. SNAP is common in individuals with normal cognition (NC), but its underlying pathophysiology is understudied, while being relevant for clinical trial design and treatment approaches. We aimed to investigate the pathophysiology of individuals with NC who are amyloid-negative and tau-positive (SNAP) through cerebrospinal fluid (CSF) proteomics. Two hundred and ninety-one individuals with NC were classified based on CSF amyloid β1-42 and phosphorylated tau 181, as amyloid-negative/tau-negative (controls), amyloid-negative/tau-positive (SNAP), amyloid-positive/tau-negative and amyloid-positive/tau-positive. We measured 3102 proteins in CSF using tandem mass tag proteomic analyses. We compared protein abundance between groups using analysis of covariance and identified enriched biological pathways using Gene Ontology. We also examined differences between groups in genetic risk for Alzheimer's disease, estimated using polygenic risk scores based on genome-wide association study data. SNAP individuals with NC showed mostly increased protein levels (n = 360) compared with controls, mainly associated with neuroplasticity, angiogenesis, and protein modification and degradation. The proteomic profile of SNAP was similar to that of amyloid-positive/tau-positive individuals, while distinct from amyloid-positive/tau-negative individuals, who showed mainly decreased proteins associated with neuroplasticity. Higher levels of amyloid β1-40 and amyloid β1-42 were observed in SNAP compared with the three other groups. Polygenic risk scores analyses showed no significant differences between SNAP, amyloid-positive/tau-negative, and amyloid-positive/tau-positive individuals, while SNAP showed some genetic differences from controls, which were driven by APOE. Individuals with NC and SNAP or amyloid-positive/tau-positive status showed similar CSF proteomic profiles, while amyloid-positive/tau-negative individuals showed a distinct CSF proteomic profile. This suggests that tau, rather than amyloid, might be the main driver of the proteomic profiles in SNAP and other amyloid/tau subgroups. This may have implications for future proteomic studies and clinical trial design, as these findings highlight the importance of considering tau status in future studies.}, } @article {pmid40641055, year = {2025}, author = {Le, W and Shen, L and Guo, T and Xie, F}, title = {Spotlight on Alzheimer's disease and related dementias research in East Asia.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70479}, pmid = {40641055}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease/epidemiology/therapy/diagnosis ; Asia, Eastern/epidemiology ; *Dementia/epidemiology/therapy/diagnosis ; Biomarkers/blood ; *Biomedical Research ; Neuroimaging ; }, abstract = {With a burgeoning dementia burden driven by unique demographic, genetic, and socioeconomic factors of East Asia, the region has made significant investments in understanding disease mechanisms, developing biomarkers, and exploring therapeutic approaches. This collection highlights the current landscape of Alzheimer's disease and related dementias research in East Asia, including region-specific epidemiological insights, advances in plasma biomarkers and neuroimaging, and innovative diagnostic and treatment strategies. Despite progress, challenges such as limited access to advanced imaging, cultural barriers to autopsy, and disparities in healthcare persist.}, } @article {pmid40641016, year = {2025}, author = {Dahiya, M and Yadav, M and Kumar, A and Goyal, C}, title = {Tau Pathology in Alzheimer's Disease: Bridging Molecular Mechanisms and Targeted Therapies.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273376581250626003322}, pmid = {40641016}, issn = {1996-3181}, abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. While Aβ-targeting therapies have been a primary focus of drug development, their long-term efficacy remains uncertain. Emerging evidence suggests that tauopathy is more closely linked to cognitive decline, positioning tau as a promising therapeutic target. Tauopathies, a group of neurodegenerative disorders marked by tau dysfunction and aggregation, were historically attributed to a toxic gain-of-function. However, clinical trials targeting tau have yielded limited success, likely due to the heterogeneity of tau pathology, variable patient responses, and suboptimal therapeutic strategies. Here, we underline the need for a refined understanding of tau biology to develop effective interventions. Advancing precision medicine approaches and identifying optimal tau species for therapeutic intervention could transform tau-targeting therapies into a cornerstone in managing tauopathies. By integrating insights from genetics, pathology, and translational research, future efforts may overcome current challenges and unlock novel treatment avenues, ultimately improving patient outcomes.}, } @article {pmid40640892, year = {2025}, author = {Noh, MY and Kwon, HS and Kwon, MS and Nahm, M and Jin, HK and Bae, JS and Kim, SH}, title = {Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {82}, pmid = {40640892}, issn = {1750-1326}, support = {RS-2024-00348451//Korea Dementia Research Center/ ; }, mesh = {Humans ; *Microglia/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Biomarkers/metabolism ; Animals ; }, abstract = {Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies-including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data-offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.}, } @article {pmid40640460, year = {2025}, author = {Heimler, SR and Amick, KA and Bergstrom, J and Moliné, M and Mahapatra, G and Craft, S and Molina, AJA}, title = {Nervonic acid and 15-epi-PGA1 mediate systemic mitochondrial dysfunction in AD dementia.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {40640460}, issn = {2509-2723}, support = {R01 AG072734/AG/NIA NIH HHS/United States ; P30 AG068635/AG/NIA NIH HHS/United States ; P30 AG068635/GF/NIH HHS/United States ; R01 AG054523/GF/NIH HHS/United States ; P30 AG 072947/GF/NIH HHS/United States ; R01 AG061805/AG/NIA NIH HHS/United States ; R01 AG061805/GF/NIH HHS/United States ; }, abstract = {Systemic mitochondrial dysfunction is apparent in the pathophysiology of Alzheimer's disease (AD). However, the factors driving bioenergetic decline remain unclear. This study utilized serum samples from older adults with normal cognition, mild cognitive impairment, and dementia to identify circulating molecules that can drive mitochondrial dysfunction in the context of AD. We used mass spectrometry to measure the abundance of lipid metabolites and applied tiered selection criteria to identify candidate "mito-inhibitory" molecules. These criteria were based on correlations with (1) in vitro bioenergetic effects of whole serum samples on naïve cells, (2) the bioenergetic capacity of blood cells from the serum donor, and (3) cognition, as measured by the modified mini-mental state exam. Mito-inhibitory lipid candidates were validated by examining their bioenergetic effects on neurons, myoblasts, and fibroblasts in vitro. Our results indicate that nervonic acid and 15-epi Prostaglandin A1 (15-epi-PGA1) are elevated in participants with dementia compared to those with normal cognition. Importantly, both metabolites inhibited mitochondrial function across multiple cell types in vitro. High resolution respirometric analyses reveal that inhibitory effects from lipid treatment occur via broad inhibition of the electron transfer system (ETS) with no change in overall mitochondrial content. This study provides insights into the mechanisms underlying systemic bioenergetic decline associated with AD dementia. The identification of circulating factors that drive mitochondrial bioenergetic decline may inform the development of mitochondrial therapeutics for AD.}, } @article {pmid40639970, year = {2025}, author = {Franceschi, AM and Keir, G and Benzinger, TLS and Cogswell, PM and Ali, FZ and Petrella, JR and Prescott, JW and Whitlow, CT and Zaharchuk, G and Allen, JW and , }, title = {Clinical Role of Brain PET in Alzheimer Disease in the Era of Disease-Modifying Therapies.}, journal = {AJNR. American journal of neuroradiology}, volume = {46}, number = {8}, pages = {1521-1527}, pmid = {40639970}, issn = {1936-959X}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy ; *Positron-Emission Tomography/methods ; *Brain/diagnostic imaging/metabolism ; }, abstract = {Alzheimer disease (AD) is the leading cause of dementia, with an estimated 6.9 million Americans aged 65 and older living with Alzheimer dementia today, with this number projected to grow to 13.8 million by 2060. Amyloid and τ accumulation underpin our understanding of the pathophysiology of AD, with the abnormal accumulation of these proteins leading to neurodegeneration. With the recent approval of antiamyloid monoclonal antibody therapies for patients with early-stage Alzheimer disease by the Food and Drug Administration, there is renewed energy and focus on brain imaging for diagnosis, triage, and monitoring of patients with neurodegenerative disease. Furthermore, PET imaging of amyloid and τ has revolutionized our understanding of dementia progression and staging, and influences patient management in the clinical setting. We aim to update radiologists on the evolving role of amyloid and τ PET in clinical practice, emphasizing the need for standardized workflows and the integration of molecular imaging data with other disease biomarkers. We also discuss the clinical implications of amyloid and τ PET, including their impact on diagnosis and treatment decisions, as well as the challenges of reimbursement and workforce capacity. With recent shifts in the AD management landscape, it is crucial for radiologists to keep abreast of recent advances in clinical practice, thereby ensuring effective patient care.}, } @article {pmid40639271, year = {2025}, author = {Mao, Y and Zhang, L and Zhang, C and Qin, L and Liao, X and Zhao, L}, title = {The close relationship between trace elements (Cu, Fe, Zn, Se, Rb, Si, Cr, and V) and Alzheimer's disease: Research progress and insights.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {90}, number = {}, pages = {127692}, doi = {10.1016/j.jtemb.2025.127692}, pmid = {40639271}, issn = {1878-3252}, mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Trace Elements/metabolism ; Iron/metabolism ; Zinc/metabolism ; Silicon/metabolism ; Selenium/metabolism ; Animals ; Copper/metabolism ; Chromium/metabolism ; Vanadium/metabolism ; }, abstract = {Alzheimer's disease (AD) is a typical neurodegenerative disorder primarily characterized by the deposition of β-amyloid (Aβ) plaques and the hyperphosphorylation of tau protein, leading to the formation of neurofibrillary tangles (NFTs). These pathological changes are closely associated with the imbalance of trace element homeostasis. Trace elements are extensively involved in fundamental physiological processes, including DNA synthesis, protein synthesis, energy metabolism, and enzymatic reactions, all of which are essential for cognitive function and brain development. This review summarizes the alterations in homeostasis and the biological roles of trace elements such as copper, iron, zinc, selenium, rubidium, silicon, chromium, and vanadium, as well as their relationship with the onset and progression of AD. Additionally, we discuss recent advancements in therapeutic strategies targeting the balance of trace element ions, including metal chelators, supplements, nanomedicines, and small-molecule drugs, to provide new perspectives for AD research and treatment.}, } @article {pmid40638744, year = {2025}, author = {Keil, SA and Jansson, D and Braun, M and Iliff, JJ}, title = {Glymphatic dysfunction in Alzheimer's disease: A critical appraisal.}, journal = {Science (New York, N.Y.)}, volume = {389}, number = {6756}, pages = {eadv8269}, doi = {10.1126/science.adv8269}, pmid = {40638744}, issn = {1095-9203}, mesh = {Animals ; Humans ; *Alzheimer Disease/genetics/metabolism/physiopathology ; *Glymphatic System/metabolism/pathology/physiopathology ; Disease Models, Animal ; Aquaporin 4/genetics/metabolism ; }, abstract = {Thirteen years after the initial publication defining the glymphatic system, we critically reappraise the role of its dysfunction in Alzheimer's disease (AD). Our understanding of glymphatic function and its involvement in the pathogenesis of AD derives primarily from correlative clinical data and rodent studies. A causal role for glymphatic dysfunction in AD has not yet been established in humans. We review current approaches to assess glymphatic function clinically, which capture different features of perivascular fluid dynamics or their results. The absence of clinically suitable imaging approaches to measuring glymphatic exchange in the human brain is an obstacle to evaluating whether glymphatic function is impaired in AD populations and to developing and evaluating therapeutics to modulate glymphatic function in the treatment and prevention of AD.}, } @article {pmid40637746, year = {2025}, author = {Xu, D and Wu, J and Zhao, X and Shen, J and Lu, Z and Yang, Z}, title = {A bibliometric analysis of the current research status and hotspots regarding Aducanumab treatment for Alzheimer's disease.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40637746}, issn = {1432-1912}, abstract = {BACKGROUND: The prevalence of Alzheimer's disease is steadily increasing, and Aducanumab has garnered significant attention as a treatment since 2021. There is a growing body of research on Aducanumab and its relationship with Alzheimer's disease; however, there is currently a lack of bibliometric analysis regarding the use of Aducanumab in the treatment of Alzheimer's disease. OBJECTIVE: This study employs bibliometric methods to analyze the current research landscape and hotspots surrounding Alzheimer's disease and Aducanumab, providing a reference for subsequent investigations in this field and the promotion of Aducanumab as a treatment for Alzheimer's disease. METHODS: This study retrieved articles related to Alzheimer's disease and Aducanumab from the WOS core database, covering the period from the establishment of the database until Dec 31, 2024. After a rigorous selection process, analyses were conducted using GraphPad Prism 10, VOSviewer, and CiteSpace to obtain insights into publication and citation metrics, collaboration networks among countries, institutions, and authors, as well as clustering analysis of reference papers and keywords. RESULTS: The number of articles regarding Aducanumab treatment for Alzheimer's disease has been increasing annually, with a notable surge occurring after 2021. The three countries with the highest publication output are the United States, the United Kingdom, and China. The leading institutions in terms of publication volume are Biogen, Harvard Medical School, and the University of California, San Francisco. The top three authors contributing to this body of work are Poul F. Høilund-Carlsen, Abass Alavi, and Mona-Elisabeth Revheim. The journals with the highest publication rates include Alzheimer's & Dementia, the International Journal of Molecular Sciences, and the Journal of Alzheimer's Disease. The most cited article is "Lecanemab in Early Alzheimer's Disease," authored by van Dyck CH et al., published in 2023 in the New England Journal of Medicine. The ten most frequently occurring keywords are Alzheimer's disease, Aducanumab, dementia, amyloid-beta, immunotherapy, tau, a-beta, mouse model, amyloid, and mild cognitive impairment. The keyword and cluster "pharmacokinetics" currently represent a research hotspot in this field. CONCLUSION: This study employs bibliometric methods to reveal the publication trends related to Aducanumab in the context of Alzheimer's disease, examining collaborations among countries, regions, and authors, as well as recent research hotspots. It provides objective data that serves as a reference for scientific research and clinical practice concerning Aducanumab treatment for Alzheimer's disease.}, } @article {pmid40637583, year = {2025}, author = {Bonomi, CG and Motta, C and Di Donna, MG and Poli, M and Koch, G and Martorana, A}, title = {Rethinking dementia in the oldest old: Lessons to learn for the diagnosis and treatment of Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00312}, pmid = {40637583}, issn = {1673-5374}, } @article {pmid40637522, year = {2025}, author = {Nonino, F and Colosimo, C and Massacesi, L}, title = {[Lecanemab and Alzheimer-Perusini's disease: between therapeutic hopes and regulatory challenges].}, journal = {Recenti progressi in medicina}, volume = {116}, number = {7-8}, pages = {407-410}, doi = {10.1701/4530.45309}, pmid = {40637522}, issn = {2038-1840}, mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology ; *Amyloid beta-Peptides/metabolism/immunology ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use/administration & dosage ; Aged ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; }, abstract = {Alzheimer-Perusini's disease (AD) represents a growing health crisis. The lack of effective disease-modifying treatments and its increasing prevalence in the elderly population contribute to a major burden for patients and their caregivers, challenging health systems globally. The accumulation of beta-amyloid protein (Aβ) within the brain tissue plays an important pathogenic role in the inflammatory and degenerative mechanisms leading to cognitive and functional impairment. In recent years monoclonal antibodies targeting (Aβ) have been developed and one of them (lecanemab) recently received marketing authorization by the European Medicines Agency (Ema). Although they represent an important innovation in the treatment of AD, their clinical net benefit is uncertain, due to modest efficacy and the threat of potentially severe side effects. Cost, mode od delivery and complexity of programs aimed at minimizing risks for people with AD may limit access to these therapies and pose equity issues within health systems.}, } @article {pmid40636703, year = {2025}, author = {Patricio-Martínez, A and Patricio, F and Macuil-Chapuli, E and Martínez-Juárez, EÁ and Flores-Díaz, S and Cedillo-Ramírez, ML and Limón, ID}, title = {The role of probiotics, prebiotics, and postbiotics: cellular and molecular pathways activated on glial cells in Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1598011}, pmid = {40636703}, issn = {1662-4548}, abstract = {Supplementation with prebiotics and probiotics can modulate the intestinal microbiota, returning it to a more physiological state; therefore, they can be considered as a possible treatment in many prevalent conditions, including neurodegenerative diseases. Alzheimer's disease (AD) is the most common form of dementia, accounting for 60 to 70% of cases. The neuropathological features of AD include neuritic plaques (extracellular deposits of the beta-amyloid protein, Aβ), neurofibrillary tangles (resulting from hyperphosphorylation of the tau protein), a predominantly cholinergic synaptic decrease, and the presence of inflammatory markers, all these characteristics together trigger the neurodegenerative process and cognitive deterioration. The etiology of AD is multifactorial, however, in recent years evidence has been shown on the significant association between dysbiosis, neuroinflammation, and neurodegeneration. In the present review, we will discuss the role of gut microbiota in the pathogenesis of AD, as well as the underlying mechanisms that trigger the use of probiotics, prebiotics, and postbiotics in neuroinflammation. Our attention will focus on the cellular and molecular mechanisms triggered by astrocytes and microglia, cells involved in mediating neuroinflammation and neurodegeneration in AD.}, } @article {pmid40636522, year = {2025}, author = {Wang, J and Chen, Y and Chen, S and Mu, Z and Chen, J}, title = {How endothelial cell metabolism shapes blood-brain barrier integrity in neurodegeneration.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1623321}, pmid = {40636522}, issn = {1662-5099}, abstract = {BACKGROUND/OBJECTIVE: Endothelial cells, a monolayer of cells adjacent to blood vessels, play a critical role in maintaining vascular function through metabolic pathways such as glycolysis, fatty acid, and amino acid metabolism. Recent studies have revealed their significant involvement in neurodegenerative diseases, although the underlying mechanisms remain unclear. METHODS: By reviewing literature from the past decade, we summarized the metabolic alterations and functional changes of endothelial cells in neurological disorders. RESULTS: In neurodegenerative diseases such as stroke, Alzheimer's disease, multiple sclerosis, and aging, metabolic dysregulation in cerebral vascular endothelial cells disrupts their normal function and is closely associated with blood-brain barrier impairment. CONCLUSION: Aberrant endothelial cell metabolism compromises the integrity of the blood-brain barrier and exacerbates the pathological progression of neurodegenerative diseases. Our review further explores the therapeutic potential of targeting endothelial cell metabolism in various pathological contexts, aiming to provide novel insights for the prevention and treatment of related disorders.}, } @article {pmid40636521, year = {2025}, author = {Sharma, E and Mehta, D and Jadhav, N and Gujrati, G and Dhananya, S and Moorthy, M and Ramaswamy, G and Zhou, Y and Nair, S}, title = {Whole-genome sequencing shows modulation of neurodegenerative genes by Withania somnifera in human SK-N-SH cells.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1512727}, pmid = {40636521}, issn = {1662-5099}, abstract = {BACKGROUND: Aging is driven by several primary and secondary hallmarks that manifest with age, of which neurodegenerative diseases are important manifestations. The ability to decelerate or reverse aging, and promote healthy aging, has garnered great interest in recent times. In traditional medicine, Withania somnifera (WS) or Ashwagandha has been recognized for its adaptogenic and rejuvenative effects. METHODS: To investigate WS-modulated global gene expression profiles, we performed whole-genome sequencing of WS-treated human neuroblastoma SK-N-SH cells at different doses (50 and 100 μg/mL) and time points (3 h and 9 h) and validation by quantitative real-time PCR (qRT-PCR) and immunoblotting. Disease enrichment analysis for brain-related disorders was performed by DisGeNET. RESULTS: Using differential gene expression analyses, we identified 19,945 WS-modulated genes. Of these, 2,403 and 177 genes were significantly (p ≤ 0.05) upregulated and downregulated, respectively, by WS treatment. Interestingly, different patterns of gene expression were exhibited in dose-dependent (9 upregulated, 1 downregulated, 100 μg/mL 3 h vs. 50 μg/mL 3 h; 21 upregulated, 86 downregulated, 100 μg/mL 9 h vs. 50 μg/mL 9 h) and temporal kinetics (210 upregulated, 6 downregulated, 50 μg/mL 9 h vs. 50 μg/mL 3 h; 8 upregulated, 49 downregulated, 100 μg/mL 9 h vs. 100 μg/mL 3 h). Furthermore, qRT-PCR experiments validated the RNA-seq results. WS-modulated genes were implicated in Alzheimer's disease, migraine, Parkinson's disease, bipolar disorder, cognition, stress, anxiety, forgetfulness, sleep disorders, and substance abuse among others. CONCLUSION: Taken together, our transcriptomic profiling study revealed for the first time that WS may modulate key genes in neurodegenerative disorders with potential beneficial implications for brain-related disorders and healthy aging.}, } @article {pmid40636063, year = {2025}, author = {Armstrong, MJ and Grill, JD and Tropea, TF}, title = {It is time to share Alzheimer biomarker results in dementia with Lewy bodies.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {3}, pages = {e70144}, pmid = {40636063}, issn = {2352-8729}, support = {K23 NS114167/NS/NINDS NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; RF1 AG080591/AG/NIA NIH HHS/United States ; }, abstract = {UNLABELLED: There are increasing calls for sharing individual biomarker results with participants in dementia research. No studies investigate returning Alzheimer's disease (AD) biomarker results to individuals with syndromic dementia with Lewy bodies (DLB) even though most of these individuals have both pathologies. This perspective argues that AD biomarkers are valid, interpretable, and actionable, particularly relating to expected prognosis and treatment effects, in people with DLB. Thus, there is an ethical imperative to study AD biomarker result sharing in these patients. This will require revising current disclosure practices. Areas of need include unique pre- and post-test education and careful assessment of the readiness to receive results and post-result responses in people with DLB given the frequency of neuropsychiatric symptoms in this group. Studying responses to sharing AD biomarkers in people with DLB will also inform other dementia settings (e.g., returning synuclein results to individuals with syndromic AD) and neurodegenerative diseases more broadly. HIGHLIGHTS: There are increasing calls for biomarker result sharing in dementia research.No processes exist to guide result sharing in dementia with Lewy bodies (DLB).Alzheimer biomarker results in DLB are valid, interpretable, and actionable.Research is needed on the methods and effects of sharing with people with DLB.Research is needed for sharing evidence of co-pathology across neurodegenerations.}, } @article {pmid40635533, year = {2025}, author = {Tae, WS and Ham, BJ and Pyun, SB and Kim, BJ}, title = {Current Clinical Applications of Structural MRI in Neurological Disorders.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {21}, number = {4}, pages = {277-293}, pmid = {40635533}, issn = {1738-6586}, support = {2022R1F1A1074517/NRF/National Research Foundation of Korea/Korea ; RS-2023-00241730/NRF/National Research Foundation of Korea/Korea ; RS-2025-00515464/NRF/National Research Foundation of Korea/Korea ; }, abstract = {Structural magnetic resonance imaging (sMRI) plays a pivotal role in the evaluation of neurological disorders by providing high-resolution anatomical information. Recent advances in quantitative postprocessing techniques have expanded the utility of sMRI beyond visual assessments by enabling the detection of subtle morphological changes associated with various neurological and psychiatric conditions. This review summarizes current clinical applications of sMRI-based analysis, including brain volumetry, shape analysis, voxel-based morphometry (VBM), surface-based morphometry, source-based morphometry, and voxel-based lesion-symptom mapping (VLSM). Volumetric and shape-based analyses allow for assessments of region-specific atrophy and subregional morphological alterations, while VBM and surface-based morphometry provide complementary insights into tissue volumes and the architecture of the cortical surface. Source-based morphometry reveals network-level patterns of structural covariance, and VLSM directly correlates lesion locations with functional outcomes, particularly in stroke. It has been demonstrated that these methodologies are clinically relevant in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and major depressive disorder. By quantifying structural brain alterations that are not readily detectable using conventional imaging methods, these tools improve diagnostic accuracy, support prognostication, and facilitate monitoring of treatment effects. This review highlights the growing integration of sMRI postprocessing techniques into clinical neurology.}, } @article {pmid40635531, year = {2025}, author = {Park, KH and Choi, SH and Shim, Y and Youn, YC and Yang, DW and Kim, S}, title = {Use of Amyloid Positron-Emission Tomography to Diagnose Alzheimer's Disease in Clinical Practice in South Korea: Expert Recommendations.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {21}, number = {4}, pages = {251-264}, pmid = {40635531}, issn = {1738-6586}, abstract = {Amyloid positron-emission tomography (PET) is the optimal method for detecting amyloid plaque deposition in patients experiencing cognitive decline, which is essential for diagnosing Alzheimer's disease. However, its clinical application globally has been restricted by the high cost, short radiotracer half-life, and significant accessibility challenges. In particular, the lack of treatment options following diagnosis has been considered the largest obstacle to using amyloid PET as a diagnostic tool. Consequently, the current appropriate-use recommendations for amyloid PET tend to support restricting its use. However, the relatively low cost and superior accessibility of amyloid PET in South Korea have resulted in it being used much more frequently in clinical settings than in other countries. The recent introduction of disease-modifying drugs has increased the importance and frequency of amyloid PET usage. Considering these circumstances, this article presents expert opinions on the appropriate use of amyloid PET in South Korea based on existing recommendations and survey results from dementia experts in South Korea.}, } @article {pmid40635450, year = {2025}, author = {Li, J and Li, Y and Wang, Z and Yao, Y and Yao, D and Chen, K and Xia, Y}, title = {Oxytocin Intervention Mitigates Pathological and Behavioral Impairments in APP/PS1 Mice Subjected to Early Social Isolation.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {7}, pages = {e70511}, pmid = {40635450}, issn = {1755-5949}, support = {2022ZD0208500//STI 2030-Major Project/ ; 2024YFHZ0359//Sichuan Province Science and Technology Support Program/ ; }, mesh = {Animals ; *Oxytocin/pharmacology/therapeutic use ; *Social Isolation/psychology ; Mice ; *Alzheimer Disease/pathology/psychology/drug therapy/genetics/metabolism ; Mice, Transgenic ; Male ; Presenilin-1/genetics ; Gastrointestinal Microbiome/drug effects ; Amyloid beta-Protein Precursor/genetics ; Mice, Inbred C57BL ; Anxiety/drug therapy ; Depression/drug therapy ; Receptors, Oxytocin/metabolism ; Disease Models, Animal ; }, abstract = {BACKGROUND: Neuropsychiatric symptoms, such as anxiety and depression, are prevalent during the prodromal phase of Alzheimer's disease (AD). Social isolation (SI) has been implicated as a potential exacerbating factor for emotional disturbances in AD pathogenesis. Despite the well-established role of oxytocin (OXT) in regulating social behavior and mental health, its function and mechanisms in alleviating AD-related psychiatric symptoms remain poorly understood. MATERIALS AND METHODS: We utilized a 12-week SI model to assess its effects on anxiety, depression-like behaviors, and social cognition in early-stage AD mice. Through immunofluorescence, enzyme-linked immunosorbent assay, and 16S rDNA sequencing, we examined the changes in AD pathology and gut microbiota composition induced by SI, as well as the effects of OXT intervention. RESULTS: Our findings revealed that SI markedly intensified anxiety-like behaviors, depression-like phenotypes, and social cognitive impairments in AD mice. Mechanistically, SI resulted in decreased OXT levels and upregulated OXT receptor expression while also exacerbating AD-related pathological features, including increased Aβ plaque deposition, aberrant microglial proliferation, and reduced PSD-95 expression in the prefrontal cortex. Furthermore, SI induced significant changes in gut microbiota composition. OXT intervention demonstrated therapeutic efficacy by mitigating behavioral deficits, alleviating AD-related pathological damage, and restoring gut microbiota homeostasis in SI AD mice. CONCLUSION: These results underscore OXT as a promising therapeutic avenue for AD, offering novel insights into treatment strategies and identifying potential therapeutic targets through the restoration of gut homeostasis and mitigation of pathological processes.}, } @article {pmid40635217, year = {2025}, author = {Guo, L and Lin, Y and Sun, B}, title = {Highly Efficient and Eco-friendly Synthesis and Bio-activities of 1,3-benzazoles as Cu (II) Chelators in Alzheimer's Disease Therapy.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673371011250612094752}, pmid = {40635217}, issn = {1875-533X}, abstract = {INTRODUCTION: Dyshomeostasis of Cu2+ and abnormal interactions between Cu2+ and β Amyloid peptide (Aβ) can promote Aβ aggregation and oxidative stress, which are considered to trigger Alzheimer's Disease (AD). Metal chelating therapy is a promising approach for the treatment of AD. METHOD: In this study, 2-(2-hydroxyphenyl)benzazoles were synthesized via microwave irradiation promotion. Chelators inhibiting Cu2+-induced Aβ aggregation were determined through turbidity assay and BCA protein assay, while anti-oxidants were detected via HRP/Amplex red assay and fluorescent probe of DCFH-DA. Cell viability was measured by MTT assay. RESULTS: The bio-activity for inhibiting Cu2+ induced-Aβ aggregation of chelators S-1, S-3, S-4, S-5, S-7, S-10, N-5, N-9, N-10 O-2, O-4, X-N-2 was better than that of CQ. The ability of the chelators (S-1, S-10, O-2, O-5, N-9, and X-N-2) to decrease the level of ROS in Aβ+Cu2+ treated SH-SY5Y cells was better than that of CQ. The ability to attenuate Aβ-mediated cytotoxicity in SH-SY5Y cells of S-10 (O-2, O-5, and N-9) was better than that of CQ. CONCLUSION: After the evolution of the bio-activities for the treatment of AD in vitro, it was found that 4 chelators (S-10, O-2, O-5, and N-9) exhibited better bio-activities than CQ in all aspects.}, } @article {pmid40635213, year = {2025}, author = {A Shaldam, M and Carradori, S and Melfi, F and Guglielmi, P and Diomede, F and Piattelli, M and O Tawfik, H}, title = {Potential of MAO-B Inhibitors with Multi-Target Inhibition and Antioxidant Properties for the Treatment of Neurodegenerative Disorders.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575392491250630195630}, pmid = {40635213}, issn = {1875-5607}, abstract = {Millions of people worldwide are affected by neurodegenerative disorders (NDs), which include a broad range of clinical ailments that affect the brain or peripheral nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, etc. Neuronal cell death in NDs is often linked to oxidative stress; thus, antioxidant treatment can combat oxidative cell damage, and this strategy has been studied in neurodegenerative processes. Over the past 10 years, we have witnessed intense research activity on the biological potential of human monoamine oxidase (hMAO) inhibitors that have been associated with the prevention of oxidative stress and inflammation. These inhibitors have emerged as promising therapeutic agents, especially in the treatment of neurodegenerative diseases (NDs), where their core activity may help mitigate disease progression. An overview of the current state of numerous scaffolds, such as chromones, coumarins, chalcones, propargylamines, benzothiazoles, aminoisoquinolines, and the natural compounds, including ferulic acid, resveratrol, and chrysin, which combine antioxidant capability and hMAO inhibition is given in this review, with particular attention given to each scaffold's mechanism of action and structure-activity relationships (SARs), which are thoroughly discussed. Focusing on the dual mechanism of action, combining inhibition and antioxidant properties, as a potential therapy for neurodegenerative diseases, we have reviewed the different chemical classes of multi-targetdirected ligand (MTDL) inhibitors developed within this framework. Other central nervous system (CNS)-related enzymes, such as cholinesterases, carbonic anhydrases, and BACE-1, have also been explored as targets in the MTDL strategy. By understanding their biological activity, medicinal chemists can better comprehend biological activity and recommend more effective and specific ND treatments.}, } @article {pmid40633621, year = {2025}, author = {Limone, A and Di Napoli, C and De Rosa, G and Bagnoli, S and Izzo, A and Procaccini, C and Matarese, G and Nacmias, B and Lavecchia, A and Sarnataro, D}, title = {Modulation of mitochondrial quality control through autophagic pathway in familial Alzheimer's disease.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {1872}, number = {7}, pages = {120019}, doi = {10.1016/j.bbamcr.2025.120019}, pmid = {40633621}, issn = {1879-2596}, mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/pathology ; *Mitochondria/metabolism/drug effects/pathology/genetics ; *Autophagy/drug effects ; Mitophagy/drug effects ; Fibroblasts/metabolism/drug effects/pathology ; TOR Serine-Threonine Kinases/metabolism/genetics ; Signal Transduction/drug effects ; Protein Kinases/metabolism/genetics ; Ubiquitin-Protein Ligases/metabolism/genetics ; Proto-Oncogene Proteins c-akt/metabolism/genetics ; }, abstract = {Autophagy is a highly conserved cellular catabolic process recognized as an essential pathway for the maintenance of cellular homeostasis. Growing evidence implicates autophagic dysfunction in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease (AD), thus its modulation might represent an interesting therapeutic tool. Searching for a compound that stimulates autophagic pathway, led us to identify the inhibitor of RPSA receptor, NSC47924. In this study, we show that, NSC47924 down-modulated Akt-mTOR-axis pathway, the master regulator of autophagy, which was abnormally hyperactivated in fibroblasts from genetic AD-affected patients. Consistently, by monitoring the conversion of LC3, we found that inhibition of RPSA enhanced and restored the compromised autophagic flux. Moreover, by qRT-PCR analysis we found that inhibitor treatment upregulated the expression of autophagy-linked genes. Importantly, AD-affected fibroblasts exhibited massive mitochondrial network fragmentation and mitophagy defects, which were restored through the stimulation of autophagy induced by RPSA inhibition. Consistent with an efficient elimination of dysfunctional mitochondria, we found that the turnover of both the mitophagy regulators PINK1 and Parkin and the autophagic receptors p62, NDP52, OPTN, was modulated, thus restoring a highly interconnected organelle's network. In addition, the improvement of mitochondrial morphology correlated with a functional recovery, as assessed by Seahorse analysis and mitochondrial ROS production evaluation. Collectively, our findings suggest that RPSA inhibition stimulates an autophagic pathway promoting the efficient removal of damaged mitochondria, favouring the recovery of cellular homeostasis, and counteracting crucial AD pathogenic mechanisms.}, } @article {pmid40633409, year = {2025}, author = {Khaliq, A and Ahmad, F and Rehman, HU and Alanazi, SA and Haleem, H and Junaid, K and Andrikopoulou, E}, title = {Revolutionizing medical imaging: A cutting-edge AI framework with vision transformers and perceiver IO for multi-disease diagnosis.}, journal = {Computational biology and chemistry}, volume = {119}, number = {}, pages = {108586}, doi = {10.1016/j.compbiolchem.2025.108586}, pmid = {40633409}, issn = {1476-928X}, mesh = {Humans ; *Artificial Intelligence ; *Diagnostic Imaging ; Deep Learning ; }, abstract = {The integration of artificial intelligence in medical image classification has significantly advanced disease detection. However, traditional deep learning models face persistent challenges, including poor generalizability, high false-positive rates, and difficulties in distinguishing overlapping anatomical features, limiting their clinical utility. To address these limitations, this study proposes a hybrid framework combining Vision Transformers (ViT) and Perceiver IO, designed to enhance multi-disease classification accuracy. Vision Transformers leverage self-attention mechanisms to capture global dependencies in medical images, while Perceiver IO optimizes feature extraction for computational efficiency and precision. The framework is evaluated across three critical clinical domains: neurological disorders, including Stroke (tested on the Brain Stroke Prediction CT Scan Image Dataset) and Alzheimer's (analyzed via the Best Alzheimer MRI Dataset); skin diseases, covering Tinea (trained on the Skin Diseases Dataset) and Melanoma (augmented with dermoscopic images from the HAM10000/HAM10k dataset); and lung diseases, focusing on Lung Cancer (using the Lung Cancer Image Dataset) and Pneumonia (evaluated with the Pneumonia Dataset containing bacterial, viral, and normal X-ray cases). For neurological disorders, the model achieved 0.99 accuracy, 0.99 precision, 1.00 recall, 0.99 F1-score, demonstrating robust detection of structural brain abnormalities. In skin disease classification, it attained 0.95 accuracy, 0.93 precision, 0.97 recall, 0.95 F1-score, highlighting its ability to differentiate fine-grained textural patterns in lesions. For lung diseases, the framework achieved 0.98 accuracy, 0.97 precision, 1.00 recall, 0.98 F1-score, confirming its efficacy in identifying respiratory conditions. To bridge research and clinical practice, an AI-powered chatbot was developed for real-time analysis, enabling users to upload MRI, X-ray, or skin images for automated diagnosis with confidence scores and interpretable insights. This work represents the first application of ViT and Perceiver IO for these disease categories, outperforming conventional architectures in accuracy, computational efficiency, and clinical interpretability. The framework holds significant potential for early disease detection in healthcare settings, reducing diagnostic errors, and improving treatment outcomes for clinicians, radiologists, and patients. By addressing critical limitations of traditional models, such as overlapping feature confusion and false positives, this research advances the deployment of reliable AI tools in neurology, dermatology, and pulmonology.}, } @article {pmid40633205, year = {2025}, author = {Metzendorf, NG and Godec, A and Petrovic, A and Chourlia, A and Napoleone, A and Syvänen, S and Rofo, F and Hultqvist, G}, title = {Somatostatin therapy, neprilysin activation, and amyloid beta reduction: A novel approach for Alzheimer's treatment.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {189}, number = {}, pages = {118325}, doi = {10.1016/j.biopha.2025.118325}, pmid = {40633205}, issn = {1950-6007}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism ; *Neprilysin/metabolism ; *Somatostatin/pharmacology/therapeutic use/administration & dosage ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Blood-Brain Barrier/metabolism/drug effects ; Mutation ; Amyloid beta-Protein Precursor/genetics/metabolism ; Peptide Fragments/metabolism ; }, abstract = {INTRODUCTION: Neprilysin is the primary enzyme responsible for the degradation of amyloid beta (Aβ), with its levels regulated by the hormone somatostatin (SST). METHODS: We have developed a novel treatment mechanism for Alzheimer's disease (AD) by combining SST with a blood-brain barrier (BBB) transporter and a Fc fragment to extend its half-life. This treatment was tested in a murine AD model overexpressing amyloid precursor protein (APP) with the Arctic mu

@article {pmid41538772, year = {2026}, author = {Liao, YS and Wai, T and Liao, TY and Chang, HL and Chang, YL and Fu, LC}, title = {Mild Cognitive Impairment Detection System Based on Unstructured Spontaneous Speech: Longitudinal Dual-Modal Framework.}, journal = {JMIR medical informatics}, volume = {14}, number = {}, pages = {e80883}, doi = {10.2196/80883}, pmid = {41538772}, issn = {2291-9694}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; Aged ; Male ; Female ; Longitudinal Studies ; *Speech ; Aged, 80 and over ; Memory, Episodic ; China ; }, abstract = {BACKGROUND: In recent years, the incidence of cognitive diseases has also risen with the significant increase in population aging. Among these diseases, Alzheimer disease constitutes a substantial proportion, placing a high-cost burden on health care systems. To give early treatment and slow the progression of patient deterioration, it is crucial to diagnose mild cognitive impairment (MCI), a transitional stage.

OBJECTIVE: In this study, we use autobiographical memory (AM) test speech data to establish a dual-modal longitudinal cognitive detection system for MCI. The AM test is a psychological assessment method that evaluates the cognitive status of subjects as they freely narrate important life experiences.

METHODS: Identifying hidden disease-related information in unstructured, spontaneous speech is more difficult than in structured speech. To improve this process, we use both speech and text data, which provide more clues about a person's cognitive state. In addition, to track how cognition changes over time in spontaneous speech, we introduce an aging trajectory module. This module uses local and global alignment loss functions to better learn time-related features by aligning cognitive changes across different time points.

RESULTS: In our experiments on the Chinese dataset, the longitudinal model incorporating the aging trajectory module achieved area under the receiver operating characteristic curve of 0.85 and 0.89 on 2 datasets, respectively, showing significant improvement over cross-sectional, single time point models. We also conducted ablation studies to verify the necessity of the proposed aging trajectory module. To confirm that the model not only applies to AM test data, we used part of the model to evaluate the performance on the ADReSSo dataset, a single time point semistructured data for validation, with results showing an accuracy exceeding 0.88.

CONCLUSIONS: This study presents a noninvasive and scalable approach for early MCI detection by leveraging AM speech data across multiple time points. Through dual-modal analysis and the introduction of an aging trajectory module, our system effectively captures cognitive decline trends over time. Experimental results demonstrate the method's robustness and generalizability, highlighting its potential for real-world, long-term cognitive monitoring.}, } @article {pmid41537461, year = {2026}, author = {Choi, KY and Kang, S and Cook, S and Li, D and Choi, YY and Seo, EH and Han, X and Park, JE and Lee, S and Lee, S and Chung, JY and Chong, A and Choi, SM and Ha, JM and Song, MK and Lee, JS and Choo, IH and Kim, JH and Song, HC and Kim, BC and Kim, H and Farrer, LA and Gim, J and Jun, GR and Lee, KH}, title = {The Gwangju Alzheimer's & Related Dementias (GARD) cohort: Over a decade of Asia's largest longitudinal multimodal study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e70981}, doi = {10.1002/alz.70981}, pmid = {41537461}, issn = {1552-5279}, support = {25-BR-03-05//the KBRI Basic Research Program through the Korea Brain Research Institute, funded by the Ministry of Science and ICT/ ; NRF-2014M3C7A1046041//the Original Technology Research Program for Brain Science of the National Research Foundation funded by the Korean government, MSIT/ ; RS-2024-00407198//Brain Pool program funded by the Ministry of Science and ICT through the National Research Foundation of Korea/ ; 2023-ER1007-01//Korea National Institute of Health research project/ ; //by the Technology Innovation Program (20022810, Development and Demonstration of a Digital System for the evaluation of geriatric Cognitive impairment) funded By the Ministry of Trade, Industry & Energy (MOTIE, Korea)/ ; RS-2024-00433283//the Technology Innovation Program funded by the Ministry of Trade, Industry & Energy, Republic of Korea/ ; HR22C141105//Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea/ ; }, mesh = {Humans ; Longitudinal Studies ; Male ; *Alzheimer Disease/epidemiology/diagnostic imaging/genetics/diagnosis ; Female ; Aged ; *Cognitive Dysfunction/epidemiology/diagnostic imaging ; Disease Progression ; Republic of Korea/epidemiology ; Cohort Studies ; Middle Aged ; Biomarkers ; Magnetic Resonance Imaging ; Aged, 80 and over ; Neuroimaging ; Proteomics ; Genomics ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a major public health concern in Korea, with a high prevalence among older adults. A community-based longitudinal study is essential for tracking disease progression, identifying biomarkers, and developing targeted prevention and treatment strategies. The Gwangju Alzheimer's & Related Dementias (GARD) cohort was established to address these needs through a multimodal approach.

METHODS: Participants aged ≥60 years undergo comprehensive clinical evaluations, neuroimaging, and biospecimen collection for multi-omics analyses (genomics, transcriptomics, proteomics, and metagenomics) at baseline and systematic follow-up visits.

RESULTS: From over 17,000 screened individuals, 12,877 were enrolled. Baseline diagnoses include 5,123 cognitively unimpaired (CU), 3,250 mild cognitive impairment (MCI), and 2,125 AD dementia. The resource includes magnetic resonance imaging scans (n = 10,843) and extensive multi-omics data: genomic (n = 10,775), proteomic (n = 116), and microbiome (n = 595).

DISCUSSION: The integrated GARD dataset provides a powerful and scalable resource for identifying novel biomarkers, understanding disease heterogeneity, and advancing precision medicine for AD.

HIGHLIGHTS: Gwangju Alzheimer's & Related Dementias (GARD) is a large-scale, longitudinal, community-based cohort study in South Korea. The study focuses on early detection and monitoring of dementia progression. GARD includes cognitive testing, imaging, biospecimens, and multi-omics data. We aim to identify Korean-specific biomarkers predictive of cognitive decline. Supports East Asian insights and fills gaps in global Alzheimer's research.}, } @article {pmid41536422, year = {2025}, author = {Thaliath, A and Pillai, JA}, title = {Non-Cognitive Symptoms in Alzheimer's Disease and Their Likely Impact on Patient Outcomes. A Scoping Review.}, journal = {Current treatment options in neurology}, volume = {27}, number = {}, pages = {}, doi = {10.1007/s11940-025-00852-8}, pmid = {41536422}, issn = {1092-8480}, abstract = {PURPOSE OF REVIEW: Increased understanding of the pathophysiology of Alzheimer's disease (AD) has led to development of disease modifying therapies. The therapies primarily target measures of cognitive decline since AD has been thought of as a cognitive disorder. However, the non-cognitive symptoms seen in AD contribute to overall quality-of-life. This scoping review was undertaken to further our understanding of the non-cognitive features of AD.

RECENT FINDINGS: The non-cognitive symptoms in AD range from changes in sensory perception, systemic changes, and neuropsychiatric manifestations. We targeted the following non-cognitive domains: vision, olfaction, GI, muscle, sleep, circadian rhythm, immune and behavioral symptoms as it relates to AD for this review. Non-cognitive features impact the ability of individuals to perform their activities of daily living, have safety implications and lead to increased caregiver burden. The review explores non-pharmacological and pharmacological measures targeted at the non-cognitive changes in AD.

SUMMARY: Non-cognitive symptoms contribute to significant disease burden in Alzheimer's disease. It is important to screen for and provide supportive care for these symptoms to help improve clinical care. Incorporation of non-cognitive features of AD in clinical trials will help ascertain the true societal and economic impact of AD and that of potential therapeutics.

OPINION STATEMENT: Alzheimer's disease (AD) is primarily recognized as a disorder of cognition; however, non-cognitive symptoms significantly contribute to disease burden and clinical presentation. These manifestations particularly behavioral symptoms and systemic changes beyond the central nervous system impact patients' quality of life and increase caregiver stress. Often, such symptoms necessitate a transition from home-based care to more intensive settings, such as memory care facilities. As AD prevalence rises alongside an aging population, the shortage of dedicated memory care providers in community settings challenges access and quality of care. Improved awareness and early recognition of non-cognitive features among healthcare professionals can aid identification of modifiable systemic issues and allow timely behavioral management during clinical encounters. Treatment of these symptoms requires a multifaceted approach, incorporating pharmacological and non-pharmacological strategies. Non-pharmacological interventions, including tailored behavioral approaches and environmental modifications, can enhance quality of life for individuals with AD and reduce caregiver burden especially where specialized medical resources are limited.}, } @article {pmid41536056, year = {2026}, author = {Dong, J and Xu, L and Xu, X and Shi, B and Wang, Q and Xu, J and Xu, C and Kuang, H and Qu, A}, title = {Chiral Spindle-like Nanorods Reprogram Neuroinflammation by Catalyzing α-Ketoglutarate Biosynthesis.}, journal = {Journal of the American Chemical Society}, volume = {}, number = {}, pages = {}, doi = {10.1021/jacs.5c19753}, pmid = {41536056}, issn = {1520-5126}, abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide, and breakthroughs in effective intervention strategies are urgently needed. Here, we report that chiral spindle-like Fe7Se8 nanorods (NRs) promote α-ketoglutarate (AKG) biosynthesis, providing a new potential route for AD intervention through modulation of neuroimmune homeostasis. Oral administration of L-NRs significantly restored intestinal microbiota homeostasis in 3 × Tg AD model mice, markedly enriched Lactobacillus johnsonii, and enhanced biosynthesis of the metabolite AKG, which reversed cognitive impairment and neuronal degeneration in 5 × FAD mice. Moreover, AKG levels in the clinical serum and cerebrospinal fluids were found to be significantly lower in patients with AD than in healthy controls. Mechanistic studies revealed that L-NRs efficiently promoted AKG biosynthesis through scavenging reactive oxygen species (ROS) to restore the activities of three enzymes in the biosynthesis pathway. Crucially, these NRs are broken down by gastric juice into smaller nanoparticles and subsequently into ions in the intestines. Further studies explored that AKG crossed the blood-brain barrier via cooperatively mediated transport proteins, targeted microglial phenotypic switching, reprogrammed the neuroinflammatory microenvironment, and ultimately ameliorated cognitive deficits and neuronal pathological alterations. Our findings suggest that AKG might serve as a therapeutic drug for the precise treatment of neurodegenerative diseases.}, } @article {pmid41535708, year = {2026}, author = {Yu, MJ and Xiong, RQ and Wu, JW and Li, YC and Xie, JX and Zhou, HP and Ye, GY and Chang, Y and Huang, KB and Pan, SY}, title = {β-Hydroxybutyrate improves glymphatic system function and alleviates cerebral edema in mice after ischemic stroke.}, journal = {Acta pharmacologica Sinica}, volume = {}, number = {}, pages = {}, pmid = {41535708}, issn = {1745-7254}, abstract = {Cerebral edema is a severe complication following ischemic stroke. Recent studies have highlighted the crucial role of the glymphatic system (GS) in the clearance of water and macromolecules. GS dysfunction involving the disorders of AQP4 polarization may be crucial in the pathophysiology of cerebral edema. β-Hydroxybutyrate (BHB), the main component of the ketone body, has been shown to alleviate neurological deficits by restoring GS function in subarachnoid hemorrhage models and to reduce Aβ deposition in Alzheimer's disease models. In this study we investigated the effects of BHB on cerebral edema following ischemic stroke and its mechanisms. The mice were fed a ketogenic diet (KD) or a normal diet for 4 weeks before transient middle cerebral artery occlusion (MCAO). Alternatively, the mice received BHB (5 g·kg[-1]·d[-1]) or vehicle post-MCAO. By using brain section analysis, transcranial macroimaging, two-photon in vivo imaging and MRI, we demonstrated that both KD and BHB treatment significantly enhanced GS function under normal and MCAO conditions. BHB reduced cerebral edema and infarct volume post-MCAO. Notably, delayed BHB treatment initiated 10 h post-MCAO still improved GS function, but did not influence infarct volume. Furthermore, we revealed that BHB increased α1-syntrophin expression and H3K27ac levels in α1-syntrophin (Snta1) enhancer, restoring AQP4 polarization. In addition, BHB also reduced HDAC3 expression and elevated p300 expression. These results suggest that a KD and BHB treatment enhance GS function in mice and that BHB also mitigates brain edema after MCAO. The potentiation of GS function by BHB is likely mediated by the inhibition of HDAC3 activity and the increase in p300 activity, which upregulate α1-syntrophin expression and restore AQP4 polarization.}, } @article {pmid41535445, year = {2026}, author = {Schnieder, M and von Arnim, CAF}, title = {[Polypharmacy in patients with neuropsychiatric symptoms].}, journal = {Innere Medizin (Heidelberg, Germany)}, volume = {}, number = {}, pages = {}, pmid = {41535445}, issn = {2731-7099}, abstract = {Dementia, delirium, and depression are the main geriatric psychiatric syndromes, and their prevalence is increasing significantly due to demographic aging. At the same time, multimorbidity and polypharmacy lead to increased interaction rates and a higher frequency of side effects, as well as reduced adherence. In Germany, the number of dementia cases is projected to rise from the current 1.8 million to 2.8 million by 2050. The most common etiologies are Alzheimer's disease and vascular dementia. Progressive cognitive and motor function loss often results in apraxia and dysphagia, which complicate pharmacotherapy. Acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and memantine are used therapeutically. Newly approved amyloid antibodies (lecanemab, donanemab) show efficacy in the early stages of Alzheimer's disease, but carry the risk of amyloid-associated imaging abnormalities (ARIA). Dementia is considered a predisposing risk factor for delirium, which is characterized by fluctuations in attention and consciousness. Delirogenic factors include polypharmacy as well as other medications such as opioids and benzodiazepines. Due to the increased risk of mortality and stroke, neuroleptics should only be administered to geriatric patients when strictly indicated, in minimal doses, and for a limited duration. Non-pharmacological interventions take precedence. Selective serotonin reuptake inhibitors (SSRIs) are considered the first-line treatment for depressive disorders in older adults, while tricyclic antidepressants should be avoided. Regular medication reviews, reduction of anticholinergic burden, and technical aids to facilitate medication intake are essential for optimizing treatment adherence.}, } @article {pmid41533472, year = {2026}, author = {Shah, A and Kalu, U and Chen, D and Slomkowski, M and Hobart, M and Such, P and Grossberg, GT}, title = {Brexpiprazole side-effect profile in people with agitation in Alzheimer's dementia: a plain language summary.}, journal = {Current medical research and opinion}, volume = {}, number = {}, pages = {1-3}, doi = {10.1080/03007995.2025.2608578}, pmid = {41533472}, issn = {1473-4877}, } @article {pmid41533031, year = {2026}, author = {Tan, FHP and Najimudin, N and Azzam, G and Zainuddin, A and Shamsuddin, S and Mohd Kasihmuddin, MS}, title = {Geroprotective effects of Salvianolic acid A through redox and detoxification pathway activation in an aging Drosophila Alzheimer's model.}, journal = {Biogerontology}, volume = {27}, number = {1}, pages = {39}, pmid = {41533031}, issn = {1573-6768}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Drosophila melanogaster ; Disease Models, Animal ; *Aging/drug effects/metabolism ; Oxidation-Reduction ; Animals, Genetically Modified ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism/genetics ; *Caffeic Acids/pharmacology ; *Lactates/pharmacology ; Humans ; *Neuroprotective Agents/pharmacology ; Longevity/drug effects ; Peptide Fragments ; }, abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β42 (Aβ42) neurotoxic peptides that cause oxidative stress and neurodegeneration. The current study examined the neuroprotective properties of salvianolic acid A (SalA), an antioxidant polyphenol, in a Drosophila melanogaster model of AD. Transgenic flies expressing human Aβ42 were assayed for eye morphology, life span, and locomotor function after SalA diet supplementation. RNA-seq and RT-qPCR were used to quantify transcriptional regulation with SalA treatment. Aβ42 expression resulted in classic AD phenotypes, including retinal degeneration, shortened lifespan, and compromised climbing ability. Partial rescue of the rough-eye phenotype, significant prolongation of lifespan, and improved locomotor function in aging flies were induced by SalA treatment. Transcriptome profiling showed the upregulation of glutathione metabolism-associated, cytochrome P450 activity-associated, and antioxidant defence-associated genes, while muscle development-associated, cell adhesion-associated, and apoptosis-associated genes were downregulated. Network analysis identified a SalA-responsive gene module enriched in detoxification and immune pathways that was conducive to enhanced cellular resistance to Aβ42 toxicity. These findings identify a redox-regulated aging mechanism whereby SalA maintains neuronal and systemic homeostasis during aging. SalA inhibits Aβ42-induced neurotoxicity in Drosophila via promoting redox equilibrium and detoxification. These findings present SalA as a potential multi-target lead drug for AD and other age-related neurodegenerative diseases.}, } @article {pmid41531988, year = {2025}, author = {Benin, BM and Hillyer, T and Csubak, BA and Aguirre, N and Dengler-Crish, CM and Kang, C and Shin, WS}, title = {Investigation of Three Flavonoids as Potent Tau Aggregation Inhibitors and In vivo Demonstration of Myricetin.}, journal = {Pharmacological research. Natural products}, volume = {9}, number = {}, pages = {}, doi = {10.1016/j.prenap.2025.100449}, pmid = {41531988}, issn = {2950-1997}, abstract = {Neurodegenerative disorders, including Alzheimer's disease (AD), are characterized by the formation and propagation of neurotoxic tau aggregates, which arise from the misfolding and subsequent aggregation of tau proteins into fibrillary structures. While tau-targeting agents represent a promising therapeutic strategy for the prevention and treatment of various neurodegenerative diseases, they currently constitute a limited subset of the treatments undergoing clinical trials. In this study, we report the potent anti-aggregation and filament disassembly effects of three flavonols: myricetin, quercetagetin, gossypetin. We observed remarkable nanomolar-to-low-micromolar 50% inhibitory concentrations (0.57-1.21μM) and low 50% disassembly concentrations (7.5-14μM) using tau seeds derived from AD mouse model brains. Furthermore, we validated that myricetin treatment was associated with a reduction in overall phosphorylated tau (p-Tau) burden in vivo in the 3xTg AD mouse model. Notably, these reductions were associated with enhanced performance in Y-maze assessments of spatial learning and memory, supporting further preclinical evaluation, including direct brain pharmacokinetic studies and mechanism-driven investigations relevant to tauopathy therapy.}, } @article {pmid41531938, year = {2026}, author = {Mandloi, U and Giri, N and Kumar, S and Modi, G}, title = {Theranostic advances in Alzheimer's disease: structure-guided design of near-infrared fluorescent probes targeting amyloid-β and cholinergic dysfunction.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1039/d5md00713e}, pmid = {41531938}, issn = {2632-8682}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder, with unmet clinical challenges due to the lack of early diagnosis and an efficient treatment. Theranostics, an integrated approach that combines diagnosis and therapy, has emerged as a viable option, particularly with the use of near-infrared fluorescence probes (NIRFPs), which allow real-time in vivo imaging and therapeutic monitoring. This review article discusses recent breakthroughs in the rational design of alkene-bridged donor-π-acceptor (D-π-A) NIRFPs that target AD hallmarks such as amyloid-β (Aβ) aggregation and cholinergic dysfunction. We specifically focused on multifunctional probes like THK-565 (fluorescent compound), and a dihydrotetramethyl-indocyanine theranostic near-infrared probe (DTNP), which exhibit high blood-brain barrier (BBB) permeability, target selectivity, and dual imaging/therapeutic capabilities. Furthermore, emerging probes can distinguish between Aβ and cholinesterase (ChEs) with high resolution and low toxicity. Together, these molecular imaging technologies provide a game-changing platform for detection of early-stage AD and multiple intervention approaches. We explore structure-activity connections, molecular processes, and future directions for the clinical translation of NIRFP-based theranostic agents in AD.}, } @article {pmid41531926, year = {2025}, author = {Jerath, R and Malani, V}, title = {The fading self in space-disruption of default spatial representation across neurological disorders.}, journal = {Frontiers in systems neuroscience}, volume = {19}, number = {}, pages = {1655500}, doi = {10.3389/fnsys.2025.1655500}, pmid = {41531926}, issn = {1662-5137}, abstract = {Neurological disorders stem from an intermingled change to self-in-space. While many of these disorders present as spatial deficits-contralateral neglect syndrome, for example-they manifest from the same etiology: disruption to the brain's "default spatial representation" (DSR). DSR is a basic internally generated representation of space that delineates where the self is located in space-without attentional focus from an external drive. We review how pathologic disintegration of DSR is associated with anomalous activation and connectivity within distinct large-scale brain networks (e.g., the default mode network and a comprehensive attention-networked system), leading to a heterogeneous presentation of clinically assessed outcomes. The outcomes include psychogenic paralysis of limbs, left-side neglect, rectified sense of other locations, disorders of consciousness, symptoms related to autism spectrum disorder, Alzheimer's disease, schizophrenia, and depersonalization/derealization disorder. By consolidating evidence from neuroimaging, lesion-symptom mapping, and computational assessment, we aim to reconceptualize these disorders not as separate and independent maladies, but as manifestations of a deeper, shared etiology, supporting a network-based assessment strategy for diagnosis and treatment that seeks to restore self-in-space.}, } @article {pmid41531784, year = {2025}, author = {Zhang, Y and Ren, Y and Zhu, X and Liu, T and Han, R and Fang, Y and Zhao, Z and Mao, F and Wang, Y and Li, X and Li, X}, title = {Research Progress on Idebenone in Neurodegenerative Diseases.}, journal = {Aging medicine (Milton (N.S.W))}, volume = {8}, number = {6}, pages = {624-633}, doi = {10.1002/agm2.70047}, pmid = {41531784}, issn = {2475-0360}, abstract = {In recent years, significant progress has been made in understanding the therapeutic potential of idebenone (IDE), a synthetic analogue of Coenzyme Q10, in neurodegenerative diseases (NDs). This review comprehensively examines the pharmacological properties of IDE and its emerging applications in various NDs, with particular emphasis on Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, and Huntington's disease. We elucidate IDE's multifaceted neuroprotective mechanisms, including its potent antioxidant activity that reduces reactive oxygen species production, its ability to enhance mitochondrial bioenergetics, and its regulatory effects on cellular metabolism. Additionally, we critically evaluate current clinical research findings and discuss the translational potential of IDE in ND therapeutics. The accumulated evidence strongly supports IDE as a promising mitochondrial-targeted agent capable of mitigating disease symptoms and modifying disease progression in multiple neurodegenerative disorders. This review highlights both the current achievements and future directions for IDE-based interventions in ND treatment.}, } @article {pmid41531459, year = {2025}, author = {Fischer, BL and Van Hulle, CA and Norton, DL and Wyman, MF and Ennis, G and Lambrou, NH and Bouges, S and Gooding, DC and Gleason, CE}, title = {Mild Behavioral Impairment is Associated With Incident Cognitive Decline Among Dementia-Free, Racially Diverse Older Adults: Data From the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) Study.}, journal = {The American journal of geriatric psychiatry. Open science, education, and practice}, volume = {8}, number = {}, pages = {43-53}, doi = {10.1016/j.osep.2025.09.002}, pmid = {41531459}, issn = {2950-3868}, abstract = {OBJECTIVES: To determine whether MBI associates with worse cognitive performance over time and with incident cognitive decline in an older, racially/ethnically diverse cohort at early stages of cognitive change.

DESIGN: This observational cohort study followed participants from the Wisconsin Alzheimer's Disease Research Center Clinical Core (WADRC) for up to 13 visits.

SETTING: An urban university research center.

PARTICIPANTS: Participants from the WADRC Clinical Core were included in this convenience sample if they were without dementia, had undergone at least 1 cognitive assessment, and completed measures of cognitive, clinical and affective function.

MEASUREMENTS: MBI was assessed using the Neuropsychiatric Inventory. Linear mixed effects models (LME) were fit to cognitive outcomes Trailmaking Tests A and B (TMT-A, B) and Wechsler Logical Memory (LM). Cox proportional hazard models assessed whether MBI was related to risk for incident global Clinical Dementia Rating Scale (CDR >0).

RESULTS: N = 584 participants with mean age 64.6 years, range 46-92.6 years, 59.4% female and 17% African American. LME results indicated participants with MBI exhibited worse age-associated decline on TMT-B, compared to those without MBI (beta=0.008, p = 0.01, CI: 0.002, 0.01, t(337) = 2.4, p = 0.01). MBI at baseline was associated with a significant hazard ratio (HR) indicating an increased risk of decline on the CDR (HR: 2.84; HR 95% CI: 1.68 - 4.81; p = 0.0001).

CONCLUSIONS: MBI associated with worse cognitive performance and incident cognitive decline in a racially diverse, older adult sample at early stages of cognitive change. Increased awareness of the late life emergence of neuropsychiatric symptoms is warranted to assist in identification and improve prognostication and treatment of neurodegenerative disease.}, } @article {pmid41531227, year = {2026}, author = {Samudra, N and Vemuri, M and Weitlauf, J}, title = {Menopause, cognition, and Alzheimer's disease risk.}, journal = {Current opinion in obstetrics & gynecology}, volume = {}, number = {}, pages = {}, doi = {10.1097/GCO.0000000000001087}, pmid = {41531227}, issn = {1473-656X}, abstract = {PURPOSE OF REVIEW: Cognitive symptoms are common throughout the menopause transition. This review outlines a comprehensive clinical approach, grounded in recent findings, to guide clinicians in addressing menopause-related cognitive concerns and neurodegenerative disease risk for midlife women.

RECENT FINDINGS: Research highlights the benefits of lifestyle and psychosocial interventions for cognitive symptoms during the menopause transition. Addressing underlying medical and mental health conditions, as well as difficulties with sleep, chronic stress, and vasomotor symptoms, can ameliorate symptoms and reduce risk for future dementia. Cognitive changes during the menopause transition do not typically indicate dementia. A subset of women, including apolipoprotein ε4 (APOE ε4) carriers and those who experience early menopause, face heightened risk. Alzheimer's disease biomarkers are clinically available and may change in some women during the menopause transition, particularly in APOE ε4 carriers, but our understanding of these changes, as well as their relationship to menopause hormone therapy, is evolving. There is presently insufficient evidence for the role of menopause hormone therapy for the treatment of menopause-related cognitive symptoms or neurodegenerative disease prevention.

SUMMARY: While typically transient, cognitive symptoms in menopause can benefit from addressing comorbid medical and psychosocial conditions. Research into dementia risk related to changes in the menopause transition is ongoing.}, } @article {pmid41530949, year = {2026}, author = {Chen, Y and Liu, Y}, title = {Eosinophils: Pathological Mechanisms and Novel Targeted Therapeutic Strategies Across Multiple Disease Spectrums.}, journal = {Journal of leukocyte biology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jleuko/qiag009}, pmid = {41530949}, issn = {1938-3673}, abstract = {Eosinophils are a type of white blood cell belonging to the granulocyte family. Their cytoplasm contains eosinophilic granules that hold various biologically active substances. They perform diverse functions, participating in inflammatory responses, immune defense, and tissue repair. Eosinophils are implicated in the pathogenesis of multiple diseases, including infectious diseases, allergic disorders, and hematological conditions. Moreover, increasing research in recent years has revealed significant associations between eosinophils and autoimmune diseases, solid tumors, coronary atherosclerotic heart disease, and even Alzheimer's disease. They participate in disease onset and progression through the release of toxic proteins, cytokines, and chemokines, as well as through interactions with other cells. Focusing on the biological characteristics and functions of eosinophils facilitates the elucidation of disease mechanisms associated with related disorders. This, in turn, provides further direction for eosinophil-targeted research and therapeutic strategies, including the research and development of drugs that modulate their function, targeted therapies, immunotherapies, and cell therapies. This paper provides a comprehensive review of the structure, function, and role of eosinophils in related diseases, along with potential future therapeutic strategies. It aims to deepen the understanding of researchers and clinicians, thereby facilitating their application in further research, as well as in clinical disease diagnosis and treatment analysis.}, } @article {pmid41353403, year = {2025}, author = {Bhargavan, B and Annadurai, N and Kanmogne, GD}, title = {Glycogen synthase kinase-3 activation and dysregulation of amyloid transport receptors expression and shedding in HIV-induced Alzheimer's disease-like pathology: modulatory effects of CCR5 antagonists.}, journal = {Acta neuropathologica communications}, volume = {14}, number = {1}, pages = {16}, pmid = {41353403}, issn = {2051-5960}, support = {1R21 MH123303 and 1R01 MH132517/MH/NIMH NIH HHS/United States ; 1R21 MH123303 and 1R01 MH132517/MH/NIMH NIH HHS/United States ; }, abstract = {UNLABELLED: Neurocognitive impairments occur in about 50% of HIV-infected humans and are associated with Alzheimer’s disease (AD)-like brain pathologies, including increased amyloid-beta1-42(Aβ42) and phospho-Tau. We previously demonstrated that HIV-infected humanized mice develop these AD-like pathologies associated with neurodegeneration. The underlying mechanisms are unknown. Here, we investigate whether HIV-induced Aβ and phospho-Tau involve dysregulation of transporters and kinases that regulate Tau phosphorylation and Aβ clearance, and the effects of CCR5 antagonists on these effectors. We analyzed human and animal (humanized mice) brain tissues, microvessels, plasma/serum, and human brain microvascular endothelial cells (HBMEC) for effects of HIV-1 infection, maraviroc treatment, and CCR5 knockdown/overexpression on Aβ, phospho-Tau, low-density lipoprotein receptor–related protein-1(LRP1), receptor for advanced glycation end-products (RAGE), and GSK-3α/β transcription, expression, and activation, LRP1 and RAGE cleavage/shedding, Aβ endothelial uptake and transport/clearance. HIV infection significantly increased phospho-Tau (serine396, serine199, threonine181), Aβ42 and GSK-3α/β activation in humans and animals’ brain cortex. HIV significantly decreased LRP1 and increased RAGE transcription and expression in brain tissues and microvessels, with accentuated LRP1 and RAGE dysregulation in humans with neurocognitive impairments. HIV significantly increased soluble (s)LRP1 and decreased sRAGE. Maraviroc abrogated HIV-induced CNS GSK-3α/β activation and Tau hyperphosphorylation, prevented LRP1 downregulation and RAGE upregulation, significantly decreased sLRP1 and increased sRAGE, increased Aβ42 efflux eightfold and decreased brain Aβ42 levels 11.7-fold. Maraviroc abrogated Aβ42-induced decrease in HBMEC tightness, significantly decreased endothelial RAGE, increased LRP1, and Aβ42 endothelial transport via LRP1 crosstalk. CCR5 knockdown blocked maraviroc-induced increased endothelial Aβ transport. These data suggest that therapeutically targeting CCR5 can abrogate HIV-induced GSK-3α/β activation and phospho-Tau, prevent LRP1 downregulation and shedding and increase brain Aβ efflux/clearance, prevent RAGE upregulation, Aβ brain influx, and AD-like neuropathology.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-025-02197-4.}, } @article {pmid41339497, year = {2025}, author = {Babu, T and Mahendran, R and Ajitha, P and Rajendran, S}, title = {Intra-scale interaction and cross-scale fusion network for detecting the progression of neurodegeneration in Alzheimer's disease.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {1377}, pmid = {41339497}, issn = {2045-2322}, abstract = {Alzheimer’s disease (AD), one of the most widespread neurodegenerative disorders, can be mitigated through early recognition and treatment. Recent research has shown that multimodal fusion is effective for the early-stage diagnosis of AD. However, most existing methods do not adequately account for the differences in data modality domains, their interconnections, and relative relevance.In this paper, we introduce a robust Intra-scale Interaction and Cross-scale Fusion Network (ISI-CSFN) for AD progression detection. The proposed model employs a linearized convolutional attention module to enable interaction between global information captured by the Cascaded Transformer (CTransformer) and local features extracted by the Depthwise Separable Convolution Network (DSCN). This mechanism enhances the discriminative ability for AD progression detection by allowing each modality-specific branch to incorporate complementary contextual representations from the others while maintaining the integrity of its own features.Furthermore, the model integrates background (BG) information with multimodal temporal data for simultaneous prediction of several cognitive score variables. The proposed method achieves strong results for both regression and multi-class progression tasks. Specifically, the accuracy of our approach is 97.26% for NC vs. AD, 89.25% for NC vs. sMCI, and 84.74% for NC vs. pMCI classifications. In addition, the model attains the highest correlation coefficient and the lowest root mean square error (RMSE) across several clinical score regression tasks.}, } @article {pmid41530554, year = {2026}, author = {Taylor, WD and Gerlach, AR and Szymkowicz, SM and Gujral, S and Andreescu, C}, title = {Remission is insufficient: predictors and mechanistic models of recurrence in late-life depression.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {41530554}, issn = {1740-634X}, support = {R01 MH121620/MH/NIMH NIH HHS/United States ; R01 MH123662/MH/NIMH NIH HHS/United States ; R33 MH122464/MH/NIMH NIH HHS/United States ; K01 MH133913/MH/NIMH NIH HHS/United States ; K23 MH125074/MH/NIMH NIH HHS/United States ; R01 MH108509/MH/NIMH NIH HHS/United States ; R01 MH121619/MH/NIMH NIH HHS/United States ; }, abstract = {While achieving remission is the goal of acute antidepressant treatment, recurrence of new depressive episodes following remission is unfortunately common in clinical populations with Major Depressive Disorder, including older adults with Late-Life Depression (LLD). The neurobiological factors underlying this risk are poorly understood, limiting our ability to identify potential preventive mechanistic targets. Beyond the limited prognostic utility achieved from individual psychiatric history, it remains challenging to clinically stratify individual risk. This review examines factors influencing the recurrence of depressive episodes following remission in LLD, focusing on cognitive, behavioral, social, and environmental aspects. It additionally considers neuroimaging-based biomarkers related to recurrence risk as well as discussing evidence for and limits of maintenance treatment to prevent recurrence. The paper proposes possible mechanisms contributing to recurrence, including physiological and behavioral responses to stressors, the influence of Alzheimer's disease neuropathology, and conceptualizing repeat depressive episodes within the accelerated aging hypothesis of LLD. A dynamical landscape model of depression recurrence is proposed to elucidate the interplay between different mood states, resilience, and treatment response. This synthesis then highlights avenues for future research, focusing on areas of potential significance ranging from risk stratification to tertiary prevention efforts that may improve both long-term affective and cognitive symptoms.}, } @article {pmid41530008, year = {2026}, author = {Feldman, OJ and Herrmann, N and Ruthirakuhan, M and Gallagher, D and L G Verhoeff, NP and Kiss, A and Black, SE and Lanctôt, KL}, title = {Assessment of clinical factors that predict response to nabilone for agitation in Alzheimer's disease: A post hoc analysis of a randomized placebo-controlled trial.}, journal = {International psychogeriatrics}, volume = {}, number = {}, pages = {100183}, doi = {10.1016/j.inpsyc.2026.100183}, pmid = {41530008}, issn = {1741-203X}, abstract = {INTRODUCTION: Previously, nabilone showed a medium effect size for treating agitation in moderate-to-severe Alzheimer's disease (AD), but response varied. These post hoc analyses aimed to identify a group of clinical characteristics that predicted treatment response.

METHODS: Data from a double-blind, placebo-controlled crossover trial in AD agitation were used. Nineteen clinical characteristics were categorized (presence/absence) and evaluated for relation to agitation response (change on Cohen-Mansfield Agitation Inventory (CMAI)). Characteristics with a ≥ 8 point response difference between categories were included in a multivariable analysis model to calculate individual predicted response. Linear mixed-effects models with Satterthwaite's approximation evaluated the impact of treatment on the relationship between predicted and observed responses.

RESULTS: Thirty-nine participants (77 % male, mean [SD] age 87 [10.2], standardized Mini-Mental State Exam (sMMSE) 6.5 [6.8]) were enrolled. Variable selection identified five characteristics related to greater nabilone efficacy: higher pain (Pain Assessment in Advanced Dementia score ≥3) (difference [SE] in CMAI response = -18.8 [3.2]), greater appetite and eating disorders (-16.4 [5.5]), greater apathy (-14.0 [5.5]), less cognitive impairment (sMMSE greater than 10) (-16.5 [4.2]) and no concomitant cholinesterase inhibitors (-13.9 [4.4]). For those with a predicted response in the top tertile based on those five characteristics, 82 % responded, compared with 40 % in the lowest tertile. A treatment-by-tertile interaction (F(2,29) = 8.48, p = 0.001) indicated observed treatment response varied across tertiles.

CONCLUSION: A reliable clinical profile of persons with AD related agitation likely to respond to nabilone may be established with additional research.}, } @article {pmid41528665, year = {2026}, author = {Kumar, A and Rakshit, D and Saharia, N and Tiwari, P and Mugale, MN and Mishra, A}, title = {Dietary Isoflavone Biochanin A Attenuates Aluminium Chloride-Induced Sporadic Alzheimer's Disease and Associated Neurobehavioral Alterations Through NRF2-HO1 Pathway Activation and NLRP3 Inflammasome Suppression.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {359}, pmid = {41528665}, issn = {1559-1182}, mesh = {Animals ; *Genistein/pharmacology/therapeutic use/administration & dosage ; Aluminum Chloride ; *Alzheimer Disease/chemically induced/metabolism/drug therapy/pathology ; *NF-E2-Related Factor 2/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Inflammasomes/metabolism/drug effects ; Male ; Signal Transduction/drug effects ; Mice ; Oxidative Stress/drug effects ; *Behavior, Animal/drug effects ; *Heme Oxygenase-1/metabolism ; Amyloid beta-Peptides/metabolism ; Neuroprotective Agents/pharmacology ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD), a debilitating neurodegenerative disorder, currently lacks effective curative treatments. Growing evidence implicates aluminium, a widely prevalent environmental metal, in the pathogenesis of AD due to its ability to induce oxidative stress, neuroinflammation, cholinergic dysfunction, and amyloid-beta (Aβ) deposition, ultimately leading to cognitive decline. Biochanin A (BCA), a naturally occurring isoflavone, exhibits well-documented antioxidant, anti-inflammatory, and neuroprotective activities, including acetylcholinesterase (AChE) inhibition. However, its specific therapeutic potential in AD models has remained largely unexplored. This study evaluates the protective effects of BCA against aluminium chloride (AlCl3)-induced AD-like pathology in mice. Animals received daily oral administration of AlCl3 (100 mg/kg) for 6 weeks, with or without concurrent BCA treatment (5, 10, and 20 mg/kg). During the final week, comprehensive neurobehavioral assessments were conducted. Thereafter, hippocampal tissues were analyzed for biochemical, molecular, and elemental analyses, and intact brains were examined histologically. AlCl3 exposure significantly impaired neurobehavioral performance, elevated oxidative stress, disrupted cholinergic function, intensified neuroinflammation, promoted amyloid aggregation, and induced neurodegeneration. Notably, BCA supplementation dose-dependently ameliorated these pathological alterations. BCA treatment improved neurobehavioral deficits (P < 0.05), reduced oxidative markers (P < 0.01), restored cholinergic function by lowering AChE activity (P < 0.01), attenuated inflammatory mediators (P < 0.01), reduced amyloid and aluminium deposition (P < 0.001), and alleviated AlCl3-induced neurodegeneration. Overall, our findings indicate that BCA confers neuroprotection primarily through activation of the NRF2-HO-1 signaling pathway and through suppression of the NLRP3 inflammasome, highlighting its promise as a potential therapeutic candidate for AD.}, } @article {pmid41527747, year = {2026}, author = {Heo, RJ and Negida, A and Barrett, MJ and Chrenka, EA and Bayram, E and Kane, JPM and Werner, AM and Rossom, RC and Wyman-Chick, KA}, title = {Cholinesterase inhibitors for patients with dementia: Patterns of prescribing and disparities in treatment.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251411418}, doi = {10.1177/13872877251411418}, pmid = {41527747}, issn = {1875-8908}, abstract = {BackgroundCholinesterase inhibitors (ChEIs) are cornerstones of the symptomatic treatment of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) and are also prescribed for vascular dementia (VaD). Despite their widespread use, patterns of ChEI prescribing are unclear.ObjectiveOur objective was to examine the prevalence, timing, and types of ChEI prescriptions before and after dementia diagnosis.MethodsWe analyzed electronic health record and claims data for patients diagnosed with AD, DLB, or VaD between October 2015 and August 2022 from a large U.S. healthcare system. ChEI claims (donepezil, rivastigmine, galantamine) were identified in the ±3 years surrounding dementia diagnosis. Repeated measures logistic regression was used to estimate the likelihood of ChEI fills by time-period, dementia type, and time x dementia type interaction to determine if change in prescription patterns significantly differed by diagnosis.ResultsAmong 3166 eligible patients, DLB had the highest prevalence of ChEIs both pre-and post-diagnosis compared to patients with AD and VaD. Post-diagnosis, donepezil was the most common, while galantamine use was sparse. After adjusting for demographics, patients with VaD had lower rates of ChEIs relative to AD (OR: 0.34, 95% CI 0.26-0.45). In the fully adjusted model, females (OR: 0.81, 95% CI: 0.71-0.91) and patients from ethnoracially minoritized populations (OR: 0.74, 95% CI: 0.62-0.88) were less likely to fill ChEI prescriptions.ConclusionsDonepezil was the most frequently filled ChEI across dementias. Patients with DLB had the highest prevalence of ChEIs pre- and post-diagnosis. The potential disparities in treatment we identified should be investigated further.}, } @article {pmid41527739, year = {2026}, author = {Le, J and Hu, X and Jiang, Y and Wang, Q and Ma, Q and Cui, W}, title = {Insights into phosphoproteomic studies and prospects of phosphoproteins as biomarkers for brain disorders.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251411546}, doi = {10.1177/13872877251411546}, pmid = {41527739}, issn = {1875-8908}, abstract = {The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.}, } @article {pmid41527682, year = {2026}, author = {Zohud, O and Lone, IM and Midlej, K and Iraqi, FA}, title = {The complexity of dementia development and its comorbidities: The collaborative cross-mouse population for multivarious tasks approach.}, journal = {Animal models and experimental medicine}, volume = {}, number = {}, pages = {}, doi = {10.1002/ame2.70131}, pmid = {41527682}, issn = {2576-2095}, support = {//A core fund from Tel Aviv University/ ; }, abstract = {The rising incidence of dementia and associated neurodegenerative disorders poses a growing public health challenge. These conditions have traditionally been studied as isolated central nervous system disorders; however, emerging evidence suggests that broader systemic factors, including chronic inflammation, immune dysregulation, metabolic dysfunction, and genetic susceptibility, may also play a role. This review examines the interconnection between autoimmune diseases and metabolic syndromes in the pathogenesis and exacerbation of neurodegeneration. Conditions such as rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus have been associated with a heightened risk of developing dementia through chronic immune activation, blood-brain barrier disruption, and neuroinflammatory signaling. Similarly, metabolic disorders such as diabesity promote insulin resistance and oxidative stress, accelerating cognitive decline. The review also discusses glaucoma as a neurodegenerative condition with autoimmune features, underscoring the need for expanded classification and treatment strategies. A key focus is the utilization of the Collaborative Cross (CC) mouse model, which enables the study of gene-environment interactions across genetically diverse backgrounds. Findings from CC mice reveal strain-dependent susceptibility to inflammation, cognitive impairment, and gut-brain axis dysfunction, providing a translational bridge to human variability. This review highlights the importance of integrating precision-based approaches to dementia research that consider systemic influences. Advancing our understanding of these multiorgan interactions holds potential for designing precision-based therapeutic approaches to postpone the onset or reduce the incidence of neurodegenerative conditions.}, } @article {pmid41527663, year = {2025}, author = {Barbati, SA and Carota, G and Partsinevelos, K and Di Pietro, L and Privitera, A and Cardaci, V and Graziani, A and Mangione, R and Lazzarino, G and Tavazzi, B and Di Pietro, V and Maiani, E and Bellia, F and Amorini, AM and Lazzarino, G and Baba, SP and Caruso, G}, title = {Preclinical evidence and therapeutic perspectives on carnosine for the treatment of neurodegenerative disorders.}, journal = {AIMS neuroscience}, volume = {12}, number = {4}, pages = {444-513}, doi = {10.3934/Neuroscience.2025025}, pmid = {41527663}, issn = {2373-7972}, abstract = {Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide widely distributed in mammalian tissues, especially skeletal and cardiac muscle cells, and, to a lesser extent, in the brain. While early interest in carnosine was given because of its role in muscle cell metabolism and athletic performance, it has more recently gained attention for its potential application in several chronic diseases. Specifically, brain aging and neurodegenerative disorders have received particular attention, as a marked reduction in carnosine levels has been described in these conditions. Carnosine exerts a wide range of biological activities, including antioxidant, anti-inflammatory, anti-glycation, metal-chelating, and neuroprotective properties. Mechanistically, it acts by inhibiting the production of advanced glycation end products (AGEs), buffering cellular pH, and regulating intracellular nitric oxide signaling and mitochondrial function. Its safety profile, the lack of toxicity, and significant side effects support its application for long-term therapeutic use. In this review, we aim to recapitulate and discuss the effects, dosages, and administration routes of carnosine in preclinical in vivo models, with a particular focus on neurodegenerative disorders where it has been shown to reduce oxidative stress, suppress neuroinflammation, modulate protein aggregation, and preserve cognitive function, all key features of neurodegeneration. Despite promising findings, there are gaps in the knowledge on how carnosine affects synaptic plasticity, neuronal remodeling, and other processes that play a central role in the pathophysiology of neurodegenerative disorders. Additionally, clinical translation remains challenging due to inconsistencies across in vivo studies in terms of dosage, treatment duration, routes of administration, and disease models, which affect reproducibility and cross-study comparability. Therefore, while carnosine emerges as a multifunctional and well-tolerated molecule, further research is needed to clarify its therapeutic relevance in human diseases. In this review, we also address future perspectives and key methodological challenges that must be overcome to effectively translate carnosine's biological potential into clinical practice.}, } @article {pmid41527522, year = {2026}, author = {Richardson, TI and Klein, RC and Huang, K and Zhang, J and Mesecar, AD and Dage, JL and Clayton, B and Lamb, BT and Palkowitz, AD}, title = {Next-generation Alzheimer's therapeutics: target assessment and enablement at the Indiana University School of Medicine-Purdue University TREAT-AD Center.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e70964}, doi = {10.1002/alz.70964}, pmid = {41527522}, issn = {1552-5279}, support = {U54AG065181/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Drug Discovery/methods ; Indiana ; United States ; National Institute on Aging (U.S.) ; Schools, Medical ; }, abstract = {The incidence of Alzheimer's disease (AD) continues to increase, despite decades of effort to develop disease-modifying therapies. In response, the National Institute on Aging (NIA) established the TaRget Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) centers to address the gap between basic research and translational drug discovery. Situated within a robust AD research environment, the Indiana University School of Medicine (IUSM)-Purdue University TREAT-AD Center is one of two National Institutes of Health (NIH)-supported centers funded to accomplish this mission. With a focus on novel biological targets beyond amyloid and tau, our center has assembled the necessary components of a drug discovery engine: project and data management, bioinformatics and computational science, structural biology and biochemistry, assay development and pharmacology, and molecular design and synthesis of small molecules, antibodies, and oligonucleotides. Our objective is to deliver Target Enabling Packages (TEPs) within an open science framework, making data, methods, and research tools broadly accessible through the AD Knowledge Portal. HIGHLIGHTS: The Indiana University School of Medicine (IUSM)-Purdue TREAT-AD Center develops Target Enabling Packages (TEPs) to advance novel targets for the treatment of Alzheimer's disease (AD). The center is overseen by an administrative core and operates through four technical cores - bioinformatics, structural biology, assay development, and medicinal chemistry - within a milestone-driven and open science framework. Multi-omics, systems biology, and machine learning (ML) approaches guide the nomination of high-priority targets beyond amyloid and tau. Cross-core workflows provide structural insights into novel biological targets, validated assays, biomarkers, and molecular probes that enable lead optimization. All data, methods, and tools are openly shared through the AD Knowledge Portal to accelerate global efforts in AD drug discovery.}, } @article {pmid41527496, year = {2026}, author = {Kalita, T and Shakya, A and Ghosh, SK and Singh, UP and Bhat, HR}, title = {Microwave-Assisted Synthesis and In Vitro Anti-Alzheimer Evaluation of Novel 1,3,5-Triazine-Nicotinic Hydrazide Derivatives as Acetylcholinesterase and Butyrylcholinesterase Inhibitors.}, journal = {Journal of biochemical and molecular toxicology}, volume = {40}, number = {1}, pages = {e70685}, doi = {10.1002/jbt.70685}, pmid = {41527496}, issn = {1099-0461}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; *Butyrylcholinesterase/metabolism/chemistry ; *Alzheimer Disease/drug therapy/enzymology ; *Acetylcholinesterase/metabolism/chemistry ; Animals ; Humans ; *Triazines/chemistry/pharmacology/chemical synthesis ; *Microwaves ; Cell Line, Tumor ; Molecular Docking Simulation ; Male ; *Hydrazines/chemistry/pharmacology/chemical synthesis ; Rats ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder posing major global health challenges due to its complex pathophysiology and increasing prevalence among the elderly. In the present work, the molecular hybridization technique was utilized to design and synthesize nicotinic hydrazide-1,3,5-triazine hybrids. Accordingly, this study aimed to design, perform in silico screening, synthesize, and evaluate the in vitro and in vivo anti-AD potential of the proposed compounds. Docking studies revealed that the compounds displayed key interactions with catalytic site and peripheral anionic site residues. Based on binding affinity, ten compounds were synthesized and characterized using different spectroscopic techniques. In vitro AChE and BChE inhibitory assays revealed that the compound 4A36 showed the highest inhibitory ability with log IC50 values of 5.97 μM against AChE and 4.57 μM against BChE. In addition, cytotoxicity screening revealed that 4A36 was non-toxic in SH-SY5Y neuroblastoma cells in the concentration range of 15.625-250 µg/mL. Acute oral toxicity evaluation of the compound revealed no adverse effects up to 175 mg/kg b.w. Further, in vivo studies using the scopolamine-induced model further validated the therapeutic promise of the compound. At a dose of 30 mg/kg b.w., the compound demonstrated significant improvements in learning and memory, reduced MDA levels with concurrent elevation of antioxidant enzymes SOD and Catalase, and reduced AChE activity in hippocampal tissue. Histopathological observations revealed that treatment groups, especially at higher dose (30 mg/kg b.w.), preserved the granular layer of the dentate gyrus and improved neuronal integrity compared to the disease control. These findings indicate that 4A36 at a dose of 30 mg/kg b.w. may be considered as a promising lead compound in AD.}, } @article {pmid41527161, year = {2026}, author = {Cheng, CM and Tsai, MJ and Tseng, CC and Lin, YS and Lin, YS and Chen, LY and Liu, MN and Fuh, JL}, title = {Pharmacological management of agitation in dementia: An evidence-based review with expert consensus.}, journal = {Journal of the Chinese Medical Association : JCMA}, volume = {}, number = {}, pages = {}, doi = {10.1097/JCMA.0000000000001342}, pmid = {41527161}, issn = {1728-7731}, abstract = {Agitation is a frequently occurring and challenging neuropsychiatric symptom of Alzheimer's disease (AD) that substantially affects quality of life, caregiver burden, and healthcare utilization. Non-pharmacological interventions, especially trigger identification, environmental adjustments, and supportive activities, remain the first-line approach for treating agitation. Pharmacological treatment should be considered only when non-drug measures are insufficient or when agitation causes severe distress or safety risks. This consensus integrates evidence up to June 2025, the Taiwan Ministry of Health and Welfare approvals, and Taipei Veterans General Hospital expert opinion. Among the approved agents, brexpiprazole demonstrated the strongest evidence and most favorable safety profile. Risperidone and aripiprazole are effective, but require careful monitoring for cerebrovascular and extrapyramidal risks. Selected antidepressants, particularly citalopram and agomelatine, should be considered when safety is prioritized. Anticonvulsants, acetylcholinesterase inhibitors, and memantine have limited efficacy and should be reserved for refractory cases. Long-term or routine pharmacological use is not supported by current evidence. Future research should focus on identifying responsive patient subgroups, optimizing dosing strategies, and integrating medications into individualized, multidisciplinary care plans.}, } @article {pmid41526725, year = {2026}, author = {Li, R and Berlowitz, D and Mez, J and Silver, B and Wang, X and Hu, W and Goodwin, R and Keating, H and Liu, W and Lin, H and Yu, H}, title = {Early prediction of Alzheimer's disease using longitudinal electronic health records of US military veterans.}, journal = {Communications medicine}, volume = {6}, number = {1}, pages = {23}, pmid = {41526725}, issn = {2730-664X}, abstract = {BACKGROUND: Early prediction of Alzheimer's disease is important for timely intervention and treatment. We examine whether machine learning on longitudinal electronic health record notes can improve early prediction of Alzheimer's disease.

METHODS: From Veterans Health Administration records (2000 to 2022), we studied 61,537 individuals diagnosed with Alzheimer's disease and 234,105 without, aged 45-103 years, 98.4% were male. From clinical notes, we quantified the frequency of subjective cognitive decline and Alzheimer's disease-related keywords, and applied statistical machine learning models to assess their ability to predict future diagnosis.

RESULTS: Here we show that Alzheimer's-related keywords (e.g., "concentration," "speaking"), occur more often in notes of individuals who later develop Alzheimer's disease than in controls. In the 15 years preceding diagnosis, cases demonstrate an exponential increase in keyword mentions (from 9.4 to 57.7 per year), whereas controls show a slower, linear increase (8.2 to 20.3). These trends are consistent across demographic subgroups. Random forest models using these keywords for prediction achieve an area under receiver operating characteristic curve from 0.577 at ten years before diagnosis to 0.861 one day before diagnosis, consistently outperforming models using only structured data.

CONCLUSIONS: Signs and symptoms of early Alzheimer's disease are reported in clinical notes many years before a clinical diagnosis is made and the frequency of these signs and symptoms, approximated by keywords, increases the closer one is to the diagnosis. A simple keyword-based approach can capture these signals and can help identify individuals at high risk of future Alzheimer's disease.}, } @article {pmid41524953, year = {2026}, author = {O'Mara, A and Mody, BP and Mammi, M and Simjian, T and Ghattas, K and Kaliki, S and Le, NPM and Liew, A and Migliore, M and Mekary, RA}, title = {The effect of GLP-1 receptor agonists on cognition in nondiabetic patients with mild cognitive impairment or alzheimer's disease: a meta-analysis of randomized controlled trials.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {1}, pages = {149}, pmid = {41524953}, issn = {1590-3478}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Cognitive Dysfunction/drug therapy ; *Glucagon-Like Peptide-1 Receptor Agonists ; Randomized Controlled Trials as Topic ; *Cognition/drug effects ; }, abstract = {BACKGROUND: Currently, the cognitive impact of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) remains unclear in non-diabetic patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI), despite their widespread use for type 2 diabetes. This meta-analysis summarized cognitive outcomes from randomized controlled trials (RCTs) of GLP-1 RAs in non-diabetic patients with AD or MCI.

METHODS: PubMed, Cochrane Library, and Embase were searched for studies through October 27, 2024. Pooled standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated using random-effects models. Sensitivity analyses addressed variations in cognitive assessment methodologies. Between-study heterogeneity was evaluated using the I² index.

RESULTS: Four RCTs comprising 112 patients (61 placebo, 51 treatment) were included. For cognitive tests where higher scores indicate better outcomes, no significant difference was observed between GLP-1 RA and placebo groups (pooled SMD: -0.10, 95% CI: -0.53, 0.34; I² = 23.9%). Sensitivity analyses yielded consistent results. Analysis of the Alzheimer's Disease Assessment Scale-Cognitive subscale from two studies, where lower scores indicate better outcomes, similarly showed no significant treatment effect (SMD: 0.07, 95% CI: -0.47, 0.62; I² = 0%).

CONCLUSION: There was no evidence that GLP-1 RAs improved cognitive outcomes compared to placebo in non-diabetic patients with AD or MCI. Further research is needed to clarify their neuroprotective potential and explore alternative therapeutic strategies for cognitive decline.}, } @article {pmid41524814, year = {2026}, author = {Tripathi, P and Shah, J}, title = {Valacyclovir Mitigates Amyloid Plaque Deposition, P-Tau Aggregation, and Neuroinflammation in Streptozotocin induced Alzheimer's Disease Rat Model.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {356}, pmid = {41524814}, issn = {1559-1182}, support = {GSBTM/MD/PROJECTS/SSA/4887/2016-17//Gujarat State Biotechnology Mission, Government of Gujarat, India./ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; *tau Proteins/metabolism ; Streptozocin ; Male ; *Valacyclovir/pharmacology/therapeutic use ; Disease Models, Animal ; *Plaque, Amyloid/drug therapy/metabolism/pathology ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Rats ; Amyloid beta-Peptides/metabolism ; Rats, Wistar ; *Protein Aggregates/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's Disease (AD), a leading cause of dementia, is a known neurodegenerative disorder. Affecting millions of people worldwide, AD pathogenesis involves diverse risk factors such as lifestyle, environmental, and metabolic conditions that accelerate sporadic AD. Very recently, backed with substantial evidence, herpes simplex virus-1 (HSV-1) has been recognized as a potential causative factor that may play a pivotal role in sporadic AD. Latent virus is estimated to activate key underlying pathways, preferably Aβ and p-tau, to cause AD. Additionally, Antivirals such as Valacyclovir have emerged to impart a potential neuroprotective role in AD. Present research aimed to explore the neuroprotective role and mechanism of Valacyclovir in the streptozotocin-induced Alzheimer's disease model in rats. A single dose of 3 mg/kg ICV (intracerebroventricular) Streptozotocin (STZ) was administered to induce AD in rats. Two doses of Valacyclovir, i.e., 100 mg/kg and 150 mg/kg were evaluated with Donepezil 5 mg/kg as standard. Post 21 days of treatment, Valacyclovir demonstrated dose-dependent improvement in neurobehavioral parameters. Further, AD-specific parameters i.e. Aβ1-40 and Aβ1-42, p-tau, and BACE-1 were significantly (p < 0.001) reduced with parallel reduction in inflammatory (p < 0.001) and oxidative stress markers. Additionally, Valacyclovir also increased the levels of amyloid clearance enzymes i.e., neprilysin (NEP) (p < 0.001) and insulin-degrading enzyme (IDE) (p < 0.001). Results suggest promising neuroprotective action of valacyclovir via reducing Aβ-amyloid protein, p-Tau, BACE-1, as well as demonstrating anti-inflammatory and antioxidant activity.}, } @article {pmid41524585, year = {2026}, author = {Hu, G and Li, W and Lei, X and Yao, Y and Ye, S}, title = {Aloe-emodin attenuated Aβ-induced tau phosphorylation by autophagy-NLRP3 inflammasome pathway.}, journal = {Neuroreport}, volume = {}, number = {}, pages = {}, doi = {10.1097/WNR.0000000000002246}, pmid = {41524585}, issn = {1473-558X}, support = {82205235//the National Natural Science Foundation of China/ ; 2022AH050502//The Key Project Foundation of Natural Science Research of Anhui University of Chinese Medicine/ ; 2022rcyb028//The Talent Support Program of Anhui University of Traditional Chinese Medicine/ ; YQYB2024028//Anhui Province 2024 Action Project for Training Young and Middle aged Teachers in Universities/ ; }, abstract = {OBJECTIVE: Anthraquinone derivative aloe-emodin, extracted from Chinese herbs has been confirmed with various pharmacological effects, including anti-inflammatory and neuroprotective properties, particularly in Alzheimer's disease, but the exact mechanism of action remains unclear.

METHODS: In this study, the PC12 cells were induced by amyloid β-protein (Aβ) to establish an in vitro model of Alzheimer's disease. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine staining, transmission electron microscopy, real-time quantitative PCR, western blot, ELISA, coimmunoprecipitation (Co-IP), and immunofluorescence were employed to evaluate effect of aloe-emodin on the survival and expression of related genes and proteins in PC12 cells induced by Aβ.

RESULTS: We found that 5 μM aloe-emodin significantly enhanced cell survival and proliferation. It also increased the mRNA and protein expression of Beclin-1 and LC3II, while decreasing the mRNA expression of P62, PI3K, AKT, mechanistic target of rapamycin (mTOR), NOD-like receptor protein 3 (NLRP3), and caspase-1, as well as the protein expression of P62, NLRP3, cleaved-caspase-1, p-PI3K, p-AKT, p-mTOR, interleukin-18 (IL-18), and IL-1β. Additionally, aloe-emodin reduced the intensity of p-tau fluorescence. The Co-IP results demonstrated a direct interaction between NLRP3 and LC3. Interestingly, aloe-emodin exhibited effects comparable to those of RAPA, an mTOR inhibitor.

CONCLUSION: These findings demonstrate that aloe-emodin offers neuroprotective benefits by reducing NLRP3-mediated inflammation and promoting autophagy, thereby providing a novel perspective on the treatment of Alzheimer's disease.}, } @article {pmid41524357, year = {2025}, author = {Guzanova, EV and Zorkova, AV and Sorokina, TA and Goncharov, VV and Voronina, DS and Beschastnova, IA}, title = {[Frequency of nutritional deficiency in patients with Alzheimer's disease and Parkinson's disease].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {12}, pages = {113-119}, doi = {10.17116/jnevro2025125121113}, pmid = {41524357}, issn = {1997-7298}, mesh = {Humans ; Aged ; *Parkinson Disease/complications ; *Alzheimer Disease/complications ; Male ; Female ; Middle Aged ; Aged, 80 and over ; *Malnutrition/epidemiology/etiology/diagnosis/diet therapy ; Nutritional Status ; Nutrition Assessment ; Incidence ; Body Mass Index ; }, abstract = {OBJECTIVE: To determine the incidence of nutritional deficiencies in patients with Alzheimer's disease (AD) and Parkinson's disease (PD) and, if identified, to correct them.

MATERIAL AND METHODS: 111 patients with neurodegenerative diseases AD and PD aged 50 to 89 years) were examined. Patients were examined twice: at the initial visit and 2 months later. During the first visit, a neurological examination and neuropsychological assessment were performed, and anxiety and depression levels were determined. Nutritional status was assessed using the Mini Nutritional Assessment (MNA) questionnaire, and body mass index (BMI) was calculated. For laboratory confirmation of malnutrition, hemoglobin, albumin, lipid profile, urea, and creatinine levels were assessed. All patients at risk of malnutrition were given dietary recommendations. The patient's family discussed adherence to a dietary regimen and maintaining a nutritious diet. To treat malnutrition, patients were also recommended to receive enteral nutrition supplements at a rate of 30-35 kcal/kg of body weight for outpatients (a total of at least 400 kcal/day) and 1 g of protein/kg of body weight/day. For this purpose, Fresubin protein was used, individually adjusted from 2 to 6 measuring spoons (12-36 g of protein). In the presence of dysphagia, depending on the severity of the swallowing disorder, a diet with a modified consistency was prescribed: Fresubin Cream 2 kcal, Fresubin Yogurt, Fresubin Condensed Level 2, and Fresubin Condensed Level 1. At the second visit (2 months later), treatment effectiveness was assessed.

RESULTS: Among the examined patients, AD was diagnosed in 66 (59.5%) patients, and PD in 45. (40.5%). malnutrition/risk of malnutrition was detected in 31 (28%) patients. In the group of patients with AD who had malnutrition/risk of malnutrition, 15 (62.5%) patients had malnutrition, 9 (37.5%) had the risk of malnutrition. Among patients with PD, 3 (42.9%) patients were diagnosed with malnutrition, 4 (57.1%) had the risk of malnutrition. Patients with AD who had moderate and severe dementia had significantly more often malnutrition and risk of malnutrition (p<0.05). Patients with PD at a more severe stage of the disease and, accordingly, with more pronounced movement disorders, had significantly more often malnutrition and the risk of malnutrition (p<0.05). A moderate correlation was obtained between dysphagia, oral apraxia, tooth loss, chewing disorder and malnutrition and the risk of malnutrition in patients with AD and PD (r=0.3, p<0.001). The value of laboratory parameters, such as increased creatinine, decreased albumin and hemoglobin, statistically significantly correlated with malnutrition and the risk of malnutrition (p<0.05). The study found a statistically significant association between depression, affective disorders, and malnutrition and the risk of malnutrition in patients with AD and PD (p<0.05). When examining patients malnutrition and the risk of malnutrition at the second visit, BMI increased in all patients.

CONCLUSION: Malnutrition and the risk of malnutrition occur in more than a quarter of patients with AD and PD. The risk of malnutrition increases in moderate and severe stages of the disease. Malnutrition is more common in AD compared to PD. Malnutrition and the risk of malnutrition were significantly associated with the presence of depression, affective disorders, as well as with chewing disorders, tooth loss, dysphagia, and oral apraxia. Early recognition of the risks of malnutrition is important for the timely correction of modifiable factors for the development of malnutrition, including the organization of adequate nutrition for the patient, dental prosthetics, Adjustment of the treatment regimen for the underlying disease, treatment of depressive episodes, and affective disorders. If a diagnosis of malnutrition is made, it is necessary to calculate and replenish the patient's energy and fluid needs, including the inclusion of additional enteral nutrition in the comprehensive treatment strategy.}, } @article {pmid41524345, year = {2025}, author = {Yusupov, FA and Abdykadyrov, MS}, title = {[Neurogenesis in neurodegeneration: multifactorial regulation, mechanisms of impairment, and therapeutic strategies].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {12}, pages = {14-21}, doi = {10.17116/jnevro202512512114}, pmid = {41524345}, issn = {1997-7298}, mesh = {Humans ; *Neurogenesis/physiology ; *Alzheimer Disease/physiopathology/metabolism/therapy ; *Neurodegenerative Diseases/physiopathology/therapy ; *Parkinson Disease/physiopathology/therapy/metabolism ; Animals ; }, abstract = {OBJECTIVE: To systematize current data on neurogenesis and its role in the pathogenesis of neurodegenerative conditions, such as Alzheimer's disease and Parkinson's disease, with a focus on molecular mechanisms of regulation, the nature of disorders in neurodegeneration, and the evaluation of therapeutic approaches aimed at stimulating neurogenesis.

MATERIAL AND METHODS: Research papers published in scientific databases, mainly Scopus, PubMed, and Google Scholar, over the past 5 years were used for this review. Special attention was paid to studies on neurogenesis and its role in the pathogenesis of neurodegenerative diseases. The review included studies that met the following criteria: publications from the past five years reporting current neurogenesis data, using clearly identified experimental and clinical techniques, published in peer-reviewed international journals with a high impact factor, and providing reliable statistics to support the results.

UNLABELLED: Studies with a limited sample size and insufficient statistical significance, those lacking a transparent methodology or exhibiting a low level of data reproducibility, reviews without a clear focus on neurogenesis or its connection to neurodegenerative diseases, and studies providing insufficient information on the applied technologies and analysis methods were excluded.

RESULTS: Modern research has significantly expanded the understanding of neurogenesis and its role in neurodegenerative diseases. Neurogenesis has been confirmed to occur in specific areas of the adult brain, including the hippocampus, where it is involved in cognitive processes such as learning, memory consolidation, spatial adaptation, cognitive flexibility, and regulation of affective behavior. However, the extent and functional significance of neurogenesis in different brain regions remain a matter of debate. The effect of neurodegenerative diseases on neurogenesis varies: in Alzheimer's disease, studies in animal models demonstrate its impairment; however, data on humans are inconsistent: a decrease in neurogenesis is observed in the early stages of the disease, but in some cases, its increase is reported, likely as a compensatory mechanism. Factors influencing neurogenesis in Alzheimer's disease include β-amyloid and tau protein accumulation, neuroinflammation, mitochondrial dysfunction, and oxidative stress. Parkinson's disease is associated with a decrease in neurogenesis in the subventricular zone and hippocampus due to the degeneration of dopaminergic neurons and the accumulation of α-synuclein; however, deep brain stimulation is able to enhance neuronal proliferation. Therapeutic strategies include pharmacological approaches aimed at stimulating neurogenesis, such as the use of neurotrophic factors, acetylcholinesterase inhibitors, selective serotonin reuptake inhibitors, Wnt and EGFR signaling pathway modulators, uric acid, and MFG-E8, as well as non-pharmacological methods, including physical activity, enriched environment, cognitive training, electrical stimulation, and music therapy.

CONCLUSION: Neurodegenerative diseases are a significant problem in modern healthcare, requiring an in-depth study of the mechanisms of neurogenesis and its role in pathogenesis. Despite conflicting evidence on neurogenesis in adult humans, animal model studies and cellular technologies demonstrate prospects for its therapeutic stimulation. Pharmacological and non-pharmacological methods, including the use of neurotrophic factors, electrical stimulation, and cognitive training, as well as cellular and gene therapy, are the basis of new intervention strategies. However, the issues of controlling the differentiation and integration of new neurons, as well as the ethical aspects associated with the use of stem cells, remain unresolved. Further interdisciplinary research aimed at studying the regulatory mechanisms of neurogenesis and its therapeutic potential may lead to the development of effective treatment strategies that can slow or even reverse the progression of neurodegenerative diseases. It highlights the need to integrate advanced technologies and approaches in modern neuroscience and clinical practice.}, } @article {pmid41523330, year = {2025}, author = {Raphael, DL}, title = {Neuropsychiatric symptoms in mild cognitive impairment and early Alzheimer's disease: Clinical pattern and diagnostic implications.}, journal = {AIMS neuroscience}, volume = {12}, number = {4}, pages = {676-705}, pmid = {41523330}, issn = {2373-7972}, abstract = {BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are widely recognized for their hallmark cognitive deficits, typically characterized by progressive cognitive deterioration. However, neuropsychiatric symptoms (NPS), including depression, apathy, anxiety, irritability, and sleep disturbances, are increasingly prevalent in the early stages of these conditions and significantly influence the disease trajectory and patient outcomes. Importantly, neuropsychiatric symptoms often precede overt memory loss by several years, with subtle mood and behavioral disturbances serving as early pre-diagnostic markers of an underlying Alzheimer's pathology. Their presence complicates the diagnosis, accelerates the disease progression, and intensifies the caregiver burden. However, distinguishing NPS arising from neurodegeneration and primary psychiatric disorders remains a profound diagnostic challenge, thus delaying timely intervention and obscuring early disease recognition.

OBJECTIVE: This structured narrative review examines the diagnostic complexities, clinical impact, and current management of NPS in early-stage Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI), alongside the biological underpinnings, clinical relevance, diagnostic challenges, and treatment perspectives. We argue that understanding and managing NPS is essential to improve the clinical outcomes, reduce the caregiver burden, and guide therapeutic innovation.

METHODS: A structured narrative review of peer-reviewed studies published between 2012 and 2025 was conducted using PubMed, MEDLINE, Scopus, PsycINFO, Google Scholar, and CINAHL. The included studies investigated NPS prevalence, neurobiological correlations, and management strategies in individuals with AD or MCI.

FINDINGS: NPS affects up to 80% of individuals with early AD or MCI, often preceding cognitive decline. The current management strategies heavily rely on non-pharmacological interventions such as caregiver support, behavioral activation, and structured routines, while pharmacological options remain limited by modest efficacy and safety concerns.

DISCUSSION: Advancing knowledge of NPS and their association with cognitive decline is critical to establish more precise diagnostic criteria and to inform personalized therapeutic approaches. Future research should emphasize biomarker-driven diagnostics and the development of novel, targeted interventions that simultaneously address cognitive and neuropsychiatric domains to optimize outcomes for patients and caregivers. This study contributes to the field by reframing NPS as potential early biomarkers in the trajectory of MCI and dementia progression.}, } @article {pmid41522467, year = {2026}, author = {Williams, DM and Heikkinen, S and Hiltunen, M and , and Davies, NM and Anderson, EL}, title = {The proportion of Alzheimer's disease attributable to apolipoprotein E.}, journal = {NPJ dementia}, volume = {2}, number = {1}, pages = {1}, pmid = {41522467}, issn = {3005-1940}, abstract = {Variation in the APOE gene strongly affects Alzheimer's disease (AD) risk. However, the proportion of AD burden attributable to this variation requires clarification, which would help to elucidate the scope of strategies targeting apolipoprotein E (APOE) for AD prevention and treatment. We estimated the extents to which clinically diagnosed AD, AD neuropathology and all-cause dementia are attributable to the common APOE alleles in four large studies. First, we used data on 171,105 and 289,150 participants aged ≥60 years from UK Biobank (UKB) and FinnGen, respectively. AD and all-cause dementia were ascertained from linked electronic health records in these cohorts. Second, we examined amyloid-β positivity from amyloid positron emission tomography scans of 4415 participants of the A4 Study. Third, we analysed data from the Alzheimer's Disease Genetics Consortium (ADGC), where neuropathologically confirmed AD cases were compared to pathology-negative, cognitively intact controls (N = 5007). In each analysis, we estimated outcome risk among carriers of APOE risk alleles ε3 and ε4, relative to individuals with an ε2/ε2 genotype, and calculated attributable fractions to show the proportions of the outcomes due to ε3 and ε4. For AD, fractions ranged from 71.5% (95% confidence interval: 54.9%, 81.7%) in FinnGen to 92.7% in the ADGC (82.4, 96.5%). In A4, 85.4% (17.5, 94.5%) of cerebral amyloidosis was attributable to ε3 and ε4. The proportions of all-cause dementia attributable to ε3 and ε4 in UKB and Fin-Gen were 44.4% (95% CI: 18.2%, 62.2%) and 45.6% (30.6%, 56.9%), respectively. Without strong underlying risks from APOE ε3 and ε4, almost all AD and half of all dementia would not occur. Intervening on APOE should be prioritised to facilitate dementia prevention.}, } @article {pmid41522370, year = {2026}, author = {Foley, KE and Weekman, EM and Wilcock, DM}, title = {Acute anti-Aβ antibody exposure induces microglial changes and significantly alters chemokine signaling.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {1}, pages = {e70201}, pmid = {41522370}, issn = {2352-8737}, abstract = {INTRODUCTION: While the anti-amyloid-lowering immunotherapies provide the first disease-targeting therapies for the treatment of Alzheimer's disease, there remain harmful adverse events causing hesitation among patients, families, physicians, and regulatory bodies. Though these drugs have been repeatedly proven to lower brain amyloid plaque burden, the specific cellular mechanisms and pathways by which the immunotherapy impacts the brain remain unclear.

METHODS: This study aimed to transcriptionally profile the brain's immediate immune response to anti-amyloid beta (anti-Aβ) antibodies. To evaluate acute cellular priorities, we intracranially injected anti-Aβ antibody (3D6) or an isotype-matched control immunoglobulin G (IgG) antibody and performed single-cell sequencing analysis after 3 days.

RESULTS: We found reduced numbers of a motile microglia cluster and homeostatic microglia in the 3D6 antibody-injected cortex compared to the IgG-injected cortex. It was also found that chemokine/cytokine signaling was enriched across homeostatic-proinflammatory microglia, interferon-responding microglia, and disease-associated microglia 2 (DAM2) following 3D6 antibody injection. We explored "CCL" signaling, which suggested a change in outgoing signaling coordinated by all microglia types targeting homeostatic microglia, surprisingly not targeting DAM1 or DAM2. We then analyzed enriched signaling pathways clustered by k-means river plots and identified pathways enriched and dampened with acute 3D6 treatment.

DISCUSSION: Together these data supply evidence for significant involvement of microglia in the anti-Aβ response in the brain after just 3 days. Most interestingly, there are changes in cytokine/chemokine signaling across microglia subtypes, specifically with communication in CCL pathways targeting homeostatic microglia and T cells. These acute signaling changes provide novel insights and generate unique hypotheses on the brain's immediate immune reaction to anti-Aβ antibody.

HIGHLIGHTS: Intracranially injected anti-amyloid beta (anti-Aβ) antibody promotes an immediate microglial response.3D6 exposure resulted in fewer homeostatic and motile microglia subtypes.Acute 3D6 enriches for chemokine/cytokine signaling pathways.}, } @article {pmid41522368, year = {2026}, author = {Scheltens, P and Atri, A and Feldman, HH and Zetterberg, H and Sano, M and Johannsen, P and Colombo, TL and Bardtrum, L and Jeppesen, R and Hansen, CT and Cummings, JL}, title = {Baseline characteristics from evoke and evoke+: Two phase 3 randomized placebo-controlled trials of semaglutide in participants with early-stage symptomatic Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {1}, pages = {e70200}, pmid = {41522368}, issn = {2352-8737}, abstract = {INTRODUCTION: The glucagon-like peptide-1 receptor agonist semaglutide may impact neuroinflammation and reduce neurodegeneration. We present baseline characteristics of participants enrolled in the evoke (NCT04777396) and evoke+ (NCT04777409) trials, referred to as "evoke (+)" hereafter.

METHODS: Evoke (+) are two ongoing global, multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trials investigating semaglutide in participants with early-stage symptomatic Alzheimer's disease (AD) with confirmed amyloid positivity (by positron emission tomography or cerebrospinal fluid testing). Inclusion criteria are the same for both trials, except that by design, evoke+ also includes participants with significant small vessel pathology. Both trials include a 12-week screening phase before randomization (1:1) to receive oral semaglutide titrated to 14 mg or placebo for 156 weeks. Baseline data were summarized and analyzed descriptively. Additionally, data were pooled and assessed by five main geographical regions.

RESULTS: Evoke (+) recruited 9996 participants from 566 sites in 40 countries. The mean (standard deviation) age of participants was 71.8 (7.1) and 72.6 (7.1) years in evoke and evoke+, respectively; more participants were female than male (female: 53.0% and 51.9%, respectively) and most had a Clinical Dementia Rating (CDR) global score of 0.5 (72.8% and 71.4%; CDR global score of 1: 26.5% and 27.6%). Both trial populations had similar demographics, and clinical and cognitive baseline characteristics, except that 2.8% of participants in evoke+ had magnetic resonance imaging-documented significant small vessel pathology as per protocol inclusion criteria. Regional-level data demonstrated some differences in AD treatment characteristics, including cholinesterase inhibitor use of 41.7% in North America versus 61.6% in Asia.

DISCUSSION: Evoke (+) are the only large-scale, phase 3 trials investigating the longer-term efficacy and safety of semaglutide in early AD as a potential disease-modifying treatment. The baseline characteristics from evoke (+) reflect a varied, global population with early-stage symptomatic AD. Primary readouts are expected in the second half of 2025.

HIGHLIGHTS: evoke and evoke+ are the only large-scale randomized controlled trials (RCTs) investigating the longer-term efficacy and safety of semaglutide in early AD.Baseline characteristics reflect a varied, global population.The trials' primary readouts are expected in the second half of 2025.}, } @article {pmid41521630, year = {2026}, author = {K, A and B, SK and Reddy, SG and Kugabalasooriar, S}, title = {Innovations in Nanobot and Microbot Propulsion for Targeted CNS Drug Delivery Across the Blood-Brain Barrier.}, journal = {Critical reviews in analytical chemistry}, volume = {}, number = {}, pages = {1-30}, doi = {10.1080/10408347.2025.2612631}, pmid = {41521630}, issn = {1547-6510}, abstract = {The transport of therapeutic molecules to the brain is one of the largest challenges of contemporary medicine because of the restrictive nature of the blood-brain barrier (BBB), which blocks the penetration of almost all biological therapeutics and most small-molecule drugs. This is a major limitation to the treatment of such neurological diseases as Parkinson's disease (PD), glioblastoma, and Alzheimer's disease. To beat these obstacles, there must be advanced delivery systems that can be precise, be released under control, and move without being invasive. Over the past decade, there have been innovations in micro and nanorobotic technologies, which provide a groundbreaking model that incorporates innovations in materials science, analytical chemistry, and biomedical engineering. Such engineered nanorobots are magnetically controlled, polymeric, or biologically derived nanorobots, which can be magnetically, acoustically, optically, or chemically controlled, and can cross the BBB with greater specificity. It has also been possible to follow the behavior of nanorobots at a direct visualization level in biological systems due to the development of analytical tools, especially imaging, real-time monitoring, and in situ sensing, which allows the behavior of nanorobots to be evaluated rigorously in terms of motions, shape transformation, and drug release profiles. The present review gives a detailed description of the propulsion-based nanorobotic drug delivery systems to the central nervous system (CNS), including structural components, modes of actuation, and protocols of analysis. The review explains that the combined effects of physicochemical features, external stimuli, and interactions between biointerfaces influence permeability via the BBB and accuracy of therapeutic response.}, } @article {pmid41521126, year = {2026}, author = {Sankhe, K and Ruthirakuhan, M and Andreazza, AC and Brawman-Mintzer, O and Craft, S and Herrmann, N and Ismail, Z and Lerner, AJ and Levey, AI and Mintzer, J and Padala, PR and Perin, J and Porsteinsson, AP and Rosenberg, PB and Shade, D and Tumati, S and van Dyck, CH and Lanctôt, KL}, title = {Peripheral biomarkers associated with apathy and predicting response to methylphenidate: Secondary analysis of the Apathy in Dementia Methylphenidate Trial 2 (ADMET2) study.}, journal = {International psychogeriatrics}, volume = {}, number = {}, pages = {100181}, doi = {10.1016/j.inpsyc.2025.100181}, pmid = {41521126}, issn = {1741-203X}, abstract = {BACKGROUND: In Apathy in Dementia Methylphenidate Trial 2 (ADMET2), apathy in Alzheimer's disease improved with methylphenidate (MPH) in a randomized, placebo-controlled trial, though response varied. Here we evaluated serum biomarkers for their association with apathy and with treatment response.

METHODS: All ADMET2 participants with available blood samples were included. Markers of inflammation [interleukin (IL)-6, IL-10, Tumor Necrosis Factor (TNF)], oxidative stress [lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane (8-ISO)] and neuronal injury [neurofilament light (NfL), S100B] were assessed and values log-transformed. Neuropsychiatric Inventory-apathy (NPI-A) measured apathy. Least Absolute Shrinkage and Selection Operator (LASSO) regression was performed for feature selection of baseline markers predicting NPI-A at Month-6 (M6). Univariate analyses examined individual biomarker effects and multivariable models evaluated their combined effects. Treatment interactions, baseline and change in biomarker levels in treatment responders (≥4 change in NPI-A) and remitters (M6 NPI-A=0) were explored.

RESULTS: In the ADMET2 biomarker subset (n = 44, MPH:21, age:75 years, MMSE:20.2), higher baseline TNF was associated with higher M6 NPI-A [B(SE)= 6.86 (1.71), p = .0003], and multivariable models found lower baseline TNF [B(SE)= 8.28(1.61), p < .001] and higher baseline S100B [B(SE)= -6.41(1.95), p = .002] were associated with lower M6 NPI-A. Exploratory analyses suggested that higher baseline NfL significantly interacted with treatment to predict lower M6 NPI-A [B(SE)= -8.36(4.21), p = .05], only when adjusting for cognition. MPH remitters had lower baseline TNF [B(SE)= -0.27(0.10), p = .02], higher baseline NfL [B(SE)= 0.33(0.14), p = .03], and a greater decrease in IL-6 [B(SE)= -0.44 (0.17), p = .02].

CONCLUSIONS: Inflammatory and neuronal injury biomarkers may have prognostic value and may potentially inform treatment response and remission outcomes in apathy. Apathy in Dementia Methylphenidate Trial 2 (ADMET2), NCT02346201, https://clinicaltrials.gov/study/NCT02346201.}, } @article {pmid41520868, year = {2026}, author = {Bajinka, O and Jallow, L and Ozdemir, G}, title = {A multi-target therapeutic framework for Alzheimer's disease: an integrative mechanistic review.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2026.01.010}, pmid = {41520868}, issn = {1873-7544}, abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a multifactorial network disorder in which amyloid and tau pathology interact with mitochondrial dysfunction, neuroinflammation, metabolic impairment, vascular dysregulation, and synaptic failure. This review provides an integrative, systems-level synthesis of these mechanisms with emphasis on diagnostic and therapeutic implications.

METHODS: A structured narrative review was conducted using PubMed, Scopus, Web of Science, and Embase (2010-2025). Eligible studies included clinical trials, biomarker validation studies, cohort analyses, and mechanistic investigations. Evidence was synthesized by mechanistic domain with focus on cross-system interactions and translational relevance.

FINDINGS: Convergent data indicate that soluble Aβ species, tau propagation, glial dysregulation, insulin resistance, mitochondrial bioenergetic failure, lipid imbalance, and BBB dysfunction form a self-reinforcing neurodegenerative network. Diagnostic advances-including plasma p-tau181/217, Aβ42/40 ratio, GFAP, sTREM2, neuronal exosomes, and multimodal machine-learning models-enable earlier staging and refinement of therapeutic selection. Therapeutic development is shifting from linear amyloid removal to multi-target strategies incorporating anti-tau agents, glial-modulating compounds, metabolic and microbiome interventions, medical nutrition, and multidomain lifestyle programs. Across trials, combined strategies targeting interacting mechanisms demonstrate stronger biomarker and cognitive effects than single-axis approaches.

CONCLUSIONS: AD management requires a systems-oriented therapeutic architecture in which interventions are selected based on mechanistic dominance, biomarker stage, and potential synergy. We outline a multi-target strategy integrating amyloid/tau modulation, neuroimmune regulation, metabolic-vascular stabilization, and synaptic support. Future work should prioritize biomarker-guided stratification, treatment sequencing, and prevention-oriented combination designs.}, } @article {pmid41520543, year = {2025}, author = {Xue, R and Wang, F and Zhang, B and Wu, J and Zhang, N and Sun, C}, title = {Carrier-free nanoassembly with dual antioxidant and anti-inflammatory activities camouflaged by melanoma cell membrane for tau-targeted therapy of Alzheimer's disease.}, journal = {Biomaterials}, volume = {329}, number = {}, pages = {123970}, doi = {10.1016/j.biomaterials.2025.123970}, pmid = {41520543}, issn = {1878-5905}, abstract = {Targeting phosphorylated tau (p-tau) across the blood-brain barrier (BBB) represents a critical prerequisite for attenuating tau pathology and disease progression in Alzheimer's disease (AD) by alleviating oxidative stress and neuroinflammation. To address this challenge, we developed a novel carrier-free selenium-based nanoassembly stabilized by hydroxyl-rich fingolimod (FTY720), a sphingosine analogue. Following camouflaging with melanoma cell membranes and further functionalizing with T807, the resulting nanocomposite (FSMT) demonstrated robust capacity for BBB crossing and target p-tau both in vitro and in vivo. Additionally, FTY720 and nano-selenium exert remarkable antioxidant and anti-inflammatory effects by modulating the GSK-3β and NF-κB signaling pathways, respectively, thereby attenuating tau hyperphosphorylation and preventing neuronal cell death. In an okadaic acid-induced AD mouse model, the FSMT treatment not only significantly ameliorated oxidative stress and neuroinflammation, but also improved spatial learning and memory impairments. The reduction in abnormal tau aggregation following treatment was confirmed by PET-CT imaging. Overall, this p-tau-targeted biomimetic nanocomposite demonstrated excellent biocompatibility and therapeutic efficacy, presenting a translatable strategy for treating AD and other neurological disorders through analogous mechanisms.}, } @article {pmid41520099, year = {2026}, author = {Mao, C and Wang, W and Huang, X and Wu, M and Wang, Y and Wang, T and Qiu, Y and Chu, S and Jin, W and Jiang, Y and Bao, J and You, Y and Li, Y and Dong, L and Feng, F and Huo, L and Qiu, L and Gao, J}, title = {Real world clinical practice of lecanemab at PUMCH dementia cohort: focus on dynamic imaging and biomarker evolution.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-025-01943-z}, pmid = {41520099}, issn = {1758-9193}, support = {2021-I2M-1-020//CAMS Innovation fund for medical sciences (CIFMS)/ ; 2022-PUMCH-A-254//National High Level Hospital Clinical Research Funding/ ; 2020YFA0804500, 2020YFA0804501//National Key Research and Development Program of China/ ; }, abstract = {BACKGROUND: Lecanemab is an anti-Aβ antibody approved in China for mild cognitive impairment (MCI) and mild dementia. Real-world application requires comprehensive assessment beyond MMSE scores, considering factors like ARIA risk. This single-center, real-world study aims to evaluate its efficacy in an expanded population, observe biomarker changes, and assess its safety profile in clinical practice.

METHODS: We recruited adults aged 40-90 with early AD from the PUMCH Dementia Cohort. A total of 42 patients received lecanemab treatment, of whom 29 completed the 6-month treatment evaluation. Participants had confirmed amyloid and tau pathology and met clinical criteria (CDR ≤ 1, CDR-SB ≤ 8and MMSE ≥ 18). Comprehensive assessments included neuropsychological testing, CSF and plasma biomarkers (Lumipulse G1200), multi-sequence 3T MRI (volumetric and ALPS index analysis), and amyloid/tau PET imaging (Centiloid quantification). All were monitored for adverse reactions. Matched control groups (matched for sex, age, APOE genotype, disease severity, and baseline therapy) were established for comparison of longitudinally changes in cognitive function, daily living ability and structure MRI.

RESULTS: Treatment was effective even for patients with lower MMSE scores but still classified as having mild dementia by CDR. A significant median Centiloid reduction of 30.9 was observed, with a 24.1% amyloid PET negativity rate after six months. While scores on cognitive and functional scales (CDR-SB, ADL) significantly worsened, indicating disease progression, the rate of progression was significantly slower compared to the control group. Structural MRI showed significant volume reduction in multiple brain regions and increased ventricular volume post-treatment, with no statistically significant change in the ALPS value. The rate of brain volume reduction is faster than that in the control group. Plasma biomarker dynamics (Aβ42, GFAP) indicated effective disease-modifying therapy. Greater Centiloid reduction was linked to more brain volume loss, higher baseline Centiloid levels, higher plasma Aβ42 increase and older age of onset. APOE ɛ4 homozygotes showed less Centiloid reduction. A favorable safety profile was observed, with a 7.1% incidence of asymptomatic, mild ARIA.

CONCLUSIONS: This study confirms the clinical efficacy, biomarker changes, and safety profile of lecanemab treatment over a 6-month period, demonstrating its positive therapeutic value and a favorable safety profile in the Chinese population with AD.}, } @article {pmid41519279, year = {2026}, author = {Cai, M and Wang, S and Liu, M and Lai, B and Chen, C and Ding, J and Wang, X}, title = {Elevated FKBP5 expression associates with epilepsy-related molecular changes and promotes neuronal hyperexcitability.}, journal = {Brain research}, volume = {}, number = {}, pages = {150157}, doi = {10.1016/j.brainres.2026.150157}, pmid = {41519279}, issn = {1872-6240}, abstract = {OBJECTIVE: Epilepsy is one of the neurological disorders, characterized by recurrent, spontaneous seizures arising from neuronal hyperexcitability and hypersynchrony in the brain. The mechanisms of epilepsy are intricate and remain elusive. FKBP5 has emerged as a significant protein implicated in neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). This study aims to investigate the role of FKBP5 in a kainic acid (KA)-induced intrahippocampal epilepsy model and assessed how FKBP5 gain-of-function and FKBP51 inhibition influence neurotransmitter dynamics and neuronal excitability.

METHODS: We examined the expression of FKBP5 in the hippocampus of the kainic acid (KA)-induced epilepsy model. To explore the impact of FKBP5 on neuronal activity, we overexpressed FKBP5 in primary cortical neurons and astrocytes, assessing extracellular glutamate levels in neuron-astrocytes co-cultures with or without the FKBP51-selective inhibitor SAFit2 (250 nM). Intrinsic excitability, voltage-gated Na[+] currents, and network activity were evaluated using whole-cell patch-clamp recordings and high-density microelectrode arrays (HD-MEAs).

RESULTS: We observed an elevated level of FKBP5 in the hippocampus of a kainic acid (KA)-induced chronic epilepsy mouse model, whereas cortical FKBP5 did not show clear changes across the examined post-insult time points.. Moreover, FKBP5 overexpression induced a remarkable increase in the extracellular glutamate level in co-cultured primary cortical neurons and astrocytes. Intriguingly, FKBP5 overexpression modifies the electrophysiological properties of primary neurons, resulting in increased intrinsic excitability and enhanced Na[+] currents. Additionally, the network activity exhibits hyperexcitability with FKBP5 overexpression. Notably, SAFit2 treatment was also associated with elevated extracellular glutamate in the co-culture system, while intracellular FKBP5 and EAAT2 protein levels showed no significant group differences in the current dataset.

CONCLUSION: These findings suggested that FKBP5 played a significant role in regulating neuronal excitability and extracellular glutamate homeostasis. However, due to discrete sampling and the lack of continuous seizure monitoring, the present in vivo data do not establish a definitive causal contribution of FKBP5 to epileptogenesis, warranting future studies integrating longitudinal EEG and cell-type-specific manipulations.}, } @article {pmid41519243, year = {2026}, author = {Sharma, K and Shahid, M and Patel, R and Islam, A}, title = {Insights into Mechanism of Ionic Liquids for Protein Stability: Future Implications for Neurodegeneration Treatment.}, journal = {Ageing research reviews}, volume = {}, number = {}, pages = {103024}, doi = {10.1016/j.arr.2026.103024}, pmid = {41519243}, issn = {1872-9649}, abstract = {Neurodegenerative diseases are characterized by a gradual loss of neurons, cellular dysfunction, loss of intricate synaptic networks and brain damage, which are going to be the second leading cause of death in future. These proteinopathies are marked by abnormal amyloid fibril deposition, aberrant aggregation of misfolded proteins via polymerization, where protein aggregates serve as key pathological hallmarks in Alzheimer's, Parkinson's, and multiple system atrophy disorders. These toxic aggregates accumulate in the brain and disrupt neuronal function targeting motor neurons, spinal cord, and ultimately leading to respiratory failure and death. As population age, the prevalence of these neuronal disorders rises significantly, emphasizing to approach effective treatment for risk reduction. In the pursuit of developing effective anti-amyloidogenesis therapeutic agents, ionic liquids (ILs) continue to receive least attention. ILs have emerged as promising substitute for conventional solvents, owing to their unique physicochemical properties that facilitate protein refolding, mitigate denaturation, amyloidogenesis, and prevent aggregation. This review critically addresses intricate IL-protein interactions, dictated by anions-cations composition of ILs, their polarity, hydrophobicity, kosmotropicity, chaotropicity, amphiphillicity, and network, which modulate protein behavior and support structural and functional integrity. This article also underscores the need for precision in IL selection, ensuring their properties align with the desired structural outcome. We showcase ILs as a promising therapeutic avenue for neurodegenerative diseases, demonstrating their potential to modulate pathological protein aggregation and enhance protein homeostasis. Lastly, this review of outstanding research works, account for current lacunae that will guide future perspectives for the rational designing of IL for protein stabilization and offers new strategies for addressing underlying mechanism of ageing disorders.}, } @article {pmid41519166, year = {2026}, author = {Zhao, P and Cao, Z and Rozpędek-Kamińska, W}, title = {Receptor Tyrosine Kinases in Alzheimer's Disease: Mechanistic Insights and Therapeutic Implications.}, journal = {Neurochemistry international}, volume = {}, number = {}, pages = {106117}, doi = {10.1016/j.neuint.2026.106117}, pmid = {41519166}, issn = {1872-9754}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder whose pathogenesis remains incompletely understood. It is considered one of the most costly, fatal, and socially burdensome diseases of the twenty-first century. Previous studies have shown that receptor tyrosine kinases (RTKs) play an important role in the pathological progression of AD. RTKs regulate amyloid-beta (Aβ) deposition and Tau hyperphosphorylation, thereby influencing neuronal survival, synaptic plasticity, and spatial cognitive function in patients with AD. From a therapeutic perspective, RTK-targeted interventions offer new avenues for AD treatment. Inhibiting specific RTKs can reduce Aβ production and pathological Tau phosphorylation, thereby slowing disease progression. Conversely, activating selected neuroprotective RTKs can promote neuronal survival, restore synaptic function, and ameliorate cognitive impairment. Several small-molecule inhibitors and monoclonal antibodies targeting RTKs have already demonstrated promising therapeutic potential in preclinical studies. Overall, this review systematically summarizes the clinical features and mechanisms of AD, as well as the current applications and future challenges of RTK-based research in neurodegenerative diseases, providing theoretical guidance for the development and repurposing of novel multi-pathway RTK-directed therapies.}, } @article {pmid41518900, year = {2025}, author = {Loraine, A and Farr, SA and Niehoff, ML and Larrea, IG and Ganev, Y and Samanta, J and Rahman, K and Crider, AM and Sandoval, K and Witt, KA}, title = {Dual sigma receptor 1 and 2 modulator improves memory behavior in mouse model of age-related cognitive decline.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {393}, number = {2}, pages = {103795}, doi = {10.1016/j.jpet.2025.103795}, pmid = {41518900}, issn = {1521-0103}, abstract = {Sigma-1 (S1R) and sigma-2 (S2R) receptors are promising targets for treating Alzheimer disease (AD), playing important roles in cognitive function, with potential to mitigate neuropathology. The dual S1R/S2R receptor modulator (+/-)-cis-1-n-Butyl-8-methoxy-1,2,3a,4,5,9b-hexahydrobenz[e]indole hydrochloride (BBZI) was evaluated in the senescence-accelerated mouse prone 8 model of cognitive decline and AD as to behavior and hippocampal expression effects. Chronic BBZI treatment (0, 0.001, 0.01, 0.1, 1.0, or 10 mg/kg, i.p. daily, 27-days) was evaluated using a behavioral battery including open field activity (day-15), elevated plus maze (day-16), Y-maze (day-22), T-maze foot-shock avoidance (days 20 and 27), and novel object recognition (days 23 and 24). No changes were observed in open field, elevated plus maze, Y-maze, or novel object recognition tests at any dose of BBZI as compared with vehicle. BBZI enhanced T-maze foot-shock memory retention at 0.1 (P < .05, Bonferroni) and 1.0 mg/kg (P < .001, Bonferroni) compared with vehicle (day-27). In a separate cohort, a single-injection of BBZI (0, 0.001, 0.01, 0.1 & 1.0 μg, i.c.v.) with testing 7-days later showed a significant effect in the T-maze foot-shock test (P = .011) and enhanced memory retention behavior at 0.01 μg compared with vehicle (P < .05, Bonferroni). Poly(A) RNA sequencing evaluation of hippocampal tissue 24-hours after intracerebroventricular administered BBZI (1.0 μg/μL) versus vehicle showed unique gene expression changes, with notable effects relevant to mitochondrial energetics and synaptic function. Gene enrichment analysis identified affiliations with pathways involved in neurodegenerative disease. This data supports dual S1R/S2R receptor modulation as a promising strategy for AD treatment and identifies potential gene pathways involved. SIGNIFICANCE STATEMENT: Dual sigma receptor 1 and 2 modulator BBZI improved memory behavior in senescence-accelerated mouse prone 8 mice. Evaluation of senescence-accelerated mouse prone 8 hippocampal tissue 24 hours after BBZI (1.0 μg/μL i.c.v.) versus vehicle administration identified gene changes related to mitochondrial energetics and synaptic function. BBZI to mitigates cognitive decline behavior, impacting hippocampal genes critical for brain function.}, } @article {pmid41518808, year = {2026}, author = {Qu, J and Jiang, X and Ma, Y and Sheng, X and Pi, C and Wang, Y and Xu, Q and Li, R and Wang, P and Qian, D and Wang, J and Yi, Z and Yi, J and Wen, L and Liu, S}, title = {Unveiling the gut-brain axis: How chronic exposure to arsenic-induced microglial pyroptosis drives Alzheimer's disease-like pathology.}, journal = {Journal of hazardous materials}, volume = {503}, number = {}, pages = {141087}, doi = {10.1016/j.jhazmat.2026.141087}, pmid = {41518808}, issn = {1873-3336}, abstract = {Arsenic, a pervasive environmental contaminant in groundwater, poses a severe global threat to public health. Chronic arsenic exposure has been linked to neurological impairment, however, its specific pathogenic mechanism and whether the gut-brain axis plays a key role remain unclear. This study investigated the role of gut microbiota and its metabolite indoxyl sulfate (IS) in mediating chronic exposure to arsenic-induced cognitive impairment and Alzheimer's disease (AD)-like pathology, with a specific focus on microglial pyroptosis. We found that chronic arsenic exposure induced cognitive dysfunction and intestinal barrier injury, disrupted gut microbiota composition, promoted IS accumulation in serum and brain, and activated the AhR/NF-κB/NLRP3 signaling pathway, triggering microglial pyroptosis and elevating AD-like pathological markers in mice. Meanwhile, fecal microbiota transplantation (FMT) from arsenic-exposed mice recapitulated cognitive impairment, elevated IS levels, and neuroinflammation in recipient mice. Furthermore, arsenic upregulated hepatic IS-synthesis genes (CYP2E1, Sult1d1) and downregulated renal IS-excretion gene (ABCG2). In vitro, arsenic and IS co-exposure promoted M1 polarization and enhanced pyroptosis by activating the AhR/NF-κB/NLRP3 signaling pathway, while suppressing phagocytosis-related proteins (TREM2, SYK and CD36). Furthermore, SiAhR treatment could alleviated microglial inflammatory injury and enhancing the microglia's phagocytic capacity induced by arsenic and IS co-exposure in BV2 cells through inhibiting the AhR/NF-κB/NLRP3-mediated pyroptosis signaling pathway. In conclusion, chronic arsenic exposure induced cognitive impairment and AD-like pathological via the gut microbiota-AhR-pyroptosis cascade, where in IS accumulation served a key mediator. These findings provide new insights into preventing arsenic-related cognitive damage.}, } @article {pmid41518572, year = {2026}, author = {Zhang, Z and Zhang, M and Cao, Z and Zhao, H and Li, X and Luo, P}, title = {Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease.}, journal = {Apoptosis : an international journal on programmed cell death}, volume = {31}, number = {1}, pages = {11}, pmid = {41518572}, issn = {1573-675X}, support = {82171363//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Apoptosis/genetics ; *Ribosomes/metabolism/genetics ; *Neoplasms/genetics/metabolism/pathology ; *Stress, Physiological ; Animals ; Tumor Suppressor Protein p53/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Cell Nucleolus/metabolism ; Signal Transduction ; Chromosomal Proteins, Non-Histone ; }, abstract = {Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer's disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.}, } @article {pmid41518096, year = {2026}, author = {Mai, D and Li, Z and Cao, Z and Lin, P and Tan, J and Li, R and Ye, Q}, title = {Metabolomics-Driven Integration of Traditional Chinese Medicine for Neurological Disorders: From Precision Diagnosis to Therapeutic Innovation.}, journal = {Phytotherapy research : PTR}, volume = {}, number = {}, pages = {}, doi = {10.1002/ptr.70182}, pmid = {41518096}, issn = {1099-1573}, support = {20251026//Guangdong Provincial Department of Traditional Chinese Medicine/ ; SEZYY2023A13//the Second Traditional Chinese Medicine Hospital of Guangdong Province/ ; }, abstract = {Neurological disorders are leading causes of disability and death worldwide, yet many patients still face delayed diagnosis, limited disease-modifying options and substantial treatment-related adverse effects. Traditional Chinese medicine (TCM) provides holistic, multi-target interventions through acupuncture, herbal formulas and adjunctive therapies, but its mechanisms remain insufficiently defined. Metabolomics, which enables system-wide profiling of small-molecule metabolites, offers an objective way to characterise disease-related metabolic networks and quantify the global effects of TCM. We systematically searched PubMed, Web of Science and China National Knowledge Infrastructure for studies published between January 2005 and June 2025 that evaluated TCM-related interventions for neurological disorders and reported metabolomic outcomes. Peer-reviewed animal and clinical studies were included, whereas reviews, conference abstracts, methodological-only papers and non-neurological studies were excluded. Across Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), ischaemic stroke (IS), epilepsy and high-altitude cerebral oedema (HACE), consistent alterations were identified in amino acid, lipid and energy-related pathways, such as nicotinamide and lysophosphatidylcholine species in AD, branched-chain amino acids in PD and phenylalanine and asymmetric dimethylarginine in MS. Metabolomics studies indicate that acupuncture and herbal formulas can jointly modulate neurotransmitter balance, cerebral energy metabolism, oxidative stress, neuroinflammation and blood-brain barrier integrity. Emerging spatial metabolomics based on mass spectrometry imaging links individual TCM components, including ginsenosides and Astragalus membranaceus-Carthamus tinctorius decoctions, to region-specific metabolic reprogramming in the cortex, hippocampus and thalamus. However, most metabolite-disease associations are correlative and are constrained by small sample sizes, heterogeneous designs and lack of technical standardisation. Metabolomics therefore provides a quantitative framework to dissect the multi-target mechanisms of TCM in neurology and to connect molecular changes with functional outcomes. Standardised workflows, larger multicentre clinical studies and integration of spatial metabolomics, multi-omics and artificial-intelligence-based analysis are required to translate these findings into TCM-informed precision diagnosis and personalised treatment for neurological disorders.}, } @article {pmid41517979, year = {2026}, author = {Bachhav, SS and Florian, H and Boiser, J and Wang, Y and Shiller, DD and Graab, U and Lynch, SY and Graff, O and Xiong, H}, title = {Safety, Tolerability, and Pharmacokinetics of Single Doses of ABBV-916, an Anti-Amyloid Antibody, in Healthy Participants.}, journal = {Clinical and translational science}, volume = {19}, number = {1}, pages = {e70419}, pmid = {41517979}, issn = {1752-8062}, mesh = {Humans ; Male ; Female ; Double-Blind Method ; Healthy Volunteers ; Adult ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Middle Aged ; Dose-Response Relationship, Drug ; *Antibodies, Monoclonal, Humanized/administration & dosage/pharmacokinetics/adverse effects ; Infusions, Intravenous ; Alzheimer Disease/drug therapy ; Injections, Subcutaneous ; Young Adult ; }, abstract = {Amyloid-beta (Aβ) plaque brain clearance is one of the promising disease-modifying treatment approaches to slow cognitive decline in Alzheimer's disease (AD). ABBV-916, an anti-amyloid antibody, was being developed as an early AD disease-modifying treatment. A phase 1, randomized double-blind, placebo-controlled single ascending dose (SAD) study investigated the safety, tolerability, pharmacokinetics (PK), and immunogenicity of ABBV-916 in healthy participants. Five groups of participants were enrolled and randomized 6:2 to receive ABBV-916 (100, 300, 1000, or 3000 mg) or placebo by intravenous (IV) infusion or subcutaneous (SC) injection (300-mg dose only). After dosing, participants were followed for 20 weeks for assessments. Cerebrospinal fluid (CSF) samples were collected after dosing 1000 mg IV for determination of ABBV-916 levels in the CSF. ABBV-916 single doses up to 3000 mg were well tolerated in healthy participants. No clinically significant laboratory findings, amyloid-related imaging abnormalities, or serious adverse events were reported. The ABBV-916 PK profile exhibited dose-related increases in maximum concentration and area under the plasma concentration-time curve with terminal elimination half-life ranging from 29 to 40 days across the cohorts. The estimated absolute bioavailability after SC dosing was 51%. The average CSF-to-serum partition ratio was 0.12% (range 0.10%-0.21%). Positive anti-drug antibody was detected in < 7% of participants, which was transient, at low titer, and did not affect ABBV-916 PK. This study demonstrated desirable safety, tolerability, and PK profile of ABBV-916 after single-dose administration in healthy participants. The data supported further evaluation of ABBV-916 multiple IV and SC doses in patients with AD.}, } @article {pmid41517961, year = {2026}, author = {Vilor-Tejedor, N and Danso, S and Albanus, RD and Billingsley, K and Evans, TE and Lee, LY and Wang, S and Jiang, J and Liu, H and Ross, J and Chilla, G}, title = {Advancing global dementia research through equity and inclusion.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e71069}, pmid = {41517961}, issn = {1552-5279}, support = {//Alzheimer's Disease Data Initiative/ ; RYC2022-038136-I//Spanish Ministry of Science and Innovation-State Research Agency,/ ; PID2022-143106OA-I00//European Union FSE+/ ; 23S06083-001//European Union FEDER/ ; //Ajuntament de Barcelona/ ; //la Caixa Foundation/ ; VCID-UMD-26-1514428//AD Strategic Fund: Vascular Contributions to Cognitive Impairment and Dementia-Understanding Mechanisms of Dysfunction/ ; 25AARF-1377279 (2025-2029)//Alzheimer's Association Research postdoctoral fellowship/ ; WE.03-2024-07(2025-2027)//Alzheimer's Association Research postdoctoral fellowship/ ; //Intramural Research Programs of the National Institute on Aging (NIA)/ ; //National Institute of Neurological Disorders and Stroke (NINDS)/ ; Z01-AG000949//National Institutes of Health (NIH), Department of Health and Human Services/ ; 1ZIANS003154//National Institutes of Health (NIH), Department of Health and Human Services/ ; P30AG072976//National Institutes of Health (NIH), Department of Health and Human Services/ ; R01AG081693//National Institutes of Health (NIH), Department of Health and Human Services/ ; }, mesh = {Humans ; *Dementia ; *Biomedical Research ; Global Health ; }, abstract = {Despite the global burden of dementia, research remains dominated by high-income, Western populations, limiting the generalizability and equity of findings. In this Perspective, we highlight the importance of diversity and inclusion in dementia research, not only in study participants but also in the researchers, study design, and funding priorities. We describe how the lack of representation creates knowledge gaps and delays progress in prevention, diagnosis, and treatment. We also present examples of initiatives that are working to change this, including the Alzheimer's Disease Data Initiative and the William H. Gates Sr. Fellowship program, which supports open science, international collaboration, and early-career researchers from underrepresented regions. These efforts demonstrate that diversity is not only an ethical goal, but a scientific need. More inclusive and global research could lead to discoveries that are more generalizable, more globally applicable, and better able to inform strategies to address dementia across all communities. HIGHLIGHTS: Prioritize representation in datasets across ethnicity, geography, sex/gender, and socio-economic status. Support early-career researchers from underrepresented regions with long-term funding and mentorship. Standardize and adapt tools (cognitive, clinical, genomic) across cultural and linguistic contexts. Promote open science through equitable, federated data sharing platforms, and embed community engagement from research design to dissemination. Value diversity as a driver of discovery, not as a confounder.}, } @article {pmid41517810, year = {2026}, author = {Lee, S and Chang, JW}, title = {From Ablation to Neuromodulation Platform: The Evolving Role of Magnetic Resonance-Guided Focused Ultrasound in Functional Neurosurgery.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {22}, number = {1}, pages = {17-41}, doi = {10.3988/jcn.2025.0563}, pmid = {41517810}, issn = {1738-6586}, support = {/HI/NHLBI NIH HHS/United States ; }, abstract = {Magnetic resonance-guided focused ultrasound (MRgFUS) has rapidly evolved from an experimental concept into a versatile platform in functional neurosurgery. Initially pioneered as a noninvasive thermal ablation modality for essential tremor, MRgFUS has since gained regulatory approval and demonstrated durable long-term efficacy. Its clinical applications have expanded to include Parkinson's disease, chronic pain, psychiatric disorders, and investigational use in dystonia, epilepsy, and brain tumors. Beyond lesioning, low-intensity focused ultrasound enables reversible neuromodulation and transient blood-brain barrier opening, facilitating drug and gene delivery in conditions such as Alzheimer's disease and glioblastoma. Comparative analyses highlight MRgFUS as an incisionless alternative to traditional modalities like deep brain stimulation, radiofrequency ablation, and radiosurgery, offering unique advantages in precision, safety, and patient acceptability while retaining certain limitations, including irreversibility and eligibility constraints due to skull properties. Emerging innovations-such as dual-target strategies, staged bilateral procedures, adaptive focusing technologies, and integration with immuno- or gene therapies-are expanding its therapeutic potential. Collectively, these advances position MRgFUS as not only an ablative tool but also a transformative neuromodulation platform with broad implications for the treatment of movement disorders, neuropsychiatric disease, and neurodegeneration.}, } @article {pmid41517524, year = {2025}, author = {Abboud, I and Xu, E and Xu, S and Alhasany, A and Wang, Z and Wu, X and Astraea, N and Jiang, F and Hu, ZJ and Chan, JW}, title = {Emerging Oculomic Signatures: Linking Thickness of Entire Retinal Layers with Plasma Biomarkers in Preclinical Alzheimer's Disease.}, journal = {Journal of clinical medicine}, volume = {15}, number = {1}, pages = {}, pmid = {41517524}, issn = {2077-0383}, support = {UL1 TR001872/NH/NIH HHS/United States ; }, abstract = {Background/Objectives: Alzheimer's disease (AD) is the leading cause of dementia, which is an inevitable consequence of aging. Early detection of AD, or detection during the pre-AD stage, is beneficial, as it enables timely intervention to reduce modifiable risk factors, which may help prevent or delay the progression to dementia. On the one hand, plasma biomarkers have demonstrated great promise in predicting cognitive decline. On the other hand, in recent years, ocular imaging features, particularly the thickness of retinal layers measured by spectral-domain optical coherence tomography (SD-OCT), are emerging as possible non-invasive, non-contact surrogate markers for early detection and monitoring of neurodegeneration. This pilot study aims to identify retinal layer thickness changes across the entire retina linked to plasma AD biomarkers in cognitively healthy (CH) elderly individuals at risk for AD. Methods: Eleven CH individuals (20 eyes total) were classified in the pre-AD stage by plasma β-amyloid (Aβ)42/40 ratio < 0.10 and underwent SD-OCT. A deep-learning-derived automated algorithm was used to segment retinal layers on OCT (with manual correction when needed). Multiple layer thicknesses throughout the entire retina (including the inner retina, the outer retina, and the choroid) were measured in the inner ring (1-3 mm) and outer ring (3-6 mm) of the Early Treatment Diabetic Retinopathy Study (ETDRS). Relationships between retinal layers and plasma biomarkers were analyzed by ridge regression/bootstrapping. Results: Results showed that photoreceptor inner segment (PR-IS) thinning had the largest size effect with neurofilament light chain. Additional findings revealed thinning or thickening of the other retinal layers in association with increasing levels of glial fibrillary acidic protein and phosphorylated tau at threonine 181 and 217 (p-tau181 and p-tau217). Conclusions: This pilot study suggests that retinal layer-specific signatures exist, with PR-IS thinning as the largest effect, indicating neurodegeneration in pre-AD. Further research is needed to confirm the findings of this pilot study using larger longitudinal pre-AD cohorts and comparative analyses with healthy aging adults.}, } @article {pmid41516328, year = {2026}, author = {Cipriano, GL and Floramo, A and Argento, V and Oddo, S and Artimagnella, O}, title = {Mutant Tau (P301L) Enhances Global Protein Translation in Differentiated SH-SY5Y Cells by Upregulating mTOR Signalling.}, journal = {International journal of molecular sciences}, volume = {27}, number = {1}, pages = {}, pmid = {41516328}, issn = {1422-0067}, support = {RRC-2025-23686388//Ministero della Salute/ ; }, mesh = {Humans ; *TOR Serine-Threonine Kinases/metabolism/genetics ; *tau Proteins/genetics/metabolism ; *Protein Biosynthesis ; *Signal Transduction ; Up-Regulation ; Cell Line, Tumor ; *Mutation ; Neurons/metabolism ; Sirolimus/pharmacology ; Cell Differentiation ; }, abstract = {Altered protein synthesis plays a key role in ageing and multiple neurodegenerative diseases. In Alzheimer's disease and other tauopathies, the intracellular accumulation of hyperphosphorylated Tau disrupts several cellular processes, including mRNA translation. Although Tau interacts with ribosomal proteins and modulates translational selectivity, its effects on global protein synthesis remain poorly understood. Studies report reduced translation in later disease stages but increased translation early in pathology. To clarify Tau's impact in human neurons, we used SH-SY5Y cells overexpressing the P301L mutant form of Tau and quantified global protein synthesis using the SUnSET (Surface Sensing of Translation) puromycin-incorporation assay. We found that Tau-P301L expression greatly increased global translation by upregulating mTOR/S6 pathway. These effects were abolished by rapamycin treatment, indicating that Tau-driven translational upregulation is mTOR-dependent. Given that impaired translational control can disrupt synaptic plasticity and memory, Tau-induced alterations in protein synthesis may contribute to tauopathy progression and identify mTOR signalling as a potential therapeutic target.}, } @article {pmid41516246, year = {2025}, author = {Kvetnoy, I and Kheyfets, O and Safaniev, L and Kheifets, V and Mironova, E and Kvetnaia, T and Mazzoccoli, G and Prashchayeu, K and Gavrilova, A}, title = {Signaling Molecules and Diagnosis of Cognitive Disorders: Current State and Prospects.}, journal = {International journal of molecular sciences}, volume = {27}, number = {1}, pages = {}, pmid = {41516246}, issn = {1422-0067}, mesh = {Humans ; Biomarkers/metabolism ; *Signal Transduction ; *Alzheimer Disease/metabolism/diagnosis ; Dementia, Vascular/metabolism/diagnosis ; *Cognition Disorders/diagnosis/metabolism ; *Cognitive Dysfunction/diagnosis/metabolism ; }, abstract = {Cognitive disorders present significant medical and social challenges nowadays, due to their high prevalence, progressive course and a lack of effective methods for treatment of neurodegenerative diseases and comorbid pathologies. An important area of research is the identification of molecular biomarkers that reflect early pathophysiological changes and facilitate a more accurate biological characterization of cognitive impairment. This study provides an overview of the most relevant signaling molecules for diagnosing cognitive disorders. It presents data on the effectiveness of using comprehensive panels of molecular biomarkers in clinical practice, including β-amyloid, CD34, claudin, DRP1, endothelin-1, NF-kB, PINK1, RAGE, S100, α-synuclein, and tau protein, in patients with Alzheimer's disease (AD) and vascular dementia (VD). The study results demonstrate that cumulative changes in the expression of signaling molecules reflect various neurodegenerative and vascular-associated biological processes. The data obtained are comparative in nature and require further validation before potential clinical application.}, } @article {pmid41515488, year = {2026}, author = {Huang, Y and Li, X and Dai, L and Cheng, M and Zhao, L and Shen, Y and Xie, J and Luo, X}, title = {Antioxidant, Anti-Inflammatory, and Chemical Composition Analysis of In Vitro Huperzia serrata Thallus and Wild Huperzia serrata.}, journal = {Molecules (Basel, Switzerland)}, volume = {31}, number = {1}, pages = {}, pmid = {41515488}, issn = {1420-3049}, support = {20232ACB2050009//Natural Science Foundation of Jiangxi Province, China/ ; 32060074//National Natural Science Foundation of China/ ; 20204BCJ22024//Major Academic and Technical Leader Training Project of Jiangxi Province/ ; }, mesh = {*Antioxidants/pharmacology/chemistry ; *Anti-Inflammatory Agents/pharmacology/chemistry ; *Huperzia/chemistry ; Animals ; *Plant Extracts/chemistry/pharmacology ; Mice ; Sesquiterpenes/pharmacology/chemistry ; Alkaloids/pharmacology/chemistry ; RAW 264.7 Cells ; }, abstract = {Huperzine A is a preferred treatment option for Alzheimer's disease. Huperzia serrata (Thunb. ex Murray) Trev. (H. serrata) has garnered significant attention for its ability to produce Huperzine A (HupA). However, natural populations of wild H. serrata (WH) are rapidly declining. Fortunately, our group obtained two types of H. serrata thalli (OT and ST) capable of stably producing Huperzine A, which have the potential to serve as an alternative resource to WH. To evaluate the feasibility of this strategy, we conducted a comprehensive assessment of both WH and H. serrata thallus. The results indicated that compared to WH, ST and OT exhibited stronger anti-inflammatory and antioxidant activities, with lower cytotoxicity. Notably, ST demonstrated a strong radical scavenging activity, reaching 93.23% (DPPH at 0.2 μg/mL) and 99.87% (ABTS at 4 μg/mL), and reduced nitrite production from 10.29 μM to 6.51 μM at 50 µg/mL. GC-MS and widely targeted metabolomics analyses revealed that the higher antioxidant and anti-inflammatory activities for ST and OT were due to higher concentrations of phenolic acids and flavonoids compared to WH. In addition, the HupA content in ST reached 36.56% of that found in WH. KEGG enrichment analysis revealed that the flavonoid, phenylalanine, and phenylpropanoid biosynthesis pathways may be involved in regulating the antioxidant activity. P-coumaroyl quinic acid and caffeoyl quinic acid are the crucial metabolites for antioxidant activity. These findings suggested that the H. serrata thallus could serve as a sustainable alternative to WH.}, } @article {pmid41514478, year = {2026}, author = {Noman, M and Qadir, H and Ahmed, S and Rehman, NU and Shah, FA and Riaz, M and Ahmad, N and Ul-Haq, Z and Irshad, N}, title = {Santonin Attenuates Alzheimer's-Like Pathology via Multitarget Modulation of the NLRP3 Inflammasome, BDNF Signaling, and Amyloidogenic Pathways: An Integrated Experimental and Computational Study.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.5c00957}, pmid = {41514478}, issn = {1948-7193}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant cause of dementia, characterized by amyloid β (Aβ) plaques and tau tangles that disrupt neurons in memory-related brain regions. This study explores the therapeutic potential of santonin using integrated in silico, in vitro, and in vivo approaches. Molecular docking identified santonin as a promising acetylcholinesterase, NOD-like receptor family, pyrin domain-containing 3 (NLRP3), brain-derived neurotrophic factor (BDNF), and nuclear factor kappa B (NF-κB) ligand with significant binding affinities and supportive interaction scores supported by molecular dynamics simulations with significant multitarget therapeutic relevance. In vitro assays demonstrated that santonin has measurable inhibition of cholinesterase enzymes, showing significant effects on butyrylcholinesterase and acetylcholinesterase enzymes. Behavioral analysis revealed that santonin produced dose-dependent improvements in memory and exploratory behaviors, indicating significant neuroprotective effects against streptozotocin (STZ)-induced impairments. Histological analysis showed that santonin preserved neuronal architecture, enhanced neuronal density, and reduced Aβ deposition in STZ-treated brains using hematoxylin and eosin, Congo red, and Nissl analysis. These effects were evident in the cortical and hippocampal regions. Santonin exhibited strong antioxidant effects, mitigating induced enzyme depletion and oxidative marker elevation. Santonin effectively mitigated STZ-induced Aβ buildup and provided protective effects. Santonin modulated marker expression in STZ-treated brains by reducing the amyloid precursor protein, Tau, toll-like receptor 4, NLRP3, discs large MAGUK scaffold protein 4, and BDNF. Santonin reduces neuroinflammation and neurotrophic signaling in the early stages of AD, which suggests that it may be used as a treatment. However, more research is needed to confirm its effectiveness.}, } @article {pmid41514416, year = {2026}, author = {Tian, Q and Liu, M and Zhong, F and Liu, X and Lü, Y}, title = {Lecanemab treatment for mild alzheimer's disease with high risk of cerebral hemorrhage: a case report.}, journal = {BMC neurology}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12883-025-04581-y}, pmid = {41514416}, issn = {1471-2377}, abstract = {BACKGROUND: Lecanemab has been approved for the treatment of mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia based on the efficacy in slowing cognitive decline and preliminary safety data from the phase Ⅲ Clarity AD trial. However, this trial excluded patients with high risk of cerebral hemorrhage, such as individuals with intracranial aneurysms or > 4 microhemorrhages.

CASE PRESENTATION: A 70-year-old male with mild AD, intracranial aneurysm, microhemorrhages, and APOE ε3/ε4 genotype received lecanemab after multidisciplinary evaluation and informed consent. Over six months of intensive monitoring, cognitive function stabilized with no deterioration, daily activities were preserved, microhemorrhages remained stable (with one new small lesion noted at 3 months), and no aneurysm rupture or severe adverse events (including amyloid-related imaging abnormalities) occurred.

CONCLUSIONS: This case suggests that, despite hemorrhage risks, lecanemab may have a manageable risk-benefit profile in selected real-world AD patients under intensive monitoring and multidisciplinary care, with its application beyond clinical trial criteria requiring more nuanced and individualized consideration.}, } @article {pmid41513640, year = {2026}, author = {Abdulkhaliq, AA and Kim, B and Almoghrabi, YM and Khan, J and Ajoolabady, A and Ren, J and Bahijri, S and Tuomilehto, J and Borai, A and Pratico, D}, title = {Amyloid-β and Tau in Alzheimer's disease: pathogenesis, mechanisms, and interplay.}, journal = {Cell death & disease}, volume = {17}, number = {1}, pages = {21}, pmid = {41513640}, issn = {2041-4889}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Animals ; Brain/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disease and the most prevalent type of dementia characterized by pathological deposition of amyloid-β plaques/deposits and tau tangles within the brain parenchyma. This progressive ailment is featured by irreversible cognitive impairment and memory loss, often misdiagnosed as the consequence of old age in elderlies. Pathologically, synaptic dysfunction occurs at the early stages and then progresses into neurodegeneration with neuronal cell death in later stages. In this review, we aimed to critically discuss and highlight recent advances in the pathological footprints of amyloid-β and tau in AD. Specifically, we focused our attention on the interplay and synergistic effects of amyloid-β and tau in the pathogenesis of AD. We hope that our paper will provide new insights and perspectives on these pathological features of AD and spark new ideas and directions in AD research and treatment.}, } @article {pmid41513181, year = {2026}, author = {Vyas, J and Jamenis, AS and Kaku, K and Shah, Y and Miner, KM and Bhatia, TN and Kim, RE and Bai, R and Hamel, E and Leak, RK and Gangjee, A}, title = {Discovery of multitargeting single agents as a novel route to the potential treatment of neurodegenerative diseases.}, journal = {Bioorganic & medicinal chemistry letters}, volume = {133}, number = {}, pages = {130536}, doi = {10.1016/j.bmcl.2026.130536}, pmid = {41513181}, issn = {1464-3405}, abstract = {There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have recently discovered first-in-class novel single agents (compounds 1 and 2) that mildly inhibit clinically important kinases and subtly favor microtubule stability at concentrations that show no evidence of neuronal toxicity in primary neurons, while maintaining their ability to penetrate the CNS in vivo. It is important to note that the effects of these analogs are mild and are predicated on avoiding neurotoxicity. These multitargeting single agents provide a new structural modality with the potential to influence treatments for Parkinson's and Alzheimer's disease and serve as lead compounds for further optimization.}, } @article {pmid41511604, year = {2026}, author = {Babaker, MA and Alazabi, NI and Yousef, EM and Haredy, SA and Algohary, AM and Mansour, DF and Ahmed-Farid, OA}, title = {Taurine Mitigates Spironolactone-Induced Hyperkalemia and Cognitive Dysfunction: A Biochemical and Histological Study in a Rat Model.}, journal = {Applied biochemistry and biotechnology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s12010-025-05513-9}, pmid = {41511604}, issn = {1559-0291}, abstract = {Spironolactone (SPR), a widely used potassium-sparing diuretic, frequently causes hyperkalemia, leading to significant cardiovascular and neurological complications. Taurine, a semi-essential amino acid with known antioxidant and neuroprotective effects, was hypothesized to mitigate these adverse effects. This study investigated taurine's efficacy against SPR-induced hyperkalemia and associated cognitive dysfunction in a rat model. Adult male Sprague-Dawley rats were treated for four weeks with SPR, SPR + galantamine (an AChE inhibitor widely used in the treatment of Alzheimer's disease), or SPR + varying concentrations of taurine, followed by assessment of cognitive, biochemical, and histopathological alterations. SPR administration significantly increased serum potassium levels (~7.5 mEq/L), induced cognitive deficits, disrupted neurotransmitter balance (e.g., altered GABA and glutamate levels), and caused reactive astrocytic swelling in key brain regions. Taurine demonstrated a dose-dependent protective effect against SPR-induced neurotoxicity by mitigating hyperkalemia and associated cognitive impairments. Biochemically, taurine restored neurotransmitter balance by increasing GABA and reducing the excitotoxic glutamate levels. Histological analysis further confirmed taurine's neuroprotective effects, showing preserved cortical structures and reduced astrogliosis, especially at the highest concentration (5%). Our correlation analysis reveals complex regulatory mechanisms underlying neurotransmitter balance in the brain. These findings suggest taurine as a promising therapeutic agent for alleviating SPR-induced neurological side effects. Further studies are needed to explore taurine's long-term effects and clinical applications in managing hyperkalemia-related cognitive dysfunctions.}, } @article {pmid41511339, year = {2025}, author = {Yu, H and Josi, RR and Khanna, A and Khismatullin, DB}, title = {Low-Density Lipoproteins Induce a Pro-Inflammatory, Chemotactic Mox-like Phenotype in THP-1-Derived Human Macrophages.}, journal = {Cells}, volume = {15}, number = {1}, pages = {}, pmid = {41511339}, issn = {2073-4409}, support = {1R01HL127092-01A1/NH/NIH HHS/United States ; }, mesh = {Humans ; *Lipoproteins, LDL/pharmacology ; *Macrophages/metabolism/drug effects ; *Chemotaxis/drug effects ; Phenotype ; THP-1 Cells ; *Inflammation/pathology/metabolism ; Mast Cells/metabolism/drug effects ; Interleukin-6/metabolism ; Cytokines/metabolism ; Cell Differentiation/drug effects ; }, abstract = {Murine macrophages exposed to oxidized low-density lipoprotein (oxLDL) polarize into a distinct Mox phenotype characterized by impaired phagocytic and chemotactic function. Although implicated in atherosclerosis, this phenotype has not been confirmed in human macrophages. Drawing parallels to human tumor-associated macrophages, and in contrast to the murine cell response, we hypothesize that LDL/oxLDL induces a hybrid Mox-like state in human macrophages, marked by the simultaneous secretion of pro-inflammatory cytokines and anti-inflammatory factors, potentially exacerbating vascular inflammation and atherogenesis. To test this, THP-1 human monocytes were differentiated into resting macrophages, then polarized into M1-like and M2-like phenotypes, followed by treatment with native LDL, oxLDL, IL-6, or their combinations. ELISA results showed that oxLDL or LDL with IL-6 polarized resting and M1-like macrophages into a Mox-like phenotype that secreted TNF-α and TGF-β1 at levels comparable to M1- and M2-like cells, respectively. The pro-inflammatory nature of Mox-like macrophages was supported by increased THP-1 adhesion to vascular endothelial cells exposed to the macrophage-conditioned media. In microfluidic assays, LUVA human mast cells migrated toward media from Mox-like macrophages, indicating enhanced chemotaxis. In summary, the pro-inflammatory Mox-like state is triggered in human macrophages by oxLDL or LDL combined with IL-6, a key regulator of the inflammatory acute-phase response. Unlike in murine cells, this state is marked by high chemotactic activity driven by TGF-β1 secretion, which promotes mast cell recruitment and contributes to atherosclerotic plaque development and Alzheimer's disease.}, } @article {pmid41510854, year = {2026}, author = {Tyagi, S and Murali, N and Singh, SK and Babtiwale, SR and Padhi, BK and Lakshmi, NRA and Gandhi, AP}, title = {A Systematic Review to Evaluate the Effect of Neflamapimod on Cognitive Function and Progression of Dementia.}, journal = {Neurology India}, volume = {74}, number = {1}, pages = {12-19}, doi = {10.4103/neurol-india.Neurol-India-D-25-00227}, pmid = {41510854}, issn = {1998-4022}, mesh = {Humans ; *Cognition/drug effects ; Disease Progression ; *Dementia/drug therapy ; *Alzheimer Disease/drug therapy ; *Lewy Body Disease/drug therapy ; }, abstract = {Treatment options for dementia mainly comprise of symptomatic treatment, as no disease-modifying therapy currently exists that directly reduces the pathology. This systematic review assessed the effectiveness of neflamapimod (VX-745), a p38α kinase inhibitor, as a therapeutic agent for treating dementia, including Alzheimer's disease (AD) and Lewy Body Dementia (LBD). The systematic review evaluated the therapeutic effect of neflamapimod on dementia. Five electronic databases were included in the systematic review: PubMed, Embase, ProQuest, Cochrane Library, and Web of Science, which were searched until May 5, 2024. Two independent reviewers conducted title and abstract screening, followed by full-text review and data extraction, with disagreements resolved by a third reviewer. The risk of bias in the included studies was assessed using the ROB 2.0 tool. PROSPERO Registration ID: CRD42024542377. The review identified clinical results, biomarker effects, and mechanistic insights from two key trials. Due to the inclusion of only two eligible studies with varying methodologies and outcome measures, a meta-analysis could not be performed. While the primary cognitive outcomes, such as "neuropsychological test battery (NTB)" and "Hopkins Verbal Learning Test-Revised (HVLT-R)" were not statistically different, episodic memory, executive function, attention, gait dysfunction, and motor issues showed improvements, especially in patients with elevated plasma tau181, a marker for AD pathology. Biomarker analysis also indicated a statistically significant reduction in cerebrospinal fluid (CSF) tau and phosphorylated tau biomarkers, which are closely related to neuroinflammation and synaptic impairment in dementia. The findings of the current review suggested that while the cognitive effects of neflamapimod remain uncertain, its ability to influence disease-specific biomarkers makes it a potential drug to be used in dementia. This review connects biological and clinical outcomes, paving the way for future advancements in dementia treatment strategies.}, } @article {pmid41510732, year = {2026}, author = {Adhikari, B and Venkatesh, DN and Puri, V and Sharma, A}, title = {Therapeutic Implications of Nutraceutical Nanotechnology for the Treatment of Chronic Diseases.}, journal = {Current drug metabolism}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892002415344251122122358}, pmid = {41510732}, issn = {1875-5453}, abstract = {Nanotechnology possesses therapeutic value in managing chronic disease, but it has limitations like as solubility, stability, and targeted delivery in clinical applications. The review explores how nanotechnology-based delivery systems improve the efficacy, bioavailability, and targeted actions of nutraceutical compounds. Health benefits, sustainable nanotechnology, market size, and growth forecasts have shown positive results in this industry over the last two decades. The disease-like respiratory, diabetes, Alzheimer's and Parkinson's, and breast cancer top focused sectors for this nutraceuticals sector. Most literature has been collected from 2020-2025 using PubMed, Scopus, Google Scholar, and Web of Science. The different criteria included preclinical, clinical, and nanotechnology-integrated nutraceutical studies. The liposomes, dendrimers, nanoemulsions, and polymeric nanoparticles significantly enhance the stability and delivery of key bioactive as example like curcumin, resveratrol, and omega-3. Early-stage clinical trials show promise for diseases like Alzheimer's, diabetes, and cancer. Nanotechnology is the reshaping of nutraceutical therapy, through regulatory, toxicology, and large-scale validation gaps persist. Future work must focus on green synthesis, long-term safety, and harmonized approval pathways. Despite this, the industry still needs collaboration between academic researchers, scientists, and regulatory bodies to start the next generation of clinical trials and treatments that can reduce the risk of diseases and death in the future.}, } @article {pmid41510728, year = {2026}, author = {González-Jiménez, KA and Herrera-Mayorga, EV and Paredes Sánchez, FA and Niño-García, N and Torres-Castillo, JA and Martínez-Padrón, HY and Sánchez-Sánchez, M}, title = {New Drug Therapies Against Targeting Neurodegenerative Diseases: A Comprehensive Review.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249397580251117044621}, pmid = {41510728}, issn = {1875-6166}, abstract = {Neurodegenerative diseases encompass well-characterized behavioral, cognitive, and movement disorders that affect older people, impacting all facets of daily life. In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease. In Parkinson's disease, most drugs were approved several decades ago; however, new Phase II clinical trials point to monoclonal antibodies as a promising approach, and the report of alkaloids also suggests various therapeutic targets against this disease. Pick's disease has a low prevalence; currently, no drugs are approved by government agencies. However, thanks to molecular tools, it has been possible to elucidate therapeutic targets implicated in the appearance of the disease. α-synuclein is the main therapeutic target in Lewy body disease; most of the reported molecules are in clinical Phases I and II. Additionally, drug repositioning may emerge as a viable option in the search for effective treatments against this disease. In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition. Altered emotions and progressive damage in some brain regions characterize schizophrenia and vascular dementia. Combinations of tricyclic drugs are a trend that aims to increase the cognitive performance of patients with schizophrenia. In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases.}, } @article {pmid41510718, year = {2026}, author = {Prabakaran, A and Sivaperuman, A and Natarajan, R and Nagarajan, NC and Solomon, VR}, title = {Innovative Approaches to Alzheimer's Treatment: Utilizing Tacrine Hybrids to Inhibit Amyloid Beta Aggregation as a Strategic Focus.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575422492251116190843}, pmid = {41510718}, issn = {1875-5607}, abstract = {Alzheimer's disease (AD) is a complex and progressive brain disorder marked by memory loss, cognitive decline, and behavioral changes. One of its defining features is the build-up of amyloid plaques, clumps of β-amyloid (Aβ) peptides, in the brain, along with the formation of neurofibrillary tangles. These Aβ peptides are generated when the amyloid precursor protein (APP) is cleaved by enzymes, with β-secretase (BACE1) playing a key role in the first step of this process. Because BACE1 starts the cascade that leads to harmful Aβ build-up, it has become an important target in the search for effective Alzheimer's treatments. As Aβ accumulates in neurons, it disrupts communication between brain cells and triggers oxidative stress, which worsens damage and accelerates disease progression. This is often exacerbated by imbalances in metal ions, such as copper and iron. While tacrine, an early acetylcholinesterase inhibitor, has shown benefits in managing AD symptoms, its limitations have led researchers to explore improved versions. One promising direction is the development of tacrine-based hybrid molecules. By combining tacrine with other chemical groups that have anti-β-amyloid (Aβ) effects, antioxidant properties, and metal-chelating properties, scientists aim to create compounds that target multiple aspects of the disease simultaneously. This review examines the emerging potential of tacrine hybrids, particularly their capacity to inhibit BACE1 and prevent Aβ aggregation, providing new hope for more effective and disease-modifying therapies for Alzheimer's disease.}, } @article {pmid41510716, year = {2026}, author = {Bano, A and Khan, AA and Kushwaha, SP and -, A and Zaidi, SMH and Misbahul Hasan, S and Fatima, A}, title = {Indole Scaffolds in Neurological Therapeutics: Synthesis, Structure-Activity Relationships and Drug-Receptor Interactions.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575415521251021091530}, pmid = {41510716}, issn = {1875-5607}, abstract = {INTRODUCTION: Indole is a privileged heterocyclic scaffold that plays a crucial role in medicinal chemistry due to its strong ability to bind to various biological receptors and interact with diverse molecular targets. Indole exhibits both biological and chemical significance. Its structural versatility allows for precise chemical modifications, making it an essential framework in drug discovery. This review discusses the structure-activity relationships, synthesis, and interactions of indole derivatives, particularly in relation to targets within the central nervous system.

METHODS: A detailed literature survey was conducted using databases such as Google Scholar, Elsevier, PubMed, ACS, PubChem, ScienceDirect, and RSC to understand the structural modifications of indole derivatives and their therapeutic potential. Both research and review articles related to indole- based compounds were thoroughly studied to prepare this review article.

RESULTS: There are over 40 FDA-approved drugs containing an indole nucleus used to treat various diseases, underscoring its potential in neurotherapeutics. This review highlights innovative synthetic strategies, including green chemistry approaches, that improve the drug-likeness and bioavailability of indole derivatives. Indole continues to be an indispensable scaffold in the development of novel therapeutics aimed at addressing the growing burden of neurological disorders.

DISCUSSION: This review aims to provide a comprehensive analysis of the therapeutic potential of indole-based compounds for the treatment of neurological disorders. However, challenges like blood-brain barrier permeability and long-term safety must be addressed for clinical success. Nonetheless, this review will help in designing and developing newer indole-based molecules in the discovery of neurological drug development.

CONCLUSION: Due to its broad spectrum of biological activities and favorable pharmacokinetic properties, indole is an impressive scaffold for the treatment of various neurological disorders. Indole demonstrates remarkable therapeutic potential against a range of central nervous system-related conditions, including Alzheimer's disease, epilepsy, migraine, stroke, Parkinson's disease, prion disease, amyotrophic lateral sclerosis, and Huntington's disease.}, } @article {pmid41510572, year = {2026}, author = {Tang, C and Han, K and Wen, X and Zhang, J and Sun, W and Yue, X and Shi, L and Liu, Z and Zhao, J and Yan, C and Liu, M and Yao, Z and Kong, Z and Liu, Y and Fu, Z and Zhao, X and Yang, Z and Han, M and Chen, C and Xing, Z and Zhou, X and Yang, F and Zhang, Y and Jiang, X}, title = {Synthetic Disaggregators Enhance Central-Peripheral Amyloid-β Clearance in Alzheimer's Disease.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {}, number = {}, pages = {e20002}, doi = {10.1002/adma.202520002}, pmid = {41510572}, issn = {1521-4095}, support = {2024YFA0918400//National Key Research and Development Program of China/ ; 82350125//National Natural Science Foundation of China/ ; 82425056//National Natural Science Foundation of China/ ; 82173763//National Natural Science Foundation of China/ ; 82303810//National Natural Science Foundation of China/ ; ZR2022ZD18//Fundamental Research Funds of Shandong Province/ ; ZR2023QH224//Natural Science Foundation of Shandong Province/ ; 2022M721967//China Postdoctoral Science Foundation/ ; 2024T170524//China Postdoctoral Science Foundation/ ; SYS202202//Shandong Provincial Laboratory Project/ ; NO.tsqnz20221165//Taishan Scholar Foundation of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; 2025CXPT177//Key R&D Program of Shandong Province/ ; }, abstract = {Pathogenic amyloid-β (Aβ) accumulation defines Alzheimer's disease (AD), directly inflicting neuronal damage and driving chronic neuroinflammation. While both central microglia and peripheral macrophages are critical for Aβ clearance, their functional impairment in AD inexorably leads to escalating Aβ burden and disease progression. We here report an in situ engineered synthetic Aβ disaggregator (SAD) delivered to macrophages via neuroprotective DHA-based lipid nanoparticles (DLNPs). This platform transcends current therapeutic limitations by not only potently dismantling neurotoxic Aβ aggregates but also by fundamentally reprogramming peripheral macrophages to enhance Aβ clearance. Specifically, our results demonstrate that DLNPs effectively reprogram peripheral macrophages to produce and secrete cerebral-penetrating SAD both in vitro and in vivo. The SAD can promote cerebral Aβ disaggregation, thereby inhibiting neuroinflammatory pathology progression. Moreover, the DLNPs efficiently reprogram the peripheral macrophages to enhance phagocytosis, further facilitating drainage of Aβ and reducing cerebral Aβ accumulation in mouse models. Collectively, these findings uncover a dual-action mechanism of SAD through the synergistic interplay of direct Aβ disaggregation and enhanced macrophage-mediated clearance. In sum, our findings establish that the central-peripheral targeting therapeutic strategy significantly reversed AD pathology, highlighting the therapeutic potential of mRNA-based in situ fusion protein in AD treatment.}, } @article {pmid41510365, year = {2026}, author = {Wang, Y and Alexander, GC and Mehta, HB}, title = {Treatment of type 2 diabetes among medicare beneficiaries with and without alzheimer's disease: A retrospective cohort study.}, journal = {Journal of diabetes and metabolic disorders}, volume = {25}, number = {1}, pages = {25}, pmid = {41510365}, issn = {2251-6581}, abstract = {PURPOSE: While Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) commonly co-occur in older adults, little is known regarding whether and how the treatment of T2DM varies by AD status. This study aimed to compare and contrast T2DM treatment among individuals with and without AD.

METHODS: We conducted a retrospective cohort study using 20% Medicare Fee-for-Service claims data from 2016 to 2020. The primary outcome was initiation of any antidiabetic medication within one year of T2DM diagnosis, and we also examined initiation patterns across specific drug classes. We used multivariable logistic regression to estimate adjusted odds ratios for the association between AD and treatment initiation.

RESULTS: Among 388,359 beneficiaries newly diagnosed with T2DM, 9,584 had AD. Within one year, overall treatment initiation was lower for individuals with AD compared to those without. At initiation, individuals with AD were more likely to receive insulin and less likely to receive metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, or glucagon-like peptide-1 (GLP-1) receptor agonists. In adjusted models, AD was associated with lower odds of antidiabetic treatment initiation, and among those initiating treatment, lower odds of initiating newer agents such as GLP-1 receptor agonists and SGLT2 inhibitors.

CONCLUSION: Beneficiaries with AD were less likely to initiate antidiabetic therapy, particularly newer agents. Future work could explore the basis for these differences.}, } @article {pmid41510304, year = {2025}, author = {Wang, Y and Zhou, M and Tang, Z and Xiong, C and Asken, B and Yang, B and Su, J and Zhou, X and Song, Q}, title = {CauReL: Dynamic Counterfactual Learning for Precision Drug Repurposing in Alzheimer's Disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-8206648/v1}, pmid = {41510304}, issn = {2693-5015}, abstract = {Alzheimer's disease has few effective therapies, and decades of amyloid- and tau-focused trials have delivered only modest benefit with substantial toxicity. Drug repurposing using real-world data offers a faster and lower-risk route to new treatments, yet current approaches typically average effects across populations, model disease onset and progression separately, and provide little insight into which patients are most likely to benefit. We present CauReL, a dynamic counterfactual representation learning framework that enables transparent, patient specific estimation of treatment effects from large-scale electronic health records for precision drug repurposing in AD. CauReL first learns balanced latent representations of treated and untreated patients using Integral Probability Metric regularization, then jointly predicts two clinically linked outcomes, incident AD and time from mild cognitive impairment (MCI) to AD, to generate paired counterfactual outcomes for every individual. A counterfactual explanation module quantifies how clinical features shape benefit at the patient level, and uplift trees transform complex heterogeneity into simple, rule-based subgroups suitable for trial enrichment and clinical decision support.Using independent cohorts from OneFlorida + and All of Us, we screened outpatient prescriptions with at least 20 percent exposure among 28,605 individuals with mild cognitive impairment, of whom 4,990 progressed to Alzheimer's disease. CauReL substantially improved covariate balance and distributional overlap across drug cohorts and achieved strong predictive accuracy for both incidence (AUC greater than 0.90) and progression timing (C index 0.81 to 0.84; Spearman 0.80 to 0.86). Twenty drugs showed consistent protective associations, with four emerging as highly reproducible across both networks, the metabolic agents liraglutide and empagliflozin and the neuroactive agents entacapone and amantadine. These drugs were associated with meaningful absolute risk reductions and clinically significant delays in progression from mild cognitive impairment to Alzheimer's disease. Metabolic drugs produced the strongest benefits in individuals with diabetes, obesity, or cardiovascular disease, whereas neuroactive drugs provided broadly consistent protection across most subgroups.CauReL is available as an open source Python package with a companion web server for direct application to new cohorts or disease settings (https://caurel.site/). This work delivers a scalable and interpretable framework for prioritizing repurposable drugs and designing targeted clinical trials for the patients most likely to benefit.}, } @article {pmid41510223, year = {2025}, author = {Jiang, L and Tucker, A and Sepehri, C and Patel, D and Wang, Q and Yuan, S and Sherman, E and Chen, Y and Beh, J and Downey, A and Goldberg, D and Gniadzik, W and Ma, X}, title = {Inhibition of N6-Methyladenosine Accumulation by Targeting METTL3 Mitigates Tau Pathology and Cognitive Decline in Alzheimer's Disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, doi = {10.21203/rs.3.rs-8379573/v1}, pmid = {41510223}, issn = {2693-5015}, abstract = {Dysregulation of N6-methyladenosine (m6A) modification of RNA has emerged as a novel feature of Alzheimer's disease (AD). Here, we investigate the relationship between m6A modification and AD pathology, and the therapeutic potential of modulating excessive m6A via its "writer" methyltransferase METTL3 in a humanized P301S tau transgenic mouse model of AD (PS19). We observed significantly elevated m6A levels in human post-mortem AD frontal cortex tissue compared to healthy controls, which positively correlated with hyperphosphorylated tau and amyloid-β (Aβ) deposition. These effects were recapitulated in the PS19 tau mice model of AD. Importantly, treatment of PS19 mice with the METTL3 inhibitor STM2457 reduced excessive m6A, alleviated tau pathology, and attenuated neurodegeneration. Behavioral assessments further demonstrated that STM2457-treated PS19 mice exhibited significantly improved learning and memory relative to untreated PS19 mice. Our results identify m6A as a critical contributor to AD pathogenesis and demonstrate that pharmacological inhibition of METTL3 represents a promising therapeutic strategy to improve cognition in AD.}, } @article {pmid41509358, year = {2026}, author = {Jati, S and Kal, S and Munoz-Mayorga, D and Tang, K and Sahoo, D and Chen, X and Mahata, SK}, title = {Catestatin ameliorates tauopathy and amyloidogenesis via adrenergic inhibition.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.01.04.697519}, pmid = {41509358}, issn = {2692-8205}, abstract = {Neurodegenerative disorders like Alzheimer's disease (AD), Corticobasal Degeneration (CBD), and Progressive Supranuclear Palsy (PSP) are characterized by Tau aggregation, synaptic dysfunction, neuroinflammation, and progressive cognitive decline. Although metabolic dysregulation and neuropeptide imbalance have been linked to these disorders, the functional consequences of such imbalance and its potential for therapeutic reversal remain poorly understood. Our previous work identified chromogranin A (CgA), which encodes a pro-hormone for several metabolic peptides, as a key regulator of Tau pathology. Here, we investigate Catestatin (CST), a CgA-derived peptide that is a potent inhibitor of catecholamine release and has been shown to increase insulin sensitivity and lower peripheral blood pressure. We report significant reductions in CST levels in the hippocampus and cortex of AD brains, as well as in the frontal cortex of CBD and the basal ganglia of PSP. Supplementing CST in cortical neuronal cultures and organotypic slice cultures (OTSC) decreased Tau phosphorylation and aggregation. In vivo , CST administration in PS19 Tauopathy mice reduced pathological Tau species, attenuated gliosis, and improved cognitive function. CST treatment also lowered amyloid plaque burden and neuroinflammation in 5xFAD mice. Mechanistically, CST decreased epinephrine (EPI) levels in both PS19 and 5xFAD mice and suppressed downstream protein kinase A (PKA) hyperactivation in PS19 and OTSC. These findings reveal a previously unrecognized neuropeptidergic mechanism linking CST deficiency to elevated adrenergic receptor (ADR)-EPI-PKA stress signaling and Tauopathy-driven neurodegeneration, suggesting CST replacement as a promising therapeutic approach.}, } @article {pmid41509252, year = {2026}, author = {Jesudason, CD and Rangel-Barajas, C and Beach, CJ and Beck, DE and Caballero-Floran, IH and Clayton, WB and Da Silva, L and David, JC and Doolen, S and Faulkner, AN and Hamdani, AK and Huhe, H and Huynh, K and Imhoff, RD and Javens-Wolfe, J and Mason, ER and Moussaif, M and Singhal, K and Soni, DM and van Buuren-Milne, M and Williams, SP and Angus, SP and Chu, S and Dage, JL and Hipskind, PA and Johnson, TS and Kaddurah-Daouk, R and Lamb, BT and Meikle, PJ and Mesecar, AD and Palkowitz, AD and Quinney, SK and Sukoff Rizzo, SJ and Oblak, AL and Richardson, TI}, title = {Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41509252}, issn = {2692-8205}, abstract = {Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP1), encoded by the gene INPP5D, is a lipid phosphatase that negatively regulates immune receptor signaling in hematopoietic cells and microglia. Here, we describe a pyridyl-pyrazole-piperidine scaffold and the lead compound 3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine (32), which demonstrates SHIP1 target engagement, brain exposure, and evidence of a central pharmacodynamic response in vivo. Structure-activity relationship studies, guided by biochemical and cellular assays using multiple human and murine protein constructs and cells, identified SHIP1-active ligands. A thermal shift assay using full-length SHIP1 was used to assess compounds for cellular target engagement, while studies in IL-4 conditioned THP-1 cells was used to demonstrate changes in downstream AKT signaling. Targeted lipidomics revealed changes in the overall phosphoinositide pool consistent with SHIP1 target engagement and reduction of phospho-AKT levels. In a protein-lipid overlay assay, compound 32 induced changes in the relative association of SHIP1 with multiple phosphatidylinositols on a membrane surface. In high-content cellular imaging assays, compound 32 enhanced the uptake of myelin/membrane debris and fibrillar amyloid by primary murine microglia, phenocopying a genetic model with reduced SHIP1 expression. Finally, oral administration of compound 32 resulted in brain exposure sufficient to alter gene expression and reduce IL-1β levels as pharmacodynamic markers of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer's disease. Collectively, these results define a scaffold with SHIP1 target engagement, CNS exposure, and in vivo activity, providing a foundation for the optimization of brain-penetrant SHIP1 ligands suitable for further mechanistic studies and therapeutic development for the treatment of Alzheimer's disease.}, } @article {pmid41509242, year = {2025}, author = {Kumari, R and Bowen, C and Srivastava, U and Brandelli, AD and Kumar, P and Kour, D and Malepati, S and Jang, WE and Bromwich, M and Zeng, H and Sing, A and Sloan, SA and Wulff, H and Rangaraju, S}, title = {Kv1.3 inhibition alleviates neuropathology via neuroinflammatory and resilience pathways in a mouse model of Aβ pathology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.25.696456}, pmid = {41509242}, issn = {2692-8205}, abstract = {Inhibition of voltage-gated potassium channel Kv1.3 is a therapeutic strategy to curb microglia-mediated neuroinflammation in neurodegeneration, although the cellular and signaling mechanisms of disease-modification by Kv1.3 blockers are unclear. In this study, we delineate protective mechanisms of Kv1.3 blockade in a mouse model of Alzheimer's disease (AD) pathology using comprehensive transcriptomics and proteomics profiling of brain, corresponding with neuropathological effects of two translationally relevant Kv1.3 blockers, namely small molecule PAP-1 and peptide ShK-223. Following 3 months of treatment, both molecules reduced Ab plaque burden. Single nuclear RNA seq (snRNA seq) of brain nuclei showed that PAP-1 disproportionately impacted oligodendrocytes and microglia and increased crosstalk between neurons and astrocytes with endothelial cells. In contrast, ShK-223 had pronounced effects on glutamatergic neurons and astrocytes. Both blockers increased expression of myelination genes in oligodendrocytes and synaptic genes in neurons. Neuroprotective effects of PAP-1 were further confirmed by bulk brain transcriptomics and proteomics whereby PAP-1 increased levels of synaptic, cognitive resilience and mitochondrial proteins, while decreasing glial and immune pathways including STAT1/3 phosphorylation. Using proximity labeling and co-immunoprecipitation, we found that Kv1.3 interacts with STAT1/3 in microglia. Using microglial cell lines and primary microglia, we discovered a preferential functional coupling between Kv1.3 and type 2 but not type 1 IFN signaling. Brain-level disease modification by Kv1.3 blockade was reflected in the cerebrospinal fluid (CSF) via reduced levels of neurofilament-light (NEFL) and resilience protein RPH3A, both of which are increased in human AD CSF. Together, this study demonstrates functional links between Kv1.3 channels and type 2 IFN signaling and reveals distinct cellular effects of Kv1.3 blockers in AD pathology that correspond with reduced neuropathology and neuroinflammation, augmentation of resilience and neuro-vascular pathways, along with biomarkers of therapeutic effect.}, } @article {pmid41508224, year = {2025}, author = {Ma, YJ and Deng, SX and Liao, ZH and Gao, MH and Ding, HX and Xu, ZQ and Lu, YT and Yang, C and Wang, Q}, title = {[Treatment of Alzheimer's disease from gut-brain interactions based on theory of "spleen deficiency leading to obstruction of nine orifices"].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {19}, pages = {5330-5339}, doi = {10.19540/j.cnki.cjcmm.20250618.501}, pmid = {41508224}, issn = {1001-5302}, mesh = {*Alzheimer Disease/drug therapy/physiopathology/metabolism ; Humans ; *Brain/physiopathology/drug effects/metabolism ; *Spleen/physiopathology/drug effects ; Animals ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use ; Gastrointestinal Microbiome ; }, abstract = {Alzheimer's disease(AD) is the most common form of dementia. The decline in sensory function is associated with pathological damage in specific brain regions during the early stages of AD. Such decline often precedes cognitive impairment, worsens as the pathology progresses, and constitutes a high-risk factor for the onset of AD. According to traditional Chinese medicine(TCM), all orifices are connected to the brain, and the brain governs all orifices. The mind originates from and depends on both the brain and orifices, with their physiological and pathological states being closely interconnected. In AD, dysfunction of the sensory orifices is closely linked to the later-stage manifestations of impaired mental clarity and consciousness. The theory that "spleen deficiency leading to obstruction of nine orifices" emphasizes that insufficiency of the spleen and stomach is the root cause of orifice dysfunction. Both internal and external pathogenic factors in AD can damage the spleen and stomach, leading to the abnormal movement of turbid substances generated by these organs, which may transform into turbid toxins. This, in turn, gradually impairs the orifices, brain, and mind, thereby exacerbating the progression of AD. The digestive, absorptive, and transport functions of the spleen and stomach are similar to those of the gut microbiota. Spleen deficiency is a core pathological factor in diseases associated with gut microbiota dysbiosis. Such dysbiosis can lead to dysfunction in the neural, metabolic, and immune pathways involved in gut-brain interactions, constituting the biological basis for the TCM concept that "spleen deficiency leading to obstruction of nine orifices". Under the guidance of this theory, employing spleen-strengthening and cognition-enhancing drugs alongside aromatic orifice-opening drugs to support spleen function, and using ingredients that promote dampness elimination, lubrication, and blood stasis resolution to dispel pathogenic factors from the orifices, can help restore the structural balance of the gut microbiota, regulate related metabolic and immune dysfunctions, and ultimately delay the progression of AD. This article explores the etiology, pathogenesis, and therapeutic strategies of AD based on the theory of "spleen deficiency leading to obstruction of nine orifices", and interprets its biological significance from the perspective of gut-brain interactions, aiming to provide new insights for the prevention and treatment of AD.}, } @article {pmid41508200, year = {2025}, author = {Zhang, YX and Wang, J and Chen, QQ and Zhang, JL and Wang, Q and Long, YL and Zhou, SJ and Gong, ZP and Zheng, L and Huang, Y and Li, YT}, title = {[Study on quality markers of Pleione yunnanensis for "same treatment for different diseases" in liver inflammation and Alzheimer's disease based on UHPLC fingerprint and network pharmacology].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {20}, pages = {5684-5696}, doi = {10.19540/j.cnki.cjcmm.20250710.202}, pmid = {41508200}, issn = {1001-5302}, mesh = {Network Pharmacology ; *Drugs, Chinese Herbal/chemistry/therapeutic use ; *Alzheimer Disease/drug therapy/genetics/metabolism ; Chromatography, High Pressure Liquid/methods ; Humans ; Molecular Docking Simulation ; Biomarkers/analysis ; Quality Control ; }, abstract = {This study aims to screen quality markers(Q-markers) of Pleione yunnanensis for the treatment of liver inflammation and Alzheimer's disease(AD) based on the concept of "same treatment for different diseases" using ultra-high-performance liquid chromatography(UHPLC) fingerprinting combined with network pharmacology and molecular docking, and to perform quantitative analysis of the identified Q-markers. The UHPLC fingerprints of 15 batches of P. yunnanensis were established and subjected to similarity evaluation, cluster analysis(CA), principal component analysis(PCA), and orthogonal partial least squares discriminant analysis(OPLS-DA) to identify characteristic components responsible for quality variations. Network pharmacology and molecular docking were employed to explore the potential active components, related targets, and signaling pathways underlying the "same treatment for different diseases" mechanism for liver inflammation and AD. Based on the criteria of effectiveness, specificity, and measurability, Q-markers of P. yunnanensis were identified and quantified. Ten common peaks were identified in the UHPLC fingerprints of 15 batches, with eight components identified. Similarity scores ranged from 0.774 to 0.987. Chemical pattern recognition analysis identified that shancigusin H, militarine, and gymnoside Ⅴ were the major characteristic components contributing to quality differences among batches. RESULTS:: of network pharmacology and molecular docking revealed that dactylorhin A and militarine were the key active components exerting anti-inflammatory and neuroprotective effects. These components acted on 13 core targets, including SRC, CASP3, and CTNNB1, and regulated signaling pathways such as the PI3K-Akt signaling pathway and arachidonic acid metabolism. Based on the effectiveness, specificity, and measurability of Q-marker, dactylorhin A and militarine were selected as the Q-markers of P. yunnanensis. Quantitative analysis demonstrated that the content of dactylorhin A ranged from 0.527% to 2.21%, and militarine ranged from 0.731% to 2.58% across the 15 batches. The UHPLC fingerprint method and Q-marker-based quantification approach are robust and reliable, providing experimental evidence for quality control and standardization of P. yunnanensis.}, } @article {pmid41508178, year = {2025}, author = {Hou, WX and Liu, YX and Miao, JR and Zhu, ZK and Yin, Y and Liu, JL and Zhao, DY}, title = {[Mechanism of Liuwei Dihuang Pills in enhancing GPNMB expression to regulate FcγRⅡB/c-Src pathway for prevention and treatment of Alzheimer's disease].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {21}, pages = {6062-6071}, doi = {10.19540/j.cnki.cjcmm.20250805.401}, pmid = {41508178}, issn = {1001-5302}, mesh = {Animals ; *Drugs, Chinese Herbal/administration & dosage ; *Alzheimer Disease/drug therapy/genetics/metabolism/prevention & control ; Male ; Mice ; *Membrane Glycoproteins/genetics/metabolism ; Humans ; Signal Transduction/drug effects ; *src-Family Kinases/metabolism/genetics ; Hippocampus/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Memory/drug effects ; Eye Proteins ; }, abstract = {This study investigated the effect of Liuwei Dihuang Pills on the Fcγ receptor Ⅱ-b(FcγRⅡB)/c-Src tyrosine kinase(c-Src) pathway in senescence-accelerated mouse prone 8(SAMP8) by regulating the expression of the glycoprotein non-metastatic melanoma protein B(GPNMB) and explored the mechanism of the kidney-tonifying and essence-strengthening therapy in the treatment of Alzheimer's disease.(1) For the effects of Liuwei Dihuang Pills on the learning and memory ability, hippocampal β-amyloid protein(Aβ), GPNMB, and autophagy function in SAMP8 mice, eight seven-month-old male senescence-accelerated mouse resistant 1(SAMR1) mice were used as a control group, and 16 male SAMP8 mice of the same age were randomly divided into a model group and a Liuwei Dihuang Pills group. The Liuwei Dihuang Pills group was given 2.36 g·kg~(-1) concentrated Liuwei Dihuang Pills solution by gavage, while the control group and the model group were given the same volume of normal saline twice a day for four consecutive weeks. The learning and memory ability of mice in each group was detected by the Morris water maze experiment; the expression level of Aβ in the hippocampus of mice were detected by enzyme-linked immunosorbent assay(ELISA) and immunohistochemistry; the expression of GPNMB in the hippocampus of mice was detected by immunofluorescence and Western blot; the expression level of ubiquitin-binding protein p62 and microtubule-associated protein light chain 3(LC3) Ⅱ/LC3Ⅰ in the hippocampus of mice was measured by Western blot.(2) For the regulatory effect of GPNMB on the FcγRⅡB/c-Src pathway, eight seven-month-old male SAMR1 mice were used as a control group, and 24 male SAMP8 mice of the same age were randomly divided into a model group, an LV-Vector group, and an LV-GPNMB~(OE) group. The bilateral hippocampus of the LV-Vector group and LV-GPNMB~(OE) group was injected with LV-Vector and LV-GPNMB~(OE) of 2 μL/each side, respectively. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, Src homology 2 protein tyrosine phosphatase 1(SHP-1), and c-Src proteins in the hippocampus of mice.(3) For the effect of Liuwei Dihuang Pills in regulating the FcγRⅡB/c-Src pathway by increasing the GPNMB expression, 32 seven-month-old male SAMP8 mice were randomly divided into a model group, a Liuwei Dihuang Pills group, a Liuwei Dihuang Pills + LV-NC group, and a Liuwei Dihuang Pills + LV-shGPNMB group. The bilateral hippocampus of the Liuwei Dihuang Pills + LV-NC group and Liuwei Dihuang Pills + LV-shGPNMB group was injected with LV-NC and LV-shGPNMB, respectively, before the drug treatment. Western blot was used to detect the expression level of p62, LC3Ⅱ/LC3Ⅰ, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of mice. The results showed that(1) compared with those of the control group, the escape latency of the model group was significantly increased, and the time spent in the target quadrant and the effective area was significantly decreased. The expression level of Aβ, GPNMB, and p62 in the hippocampus was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the escape latency of the Liuwei Dihuang Pills group was significantly shortened, and the time spent in the target quadrant and the effective area was significantly increased. The level of Aβ was significantly decreased, and the expression level of GPNMB was significantly increased. The expression level of p62 was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(2) Compared with those of the control group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src proteins in the hippocampus of the model group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the LV-GPNMB~(OE) group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased.(3) Compared with those of the model group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills group was significantly decreased, and the level of LC3Ⅱ/LC3Ⅰ was significantly increased. Compared with those of the Liuwei Dihuang Pills group, the expression level of p62, FcγRⅡB, SHP-1, and c-Src in the Liuwei Dihuang Pills + LV-shGPNMB group was significantly increased, and the level of LC3Ⅱ/LC3Ⅰ was significantly decreased. These results indicate that Liuwei Dihuang Pills can inhibit the FcγRⅡB/c-Src pathway by up-regulating the GPNMB expression, thereby increasing autophagy levels, enhancing neuroprotective ability, and alleviating Alzheimer's disease.}, } @article {pmid41508060, year = {2025}, author = {Sun, CX and Han, XY and Xiao, YT and Liu, YX and Ye, TY}, title = {[Research progress on prevention and treatment of Alzheimer's disease with Danggui Shaoyao San].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {22}, pages = {6215-6226}, doi = {10.19540/j.cnki.cjcmm.20250626.601}, pmid = {41508060}, issn = {1001-5302}, mesh = {*Alzheimer Disease/drug therapy/prevention & control/metabolism ; *Drugs, Chinese Herbal/therapeutic use/administration & dosage ; Humans ; Animals ; }, abstract = {Alzheimer's disease is a neurodegenerative disorder associated with aging. In traditional Chinese medicine(TCM), it is classified as a syndrome of root deficiency and branch excess. Danggui Shaoyao San, a classic formula traditionally used to treat gynecological disorders, has the effects of promoting blood circulation, removing blood stasis, opening orifices, awakening the mind, strengthening the spleen, resolving phlegm, and tonifying Qi to nourish the spirit. Modern clinical studies have found that Danggui Shaoyao San can slow the progression of Alzheimer's disease and has great potential for clinical application. Recent studies indicate that Danggui Shaoyao San treats Alzheimer's disease through multi-target and multi-level mechanisms. These include clearing amyloid β(Aβ) plaques and abnormally phosphorylated tau protein, maintaining brain-gut homeostasis, reducing oxidative stress, and regulating autophagy. Its key components, paeoniflorin and ferulic acid, have also been reported to exert antioxidant, anti-inflammatory, and anti-apoptotic effects, eliminate pathological products, and regulate the cholinergic system in the brain. This paper traces the classic formula of Danggui Shaoyao San, conducts a theoretical integration of ancient and modern medical systems, and systematically summarizes and analyzes the research related to the treatment of Alzheimer's disease using Danggui Shaoyao San and its key components. It aims to provide a valuable reference for further research and modern application of Danggui Shaoyao San in the treatment of Alzheimer's disease.}, } @article {pmid41507065, year = {2026}, author = {De Rui, M and Salerno Trapella, G and Ceolin, C and Ceccato, F and Antonelli, G and Ravelli, A and Andreuzza, R and Conti, E and Sarlo, M and Coin, A and Zanforlini, BM and Bertocco, A and Curreri, C and Tizianel, I and Mapelli, D and Sergi, G and Devita, M}, title = {Effect of cognitive training on cortisol levels in patients with neurocognitive disorders.}, journal = {The journals of gerontology. Series B, Psychological sciences and social sciences}, volume = {81}, number = {2}, pages = {}, pmid = {41507065}, issn = {1758-5368}, mesh = {Humans ; *Hydrocortisone/metabolism/analysis ; Male ; Female ; Aged ; Saliva/chemistry ; *Neurocognitive Disorders/therapy/metabolism ; Middle Aged ; Italy ; *Cognitive Behavioral Therapy/methods ; Hypothalamo-Hypophyseal System/metabolism ; Case-Control Studies ; Cognitive Training ; }, abstract = {OBJECTIVES: Elevated cortisol levels are linked to a greater risk and faster progression of neurocognitive disorders (NCDs). While interventions such as exercise and mindfulness have shown benefits in reducing cortisol, the impact of cognitive training (CT) on cortisol regulation remains unexplored. This study investigated whether CT affects cortisol levels and secretion patterns in individuals with minor or major NCD and compared its effects with those of pharmacological treatment.

METHODS: Sixty-two older adults with NCD and 43 healthy controls were recruited from the University Hospital of Padua in Italy. Among patients with NCD, 34 underwent CT (CT-NCD group), and 28 received pharmacological treatment (PH-NCD group). Salivary cortisol was measured at six points during the day, at baseline, and at 3 months (T1) and 6 months (T2) post-intervention.

RESULTS: Compared with pharmacological treatment (PH), CT showed a larger percentage decrease of daily cortisol exposure area under the curve (AUC) from baseline; however, the between-group difference did not remain statistically significant after covariate adjustment, and the only robust time-point effect was in the afternoon (F(1,47)=5.13; p = .028). Morning values decreased within groups, but between-group differences in the CAR were not significant; at bedtime, CT showed only a trend towards lower cortisol than PH (p = .071). Median morning values changed from 7.75 to 6.20 in CT and from 5.80 to 5.15 in PH.

DISCUSSION: Cognitive training may help lower cortisol levels and enhance cognitive function in NCD patients, suggesting its potential as a nonpharmacological tool to modulate hypothalamic-pituitary-adrenal axis activity. Larger randomized studies are needed to confirm and extend these findings.}, } @article {pmid41506734, year = {2026}, author = {, and , }, title = {[Guidelines for the management of chronic insomnia comorbid with common neuropsychiatric disorders in adults (2025 edition)].}, journal = {Zhonghua nei ke za zhi}, volume = {65}, number = {1}, pages = {18-44}, doi = {10.3760/cma.j.cn112138-20250911-00539}, pmid = {41506734}, issn = {0578-1426}, support = {2021YFC2501400//National Key Research and Development Program of China/ ; }, mesh = {Humans ; *Sleep Initiation and Maintenance Disorders/therapy/epidemiology/complications ; *Mental Disorders/therapy/complications/epidemiology ; Comorbidity ; Adult ; Parkinson Disease ; }, abstract = {Chronic insomnia frequently co-occurs with common neuropsychiatric disorders, including migraine, stroke, Alzheimer's disease, Parkinson's disease, epilepsy, generalized anxiety disorder, depressive disorder, body distress disorder, post-traumatic stress disorder, and disorders due to use of alcohol. The prevalence of these neuropsychiatric disorders is hiher among patients with chronic insomnia than in the general population, and the conditions mutually exacerbate each other. Comorbidities not only exacerbate the severity and increases the relapse risk of each condition but also lead to a poorer prognosis, more severe impairment of social functioning, a higher all-cause mortality risk, and greater treatment challenges. Therefore, the Sleep Disorders Group, Chinese Society of Neurology and Sleep Medicine Group,China Neurologist Association have convened experts in relevant fields, based on current medical evidence, to establish guideline for the management of Chinese adults with chronic insomnia comorbid with the aforementioned 10 categories of common neuropsychiatric disorders. The aim is to standardize clinical practice and improve treatment effectiveness and cure rates.}, } @article {pmid41506537, year = {2026}, author = {Liang, YZ and Jiang, MZ and Xu, XT and Zhu, T and Guo, H and Ding, L and Zhong, H and Bao, J and Qin, LQ and Li, YH}, title = {Ameliorating effect and mechanism of p-coumaric acid liposome on cognitive dysfunction and mitochondrial damage under intermittent hypoxia.}, journal = {Life sciences}, volume = {387}, number = {}, pages = {124197}, doi = {10.1016/j.lfs.2026.124197}, pmid = {41506537}, issn = {1879-0631}, abstract = {AIMS: Alzheimer's disease (AD) has become a global public health problem. Mitochondrial dysfunction contributes to AD pathogenesis, and adequate oxygen supply is essential to maintain mitochondrial homeostasis. P-coumaric Acid (CA) is a polyphenol with anti-hypoxia and anti-AD properties. In this study, CA was formulated into a biomimetic liposome (CA-Lip) to enhance its therapeutic efficacy, and the underlying mechanisms were studied.

MATERIALS AND METHODS: APP/PS1 mice were divided into four groups: AD group, hypoxia treatment group (AD-HY group), hypoxia + CA treatment group (CA group), hypoxia + CA-Lip treatment group (CA-Lip group). Age-matched wild-type littermates were used as controls. Mice in the hypoxia treatment groups were exposed to a hypoxia chamber for 6 h daily for 8 weeks. Cognitive performance and mitochondrial function were subsequently evaluated to determine the ameliorating effects and mechanisms of CA-Lip.

RESULTS: Cognitive impairment and mitochondrial dysfunction were more pronounced in the AD-HY group than in the AD group. CA-Lip produced greater neuroprotective effects than CA. Mechanistic analyses showed that CA-Lip reduced amyloid-β (Aβ) accumulation, enhanced mitochondrial biogenesis (upregulation of PGC-1α expression), maintained mitochondrial dynamics (upregulation of MFN2 expression, and downregulation of DRP1 expression), inhibited excessive mitophagy (downregulation of PINK1 and Parkin expression), enhanced cell autophagy (upregulation of ATG7 and LC3B expression and downregulation of mTOR and P62 expression), and reduced neuronal apoptosis.

CONCLUSIONS: CA-Lip effectively ameliorates hypoxic cognitive impairment by reducing Aβ generation and improving mitochondrial function.}, } @article {pmid41505228, year = {2026}, author = {Head, E and Cohen, A and Fortea, J and McGlinchey, E}, title = {Novel insights into Alzheimer's disease through the study of individuals with Down syndrome.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e71074}, pmid = {41505228}, issn = {1552-5279}, support = {U19AG068054//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; U19AG068054//NIH/NIA/ ; P30AG066519//NIH/NIA/ ; RF1AG079519//NIH/NIA/ ; R01AG056850//NIH/NIA/ ; R21AG056974//NIH/NIA/ ; R01AG061566//NIH/NIA/ ; 1R01AG081394//NIH/NIA/ ; R61AG066543//NIH/NIA/ ; //Fondo de Investigaciones Sanitario/ ; INT21/00073//Carlos III Health Institute/ ; PI20/01473//Carlos III Health Institute/ ; PI23/01786//Carlos III Health Institute/ ; //Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Program 1/ ; //Fondo Europeo de Desarrollo Regional/ ; SLT006/17/00119//Department de Salut de la Generalitat de Catalunya/ ; //Fundación/ ; IIBSP-DOW-2020-151//Tatiana Pérez de Guzmán el Bueno/ ; H2020-SC1-BHC-2018-2020//Horizon 2020-Research and Innovation Framework Programme/ ; HPE-ADRD 24HPE1284307//Alzheimer Association/ ; }, } @article {pmid41505203, year = {2026}, author = {Lyketsos, CG and Peters, ME}, title = {Neuropsychiatric symptoms in Alzheimer's disease: Past, present, and future.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e71077}, pmid = {41505203}, issn = {1552-5279}, support = {P30AG066507//Johns Hopkins Alzheimer's Disease Research Center/ ; }, mesh = {Humans ; *Alzheimer Disease/psychology/complications ; *Cognitive Dysfunction/psychology ; Disease Progression ; *Depression/etiology ; }, abstract = {Noncognitive neuropsychiatric symptoms (NPS; e.g., depression, agitation) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. Although the importance and presence of NPS was recognized by Dr. Alois Alzheimer himself, it was a series of research roundtables in the 2010s that propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the NPS treatment pipeline includes novel therapeutics, repurposing of existing pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center, being recognized in this special issue, have played a pivotal role in the recognition and study of NPS in AD. HIGHLIGHTS: Noncognitive neuropsychiatric symptoms (NPS) are nearly universal throughout the course of Alzheimer's disease (AD), cause significant adverse impact to patients and caregivers, and are associated with more rapid progression to severe dementia. A series of research roundtables in the last decade and a half have propelled the understanding and treatment of NPS in AD forward. The mild behavioral impairment (MBI) construct was developed as a complementary behavioral analogue to mild cognitive impairment, solidifying the importance of NPS prior to dementia onset. Neurobiological underpinnings of NPS are being studied and the treatment pipeline includes novel therapeutics, repurposing of pharmaceuticals, and non-pharmacologic interventions. The Alzheimer's Disease Research Centers and The National Alzheimer's Coordinating Center have played a pivotal role in the recognition and study of NPS in AD.}, } @article {pmid41502736, year = {2025}, author = {Biswal, B and Pattnaik, S and Satapathy, BS and Maharana, L}, title = {Luliconazole-Loaded Nanoliposomes as a Repurposing Strategy to Combat Memory Dysfunction in LPS-Induced Alzheimer's Rats.}, journal = {ACS omega}, volume = {10}, number = {48}, pages = {59655-59674}, pmid = {41502736}, issn = {2470-1343}, abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder with no definitive cure. Out of several proposed pathophysiology, microbial infection has recently been identified as one of the key pathogenic contributors for the development and progression of AD. In this context, the present study aims at a repurposing strategy through luliconazole (a potent imidazole derivative)-loaded optimized nanoliposomal carriers to treat AD. Optimized luliconazole-loaded nanoliposomes (LuNLs) were developed by the conventional thin-film hydration method followed by characterization in terms of FESEM, AFM, zeta potential, average size, loading %, and drug release (in vitro). The in vivo effectiveness of the LuNLs was investigated in LPS-induced AD rats. Molecular docking and simulation analysis demonstrated a favorable docking score between luliconazole and selected AD proteins. Spherical, nanosized (52.42 nm), negatively charged (-29.9 mV) LuNLs were reported showing a sustained drug release up to 24 h. An in vivo behavioral study depicted improved cognitive behavior in the LuNLs-treated group as compared to control groups. In vivo antioxidant activity in terms of SOD, MDA, and GSH inhibition by LuNLs was found comparable to that of standard formulation-treated groups, depicting the neuroprotective behavior of LuNLs. The histopathological observation of brain tissue in the LuNLs/control group further substantiated the in vivo behavioral study data. Based on the reports, luliconazole may be used as a viable, efficacious alternative for the treatment of AD, though further preclinical studies are highly warranted.}, } @article {pmid41502722, year = {2025}, author = {Wu, H and Huang, N and Wang, K and Mi, J and Liu, Z and Wang, J and Sang, Z and Tan, Z}, title = {Development of Novel 3‑Phenylpropanamide Derivatives as BChE Inhibitors for the Treatment of Alzheimer's Disease.}, journal = {ACS omega}, volume = {10}, number = {48}, pages = {59522-59534}, pmid = {41502722}, issn = {2470-1343}, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative degenerative disorder among the elderly, featured by progressive cognitive decline and memory impairment. Due to its complex pathogenesis, there is still no effective therapeutic drug to date. Recently, selective BChE inhibition has been regarded as a potent approach for treating AD. In this work, we conducted structural optimization and structure-activity relationship studies on the previously obtained lead compound EMC-4f, and obtained the potential selective BChE inhibitor 12a (eqBChE, IC50 = 1.3 μM; huBChE, IC50 = 0.95 μM). The in vitro results exhibited that 12a showed good BBB permeability. Moreover, 12a demonstrated significant neuroprotective effects on l-Glu/Aβ25-35-induced HT22 cells injury. Further, the in vivo tests suggested that 12a remarkably alleviated mice cognitive impairment induced by scopolamine. Therefore, these data present that 12a is a promising BChE inhibitor against AD.}, } @article {pmid41502346, year = {2026}, author = {Chang, YY and Zheng, XH and Wang, MW and Zhang, QW and Gao, YT and Wang, YN and Sun, YT and Fan, HH and Li, X and Du, LD and Xie, XM and Pang, XB}, title = {Morroniside Modulates Microglia Polarization via the CX3CL1/CX3CR1/PU.1 Axis in ApoE4 Transgenic Mice.}, journal = {Phytotherapy research : PTR}, volume = {}, number = {}, pages = {}, doi = {10.1002/ptr.70177}, pmid = {41502346}, issn = {1099-1573}, support = {251111313400//Key R&D Program of Henan Province/ ; 252300421379//Natural Science Foundation of Henan/ ; 25B350004//Key Scientific Research Projects of Henan Higher Education Institutions/ ; 82501727//Natural Science Foundation of China/ ; 22508091//Natural Science Foundation of China/ ; }, abstract = {Microglia monitor disease stimulation, neuronal apoptosis, and neural repair, and their overactivation-induced inflammation plays a key role in the pathogenesis of Alzheimer's disease (AD). Morroniside (Mor), an iridoid glycoside compound in Cornus officinalis, is one of the effective active components. The effects of Mor on antioxidant stress, antiapoptosis, and nerve repair function have been widely studied, but the mechanism of Mor in AD treatment remains unclear. To study the neuroprotective effects of Mor and elucidate the molecular mechanisms underlying its improvement of AD symptoms, we used ApoE4 transgenic mice and ApoE4-transfected BV2 cells as models of AD, focusing on microglia phenotype, function, and neuroinflammation. The 10-month-old mice were randomly divided into the ApoE3 control group (ApoE3 + Veh), the ApoE4 model group (ApoE4 + Veh), and the ApoE4 + Mor 10, 20, and 40 mg/kg groups as in vivo models. The in vitro BV2-ApoE model was constructed via lentiviral transfection. The effects of Mor on cognitive function of AD models were assessed through behavioral tests, western blot, immunofluorescence staining, and ELISA to measure changes of related pathological and inflammatory factors. Mor improved the cognitive function of ApoE4 transgenic mice by reducing Aβ plaques in the brain, improving the structural lesions of hippocampal neurons, and increasing synaptic plasticity in the brain of AD mice. In addition, Mor promoted the transformation of microglia from the M1 to the M2 phenotype, inhibited the activation of the CX3CR1/PU.1 signaling axis, and alleviated the dysfunction of microglia both in vitro and in vivo. CX3CR1 siRNA and PU.1 siRNA were used further to verify the regulatory effect of Mor on microglia phenotype. Our findings indicate that Mor can inhibit neuroinflammation, reduce Aβ accumulation, and improve synaptic damage in ApoE4 mice via the CX3CL1/CX3CR1/PU.1 pathway regulating the phenotype and function of microglia. This study provides a new therapeutic candidate for the prevention and treatment of AD.}, } @article {pmid41502301, year = {2026}, author = {Abhyankar, SD and Xiao, Y and Mahajan, N and Luo, Q and Cummins, TR and Oblak, AL and Lamb, BT and Corson, TW and Bhatwadekar, AD}, title = {Müller Glial Kir4.1 Channel Dysfunction in APOE4-KI Model of Alzheimer's Disease.}, journal = {Glia}, volume = {74}, number = {3}, pages = {e70119}, pmid = {41502301}, issn = {1098-1136}, support = {R01EY027779-S1/EY/NEI NIH HHS/United States ; R01EY032080/EY/NEI NIH HHS/United States ; //Research to Prevent Blindness, Unrestricted Grant/ ; DK064466/DK/NIDDK NIH HHS/United States ; G20240315-8762//Sigma Xi Grants in Aid of Research/ ; //NIH T32, Peter J. Roach Award, Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine/ ; }, mesh = {Animals ; *Potassium Channels, Inwardly Rectifying/metabolism/genetics ; *Alzheimer Disease/metabolism/genetics/pathology ; *Ependymoglial Cells/metabolism/pathology/drug effects ; *Apolipoprotein E4/genetics/metabolism ; Kcnj10 Channel ; Disease Models, Animal ; Mice, Transgenic ; Rats ; Mice ; Mitochondria/metabolism ; Oxidative Stress/physiology ; Retina/metabolism/pathology ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD), particularly late-onset AD (LOAD), affects millions worldwide, with the apolipoprotein ε4 (APOE4) allele being a significant genetic risk factor. Retinal abnormalities are a hallmark of LOAD, and our recent study demonstrated significant age-related retinal impairments in APOE4-knock-in (KI) mice, highlighting that retinal impairments occur before the onset of cognitive decline in these mice. Müller cells (MCs), key retinal glia, are vital for retinal health, and their dysfunction may contribute to retinal impairments seen in AD. MCs maintain potassium balance via specialized inwardly rectifying K[+] channels 4.1 (Kir4.1). This study posits that Kir4.1 channels will be impaired in APOE4-KI, resulting in MC dysfunction. Additionally, we demonstrate that MC dysfunction in APOE4-KI stems from alterations in mitochondrial dynamics and oxidative stress. Kir4.1 expression and function were studied using immunofluorescence and through the whole-cell voltage clamp, respectively. In parallel, rat Müller cells (rMC-1) were used to create an in vitro model for further mechanistic studies. MitoQ was used to evaluate its potential to mitigate APOE4-induced deficits. APOE4 retinas and APOE4-transfected rMC-1 significantly reduced Kir4.1 expression, K+ buffering capacity, and increased mitochondrial damage. APOE4-transfected rMC-1 showed reduced mitochondrial membrane potential (ΔΨm) and increased mitochondrial reactive oxygen species (ROS). MitoQ treatment significantly reduced mitochondrial ROS and restored Kir4.1 expression in APOE4-expressing cells. Our results demonstrate that APOE4 causes mitochondrial dysfunction and MC impairment, which may contribute to retinal pathology in AD. MitoQ restored mitochondrial health and Kir4.1 expression in APOE4-expressing rMC-1, suggesting targeting mitochondria may offer a promising therapeutic strategy for AD.}, } @article {pmid41501928, year = {2026}, author = {Li, E and Song, F and Coppola, Q and Yack, L and Le, M and Javed, S and Pandher, N and Prufer, I and Mayzel, O and Heuer, HH and Koestler, M and Miller, BL and Boxer, AL and Vandevrede, L and Grinberg, LT and Walsh, CM and Neylan, TC}, title = {Treatment of Disturbed Sleep in Progressive Supranuclear Palsy: a randomized, remote, double-blinded, 6-week cross-over design study protocol comparing zolpidem, suvorexant, and placebo.}, journal = {Trials}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13063-025-09382-9}, pmid = {41501928}, issn = {1745-6215}, support = {A130340//Rainwater Charitable Foundation/ ; }, abstract = {BACKGROUND: Prior research identified profound sleep disruption in progressive supranuclear palsy (PSP). The hypothalamus and brainstem, areas that help regulate sleep/wake patterns, are among the earliest affected brain regions in PSP disease progression. Comparing polysomnography and quantitative-neuropathology metrics, we identified relative sparing of wake-promoting nuclei in PSP compared to Alzheimer's disease, though PSP had more disrupted sleep. It led to the hypothesis that PSP patients have hyperinsomnia (or hyposomnia, little sleep) due to degeneration of sleep nuclei with a preservation of sleep neurons, causing a system unbalance. A higher neuronal count of wake-promoting nuclei was associated with greater nocturnal wake, regardless of disease. Specifically, orexinergic wake-promoting neurons in the lateral hypothalamus, previously described as the sleep-on/off switch, are relatively spared in PSP. Thus, we hypothesized that an orexinergic antagonist may be more effective in treating sleep/wake issues in PSP than other hypnotic medications. This study protocol was established to test the safety and efficacy of an orexinergic antagonist (suvorexant) targeting the wake-promoting system and contrasts it with a GABAergic receptor agonist (zolpidem) targeting sleep-promoting systems and placebo.

METHODS: This is a remote clinical trial, designed as a double-blind, cross-over, within-subject 6-week trial, with 3 one-week-long conditions, separated by 1-week washout periods. The order of the 3 regimens is randomized and counterbalanced: placebo (microcrystalline cellulose), 15 mg/day suvorexant, 5 mg/day zolpidem. Participants are recruited from doctor and study referrals, registries, and support groups. Once onboarded, the trial coordinator maintains communication with the participant/caregiver throughout the 6 weeks. Assessments include neurological interviews, cognitive testing, and subjective questionnaire packets. Sleep and circadian rhythms are assessed through ambulatory EEG and actigraphy monitoring devices worn by the participant throughout the trial.

DISCUSSION: The study design aims to reduce participant and caregiver burden, while improving accessibility to such a study. Administering a remote clinical trial for a rare disease, however, creates unique issues that would otherwise be absent from in-person studies. Particularly, a symptom rather than disease-modifying trial is challenging to recruit for when potential disease-modifying therapeutics are available. Needing to coordinate with non-associated medical offices to attain medical records or prescriptions can cause frustrations for the potential participant, medical office, and study team. In recruitment, onboarding, and trial maintenance, this study design relies on consistent communication to support participant enrollment and satisfaction.

TRIAL REGISTRATION: Treatment of Disturbed Sleep in Progressive Supranuclear Palsy (PSP); NCT04014389. Registered on June 2, 2019.}, } @article {pmid41501420, year = {2026}, author = {Wang, XY and Zhou, WS and Gaur, U and Zhen, XC and Zheng, WH}, title = {Sigma-1 receptor positive allosteric modulator promotes neuronal survival and improves cognitive deficits in AD mice via sigma-1 receptor/ERK pathway.}, journal = {Acta pharmacologica Sinica}, volume = {}, number = {}, pages = {}, pmid = {41501420}, issn = {1745-7254}, abstract = {The sigma-1 receptor is an important new therapeutic drug target for Alzheimer's disease (AD). Here, we reported that SOMCL-668, a novel selective and potent sigma-1 receptor allosteric modulator, is neuroprotective in AD both in vitro and in vivo. SOMCL-668 promoted PC12 cells against Aβ-induced intracellular reactive oxygen species (ROS) accumulation, mitochondrial membrane potential hyperpolarization and neuronal apoptosis. Similar results were obtained in SH-SY5Y and primary cortical culture neurons. The mechanistic study showed that SOMCL-668 stimulated the phosphorylation of ERK and CREB, while pharmacological inhibition or knockout of ERK via CRISPR-Cas9 attenuated its protective effects. Further studies with the sigma-1 receptor agonists/antagonists and knockout of sigma-1 receptor via CRISPR-Cas9 indicated that the sigma-1 receptor is essential for the effect of SOMCL-668. In 3xTg-AD mice, SOMCL-668 improved the learning and memory deficits, inhibited neuronal apoptosis and oxidative stress, reduced Aβ deposition and tau protein phosphorylation via ERK/CREB pathway. Moreover, pretreatment with sigma-1 receptor antagonist BD1047 blocked the effect of SOMCL-668. These results demonstrated that SOMCL-668 provides neuroprotection in AD and its effect is mediated by the sigma-1 receptor/ERK/CREB pathway. Our findings support that SOMCL-668 can be utilized as a potential drug for the prevention and treatment of Alzheimer's disease.}, } @article {pmid41499862, year = {2025}, author = {Nadais, A and Castro, C and Martins, I and Trigo, D and Nunes, C and Henriques, AG and de Lourdes Pereira, M and da Cruz E Silva, OAB}, title = {Nanoparticle-mediated Zn delivery impacts neural protein phosphatase activity.}, journal = {Biomaterials advances}, volume = {182}, number = {}, pages = {214675}, doi = {10.1016/j.bioadv.2025.214675}, pmid = {41499862}, issn = {2772-9508}, abstract = {In recent years, the use of nanoparticles (NPs) in diagnosis and treatment of different disorders has been a matter of intensive research. Due to their physical and chemical properties, zinc oxide nanoparticles (ZnO NP) have been explored in a range of biological applications, including cancer and neurological diseases. Regarding the latter, while some studies report protective effects of ZnO NP in cultured cells and animal models, others indicate that these NPs have a harmful impact on the brain, such as promoting oxidative stress and cell death. Previous results from our group have suggested beneficial effects for zinc (Zn) cations in both modulating protein aggregation and on Alzheimer's disease (AD) pathology. In this context, the effect of encapsulated Zn as a nanoparticle on protein aggregation and its influence on protein phosphorylation events associated with AD were explored. The results herein presented show that ZnO NP contributed to a decrease in protein aggregation in neuronal cells. However, these NPs were also found to decrease PP1 and PP2A activity, potentially contributing to increased phosphorylation of tau and APP, which are AD pathology hallmarks. In conclusion, while the use of NPs as a Zn delivery system may offer benefits by reducing aggregate formation, they also appear to induce undesired molecular changes, like those observed in AD. Therefore, a holistic approach should be incorporated as we move forward in this research line, as their effects on distinct cellular processes may be dual edged.}, } @article {pmid41499318, year = {2026}, author = {Melrose, J}, title = {Roles for Electrochemical Proton Gradients in Mitochondrial Energy Production and Neurosensory Processes in Health and Disease.}, journal = {Developmental neurobiology}, volume = {86}, number = {1}, pages = {e70006}, doi = {10.1002/dneu.70006}, pmid = {41499318}, issn = {1932-846X}, support = {//Melrose Personal Research Fund/ ; }, mesh = {Humans ; Animals ; *Mitochondria/metabolism ; *Energy Metabolism/physiology ; *Protons ; *Proton-Motive Force/physiology ; *Nervous System Diseases/metabolism ; Oxidative Stress/physiology ; }, abstract = {This study reviews the roles of proton electrochemical gradients in ubiquitous mitochondrial energy production systems in cellular activation and functions in neurosensory signaling. Proton electrochemical gradients crucially shaped the evolution of life. The emergence of the proton-motive force in mitochondria was fundamental in energy production and central to the function of eukaryotic cells. Dysfunctional mitochondria, however, result in impaired formation of proton gradients and a wide spectrum of diseases. This is particularly prominent in tissues with high energetic demands, such as muscle and nervous tissues. Oxidant stress generated by dysfunctional proton conductance in the brain results in Alzheimer's and Parkinson's disease, muscular sclerosis, amyotrophic sclerosis, and Huntington's disease. In these disorders, oxidative stress, protein misfolding, and neuroinflammation lead to dysfunctional neuronal activity, neuronal damage, and death. Advancements in nanozyme-engineered synthetic enzymes offer a promising innovative approach to the treatment of these disorders. Nanozymes target proton conductance and the oxidant species they generate, scavenging oxygen free radicals and restoring redox balance, and offer neuronal protection and functional recovery of brain tissues. Neural injury and associated neurological diseases affect almost 1 billion people globally, so there is a clear need to develop effective methods that stimulate neural repair and regeneration. Glycosaminoglycans with proton capture and transport properties regulate intercellular signaling processes, synaptic functions, and cellular communication. Electroconductive hydrogels are showing impressive results in neural repair and regeneration. Glycosaminoglycans, particularly keratan sulfate, show useful electroconductive proton capture and transport properties, suggesting they may be worth evaluation in such procedures.}, } @article {pmid41499301, year = {2026}, author = {Mohasel-Roodi, M and Nozari, M and Shamsara, A and Basiri, M and Mirzaie, V and Baghalishahi, M}, title = {Effects of Dexmedetomidine on the Behavioral Outcomes in Streptozotocin-Induced Alzheimer's Disease Rats.}, journal = {Brain and behavior}, volume = {16}, number = {1}, pages = {e71196}, pmid = {41499301}, issn = {2162-3279}, support = {402000357//Kerman Neuroscience Research Center, Kerman University of Medical Sciences/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced ; *Dexmedetomidine/pharmacology/administration & dosage ; Streptozocin/pharmacology ; Rats, Wistar ; Male ; Rats ; *Behavior, Animal/drug effects ; Anxiety/drug therapy ; Maze Learning/drug effects ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; *Adrenergic alpha-2 Receptor Agonists/pharmacology ; Cognitive Dysfunction/drug therapy ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive and prevalent neurodegenerative disorder characterized by progressive cognitive decline and memory impairment. Intracerebroventricular (ICV) administration of streptozotocin (STZ) in rodents recapitulates key features of sporadic AD, including brain insulin resistance and oxidative stress. Dexmedetomidine (Dex), a highly selective α2-adrenergic receptor agonist, has demonstrated neuroprotective and anti-inflammatory properties, suggesting its potential utility as a therapeutic approach for AD.

METHODS: Seventy adult male Wistar rats were randomly allocated to seven experimental groups: Control, Sham, STZ, Sham + Dex (25 µg/kg), and STZ + Dex (25, 50, 100 µg/kg). Cognitive performance and anxiety-like behaviors were evaluated using the open-field test (OFT), elevated plus maze (EPM), Y-maze test, and Morris water maze (MWM).

RESULTS: In the Y-maze, STZ-treated rats exhibited significant reductions in spontaneous alternation behavior (p = 0.002), which were significantly reversed by Dex (25 µg/kg, p = 0.002). In the MWM, the STZ administration resulted in prolonged escape latencies and increased path lengths compared with Control animals (p < 0.05). Treatment with Dex (25 µg/kg) significantly improved spatial learning and memory retention (p < 0.05). No significant differences were observed in locomotor activity and anxiety-related behaviors in the OFT or EPM.

CONCLUSIONS: These findings indicate that Dex at 25 µg/kg attenuates STZ-induced cognitive deficits, likely through neuroprotective and anti-inflammatory mechanisms. The results highlight Dex as a promising candidate for AD therapy, though further research is required to elucidate its underlying molecular pathways. The study supports the potential repurposing of Dex for neurodegenerative disorders.}, } @article {pmid41498900, year = {2026}, author = {Lin, ZY and Cai, LL and Lin, JX and Zheng, GY}, title = {Tiaobu Xinshen Recipe Improves Cognitive Deficits by Alleviating Synaptic Ultrastructure Degradation and Reducing Amyloid β in Transgenic Mice of Alzheimer's Disease.}, journal = {Chinese journal of integrative medicine}, volume = {}, number = {}, pages = {}, pmid = {41498900}, issn = {1993-0402}, abstract = {OBJECTIVE: To investigate the effect of Tiaobu Xinshen Recipe (TXR) on cognitive function of 5xFAD transgenic mice and explore the potential mechanisms.

METHODS: Six-month-old male wild-type (WT) mice and 5xFAD transgenic mice were randomly divided into vehicle (0.9% NaCl), TXR (granules, 4.18 g/kg) and donepezil (0.625 mg/kg) groups using a random number table, respectively, which were given intragastric administration once a day for 60 d. Spatial learning and memory performance was tested with modified Morris water maze (MMWM) test. Synaptic ultrastructure in the hippocampal CA1 region was observed by transmission electron microscopy. The levels of amyloid β (Aβ), the major amyloid precursor protein (APP)-cleaving enzymes and Aβ-degrading enzymes including β-secretase, α-secretase, neprilysin (NEP) and insulin-degrading enzyme (IDE), were detected by immunohistochemistry staining and Western blot, respectively.

RESULTS: In MMWM test, when compared with the 5xFAD-vehicle group, 5xFAD-TXR group demonstrated a significantly shorter escape latency to the platform and increased number of platform crossings and time spent in target quadrant (P<0.05 or P<0.01). The ultrastructure of synapse in the hippocampal CA1 region of mice in the 5xFAD-TXR group was significantly changed, including increased numbers of mitochondria and synaptic vesicles, intact synaptic membrane, and thickened postsynaptic density. The Aβ load was markedly decreased in the cerebral cortex and hippocampus CA1 subregion of TXR-treated 5xFAD mice (P<0.05). TXR treatment decreased APP levels and increased IDE expression in brains of 5xFAD mice (P<0.01). However, TXR treatment had no effect on α- and β-secretase, and NEP in 5xFAD mice (P>0.05).

CONCLUSION: TXR improves cognitive dysfunction in 5xFAD mice by alleviating synaptic ultrastructure degradation and reducing Aβ.}, } @article {pmid41498480, year = {2026}, author = {Goodall, LS and Lennon, MJ and Sachdev, PS and Gorelick, PB and Kovacic, JC and Samaras, K}, title = {Current and Emerging Therapeutic Approaches for Vascular Cognitive Impairment and Dementia.}, journal = {Journal of the American College of Cardiology}, volume = {87}, number = {1}, pages = {77-100}, doi = {10.1016/j.jacc.2025.09.1502}, pmid = {41498480}, issn = {1558-3597}, mesh = {Humans ; *Dementia, Vascular/therapy/prevention & control ; *Cognitive Dysfunction/therapy ; }, abstract = {Cardiovascular risk factors contribute to the majority of dementia cases, with about 20% directly attributable to vascular cognitive impairment and dementia (VCID). VCID treatment developments have been slow compared with Alzheimer's disease (AD), which now has several FDA-approved symptom- and disease-modifying agents. In the second part of this JACC Seminar Series, advances and new perspectives on the management and prevention of VCID are reviewed. There is reasonable evidence that cognitive enhancers (donepezil, galantamine, and memantine) modestly improve cognition in vascular dementia (VaD), the most severe form of VCID, especially if there is associated AD pathology. Antidepressants may benefit those with depression and stroke, but they have poor efficacy in those with depression and VaD alone. Behavioral, social, and environmental interventions are first-line therapies for managing VCID-associated agitation and psychosis. Second-line antipsychotics have not been trialed in those with VaD alone, but are beneficial where AD and VaD co-exist, with risperidone and quetiapine effective in reducing psychosis and agitation. Primary prevention of VCID includes identifying and managing cardiometabolic risk factors along with manifestations of covert cerebrovascular disease. Both primary and secondary VCID prevention involve management of cardiovascular risks, specifically hypertension, diabetes mellitus, smoking, atrial fibrillation, obesity, and sedentariness. Management of vascular risk factors may moderately reduce the risk of incident cognitive impairment. Novel interventions currently being evaluated in clinical trials are discussed. The discovery and utilization of VCID and AD biomarkers will enhance the specificity and effectiveness of interventions such that a precision-medicine approach to disease-specific medical therapy may be taken.}, } @article {pmid41498479, year = {2026}, author = {Sachdev, PS and Bentvelzen, AC and Gustafson, D and Hansra, GK and Hosoki, S and Jiang, J and Lennon, MJ and Moro, MA and Saks, DG and Samaras, K and Kovacic, JC and Kalaria, R}, title = {Vascular Cognitive Impairment and Dementia: Clinical Features, Neuropathology, and Biomarkers.}, journal = {Journal of the American College of Cardiology}, volume = {87}, number = {1}, pages = {52-76}, doi = {10.1016/j.jacc.2025.11.008}, pmid = {41498479}, issn = {1558-3597}, mesh = {Humans ; Biomarkers/metabolism ; *Dementia, Vascular/diagnosis/pathology ; *Cognitive Dysfunction/diagnosis/etiology ; Risk Factors ; *Brain/pathology ; }, abstract = {Vascular cognitive impairment and dementia (VCID), ie, cognitive impairment secondary to cerebrovascular disease (CeVD), is the second most common form of dementia after Alzheimer's disease (AD), accounting for 15% to 20% of all cases. CeVD, in fact, contributes to dementia alongside other neuropathologies in up to 75% of dementia cases. CeVD and AD not only frequently co-occur in the brain, but they may also interact, and some VCID risk factors (midlife hypertension and diabetes) also increase AD risk. Because CeVD and cardiovascular disease share risk factors and pathophysiology, the cardiovascular clinician is likely to encounter both in the clinic. Moreover, common cardiac disorders, such as atrial fibrillation, heart failure, acute coronary syndrome, and valvular disease, increase VCID risk. There have been recent developments in the diagnostic criteria for VCID, with advances in risk biomarkers, treatment, and prevention of cognitive impairment and dementia. The diagnosis of VCID is a 2-step process, with the initial identification of a cognitive syndrome followed by the establishment of a predominantly vascular etiology, guided by clinical history and examination and substantiated by neuroimaging, preferably magnetic resonance imaging. Clinical presentations include an acute onset, a stepwise decline, a fluctuating course if caused by multiple strokes, or a gradual slow progression if attributable to cerebral small vessel disease. Cognitive deficits can be found in several domains, such as information-processing speed, attention, executive function, and emotional lability, sometimes referred to as the subcortical syndrome, often seen in the early stages of VCID without cortical infarcts. The diagnosis is supported by the identification of large and small infarcts, lacunes, white matter hyperintensities, dilated perivascular spaces and cerebral microbleeds using magnetic resonance imaging. This part 1 of a 2-part JACC review series describes the clinical features, pathophysiology, and biomarkers of VCID for cardiovascular clinicians who have a critical role in its early identification, management, and prevention in their patients.}, } @article {pmid41496378, year = {2026}, author = {Zhao, Y and Lu, H and Jiang, X}, title = {Advance in neuroprotective effects of proanthocyanidins (PCs): Structure, absorption, bioactivities, mechanism, and perspectives.}, journal = {Pharmacological research}, volume = {223}, number = {}, pages = {108082}, doi = {10.1016/j.phrs.2025.108082}, pmid = {41496378}, issn = {1096-1186}, mesh = {*Proanthocyanidins/chemistry/pharmacology/pharmacokinetics/therapeutic use ; Humans ; *Neuroprotective Agents/chemistry/pharmacokinetics/pharmacology/therapeutic use ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; Gastrointestinal Microbiome/drug effects ; }, abstract = {With the global population growing and aging, along with increasing environmental, metabolic, and lifestyle-related risk factors, the worldwide incidence of stroke, Alzheimer's disease (AD) and other dementias, meningitis, and other neurological disorders-along with associated mortality-has risen significantly. Proanthocyanidins (PCs), which are oligomers and polymers of flavan-3-ols, are widely distributed across the plant kingdom, including in grape seeds, cinnamon, apples, cranberries, lotus seeds, and pine bark. They represent the second most abundant class of polyphenols in nature, after lignin. A substantial body of preclinical evidence indicates that PCs exert significant neuroprotective effects through multiple mechanisms. This review provides a systematic overview of the sources, structural characteristics, and bioavailability of PCs, with a focus on their pharmacological mechanisms in nervous system disease. Specifically, it examines their roles in regulating oxidative stress, neuroinflammation, protein homeostasis, apoptosis, autophagy, and key signaling pathways, including Nrf2/HO-1, CREB/BDNF, PI3K/Akt, MAPK, and NF-κB. Furthermore, this review systematically summarized the distinct structural forms of PCs, including monomers, dimers, trimers, and polymers, and explores their structure-activity relationships (SARs) in modulating the gut-brain axis. Additionally, recent advances in PCS-based nano-delivery systems and clinical studies related to neurological disorders are summarized. Growing evidence indicates that microbial metabolism in the gut serves as a key mechanism underlying their neuroprotective effects. Finally, the potential applications of PCs as promising dietary supplements or therapeutic agents for the prevention and treatment of nervous system diseases are discussed, along with existing challenges and future perspectives.}, } @article {pmid41496364, year = {2026}, author = {Facchinetti, R and Valenza, M and Ciarla, C and Steardo, L and Serviddio, G and Palombelli, G and Verkhratsky, A and Steardo, L and Canese, R and Cassano, T and Scuderi, C}, title = {Ultramicronized palmitoylethanolamide restores astrocyte-neuron metabolic coupling and Klotho/FGF21 signaling in a triple-transgenic mouse model of Alzheimer's disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {195}, number = {}, pages = {118965}, doi = {10.1016/j.biopha.2025.118965}, pmid = {41496364}, issn = {1950-6007}, abstract = {Alzheimer's disease (AD), a multifactorial neurodegenerative disorder, is characterized by metabolic deficiency, neuroinflammation, and synaptic impairment. Astrocyte-neuron metabolic coupling regulates cerebral energy homeostasis through key metabolites such as lactate, glutamate, and taurine. We investigated the therapeutic potential of ultramicronized-palmitoylethanolamide (um-PEA) in restoring the homeostasis of these metabolites in the triple transgenic (3 ×Tg-AD) mouse model of AD. Using in vivo magnetic resonance imaging and spectroscopy (MRI/MRS) combined with Western blot, we evaluated the effects of chronic um-PEA treatment on lactate-glutamate dynamics and taurine metabolism in the frontal cortex and hippocampus of 6- and 12 month-old mice. Our findings demonstrate that 3 ×Tg-AD mice exhibit lactate accumulation, glutamine/glutamate imbalance, and taurine depletion, alongside reduced expression of metabolic processes regulators such as FGF21, Klotho, and insulin receptor. Treatment with um-PEA successfully restored these metabolic changes by: (i) rebalancing lactate-glutamate metabolism, (ii) increasing taurine synthesis and transport, (iii) upregulating FGF21, Klotho, and insulin receptor expression, and (iv) modulating the metalloproteases ADAM10 and ADAM17, which regulate Klotho processing. These results identify um-PEA as a promising metabolic modulator capable of mitigating AD-related neurodegenerative processes. By targeting astrocyte-neuron metabolism and enhancing both FGF21 and Klotho pathways, um-PEA holds significant potential as an adjunctive therapeutic strategy for AD.}, } @article {pmid41496361, year = {2026}, author = {Huzián, O and Nagy, LI and Hackler, L and Knapp, L and Kocsis, ÁK and Szöts, I and Tamás, G and Puskás, LG and Molnár, G}, title = {Novel drug candidate binds to delta subunit containing GABAA receptors and improves spatial memory.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {195}, number = {}, pages = {118970}, doi = {10.1016/j.biopha.2026.118970}, pmid = {41496361}, issn = {1950-6007}, abstract = {The hydroxyquinoline derivative Q134R is a promising drug candidate for the treatment of Alzheimer's disease with cytoprotective and cognition-enhancing properties. Radioligand binding assays showed that Q134R reduced [[35]S]TBPS binding, consistent with modulation of the picrotoxin site or conformational states that regulate TBPS accessibility. Electrophysiological recordings in mouse brain slices revealed that Q134R significantly increased tonic inhibitory currents in cortical neurogliaform and dentate gyrus granule cells, both known to express delta subunit-containing GABAA receptors. This effect was abolished in mice deficient in the GABAA delta subunit confirming the delta subunit dependency of Q134R's action. Furthermore, in a scopolamine-induced amnesia model, Q134R treatment significantly improved spatial memory performance in wild-type mice, but not in mice lacking in the delta subunit. These results suggest that Q134R enhances tonic inhibition through delta subunit-containing GABAA receptors, which may contribute to the modulation of memory processes and serve as a protective mechanism in early-stage neurodegenerations. These receptor-mediated effects likely contribute to its broader therapeutic efficacy and may complement its previously reported interactions with signaling pathways such as NFAT and HIF-1.}, } @article {pmid41495612, year = {2025}, author = {Yang, G and Zhu, D and Zhang, K}, title = {Nose-brain axis: A bridge from the nasal cavity to the central nervous system.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-01770}, pmid = {41495612}, issn = {1673-5374}, abstract = {The nose-brain axis is a direct pathway linking the nasal cavity to the central nervous system. Odors, as well as exogenous substances such as pathogens, inflammatory mediators, and drugs, can enter the cranial cavity through pathways including the olfactory nerve, trigeminal nerve, and humoral routes, thereby enabling signal transmission and material exchange from the peripheral nasal cavity to the central nervous system. In recent years, advances in multimodal visualization technologies have made it possible to dynamically monitor the nose-brain axis from the molecular level to the tissue level, providing important means for revealing its functional characteristics and pathological changes. Owing to the existence of the nose-brain axis, nasal inflammation can, through neuro-immune interactions, activate central microglia and astrocytes and induce neuroinflammation, thus promoting the onset and progression of central nervous system diseases. In addition, the nose-brain axis offers a unique route for the treatment of central nervous system disorders. Intranasal drug delivery can bypass the blood-brain barrier, act directly on the central nervous system, increase intracranial drug bioavailability, and produce rapid effects, providing new ideas for treating cross-system diseases. This review systematically summarizes the anatomical pathways of the nose-brain axis, visualization monitoring technologies, and mechanisms by which nasal inflammation affects the central nervous system. It also reviews advances in intranasal drug delivery for emotional disorders, migraine, Parkinson's disease, and Alzheimer's disease, aiming to provide new strategies for studying the mechanisms by which nasal inflammation influences the central nervous system and for cross-system targeted therapy.}, } @article {pmid41495456, year = {2026}, author = {Chen, Z and Bi, S and Shan, Y and Wang, F and Wang, Y and Qi, Z and Wang, T and Li, X and Li, S and Xiao, H and Wang, S and Cui, B and Qi, Z and Han, Y and Yan, S and Lu, J and , }, title = {MRI-to-PET synthesis via deep learning for amyloid-β quantification in Alzheimer's disease.}, journal = {European radiology}, volume = {}, number = {}, pages = {}, pmid = {41495456}, issn = {1432-1084}, support = {82102010//National Natural Science Foundation of China/ ; 82394434//National Natural Science Foundation of China/ ; }, abstract = {OBJECTIVES: Amyloid-β (Aβ) PET is crucial for diagnosing and monitoring Alzheimer's disease (AD), but its high cost and radiation exposure limit its use. Deep learning techniques make it possible to generate PET from structured MRI data. In this study, we built a deep learning model to generate 3D synthetic Aβ PET images from structural MRI.

MATERIALS AND METHODS: The generative adversarial network with share parameters (ShareGAN) model was trained and tested with 1009 Aβ PET and paired MRI images from the Alzheimer's Disease Neuroimaging Initiative database and three tertiary hospitals in China. The 3D synthetic model operates on the whole volume rather than 2D image slices, realistically reproducing minor discrepancies between neighboring image planes. ShareGAN-based PET images were evaluated using quantitative metrics and visual assessment. Pearson correlation coefficient and Bland-Altman analyses were used to assess the correlation and concordance between synthetic and real PETs.

RESULTS: 3D Synthetic PET images showed high similarity and correlation with real Aβ PET in external testing sets 1 and 2 in terms of structural similarity index measure (0.898, 0.899), peak signal-to-noise ratio (34.690, 34.725), mean absolute error (0.031, 0.031), and standardized uptake value ratio (R = 0.758, 0.828). The diagnostic accuracy of PET positive or negative status in external testing sets 1 and 2 was 88.5% and 89.4%, respectively.

CONCLUSION: MRI-based 3D synthetic Aβ PET images can serve as a safe and cost-effective tool for Aβ status visualization, providing PET-eligible patients with Aβ PET-like imaging analysis to guide subsequent real Aβ PET scans.

KEY POINTS: Question Amyloid-β (Aβ) PET limitations (high cost, radiation, limited access) hinder early Alzheimer's disease (AD) detection. Clinical practice urgently requires a suitable supplementary method for Aβ pathology assessment. Findings AI-synthesized 3D Synthetic Aβ PET from structural MRI demonstrated strong consistency with real PET and effectively triaged high-risk patients for confirmatory scans. Clinical relevance This non-invasive, cost-effective method holds the promise of enabling wider Aβ pathology screening, reduces unnecessary PET scans, and supports early intervention in resource-limited settings, while preserving diagnostic rigor for treatment decisions.}, } @article {pmid41494605, year = {2026}, author = {Viqueira, L and Navarro, E and Negredo, P and Bernal, JA and Rodríguez-Franco, MI and Tortosa, E and López, MG}, title = {Long-term NRF2-driven microglial repopulation mitigates microgliosis, neuronal loss and cognitive deficits in tauopathy.}, journal = {Brain, behavior, and immunity}, volume = {133}, number = {}, pages = {106253}, doi = {10.1016/j.bbi.2026.106253}, pmid = {41494605}, issn = {1090-2139}, abstract = {Tauopathies, including Alzheimer's disease, feature chronic microglial reactivity that drives neuroinflammation and disease progression. Pharmacological microglial depletion and subsequent repopulation using colony-stimulating factor 1 receptor inhibitors have emerged as a potential therapeutic strategy to reprogram dysfunctional microglia. Despite promising short-term results, the long-term efficacy and pharmacological modulation of repopulated microglia remain poorly understood. Here, we investigated the long-term effects of microglial repopulation alone and in combination with the activation of the cytoprotective nuclear factor erythroid 2 p45-related factor 2 (NRF2) in an in vivo AAV-hTau[P301L] induced model. Integrating different behavioural, immunohistological and transcriptomic analysis, we evaluated cognitive function, tau pathology, neuronal survival and glial reactivity. We found that, whereas microglial repopulation alone did not significantly affect disease progression, NRF2-driven microglial replenishment sustained cognitive function, prevented hippocampal neuronal loss and restored microglial phenotype. Transcriptomic analyses further revealed that the combined treatment modulated tau- associated mitochondrial gene expression changes. These results highlight the importance of shaping the fate of self-renewed microglia and propose NRF2-mediated microglial repopulation as a potential pharmacological strategy for the treatment of tauopathies.}, } @article {pmid41493713, year = {2026}, author = {Hoveizi, E and Doraghi, K and Rostami, E}, title = {Fabrication and Characterization of Resveratrol-Loaded Solid Lipid Nanoparticles: Evaluation of Neuroprotective, Neurobehavioral, and Molecular Outcomes.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {346}, pmid = {41493713}, issn = {1559-1182}, support = {SCU.SB1403.12464//Shahid Chamran University of Ahvaz/ ; }, mesh = {*Resveratrol/pharmacology/administration & dosage/chemistry ; Animals ; *Nanoparticles/chemistry/ultrastructure ; *Neuroprotective Agents/pharmacology/administration & dosage/chemistry ; Male ; Rats ; Oxidative Stress/drug effects ; *Lipids/chemistry ; Antioxidants/pharmacology ; Neural Stem Cells/drug effects/metabolism ; *Behavior, Animal/drug effects ; Rats, Sprague-Dawley ; Interleukin-1beta/metabolism ; Memory/drug effects ; }, abstract = {Neurodegenerative processes involve oxidative stress, inflammation, and disrupted signaling, which contribute to cognitive decline. Resveratrol offers neuroprotection but suffers from poor solubility and bioavailability. Solid lipid nanoparticles (SLNs) can improve solubility, stability, and neural targeting, thereby enhancing efficacy. This study investigates whether SLN/resveratrol treatment modulates neuroprotective targets (HSP70, IL-1β) and antioxidant enzymes (CAT, GPX, SOD) in vitro and whether it improves inactive avoidance memory in an animal model. SLNs were produced by melting tripalmitin and palmitic acid, adding resveratrol, Tween, and butanol, then combining with water and stirring for 1 day. The resulting formulations were characterized using FTIR, electron microscopy, and DLS. Neural stem cells (NSCs) were treated with SLNs, resveratrol, and SLN/resveratrol, and the expression of oxidative stress enzymes, HSP70, and IL-1β was analyzed. In vivo, a passive avoidance memory model was induced in rats via electrical destruction of the nucleus basalis of Meynert. Molecular analysis showed that resveratrol increased HSP70 expression by 3.1-fold and significantly decreased IL-1β levels. SLN treatment had no notable effect on these genes, but the SLN/resveratrol increased HSP70 expression by fourfold and significantly reduced IL-1β. Resveratrol significantly upregulated the antioxidant enzymes CAT and GPX, whereas SLNs alone had no effect. The SLN/resveratrol also markedly enhanced CAT and GPX levels. Behavioral tests demonstrated that the SLN/resveratrol treatment improved passive avoidance memory in the Alzheimer's model. Collectively, these results indicate that SLN/resveratrol robustly enhances neuroprotection by modulating signaling pathways, reducing oxidative stress, and improving memory, with the SLN delivery system potentially increasing bioavailability and neural exposure.}, } @article {pmid41493675, year = {2026}, author = {Usman, AS and Manoharan, SD and Che Mohd Nassir, CMN and Abdul Hamid, H and Hein, ZM and Norazit, A and Murthy, J and Zainol, M and Kamaruzzaman, MA and Chiroma, SM and Mustapha, M and Mohd Moklas, MA and Mehat, MZ}, title = {Neuroprotective Effects of Ficus deltoidea in Alzheimer's Disease-Like Rat Model: Insights from Behavior, Histology, and Amyloid Pathology.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {345}, pmid = {41493675}, issn = {1559-1182}, support = {(FRGS/1/2021/SKK0/UPM/02/15)//the Ministry of Higher Education under the Fundamental Research Grant Scheme/ ; }, mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *Ficus/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Rats, Wistar ; Disease Models, Animal ; *Plant Extracts/pharmacology/therapeutic use ; Plaque, Amyloid/pathology/drug therapy ; Amyloid beta-Peptides/metabolism ; Hippocampus/pathology/drug effects/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Maze Learning/drug effects ; Rats ; *Behavior, Animal/drug effects ; Spatial Memory/drug effects ; Aspartic Acid Endopeptidases/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and accumulation of amyloid-β (Aβ) plaques. While current treatments offer limited efficacy, medicinal plants such as Ficus deltoidea (FD), a traditional remedy, have shown promise due to their neuroprotective and anti-inflammatory properties. An AD-like phenotype was induced in male Wistar rats using D-galactose and aluminum chloride over 70 days. FD extract was administered orally at 50, 100, and 200 mg/kg. Spatial memory was evaluated using the T-maze test. Histological analyses of the hippocampi's Cornu Ammonis 1 and 3 (CA1 and CA3) regions were conducted via hematoxylin and eosin (H&E) staining, and Aβ plaques deposition was assessed with Congo red. Enzyme-linked immunosorbent assay (ELISA) was used to quantify hippocampal levels of Aβ (1-42) and β-secretase-1 (BACE-1). FD treatment significantly enhanced spatial memory, preserved pyramidal neuron integrity in CA1 and CA3, and reduced amyloid plaque formation. Biochemically, FD markedly decreased hippocampal Aβ (1-42) and BACE-1 concentrations in a dose-dependent manner. Thus, FD exhibits multi-target neuroprotective effects in an AD-like model, potentially via modulation of amyloidogenic pathways. Further studies are warranted to explore its mechanisms and therapeutic potential in other brain regions implicated in AD.}, } @article {pmid41493656, year = {2026}, author = {Cicero, CE and Angelini, L and Abbadessa, G and Bruno, M and Fiume, G and Nucera, B and Ornello, R and Arabia, G and Giuliano, L and Guarnieri, B and Lugaresi, A and Perani, D and Sacco, S and Tassorelli, C and Nicoletti, A and Pellecchia, MT and , }, title = {Sex and gender-related differences in neurological diseases: current challenges and recommendations for clinical practice.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {1}, pages = {108}, pmid = {41493656}, issn = {1590-3478}, mesh = {Humans ; *Nervous System Diseases/therapy/epidemiology ; Female ; *Sex Characteristics ; Male ; Pregnancy ; }, abstract = {Neurological diseases include a large variety of conditions ranging from inflammatory, vascular and neurodegenerative disorders to epilepsy and headache. The impact of sex and gender on various aspects of these conditions (epidemiology, risk factors, pathophysiology, clinical features, treatment, and management of pregnancy and breastfeeding) is still not entirely taken into consideration, despite a rapidly increasing body of evidence. This position paper covers six neurological conditions (Alzheimer's Disease, Cerebrovascular disease, Parkinson's disease, Epilepsy, Headache disorders, Multiple Sclerosis) providing an overview of available evidence on sex and gender differences, identifying knowledge gaps and providing recommendations for clinical practice and future studies. We recommend taking into consideration modifiable sex and gender specific risk factors, the role of hormones across women's lifespan and a personalized treatment approach based on gender. We also recommend that future efforts should be devoted to increase the representation of women in clinical studies, to promote sex and gender-based guideline production and to better characterize the safety profile in pregnancy of newer drugs.}, } @article {pmid41491579, year = {2026}, author = {Kamali, M and Ansari, M and Nooraee, P and Tajadini, H and Kamali, H and Dehesh, T and Ashrafzadeh, A and Sharififar, F}, title = {Preliminary clinical evaluation of capsules containing standard hydroalcoholic extract of Myrtus communis L. in patients with mild to moderate Alzheimer' disease: a randomized, double-blind parallel-group clinical trial.}, journal = {BMC complementary medicine and therapies}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12906-025-04994-9}, pmid = {41491579}, issn = {2662-7671}, abstract = {BACKGROUND: This study evaluated the effectiveness of Myrtus communis L. extract, known for its antioxidant and anticholinesterase properties, to enhance cognitive function and mitigate disease progression in individuals with mild to moderate Alzheimer's disease (AD).

METHODS: Fifty elderly patients with mild to moderate AD residing in a Kerman nursing home were enrolled in a randomized, placebo-controlled trial conducted between November 2019 to February 2020. Participants were randomly assigned to either an intervention group (n = 25), receiving M. communis L. capsules (500 mg each capsule), or a control group (n = 25), receiving placebo capsules. Cognitive function was assessed at baseline and after four weeks using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR) scales. Statistical analyses, performed using SPSS version 22, considered a significance level of p < 0.05.

RESULTS: All fifty patients completed the four-week trial. Baseline characteristics-including sex, mean age, and education level-were well-matched between the intervention and control groups. After four weeks of treatment, the intervention group demonstrated a statistically significant improvement in cognitive function, as evidenced by significantly higher MMSE scores compared to the placebo group (23.4 ± 0.25 vs. 19.6 ± 0.25; p < 0.0001). Concurrently, the intervention group exhibited a significant reduction in dementia severity, indicated by lower CDR scores compared to the control group (0.8 ± 0.04 vs. 1.5 ± 0.04; p < 0.0001).

CONCLUSIONS: These findings suggest that M. communis L. holds promise as a potential complementary therapy for AD, capable of improving cognitive function and potentially slowing disease progression. However, further research is necessary to corroborate these results, elucidate the underlying mechanisms of action, and optimize treatment parameters before definitive conclusions can be drawn.

TRIAL REGISTRATION: irct.ir, ID: 20170702034861N8. Registered on 26/08/2019.}, } @article {pmid41491073, year = {2026}, author = {Wasim, R and Azmi, S and Ahmad, A and Srivastava, A}, title = {NLRP3 inflammasome and Alzheimer's disease: bridging inflammation and neurodegeneration.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {41491073}, issn = {1568-5608}, abstract = {The progressive neurodegenerative disease known as Alzheimer's disease (AD) is characterized by widespread neuronal death, memory loss, and cognitive decline. The NLRP3 inflammasome has emerged as a key modulator of neuroinflammation, which is increasingly implicated in the pathophysiology of AD. In response to endogenous and pathogenic danger signals, the innate immune system's multiprotein complex known as the NLRP3 inflammasome is activated. Pyroptosis and neuroinflammatory cascades are eventually triggered by its activation, which causes caspase-1 to be cleaved and pro-inflammatory cytokines like interleukin-1β and interleukin-18 to be released. NLRP3 activation is strongly stimulated by tau aggregation and β-amyloid plaques in AD, which accelerates neuronal damage and prolongs chronic inflammation. The control and activation of inflammasomes are involved in both canonical and non-canonical pathways as well as mitochondrial dysfunction. Significantly, animal models indicate that NLRP3's therapeutic potential is highlighted by the reduction of amyloid burden and amelioration of cognitive decline that results from its inhibition or genetic deletion. Small-molecule inhibitors and natural substances that can alter NLRP3 activity have been discovered recently, providing intriguing approaches to AD treatment. Despite tremendous advancements, issues with medication selectivity and blood-brain barrier penetration still need to be resolved before these discoveries can be used in clinical settings. Comprehending the complex relationship between NLRP3 activation and Alzheimer's pathology may open the door to new, focused treatments meant to slow or stop the progression of the illness.}, } @article {pmid41490490, year = {2026}, author = {Wang, W and Huang, R and Lv, L and Ma, X and Li, Z and Zhang, Y and Wu, J and Wu, S and Xu, J and Hu, Y and Turck, CW and Li, H and Hu, X}, title = {Long-term effects of forty-hertz auditory stimulation as a treatment of Alzheimer's disease: Insights from an aged monkey model study.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {2}, pages = {e2529565123}, doi = {10.1073/pnas.2529565123}, pmid = {41490490}, issn = {1091-6490}, mesh = {Animals ; *Alzheimer Disease/therapy/pathology/cerebrospinal fluid ; Macaca mulatta ; tau Proteins/cerebrospinal fluid ; Disease Models, Animal ; Amyloid beta-Peptides/cerebrospinal fluid ; *Acoustic Stimulation/methods ; Male ; Female ; *Aging ; Humans ; Brain/pathology ; }, abstract = {Based mainly on rodents studies, forty-hertz (40-Hz) physical stimulation has been regarded as a potential noninvasive treatment for Alzheimer's disease (AD). Considering the brain differences between rodents and humans, the effects of 40-Hz physical stimulation need to be further validated using nonhuman primates before its clinical application. Here, we took advantage of a rare opportunity to expose nine aged rhesus monkeys (26 to 31 y old) to 40-Hz auditory stimulation. Given the strong correlation between cerebrospinal fluid (CSF) Aβ and Tau concentrations and corresponding AD pathology in brain parenchyma in clinical practice, we investigated the effects of 40-Hz stimulation on AD pathology by monitoring changes in CSF Aβ and Tau concentrations. Our results revealed that 7 consecutive days of 40-Hz auditory stimulation triggered a rapid and significant increase of Aβ levels by more than 200%, but no effect on Tau levels in the CSF. Additionally, we observed that the elevation of CSF Aβ levels persisted for more than 5 wk after cessation, which had not been reported in any previous studies. After this, a pathological examination of the temporal cortices of 4 of the experimental monkeys was carried out and the data demonstrated that all of them had prevalent extracellular Aβ senile plaque pathology, whereas Tau pathology was negative or very weak. These results provide a good explanation for the differences between the CSF Aβ and Tau protein levels. Together, these first-time results from monkeys suggest that 40-Hz auditory stimulation has strong potential of a noninvasive AD treatment method.}, } @article {pmid41490210, year = {2026}, author = {Giuffrè, GM and Battisti, F and Tudor, AM and Lenkowicz, J and Avitabile, A and Rosati, AM and Martellacci, N and Patarnello, S and Torelli, F and Cesario, A and Marra, C}, title = {Redefining management of mild cognitive impairment and Alzheimer's disease through the shift from clinical to clinical-biological diagnosis: Insights from a single-center experience.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251411461}, doi = {10.1177/13872877251411461}, pmid = {41490210}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) diagnosis has shifted from a purely clinical framework to a clinical-biological paradigm, driven by biomarker integration. This evolution is motivated by the wider availability of reliable biomarkers and the advent of disease-modifying treatments.ObjectiveTo assess changes over time in clinical characteristics, diagnostic pathways, and healthcare resource utilization in a real-world cohort of individuals with cognitive impairment attending a Memory Clinic.MethodsThis secondary data retrospective observational study analyzed two patient cohorts with newly diagnosed cognitive impairment: one from 2017-2019 and another from 2021-2023. Anonymized medical records and structured hospital data were examined using natural language processing to extract demographic and clinical information, diagnostic pathways, treatment patterns and comorbidities.ResultsThe 2021-2023 cohort was significantly younger, exhibited higher baseline Mini-Mental State Examination scores, and underwent more instrumental assessments than the 2017-2019 cohort. These findings likely reflect a shift in public awareness and attitudes toward cognitive health. AD diagnoses increased in both cohorts over time, while mild cognitive impairment diagnoses declined. The use of diagnostic combinations was more frequent in the recent cohort, in which clinical-biological diagnoses were significantly more prevalent.ConclusionsThis study provides real-world insights into the evolving landscape of cognitive impairment diagnostics and care, underscoring a shift toward earlier, biologically grounded diagnosis, supporting precision medicine in AD care. The expanded use of biomarkers reflects evolving practice standards and prepares the ground for disease-modifying therapies in AD.}, } @article {pmid41490207, year = {2026}, author = {Liu, Y and Su, H and Guan, T and Li, X and Dong, C and Hu, Z and Zhang, Y}, title = {Risk prediction of progression from normal cognitive function to Alzheimer's disease in elderly aged 65 and above based on deep learning methods.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251410937}, doi = {10.1177/13872877251410937}, pmid = {41490207}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) is a severe neurological disorder for which a complete cure is not currently available. Therefore, predicting the risk of AD in elderly individuals with normal cognitive function is crucial for early prevention, treatment, and family-provided daily care preparation.ObjectiveThis study aimed to establish a risk prediction model for the progression from normal cognitive function to AD in elderly via deep learning (DL) methods to provide a reference for clinical decision-making and the development of screening tools for the early diagnosis of AD.MethodsDeepSurv, DeepHit, and Cox models were constructed, and the consistency index (C-index), integrated Brier score (IBS), and area under the ROC curve (AUC) were used to evaluate the accuracy, calibration and discriminative power of the three prediction models.ResultsThe overall predictive ability of the model was relatively stable, with concordance indices of 0.82 (DeepSurv), 0.83 (DeepHit), and 0.81 (Cox) and IBSs of 0.08, 0.07, and 0.05, respectively. From the perspective of the C-index indicator, the consistency of the deep learning model was better than that of the Cox model.ConclusionsRisk prediction models for the progression from normal cognitive function to AD can be established using easily obtainable early-stage predictors, which are expected to be used for rapid screening of the risk of developing AD in elderly after clinical validation.}, } @article {pmid41490027, year = {2026}, author = {Yang, JW and Jiang, J}, title = {Association between varicella-zoster virus and Alzheimer's disease: A systematic review and meta-analysis of comprehensive evidence from infection, treatment to prevention.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251411573}, doi = {10.1177/13872877251411573}, pmid = {41490027}, issn = {1875-8908}, abstract = {BackgroundThe association between varicella-zoster virus (VZV) infection and Alzheimer's disease (AD) risk has shown inconsistent results. Given difficulties in early diagnosis and limited therapeutic options for AD, identifying modifiable risk factors is significant for prevention.ObjectiveTo systematically evaluate the impact of VZV infection on AD risk and explore protective effects of antiviral treatment and vaccination.MethodsWe searched PubMed and Web of Science databases up to April 2025. The Newcastle-Ottawa Scale assessed study quality. Random-effects models were used for meta-analysis using risk ratios (RR) as the primary effect measure, with sensitivity and subgroup analyses conducted.ResultsTwenty-one studies were included. Meta-analysis showed: (1) herpes zoster patients had significantly higher AD risk (RR = 1.12, 95% CI: 1.01-1.24, p = 0.04); (2) patients receiving antiviral treatment had lower AD risk (RR = 0.55, 95% CI: 0.37-0.82, p = 0.003); (3) vaccinated individuals had lower AD risk (RR = 0.72, 95% CI: 0.68-0.78, p < 0.0001). The strongest association occurred in the >70 years age group, demonstrating age as an important effect modifier.ConclusionsThis meta-analysis provides systematic evidence supporting that VZV infection increases AD risk while confirming protective effects of antiviral treatment and vaccination. These findings support including herpes zoster vaccination in preventive healthcare for elderly populations.}, } @article {pmid41488982, year = {2025}, author = {Ressa, R and Ettinger, J and Chowdhury, E and Graham, L and Ndirangu, K and Mancebo, JZ and Bodnar, C}, title = {A value assessment of patient-level outcomes and productivity loss for intravenous and subcutaneous lecanemab for patients with early Alzheimer's disease.}, journal = {Journal of medical economics}, volume = {29}, number = {1}, pages = {118-134}, doi = {10.1080/13696998.2025.2609499}, pmid = {41488982}, issn = {1941-837X}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Injections, Subcutaneous ; Markov Chains ; Patient Preference ; Administration, Intravenous ; Cost-Benefit Analysis ; Caregivers ; Efficiency ; Decision Support Techniques ; }, abstract = {AIMS: Intravenous (IV) lecanemab is approved for the treatment of patients with early Alzheimer's disease (AD); a subcutaneous (SC) option may offer additional benefits. We assessed the overall value of SC treatments, and direct/indirect outcomes associated with IV and SC lecanemab.

METHODS AND MATERIALS: For the narrative review, PubMed was searched (February 2025) for studies comparing patient preferences for IV/SC treatment administration published between 2015-2025. Study eligibility was determined using patient, intervention, comparator, outcomes, and study criteria. For the decision-analytic model, a Markov model was developed with four lecanemab treatment scenarios. Scenarios one to three included IV initiation (10 mg/kg biweekly) to month 18, followed by either IV initiation continued (10 mg/kg biweekly), SC maintenance (250 mg weekly) or IV maintenance (10 mg/kg every 4 weeks). Scenario four included SC initiation (500 mg weekly) for an 18-month period, followed by SC maintenance (250 mg weekly). Outcomes were administration time/frequency; patient, caregiver, and healthcare professional time; and caregiver productivity loss.

RESULTS: Forty-three publications reported patient treatment preferences. Most (88.4%) reported that patients preferred SC over IV. Key reasons for this were time savings (n = 13/43 studies; 30.2%), convenience (n = 11/43; 25.6%), treatment frequency (n = 12/43; 27.9%). Two studies (n = 2/43; 4.7%) reported an IV preference over SC; for three studies (n = 3/43; 7.0%), treatment preference was driven by administration frequency. Decision-analytic modeling of lecanemab treatment scenarios revealed that IV initiation to IV maintenance had the lowest number of administrations, whereas SC initiation to SC maintenance had the lowest number of treatment hours and caregiver productivity losses.

LIMITATIONS: Caution must be taken when generalizing these results for all AD patients.

CONCLUSIONS: SC treatments show value as a therapeutic option. IV and SC lecanemab availability may offer benefits to patients, caregivers, and society, and improve shared decision making.}, } @article {pmid41488470, year = {2026}, author = {Cho, Y and Lee, J and Choi, BY and Yun, JH and Han, S and Baek, SH and Park, J and Cho, Y and Kim, HK and Kim, E and Palomera, LF and Lim, J and Jeon, Y and Im, J and Hong, JM and Kim, TK and Kim, SH and Yim, JH and Jo, DG}, title = {Ramalin Ameliorates Alzheimer's Disease Pathology by Targeting BACE1, HDAC6, and MAPK Pathways.}, journal = {MedComm}, volume = {7}, number = {1}, pages = {e70518}, pmid = {41488470}, issn = {2688-2663}, abstract = {Aberrant deposition of β-amyloid (Aβ) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating β-site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen-activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, Aβ plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed Aβ oligomer-induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease-modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease-modifying candidate with the potential to drive a breakthrough approach targeting AD pathology.}, } @article {pmid41488323, year = {2025}, author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R}, title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1733659}, pmid = {41488323}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.}, } @article {pmid41487944, year = {2026}, author = {Rus Prelog, P and Zupan, M and Gregorič Kramberger, M and Frol, S}, title = {The Concomitant Use of Selective Serotonin Reuptake Inhibitors and Anti-Amyloid Treatment in Alzheimer's Disease: Balancing Benefits and Risks.}, journal = {Dementia and geriatric cognitive disorders extra}, volume = {16}, number = {1}, pages = {1-3}, pmid = {41487944}, issn = {1664-5464}, } @article {pmid41487496, year = {2025}, author = {Cheng, R and Kim, J}, title = {Intranasal delivery of iron chelators and management of central nervous system disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1709259}, pmid = {41487496}, issn = {1663-9812}, abstract = {Brain iron dyshomeostasis plays a critical role in the pathology of multiple central nervous system (CNS) disorders, including neurodegenerative and neuropsychiatric diseases. Iron chelators such as deferoxamine (DFO) and deferiprone (DFP) have demonstrated therapeutic potential in mitigating disease progression in these conditions. However, systemic administration is hindered by poor blood-brain barrier (BBB) permeability, dose-limiting toxicity, and poor patient compliance due to frequent dosing regimens. In recent years, intranasal (IN) drug delivery has emerged as a promising strategy to bypass the BBB, providing a direct nose-to-brain delivery route via olfactory and trigeminal pathways while minimizing systemic exposure. This review provides a comprehensive summary of the current status of iron chelation therapy for CNS disorders with a focus on pharmacokinetics, efficacy, and translational potential of IN administration. While IN DFO has been extensively studied in preclinical models of Alzheimer's disease and stroke, recent developments have expanded the scope to other chelators such as DFP. We compare traditional systemic routes, including oral and intravenous, with intranasal administration, highlighting their respective advantages and limitations for CNS delivery. With ongoing advances in formulation and delivery technologies, IN iron chelators provide a promising alternative for the treatment of CNS disorders characterized by impaired iron homeostasis in the brain.}, } @article {pmid41487012, year = {2026}, author = {Verma, R and Bahadur, S}, title = {A Comprehensive Review of Naringin Loaded Nano Drug Delivery System in Treatment of CNS Disorders.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128407188251116030341}, pmid = {41487012}, issn = {1873-4286}, abstract = {Citrus fruits are an abundant source of the polyphenolic phytoconstituent naringenin, which belongs to the class of flavanones. NRG shows a lot of potential as a drug for treating a number of CNS disorders, such as neuroprotective activity, antiamyloidosis, antiparkinson, antialzheimer activity, and more. However, naringenin's hydrophobic nature, which results in limited absorption, limits its therapeutic potential. In this article, we provide an outline of the variety of nanocarriers employed for delivering naringenin as carriers. Some of them include solid lipid nanoparticles, liposomes, micelles, polymeric nanoparticles, nanostructured lipid carriers, nanosuspensions, and nanoemulsions, among others. These formulations of naringenin nanomedicine have been used for the potential treatment of a series of CNS disorders. Based on various research reports, it can be said that with the right nanocarriers, naringenin proves to be a promising therapeutic alternative for the treatment of several CNS ailments, including neurological diseases, Alzheimer's, Parkinson's disease, cerebral ischemia, etc. Therefore, the present manuscript highlights the various aspects of naringenin and its pharmacological activities. Further, naringenin-loaded nanocarriers have been enlisted and discussed in detail.}, } @article {pmid41486993, year = {2026}, author = {Cai, M and Yan, S and Sun, Y and Huo, Q and Dai, X}, title = {miRNAs: Promising Biomarkers for Alzheimer's Diagnosis and Treatment.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050427877251118111643}, pmid = {41486993}, issn = {1875-5828}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaque deposition, neurofibrillary tangles of hyperphosphorylated tau protein, and chronic neuroinflammation, leading to synaptic dysfunction and cognitive decline. Current diagnostic methods rely on clinical symptoms and limited biomarkers, while available treatments only provide symptomatic relief without halting disease progression. MicroRNAs (miRNAs), small non-coding RNAs of 19-22 nucleotides, have emerged as crucial regulators of gene expression through post-transcriptional mechanisms and show distinct dysregulation patterns in AD patients' blood, cerebrospinal fluid (CSF), and brain tissues. Key miRNAs such as miR-132, miR-146a, miR-34a, and miR-125b demonstrate consistent alterations in expression levels, correlating with disease progression and offering potential as non-invasive diagnostic tools. This review comprehensively examines the dual role of miRNAs as diagnostic biomarkers and therapeutic targets for AD. We also provide an analysis of specific miRNA signatures in different biofluids (plasma, serum, CSF) and brain regions that correlate with disease stages, highlighting their potential for early and non-invasive diagnosis. Therapeutically, miRNAs modulate multiple AD-related pathways, including neuroinflammation via NF-κB signaling, Aβ production through BACE1 inhibition, and tau phosphorylation via GSK3β regulation. miRNAs also influence synaptic plasticity, mitochondrial function, and autophagy, presenting multifaceted opportunities for intervention. However, challenges, including miRNA heterogeneity, stability, and targeted delivery, remain critical impediments. Advances in nanocarriers, exosomal miRNAs, and viral vectors show promise in overcoming these obstacles, enabling precise miRNA modulation. In addition, we underscore the need for standardized protocols, further validation in clinical cohorts, and the development of cost-effective detection methods to translate miRNA-based approaches into practical diagnostics and therapies. By integrating miRNA biomarkers with existing diagnostic tools and exploring combinatorial therapeutic strategies, researchers can harness the potential of miRNAs to revolutionize AD intervention, paving the way for early detection and effective treatment of this devastating disease.}, } @article {pmid41486988, year = {2026}, author = {Ranjbari, F and Dadkhah, M and Pirdel, Z and Fathi, F}, title = {Margatoxin Peptide: Preparation and the Potential Use for Biological Applications in Cancer and Neurological Disorders.}, journal = {Protein and peptide letters}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298665415268251024053300}, pmid = {41486988}, issn = {1875-5305}, abstract = {Scorpion venom compounds are known to contain nucleotides, polypeptides, mucoproteins, lipids, biogenic amines, and other unidentified macromolecules. Several peptides in scorpion fluids have demonstrated a wide range of biological activities with strong specificity for their targeted sites. Margatoxin, isolated from the venom of the scorpion, exhibits desirable properties, including high selectivity, good permeability, and stability in cancer cells, which can be achieved at picomolar doses, thereby blocking voltage-gated K+ channels. This narrative review consolidates results from an extensive literature search conducted in major electronic databases up to September 2024. Important studies were identified using keywords associated with scorpion venom peptides, Kv1.3 channels, cancer treatment, and neurodegenerative disorders. The amino acids that make up Margatoxin have an effective molecular function in blocking voltage-gated K+ channels 1.3. Due to the abnormally high expression of voltage-gated K[7] channel 1.3 in various types of cancers, blockers of this channel can inhibit apoptosis, metabolic changes, tumor angiogenesis, invasion, and migration. On the other hand, these channel blockers have emerged as a promising therapeutic approach for neurological disorders, such as Alzheimer's and Parkinson's diseases. The strong efficacy and targeted action of margatoxin further position it as a promising drug candidate. As the number of individuals affected by cancer and neurological conditions continues to rise, research into scorpion venom peptides like margatoxin may lead to innovative therapeutic options for future treatments.}, } @article {pmid41486697, year = {2026}, author = {Pan, H and Cheng, X and Zhang, J and Hou, K and Murray, KA and Manglani, K and Zhu, C and Hsu, HK and Mekkittikul, M and Halladay, T and Mirbaha, H and Elezi, G and Abskharon, R and Sawaya, MR and Bombino, A and Williams, CK and DeTure, M and Dickson, DW and Vinters, HV and Whitelegge, JP and Harran, PG and Cole, GM and Frautschy, SA and Eisenberg, DS}, title = {In Vitro and In Vivo Evaluation of Small-Molecule Disassemblers of Pathological Tau Fibrils.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.5c00940}, pmid = {41486697}, issn = {1948-7193}, abstract = {Aggregation of the microtubule-binding protein tau is the histopathological hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, which are collectively known as tauopathies. Tau aggregation in AD patients is correlated with neuron loss, brain atrophy, and cognitive decline, and pro-aggregation tau mutations are sufficient to cause neurodegeneration and dementia in humans and tauopathy model mice. Thus, reversing tau aggregation is a potential therapeutic avenue for AD. In a previous study, we discovered CNS-11, a small molecule that disaggregates AD patient brain-extracted tau fibrils in vitro. In this study, we identify two chemical analogs of CNS-11, named CNS-11D and CNS-11G, that disaggregate AD patient brain-extracted tau fibrils and prevent seeding in a tau aggregation cell culture model. We also demonstrate that 8 weeks of treatment with either CNS-11D or CNS-11G reduces levels of insoluble tau in a mouse model of tauopathy. Our work defines the properties of two small molecules that diminish aggregation of tau in vivo and provides further support for structure-based methods to target tau for treatment of AD.}, } @article {pmid41486173, year = {2026}, author = {Silva-Llanes, I and Smith, LA and Abdelkader-Guillén, A and Jiménez-Villegas, J and Sarrió, D and Moreno-Bueno, G and Lastres-Becker, I}, title = {GASDERMIN D-mediated pyroptosis as a therapeutic target in TAU-dependent frontotemporal dementia mouse model.}, journal = {Journal of biomedical science}, volume = {33}, number = {1}, pages = {6}, pmid = {41486173}, issn = {1423-0127}, support = {PID2022-136854OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2022-137065OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; CB16/12/00295//Centro de Investigación Biomédica en Red de Cáncer/ ; CB06/05/0089//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; }, mesh = {Animals ; *Pyroptosis/genetics ; Mice ; *tau Proteins/metabolism/genetics ; Disease Models, Animal ; Humans ; *Phosphate-Binding Proteins/metabolism/genetics ; Mice, Transgenic ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; *Frontotemporal Dementia/genetics/metabolism/drug therapy/pathology ; Male ; Female ; Alzheimer Disease/genetics ; Mice, Inbred C57BL ; Aged ; Hippocampus/metabolism ; Gasdermins ; }, abstract = {BACKGROUND: Recent research has revealed a strong connection between neuroinflammation and TAU protein-related neurodegeneration. A key discovery shows that the NLRP3 inflammasome, when activated, can significantly impact TAU pathology and subsequent neuronal death. This process involves pyroptosis, a lytic form of programmed cell death driven by inflammasome activation, leading to GASDERMIN D (GSDMD) cleavage and the subsequent release of inflammatory molecules IL-1β and IL-18. In this study, we explore the role of pyroptosis and GSDMD in Alzheimer's disease (AD) and tauopathy models, focusing on the TAU-induced neuroinflammatory process and its correlation with synaptic plasticity loss.

METHODS: Hippocampal tissue from AD patients at Braak stage II-III has been analyzed using qPCR to assess pyroptosis-related gene expression. To determine the role of TAU in pyroptosis and neuroinflammation, we used two different models: one based on intracerebral injection of an adeno-associated virus that specifically overexpresses TAU in the neurons of the hippocampus (AAV-TAU[P301L]), and a transgenic mouse model Tg-TAU[P301S] at 8 and 10 months of age. Gene expression, protein levels, and neuroinflammation markers were evaluated using qPCR and immunofluorescence. Additionally, both genetic (GSDMD-deficient mice) and pharmacological (dimethyl fumarate, DMF) interventions targeting pyroptosis have been explored to assess their impact on neuroinflammation and synaptic plasticity.

RESULTS: AD patients exhibited increased expression of pyroptosis-related genes, supporting the involvement of pyroptosis in neurodegeneration. Furthermore, TAU overexpression induced pyroptosis in both mouse models, and GSDMD protein levels increased alongside reactive microglial morphology. Our data supports that TAU-induced neuroinflammation correlated with synaptic plasticity impairment. GSDMD deficiency significantly reduced pyroptosis-related markers associated to TAU, but unexpectedly worsened synaptic plasticity deficits, suggesting GSDMD may play a dual role in inflammation and synaptic function. Finally, we showed that DMF treatment suppressed pyroptosis gene expression, reduced GSDMD levels, and alleviated neuroinflammation, correlating with improved synaptic marker expression.

CONCLUSION: Our findings demonstrate that TAU-induced pyroptosis contributes to neuroinflammation and synaptic dysfunction. While GSDMD inhibition mitigates inflammation, its absence exacerbates synaptic impairment, highlighting its complex role in tauopathies. Our results indicate that DMF treatment could offer a promising therapeutic avenue to modulate pyroptosis and neuroinflammation, and restore synaptic integrity in tauopathies.}, } @article {pmid41485615, year = {2026}, author = {Pariya Gholizadeh Dangheralou, SK and Khazaeifard, F and Mehr, SR and Mansouri, SM and Rad, NR and Abbasi-Maleki, S}, title = {Evaluation of neurobiochemical and behavioral responses to carvone nanoemulsion: A neuroprotective approach for Alzheimer's disease-associated dementia in a rat model.}, journal = {Brain research}, volume = {}, number = {}, pages = {150143}, doi = {10.1016/j.brainres.2026.150143}, pmid = {41485615}, issn = {1872-6240}, abstract = {BACKGROUND: Antioxidant supplements have emerged as promising strategies to mitigate the impact of Alzheimer's disease (AD) and associated dementia. We explored the neuroprotective potential of Carvone nanoemulsion (CANO) using a rat model of AD-associated dementia.

METHOD: Our experimental groups comprised non-AD control rats (CON), untreated AD rats (AD), and AD rats treated with CANO at two different dosages: 40 mg/kg (CANO40) and 80 mg/kg (CANO80). We assessed various behavioral parameters, malondialdehyde (MDA) and brain-derived neurotrophic factor (BDNF) levels,ferric-reducing ability of plasma (FRAP).

RESULTS: AD induction caused a significant reduction in step-through latency (P < 0.001), center time (P < 0.001), the number of visits (P < 0.001), and total distance traveled (P < 0.001), time spent in open arms (P < 0.001), and both FRAP (P < 0.001) and BDNF levels (P < 0.001) in comparison to the CON group, while elevating escape latency, time in target zone and platform location latency, and MDA levels (P < 0.001). Treatment with CANO, particularly at the CANO80 dosage, significantly improved these parameters compared to the AD group, resulting in decreased time in the target zone (P < 0.001), escape latency (P < 0.001), and platform location latency (P < 0.001) and higher FRAP (P < 0.05) and BDNF levels (P < 0.05), along with decreased MDA levels (P < 0.05).

CONCLUSION: CANO, especially at the 80 mg/kg dosage, shows promise in alleviating symptoms associated with AD-associated dementia. However, further research is warranted to validate and expand upon these findings.}, } @article {pmid41485573, year = {2026}, author = {Pi, G and Zhang, L and Lei, H and Zhong, T and Zhang, F and Lu, Y and Qiu, X and Qi, Y and Dong, Y and Zhu, R and Qin, Q and Wang, J and Sarapultsev, A and Luo, S and Cheng, X and Yang, Y and Wang, JZ and Hu, D}, title = {Ursolic acid reduces Aβ-driven aggression via Gab1-mediated autophagy and dorsal hippocampal circuit modulation in Alzheimer's disease.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2025.12.054}, pmid = {41485573}, issn = {2090-1224}, abstract = {INTRODUCTION: Aggression is one of the most debilitating neuropsychiatric symptoms in Alzheimer's disease (AD), posing significant challenges for both patients and caregivers. However, the underlying mechanism remains unclear, and effective therapeutic strategies are lacking.

OBJECTIVES: This study aimed to investigate the neural circuit mechanisms underlying amyloid-beta (Aβ)-driven aggression in AD and explore the therapeutic potential of ursolic acid (UA) in alleviating this behavior.

METHODS: A combination of virus tracing, electrophysiological recording, in vivo Ca2 + recording, and a aggressive behavior test was utilized to investigate the neural circuit vulnerable to Aβ-driven aggression. optogenetic or chemogenetic manipulation was used to identify the regulation of the neural circuit on aggressive behavior. Proteomics and molecular targeting were employed to explore the underlying mechanisms of Aβ-driven aggression and evaluate UA's effects.

RESULTS: We identified that Aβ accumulation drove hyperexcitability of dorsal hippocampal CA3 (dCA3) neurons projecting to the dorsal lateral septum (dLS), thereby triggering aggressive behavior in the 5xFAD mouse model. Optogenetic activation of the dCA3-dLS circuit in wild-type mice induced aggression, whereas either optogenetic or chemogenetic inhibition of this projection alleviated aggression in 5xFAD animals. Proteomic profiling of dCA3 tissue identified Grb2-associated binding protein 1 (Gab1) as a key mediator upregulated in 5xFAD mice and normalized by ursolic acid (UA) treatment. UA reduced Aβ plaque burden, restored autophagic flux (increasing LC3B-II and decreasing p62), and suppressed dCA3-dLS circuit hyperactivity, resulting in durable attenuation of aggressive behavior. Viral knockdown of Gab1 in dCA3 mimicked UA's effects on autophagy, Aβ clearance, circuit excitability, and aggression, whereas Gab1 overexpression blocked UA's benefits.

CONCLUSION: Together, these results define a novel Gab1-dependent autophagy-circuit mechanism for Aβ-induced aggression and establish UA as a promising candidate for alleviating neuropsychiatric symptoms in AD.}, } @article {pmid41485354, year = {2025}, author = {Lin, X and Tang, L and Hu, Z}, title = {Causal relationship between tractography-based brain white matter structural connectome and risk of psychiatric disorders: A bidirectional Mendelian randomization study.}, journal = {Psychiatry research. Neuroimaging}, volume = {357}, number = {}, pages = {112131}, doi = {10.1016/j.pscychresns.2025.112131}, pmid = {41485354}, issn = {1872-7506}, abstract = {AIM: This study sought to explore the causal link between 206 tractography-derived white matter connectivity metrics in the brain and the risk of nine psychiatric disorders, employing a bidirectional two-sample Mendelian randomization (MR) approach.

METHOD: Summary datasets of 9 psychiatric disorders including anxiety disorder, Alzheimer's disease (AD), major depressive disorder (MDD), autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia, Tourette syndrome(TS), attention-deficit hyperactivity disorder (ADHD), and cannabis use disorder (CUD) were used. MR analyses were performed using the inverse variance weighted (IVW), weighted median, MR-Egger, MR-PRESSO, and MR-robust adjusted profile score (MR-RAPS) method.

RESULTS: Forward MR analysis showed that the left-hemisphere dorsal attention network to the right-hemisphere limbic network connectome was causally associated with a 32 % higher risk of anxiety disorder [odds ratio(OR) = 1.32; 95 % confidence interval (CI): 1.16, 1.51). Reverse MR analysis indicated that AD was associated with a 7 % higher risk for the left-hemisphere limbic network to the right-hemisphere control network connectome(OR = 1.07; 95 % CI: 1.03, 1.10).

CONCLUSIONS: Our MR analysis reveals causal relationships between brain white matter structural connectivity and psychiatric disorders, advancing our knowledge of the neural mechanisms that contribute to psychiatric disorders and providing evidence for targeted interventions in psychiatric treatment.}, } @article {pmid41485137, year = {2026}, author = {Zhu, Z and Steward, A and Dehsarvi, A and Roemer-Cassiano, SN and Dewenter, A and Biel, D and Hirsch, F and Frontzkowski, L and Pescoller, J and Klonowski, M and Gnörich, J and Pontecorvo, MJ and Shcherbinin, S and Schöll, M and Buckley, R and Ossenkoppele, R and Xie, F and Guo, T and , and Höglinger, G and Brendel, M and Franzmeier, N}, title = {Defining patient-centered amyloid PET thresholds for the onset of tauopathy in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e71064}, pmid = {41485137}, issn = {1552-5279}, support = {AARG-22-973496/ALZ/Alzheimer's Association/United States ; //Gerhard and Ilse Schick Foundation/ ; BMBF 01KU2203//ERAPerMed/ ; }, mesh = {Humans ; *Positron-Emission Tomography ; Male ; *Alzheimer Disease/diagnostic imaging/metabolism ; Female ; *Tauopathies/diagnostic imaging/metabolism ; Aged ; tau Proteins/metabolism ; Aged, 80 and over ; *Amyloid/metabolism ; Sex Factors ; Age Factors ; Brain/diagnostic imaging/metabolism ; Carbolines ; }, abstract = {INTRODUCTION: Amyloid-induced tauopathy drives clinical decline in Alzheimer's disease (AD). Because age and sex shape tau trajectories, defining patient-centered amyloid thresholds for tauopathy onset could facilitate pre-tauopathy AD identification and aid treatment decisions and prognosis.

METHODS: By including two samples (Alzheimer's Disease Neuroimaging Initiative [ADNI, n = 301]; and 18F-AV-1451-A05 [A05, n = 143]), we explored whether age and sex affect tauopathy transition and determined patient-centered amyloid positron emission tomography (PET) thresholds that mark tauopathy onset.

RESULTS: We found a consistent amyloid PET × age interaction on global tau PET increase in men (ADNI/A05: p = 0.0078/0.018), with younger men showing faster amyloid-associated tau accumulation. We then established patient-centered, amyloid PET-inferred tauopathy transition cut-offs. Women reached this transition at lower amyloid PET levels, and these cutoffs predicted both earlier onset and accelerated cognitive decline (p < 0.001).

DISCUSSION: This study highlights the effect of age and sex on the amyloid-to-tauopathy transition, establishes patient-centered amyloid PET thresholds for tauopathy onset, and links these thresholds to accelerated cognitive decline.

HIGHLIGHTS: Younger age is related to faster amyloid-related tau accumulation in men. We defined a series of amyloid positron emission tomography (PET) thresholds to enable patient-centered inference of amyloid-related tauopathy. Crossing the amyloid PET-defined tauopathy phase is associated with more progressive tau deposition and cognitive decline.}, } @article {pmid41484932, year = {2026}, author = {Nitzan, K and Bentulila, Z and Bregman-Yemini, N and Ayalon, N and David, D and Break, E and Sarne, Y and Doron, R}, title = {Sex-dependent effects of ultra-low-dose-THC preventive treatment on neuroinflammation and cognitive decline in 5xFAD mice.}, journal = {Biology of sex differences}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13293-025-00815-3}, pmid = {41484932}, issn = {2042-6410}, support = {3-2021-2022b//National Institute for Psychobiology in Israel, Hebrew University of Jerusalem/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) remains the most prevalent cause of dementia, yet no existing treatment effectively prevents its onset. Current therapies primarily aim to slow disease progression or manage symptoms, leaving a critical gap in preventive strategies. Recent findings suggest that ultra-low-dose tetrahydrocannabinol (ULD-THC) may exert neuroprotective effects without the adverse consequences associated with chronic THC use. This study investigates whether preventive ULD-THC treatment can mitigate neuroinflammation and early cognitive decline in the 5xFAD mouse model of AD, with a specific focus on sex differences in treatment response.

METHODS: Male and female 5xFAD mice received monthly ULD-THC injections from 3 to 5 months of age, before significant pathology emerged. At 6 months, behavioral assessments were conducted, followed by molecular analyses of hippocampal and prefrontal cortex (PFC) tissue.

RESULTS: Results indicated that ULD-THC attuned AD-related cognitive decline in both males and females, with sex-specific neuroinflammatory responses. Males exhibited reduced hippocampal inflammation, whereas females showed reduced inflammation in the PFC, suggesting distinct neuroprotective mechanisms across sexes.

CONCLUSIONS: These findings highlight ULD-THC's potential as a preventive strategy for AD, emphasizing the importance of sex-dependent therapeutic approaches. By attenuating neuroinflammatory processes before cognitive deficits fully manifest, ULD-THC offers a novel, biologically targeted approach to AD prevention. Future research should explore its long-term efficacy and translational potential in clinical settings.}, } @article {pmid41484644, year = {2026}, author = {Kim, T and Hong, YJ and Kim, M and Bae, Y and Lee, SB and Kim, SH and Lee, MA and Ko, E and Park, JW and Yang, DW}, title = {Impact of dose and compliance of antidementia medications on long-term outcomes in Alzheimer's disease: a nationwide real-world study.}, journal = {Alzheimer's research & therapy}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13195-025-01942-0}, pmid = {41484644}, issn = {1758-9193}, abstract = {BACKGROUND: Antidementia medications are widely prescribed for Alzheimer's disease (AD), but their long-term real-world effectiveness remains uncertain. This study investigated whether long-term outcomes differ according to medication dosage and compliance using nationwide data.

METHODS: Data from the Korean National Health Insurance Service (NHIS) covering 47 million individuals were analyzed. Prescription data for acetylcholinesterase inhibitors and memantine were analyzed for dosage and compliance. Among 1,704,547 dementia cases (2010-2016), 466,773 patients with clinically diagnosed AD were included. Medication dosage and compliance during the first three years after diagnosis were categorized to define optimal versus suboptimal treatment. Clinical outcomes included progression to moderate to severe dementia, institutionalization, and mortality. Multivariable logistic regression identified factors associated with outcomes.

RESULTS: Patients who maintained optimal dosage and compliance during the first three years after diagnosis showed a lower rate of progression to moderate to severe dementia than those receiving suboptimal treatments consistently across all classification criteria. Regression analyses revealed that optimal compliance and dosage were strongly associated with reduced progression (OR 0.807 and 0.704, respectively; p < 0.0001) and early mortality within five years. In contrast, mortality and institutionalization rates were not significantly different between groups except that mortality within five years.

CONCLUSIONS: Both medication dosage and persistence were independently associated with better long-term outcomes in AD. Maintaining optimal treatment during the early disease period may delay disease progression and improve survival within five years. This nationwide real-world study provides robust evidence supporting the importance of sustained, adequate antidementia therapy in clinical practice.}, } @article {pmid41484454, year = {2026}, author = {Ibrahim, M and Khalil, AM and Attia, H and Alseekh, S and Mohamed, AF and El-Yamany, MF}, title = {Gut Microbiome-Sphingolipid Metabolism-Brain Axis Interactions: Neuroprotective Effects of Amitriptyline as Functional Inhibitor of Acid Sphingomyelinase in a Mouse Model of Tauopathy.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {21}, number = {1}, pages = {3}, pmid = {41484454}, issn = {1557-1904}, mesh = {Animals ; *Sphingomyelin Phosphodiesterase/antagonists & inhibitors/metabolism ; *Gastrointestinal Microbiome/drug effects/physiology ; Mice ; *Amitriptyline/pharmacology/therapeutic use ; Mice, Transgenic ; *Tauopathies/metabolism/drug therapy ; *Brain/drug effects/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Sphingolipids/metabolism ; Disease Models, Animal ; Male ; Mice, Inbred C57BL ; }, abstract = {Tauopathies are neurodegenerative diseases characterized by accumulation of hyperphosphorylated tau protein (P-tau). The gut microbiota (GM) is symbiotic with the host and altered in neurodegenerative diseases. Amitriptyline (AMI) is a functional inhibitor of acid sphingomyelinase (ASM) which is abnormally highly expressed in brains of Alzheimer patients. Little data is known about the role of colonic ASM in management of tauopathy. Therefore, the aim of this study was to investigate the role of AMI on reversing gut dysbiosis, ceramide levels, colonic inflammation and intestinal barrier disruption in tauopathy through the bidirectional gut-brain axis. P301S transgenic mice were administered AMI for 35 days. Colonic ASM, ceramides, inflammation and membrane integrity were assessed besides fecal microbiome analysis and serum lipopolysaccharides to assess intestinal membrane disruption. Levels of hippocampal P-tau, protein phosphatase 2 A and neurogenesis were assessed along with cognitive behavior. AMI treatment significantly reduced colonic ASM, ceramide levels, increased abundance of Harryflintia, Dubosiella, and Parasutterella and decreased abundance of Lactobacillus, Lachnoclostridium, Oscillibacter, Oscillospiracea UCG-003, Colidextribacter, Roseburia, Butyricicoccus, and Sphingomondales. In contrast, P301S mice displayed an altered GM profile with enriched Firmicutes and Clostridia, and low proportions of Bacteroidota- a phylum associated with intestinal barrier protection-, and Ruminococcaceae. Also, AMI treatment decreased inflammation and restored colonic membrane integrity with subsequent decrease in serum lipopolysaccharides, P-tau in hippocampus and improvement in cognitive behaviour and neurogenesis. The current results indicate that AMI has neuroprotective effects against tauopathy through modulation of ASM activity, associated ceramide levels, GM composition, colonic inflammation and membrane integrity through bidirectional gut-brain axis.}, } @article {pmid41484306, year = {2026}, author = {Huang, H and Wu, J and Fang, Z and Wang, Y and Xie, J and Guan, Y}, title = {Recent Advances of the Role of Dl-3-n-Butylphthalide in the Treatment of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {340}, pmid = {41484306}, issn = {1559-1182}, support = {202510159035//Innovation and Entrepreneurship Training Program for China Medical University Students/ ; }, mesh = {Humans ; *Benzofurans/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting approximately 55.2 million individuals globally, with complex pathogenesis involving amyloid-β (Aβ) aggregation, tau pathology, neuroinflammation, oxidative stress, and synaptic dysfunction. Current treatments offer only symptomatic relief without halting disease progression. Dl-3-n-butylphthalide (NBP), a small-molecule compound originally derived from celery seeds, has emerged as a promising multi-target therapeutic candidate for AD. Preclinical studies demonstrate that NBP exerts its therapeutic effects in AD by alleviating oxidative stress, enhancing superoxide dismutase (SOD) and glutathione activities, suppressing neuroinflammation by inhibiting NLRP3 inflammasome activation and pro-inflammatory cytokine release (e.g., IL-1β, TNF-α), reducing Aβ deposition and tau hyperphosphorylation, promoting autophagy, and improving synaptic plasticity. A meta-analysis of six trials (n = 851) confirmed that NBP improves Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores with a favorable safety profile, primarily mild gastrointestinal symptoms and transient liver enzyme elevations. This review systematically summarizes recent advances in NBP research, integrating both preclinical mechanisms and clinical evidence, and highlights its potential as a novel multi-target strategy for AD treatment. Further large-scale, long-term trials are warranted to validate its efficacy and explore optimized delivery systems and combination therapies.}, } @article {pmid41483724, year = {2025}, author = {Strain, JF and Rahmani, M and Phuah, CL and Dierker, D and Luo, J and Owen, C and Vlassenko, AG and Jafri, H and Bourgeat, P and Fripp, J and Jin, L and Moulder, K and Benzinger, T and Xiong, C and Lee, JM and Weiner, M and Masters, CL and Morris, JC and Womack, K and Goyal, MS and , }, title = {Regional growth rates of white matter hyperintensities are associated with beta-amyloid burden.}, journal = {Neurobiology of aging}, volume = {160}, number = {}, pages = {22-32}, doi = {10.1016/j.neurobiolaging.2025.12.006}, pmid = {41483724}, issn = {1558-1497}, abstract = {There is increasing evidence for an association between white matter hyperintensities (WMH) and brain beta-amyloid deposition. How WMH are longitudinally associated with brain beta-amyloid burden requires further investigation, particularly with respect to co-existent vascular risk factors and differences across white matter regions. We measured WMH on MRI and vascular risk factors in a combined neuroimaging data set of cognitively normal and individuals with dementia comprised of the ADNI, AIBL and OASIS3 studies, which includes harmonized centiloid estimates of beta-amyloid burden from PET imaging. WMH were measured using the TrUE-Net algorithm. Vascular risk factors were extracted from provided clinical data and used to calculate individual revised Framingham Stroke Risk Profile (FSRP) scores. Linear mixed effects modelling was used to determine the relationship between the growth rate of WMH and baseline beta-amyloid burden, controlling for age, sex, APOE4 status, and vascular risk factors. 1243 participants [49 % female, mean age 71.7 y (SD 7.6 y)] had at least 3 brain MRIs. Linear mixed models demonstrate robust independent cross-sectional relationships between WMH and baseline beta-amyloid burden (beta coefficient=0.27, p < 0.001), age (beta coefficient=0.04, p < 0.001) and vascular risk factors (beta coefficient=0.25, p < 0.001). Growth rates of WMH increased with baseline beta-amyloid burden (slope=0.021, p < 0.001) and decreased with anti-hypertensive medications (slope=-0.019, p = 0.002), above and beyond age, APOE4 status, and other vascular risk factors. The longitudinal association for beta-amyloid burden persisted in a similar analysis for parietal WM. Our study suggests that in Alzheimer disease research cohorts, WMH progression is associated with age and beta-amyloid burden, particularly in parietal white matter, and slowed by anti-hypertensive treatment.}, } @article {pmid41482856, year = {2026}, author = {Kalita, R and Sarma, A and Baruah, H and Zaman, A and Goswami, D}, title = {Nose to Brain Delivery of Curcumin Loaded Therapeutic Nanostructures for Neurodegenerative Diseases.}, journal = {Biopharmaceutics & drug disposition}, volume = {}, number = {}, pages = {}, doi = {10.1002/bdd.70021}, pmid = {41482856}, issn = {1099-081X}, abstract = {Neurodegenerative diseases are progressive disorders that damage and eventually kill neurons in the central nervous system (CNS). In recent years, various research has been done on reliable and effective treatment methods for the most common neurodegenerative diseases such as Parkinson's, Alzheimer, and Migraine diseases. Different neurodegenerative disorders such as Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic, Lewy body disease can be treated by curcumin, which is a strong antioxidant polyphenol with neuroprotective and anti-amyloid properties. However, Blood-brain barrier (BBB) and blood cerebrospinal fluid barrier restricts the permeation of curcumin to the brain leads poor distribution of the drug in brain tissue. The intranasal pathway holds promise for enhancing the treatment of CNS disorders since it bypasses the BBB and increases the brain bioavailability of drug. As nanotechnology continues to improve, research on the delivery of drug through intranasal route has grown significantly in last 10 years. Several nanocarriers have been developed such as nano-emulsions, microspheres, dendrimers, liposomes, carbon-based nanoformulation, and nanoparticles to deliver curcumin to the brain via intranasal route for the treatment of neurodegenerative diseases. This study provided a thorough analysis of several curcumin nano-formulations used in intranasal pathway as a novel treatment for neurodegenerative diseases.}, } @article {pmid41482153, year = {2025}, author = {Yan, Y and Su, J and Xie, M and Kong, Y and Wang, C and Yuan, G and Fang, Y and Hwang, K and Kim, CY and Han, H and Zhang, Z}, title = {Low Intensity Ultrasound-facilitated exosome delivery promotes hippocampal neurogenesis in Alzheimer's disease.}, journal = {Brain stimulation}, volume = {}, number = {}, pages = {103015}, doi = {10.1016/j.brs.2025.103015}, pmid = {41482153}, issn = {1876-4754}, abstract = {BACKGROUND: Low-intensity ultrasound (LIUS) and human adipose-tissue mesenchymal stem cell-derived exosomes (hADSC-Exos) have shown neuroprotective potential, but their combined effects in Alzheimer's disease (AD) remain unclear.

OBJECTIVE: To evaluate the safety and efficacy of intranasal hADSC-Exos alone or combined with LIUS in APP/PS1 mice, and explore underlying molecular mechanisms.

METHODS: Female APP/PS1 mice (30 weeks) were randomized into five groups (n=6). Treatments included intranasal hADSC-Exos, LIUS, or both for 2 months. Behavioral tests, histology, and hippocampal RNA-seq were performed.

RESULTS: LIUS enhanced Exo uptake in HT22 cells by ∼8% without toxicity. Combined treatment improved learning and memory (escape latency ↓45 s→20 s; P<0.01), increased neurogenesis markers (GFAP/SOX2, DCX, Ki67), and reduced amyloid and microglial activation. RNA-seq identified 93 specific DEGs in the combination group, with enrichment in synaptic and mitochondrial pathways. Fos and Kcnj13 were top DEGs and both downregulated after therapy (P<0.05).

CONCLUSIONS: Intranasal hADSC-Exos combined with LIUS is safe, enhances brain delivery, and synergistically improves cognition and neurogenesis in AD mice. The Fos-Kcnj13 axis may mediate these effects, suggesting a promising noninvasive therapeutic strategy.}, } @article {pmid41482111, year = {2025}, author = {Zheng, R and Liu, X and Liao, Z and Wan, R and Qiu, G and Li, M and Tang, C and Zhou, R and Song, J}, title = {Electroacupuncture ameliorates tau-driven cognitive decline by modulating NF-κB/NLRP3 inflammasome signaling in P301S mice.}, journal = {Experimental neurology}, volume = {398}, number = {}, pages = {115637}, doi = {10.1016/j.expneurol.2025.115637}, pmid = {41482111}, issn = {1090-2430}, abstract = {Alzheimer's disease (AD) progression is driven by a vicious cycle wherein pathological Tau hyperphosphorylation promotes microglial activation and NF-κB/NLRP3 inflammasome signaling, leading to excessive secretion of proinflammatory cytokines that reciprocally exacerbate Tau pathology. While pharmacological NLRP3 inhibitors hold therapeutic potential for AD, critical barriers-including poor blood-brain barrier penetration, suboptimal target selectivity, and safety concerns-persist. This study investigated whether electroacupuncture (EA), a non-pharmacological neuromodulatory approach, could disrupt this Tau-inflammasome cycle. Using P301S Tau transgenic mice, two EA regimens were tested at the GV20 (Baihui) acupoint: 6-month-old mice receiving a 1-month EA intervention, and 6-month-old mice undergoing a prolonged 3-month EA intervention. Cognitive function was evaluated via Y-maze, novel object recognition (NOR), and Morris water maze (MWM) tests, while corticospinal function was assessed using tail-suspension limb-clasping scoring. Hippocampal Tau pathology and inflammatory signaling were analyzed by Western blot and immunohistochemistry, targeting total Tau, phosphorylated Tau, NF-κB, NLRP3, caspase-1, IL-1β, IL-18, TNF-α, and microglial morphology. Short-term (1-month) EA treatment significantly improved spatial working memory and recognition memory. Mechanistically, EA reduced p-Tau levels, suppressed NF-κB activation (decreased p-P65/P65 ratio), downregulated NLRP3 inflammasome components (NLRP3, cleaved caspase-1) and proinflammatory cytokines (IL-1β, IL-18 and TNF-α), and mitigated microglial hyperactivation. Importantly, long-term (3-month) EA treatment persistently suppressed p-Tau accumulation and neuroinflammation, thereby consolidating cognitive benefits even in P301S mice with severe corticospinal dysfunction. These findings establish EA as a multi-targeted immunomodulatory strategy that attenuates Tau-driven neuroinflammation through the TNF-α/NF-κB/NLRP3 signaling axis, highlighting its potential as a safe, non-pharmacological adjunct or alternative therapy for AD and related tauopathies.}, } @article {pmid41482107, year = {2025}, author = {Chen, X and Yao, H and Ma, S and Zhu, H and Xu, Y and Zhu, Y and Ying, Y and Wang, L and Zhang, Q and Zheng, C and Zhou, Y and Tong, Z and Huang, K and Shentu, Y}, title = {FGF22/FGFR2/YAP modulates ferroptosis to suppress neurodegeneration and cognitive impairment in Alzheimer's disease.}, journal = {Experimental neurology}, volume = {398}, number = {}, pages = {115630}, doi = {10.1016/j.expneurol.2025.115630}, pmid = {41482107}, issn = {1090-2430}, abstract = {Ferroptosis, a programmed cell death triggered by iron accumulation and lipid peroxidation, has been increasingly recognized as a critical mechanism underlying neurodegenerative processes, including Alzheimer's disease (AD). The mechanosensitive regulator YAP is implicated in AD progression and ferroptosis. Here we confirmed that FGF22, a fibroblast growth factor, amelitorated cognitive deficits in β-Amyloid (1-42) (Aβ1-42) treated AD model mice through the FGFR2/YAP pathway, which was further ascertained by various biochemical analyses. Additionally, FGF22 treatment effectively reduced ferroptosis and neuronal apoptosis, thereby attenuating synaptic impairments and neuronal injury in the AD model mice and Aβ1-42-exposed HT22 cells. Collectively, the data presented herein implicate FGF22 as a potential neuroprotective agent in AD models, with its efficacy likely mediated through engaging of the FGFR2/YAP signaling axis.}, } @article {pmid41481960, year = {2026}, author = {Fazal, F and Dar, NJ and Ahamad, S and Khan, S and Bano, N and Saha, S and Nazir, A and Bhat, SA}, title = {cGAS-STING signaling in Alzheimer's disease: Microglial mechanisms and therapeutic opportunities.}, journal = {Molecular aspects of medicine}, volume = {107}, number = {}, pages = {101444}, doi = {10.1016/j.mam.2025.101444}, pmid = {41481960}, issn = {1872-9452}, abstract = {Alzheimer's disease (AD) is increasingly recognized as a neuroinflammatory disorder driven by microglial dysfunction. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a critical role in neuroinflammation and has been strongly implicated in the pathology of AD. Chronic activation of cGAS-STING contributes to neurodegeneration by driving persistent type I interferon release and excessive pro-inflammatory cytokine production. However, the pathway exhibits context-dependent effects. Transient activation promotes antiviral defense, autophagy, and cellular quality control in the central nervous system. Sustained engagement exacerbates neuroinflammation and synaptic loss. Preclinical studies demonstrate that pharmacological inhibitors (such as NR, TSG, H-151, TDI-6750, TDI-8246) mitigate amyloid beta and tau pathology, attenuate microglial reactivity, and enhance cognitive outcomes. Yet, its essential physiological roles, including antimicrobial immunity and autophagy regulation, pose challenges for therapeutic targeting. This potentially disrupts neuroimmune homeostasis. In this review, we highlight the role of cGAS-STING in AD and explore its potential as a therapeutic target using small-molecule drug candidates. Despite these promising findings, challenges remain, including optimizing blood-brain barrier (BBB) penetration, ensuring immune specificity, and addressing long-term safety concerns. Due to these challenges, no cGAS-STING inhibitors have entered clinical trials for AD. However, the future of AD treatment may involve modulation of neuroinflammatory pathways, with cGAS-STING inhibitors playing a central role in reshaping neuroimmune homeostasis.}, } @article {pmid41481335, year = {2026}, author = {Noreen, S and Nazir, R and Khan, M and Shah, SA}, title = {Schiff Base Complex rescues mice against scopolamine-induced cognitive dysfunction.}, journal = {Drug and chemical toxicology}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/01480545.2025.2606103}, pmid = {41481335}, issn = {1525-6014}, abstract = {Alzheimer's disease (AD) is a common and debilitating neurodegenerative disease characterized by progressive cognitive impairment, and oxidative stress is a recognized contributor. Despite numerous studies, effective treatments remain scarce. This study synthesized and assessed the neuroprotective effects of a Schiff base complex, Copper(II) 4-(benzylideneamino)-3-hydroxynaphthalene-1-sulfonic acid [Cu(BAHN)2], against scopolamine-induced (SCOP) cognitive and synaptic deficits in adult albino mice. Eight-week-old male BALB/c mice were randomly split into 4 groups: (1) controls (normal saline, 0.9%), (2) SCOP (1 mg/kg), (3) SCOP and Schiff base complex (30 mg/kg) and (4) Schiff base complex alone (30 mg/kg). Cognitive function was assessed using the Morris Water Maze (MWM) and Y-maze test. To assess the biochemical effects of the complex, antioxidant enzyme activities, and western blot analyses were performed. Treatment with the Schiff base complex significantly restored the activity of important antioxidant enzymes-catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and reduced glutathione (GSH) which were decreased by SCOP exposure. In addition, lipid peroxidation (LPO) rates were decreased. The complex also counteracted SCOP-induced decreases in both pre- and post-synaptic proteins, in line with improved behavioral performance in both cognitive challenges. Mechanistically, the compound activated phosphorylated Akt (p-Akt) and upregulated Nrf2 signaling, as well as downregulating nuclear factor kappa B (NF-kB) and interleukin-1β (IL-1β), show a decrease in neuroinflammation. In summary, these data suggest that the Schiff base complex reduces the oxidative, inflammatory, and synaptic deleterious effects of SCOP, probably, by regulating the p-Akt/Nrf2 pathway. Additional mechanistic studies are needed to understand its potential therapeutic implications in dementia.}, } @article {pmid41481312, year = {2026}, author = {Banik, A and Amaradhi, R and Sau, M and Rawat, V and Dingledine, R and Ganesh, T}, title = {Antagonism of the EP2 Receptor Reveals Sex-Specific Protection in a Two-Hit Mouse Model of Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.5c00780}, pmid = {41481312}, issn = {1948-7193}, abstract = {Neuroinflammation is evident in Alzheimer's disease (AD) brains, exacerbating the pathology and ensuing cognitive deficits in patients. The prostaglandin-E2 receptor EP2 emerged as a neuroinflammatory target in several neurodegenerative diseases, including AD. Antagonism of EP2 mitigates neuroinflammation and cognitive deficits in status epilepticus and stroke models. Here, we investigated the efficacy of a potent and selective EP2 antagonist TG11-77.HCl on the cognitive behavior and neuroinflammation in a two-hit 5xFAD mouse model of AD. We exposed adult 5xFAD mice on B6SJL genetic background and their nontransgenic littermates to a low dose of lipopolysaccharide and administered TG11-77.HCl or the vehicle in the drinking water for 12 weeks. Mice were subjected to Morris water maze and Y-maze testing during their last week of drug treatment. Blood samples were subjected to complete blood count (CBC) analysis and brain tissues were processed to examine the levels of inflammatory transcripts and glial marker expression (mRNA), followed by the quantification of congophilic amyloid deposition and microglial activation (IBA[+]) in the brain by immunohistochemistry. TG11-77.HCl treatment enhanced the spatial memory performance and ameliorated mRNA expression of proinflammatory mediators, chemokines, and cytokines in the neocortex of 5xFAD males only and attenuated astroglia and microglia activation in both male and female 5xFAD mice and the congophilic amyloid load in 5xFAD males only. CBC analysis revealed no changes in peripheral inflammation, irrespective of sex, on treatment with TG11-77.HCl. This study reveals sex-specific protection of selective EP2 antagonism in a two-hit mouse model of AD and supports a prudent therapeutic strategy against neuroinflammation and associated cognitive impairment in AD.}, } @article {pmid41480618, year = {2025}, author = {Hu, G and Gogzheyan, C and Panja, S and Sil, S and Gendelman, HE}, title = {Extracellular vesicle-based therapies for neurodegenerative diseases.}, journal = {NeuroImmune pharmacology and therapeutics}, volume = {4}, number = {4}, pages = {377-390}, pmid = {41480618}, issn = {2750-6665}, abstract = {Extracellular vesicles (EVs) are mediators of neurodegeneration and emerging therapeutic tools for central nervous system disorders. On the one hand, they help spread beta amyloid, tau, α-synuclein, TDP-43, and mutant SOD1, contributing to the signs and symptoms of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's Diseases. By activating glial cells, they promote chronic neuroinflammation through carrying cytokines, inflammasomes, and chemokines. On the other hand, EVs' ability to transport neuroregulatory products and cross the blood-brain barrier makes them ideal vehicles for drug delivery. Their function can be surface-modified to deliver targeted therapies, including anti-inflammatory and neuroprotective regulatory RNAs, proteins, and lipids, as well as factors that help maintain neural homeostasis. Notably, we suggest that colostrum-derived EVs, enriched with growth factors and immune-regulatory microRNAs, offer a natural, scalable, and biocompatible source for neuroprotective treatment. Although EVs can act as "Janus-faced" entities - serving both as disease initiators and versatile therapeutic vehicles - controlling their activity can enable immune-based therapeutics for neurodegenerative diseases.}, } @article {pmid41480410, year = {2026}, author = {Tang, S and Luo, W and Wu, S and Yuan, M and Wen, J and Zhong, G and Shen, L and Jiang, W and Cheng, C and Wu, X and Xiao, X}, title = {Hippocampus-targeted BDNF gene therapy to rescue cognitive impairments of Alzheimer's disease in multiple mouse models.}, journal = {Genes & diseases}, volume = {13}, number = {2}, pages = {101649}, pmid = {41480410}, issn = {2352-3042}, abstract = {Brain-derived neurotrophic factor (BDNF) can protect neurons from apoptosis and maintain normal synaptic structures, indicating a significant potential for Alzheimer's disease (AD) treatment. However, the method of in vivo BDNF delivery requires further optimization, and the therapeutic efficacy of BDNF in AD animal models needs to be further evaluated. Here, we demonstrated that a newly engineered adeno-associated virus (AAV) serotype termed AAVT42 showed better tropism for neurons than AAV9 in the central nervous system (CNS). We analyzed the therapeutic potentials of AAVT42-delivered BDNF in three AD mouse models: amyloid precursor protein/presenilin-1 (APP/PS1), rTg4510, and 3 × Tg. Long-term BDNF expression in the hippocampus mitigated neuronal degeneration or loss in these AD mice, and alleviated their cognitive impairment, with no discernible effect on amyloid-β deposition or tau phosphorylation. Furthermore, transcriptomic analysis in 3 × Tg mice revealed that BDNF orchestrated the up-regulation of genes associated with neuronal structural organization and synaptic transmissions, such as Neuropeptide Y (Npy), Corticotropin-releasing hormone (Crh), Tachykinin precursor 1 (Tac1), and the down-regulation of Bone morphogenetic proteins (Bmps). Our study highlighted the efficacy of AAVT42 in gene delivery to CNS and validated the therapeutic benefits of BDNF in treating AD, which will be useful for future translational research on AD treatment using an AAV delivery system.}, } @article {pmid41479956, year = {2025}, author = {Massara, M and Vedovelli, L and Masina, F and M J Edelstyn, N and Silvia Bisiacchi, P and Di Rosa, E}, title = {From cigarettes to compulsions: a longitudinal study in de novo Parkinson's disease.}, journal = {Frontiers in psychology}, volume = {16}, number = {}, pages = {1708535}, pmid = {41479956}, issn = {1664-1078}, abstract = {INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Among the environmental and lifestyle factors associated with disease onset, cigarette smoking represents one of the most paradoxical. While substantial evidence has demonstrated a protective effect of smoking against the development of PD, smoking appears to worsen symptomatology, particularly by exacerbating impulsive-compulsive behaviors (ICBs) in people with PD (PwPD). However, longitudinal studies examining the effects of cigarette smoking on the progression of PD remain limited. Moreover, recent studies often involve mixed samples of treated and untreated PwPD, potentially confounding the impact of dopamine replacement therapy with that of smoking on ICBs.

METHODS: In the present study, we investigated a cohort of de novo PwPD, tracking their motor, cognitive, affective, and behavioral outcomes over 5 years, to better clarify the role of smoking in disease progression. Data were obtained from the Parkinson's Progression Markers Initiative and included 166 PwPD (119 non-smokers and 47 former smokers) and 79 healthy controls (48 non-smokers and 31 former smokers).

RESULTS: Our results revealed that a significantly higher percentage of former-smoker PwPD (28%) exhibited at least one ICB compared to non-smoker PwPD (13%; Pearson's [2](1) = 5.45, p = 0.02). No other significant differences between non-smokers and former smokers emerged in motor or non-motor symptoms, either in PwPD or in healthy individuals.

DISCUSSION: In conclusion, the novelty of our findings lies in showing that smoking-related influences on impulsive-compulsive behaviors in PD are most evident at the de novo stage, before any dopaminergic treatment. This temporal specificity may help resolve previous inconsistencies in the literature and underscores the importance of distinguishing between environmental and pharmacological effects on symptom development.}, } @article {pmid41478829, year = {2026}, author = {Meade, J and Mesa, H and Alamgir, S and Bieniecka, I and Liu, L and Zhang, Q}, title = {Synaptic toxicity of OGA inhibitors and the failure of ceperognastat.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100456}, doi = {10.1016/j.tjpad.2025.100456}, pmid = {41478829}, issn = {2426-0266}, abstract = {O-GlcNAcase inhibitors (OGAi) have emerged as a promising therapeutic strategy in Alzheimer's disease (AD) by enhancing O-GlcNAcylation, which competes with tau phosphorylation and reduces tau aggregation. However, the Phase II clinical trial failure of ceperognastat, marked by accelerated cognitive decline in the treatment group, has raised significant safety concerns. Here, we examined the acute synaptic effects of three structurally distinct OGAi compounds-ceperognastat, ASN90, and MK8719-in mouse hippocampal slices. Electrophysiological recordings revealed suppression of both short- and long-term synaptic plasticity, including paired-pulse facilitation/depression and long-term potentiation. Immunohistochemical analysis confirmed disrupted synaptic protein levels (increased PSD-95, reduced Synaptophysin 1) and a biphasic shift in tau phosphorylation. These convergent findings suggest a class-wide synaptotoxic mechanism and call for a great caution in the development of disease-modifying therapies in AD. We argue that preclinical drug screening for synaptic functionality is essential in CNS-targeted therapeutic pipelines.}, } @article {pmid41478820, year = {2026}, author = {Wang, P and Wu, X and Sun, F and Zhang, H and Jiang, Y and Wang, Q and Ding, H and Zhou, Y and Liu, F and Liu, H}, title = {Multi-omics integration reveals shared genetic architecture between metabolic markers and gray matter atrophy in Alzheimer's Disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100452}, doi = {10.1016/j.tjpad.2025.100452}, pmid = {41478820}, issn = {2426-0266}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by widespread gray matter volume (GMV) reductions. Emerging evidence links glucose and lipid metabolic dysregulation to AD pathophysiology. However, the extent to which AD-related GMV alterations and metabolic traits share a common genetic basis remains poorly understood.

OBJECTIVES: To explore the shared genetic architecture between GMV alterations in AD and metabolites related to glucose and lipid metabolism, aiming to provide biological insights into the prevention and treatment of AD.

DESIGN: This is a multimodal, cross-disciplinary study combining neuroimaging meta-analysis, transcriptome-neuroimaging association analysis, conjunctional false discovery rate (conjFDR) analysis, and functional enrichment analysis to identify the shared genetic architecture between AD-related brain structural alterations and metabolic traits.

SETTING: Public databases and European populations.

PARTICIPANTS: The meta-analysis included 49 studies (1945 CE patients and 2598 controls). The largest genome-wide association study (GWAS) summary statistics were used for AD (Ncase = 39,918; Ncontrol =358,140), two glycemic traits-glucose (GLU, N = 459,772) and glycated hemoglobin (HbA1c, N = 146,864), and three lipid traits (N = 1320,016)-high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG).

MEASUREMENTS: We conducted a voxel-based morphometric meta-analysis of GMV in AD by systematically reviewing 49 neuroimaging studies, identified through a literature search in PubMed and Web of Science using a predefined search strategy. Building upon these neuroanatomical findings, we performed a transcriptome-neuroimaging association analysis using data from the Allen Human Brain Atlas to identify genes spatially correlated with GMV alterations. To further explore the shared genetic architecture, we integrated GWAS summary statistics for AD and five metabolic markers using conjFDR analysis. Finally, functional enrichment analyses were performed to elucidate the biological relevance of the identified genes through this integrative framework.

RESULTS: Consistent GMV reductions in AD were observed in the bilateral middle temporal gyrus, right superior temporal gyrus, and other key subcortical regions. The conjFDR analysis identified 20, 17, 78, 87, and 82 genes shared between AD-related GMV reductions and GLU, HbA1c, HDL-C, LDL-C, and TG, respectively. Notably, 6 genes were shared across all five metabolic markers. Enrichment analysis implicated these genes in biological processes related to Aβ aggregation and phosphatidylinositol metabolism.

CONCLUSIONS: This study reveals a convergent genetic architecture underlying AD-related GMV atrophy and metabolic dysfunction. These findings may offer novel insights into the molecular interplay between systemic metabolism and neurodegeneration in AD and highlight potential targets for therapeutic strategies.}, } @article {pmid41478818, year = {2026}, author = {Mummery, CJ and Li-Hsian, CC and Lasagna-Reeves, CA and Ossenkoppele, R and Rowe, CC and Scharre, DW and Wang, H and Kyaga, S and Cummings, JL}, title = {Tau in Alzheimer's disease: Shaping the future patient journey.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100447}, doi = {10.1016/j.tjpad.2025.100447}, pmid = {41478818}, issn = {2426-0266}, abstract = {Alzheimer's disease is a complex and multifactorial disease characterized by two key pathological hallmarks: amyloid-beta plaques and tau neurofibrillary tangles. Recent progress has led to the development and approval of disease-targeted therapies for Alzheimer's disease in the form of anti-amyloid-beta monoclonal antibodies. However, findings suggest that amelioration of multiple pathological drivers may be required to maximize clinical effect. An increasing body of evidence suggests that tau is a critical player in Alzheimer's disease pathophysiology, contributing significantly to neurodegeneration and cognitive decline. There are now several tau-targeting drugs in clinical development. In this review, we build on research and advancements in the field of tau to envision how an increasing focus on tau could shape the future Alzheimer's disease patient journey. We highlight the potential of tau as both a promising therapeutic target and a valuable biomarker, with the potential to inform treatment decisions and provide insight into disease trajectories. We also consider what a greater focus on tau may bring to an already evolving patient care pathway characterized by an increased influx of patients presenting earlier in the disease continuum, changes in workflow and infrastructural requirements, and increased complexity in treatment decision-making, treatment administration, treatment monitoring, and patient tracking. This review underscores the critical changes that may be required and knowledge gaps to be elucidated to ensure healthcare system preparedness for additional classes of disease-targeted therapy to move toward a next-generation, individualized treatment approach to Alzheimer's disease diagnosis and care.}, } @article {pmid41478817, year = {2026}, author = {Qi, L and Zheng, F and Tu, M and Abdullah, R and Zhao, Y and Su, X and Zhou, D and Peng, G}, title = {Safety profiles of lecanemab: A systematic review and meta-analysis of randomized controlled trials and real-world evidence.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100473}, doi = {10.1016/j.tjpad.2025.100473}, pmid = {41478817}, issn = {2426-0266}, abstract = {BACKGROUND: Safety profiles of lecanemab, an anti-amyloid-β antibody for the treatment of early Alzheimer's disease (AD), remain uncertain and may vary between randomized controlled trials (RCTs) and real-world evidence (RWE) studies.

OBJECTIVES: This systematic review and meta-analysis aimed to evaluate the safety, tolerability, and acceptability of lecanemab based on findings from both RCTs and emerging RWE studies.

METHODS: We systematically searched major databases and clinical trial registries from their inception to June 2025. Random-effects meta-analyses were performed to estimate the pooled incidence of key safety outcomes, including amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation (due to ARIA, adverse events [AEs], or any cause). The risk of ARIA according to the ApoE4 genotype was assessed via relative risk (RR). This study was registered with PROSPERO (No. CRD420251110679).

RESULTS: A total of two RCTs and five RWE studies encompassing 1576 patients were included. The pooled ARIA incidence was 19% (95% CI: 16%-23%), which was significantly modulated by ApoE4 status (RR 1.45 for heterozygotes, 3.54 for homozygotes vs noncarriers) and the pooled symptomatic ARIA incidence was 3% (95% CI: 2%-4%). IRRs occurred in 26% (95% CI: 19%-34%), with heterogeneity reduced in patients receiving specific pre-infusion prophylaxis. The pooled rate of discontinuation due to AEs was 8% (95% CI: 5%-11%), with discontinuation due to ARIA occurring in 5% (95% CI: 3%-7%) of patients in RWE studies.

CONCLUSIONS: Lecanemab-related ARIA demonstrates a clear ApoE4 gene-dose effect, supporting routine ApoE4 genotyping before treatment. Standardizing pre-infusion prophylaxis may reduce variability in IRRs incidence, while prompt recognition and management of ARIA are critical for improving treatment tolerability. These findings provide important evidence to support the safe clinical use of lecanemab.}, } @article {pmid41478541, year = {2025}, author = {Zafar, I and Khan, MS and Jamal, A and Shafiq, S and Bahwerth, FS and Khan, NU}, title = {Precision therapeutic strategies for Alzheimer's disease: Amyloid β-targeted foundations and multimodal next-generation approaches.}, journal = {Molecular and cellular neurosciences}, volume = {136}, number = {}, pages = {104070}, doi = {10.1016/j.mcn.2025.104070}, pmid = {41478541}, issn = {1095-9327}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia and a significant unmet medical challenge, pathologically characterized by amyloid β (Aβ) aggregation, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. Although Aβ has long been a central therapeutic target, clinical translation has historically been hindered by late-stage intervention, inadequate blood-brain barrier (BBB) penetration, and the molecular heterogeneity of AD. Recent advances with Aβ-targeted monoclonal antibodies, particularly lecanemab and donanemab, have provided the first clinical evidence of disease modification, demonstrating robust amyloid clearance and measurable slowing of cognitive decline in early-stage AD. These results validate the Aβ hypothesis but also highlight persistent barriers, including amyloid-related imaging abnormalities (ARIA), questions about the durability of benefit, challenges in patient stratification, and the high economic burden of biologics. To overcome these limitations, next-generation strategies are emerging that extend beyond single-pathway targeting toward multimodal and precision-based frameworks. Innovative approaches include tau-directed therapies to prevent the propagation of neurofibrillary tangles, immunomodulatory strategies to enhance microglial clearance of aggregated proteins, and neuroprotective interventions to counteract oxidative and inflammatory stress. Concurrently, nanotechnology-based drug delivery systems are being engineered to efficiently traverse the BBB and deliver multifunctional payloads, while artificial intelligence (AI)- driven discovery platforms are accelerating target identification, biomarker integration, and patient stratification. Future perspectives emphasize the importance of preclinical-stage intervention, long-term efficacy trials, and the adoption of personalised treatment paradigms that integrate genomic, biomarker, and digital profiling to optimise outcomes. Collectively, these advances signal a paradigm shift in AD therapeutics, positioning Aβ-targeted therapies as a foundation while paving the way for combination strategies that more effectively address the disease's multifactorial nature.}, } @article {pmid41478465, year = {2025}, author = {Bandarupalli, T and Noonan, C and Hansen, K and Weaver, R and Baumann, K and Banks, WA and Erickson, MA and Rhea, EM}, title = {Acute peripheral versus central inhibition of insulin receptors differentially alters cytokine and blood-brain barrier responses to an inflammatory stimulus.}, journal = {Brain, behavior, and immunity}, volume = {133}, number = {}, pages = {106251}, doi = {10.1016/j.bbi.2025.106251}, pmid = {41478465}, issn = {1090-2139}, abstract = {The blood-brain barrier (BBB)'s role in protecting the brain from exposure to harmful circulating factors has led to its disruption being implicated in neurodegenerative diseases such as vascular dementia and Alzheimer's disease. Insulin resistance, defined by an impaired response to insulin, is a common feature of metabolic disorders and neurodegenerative diseases. Importantly, individuals can possess peripheral insulin resistance independent of central insulin resistance and vice versa. States of insulin resistance, like diabetes mellitus for peripheral insulin resistance and Alzheimer's disease for central insulin resistance, are associated with inflammation and BBB disruption. However, the contributions of acute impairment of insulin receptor signaling solely in the periphery versus the brain to inflammation and BBB disruption are not clear. As central vs peripheral insulin resistance could have different effects on inflammation, we characterized the effects of acute central versus peripheral insulin receptor inhibition with or without an inflammatory insult, using lipopolysaccharide (LPS) as a prototypic immune stimulus. Male CD-1 mice were treated with an insulin receptor antagonist (S961), peripherally (intraperitoneal) or centrally (intranasal). This treatment was then followed by an intraperitoneal administration of either saline or LPS 30 min later, at a single 3 mg/kg dose known to cause inflammation and BBB disruption. Assays of BBB disruption and brain and serum collection were done 28 h after the injections. Metabolic hormones, cytokines, and the acute phase protein serum amyloid a (SAA) were then measured in serum and brain homogenates. In the absence of LPS, central S961 reduced serum hormones including ghrelin, gastric inhibitory peptide (GIP), and glucagon. Peripheral S961 significantly increased many cytokines in both brain and blood, whereas central S961 decreased serum SAA and increased a few cytokines. BBB integrity was not affected by S961 alone, but central S961 decreased LPS-induced BBB disruption and also lowered serum levels of SAA. These findings highlight the differential effects of peripheral versus central insulin receptor inhibition on cytokine responses and BBB integrity in the presence and absence of acute inflammation, elucidating differences in the molecular mechanisms for insulin receptor signaling depending on the location of signaling dysfunction. The results suggest a potential neuroprotective role of acute central insulin inhibition during acute inflammation.}, } @article {pmid41478424, year = {2025}, author = {Zhang, Y and Chen, L and Jin, J and Xin, Y and Wang, J and Zhang, A}, title = {Therapeutic application of fecal microbiota transplantation for neurological diseases: Exploring novel mechanisms and perspectives.}, journal = {Experimental neurology}, volume = {398}, number = {}, pages = {115631}, doi = {10.1016/j.expneurol.2025.115631}, pmid = {41478424}, issn = {1090-2430}, abstract = {Recently, fecal microbiota transplantation (FMT) has garnered widespread attention as an emerging therapeutic approach in the field of neurological disorders. In this study, we review the research progress of FMT in treating neurological disorders. First, the development, safety, and efficacy of FMT are introduced. Subsequently, the application and potential mechanisms of FMT in neurodegenerative diseases (such as Parkinson's disease and Alzheimer's disease), neurodevelopmental disorders (such as autism spectrum disorder and attention deficit hyperactivity disorder), and other neurological conditions are elaborated in detail. Particularly, we explore the pivotal role of the microbiota-gut-brain axis in FMT for treating neurological disorders, as well as how FMT influences neurological function by regulating the gut microbiota and its metabolites, immune system and inflammatory responses, and neurotransmitters. However, FMT also faces numerous challenges in the treatment of neurological disorders, such as ethical issues, safety concerns, and standardization problems. Therefore, this review also prospects the future development directions of FMT in the treatment of neurological diseases, including personalized therapy and combination therapies. FMT may be a feasible and promising option for treating various neurological disorders, but a comprehensive understanding of its working principles and continuous improvement of its application in clinical practice are still ongoing.}, } @article {pmid41477991, year = {2025}, author = {Hu, H and Cheng, Q and Li, D and Li, Y and Li, X and Chen, Y and Guo, Y and Tian, S and Jiang, Y and Chen, Y and Liu, Y and Li, S}, title = {Ponicidin ameliorates Alzheimer's disease through dual inhibition of RIPK1-mediated neuroinflammation and necroptosis.}, journal = {International immunopharmacology}, volume = {171}, number = {}, pages = {116095}, doi = {10.1016/j.intimp.2025.116095}, pmid = {41477991}, issn = {1878-1705}, abstract = {Ponicidin (Pon), a diterpenoid isolated from Rabdosia rubescens, exhibits a broad range of pharmacological activities, including anti-inflammatory effects. However, its therapeutic potential in Alzheimer's disease (AD), particularly in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated neuroinflammation and necroptosis, remains underexplored. This study aims to investigate the mechanism through which Pon targets RIPK1 to alleviate AD pathogenesis. The interaction between Pon and RIPK1 was confirmed using bio-layer interferometry (BLI) and drug affinity responsive target stability (DARTS) assays. In vitro, the effects of Pon on inflammatory responses and necroptosis were evaluated in BV2 microglial cells (BV2 cells) and HT22 hippocampal neuronal cells (HT22 cells) using Enzyme-linked immunosorbent assay (ELISA), Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Western blotting (WB), and flow cytometry. In vivo, Pon's therapeutic efficacy was assessed in the 5 × FAD transgenic mouse model of AD through behavioral tests, histological analysis, and biochemical assays. Pon was found to bind RIPK1 with high affinity (KD = 135 nM) and enhance RIPK1's resistance to proteolytic degradation. In microglial cells, Pon effectively inhibited the release of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) by disrupting the RIPK1-janus kinase 1 (JAK1)-signal transducer and activator of transcription 1 (STAT1) signaling pathway. In neurons, Pon suppressed RIPK1-mediated necroptosis by blocking the RIPK1-RIPK3-mixed lineage kinase domain-like protein (MLKL) cascade. Behavioral analysis of 5 × FAD mice revealed that Pon treatment significantly improved cognitive function, reduced amyloid-beta (Aβ) plaque deposition, and alleviated neuroinflammation and necroptosis in the brain. Pon exerts dual neuroprotective effects by targeting RIPK1, mitigating both neuroinflammation and necroptosis, two critical pathological processes in AD. These findings underscore Pon's potential as a disease-modifying therapy for AD and provide a foundation for the clinical development of natural product-derived RIPK1 inhibitors in neurodegenerative diseases.}, } @article {pmid41477911, year = {2026}, author = {Yu, W and Zhuang, D and Wang, K and Qu, Y}, title = {JWX-A1223 attenuates cognitive deficits and tau protein hyperphosphorylation via the Akt/GSK3β pathway in APP/PS1 mice.}, journal = {Archives of physiology and biochemistry}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/13813455.2025.2610481}, pmid = {41477911}, issn = {1744-4160}, abstract = {BACKGOUND: Alzheimer's disease (AD) is a neurodegenerative disorder marked by cognitive decline, affecting memory, thinking, and behaviour. Its neuropathology includes amyloid plaques and neurofibrillary tangles in the brain.

MATERIALS: Amyloid plaques consist of misfolded beta-amyloid protein, while tangles are made of hyperphosphorylated tau protein.

METHOD: After treatment with JWX-A1223, the APP/PS1 mice showed significant cognitive improvement in the Morris water maze test. They had shorter escape latency, reduced swimming distance, and longer stay time in the target quadrant, indicating enhanced spatial learning and memory.

RESULTS: The treatment with JWX-A1223 also significantly reduced the phosphorylation levels of tau protein at Ser202, Ser396 and Ser404 sites in the cerebral cortex and hippocampus of mice, while increasing the phosphorylation levels at Ser473 site of Akt and Ser9 site of GSK3β.

CONSLUSION: It indicates that by regulating the activity of the Akt/GSK3β pathway, it alleviates the excessive phosphorylation of tau protein and thereby improves cognitive impairment.}, } @article {pmid41477735, year = {2026}, author = {Tsai, HR and Lin, YJ and Loh, CH and Lee, YC and Huang, HK}, title = {Risk of Alzheimer Disease and Related Dementia after Retinal Vascular Occlusion: A Nationwide Cohort Analysis.}, journal = {Ophthalmology. Retina}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.oret.2025.10.017}, pmid = {41477735}, issn = {2468-6530}, abstract = {PURPOSE: To evaluate the risk of developing Alzheimer disease (AD) and related dementia in patients with newly diagnosed retinal vascular occlusion.

DESIGN: A nationwide population-based cohort study using claims data from Taiwan's National Health Insurance Research Database (NHIRD).

PARTICIPANTS AND CONTROLS: A total of 39 540 individuals with diagnoses of retinal vascular occlusion between 2011 and 2019 in Taiwan and 395 400 age- and sex-matched nonretinal vascular occlusion individuals without prior diagnoses of any dementia.

METHODS: Patients with newly diagnosed retinal vascular occlusion were identified in the NHIRD, and baseline characteristics were collected. The study endpoints, including AD, vascular dementia (VD), and all-cause dementia, were determined by ≥2 separate outpatient diagnoses or a single discharge diagnosis. Inverse probability of treatment weighting (IPTW) was applied to balance baseline covariates and control potential confounders. Cox proportional hazards models were used to estimate the hazard ratio (HR) for each outcome.

MAIN OUTCOME MEASURES: Development of AD, VD, and all-cause dementia.

RESULTS: After IPTW, 38 522 patients with retinal vascular occlusion and 395 740 nonretinal vascular occlusion individuals were included. Patients with retinal vascular occlusion had increased risks of AD (HR, 1.57; 95% confidence interval [CI], 1.39-1.80), VD (HR, 1.76; 95% CI, 1.58-1.95), and all-cause dementia (HR, 1.58; 95% CI, 1.50-1.65). Both retinal artery occlusion and retinal vein occlusion were associated with increased risks of AD (HR, 1.59; 95% CI, 1.14-2.23; and HR, 1.58; 95% CI, 1.39-1.80, respectively), VD (HR, 1.79; 95% CI, 1.32-2.43; and HR, 1.77; 95% CI, 1.59-1.98, respectively), and all-cause dementia (HR, 1.62; 95% CI, 1.42-1.86; and HR, 1.58; 95% CI, 1.52-1.67, respectively).

CONCLUSIONS: Patients with retinal vascular occlusion had moderately increased risks of AD and related dementias. Therefore, monitoring for dementia symptoms in patients with retinal vascular occlusion may facilitate earlier detection and intervention.

FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.}, } @article {pmid41477525, year = {2025}, author = {Zheng, M and Hong, X and Liao, P and Huang, H and Zhang, Y and Xu, W and Li, H}, title = {Plant-Derived Exosome-Like Nanoparticles: A Promising Therapeutic for Neurological Disorders and Drug Delivery.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {15769-15791}, pmid = {41477525}, issn = {1178-2013}, mesh = {Humans ; *Exosomes/chemistry ; *Nanoparticles/chemistry ; Animals ; *Nervous System Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; *Drug Delivery Systems/methods ; *Plants/chemistry ; }, abstract = {Neurological disorders, including ischemic stroke, Alzheimer's disease, and Parkinson's disease, exhibit high incidence rates and pose significant health challenges. Current pharmacological treatments often fail to adequately address clinical needs due to obstacles such as limited penetration of the blood-brain barrier and suboptimal efficacy. Plant-derived exosome-like nanoparticles (PELNs) have emerged as promising therapeutic agents due to their superior biocompatibility, low toxicity, ability to traverse the blood-brain barrier, and abundance of lipids, microRNAs, and other bioactive compounds. This review provides a comprehensive overview of recent advancements in PELNs preparation technologies, elucidates the mechanisms of action of their principal bioactive components, and explores their therapeutic applications across various neurological disorders, thereby offering a theoretical foundation for the development of related treatment strategies. Nonetheless, researches on PELNs continue to encounter significant challenges. At the production level, there is an absence of standardized isolation protocols, and the yields remain inadequate to satisfy clinical requirements. Clinically, the efficacy in humans has yet to be established, and the available safety data are insufficient. Technically, the lack of standardized storage conditions and the susceptibility of biological stability to external factors further complicate the field. This review delineates these challenges to offer insights for advancing both fundamental research and the clinical translation of PELNs.}, } @article {pmid41477168, year = {2025}, author = {Xiao, Y and Li, H and Han, X and Liu, Y and Sun, J and Sun, C and Wang, Y and Ye, T and Cheng, X}, title = {Qi-Fu-Yin ameliorates physiological frailty in male 5xFAD mice through remodeling the gut microbiota and modulating the cerebral cortex metabolism.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1622286}, pmid = {41477168}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease that can only be managed rather than cured, bringing a substantial burden to society. Frailty and cognition are intertwined in a cycle of decline, affecting the prognosis of AD. Qi-Fu-Yin (QFY) is a classic prescription in traditional Chinese medicine for dementia. While most studies have focused on cognitive impairment, research on physiological frailty remains relatively scarce in AD, especially in 5xFAD mice. We aimed to investigate the impacts of QFY on the physiological frailty of male 5xFAD mice.

METHODS: Male 5xFAD mice received QFY, followed by grip strength test, rotarod test, grading score of frailty, lipofuscin staining, SA-β-gal and Aβ co-staining. The metabolite alteration and the intestinal flora composition were analyzed by non-targeted metabolomics and 16S rRNA sequencing. Moreover, Spearman's correlation analysis was used to integrate behavioral results, differentially expressed metabolites, and altered bacterial genera.

RESULTS: We discovered that QFY improved grip strength, riding time, score of frailty, lipofuscin deposition, SA-β-gal, and Aβ in male 5xFAD mice. The results of untargeted metabolomics showed that metabolites such as proline, PS (18:1/18:0), and PFSA-CI were downregulated in the male 5xFAD mice compared with C57BJ/6JXSJL mice, while PE (18:1/18:1) was upregulated. QFY treatment reversed these changes, restoring metabolite levels toward those of C57BJ/6JXSJL mice. Arginine and proline metabolism, alanine, aspartate and glutamate metabolism, and butyrate metabolism were filtered out as the important metabolic pathways between the C57BJ/6JXSJL mice and the male 5xFAD mice, as well as between the 5xFAD mice and the 5xFAD mice with QFY treatment. Moreover, Ruminococcaceae, Subdoligranulum, Bacteroides, Alistipes, Rikenellaceae_RC9_gut_group, and Odoribacter, which were lower in male 5xFAD mice, were improved after QFY intervention.

DISCUSSION: The differential intestinal flora might improve the metabolism of brain tissue as well as muscle strength and coordination through Short-chain fatty acids (SCFAs). The differential metabolites caused by QFY intervention also have an improving effect on physiological frailty. We suggest that QFY exerts protective impacts against the physiological frailty in AD by adjusting the muscle-gut-brain axis.}, } @article {pmid41477167, year = {2025}, author = {Garcia, ML and Denton, AR and Jackson, NL and Scofield, MD and McMahon, LL}, title = {Pharmacologically increasing O-GlcNAcylation increases complexity of astrocytes in the dentate gyrus of TgF344-AD rats.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1690410}, pmid = {41477167}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) pathology begins two or three decades prior to the onset of cognitive symptoms and is characterized by amyloid-β (Aβ) and hyperphosphorylated tau (pTau) accumulation, reactive glial cells, increased inflammation, and neuronal degeneration in later stages. Preclinical studies report that increasing the post-translational modification, O-GlcNAcylation, involving the addition of a single N-acetylglucosamine (GlcNAc) moiety to serine or threonine residues, can reduce amyloidogenic processing of amyloid precursor protein (APP) and compete with serine phosphorylation on tau, decreasing hyperphosphorylated tau accumulation. Protein O-GlcNAcylation can have anti-inflammatory effects, suggesting the possibility that increasing O-GlcNAcylation may decrease reactive gliosis and other pathological changes in AD.

METHODS: This study aimed to assess the possible beneficial effects of pharmacologically enhancing O-GlcNAcylation by inhibiting O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc moieties, on progressive AD pathology using female TgF344-AD rats. The selective OGA inhibitor thiamet-G [TMG; 10 mg/kg, subcutaneously (s.c.)] was administered three times per week for 3 months starting at 6 months of age, a time point when Aβ pathology is evident in the hippocampus. Western blot analysis was used to measure protein levels of GFAP, Iba-1, and Aβ. Immunohistochemistry and confocal imaging were used to assess Aβ plaques, astrocyte and microglia complexity, and degeneration of tyrosine hydroxylase-positive (TH+) axons.

RESULTS: In TgF344-AD rats, we found significantly increased astrocyte complexity, defined as increased process length and branches, increased numbers of microglia, loss of noradrenergic axons (NA), and significant Aβ plaques compared to WT, confirming previous work by us and others. Notably, pharmacologically increasing O-GlcNAcylation further increased astrocyte complexity in TgF344-AD rats, specifically those located in close proximity to Aβ plaques, while microglia morphology and Aβ staining were unaffected. O-GlcNAcylation was not able to lessen the loss of TH + axons in TgF344-AD rats, although fewer dystrophic axons were observed, suggesting a possible beneficial effect.

DISCUSSION: Our findings demonstrate that increasing O-GlcNAcylation in TgF344-AD rats using a cyclical treatment protocol at a time when Aβ pathology is already significant does not provide broad beneficial effects on Aβ accumulation, microglial reactivity, or noradrenergic axon loss, although there appears to be fewer dystrophic axons. Importantly, increasing O-GlcNAcylation in TgF344-AD rats has dual beneficial effects on astrocyte reactivity. Astrocytes in close proximity to Aβ plaques are more complex with longer processes and more branches compared to those in saline-treated TgF344-AD rats at the same distance, enabling them to surround plaques and protect nearby neurons. Astrocytes located at more distal locations from plaques are less reactive than those at the same distance in saline-treated TgF344-AD rats, permitting a less pathological local environment for nearby neurons. Our findings offer new insights into the possible mechanisms that might contribute to the beneficial therapeutic effects of increasing O-GlcNAcylation during progressive AD pathology.}, } @article {pmid41476782, year = {2025}, author = {Zhu, Y and Liu, H and He, M and Xu, Z and Sun, L and Wu, Z and Niu, X and Huang, S and Wang, J and Ran, X}, title = {Epidemiology and Risk Factors Characteristics of Alzheimer's Disease in Southwestern China: A Cross-Sectional Study.}, journal = {Clinical interventions in aging}, volume = {20}, number = {}, pages = {2685-2704}, pmid = {41476782}, issn = {1178-1998}, mesh = {Humans ; *Alzheimer Disease/epidemiology ; China/epidemiology ; Female ; Male ; Risk Factors ; Aged ; *Cognitive Dysfunction/epidemiology ; Cross-Sectional Studies ; Aged, 80 and over ; Middle Aged ; Prevalence ; Rural Population ; Sex Factors ; Age Factors ; Educational Status ; Comorbidity ; Logistic Models ; }, abstract = {BACKGROUND: To address the regional heterogeneity of Alzheimer's disease, a large-scale epidemiological study of 12,421 elderly individuals was conducted in southwestern China to depict its unique risk characteristics.

METHODS: A total of 12,421 subjects were selected via cluster sampling from southwestern China after low quality data were filtered out. On the basis of investigations and medical imaging examinations, three groups were distinguished: the AD, mild cognitive impairment (MCI), and normal control groups. The risk factors for AD and MCI were analysed via a multivariate logistic regression model.

RESULTS: This study identifies a high burden of cognitive impairment in southwestern China, with 22.07% of adults aged ≥60 years exhibiting cognitive decline and 5.81% diagnosed with Alzheimer's disease rates surpassing national and global averages. Key risk factors included age >80 years, female sex, low education, rural residence, surgical history, and urological comorbidities. These findings underscore the need for region-specific prevention strategies, prioritizing older, less-educated rural women through combined cognitive and vascular interventions, while integrating cognitive screening into primary care in underserved areas for early detection and intervention.

CONCLUSION: Elderly individuals in southwestern China exhibit a high prevalence of cognitive impairment, with AD associated with complex risk factors including established contributors like advanced age, dementia family history, alcohol abuse, and multisystem comorbidities-while notably identifying surgical history and urolithiasis as region specific risk signals. These findings underscore regional, environmental, and ethnic influences on AD pathogenesis, requiring tailored prevention/treatment. Future priorities include integrating brief cognitive screening into primary care, targeting high-risk groups (eg, undereducated rural elderly women), and establishing prospective cohorts to clarify causal links between urolithiasis, surgical history, and cognitive decline for refined region-adapted AD prevention.}, } @article {pmid41476179, year = {2025}, author = {Taheri, E and Raeeszadeh-Sarmazdeh, M}, title = {Evaluating the effect of minimal TIMP variants on protecting and transport across the rat brain microvascular cells (RBMEC).}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {1020}, pmid = {41476179}, issn = {2045-2322}, mesh = {Animals ; Rats ; *Blood-Brain Barrier/metabolism/drug effects ; *Endothelial Cells/metabolism/drug effects ; Matrix Metalloproteinase 9/metabolism ; *Brain/blood supply/metabolism ; *Microvessels/cytology/metabolism ; *Tissue Inhibitor of Metalloproteinase-3/metabolism/genetics/pharmacology ; *Tissue Inhibitor of Metalloproteinase-1/metabolism/genetics/pharmacology ; Tight Junctions/metabolism ; *Tissue Inhibitor of Metalloproteinases/metabolism/genetics/pharmacology ; Zonula Occludens-1 Protein/metabolism ; Cells, Cultured ; Biological Transport ; Capillary Permeability ; }, abstract = {Tissue inhibitors of metalloproteinases (TIMPs), endogenous inhibitors of matrix metalloproteinases (MMPs), can be tailored to regulate MMP activity and mitigate the disruptive effects of specific MMPs when dysregulated in diseases. MMPs, especially MMP-9, are major contributors to the degradation of extracellular matrix components, leading to BBB disruption in neurological disorders. The upregulation of MMPs undermines blood-brain barrier (BBB) integrity and drives neuroinflammation. Engineering minimal protein variants offers enhanced modularity, tissue penetration, and BBB permeability. Minimal TIMP variants were engineered, aiming to improve their therapeutic reach across both sides of the BBB, particularly when delivery to the brain is essential. In this study, we assessed the protective effects of mTC1 and mTC3 on BBB integrity using an in vitro model of rat brain microvascular endothelial cells (RBMECs). Barrier function was evaluated following treatment with recombinant MMP-9, either alone or co-treated with native TIMP-1, TIMP-3, or the engineered minimal variants. MMP-9 induced a dose-dependent increase in BBB permeability, reflected by a decrease in trans-endothelial electrical resistance (TEER) and increased paracellular transport of fluorescent tracers. Co-treatment with TIMP-1, TIMP-3, mTC1, or mTC3 significantly attenuated MMP-9-mediated disruption of tight junctions of RBMECs, preserving TEER values and reducing permeability. Immunofluorescence staining for tight junction proteins, ZO-1 and occludin, further validated the preservation of endothelial integrity in the presence of wild-type human TIMPs and engineered TIMP variants. These findings underscore the potential of engineered minimal TIMPs as molecular tools to stabilize the BBB and support their future application in mechanistic studies focused on BBB protection.}, } @article {pmid41476028, year = {2026}, author = {Zhang, W and Liu, H and Zhang, C and Li, Y and Fang, K and Zhou, Y and Weng, L and Fang, L and Luo, Y and Xiao, H and Zhou, L and Jiao, B and Shen, L}, title = {Six-month follow-up of ARIA-H and iron deposition in real-world lecanemab therapy for Alzheimer's disease: Evidence from a Chinese 7T MRI cohort.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {1}, pages = {e71044}, pmid = {41476028}, issn = {1552-5279}, support = {U22A20300 82371434//National Natural Science Foundation of China/ ; 2021ZD0201803//STI2030-Major Projects/ ; 2023YFC3603700//the National Key R&D Program of China/ ; 2024JJ2097//the Outstanding Youth Fund of Hunan Provincial Natural Science Foundation/ ; 2024PT5108//the Scientific Research Program of FuRong Laboratory/ ; SMIDF-150-2025A19//the Brain Health Youth Fund of Shanghai Medical Innovation & Development Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Magnetic Resonance Imaging/methods ; Male ; Female ; *Iron/metabolism ; Aged ; Amyloid beta-Peptides/blood ; Follow-Up Studies ; Biomarkers/blood ; *Brain/diagnostic imaging/metabolism/drug effects ; tau Proteins/blood ; Cohort Studies ; China ; Middle Aged ; Peptide Fragments/blood ; East Asian People ; }, abstract = {INTRODUCTION: With the approval of lecanemab for treating Alzheimer's disease (AD), there is an urgent need to evaluate its safety and treatment effects on biomarkers in real-world practice.

METHODS: Patients receiving lecanemab (n = 72) underwent routine 3T and 7T magnetic resonance imaging (MRI) for amyloid-related imaging abnormality (ARIA) monitoring. Longitudinal changes of iron deposition assessed by quantitative susceptibility mapping (QSM) and its association with plasma biomarkers were further evaluated.

RESULTS: With use of 7T MRI, we identified characteristic perivascular features and detected ARIA with hemorrhages/hemosiderin deposition (ARIA-H) ≈4 months earlier than with 3T. QSM detected post-treatment regional susceptibility reductions. Decreased susceptibility in the temporal, frontal lobes, and the thalamus was associated with plasma amyloid beta 42 (Aβ42) and tau phosphorylated at threonine 217 (p-tau217) changes.

DISCUSSION: 7T MRI provides superior ARIA-H detection and iron dynamics monitoring, supporting its role in risk stratification and therapy assessment for lecanemab-treated patients. Iron deposition measured by QSM may serve as a promising neuroimaging marker for amyloid-targeting treatments.

HIGHLIGHTS: Using 7T magnetic resonance imaging (MRI), this study for the first time visualized amyloid-related imaging abnormality with hemorrhages/hemosiderin deposition (ARIA-H) at a submillimeter resolution, characterized by aggregated, clustered cerebral microbleeds in a perivascular distribution, suggesting overlapping pathology with cerebral amyloid angiopathy. The susceptibility-weighted imaging sequence on 7T MRI enabled detection of ARIA-H up to 4 months earlier. Plasma amyloid beta 42 (Aβ42) and tau phosphorylated at threonine 217 (p-tau 217) levels are sensitive biomarkers for amyloid targeted therapy. Quantitative susceptibility mapping (QSM) analysis demonstrated reduced cortical iron burden post-treatment, which has significant associations with plasma Aβ42 and p-tau 217 levels, highlighting QSM-derived iron quantification as a promising neuroimaging indicator for amyloid-targeted therapeutics.}, } @article {pmid41475761, year = {2026}, author = {Mei, J and Shi, X and Chen, M and Li, Z and Cui, Y and Fang, C and Wu, X and Chen, X and Zeng, K and Yang, L}, title = {Chitosan/selenium nanoparticles Pickering emulsion prolong quercetin retention time to ameliorates cognitive disorder: Focus on restoring the metabolic disorder and gut microbiota.}, journal = {Carbohydrate polymers}, volume = {375}, number = {}, pages = {124804}, doi = {10.1016/j.carbpol.2025.124804}, pmid = {41475761}, issn = {1879-1344}, mesh = {*Quercetin/chemistry/pharmacology/administration & dosage/pharmacokinetics ; Animals ; *Gastrointestinal Microbiome/drug effects ; *Chitosan/chemistry ; Emulsions/chemistry ; *Nanoparticles/chemistry ; *Selenium/chemistry ; Mice ; Male ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy ; Brain/metabolism/drug effects ; }, abstract = {Gut microbiota influence brain inflammation and cognitive impairment by regulating lipid metabolism. The therapeutic efficacy of quercetin (Que) in Alzheimer's disease (AD) treatment is significantly limited by its poor water solubility and short residence time in vivo. Herein, Chitosan (CS) modified selenium nanoparticles was used to prepare a high-loading Pickering emulsion (Que-CS/Se-PE), improving bioaccessibility of Que. Simulated gastrointestinal fluid experiments demonstrate that Que-CS/Se-PE exhibits strong stability under acidic conditions. In vitro digestion studies indicate that Que-CS/Se-PE enables QUE to target intestinal fluids and release slowly. In vivo imaging revealed that the gastrointestinal retention time of Que-CS/Se-PE was up to 48 h. In HFD + D-gal-induced mice, Que-CS/Se-PE treatment reduced serum TC and brain TNF-α levels by 40.8 % and 31.5 %, respectively, indicating substantial improvement in lipid metabolism and neuroinflammation. Behavioral tests showed that Que-CS/Se-PE improved cognitive performance, with preference index elevated by 2.1-fold. Moreover, the relative abundances of Akkermansia, Lactobacillus, and Bacteroidota increased by 2.7-, 17.8-, and 4.7-fold, respectively. In conclusion, Que-CS/Se-PE exhibits interfacial stability, excellent adhesion, and sustained-release properties, significantly prolonging the retention time of quercetin in vivo and enhancing its bioavailability. Furthermore, it modulates lipid metabolism and gut microbiota, and finally ameliorates cognitive impairment in obesity and age-related AD.}, } @article {pmid41474058, year = {2026}, author = {Naftchi-Ardebili, K and Singh, K and Popelka, GR and Pauly, KB}, title = {A deep-learning model for one-shot transcranial ultrasound simulation and phase aberration correction.}, journal = {Medical physics}, volume = {53}, number = {1}, pages = {e70259}, pmid = {41474058}, issn = {2473-4209}, support = {R01 Grant EB032743//National Science Foundation/ ; }, mesh = {*Deep Learning ; Humans ; *Image Processing, Computer-Assisted/methods ; Skull/diagnostic imaging ; Ultrasonography ; Tomography, X-Ray Computed ; }, abstract = {BACKGROUND: Transcranial ultrasound is a promising non-invasive neuromodulation technique with applications, including neuronal activity modulation, blood-brain barrier opening, targeted drug delivery, and thermal ablation. Its ability to deliver focused ultrasound waves to precise brain regions has led to over 50 clinical trials targeting conditions such as opioid addiction, Alzheimer's disease, dementia, epilepsy, and glioblastoma. However, skull heterogeneity complicates accurate focal spot prediction and energy delivery, requiring rapid yet precise phase aberration correction in clinical workflows.

PURPOSE: To address the trade-off between computational efficiency and accuracy in current focus prediction methods, we introduce TUSNet, a deep learning framework for rapid and accurate transcranial ultrasound pressure field and phase aberration correction computation.

METHODS: TUSNet, an end-to-end neural network, was trained to predict both 2D transcranial ultrasound pressure fields and phase corrections. TUSNet was trained on 180432 synthetic skull Computed Tomography (CT) segments, and tested on 1232 real skull CT segments. Its performance was benchmarked against k-Wave, a MATLAB-based acoustic simulation package, evaluating computation speed, focal spot accuracy, phase correction accuracy, and pressure magnitude estimation.

RESULTS: TUSNet computed pressure fields and phase corrections in 21 ms, which is over 1200 × $\times$ faster than k-Wave, while achieving 98.3% accuracy in peak pressure magnitude estimation and a mean focal positioning error of only 0.18 mm relative to k-Wave ground truth. End-to-end training took approximately 8 h on 4x NVIDIA A100 80 GB GPUs.

CONCLUSIONS: TUSNet demonstrates that deep learning can provide accurate and rapid estimates of phase aberrations and transcranial pressure fields, offering a promising direction for accelerating ultrasound treatment planning. While the present validation is based on simulated, noise-free ultrasound fields, the results establish a foundation that future experimental studies can build on to assess performance under real-world clinical conditions.}, } @article {pmid41473419, year = {2026}, author = {Tonegawa-Kuji, R and Karavani, E and Danziger, M and Zhang, P and Hou, Y and Zhou, Y and Bykova, M and Pieper, AA and Rosen-Zvi, M and Cummings, J and Cheng, F}, title = {Critical evaluation of real-world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {12}, number = {1}, pages = {e70193}, pmid = {41473419}, issn = {2352-8737}, abstract = {INTRODUCTION: Repurposing Food and Drug Administration (FDA)-approved drugs could accelerate treatment development for Alzheimer's disease (AD).

METHODS: Using the MarketScan claims database (2011 to 2020), we applied a trial emulation approach in two base cohorts: (1) individuals with mild cognitive impairment (MCI cohort) and (2) individuals aged ≥70 years (over-70 cohort). We evaluated drugs represented in clinical trials for AD, comparing them with same-class or active comparators. Covariate-adjusted hazard ratios (HRs) were estimated using inverse-probability-weighted Cox models.

RESULTS: A total of 6 out of 38 (16%) drugs in the MCI cohort and 10 out of 53 (19%) drugs in the over-70 cohort were associated with a lower AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion (vs escitalopram; HR 0.57, 95% confidence interval [CI] [0.49, 0.66]), trazodone (vs sertraline; HR 0.82, 95% CI [0.74, 0.91]), venlafaxine (vs escitalopram; 0.72, 95% CI [0.62, 0.84]), and zolpidem (vs lorazepam; HR 0.69, 95% CI [0.56, 0.85]) were associated with a lower AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort (vs metformin; HR 0.74, 95% CI [0.59, 0.93]).

DISCUSSION: This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Findings may inform future trial designs.

HIGHLIGHTS: Repurposing FDA-approved drugs originally developed for other diseases could accelerate treatment development for AD.We identified repurposable drugs that are in current or complete clinical trials of AD and emulated trials for these agents using a large-scale insurance claims-based database.Among 54 drugs evaluated, 6/38 (16%) drugs in the MCI cohort and 10/53 (19%) in the over-70 cohort were associated with reduced AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion, trazodone, venlafaxine, and zolpidem were associated with reduced AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort.A minority of repurposed table drugs that are in current or completed clinical trials for AD and meet criteria for inclusion in this study showed no effect in our trial emulation studies.This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Building on our findings, integrating real-world evidence can inform future trials and accelerate drug development for AD.}, } @article {pmid41473323, year = {2025}, author = {Salian, VS and Veerareddy, V and Tang, X and Xiao, Y and Kalari, KR and Kashyap, PC and Kandimalla, KK}, title = {Molecular Mechanisms Underlying the Regulation of VCAM-1 Expression by the Short-Chain Fatty Acid Butyrate.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.15.694447}, pmid = {41473323}, issn = {2692-8205}, abstract = {Over the past decade, cerebrovascular inflammation has been increasingly recognized as a contributor to the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD). One of the molecular hallmarks of cerebrovascular inflammation is the increased expression of vascular cell adhesion molecule (VCAM)-1 on blood-brain barrier (BBB) endothelial cells. Exposure to amyloid beta (Aβ) peptides, one of the primary hallmarks of AD, and pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) induces VCAM-1 expression on the BBB endothelium, which facilitates extravasation of leukocytes into the brain thereby promoting an inflammatory response. Therefore, it is crucial to explore therapeutic agents that can inhibit VCAM-1 expression induced by Aβ and TNF-α. Short-chain fatty acids, such as butyrate, produced by the gut microbiota as byproducts of dietary fiber metabolism, are recognized for their anti-inflammatory properties. In this study, we successfully tested the hypothesis that butyrate mitigates Aβ and TNF-α-induced VCAM-1 expression in polarized human cerebral microvascular endothelial cell monolayers, a widely used BBB in vitro model. Our findings indicated that pre-treatment with butyrate significantly reduced Aβ42 and TNF-α mediated upregulation of VCAM-1. Furthermore, we have shown STAT3/GATA6 axis as a key mediator of anti-inflammatory effects of butyrate. These findings provide mechanistic insight into butyrate's protective role and highlight its potential to mitigate Aβ and TNF-α-induced cerebrovascular inflammation in AD.}, } @article {pmid41473097, year = {2025}, author = {Kang, MH and Kang, MA and Jeon, HJ and Shin, HC and Moon, H and Lee, DG and Park, HM}, title = {Evaluation of the safety and efficacy of a donepezil depot injection in dogs with canine cognitive dysfunction.}, journal = {Frontiers in veterinary science}, volume = {12}, number = {}, pages = {1724060}, pmid = {41473097}, issn = {2297-1769}, abstract = {Canine cognitive dysfunction (CCD) is an age-related neurodegenerative disorder for which effective treatments remain limited, and objective diagnostic and therapeutic assessment tools using biomarkers or neuroimaging are still lacking compared with human Alzheimer's disease. This study evaluated the safety and efficacy of a long-acting donepezil depot injection in dogs with CCD, using behavioral scores and serum neurofilament light chain (NfL) as primary outcomes, with baseline MRI for diagnostic support. Thirty-two dogs with clinically diagnosed CCD were randomly assigned to a high-dose group (n = 11), a low-dose group (n = 11), or a control group (n = 10). Diagnosis was established based on the Canine Cognitive Dysfunction Rating Scale (CCDR), the CAnine DEmentia Scale (CADES), and DISHAA scoring, and baseline MRI was performed in selected dogs with owner consent. A single intramuscular injection of donepezil depot was administered on day 0, and evaluations were conducted on days 14 and 28. The high-dose group showed significant improvements in CCDR, CADES, and DISHAA at both 14 and 28 days, whereas the low-dose group improved primarily at day 28, with earlier effects limited to CADES (p < 0.05). At day 28, both treatment groups had significantly lower serum NfL levels than controls (p < 0.05), while within-group values remained stable. Quality-of-life scores improved in activity, sociability, overall condition, and global QoL. Adverse events were mild and transient. These findings suggest that a single intramuscular injection of long-acting donepezil depot demonstrates favorable safety and potential efficacy in dogs with CCD, with improvements in behavioral scores and NfL supporting its therapeutic potential and highlighting the value of integrating clinical and biomarker-based assessments in future CCD management.}, } @article {pmid41471864, year = {2025}, author = {Cao, S and Shi, X and Chen, Y and Liu, T and Hu, J and Dong, X and Chen, H and Dai, J and Yin, H}, title = {Gut Microbiota-Targeted Photobiomodulation Ameliorates Alzheimer's Pathology via the Gut-Brain Axis: Comparable Efficacy to Transcranial Irradiation.}, journal = {Microorganisms}, volume = {13}, number = {12}, pages = {}, pmid = {41471864}, issn = {2076-2607}, support = {62175261//National Natural Science Foundation of China/ ; 2023YFB3609103//National Key R&D Program of China/ ; 2021-I2M-1-058//Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences/ ; 24JCZDJC00240//Natural Science Foundation of Tianjin/ ; }, abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder with limited effective and affordable therapies. Photobiomodulation (PBM) offers a safe, non-invasive treatment strategy, yet conventional transcranial PBM (tc-PBM) is restricted by low skull penetration. To overcome this limitation, gut microbiota-targeted PBM (gm-PBM) has been proposed to modulate the gut-brain axis, though its efficacy and mechanisms remain unclear. Here, six-month-old APPswe/PS1dE9 mice received gm-PBM or tc-PBM (810 nm, 25 mW/cm[2], 20 min/day for 4 weeks). Behavioral testing revealed that both treatments improved spatial learning and memory, while histological analyses showed reduced amyloid-β deposition and microglial shift toward an anti-inflammatory phenotype. Notably, gm-PBM specifically enriched short-chain fatty acid-producing bacteria, elevated propionate, butyrate, and secondary bile acids, and restored intestinal barrier integrity, whereas tc-PBM induced minimal microbiota changes. These findings suggest that gm-PBM confers neuroprotective effects comparable to or exceeding tc-PBM through modulation of the gut microbiota-metabolism-immune axis, highlighting its potential as a non-invasive and cost-effective therapeutic approach for AD.}, } @article {pmid41471351, year = {2025}, author = {Makhaeva, GF and Utepova, IA and Rudakova, EV and Kovaleva, NV and Boltneva, NP and Zyryanova, EY and Musikhina, AA and Lazarev, VF and Vladimirova, SA and Guzhova, IV and Ganebnykh, IN and Astakhova, TY and Timokhina, EN and Chupakhin, ON and Charushin, VN and Richardson, RJ}, title = {1-Azinyl-1'-Alkenylferrocenes with Anticholinesterase, Antioxidant, and Antiaggregating Activities as Multifunctional Agents for Potential Treatment of Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {12}, pages = {}, pmid = {41471351}, issn = {1424-8247}, support = {24-63-00016//Russian Science Foundation/ ; }, abstract = {Background/Objectives: This study focused on synthesizing novel alkenyl derivatives of azinylferrocenes and evaluating their potential as Alzheimer's disease (AD) therapeutics. Methods: 1-Azinyl-1'-acetylferrocenes were obtained by regioselective acetylation of azinylferrocenes, followed by the Wittig reaction or reduction of 1-azinyl-1'-acetylferrocenes and subsequent dehydration of the resulting alcohols. The synthesized compounds underwent the following biological activity testing relevant to AD: inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and off-target carboxylesterase (CES); antioxidant capacity (ABTS and FRAP assays); inhibition of Aβ42 self-aggregation (thioflavin method); blocking AChE-induced β-amyloid aggregation (propidium displacement); and cytotoxicity in SH-SY5Y and MSC-Neu cells (MTT assay). Results: Quinoline and bipyridine derivatives demonstrated effective cholinesterase inhibition, especially quinoline 7b (AChE IC50 3.32 μM; BChE IC50 3.68 μM), while acridine derivatives were poor inhibitors. Quantum chemical (QC) calculations predicted that acridine derivatives were especially prone to form stable dimers. Molecular docking into protein targets generated by an AlphaFold3 reproduction code showed that these dimers were too bulky to access enzyme active sites, yet they could bind to protein surfaces to inhibit Aβ42 self-aggregation and displace propidium from the AChE peripheral anionic site. All compounds showed high antioxidant activity in ABTS and FRAP assays, with quinoline derivatives being 2-4 times more potent than Trolox. QC calculations supported these findings. Quinoline and bipyridine derivatives also exhibited low cytotoxicity and scant CES inhibition. Conclusions: Overall, the synthesized ferrocenes, particularly the quinoline and bipyridine derivatives, appear promising for further research as multifunctional therapeutic agents targeting AD due to their anticholinesterase, antiaggregating, and antioxidant activities combined with low toxicity.}, } @article {pmid41471079, year = {2025}, author = {Trasca, DM and Dorin, PI and Carmen, S and Varut, RM and Singer, CE and Radivojevic, K and Stoica, GA}, title = {Artificial Intelligence in Biomedicine: A Systematic Review from Nanomedicine to Neurology and Hepatology.}, journal = {Pharmaceutics}, volume = {17}, number = {12}, pages = {}, pmid = {41471079}, issn = {1999-4923}, abstract = {Background/Objectives: This review evaluates the expanding contributions of artificial intelligence (AI) across biomedicine, focusing on cancer therapy and nanomedicine, cardiology and medical imaging, neurodegenerative disorders, and liver disease. Core AI concepts (machine learning, deep learning, artificial neural networks, model training/validation, and explainability) are introduced to frame application domains. Methods: A systematic search of major biomedical databases (2010-2025) identified English-language original studies on AI in these four areas; 203 articles meeting PRISMA 2020 criteria were included in a qualitative synthesis. Results: In oncology and nanomedicine, AI-driven methods expedite nanocarrier design, predict biodistribution and treatment response, and enable nanoparticle-enhanced monitoring. In cardiology, algorithms enhance ECG interpretation, coronary calcium scoring, automated image segmentation, and noninvasive FFR estimation. For neurological disease, multimodal AI models integrate imaging and biomarker data to improve early detection and patient stratification. In hepatology, AI supports digital histopathology, augments intraoperative robotics, and refines transplant wait-list prioritization. Common obstacles are highlighted, including data heterogeneity, lack of standardized acquisition protocols, model transparency, and the scarcity of prospective multicenter validation. Conclusions: AI is emerging as a practical enabler across these biomedical fields, but its safe and equitable use requires harmonized data, rigorous multicentre validation, and more transparent models to ensure clinical benefit while minimizing bias.}, } @article {pmid41471033, year = {2025}, author = {Park, YC and Seol, E and Lee, J and Hong, JH and Jung, JG and Sunwoo, J}, title = {Pharmacokinetic Evaluation of GB-5001, a Long-Acting Injectable Formulation of Donepezil, in Healthy Korean Participants: Population Pharmacokinetics with Phase 1 Study.}, journal = {Pharmaceutics}, volume = {17}, number = {12}, pages = {}, pmid = {41471033}, issn = {1999-4923}, support = {Not applicable//G2GBIO Inc./ ; }, abstract = {Background/Objectives: Oral donepezil, an acetylcholinesterase (AChE) inhibitor for Alzheimer's disease, faces adherence challenges. Long-acting injectable (LAI) formulations like GB-5001 aim to enhance adherence by reducing dosing frequency. This Phase 1, open-label, active-controlled, dose-escalation study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GB-5001 in healthy male adults. Methods: Participants were assigned to cohorts receiving GB-5001A or GB-5001D (LAI formulations) via intramuscular (IM) or subcutaneous (SC) injection, or oral Aricept[®]. Safety, PK, and PD (AChE inhibition) were assessed. The influence of CYP2D6 phenotype was explored, and modeling/simulation was performed. Results: Fifty healthy male participants completed the study. After IM administration, GB-5001A (70 mg, 140 mg, 280 mg) showed dose-dependent increases in exposure (AUCinf and Cmax), resulting in significantly extended exposure compared to oral Aricept[®] 10 mg. No serious adverse events were reported; the most common AEs were mild injection site reactions, which occurred in all treatment groups except the GB-5001A IM 70 mg group and the Aricept group. GB-5001A also demonstrated sustained AChE inhibition. Conclusions: GB-5001A, an LAI donepezil, showed favorable safety, dose-proportional PK, and sustained plasma exposure. It achieved a 3-4-fold longer half-life than oral donepezil. These findings, supported by modeling, highlight GB-5001A's potential as a once-monthly IM alternative for Alzheimer's disease treatment.}, } @article {pmid41469705, year = {2025}, author = {Li, T and Zhang, J and Song, H and Zhang, R and Fan, F and Huang, Z and Zeng, ML and Peng, BW and Zhang, J}, title = {Border-associated macrophages: an emerging perspective from physiological basis and multi-disease roles to the mechanism of vascular cognitive impairment and dementia.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {302}, pmid = {41469705}, issn = {1742-2094}, support = {82501747//the Natural Science Foundation of China/ ; 82571371//the Natural Science Foundation of China/ ; 2025AFC006//the Natural Science Foundation of Hubei Province/ ; PTXM2025032//Medical Sci-Tech Innovation Platform of Zhongnan Hospital, Wuhan University/ ; ZY2023Z018//Key projects of Traditional Chinese Medicine Scientific research in 2023-2024 by Hubei Provincial Administration of Traditional Chinese Medicine/ ; }, mesh = {Humans ; *Cognitive Dysfunction/pathology/immunology/metabolism ; *Dementia, Vascular/pathology/immunology/metabolism/physiopathology ; Animals ; *Macrophages/pathology/metabolism/immunology ; *Brain/pathology/immunology/metabolism ; }, abstract = {Brain border-associated macrophages (BAMs) are resident immune cells at the border of the central nervous system (CNS), and their physiological functions and roles in neurological diseases have been widely reported. However, the specific mechanisms by which BAMs contribute to vascular cognitive impairment and dementia (VCID) remain unclear. This article systematically reviews the subsets, origin and differentiation, molecular markers of BAMs, and their research progress in various brain diseases such as hypertension, Alzheimer's disease (AD), and stroke. On this basis, this article deeply analyzes the potential hypotheses of BAMs' involvement in the pathogenesis of VCID, including their regulation of neurovascular unit (NVU) homeostasis, their core role in neuroimmune inflammation, their impact on the lipid metabolism pathways in the CNS, and their involvement in the pathogenesis of vascular risk factor-related cognitive impairment (VRFCI). The mechanistic hypotheses proposed in this article aim to provide new perspectives for understanding the pathophysiology of VCID and may open up new directions for the development of early intervention and targeted treatment strategies.}, } @article {pmid41469664, year = {2025}, author = {Yu, X and Xiao, H and Bao, S and Dong, Y and Dong, Z and Zhao, J and Wang, G and Meng, X and Wang, F}, title = {Cigarette smoke-induced lung-brain barrier dysfunction drives neurocognitive impairment via inflammatory spill-over.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {10}, pmid = {41469664}, issn = {1742-2094}, support = {2024CX129//the Graduate Innovation Fund of Jilin University/ ; Not applicable//the Medical Basic Research Innovation Center of Airway Disease in North China/ ; Not applicable//Key Laboratory of Pathobiology/ ; 20200601011JC//Key Laboratory of Precision Infectious Diseases, Jilin Province/ ; 2022C036//Engineering Laboratory for Precision Prevention and Treatment of Common Diseases, Jilin Province/ ; 20230204055YY//Department of Science and Technology of Jilin Province: Key Scientific and Technological Research and Development Projects/ ; }, abstract = {BACKGROUND: Although the association between cigarette smoke (CS)-induced chronic obstructive pulmonary disease (COPD) and neurocognitive disorders is recognized, the underlying mechanisms remain unclear. To date, no studies have linked alterations in lung and brain barrier permeability to the “spill-over” of inflammatory factors in CS induced COPD-related neurocognitive disorders (COPD-NCDs).

METHODS: Using GWAS data, a two-sample Mendelian randomization (MR) analysis was conducted to explore the genetic associations between COPD and neurocognitive disorders (dementia, Alzheimer’s disease, etc.). A BALB/c female mouse model with CS exposure (9 cigarettes/day × 24 weeks) was established. Cognitive functions were evaluated using open field tests, novel object recognition tests, and Morris water maze tests. Histopathological changes were observed by HE and Masson staining. Cellular and molecular profiles in brain tissues were analyzed by single-cell RNA sequencing. Levels of inflammatory factors were detected by ELISA. Barrier permeability changes in the lungs and brain were assessed by using Evans Blue staining. Tight junction proteins in lung and brain tissues were measured by immunofluorescence and Western blotting.

RESULTS: MR analysis revealed causal associations between COPD and Alzheimer’s disease, dementia, depression, anxiety, and Parkinson’s disease. CS-exposed mice exhibited COPD phenotypes (emphysema, reduced lung function) and cognitive impairments (memory deficits, anxiety-like behaviors). Activation of microglia/astrocytes and decreased neuronal/synaptic marker expression were observed in the hippocampus. Increased leakage of Evans blue staining in the lungs and brain, along with downregulated expression of tight junction proteins (Occludin, Claudin1, ZO-1), indicated increased blood-brain barrier (BBB) permeability. Elevated levels of inflammatory factors (IL-1β, IL-6, TNF-α) were detected in lung tissues, brain tissues and serum.

CONCLUSIONS: CS exposure disrupts lung barrier function, leading to the “spill-over” of inflammatory factors to the brain via the lung-brain axis. This increases BBB permeability, triggering neuroinflammation, impairing hippocampal neuronal and synaptic function, and ultimately causing neurocognitive disorders. This study elucidates a novel mechanism of COPD-NCDs, which may provide new targets for the treatment of COPD-NCDs.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03629-7.}, } @article {pmid41468784, year = {2025}, author = {Palanivel, V and Salkar, A and Shenoy, A and Eva, TA and Perera, R and Chitranshi, N and Gupta, V and You, Y and Mirzaei, M and Graham, SL and Gupta, V and Basavarajappa, D}, title = {Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.}, journal = {Neuropeptides}, volume = {115}, number = {}, pages = {102583}, doi = {10.1016/j.npep.2025.102583}, pmid = {41468784}, issn = {1532-2785}, abstract = {Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.}, } @article {pmid41467972, year = {2025}, author = {Chang, ST and Wu, HY and Chiu, YL and Chuang, YF}, title = {Anti-herpetic treatment reduces dementia risk: A systematic review and meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251409323}, doi = {10.1177/13872877251409323}, pmid = {41467972}, issn = {1875-8908}, abstract = {BackgroundHuman herpesvirus (HHV) infections, particularly for herpes simplex virus (HSV) and varicella-zoster virus (VZV), may increase dementia risk, yet the protective effects of anti-herpetic medications remained unclear.ObjectiveThis systematic review and meta-analysis of observational studies aimed to examine the association between anti-herpetic medications and dementia, focusing on HSV or VZV-related infections.MethodsThis study followed PRISMA guidelines (CRD42022368318). Cohort or nested case-control studies published from databases' inception to December 2024 were systematically searched in PubMed, MEDLINE, Embase, Cochrane Library, PsycINFO, and Web of Science. Eligible studies evaluated anti-herpetic medications (e.g., acyclovir, famciclovir, ganciclovir, valacyclovir, valganciclovir) and dementia risk in non-demented adults aged ≥50. Pooled adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) were analyzed using random-effects models. Subgroup and meta-regression analyses were performed to explore potential sources of heterogeneity and effect modifiers.ResultsFourteen cohort studies involving more than 10 million older adults were included. To demonstrate the effects of anti-herpetic medications in various clinical scenarios, the meta-analysis compared: diagnosed and treated versus diagnosed but untreated (aHR=0.77, 95% CI: 0.67-0.89); treated versus untreated regardless of diagnosis (aHR=0.90, 95% CI: 0.87-0.94); and diagnosed and treated versus neither diagnosed nor treated (aHR=0.87, 95% CI: 0.78-0.97). Subgroup analysis and meta-regression identified infection severity as a significant modifier (p < 0.0001), explaining 89.01% of heterogeneity.ConclusionsThis systematic review and meta-analysis reveals notable protective effect of anti-herpetic medication usage on dementia, and the effect is especially pronounced in patients with severe alpha herpesvirus infections.}, } @article {pmid41467438, year = {2025}, author = {Zhao, J and Wang, J and Guo, X}, title = {Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00924}, pmid = {41467438}, issn = {1673-5374}, abstract = {Organoid technology, as an innovative approach, has shown great potential in disease modeling, target screening, and the development of treatment strategies. However, traditional organoids still have three major limitations in research: the absence of specific cell types, the lack of blood-brain barrier structure, and insufficient reproducibility of experimental results. In recent years, researchers have gradually overcome these limitations by introducing innovative techniques such as advanced culture methods, microfluidic systems, bioprinting, organoid transplantation, and assembloid construction. This progress has facilitated the widespread application of organoids in the study of neurodegenerative diseases. This paper aims to systematically review the technological innovations of organoids in the study of neurodegenerative diseases. By summarizing classical organoid construction strategies and their limitations, it emphasizes the value of organoids in comprehensive applications within neurodegenerative disease research. In this review, we focus on five specific neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Research in these diseases demonstrates that organoids improve experimental accessibility and reduce development cycles in disease modeling, target discovery, and therapeutic strategy formation. Using customized equipment and gene editing techniques, these organoids can be tailored to specific needs, providing pathophysiologically relevant disease models and enhancing our understanding of neurodegenerative diseases. Although organoid technology has demonstrated significant advantages in disease research, its potential for treating neurodegenerative diseases has not yet been fully explored, which may become an important direction for future research.}, } @article {pmid41467376, year = {2025}, author = {Alexandrova, EG and Abakumova, TR and Ziganshina, LE}, title = {Use of nootropics in Alzheimer's disease: An analysis of regulatory positions and drug policies in the countries of the Commonwealth of Independent States.}, journal = {The International journal of risk & safety in medicine}, volume = {}, number = {}, pages = {9246479251410817}, doi = {10.1177/09246479251410817}, pmid = {41467376}, issn = {1878-6847}, abstract = {ObjectiveTo analyse regulatory positions and drug policies of the Commonwealth of Independent States (CIS), compared to those of the EU, UK, USA i of the nootropics, used in Russia for Alzheimer's disease.MethodsWe searched E-library to reveal the list of nootropics used and studied in Russia for Alzheimer's disease. We assessed official pharmaceutical registries of nine countries for registration status of identified nootropics, 7 National Essential Medicines Lists (EML), and four clinical practice guidelines (CPG) on Alzheimer's disease. We compared the results of Russia with other countries regulatory and policy positions.ResultsE-Library searches identified 11 nootropicspiracetam, citicoline, idebenone, vinpocetine, choline alfoscerate, Cerebrolysin®, Kortexin®, ethylmethylhydroxypyridine succinate, glycine, nicergoline, nimodipine. Eight nootropic have registration for use in all CIS countries (excluding idebenone, nimodipine), four (piracetam, nimodipine, nicergoline, idebenone) - in UK, nimodipine - in the USA, and idebenone - in EU. National EMLs included: nine nootropics (Russia), 8 - Belarus and Kazakhstan, 4 - Uzbekistan, 2 - Armenia. The studied nootropic agents are not included on the WHO Model EML and on the National EML of the Kyrgyz Republic. They are not listed in the CPG for Treatment of dementia and Alzheimer's disease in the USA, the EU, and the UK. Russian CPGs for Alzheimer's disease recommend Cerebrolysin® and choline alfoscerate.ConclusionsThe studied nootropics are registered for use and listed on National EMLs of Russia, Armenia, Belarus, Kazakhstan, Uzbekistan. None is included on the WHO Model EML and the National EML of Kyrgyzstan, Only CPG of the RF recommend using two nootropics as adjuvant therapy of Alzheimer's disease, Cerebrolysin® and choline alfoscerate. CPG of the European Union, the United Kingdom, and the USA do not mention nootropics as potential treatment options for Alzheimer's disease.}, } @article {pmid41466363, year = {2026}, author = {de Magalhães, CG and Moldakozhayev, A and Lopez, MV and Bowman, GL and Chhatwal, JP and Kellis, M and Mohs, R and Nisenbaum, L and Quiroz, YT and Raju, RM and Sperling, RA and Moqri, M and Gladyshev, VN}, title = {The Right Person, the Right Treatment, at the Right Time in Alzheimer's Disease: Insights From the 2025 Brain Aging Symposium.}, journal = {Aging cell}, volume = {25}, number = {1}, pages = {e70351}, pmid = {41466363}, issn = {1474-9726}, mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism ; *Brain/pathology/metabolism ; *Aging/pathology ; Biomarkers/metabolism ; }, abstract = {On October 22nd, 2025, Brain Aging Symposium took place at Harvard Medical School bringing together leading researchers from academia and partner organizations to discuss recent advances in measuring and monitoring human brain aging trajectories, with a particular focus on Alzheimer's disease (AD). A central theme emerged: achieving "the right treatment for the right person and the right time" through precision medicine approaches. Key advances included the unprecedented validation of plasma-based biomarkers, particularly brain-derived p-Tau217 that can identify seeding AD pathology with remarkable specificity, making large-scale screening newly feasible. Integrating multi-level "omic" modalities, spanning genetic information, molecular biomarkers of nutrition, lipid and protein signatures, neuroimaging measures, cognitive assessments, and lifestyle factors, enhances disease risk modeling and trajectory prediction beyond the capacity of any single marker. Early findings highlight critical roles for nutritional and lipid metabolism, and myelin integrity in brain aging, with cell and sex-specific vulnerabilities identified in response to nutrition, social isolation, and metabolic stress. Computational approaches that combine single-cell genomics, epigenomics, and artificial intelligence have been shown to accelerate causal discovery and therapeutic development. However, significant challenges remain: current biomarkers explain only half the variance in cognitive decline, racial and ethnic differences in biomarker levels lack mechanistic understanding, and scalable tools for comprehensive brain aging assessment are needed. The symposium underscored that preventing AD will require intervening during the preclinical asymptomatic phase. These multimodal screening platforms, coupled with mechanistically driven therapeutics, reduction in modifiable risk factors, including nutrition, vascular health, and social determinants of health, could profoundly impact the field.}, } @article {pmid41465832, year = {2025}, author = {Pilśniak, J and Węgrzynek-Gallina, J and Bednarczyk, B and Buczek, A and Pilśniak, A and Chmiela, T and Jarosińska, A and Siuda, J and Holecki, M}, title = {The Role of Glucagon-like Peptide-1 Receptor Agonists in Alzheimer's and Parkinson's Disease: A Literature Review of Clinical Trials.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {12}, pages = {}, pmid = {41465832}, issn = {2075-1729}, abstract = {Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes and obesity due to their metabolic effects. Emerging evidence suggests they may also have neuroprotective effects, indicating their potential as disease-modifying therapies in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Preclinical studies in animal models have demonstrated that GLP-1RAs can reduce neuroinflammation, oxidative stress, neuronal apoptosis, and pathological protein aggregation, while enhancing glucose metabolism and mitochondrial function. This narrative review analyzed results from human clinical trials evaluating GLP-1RAs in AD and PD, based on a search of four databases (Web of Science, Medline, Embase, and Clinical Trials). The analysis included eleven studies. In AD, clinical trials suggest that GLP-1RAs such as liraglutide and semaglutide may enhance brain glucose metabolism, facilitate glucose transport across the blood-brain barrier, and benefit neuronal networks. However, most studies did not demonstrate improvements in cognitive functions or radiological markers. Short-term clinical trials of GLP-1RAs, including exenatide and lixisenatide, demonstrated promising effects on motor and selected non-motor symptoms in patients with PD, but their disease-modifying effects remain unproven. GLP-1RAs showed a favorable safety profile. Despite promising findings, small study populations, heterogeneous protocols, and short observation periods limit definitive conclusions. Further larger, long-term studies are needed, particularly to clarify the risk-benefit balance, weight control, and long-term outcomes.}, } @article {pmid41465466, year = {2025}, author = {Xu, C and Owen, JE and Gislason, T and Benediktsdottir, B and Ye, J and Robinson, SR}, title = {Limited Microvascular Remodelling Occurs in the Aged Human Hippocampus in Obstructive Sleep Apnoea.}, journal = {International journal of molecular sciences}, volume = {26}, number = {24}, pages = {}, pmid = {41465466}, issn = {1422-0067}, support = {Not applicable//RMIT University/ ; }, mesh = {Humans ; *Sleep Apnea, Obstructive/pathology/physiopathology/therapy ; Male ; Middle Aged ; Female ; Aged ; *Hippocampus/blood supply/pathology ; *Microvessels/pathology/physiopathology ; Adult ; *Aging/pathology ; *Vascular Remodeling ; Continuous Positive Airway Pressure ; }, abstract = {In mice, intermittent hypoxia is associated with an increase in microvessels in the hippocampus, whereas in humans with obstructive sleep apnoea (OSA), microvessels are lost from the heart and retina. The present study investigated microvascular changes in the hippocampus of patients with OSA, and whether patient age or use of continuous positive airway pressure (CPAP) influence microvascularisation. Using autopsy samples from 31 people with confirmed OSA, microvessels were immunolabelled and quantitatively analysed. Compared to the Low OSA group, the High OSA group had larger mean microvessel diameters in the fimbria and CA4, and greater mean microvessel length in the fimbria, which are indicative of microvascular remodelling. An absence of angiogenesis was indicated by similar mean vessel counts in both OSA severity groups. Increased age was associated with microvascular remodelling in the fimbria only. Treatment with CPAP was not associated with changed patterns of microvascularisation. We conclude that: (i) no evidence was found for angiogenesis in the human hippocampus in OSA or ageing; (ii) increased OSA severity is associated with microvascular remodelling in the fimbria and CA4; (iii) microvascular remodelling does not appear to be influenced by CPAP use; (iv) limited adaptability of the microvasculature may underpin the vulnerability of the hippocampus to hypoxic injury, particularly in severe OSA.}, } @article {pmid41465142, year = {2025}, author = {Machowska, M and Leszek, J and Mikołajczyk-Tarnawa, A and Głowacka, K and Trypka, E and Rąpała, M and Piechota, J and Wiela-Hojeńska, A}, title = {The Diagnostic Reliability of BIN1 and TOMM40 Genotyping in Assessing Dementia Risk.}, journal = {Genes}, volume = {16}, number = {12}, pages = {}, pmid = {41465142}, issn = {2073-4425}, support = {RPDS.01.02.01-02-0002/20//Regional Operational Programme of the Lower Silesian Voivodeship 2014-2020, co-financed by the European Union, European Regional Development Fund/ ; }, mesh = {Humans ; *Mitochondrial Precursor Protein Import Complex Proteins/genetics ; Male ; Female ; Aged ; *Cognitive Dysfunction/genetics/diagnosis ; *Tumor Suppressor Proteins/genetics ; Polymorphism, Single Nucleotide ; *Adaptor Proteins, Signal Transducing/genetics ; *Alzheimer Disease/genetics/diagnosis ; *Nuclear Proteins/genetics ; Genotype ; *Dementia/genetics/diagnosis ; *Membrane Transport Proteins/genetics ; Genetic Predisposition to Disease ; Case-Control Studies ; Aged, 80 and over ; Middle Aged ; }, abstract = {OBJECTIVES: Alzheimer's disease (AD) and other dementias represent a growing public health concern, highlighting the need for reliable biomarkers for early diagnosis and treatment monitoring. This study evaluated the potential utility of BIN1 and TOMM40 genotyping in diagnosing mild cognitive impairment (MCI) and early-stage dementia.

METHODS: The BIN1 rs744373 and TOMM40 rs2075650 polymorphisms were genotyped in a cohort of 105 individuals diagnosed with MCI or dementia and in 164 cognitively healthy controls. Genotype distributions were compared between the groups, and the potential role of these variants in diagnostic assessment was explored.

RESULTS: A significantly higher frequency of the TOMM40 rs2075650 GG genotype was observed in patients with AD compared with cognitively healthy controls. In contrast, no statistically significant differences in genotype distribution were found among individuals with mild MCI, vascular dementia, or mixed dementia. Furthermore, the distribution of BIN1 rs744373 alleles did not differ significantly across the analyzed groups.

CONCLUSIONS: Data on the effects of BIN1 rs744373 and TOMM40 rs2075650 polymorphisms in MCI and dementia remain limited and inconsistent. In our study, significant differences were observed only for the TOMM40 rs2075650 GG genotype and G allele, which were more frequent in Alzheimer's disease patients than in controls. No significant associations were found for MCI, vascular dementia, or mixed dementia, nor for the BIN1 rs744373 polymorphism. These results suggest that TOMM40 rs2075650 genotyping may serve as an additional marker for assessing AD risk.}, } @article {pmid41463129, year = {2025}, author = {Eroglu, B and Velez, D and Jones, K and Deak, F and Eroglu, A}, title = {Amelioration of Alzheimer's Disease Pathology in Zebrafish by Photobiomodulation.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41463129}, issn = {2227-9059}, abstract = {Background/Objectives: The zebrafish is a widely used research model due to its characteristics, such as being transparent during development, sharing 70% of its genes with humans, and having conserved features of vertebrate aging, including deterioration of mitochondrial and cognitive functions. While affecting approximately 15% of the world population, neurodegenerative diseases, such as Alzheimer's disease (AD), are currently incurable, requiring testing of alternative treatment strategies. Hence, this study was conducted to test the hypothesis that an optimized photobiomodulation (PBM) therapy improves AD pathology through its multifaceted beneficial effects, including enhancing mitochondrial function and reducing oxidative stress and neuroinflammation. Methods: A pharmacological zebrafish model of AD was developed by adding small amounts (100 nM) of okadaic acid (OKA) directly to fish tanks for nine days. Next, some of OKA-treated and control zebrafish were subjected to an optimized near-infrared PBM therapy while others remain untreated. Results: When examined after OKA treatment, zebrafish brains displayed histological hallmarks of AD including, neurofibrillary tangles, vacuoles, and neuroinflammation. Behavioral tests using a T-maze revealed that OKA-treated zebrafish spent significantly less time in the reward arm than untreated controls (15.2% vs. 50%). In contrast, a sequential PBM therapy significantly reduced formation of neurofibrillary tangles, vacuoles, neuroinflammation, and improved mitochondrial biogenesis in brains of OKA-treated zebrafish while also improving their cognitive function as evidenced by being able to recall the reward arm and spending more time there similar to controls (55 and 57%, respectively). Conclusions: These findings suggest that (1) a fast, cost-effective zebrafish AD model can be developed using OKA treatment and (2) PBM therapy holds promise to ameliorate AD pathology.}, } @article {pmid41463053, year = {2025}, author = {N F Guimarães, G and Dos Santos Cardoso, F and Gamboa, L and W Barrett, D and Gonzalez-Lima, F}, title = {Abdominal Photobiomodulation and the Gut-Brain Axis: A Systematic Review of Mechanistic and Translational Evidence.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41463053}, issn = {2227-9059}, abstract = {Background/Objectives: Bidirectional communication between the gut and brain is central to neurological and psychiatric health, and abdominal photobiomodulation (PBM) has emerged as a promising non-invasive way to modulate this axis by targeting intestinal mitochondria, epithelial integrity, and the microbiota. We systematically reviewed preclinical and clinical evidence on abdominal PBM, alone or in combined protocols, reporting microbiome, metabolic, or neurobehavioral outcomes. Methods: Following PRISMA 2020 recommendations, we searched MEDLINE, Scopus, Web of Science, and ScienceDirect through May 2025 for animal and human studies applying PBM to the abdomen and reporting gut-related, metabolic, or brain-related outcomes. Results: Nine studies met the eligibility criteria (five human, four animal). Human trials, mainly in Parkinson's and Alzheimer's disease, used 630-904 nm light and reported gains in mobility, balance, cognition, and olfaction; one trial also showed microbiota modulation with a decreased Firmicutes:Bacteroidetes ratio. Animal models revealed cognitive improvement, reduced neuroinflammation, dopaminergic neuroprotection, and microbial rebalancing. Mechanistic findings converged on enhanced mitochondrial bioenergetics, redox and anti-inflammatory signaling, vagal activation, and short-chain fatty acid-mediated effects. Conclusions: Current evidence, though limited by small samples, heterogeneous dosimetry, combined treatment sites, and few sham-controlled human trials, suggests that abdominal PBM can influence the gut-brain axis through converging mitochondrial, immune, and microbial mechanisms. Adequately powered randomized trials with standardized dosimetry, validated mechanistic biomarkers, and integrative multi-omics analyses are needed to clarify causal pathways and optimize translational applications.}, } @article {pmid41462869, year = {2025}, author = {Sarbu, M and Ica, R and Biricioiu, MR and Dehelean, L and Zamfir, AD}, title = {Glycosphingolipids in Dementia: Insights from Mass Spectrometry and Systems Biology Approaches.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41462869}, issn = {2227-9059}, support = {PN-IV-P2-2.1-TE-2023-0175//UEFISCDI/ ; UAV-IRG-1-2025-8//Aurel Vlaicu University of Arad, Romania/ ; }, abstract = {This narrative literature review synthesizes recent evidence on glycosphingolipid (GSL) dysregulation in dementia, emphasizing discoveries enabled by mass spectrometry (MS) and systems biology. Focusing on the research published within the last decade, we selected studies that are relevant to GSL alterations in dementia and notable for their methodological advances. The findings were conceptually integrated to emphasize key molecular, analytical, and systems-level aspects across the major dementia types. The results from MS-based glycolipidomics in Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, Parkinson's disease dementia, and Huntington's disease consistently indicate altered GSL metabolism and shared molecular vulnerabilities in neuronal lipid regulation. At the same time, distinct GSL signatures differentiate individual dementias, reflecting the disease-specific mechanisms of neurodegeneration. The literature also reveals that recent advances in high-resolution MS and integrative analytical workflows have shifted GSL research from descriptive to mechanistic, facilitating the detailed mapping of species linked to neuroinflammation, protein aggregation, and synaptic dysfunction. Systems-level analyses combining MS data with other omics approaches increasingly depict GSLs as active regulators of neuronal function rather than inert membrane components. At the same time, emerging trends position GSLs as promising early biomarkers and potential therapeutic targets, while the growing use of artificial intelligence in MS data analysis is accelerating the detection of their subtle patterns, improving cross-disease comparisons. Together, these results reinforce the major role of MS-based platforms in discovering dementia-associated GSLs, identifying therapeutic targets, and influencing future strategies for diagnosis and treatment.}, } @article {pmid41462867, year = {2025}, author = {Fonseca, N and Nunes, M and Silva, PMA and Bousbaa, H and Ricardo, S}, title = {Galanthamine Fails to Reverse P-gp-Mediated Paclitaxel Resistance in Ovarian Cancer Cell Lines.}, journal = {Biomedicines}, volume = {13}, number = {12}, pages = {}, pmid = {41462867}, issn = {2227-9059}, abstract = {Background: Ovarian cancer has the poorest prognosis of all gynecological malignancies, largely due to its chemoresistance, which poses significant treatment challenges. In this context, drug repurposing emerges as an innovative strategy that employs non-cancer treatments to interact with various signaling pathways, enhancing chemotherapy efficacy while minimizing toxicity. This study investigated the cytotoxic effects of galanthamine, currently used as an Alzheimer's disease, as a potential treatment for high-grade serous carcinoma, both individually and in combination with paclitaxel. Methods: The Presto Blue assay, viability marker assessments, immunocytochemical analysis of apoptosis, and a cumulative assay were employed to evaluate the functionality of P-glycoprotein. Results: The results indicated that galanthamine did not demonstrate cytotoxic or synergistic effects in either high-grade serous carcinoma cell line tested, suggesting that it is not a viable strategy for overcoming paclitaxel resistance in this context. The immunocytochemistry analysis indicated that galanthamine does not affect the expression of proteins related to cell viability and proliferation and is not associated with chemoresistance. Additionally, functional assays showed that galanthamine treatment did not affect its drug efflux function at the cellular level. Conclusions: Overall, the results indicate that galanthamine is unsuitable for reversing paclitaxel resistance despite some literature suggesting its potential interaction with P-glycoprotein.}, } @article {pmid41461739, year = {2025}, author = {Palachai, N and Buranrat, B and Pariwatthanakun, C and Noisa, P and Mairuae, N}, title = {Neuroprotective effects of Cratoxylum formosum (L.) leaf extract on β-amyloid-induced injury in human neuroblastoma SH-SY5Y cells.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {44730}, pmid = {41461739}, issn = {2045-2322}, support = {//the Faculty of Medicine, Mahasarakham University/ ; //Thai Traditional Medical Knowledge Fund/ ; }, mesh = {*Clusiaceae ; *Plant Extracts/chemistry/pharmacology/therapeutic use ; Drug Evaluation, Preclinical ; Humans ; Cell Line, Tumor ; *Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; *Amyloid beta-Peptides ; *Neuroprotective Agents/analysis/pharmacology/therapeutic use ; MAP Kinase Signaling System/drug effects ; Flavonoids/analysis ; Peptide Fragments ; }, abstract = {In Alzheimer's disease (AD), Amyloid beta peptide (Aβ), the primary constituent of senile plaques, has been documented as triggering oxidative stress and leading to the death of neuronal cells. Therefore, this research aims to investigate how the Cratoxylum formosum (L.) leaf extract mitigates oxidative stress and cellular damage induced by Aβ in SH-SY5Y cells. The SH-SY5Y cells were treated with Cratoxylum formosum (L.) extract both with and without Aβ25-35. Neuroprotection was evaluated through viability and lactate dehydrogenase (LDH) assays, accompanied by an analysis of various mechanisms including caspase-3/7 activity, levels of reactive oxygen species (ROS), phosphorylation of protein kinase B (Akt), extracellular signal-regulated kinase 1/2 (ERK1/2), and cAMP-responsive element binding protein (CREB), expression of B-cell lymphoma 2 (Bcl-2) proteins, as well as catalase (CAT) and superoxide dismutase (SOD) activities. Results indicated an escalation in oxidative stress in cells exposed to Aβ, evidenced by increased ROS levels. Aβ further exacerbated caspase-3/7 activity, LDH release, and a decline in cell viability. Conversely, treatment with Cratoxylum formosum (L.) extract exhibited a concentration-dependent reduction in Aβ-induced neurotoxicity, manifesting in enhanced cell survival, reduced LDH release and ROS production, and suppression of caspase-3/7 activity. Moreover, it led to increased phosphorylation of Akt, ERK1/2, CREB, upregulated expression of Bcl-2 proteins, and enhanced activity of SOD and CAT. High-performance liquid chromatography (HPLC) analysis identified chlorogenic acid, 1,5-dicaffeoylquinic acid, and ferulic acid as the major phenolic constituents of Cratoxylum formosum (L.) extract. These results imply that the extract may provide protective effects against Aβ-induced neurotoxicity, although further studies are required to clarify its role in AD.}, } @article {pmid41461684, year = {2025}, author = {Saremi, M and Safari, S and Alikhani, MY and Komaki, A and Siadat, SD and Asghari, B}, title = {Evidence for neuroprotection by Bacillus coagulans ATCC 7050 via synaptic plasticity and oxidative balance in Alzheimer's disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {44690}, pmid = {41461684}, issn = {2045-2322}, support = {Grant Number: 140303292888//Vice Chancellor for Research and Technology, Hamadan University of Medical Sciences/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Oxidative Stress/drug effects ; Male ; *Neuronal Plasticity/drug effects ; Rats ; Rats, Wistar ; *Bacillus coagulans/physiology ; Disease Models, Animal ; Hippocampus/metabolism ; Amyloid beta-Peptides ; *Probiotics/pharmacology/administration & dosage ; Long-Term Potentiation ; *Neuroprotection ; Superoxide Dismutase/metabolism ; Memory, Short-Term ; Glutathione Peroxidase/metabolism ; Malondialdehyde/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic impairment, and oxidative stress. Probiotics with antioxidant and anti-inflammatory properties have been proposed as potential adjunctive strategies. This study examined whether oral administration of Bacillus coagulans ATCC 7050 could attenuate hippocampal oxidative stress, modulate synaptic plasticity, and influence spatial working memory in an Aβ1-42-induced rat model of AD. Adult male Wistar rats were assigned to Sham, AD, BC (probiotic only), and AD + BC groups. Working memory was assessed by Y-maze, synaptic function by perforant path-dentate gyrus long-term potentiation (LTP) recordings, and oxidative status by hippocampal malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) assays. AD rats exhibited reduced alternation percentage, impaired LTP (fEPSP slope and PS amplitude), elevated MDA, and decreased SOD and GPx activities versus Sham. B. coagulans treatment improved alternation percentage without affecting total entries, preserved PS amplitude from 30 min post-HFS, reduced MDA, and restored SOD activity, with partial GPx recovery. fEPSP slope remained reduced. These findings suggest B. coagulans ATCC 7050 mitigates oxidative stress, preserves neuronal excitability, and improves working memory in an Aβ-based AD model, supporting further investigation of its potential as a safe adjunct in early-stage disease.}, } @article {pmid41461311, year = {2025}, author = {Li, R and Wu, X and Yao, J and Chen, J and Shui, X and Zheng, X and Tian, W and Wang, L and Zhou, Y and Zhang, T and Chen, D and Liu, Y and Lee, TH}, title = {Selective degradation of DAPK1 via a novel hydrophobic tagging attenuates tau pathology in Alzheimer's disease.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2025.12.037}, pmid = {41461311}, issn = {2090-1224}, abstract = {INTRODUCTION: The upregulation of death-associated protein kinase 1 (DAPK1) is involved in tau hyperphosphorylation, neuronal apoptosis and cognitive dysfunction, which are key pathological features of Alzheimer's disease (AD). This result suggests that DAPK1 is novel therapeutic target for AD.

OBJECTIVES: This study aimed to evaluate the efficacy and mechanism of action of CJ1, a novel hydrophobic tagging (HyT)-based degrader, in targeting DAPK1 and alleviating in AD.

METHODS: A library of HyT-based bifunctional molecules was synthesized and systematically screened for their ability to degrade DAPK1 in vitro. CJ1 emerged as the most potent candidate degrader of DAPK1, and its capacity to induce DAPK1 degradation via the proteasome system was further evaluated. Its effects on tau phosphorylation and neuronal viability were evaluated in multiple cellular models. The in vivo efficacy of systemic CJ1 administration was assessed in two tau-related pathology (tauopathy) mouse models, AAV-hTau-P301L and hTau transgenic mice. Behavioral, biochemical, and histological analyses were performed to evaluate cognitive function, tau pathology, neuroinflammation, neurodegeneration, and safety.

RESULTS: CJ1 selectively promoted the posttranslational degradation of DAPK1 by the proteasome system without affecting DAPK1 mRNA expression. In vitro studies demonstrated that CJ1 significantly reduced tau phosphorylation at multiple AD-related sites. In vivo, CJ1 effectively penetrated the blood-brain barrier, decreased the levels of both the soluble and insoluble forms of hyperphosphorylated tau, and suppressed the formation of neurofibrillary tangles. Additionally, CJ1 treatment restored synaptic and dendritic structures, enhanced spatial learning and memory, attenuated neuroinflammatory responses, preserved neuronal populations, and produced no evidence of systemic toxicity.

CONCLUSION: CJ1 functions as a potent and selective degrader of DAPK1, exerting neuroprotective effects by reducing tau hyperphosphorylation and preserving neuronal structural integrity. These findings support DAPK1 as a promising therapeutic target and suggest that further preclinical studies are warranted to evaluate CJ1 as a potential treatment for tauopathies associated with AD.}, } @article {pmid41460672, year = {2025}, author = {Sun, L and Wei, G and Ji, F and Ding, Y and Fan, J and Xu, Y and He, C and Zhou, Y and Liu, Z and Sun, Z and Zhou, D}, title = {Proteome-wide association study identifies novel Alzheimer's disease-associated proteins.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251409352}, doi = {10.1177/13872877251409352}, pmid = {41460672}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disease with limited prevention and treatment options.ObjectiveWe aimed to identify proteins with genetically regulated plasma levels associated with AD and its related phenotypes.MethodsWe conducted a proteome-wide association study (PWAS) using Olink-based plasma proteomes (N = 45,540) from the UK Biobank Pharma Proteomics Project (UKB-PPP) and a large-scale genome-wide association study for AD (N case = 85,934, N control = 401,577). To validate and expand these findings, we conducted longitudinal analyses of AD and mild cognitive disorder (MCD) over a 13.7-year follow-up, along with genetic-based PWAS analyses and cross-sectional studies on hippocampal volume. Protein-protein interaction networks were constructed to explore mechanistic association.ResultsWe identified 30 AD-associated plasma proteins by PWAS, including 17 previously reported and 13 novel candidates (including FES, LRP11, and HDGF). Longitudinal cohort studies supported the role of PILRB and FES in AD and/or MCD. Additionally, the genetically determined higher levels of LRP11 were found to be associated with an increased hippocampal volume, including its subdivisions, along with a reduced risk of AD. In contrast, higher plasma levels of HDGF were linked to a decreased hippocampal volume, accompanied by an increased risk of AD. Protein-protein interaction analysis linked PILRA, PILRB, FES, and LRP11 to several pathological proteins associated with AD, including BIN1, ABCA7, and SORL1.ConclusionsThis study identified 13 novel candidates, with potential roles in hippocampal volume and AD risk, providing insights into disease mechanisms.}, } @article {pmid41460605, year = {2025}, author = {Fassbender, RV and Kehm, C and Otta, AL and Fink, GR and Onur, OA}, title = {Repetitive transcranial magnetic stimulation enhances alpha power in Alzheimer's disease patients.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251406972}, doi = {10.1177/13872877251406972}, pmid = {41460605}, issn = {1875-8908}, abstract = {BackgroundWith Alzheimer's disease (AD) presenting an ongoing challenge, innovative treatment methods are essential. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising noninvasive intervention, particularly targeting alpha band oscillations associated with AD-related cognitive decline.ObjectiveThis study aimed to investigate the effects of low-intensity rTMS over posterior cortical areas on alpha band oscillations and memory performance in AD patients compared to age-matched healthy controls.MethodsIn a single-blinded, sham-controlled rTMS-EEG study, we examined 14 amyloid-positive AD patients and 14 age-matched healthy controls. Continuous EEG was recorded at rest (eyes closed) before, during, and after stimulation. During stimulation, participants completed an episodic memory task.ResultsWe were able to demonstrate that during rTMS alpha power increased compared to sham, with a notable 25% increase observed in AD patients. However, comparison of memory performance under the sham and stimulation conditions revealed no significant stimulation effect.ConclusionsThese findings support and extend current knowledge of noninvasive brain stimulation mechanisms. Our results suggest that alpha frequency-tuned rTMS over posterior cortical areas can modulate pathological brain activity in AD patients even at low intensities. Given the limited sample size and moderate effect sizes, results should be interpreted with caution. Nevertheless, our results warrant further studies with long-term EEG-rTMS protocols to evaluate the potential therapeutic benefit.}, } @article {pmid41460506, year = {2025}, author = {Bernard, PJ and Więckowska, A and Grosjean, S and Godyń, J and Sałat, K and Detka, J and Palacz, N and Tyrybon, W and Jończyk, J and Szałaj, N and Zaręba, P and Martin, H and Maj, M and Jozwiak, K and Marco-Contelles, J and Ismaili, L}, title = {First Sustainable One-Pot Tandem Hantzsch Multicomponent Reaction/Click Reaction Approach for Novel Multitarget-Directed Ligands in Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1021/acschemneuro.5c00806}, pmid = {41460506}, issn = {1948-7193}, abstract = {This study explores novel multitarget-directed ligands (MTDLs) showing anticholinesterase, antioxidant, neuroprotective, and calcium channel inhibitory activities, as promising compounds for Alzheimer's disease (AD) treatment. The rational design combined dihydropyridines (DHPs), known for calcium channel blocking and neuroprotective properties, with tacrine, a cholinesterase inhibitor. The key innovation of this work lies in the one-pot tandem Hantzsch multicomponent/click reaction used to synthesize new 18 DHPs IIIa-r. This sustainable and original approach aligns with green chemistry principles by reducing waste, energy consumption, and derivatives formation. Notably, DHP IIIj and IIIk demonstrated a multitarget profile and effectively reversed scopolamine-induced amnesia in a mouse model, showcasing its antiamnesic properties. These results suggested that DHP IIIj and IIIk hold promise as innovative therapeutic candidates for AD, validating the potential of MTDL strategy and highlighting the one-pot tandem synthesis as a significant advancement in medicinal chemistry.}, } @article {pmid41460033, year = {2026}, author = {Hu, XH and Jin, Q and Xie, JL and Wu, CL and Pan, JP}, title = {Docosahexaenoic acid modulates microglial autophagy via miR-589-5p/toll-like receptor 4 axis in Alzheimer's disease.}, journal = {Neuroreport}, volume = {37}, number = {2}, pages = {77-85}, doi = {10.1097/WNR.0000000000002236}, pmid = {41460033}, issn = {1473-558X}, mesh = {*Alzheimer Disease/metabolism ; *Autophagy/drug effects ; *MicroRNAs/metabolism ; *Docosahexaenoic Acids/pharmacology ; *Toll-Like Receptor 4/metabolism/drug effects ; Humans ; *Microglia/drug effects/metabolism ; Animals ; Male ; Mice ; Female ; Aged ; Amyloid beta-Peptides ; Cell Line ; }, abstract = {OBJECTIVE: To investigate the neuroprotective mechanism by which docosahexaenoic acid (DHA) promotes microglial autophagy via the miR-589-5p/toll-like receptor 4 (TLR4) axis in Alzheimer's disease.

METHODS: In vitro, BV2 microglial cells were treated with Aβ25-35 to establish an Alzheimer's disease model and subjected to DHA treatment with or without miR-589-5p inhibition and TLR4 overexpression. Cytotoxic effects were assessed by methylthiazolyldiphenyl-tetrazolium bromide assays. Autophagy markers (LC3-II/I ratio, Beclin1, and p62) were evaluated by Western blot and immunofluorescence. The miR-589-5p/TLR4 interaction was assessed using dual luciferase assays. For clinical validation, peripheral blood samples from healthy controls, patients with mild Alzheimer's disease, and patients with severe Alzheimer's disease (n = 30 each) were analyzed for miR-589-5p and TLR4 mRNA expression via quantitative reverse transcription PCR (qRT-PCR).

RESULTS: In cellular assays, DHA significantly enhanced autophagy by increasing the LC3-II/I ratio and Beclin1 expression while decreasing p62 levels (P < 0.05). Mechanistic validation showed that miR-589-5p inhibition abolished DHA's autophagy-promoting effects, while TLR4 overexpression reversed these benefits. Conversely, miR-589-5p mimic treatment rescued autophagy even under TLR4 overexpression conditions. Dual-luciferase assays confirmed that miR-589-5p directly targets TLR4. Clinically, qRT-PCR analysis revealed that miR-589-5p expression was downregulated and TLR4 expression was upregulated in Alzheimer's disease patients compared to healthy controls, and these alterations were correlated with disease severity (P < 0.05).

CONCLUSION: DHA enhances microglial autophagy via a novel miR-589-5p/TLR4 regulatory axis, a potential Alzheimer's disease therapy and biomarker for Alzheimer's disease progression.}, } @article {pmid41460031, year = {2026}, author = {Fu, C and Kan, Y and Guo, K and Jiang, L and Zhang, Y and Dong, H and Xie, J}, title = {Tenuigenin ameliorates Alzheimer's disease by targeting MAP2K1: integrated evidence from network pharmacology and experimental validation.}, journal = {Neuroreport}, volume = {37}, number = {2}, pages = {53-66}, doi = {10.1097/WNR.0000000000002239}, pmid = {41460031}, issn = {1473-558X}, support = {gzwkj2025-129//Science and Technology Fund Project of the Guizhou Provincial Health Commission/ ; gzwkj2025-130//Science and Technology Fund Project of the Guizhou Provincial Health Commission/ ; 20222121020675//Project of the Heilongjiang Provincial Health and Family Planning Commission/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Network Pharmacology/methods ; *Neuroprotective Agents/pharmacology ; *Drugs, Chinese Herbal/pharmacology ; Molecular Docking Simulation ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; }, abstract = {OBJECTIVE: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder primarily characterized by progressive cognitive impairment and synaptic dysfunction. Despite substantial research efforts, effective therapeutic options remain limited. Tenuigenin (TEN), a principal bioactive constituent isolated from the traditional Chinese medicinal herb Polygala tenuifolia, has demonstrated promising neuroprotective effects.

METHODS: This study adopted a comprehensive multitiered approach, combining network pharmacology, machine learning, molecular modeling, and in-vitro experiments, to elucidate the therapeutic targets and mechanisms of TEN in AD. Computational analyses identified mitogen-activated protein kinase kinase 1 (MAP2K1) as a critical target, mediating the effects of TEN. Gene set enrichment analysis indicated that TEN could activate the 26S proteasome pathway, promoting the degradation of neurotoxic proteins, such as amyloid-β (Aβ), thereby reducing their pathological accumulation.

RESULTS: Immune infiltration analysis further revealed that TEN could modulate the distribution of activated natural killer cells and M0 macrophages, playing a role in restoring immune balance in the AD microenvironment. Molecular docking and dynamics simulations demonstrated strong binding affinity and structural compatibility between TEN and MAP2K1. Experimental validation using Aβ-treated SH-SY5Y cells indicated that TEN significantly enhanced cell viability and suppressed MAP2K1 protein expression.

CONCLUSION: In conclusion, this study provided the first integrated evidence that TEN exerts neuroprotective effects in AD by targeting MAP2K1. These findings highlight the multitarget, multipathway therapeutic potential of TEN and support its development as a natural agent for AD prevention and treatment.}, } @article {pmid41458258, year = {2026}, author = {Jing, C and Li, J and Yu, D and Chao, M and Yan, H and Ge, K and Ma, G and Wang, J and Gao, F and Zhang, G}, title = {Heterotrimetallic Au@Cu2Se nanozymes target inflamed neurons via suppression of oxidative stress and apoptosis to alleviate Alzheimer's disease.}, journal = {Materials today. Bio}, volume = {36}, number = {}, pages = {102646}, pmid = {41458258}, issn = {2590-0064}, abstract = {Neuronal dysfunction mediated by oxidative stress and amyloid-β (Aβ) deposition is widely recognized as a core mechanism in the pathogenesis of Alzheimer's disease (AD). Aβ oligomers specifically interact with key mitochondrial proteins-such as alcohol dehydrogenase, cyclophilin D, and ATP synthase-markedly increasing reactive oxygen species (ROS) production, which leads to mitochondrial membrane potential collapse and disruption of energy metabolism. Although cuprous selenide and gold nanospheres can mimic the catalytic activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD), effectively scavenge excess ROS, restore mitochondrial membrane potential, and promote ATP synthesis through synergistic action, their therapeutic potential is limited by poor targeting specificity in vivo. Moreover, while antioxidant nanoagents show promise in mitigating oxidative stress, their non-specific distribution often necessitates high doses, raising potential off-target toxicity concerns and reducing treatment efficacy. Therefore, developing a delivery system that combines multifunctional neuroprotection with precise targeting to diseased microenvironments remains an urgent need. To address this, we functionalized the surface of Au@Cs nanoparticles with hyaluronic acid (HA) to construct a CD44-targeted Au@Cs-HA-PEG nanosystem. By taking advantage of the high expression of CD44 in microglia and astrocytes under inflammatory conditions, the precise targeting of inflammatory regions in the brains of AD model mice was promoted. In vitro experiments demonstrated that Au@Cs-HA-PEG effectively reduced ROS levels in HT22 cells, reversed mitochondrial membrane potential attenuation, and restored neuronal function. In vivo results showed that these nanoparticles achieved rapid brain enrichment, significantly reduced Aβ plaque deposition and neuroinflammation, and markedly improved learning, memory, and cognitive abilities in AD mice. In conclusion, this study confirms that the Au@Cs-HA-PEG nanosystem ameliorates cognitive dysfunction in AD mice by regulating ROS homeostasis, offering a novel strategy and experimental foundation for targeted therapy of Alzheimer's disease.}, } @article {pmid41457950, year = {2025}, author = {Algeciras-Schimnich, A and Theobald, JP and Figdore, DJ and Ashrafzadeh Kian, S and Bornhorst, JA}, title = {False positive plasma p-tau217 results associated with heterophilic antibody interference: A potential clinical pitfall.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e71045}, pmid = {41457950}, issn = {1552-5279}, mesh = {Humans ; *tau Proteins/blood/immunology ; *Alzheimer Disease/blood/diagnosis ; *Antibodies, Heterophile/blood ; False Positive Reactions ; Amyloid beta-Peptides/blood ; Biomarkers/blood ; Immunoassay ; Phosphorylation ; Female ; Male ; Aged ; Peptide Fragments ; }, abstract = {INTRODUCTION: Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as one of the most promising blood-based biomarkers for Alzheimer's disease (AD). While rare, heterophilic antibodies (HAb) are a persistent potential confounding factor in immunoassays.

METHODS: Potential HAb interference in the Lumipulse G pTau217 assay in samples exhibiting concentrations > 10 pg/mL were investigated. Samples were subjected to HAb blocking reagent (HBT), and in some cases, polyethylene glycol (PEG) precipitation and serial dilutions.

RESULTS: In 14 of the 15 suspected HAb cases, HBT treatment greatly reduced measured p-tau217 concentrations. and in one of three specimens selected for further investigation, reduced Aβ42 concentrations PEG precipitation in the three selected samples also reduced p-tau217 concentrations, while serial dilution yielded mixed effects. Control specimens were unaffected by sample treatment or dilutions.

DISCUSSION: HAb may result in falsely elevated p-tau217 and p-tau217/Aβ42 ratio. HAb interference should be considered in cases of unusually high p-tau217 concentrations prior to clinical interpretation.

HIGHLIGHTS: Potential heterophile antibody (HAb) interference in the Lumipulse p-tau217 immunoassay was investigated. Investigation was performed using HAb blocking reagent, and in some cases also using PEG precipitation . Patients with p-tau217 concentrations > 10 pg/mL exhibited positive HAb interference in 14 of 15 cases. HAb interference can lead to falsely positive p-tau217/Aβ42 ratios.}, } @article {pmid41457949, year = {2025}, author = {Chen, Q and Wen, Q and Zhong, T and Liu, J and Gao, H}, title = {Deep cervical lymphaticovenous anastomosis for Alzheimer's disease: A narrative review.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e71038}, pmid = {41457949}, issn = {1552-5279}, support = {No.B2025292//Medical Scientific Research Foundation of Guangdong Province/ ; GMUCR2025-02028//Plan on enhancing scientific research in GMU，Guangdong, China/ ; }, mesh = {Humans ; *Alzheimer Disease/surgery ; *Lymphatic Vessels/surgery ; *Anastomosis, Surgical/methods ; *Glymphatic System/surgery ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder with limited treatment options. Recent discoveries of the glymphatic system and meningeal lymphatic vessels (MLVs) have highlighted their critical role in clearing metabolic waste-including amyloid beta and tau proteins-from the brain. Dysfunction of these systems contributes to AD pathogenesis by impairing the clearance of neurotoxic proteins. Deep cervical lymphaticovenous anastomosis (dcLVA) is an innovative microsurgical technique designed to enhance cerebral waste drainage by anastomosing deep cervical lymphatic channels to adjacent veins. This narrative review synthesizes current evidence on the mechanisms, applications, and emerging perspectives of dcLVA for AD. Early studies suggest potential short-term improvements in cognitive scores and neuroimaging biomarkers after surgery, with an acceptable safety profile. However, the evidence is limited to small prospective cohorts and case reports, underscoring the need for larger, randomized controlled trials to validate its efficacy and long-term benefits. dcLVA represents a promising surgical intervention for select patients, particularly those with moderate-to-severe AD who have failed conventional pharmacotherapy, but it requires careful patient selection and further investigation. HIGHLIGHTS: This review proposes deep cervical lymphaticovenous anastomosis (dcLVA) as a mechanism driven surgery that may enhance clearance of amyloid beta (Aβ) and tau through the brain, meningeal, and deep cervical drainage pathways. Early human evidence from a single arm cohort and case reports suggests short term cognitive and imaging signals with acceptable perioperative safety. dcLVA is not recommended as a first line option for early Alzheimer's disease (AD) and may be considered for moderate to severe AD or for patients who are refractory to pharmacotherapy and have objective evidence of drainage impairment. Standardized patient selection and longitudinal imaging and biomarker monitoring are recommended, including Aβ and tau positron emission tomography (PET), diffusion tensor imaging (DTI) analysis along the perivascular space, and cerebrospinal fluid (CSF) or plasma panels. Systemic safety remains an important uncertainty, and future trials should include longitudinal surveillance of hepatic, renal, and hematologic function. Multicenter randomized controlled trials (RCTs) are urgently needed with 12 month Clinical Dementia Rating Sum of Boxes (CDR SB) as a primary endpoint, transparent reporting, and evaluation of combination strategies with anti Aβ therapies.}, } @article {pmid41457120, year = {2025}, author = {Jiang, T and Ma, W and Dong, W and Zhou, H and Mao, X}, title = {Ferroptosis-associated transcriptional factors in neurological diseases: molecular mechanisms and therapeutic prospects.}, journal = {Experimental & molecular medicine}, volume = {}, number = {}, pages = {}, pmid = {41457120}, issn = {2092-6413}, abstract = {Ferroptosis, a newly discovered type of regulatory cell death with iron-dependent accumulation of lipid peroxides, is widely discussed in a plethora of neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and spinal cord injury. There are many preclinical and clinical evidences supporting the critical role of ferroptosis in these neurologic conditions, despite the molecular machinery by which ferroptosis modulates brain dysfunction remains uncharacterized. Transcription factors (TFs) are core components of the machinery that manipulates ferroptosis process genetically. Until now, there is no report on the summarization of role of ferroptosis-associated TFs in neurological diseases. Therefore, here we provided the basic knowledge regarding the regulation of TFs on ferroptotic processes including iron metabolism, antioxidant defense and lipid peroxidation. In addition, we also discussed the recent advances in our understanding of ferroptosis-related TFs in the emerging hallmarks of neurological diseases. The fact that Nrf2 activator RTA-408 is approved for clinical evaluation (phase 2 clinical trial) of its efficacy and safety in patients with Alzheimer's disease supports this notion. Future research on proteolysis-targeting chimera (PROTAC) and gene therapy holds promise for optimization of neurological disease treatment.}, } @article {pmid41456743, year = {2025}, author = {Tait, S and Fratini, F and Boussadia, Z and Gaddini, L and Marra, M and Le Pera, L and Venturini, G and Ferrante, A}, title = {Investigation of dipyridamole-elicited signaling in the brain of Niemann Pick type C mice: A multi-omic study.}, journal = {Brain research bulletin}, volume = {234}, number = {}, pages = {111708}, doi = {10.1016/j.brainresbull.2025.111708}, pmid = {41456743}, issn = {1873-2747}, abstract = {Niemann Pick type C1 (NPC1) is a rare, fatal disorder characterized by endo-lysosomal (EL) lipid accumulation that leads to damage of both peripheral organs and central nervous system, with cerebellum and hippocampus being particularly affected. Currently very few therapeutic options exist in Europe for NPC. In fact, miglustat is the only approved drug and L-acetylleucine was recently granted for marketing authorization by European Medicine Agency. Thus, the identification of new treatments is mandatory. We have previously demonstrated that dipyridamole (DIP), an approved medicine that is clinically employed as an antiplatelet agent, could rescue recognition memory and increase hippocampal expression of calbindin. On the contrary, the drug was unable to improve cerebellar-dependent motor function. In order to elucidate the mechanism of these region-specific changes induced by DIP, in this work we performed a multi-omic analysis of genes and proteins modulated by the treatment in the hippocampus and cerebellum of a mouse model of NPC1 (Npc1[-/-]). Our results revealed that DIP significantly affected various pathways in the hippocampus at protein level, but it had no significant impact on pathways in the cerebellum (either at gene or protein level). Interestingly, the most affected pathways in the hippocampus of Npc1[-/-] mice administered with DIP were those related to cGMP-PKG activation and to mitochondrial function. Our results paved the way to test DIP in experimental models of other neurodegenerative disorders, such as Alzheimer's disease that is similarly marked by hippocampal and mitochondrial dysfunctions.}, } @article {pmid41456527, year = {2025}, author = {Li, X and Ji, W and Wu, X and Cai, J and Zheng, M and Zhang, X and Liu, P and Wang, G and Li, X and Wang, S and Huo, Z and Wang, Q and Song, Z and Li, D and Zhou, S and Sun, H and Ma, X and Zou, L and Gao, W}, title = {Cerebralcare Granule® restores intracranial lymphatic drainage system to support proactive brain health in Alzheimer's disease models.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {150}, number = {}, pages = {157617}, doi = {10.1016/j.phymed.2025.157617}, pmid = {41456527}, issn = {1618-095X}, abstract = {BACKGROUND: Impairment of the intracranial lymphatic drainage system significantly contributes to Alzheimer's disease (AD) by facilitating the accumulation of neurotoxic amyloid-β (Aβ) and tau proteins. Restoring lymphatic function offers a promising preventive strategy against early-stage AD pathology.

PURPOSE: This study aimed to evaluate the effects and mechanisms of Cerebralcare Granule® (CG), a traditional Chinese medicine formula, on cognitive impairment and pathological markers in AD mouse models by modulating intracranial lymphatic clearance pathways.

METHODS: Six-month-old APP/PS1 transgenic mice and wild-type controls received oral administration of CG or donepezil for two months. Behavioral assessments included the Morris water maze, open field, Y-maze, novel object recognition, and passive avoidance tests. Immunohistochemistry, immunofluorescence, and Western blot analyses were used to assess Aβ deposition, glymphatic clearance, astrocytic aquaporin-4 (AQP4) polarization, meningeal lymphangiogenesis, and blood-brain barrier integrity. Tracer-based in vivo imaging confirmed improved CSF influx and efflux dynamics. Brain-penetrant compounds of CG were identified using UPLC-MS/MS, MALDI-TOF-MS imaging, and network pharmacology.

RESULTS: CG treatment significantly improved cognitive performance, reduced Aβ burden, enhanced glymphatic transport, and promoted meningeal lymphatic drainage in APP/PS1 mice. CG restored perivascular AQP4 polarization, improved cerebrospinal fluid-interstitial fluid exchange, facilitated waste removal to cervical lymph nodes, and protected the integrity of the blood-brain barrier. Major brain-penetrant compounds-paeoniflorin, rhynchophylline, and ethyl gallate-were found to target lymphatic signaling pathways (AQP4, VEGFC, VEGFR3, PROX1) effectively.

CONCLUSION: CG exerts protective effects against cognitive impairment and AD pathology by reinforcing the structural and functional integrity of the intracranial lymphatic drainage system, highlighting a novel therapeutic avenue for proactive brain health management in early-stage AD.}, } @article {pmid41456355, year = {2026}, author = {Haixia, T and Bo, X}, title = {Exercise impact on IRE1α signaling: Novel insights into Alzheimer's disease prevention and treatment.}, journal = {Biochemical and biophysical research communications}, volume = {797}, number = {}, pages = {153156}, doi = {10.1016/j.bbrc.2025.153156}, pmid = {41456355}, issn = {1090-2104}, mesh = {*Alzheimer Disease/prevention & control/therapy/metabolism/pathology ; Humans ; *Signal Transduction ; Endoplasmic Reticulum Stress ; *Endoribonucleases/metabolism ; Animals ; *Protein Serine-Threonine Kinases/metabolism ; *Exercise/physiology ; }, abstract = {Endoplasmic reticulum stress (ERS) and its downstream signaling play a central role in neuroinflammation in Alzheimer's disease (AD). Among them, IRE1α, as a key sensor of ER stress, is a pivotal molecule connecting stress to inflammation. Its aberrant activation drives neuroinflammation, which in turn exacerbates Aβ deposition, Tau pathology, and cognitive decline. Therefore, targeting the IRE1α signaling pathway has become a potential strategy for AD intervention. Recent studies suggest that exercise can alleviate ER stress and directly or indirectly inhibit the excessive activation of IRE1α, thereby reducing its downstream inflammatory signals. This review aims to systematically elucidate the pathogenic mechanism of the IRE1α inflammatory signaling pathway in AD. It also focuses on exploring the evidence of the neuroprotective effect of exercise through regulating this pathway, providing new theoretical basis and direction for exercise-based prevention and treatment of AD.}, } @article {pmid41455872, year = {2025}, author = {Marei, HE}, title = {Epigenetic Editing in Neurological and Neuropsychiatric Disorders: Pioneering Next-Gen Therapeutics for Precision Gene Control.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {330}, pmid = {41455872}, issn = {1559-1182}, mesh = {Humans ; *Epigenesis, Genetic/genetics ; *Gene Editing/methods ; *Nervous System Diseases/genetics/therapy ; Animals ; *Mental Disorders/genetics/therapy ; *Genetic Therapy/methods ; *Precision Medicine/methods ; Epigenome Editing ; }, abstract = {Epigenetic editing has emerged as a promising approach in the treatment of neurological and neuropsychiatric disorders, enabling the precise and enduring modification of genes associated with these conditions. Interventions that focus on chromatin, such as programmable systems like CRISPR/dCas9, zinc-finger proteins, and TALEs linked to epigenetic effector domains, enable the modification of DNA methylation, histone modifications, and noncoding RNA control at specific loci. This work integrates current progress in understanding the epigenetic landscape of neurological neuropsychiatric disorders, highlighting the functions of DNA methylation (de novo vs maintenance, active versus passive demethylation), histone remodeling, and context-dependent gene regulation. We emphasize that the dysregulation of these processes is essential to diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and major psychiatric disorders. Innovative therapeutic approaches, including KRAB- and TET-based repressors, "hit-and-run" epigenome editing, and targeted noncoding RNA regulation, are analyzed alongside translational methodologies that utilize gene therapy vectors, nanoparticle delivery systems, and inducible expression mechanisms. We also examine proof-of-concept studies that demonstrate how to prevent gene expression and alter the transcriptional networks of diseased cells in living organisms. We identify current challenges, including off-target effects, delivery issues, inadequate understanding of long-term stability, and the need for reliable diagnostics, while highlighting the translational promise of combining epigenetic clearance with biogenesis and repair. This review is aimed at providing a comprehensive and critical examination of the molecular principles, therapeutic strategies, and translational obstacles associated with epigenetic editing in neurological and neuropsychiatric disorders, thereby facilitating the development of next-generation precision therapies.}, } @article {pmid41455863, year = {2025}, author = {Elbermawy, Y and El-Desouky, S and Arafa, RK and Elfarrash, S and Bassiouny, A}, title = {Synergistic Neuroprotection in Tauopathic Mice via Green-Synthesized Silver Nanoparticles Co-delivering Methylene Blue and Moringa oleifera.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {331}, pmid = {41455863}, issn = {1559-1182}, mesh = {Animals ; *Methylene Blue/pharmacology/administration & dosage/therapeutic use ; *Moringa oleifera/chemistry ; *Metal Nanoparticles/chemistry/administration & dosage ; *Silver/chemistry/pharmacology ; *Neuroprotective Agents/pharmacology/administration & dosage/therapeutic use ; *Neuroprotection/drug effects ; Mice, Transgenic ; Mice ; *Green Chemistry Technology/methods ; *Tauopathies/drug therapy/pathology/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Plant Extracts/administration & dosage/pharmacology ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited therapeutic options.Most current treatments target only a single pathogenic pathway. We developed an innovative green-synthesized silver nanoparticle formulation for the co-delivery of methylene blue (MB), a tau aggregation inhibitor, and Moringa oleifera (MO) extract, an antioxidant and anti-inflammatory agent. Silver nanoparticles act as multifunctional carriers, improving drug stability and brain delivery, yielding the combined formulation MOMB-Ag-NPs. MOMB-Ag-NPs were synthesized and characterized using ultraviolet-visible spectroscopy (UV-Vis), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy-dispersive X-ray (EDX) analysis. Homozygous P301S tau transgenic mice were assigned to four groups: saline (0.9%, i.p.), MB (4 mg/kg/day, i.p.), MO (260 mg/kg/day, oral), or MOMB-Ag-NPs (4 mg/kg/day MB equivalent, i.p.) for 60 days. In vitro GSK-3β inhibition assays and molecular docking analyses assessed mechanistic interactions. Neuroprotective efficacy was evaluated through survival, behavioral tests, immunohistochemistry, ELISA, and Western blotting. MOMB-Ag-NPs displayed spherical morphology (10-25 nm), high stability, and efficient MB encapsulation (EE 54.7%, DL 93.5%). Both MO and MB inhibited GSK-3β in vitro (IC50 = 9.41 and 65.77 µg/mL), corroborated by molecular docking. In vivo, MOMB-Ag-NPs significantly improved locomotor activity, and cognitive performance. Treated mice showed reduced astrogliosis, decreased pro-inflammatory cytokines (TNF-α, IL-6), enhanced autophagy (LC3β), increased antioxidant defenses (SOD), and differential modulation of the AKT/GSK-3β pathway. This study provides novel evidence that a green-synthesized MB and MO nanoformulation exerts synergistic neuroprotective effects in tauopathy mice, highlighting the translational promise of multitarget strategies for AD treatment.}, } @article {pmid41455134, year = {2026}, author = {Du, O and Wu, YJ and Li, MY and Du, JR}, title = {The role of HMGB1 in central nervous system (CNS) diseases: mechanisms and therapeutic perspectives.}, journal = {Cytokine}, volume = {198}, number = {}, pages = {157099}, doi = {10.1016/j.cyto.2025.157099}, pmid = {41455134}, issn = {1096-0023}, mesh = {Humans ; *HMGB1 Protein/metabolism ; *Central Nervous System Diseases/metabolism/therapy/pathology ; Animals ; Biomarkers/metabolism ; }, abstract = {Central nervous system (CNS) diseases represent a major global health burden and are among the leading causes of disability and mortality worldwide. The pathological mechanisms underlying CNS disorders are complex and multifactorial, involving processes such as neuroinflammation, oxidative stress, neuronal damage, and synaptic dysfunction. High-mobility group box 1 (HMGB1), a member of the high-mobility group box (HMGB) protein family, is predominantly localized in the nucleus under physiological conditions, where it contributes to DNA repair, transcriptional regulation, and other cellular functions. However, in various CNS pathologies-including stroke, traumatic brain injury (TBI), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), glioblastoma (GBM), epilepsy, depression, multiple sclerosis (MS), and schizophrenia-HMGB1 is released or secreted into the extracellular space. There, it plays a key role in regulating neuroinflammation, cell death, cell migration, and tissue damage and repair, thereby contributing to disease pathogenesis and progression. HMGB1 not only functions as a critical regulator in the progression of CNS diseases but also serves as a biomarker for predicting poor clinical outcomes. Moreover, a growing body of evidence indicates that therapeutic strategies targeting HMGB1 can significantly alleviate pathological damage in various CNS disorders, highlighting its potential as a promising therapeutic target. This review comprehensively summarizes the structure, post-translational modifications, release mechanisms, and receptor systems of HMGB1, along with its roles and mechanisms in CNS diseases. It also discusses the potential of HMGB1 as a biomarker and examines emerging HMGB1-targeted therapeutic strategies, aiming to provide a theoretical foundation for the treatment and drug development of CNS disorders.}, } @article {pmid41454738, year = {2025}, author = {Takeda, T and Toritsuka, M and Tamakoshi, H and Iwata, N and Makinodan, M}, title = {Immune involvement in neuropsychiatric disorders: Insights from single-cell transcriptomic studies.}, journal = {Psychiatry and clinical neurosciences}, volume = {}, number = {}, pages = {}, doi = {10.1111/pcn.70018}, pmid = {41454738}, issn = {1440-1819}, support = {JPMJMS239F-1-2//Moonshot Research and Development Program/ ; 21gm6310015h0002//Japan Agency for Medical Research and Development/ ; 21uk1024002h0002//Japan Agency for Medical Research and Development/ ; 21wm04250XXs0101//Japan Agency for Medical Research and Development/ ; 22gm1510009h0001//Japan Agency for Medical Research and Development/ ; 24gm1910004s0402//Japan Agency for Medical Research and Development/ ; 24wm0625510h0001//Japan Agency for Medical Research and Development/ ; 23H04173//Japan Society for the Promotion of Science/ ; 24K02386//Japan Society for the Promotion of Science/ ; }, abstract = {Neuropsychiatric disorders pose profound challenges to both research and treatment, largely due to their clinical heterogeneity and the limited understanding of their underlying biological mechanisms. While bulk RNA sequencing (bulk RNA-seq) has been widely used to study gene expression, it cannot resolve cell-type-specific signals or detect rare cellular subpopulations. In contrast, single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) have emerged as transformative technologies, enabling transcriptomic profiling at single-cell resolution. These approaches have revealed immunological alterations across a wide range of disorders. This review introduces recent findings from sc/snRNA-seq studies of immune-related mechanisms in psychiatric disorders-including schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder-as well as in neurological conditions such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple sclerosis, and anti-NMDA receptor encephalitis. While sc/snRNA-seq overcome averaging effects of bulk RNA-seq by resolving cell types, these methods still face challenges. We outline a roadmap that integrates bulk RNA-seq and sc/snRNA-seq to mitigate the remaining gaps.}, } @article {pmid41454086, year = {2025}, author = {Mi, X and Shan, K and Ye, X and Cheng, R}, title = {AAD-2004 through clearing H2O2 reduces astrocyte proliferation and promotes neural regeneration after spinal cord injury.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-025-33322-x}, pmid = {41454086}, issn = {2045-2322}, support = {ZKKY2023003//Zhejiang Medical Association/ ; 2024KY658//Scientific Research Program of Zhejiang Medical Technology/ ; }, abstract = {To assess the effect of AAD-2004 on spinal cord injury (SCI) and to explore its mechanism, we employed an in vitro model using OGD/R-challenged astrocytes to investigate the effects of AAD-2004 against cell death (terminal deoxynucleotidyl transferase dUTP nick-end labeling, tunel), oxidative stress (H2O2 level), and the expression of the key neuroprotective factor MAP2.AAD-2004[2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] is a hydrogen peroxide(H2O2) scavenger primarily used for the treatment of amyotrophic lateral sclerosis and Alzheimer disease that has demonstrated certain neuroprotective properties. In parallel, modified allen's method was adopted, further exploring the potential molecular mechanism in vivo. Based on these conditions, histological and behavioral analysis were performed by Nissl staining, basso mouse scale and footprint analysis. The level of molecules associated with glial scar formation, nerve regeneration, axonal regeneration and H2O2 level were analyzed using western blot, immunofluorescence staining and H2O2 kit. AAD-2004 significantly improved the movement function after SCI and inhibited the proliferation of astrocytes, thus preventing the formation of glial scar by inhibiting of H2O2. At the same time, AAD-2004 promoted nerve regeneration, and the effect was due to neuronal regeneration and axonal regeneration pathways. The expression levels of GFAP and vimentin were significantly downregulated in AAD-2004-treated, and the expression level of Ki67 and PH3 were downregulated. The mean fluorescence intensity of neuronal regeneration (Neun[+]and MAP2[+]) and axonal regeneration-related (NF[+] and GAP43[+]) were significantly upregulated after AAD-2004 treatment. Scavenging H2O2 level is a viable therapeutic strategy, and that AAD-2004 is prospective, and that scavenging H2O2 facilitated nerve regeneration and inhibited glial scar formation for SCI.}, } @article {pmid41453655, year = {2026}, author = {Basri, R and Al-Kuraishy, HM and Fawzy, MN and Alruwaili, M and Batiha, GE}, title = {PACAP: A promising disease-modifying target for Alzheimer's disease.}, journal = {Life sciences}, volume = {386}, number = {}, pages = {124176}, doi = {10.1016/j.lfs.2025.124176}, pmid = {41453655}, issn = {1879-0631}, mesh = {*Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism ; Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Blood-Brain Barrier/metabolism ; }, abstract = {Alzheimer's disease (AD) is a significant public health threat, and current therapeutic approaches provide only minimal symptomatic benefit without slowing its progression. This review covers evidence for the expanding involvement of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide with significant and consistent neuroprotective properties in various experimental models of AD. We consolidate evidence that PACAP works via multiple pathways to negate primary pathological events in AD by shifting the metabolism of amyloid precursor protein from the amyloidogenic into non-amyloidogenic, inhibiting tau hyperphosphorylation, controlling neuroinflammation, and promoting synaptic plasticity. The reduced level of PACAP in clinical studies of AD patients supports its therapeutic relevance. Although concerns about PACAP pharmacokinetics and blood-brain barrier (BBB) penetration persist as serious obstacles, recent development of stable analogs and innovative delivery systems holds promise for circumventing these limitations. We also consider how established drugs (metformin, linagliptin, and statins) might provide a degree of neuroprotection in part-seeking through PACAP-related pharmacology. Taken together, the cumulative available evidence places PACAP not only as yet another promising therapeutic candidate but rather as a master regulator of neuroprotection, tackling AD's multifaceted nature. Restoration of PACAP signaling is a very distinct method to intervene in disease development, which offers immeasurable benefit in comparison to symptom relief treatment.}, } @article {pmid41452714, year = {2025}, author = {Zhang, J and Zhu, D and Hu, M and Pan, M and Chen, C}, title = {A Combination of Low-Dose Δ[9]-THC and Celecoxib as a Therapeutic Strategy for Alzheimer's Disease.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.1206}, pmid = {41452714}, issn = {2152-5250}, abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the elderly, and no effective therapies are currently available to prevent, treat, or halt its progression. Δ[9]-Tetrahydrocannabinol (Δ[9]-THC), the primary psychoactive compound in marijuana, has been considered a potential therapeutic agent, but clear evidence for its ability to prevent cognitive decline is lacking. Previous studies have demonstrated that Δ[9]-THC-induced cognitive impairments are associated with the induction of cyclooxygenase-2 (COX-2). In this study, we aimed to evaluate whether Δ[9]-THC alone or in combination with Celecoxib, a selective COX-2 inhibitor, could reduce neuropathology and improve cognitive function in AD model animals. We observed that Δ[9]-THC (3.0 mg/kg), either alone or with Celecoxib (1.0 mg/kg), significantly reduced Aβ and tau pathologies, enhanced synaptic marker expression, and prevented the onset of cognitive decline. Notably, the combination treatment produced greater improvements in spatial learning and effectively mitigated Δ[9]-THC-induced neuroinflammatory responses. Furthermore, Δ[9]-THC reversed or attenuated the dysregulated expression of synaptic and immune/inflammation-related genes and restored the downregulated expression of genes linked to AD observed in both AD patients and AD animal models, with greater efficacy when combined with Celecoxib in AD model mice. These findings suggest that the combination of low-dose Δ[9]-THC and Celecoxib holds promise as an early intervention strategy for preventing AD onset or treating mild cognitive impairment (MCI). Importantly, both Δ[9]-THC (in the form of Dronabinol and Nabilone) and Celecoxib are FDA-approved medications already in clinical use, supporting the strong translational potential of this combination therapy and its feasibility for rapid advancement to clinical trials to assess its efficacy in preventing or delaying AD onset in humans.}, } @article {pmid41452429, year = {2025}, author = {Heidari, Z and Zakaee, A and Vafadar, A and Alavimanesh, S and Charami, H and Jamali, Z and Jahromi, AH and Rakhsha, A and Savardashtaki, A}, title = {An overview of gene and cell therapy approaches for Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {10}, pmid = {41452429}, issn = {1573-7365}, mesh = {*Alzheimer Disease/therapy/genetics ; Humans ; *Genetic Therapy/methods ; *Cell- and Tissue-Based Therapy/methods ; Animals ; }, abstract = {Alzheimer's disease (AD), acknowledged as the leading cause of dementia, is defined by the accumulation of amyloid plaques and neurofibrillary tangles (NFTs) in the brain. This condition presents a significant challenge to global health due to its complex and multifaceted characteristics. Pharmacological treatments for AD mainly focus on relieving symptoms instead of addressing the fundamental progression of the condition. Currently, there are three cholinesterase inhibitors (ChEIs) that can be used for the treatment of AD: donepezil, rivastigmine, and galantamine, along with the N-methyl-D-aspartate (NMDA) receptor antagonist memantine. Although these medications can improve cognitive function and assist patients in their daily activities, it is crucial to understand that they do not halt the progression of the disease itself. Recently, innovative therapeutic strategies have been introduced for the treatment of this disease. Cell and gene therapies hold remarkable potential for the treatment of AD. Gene therapy, in particular, enables the precise modulation of AD-related genes, enhances neuroprotective factors, and mitigates the accumulation of amyloid plaques. Additionally, cell-based therapies utilizing mesenchymal stromal cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) are designed to replace lost neurons, modulate immune responses, and restore functional neural networks. Together, these innovative techniques represent significant advancement in the treatment of AD, instilling hope for enhanced patient outcomes and a higher quality of life. In this review, we emphasize the innovative cell and gene strategies, along with in vitro and preclinical studies, that explore the potential of gene and cell-based therapies as treatments for AD.}, } @article {pmid41452267, year = {2025}, author = {Cai, X and Huang, Y and Wang, T and Gao, J and Tang, Y and Zhu, C and Rong, S}, title = {Mesoporous PdPt Nanozymes with Target Peptides and Cascade Reactive Oxygen Species Scavenging for Boosting Alzheimer's Disease Treatment.}, journal = {ACS nano}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsnano.5c17413}, pmid = {41452267}, issn = {1936-086X}, abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disease that has become a major health problem nowadays. Inhibiting the aggregation of amyloid-β (Aβ) peptides has made progress in AD treatments. Here, we synthesized mesoporous PdPt nanozymes to immobilize target peptide KLVFFAED for high-efficiency AD treatment. Thanks to the high surface area of the mesoporous nanospherical structure of PdPt nanozymes, lots of KLVFFAED were grafted with a concentration as high as 439.2 μg mL[-1], amplifying inhibition activity against Aβ aggregations. Importantly, the system has a pre-eminent photothermal property in the near-infrared region and exhibits the ability to photothermally disintegrate Aβ aggregates. Moreover, the integrated superoxide dismutase/catalase mimetic activity of PdPt nanozymes also achieves cascade reactive oxygen species (ROS) scavenging to alleviate oxidative stress and neuroglial damage, thus delaying the progression of AD. Therefore, the designed system can simultaneously block Aβ aggregation, destabilize Aβ fibrils, and clear ROS, which together enhance the therapeutic effects, providing important insights into the applications of nanozymes for AD therapy.}, } @article {pmid41451887, year = {2025}, author = {Lynch, SY and Jia, J and Miles, N and Boiser, J and Buhl, DL and Graff, O and Zadikoff, C}, title = {ABBV-552 in patients with mild Alzheimer's disease: a randomized phase IIb trial.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70994}, pmid = {41451887}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Aged ; Female ; Middle Aged ; Aged, 80 and over ; Double-Blind Method ; Treatment Outcome ; Dose-Response Relationship, Drug ; Mental Status and Dementia Tests ; }, abstract = {INTRODUCTION: This proof-of-concept, dose-finding phase IIb trial evaluated treatment with ABBV-552 compared with placebo in participants with clinically diagnosed mild Alzheimer's disease (AD).

METHODS: Participants aged 50 to 90 years with a Mini-Mental State Examination score of 20 to 26 and a global Clinical Dementia Rating score of 0.5 to 1.0 were randomized 1:1:1:1 to placebo or ABBV-552 (1, 5, or 15 mg) daily. The primary endpoint was the change from baseline in the 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 14) at week 12.

RESULTS: Two hundred sixty-three participants were randomized. The least-squares mean difference (vs placebo) in change from baseline at week 12 in ADAS-Cog 14 total score (95% confidence interval) for ABBV-552 1 mg was -0.02 (-1.87, 1.83), nominal p = 0.9819; 5 mg, -0.42 (-2.25, 1.42), nominal p = 0.6545; 15 mg, 0.25 (-1.58, 2.08), nominal p = 0.7860. Treatment-emergent adverse events occurred in 48.5% of ABBV-552 recipients versus 42.2% in the placebo group; no safety concerns were identified.

DISCUSSION: ABBV-552 did not demonstrate a meaningful difference versus placebo on the primary endpoint.

HIGHLIGHTS: ABBV-552 is a small molecule that modulates the SV2A receptor in neurons ABBV-552 may enhance synaptic efficiency leading to improved cognition in patients with Alzheimer's disease (AD) Participants with mild AD were treated with either placebo, 1 mg, 5 mg, or 15 mg of ABBV-552 covering an estimated 35% to 80% SV2A receptor occupancy in a phase II randomized clinical trial Results failed to show efficacy over placebo as measured by ADAS-Cog 14 at week 12 ABBV-552 was generally safe and well tolerated.}, } @article {pmid41451871, year = {2025}, author = {Yang, T and Huhe, H and Williams, SP and Kaur, S and Ay, YA and Davis-Gilbert, ZW and Cary, GA and Paisie, C and Butler, RR and Wiley, J and Betarbet, R and Fu, H and Duong, D and Seyfried, NT and Leal, K and Carter, GW and Edwards, A and Levey, AI and Capener, JL and Drewry, DH and Hossain, MA and Oh, HJ and Axtman, AD and Sukoff Rizzo, SJ and Longo, FM and , }, title = {PAK1 inhibitor NVS-PAK1-1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e71033}, pmid = {41451871}, issn = {1552-5279}, support = {U54 AG065187/AG/NIA NIH HHS/United States ; //PhRMA Foundation/ ; //Archer Fund/ ; //Jean Perkins Foundation/ ; //NIH grants NIA U54AG065187/ ; //Applebaum Foundation Fund/ ; //The SGC is a registered charity that receives funds from Bayer AG, Boehringer Ingelheim/ ; }, mesh = {Animals ; *Dendritic Spines/drug effects/pathology/metabolism ; *p21-Activated Kinases/antagonists & inhibitors/metabolism ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; Mice, Transgenic ; *Alzheimer Disease/pathology/metabolism/drug therapy ; *Neurons/drug effects/metabolism ; Hippocampus/drug effects/pathology ; Disease Models, Animal ; Mice ; Female ; Humans ; Dibenzazepines ; Pyrrolidines ; }, abstract = {INTRODUCTION: Synaptic spine loss in Alzheimer's disease (AD) contributes to cognitive decline. p21-activated kinase 1 (PAK1), a regulator of spine integrity, is aberrantly activated in AD. We investigated whether PAK1 inhibition might preserve dendritic spines in vitro and in vivo.

METHODS: Oligomeric amyloid beta (oAβ) or tau (oTau) were applied to hippocampal neurons ± NVS-PAK1-1, a selective PAK1 inhibitor. NVS-PAK1-1 was orally administered to 5xFAD mice. The effects of NVS-PAK1-1 treatment on PAK1 activity, spine density, and the proteome were assessed using phospho-PAK1 (pPAK1) western blotting, Golgi staining, and mass spectrometry for proteomic analyses.

RESULTS: NVS-PAK1-1 prevented oAβ and oTau-induced spine loss in vitro. In 5xFAD mice, NVS-PAK1-1 demonstrated brain exposure after oral administration and reduced PAK1 activation, prevented spine loss, and partially normalized synaptic proteomic signatures in females in absence of alterations in brain or plasma Aβ.

DISCUSSION: PAK1 inhibition enhances spine resilience in AD models, supporting its therapeutic potential.

HIGHLIGHTS: p21-activated kinase 1 (PAK1) inhibitors prevent oligomeric amyloid beta (oAβ) and oligomeric tau-induced spine loss and dendritic degeneration in cultured mouse hippocampal neurons. NVS-PAK1-1, a selective PAK1 inhibitor, protects against oAβ-induced spine loss in a dose-dependent manner (EC50 = 2 nM). Oral administration of NVS-PAK1-1 achieves brain penetration and bioavailability in normal CD-1 mice, and target engagement in 5xFAD mice. Chronic NVS-PAK1-1 treatment mitigates spine loss in the somatosensory cortex of 6-month-old 5xFAD female mice. Chronic treatment with NVS-PAK1-1 restores proteomic abundance of actin cytoskeleton and dendritic spine-associated proteins, including cofilin 2 and pyruvate dehydrogenase kinases, downstream of PAK1 in young 5xFAD female mice showing spine resilience. Clinical oncology trials with other PAK1 inhibitors support potential repurposing or novel compound development for Alzheimer's disease trials.}, } @article {pmid41451412, year = {2025}, author = {Li, S and Qian, W and Zhang, Z and Chen, Y and Hou, X and Min, B and Zhou, H and Zhu, X and Ling, J and Yang, W and Cao, S}, title = {Comprehensive safety assessment of donepezil: pharmacovigilance analysis based on the FDA adverse event reporting system.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1655216}, pmid = {41451412}, issn = {1664-2295}, abstract = {BACKGROUND: Alzheimer's disease (AD) has a growing global prevalence, and the need for safe and effective treatments is urgent. Donepezil is commonly used therapeutic agents for AD but has safety controversies. The objective of this study was to thoroughly evaluate donepezil's adverse event profile using actual data.

METHODS: In this study, reports of donepezil-related adverse events were collected from the first quarter of 2004 to the fourth quarter of 2024 through the FAERS database. The association of donepezil-induced adverse events was disproportionality analyzed using Reporting odds Ratios (ROR) and Proportional Reporting Ratio (PRR) and Bayesian Confidence Propagation Neural Network (BCPNN) and Multi-item Gamma Poisson Shrinker (MGPS), among other methods.

RESULTS: A total of 26,120 ADRs with donepezil as the "first suspect" were retrieved during the reporting period. The most common AEs included nausea, vomiting, syncope, and dizziness, which were consistent with the labeling of the medication and clinical trials. Unintended major AEs such as fall, hypotension, tremor, cognitive disorder, mania, and the highest signal of pleurothotonus were also detected. The reports also collected were characterized by a high proportion of female patients (51.3%) and the time of AE induction within 30 days (41%).

CONCLUSION: Donepezil treatment needs to focus on cardiovascular and neurological adverse events, especially for women, elderly patients, or patients with co-morbidities, cardiac monitoring and dose adjustment should be strengthened. Clinics need to balance efficacy and risk, develop individualized dosing regimens, and explore novel therapeutic strategies to improve long-term safety.}, } @article {pmid41450657, year = {2025}, author = {Zhao, Y and Xi, E and Wang, Z and Gao, N and Sun, H and Zhu, G}, title = {Nanoamplifier Agents Transiently Rise the Metabolism of β‑Amyloid Peptide in Urine for the Early Diagnosis of Alzheimer's Disease.}, journal = {JACS Au}, volume = {5}, number = {12}, pages = {6169-6178}, pmid = {41450657}, issn = {2691-3704}, abstract = {Alzheimer's disease (AD) is the most common form of dementia without effective treatment. Therefore, early diagnosis for timely treatment and delayof the onset of AD are critical. At present, detecting β-amyloid (Aβ) in cerebrospinal fluid is still the most important clinical method. However, the invasive detection method is harmful and difficult to promote. Recent research has shown that Aβ was found not only in blood and cerebrospinal fluid, but also in urine, which could be used for noninvasive testing. Compared with blood/cerebrospinal fluid, the background proteins in urine are very low, but unfortunately the content of Aβ is even lower. Therefore, if the concentration of Aβ is increased with the background proteins maintained at the low level, urine could be an ideal noninvasive early detection target for AD. Gold nanoparticles (AuNP) with ultrasmall size (<6 nm) could be rapidly metabolized by the kidneys and excreted with urine, and easily regulated by the metabolic pathway between kidneys and liver by changing their size. After screening, we found 3 nm AuNP had the highest renal metabolic efficiency, and by modifying with kidney targeting peptides and Aβ antibody 6E10, the complex system (P6-Au) acted as a "Aβ-targeting renal metabolic carrier", which both metabolized rapidly through the kidneys and increased the concentration of Aβ in urine. After tail vein injection of P6-Au, the Aβ content in the urine of 5×FAD transgenic mice increased by more than 20 times within the next 24 h, which resulted in the diagnosis time being advanced from the ninth month to the fifth month and provided a new approach for early detection of AD.}, } @article {pmid41450541, year = {2025}, author = {Chen, C and Shao, Q and Zhou, S}, title = {Exploring the Mahuang Fuzi Xixin Decoction's mechanism for treating Alzheimer's disease using molecular docking and network pharmacology.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1688316}, pmid = {41450541}, issn = {1663-4365}, abstract = {OBJECTIVE: Explore the potential mechanism of Mahuang Fuzi Xixin Decoction (MFXD) in the treatment of Alzheimer's disease (AD) using network pharmacology, molecular docking approaches, and test its efficacy by in vitro experiments.

METHODS: Active components of MFXD were screened from TCMSP, BATMAN-TCM, and TCMID, with corresponding targets obtained from SwissTargetPrediction and TCMSP. AD-related differential genes were retrieved from GEO. Intersection targets were identified via Venn diagrams, followed by GO/KEGG enrichment analyses, PPI network construction, and molecular docking. In vitro validation experiments were carried out using PC12 cells induced by Aβ25-35 to simulate the pathological state of AD. For the detection of cell viability, the CCK-8 assay was employed to evaluate the protective effect of MFXD and its active components on damaged PC12 cells. Western blot analysis was used to determine the protein expression levels of key molecules involved in AD-related signaling pathways, including phosphorylated p-NF-κB p65, NF-κB p65, p-GSK-3β, GSK-3β, MMP-9, p-Tau, and Tau. Additionally, the ELISA was utilized to measure the secretion level of TNF-α in the supernatant of Aβ25-35-induced PC12 cells, so as to assess the anti-inflammatory effect of MFXD.

RESULTS: Thirty-seven active components and 230 targets of MFXD were identified, along with 4913 AD-related differentially expressed genes from GEO dataset GSE122063, yielding 47 intersection targets. GO annotation enriched these targets in processes like reactive oxygen species metabolism, components like extracellular matrix, and functions like neurotransmitter binding; several pathways were enriched in the KEGG analysis, such as TNF signaling pathway, calcium signaling pathway, and NF-κB signaling pathway. The intersection target PPI network identified MMP9, EGFR, FOS as core targets. Molecular docking results indicated that quercetin binds to the three core targets (MMP9, EGFR, FOS), while luteolin binds preferentially to EGFR and MMP9. In vitro, Aβ25-35-induced PC12 cells treated with quercetin/luteolin had concentration-dependent viability increases (all P < 0.001); 15% MFXD-containing serum restored viability to ≥ 95% (P < 0.001 vs. AD model, comparable to DHCL). Western blot showed AD model had elevated p-NF-κB p65/NF-κB p65, MMP9/β-actin, p-Tau/Tau and reduced p-GSK-3β/GSK-3β (all P < 0.05); MFXD reversed these (all P < 0.05), while DHCL only inhibited p-NF-κB p65/NF-κB p65. ELISA showed MFXD and DHCL both reduced AD model's TNF-α (all P < 0.001).

CONCLUSION: MFXD potentially exerts anti-AD effects through a multi-component, multi-target, multi-pathway approach. Its key active components (quercetin, luteolin) may act by modulating the core target MMP9. Also, MFXD can simultaneously regulate several pathways, such as the TNF signaling pathway, Calcium signaling pathway, and NF-κB signaling pathway, and target Tau protein-related pathology by restoring the phosphorylation level of GSK-3β to suppress abnormal hyperphosphorylation of Tau, and thereby alleviating pathological damage in AD.}, } @article {pmid41449667, year = {2025}, author = {Günaydin, C and Hackett, NR and Wakim, V and Sondhi, D and Kaminsky, SM and Crystal, RG}, title = {Prime Editing of Alzheimer's Disease High-Risk APOE4 Allele by Brain-Directed Adeno-Associated Virus Vectors.}, journal = {Human gene therapy}, volume = {}, number = {}, pages = {}, doi = {10.1177/10430342251401888}, pmid = {41449667}, issn = {1557-7422}, abstract = {Common variants of the apolipoprotein E (APOE) gene have a major impact on the risk of developing Alzheimer's disease (AD). Relative to homozygotes with the common E3 allele, the APOE4 variant (C112R) increases risk by 3.5-fold in E3/E4 heterozygotes and 15-fold in E4 homozygotes. Since the E3 and E4 alleles differ only by a single nucleotide, gene editing of E4 to E3 is a potential strategy to reduce AD risk in E4 homozygotes. Because the APOE pool in the brain is separate from systemic APOE, editing to treat AD would ideally be directed to the brain. Following in vitro optimization of prime editing guide RNAs, efficient prime editing expression cassettes were inserted into the adeno-associated virus (AAV) split-intein system and packaged into pairs of AAV vectors for in vivo editing. The AAV vectors were administered to human homozygous APOE4-targeted replacement mice (TRE4), and APOE4 to APOE3 editing efficiency was assessed after 4 weeks. The prime editing construct designated APOE3/4-3_10 was the most efficient at APOE4 to APOE3 conversion, both in liver following intravenous delivery and in brain following intrahippocampal delivery. To assess brain-wide editing, two AAV capsids were compared, including AAVrh.10 with administration either directly to the hippocampus or to the cerebrospinal fluid via the cisterna magna and AAV-CAP.B10 administered intravenously. Other than minor differences in APOE4/3-3_10 mediated E4 to E3 editing in the cerebellum, the different capsids and routes yielded similar editing efficacy throughout the brain. This may represent a candidate treatment to reduce the risk of AD.}, } @article {pmid41448751, year = {2025}, author = {Liu, S and Wang, L and Li, S and Xu, G}, title = {[Effects of 40 Hz light flicker stimulation on hippocampal-prefrontal neural activity characteristics during working memory tasks in Alzheimer's disease model rats].}, journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi}, volume = {42}, number = {6}, pages = {1107-1114}, pmid = {41448751}, issn = {1001-5515}, mesh = {Animals ; *Alzheimer Disease/physiopathology/therapy ; *Memory, Short-Term/physiology/radiation effects ; *Prefrontal Cortex/physiopathology ; *Hippocampus/physiopathology/physiology ; Rats, Wistar ; Rats ; Disease Models, Animal ; Male ; *Photic Stimulation ; Maze Learning ; }, abstract = {40 Hz light flicker stimulation is deemed to hold considerable promise in the treatment of Alzheimer's disease (AD). However, whether its long-term effect can improve working memory and its related mechanisms remains to be further explored. In this study, 21 adult Wistar rats were randomly divided into the AD light-stimulation group, the AD group and the control group. AD models were established in the first two of these groups, with the light-stimulation group receiving long-term 40 Hz light flicker stimulation. Working memory performance across groups was subsequently evaluated using the T-maze task. To investigate the potential neural mechanisms underlying the effects of 40 Hz light stimulation on working memory, we examined changes in neuronal excitability within the hippocampus (HPC) and medial prefrontal cortex (mPFC), as well as alterations in inter-regional synchronization of neural activity. The findings demonstrated that prolonged 40 Hz light stimulation significantly improved working memory performance in AD model rats. Furthermore, the intervention enhanced the synchronization of neural activity between the hippocampus (HPC) and medial prefrontal cortex (mPFC), as well as the efficiency of information transfer, primarily mediated by theta and low-frequency gamma oscillations. This study provides theoretical support for exploring the mechanisms of 40 Hz light flicker stimulation and its further clinical application in the prevention and treatment of Alzheimer's disease.}, } @article {pmid41448509, year = {2026}, author = {Kim, N and Jeon, JY and Seo, J and Lee, Y and Kim, HJ and Kim, JS}, title = {A combined model of convolutional neural networks and graph attention networks for improved classification of mild cognitive impairment.}, journal = {NeuroImage}, volume = {325}, number = {}, pages = {121674}, doi = {10.1016/j.neuroimage.2025.121674}, pmid = {41448509}, issn = {1095-9572}, mesh = {Humans ; *Cognitive Dysfunction/classification/diagnostic imaging ; Magnetic Resonance Imaging/methods ; Aged ; Male ; *Neural Networks, Computer ; Female ; Deep Learning ; Aged, 80 and over ; Alzheimer Disease/diagnostic imaging ; Middle Aged ; Brain/diagnostic imaging ; Convolutional Neural Networks ; }, abstract = {Mild cognitive impairment (MCI), a precursor of Alzheimer's disease (AD), underscores the importance of early diagnosis and treatment. With an aging global population, AD prevalence is rising, necessitating more precise diagnostic methods. Deep learning technology shows promise for MCI and AD classification, but existing convolutional neural network (CNN) and graph attention network (GAT) models have limitations in capturing brain structural features and detecting microlesions. To address these issues, we propose a novel approach combining a CNN and modified GAT model to improve MCI classification. Magnetic resonance imaging volume data were analyzed using a CNN, whereas cortical thickness data were modeled using a GAT, leveraging their complementary strengths. Preprocessing involved extracting brain's structural features via the CIVET pipeline, and t-SNE was used to visualize the data's high-dimensional distribution. Final classification was performed using a multilayer perceptron, integrating feature vectors from both models. Performance evaluation metrics included the area under the curve (AUC), F1-score, sensitivity, and specificity. The combined CNN-GAT model outperformed existing single-model approaches, particularly in MCI classification, effectively distinguishing subtle variations between normal aging and MCI. The combined CNN-GAT model improved MCI classification performance by addressing the limitations of existing approaches. By capturing brain structural features and inter-regional relationships, it offers significant potential for advancing early diagnosis and treatment strategies for neurodegenerative diseases. Future efforts will focus on enhancing performance through additional data optimization.}, } @article {pmid41447429, year = {2025}, author = {Chandrasekaran, A and Malek-Ahmadi, M and Decourt, B and Sabbagh, MN}, title = {Informant-Based Questionnaires in the Diagnostic Pathway for Screening of Cognitive Impairment.}, journal = {Neurology and therapy}, volume = {}, number = {}, pages = {}, pmid = {41447429}, issn = {2193-8253}, abstract = {Alzheimer's disease (AD) remains the most common form of dementia in elderly populations. Accurately diagnosing early forms of dementia and AD remains a significant clinical challenge, especially in fast-paced primary care settings. Informant-based questionnaires that rely on close caregivers of the patients, such as the Informant Questionnaire on Cognitive Decline in the Elderly, the Ascertain Dementia 8-Item, the Quick Dementia Rating System, and the Alzheimer's Questionnaire, have recently been shown to be a valuable supplement to current standards of diagnosis, such as performance-based tests. This review aimed to explore the key characteristics of various informant-based questionnaires and evaluate their efficacy in the medical setting. Analysis of each test demonstrated that informant-based assessments show a strong ability to detect cognitive impairment early on in its pathology and can highlight gradual decline over time, compared with the single-timeframe evaluations that performance-based tests provide. Informant-based questionnaires are also able to circumvent challenges associated with the patient's education level, language, and other cultural biases, thus making them useful in diverse populations. When used in conjunction with performance tests, informant-based tests can significantly streamline the diagnostic process for dementia and enhance management and treatment strategies. Further research is advised to effectively integrate these tests into routine clinical practice and establish a new standard of care.}, } @article {pmid41446880, year = {2025}, author = {van Brummelen, R and van Brummelen, AC}, title = {The role of neuro-supportive substances of natural origin in neurological conditions-A literature-based formulators' perspective.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1647092}, pmid = {41446880}, issn = {1664-2295}, abstract = {Products of natural origin are seldom tested up to a point of full acceptance, mainly due to a lack of financial viability for commercialization. Yet many come with a rich history of use and proof of concept testing. We investigated literature regarding the possible role and function of the best known of these nutraceuticals in relationship to three neurological conditions i.e. stroke, Alzheimer's - (AD) and Parkinson's disease (PD), and their potential as supportive therapies. Current studies suggest that citicoline has a neuroprotective effect in ischemic conditions, playing a role in the restoration of the barrier function of endothelial cells, activating repair mechanisms and possibly decreasing ischemic lesion size in stroke, as well as increasing dopamine availability in PD. Citicoline was also demonstrated to increase the levels of sirtuin 1 (SIRT1), thus reducing inflammation-leading to improved cognitive status and a better quality of life in cognitive impairment. N-Acetylcysteine (NAC) shows pro-cognitive effects, increasing glutathione (GSH) levels that are decreased in AD and PD patients, possibly decreasing neuroinflammation. Mechanistic studies indicate the potential neuroprotective and neurorestorative effects of resveratrol by its anti-inflammatory and anti-apoptotic activity, also increasing SIRT1 levels and promoting the outgrowth of neurite protrusions and synaptogenesis. Curcumin's anti-inflammatory effects via inhibition of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) can potentially delay progression of PD. Some nutraceuticals, e.g., citicoline, show synergism in combination with current therapies. We propose a renewed, risk-benefit approach for inclusion of the investigated nutraceuticals with limited indications in certain neurological treatment regimens.}, } @article {pmid41446876, year = {2025}, author = {Sun, Y and Chen, D and Ye, Q and You, Z and Zhao, Z and Shi, J and Sun, H and Li, S and Xu, X and Xu, Y and Zhang, P and Tang, Z}, title = {Applications of Endovascular Brain-Computer Interface in Patients with Alzheimer's Disease.}, journal = {Research (Washington, D.C.)}, volume = {8}, number = {}, pages = {1049}, pmid = {41446876}, issn = {2639-5274}, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the elderly, leading to important impairments in cognitive function and the ability to live independently. This results in substantial disability and places an increasing burden on families and society. Currently, the therapeutic approaches adopted in clinical practice predominantly hinge upon cholinesterase inhibitors and the N-methyl-d-aspartate (NMDA) receptor antagonist memantine. Nevertheless, these medications merely alleviate symptoms and fail to tackle the pathological characteristics of AD. In recent years, monoclonal antibodies such as lecanemab and donanemab against β-amyloid (Aβ) have shown good efficacy in clinical practice for early-stage AD patients. However, the early diagnosis of AD remains a challenge. Against this backdrop, endovascular brain-computer interface (EBCI) offers an integrated solution for the early diagnosis and neuroregulatory treatment of AD patients, with minimal invasiveness. This review comprehensively examines the safety and feasibility of EBCI for AD patients, focusing on 3 major application areas: early diagnosis, deep brain stimulation targeting specific brain regions, such as the fornix and the basal nuclei of Meynert, and the use of external neurofeedback devices. Furthermore, we explore future development trends in this field, including miniaturization, integration, and the exploration of deep brain regions.}, } @article {pmid41446471, year = {2025}, author = {Masna, H and Konda, M and Ganti, L}, title = {Huntington's Disease Research Over Six Decades: Global Insights, Gaps, and Future Directions.}, journal = {Cureus}, volume = {17}, number = {11}, pages = {e97567}, pmid = {41446471}, issn = {2168-8184}, abstract = {Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by expanded cytosine-adenine-guanine (CAG) repeats in the huntingtin (HTT) gene. It leads to progressive decline in motor function, cognition, and behavior, often following a prolonged pre-symptomatic phase. Although research on HD has progressed, significant gaps remain in understanding its full impact, particularly in areas such as mental health, global collaboration, and early intervention. A bibliometric analysis was conducted using the Web of Science Core Collection to evaluate global research trends in HD and its testing from 1966 to 2025. A total of 1,515 publications were analyzed for authorship patterns, contributing countries, journal sources, and frequently occurring keywords. VOSviewer software v1.6.15 (Centre for Science and Technology Studies, Leiden University, The Netherlands) was used to visualize author networks and keyword co-occurrence. Publication activity peaked in 2014 and 2018, with 101 and 96 articles published, respectively. The United States emerged as the leading contributor to HD research, followed by European countries with fewer publications. Keyword analysis revealed strong associations between HD and other neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, as well as recurring terms related to genetic testing, brain anatomy, and animal models. Limited author collaboration was observed, with only a few dense research clusters present. This analysis highlights the growing body of research on HD, particularly in genetic mechanisms and therapeutic modeling. However, the concentration of research within a few countries and author groups suggests limited global collaboration. Emerging gaps include underrepresentation of mental health impacts, disparities in geographic research output, and narrow journal dissemination. Strengthening international cooperation and diversifying research focus could accelerate progress in diagnosis, treatment, and overall patient care.}, } @article {pmid41446236, year = {2025}, author = {Fredriksen, K and Joshi, SS and Chang, A and Li, L}, title = {High-density lipoprotein mimetic peptide 4F ameliorates APOE4-associated lipid dysfunction in primary and iPSC-derived astrocytes and cerebral organoids.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.16.694774}, pmid = {41446236}, issn = {2692-8205}, abstract = {APOE is the greatest genetic risk factor for late-onset Alzheimer's disease (AD). In humans, APOE has three isoforms: APOE2 (E2), APOE3 (E3), and APOE4 (E4); E4 increases AD risk, while E3 is neutral and E2 decreases risk. In the brain, APOE is predominantly produced by astrocytes, where it binds lipids to form HDL-like particles, and plays a central role in lipid homeostasis, Aβ clearance, and neuroimmune modulation. Its lipidation state is critical for function, with E4 being poorly lipidated compared to E2 and E3, contributing to the pathogenic effects of E4 while also offering a potential therapeutic target. We have previously demonstrated that the HDL-mimetic peptide 4F increases APOE secretion and lipidation in wild-type mouse astrocytes and counteracts the inhibitory effects of Aβ42. Here, we assessed the ability of 4F to mitigate E4-associated dysfunction using primary astrocytes from humanized E3 and E4 knock-in mice and isogenic human iPSC-derived astrocytes and cerebral organoids. Results showed that 4F enhanced APOE secretion and lipidation in both cellular and organoid models in the absence or presence of aggregated Aβ42. Compared to E3 astrocytes, E4 astrocytes were prone to Aβ42-induced inhibition of APOE secretion and lipidation and increased accumulation of lipid droplets. 4F treatment ameliorated the inhibitory effects of Aβ42 and reduced lipid droplet accumulation. These findings support the therapeutic potential of HDL-mimetic peptides for E4-associated dysfunction in AD.}, } @article {pmid41446123, year = {2025}, author = {Shao, B and Kula, B and Le, H and Venkhatesh, P and Katti, P and Marshall, AG and Chittaranjan, S and Thapilyal, S and Namdar, HK and Nivedya, C and Roszczyk, A and Mobley, H and Killion, M and St John, E and Martin, P and Rodrigiuez, B and Hamilton, M and Bell, L and Wyckoff, SM and Moran, LA and Philips, M and Hubert, D and Tomeau, B and Afolabi, JM and Kirabo, A and Blanco, I and Reasonover, S and Drake, LE and Lippmann, ES and Evans, C and Santisteban, MM and Cheairs, TG and Mesenga, S and Wanjalla, C and Gaddy, J and McMillan, R and Hernandez Perez, CP and Paing, HH and Schafer, JC and Mobley, B and Berry, J and Crabtree, A and Kovtun, O and Goodwin, S and Garza Lopez, E and Dash, C and Dai, DF and Miller-Fleming, TW and Hinton, A and Smith, NA}, title = {The role of MICOS in modulating mitochondrial dynamics and structural changes in vulnerable regions of Alzheimer's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41446123}, issn = {2692-8205}, support = {UL1 TR000445/TR/NCATS NIH HHS/United States ; R01 DK133698/DK/NIDDK NIH HHS/United States ; R01 HD090061/HD/NICHD NIH HHS/United States ; R21 DK119879/DK/NIDDK NIH HHS/United States ; U19 HL065962/HL/NHLBI NIH HHS/United States ; P30 DK058404/DK/NIDDK NIH HHS/United States ; S10 RR025141/RR/NCRR NIH HHS/United States ; R01 HL147818/HL/NHLBI NIH HHS/United States ; R25 HL106365/HL/NHLBI NIH HHS/United States ; R01 HD074711/HD/NICHD NIH HHS/United States ; P50 GM115305/GM/NIGMS NIH HHS/United States ; T32 DK007563/DK/NIDDK NIH HHS/United States ; R21 TW012635/TW/FIC NIH HHS/United States ; S10 OD017985/OD/NIH HHS/United States ; P30 EY008126/EY/NEI NIH HHS/United States ; R01 HL144941/HL/NHLBI NIH HHS/United States ; I01 BX005352/BX/BLRD VA/United States ; P30 DK020593/DK/NIDDK NIH HHS/United States ; RC2 GM092618/GM/NIGMS NIH HHS/United States ; P30 CA068485/CA/NCI NIH HHS/United States ; R03 HL155041/HL/NHLBI NIH HHS/United States ; S10 OD025092/OD/NIH HHS/United States ; U01 HG006378/HG/NHGRI NIH HHS/United States ; K01 AG062757/AG/NIA NIH HHS/United States ; R00 AG065445/AG/NIA NIH HHS/United States ; K01 NS110981/NS/NINDS NIH HHS/United States ; UL1 RR024975/RR/NCRR NIH HHS/United States ; R01 NS032830/NS/NINDS NIH HHS/United States ; U01 HG004798/HG/NHGRI NIH HHS/United States ; UL1 TR002243/TR/NCATS NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; R00 DK120876/DK/NIDDK NIH HHS/United States ; D43 TW009744/TW/FIC NIH HHS/United States ; S10 MH130456/MH/NIMH NIH HHS/United States ; }, abstract = {Mitochondrial contact site and cristae organizing system (MICOS) complexes are critical for maintaining the mitochondrial architecture, cristae integrity, and organelle communication in neurons. MICOS disruption has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD), yet the spatiotemporal dynamics of MICOS-associated neuronal alterations during aging remain unclear. Using three-dimensional reconstructions of hypothalamic and cortical neurons, we observed age-dependent fragmentation of mitochondrial cristae, reduced intermitochondrial connectivity, and compartment-specific changes in mitochondrial size and morphology. Notably, these structural deficits were most pronounced in neurons vulnerable to AD-related pathology, suggesting a mechanistic link between MICOS disruption and the early mitochondrial dysfunction observed in patients with AD. Our findings indicate that the loss of MICOS integrity is a progressive feature of neuronal aging, contributing to impaired bioenergetics and reduced resilience to metabolic stress and potentially facilitating neurodegenerative processes. MICOS disruption reduced neuronal firing and synaptic responsiveness, with miclxin treatment decreasing mitochondrial connectivity and inducing cristae disorganization. These changes link MICOS structural deficits directly to impaired neuronal excitability, highlighting vulnerability to AD-related neurodegeneration. These results underscore the importance of MICOS as a critical determinant of neuronal mitochondrial health and as a potential target for interventions aimed at mitigating AD-related mitochondrial dysfunction.}, } @article {pmid41445693, year = {2025}, author = {Lee, S and Yin, L and Teopiz, KM and Wong, S and Han Le, G and Xiao, N and Stahl, S and Valentino, K and Ho, R and Zhang, MC and Greg Rhee, T and McIntyre, RS}, title = {Effects of glucagon-like peptide-1 receptor agonists on psychiatric disorders: a systematic review.}, journal = {Therapeutic advances in psychopharmacology}, volume = {15}, number = {}, pages = {20451253251396304}, pmid = {41445693}, issn = {2045-1253}, abstract = {Extant literature pertaining to the administration of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for Alzheimer's disease, Parkinson's disease, major depressive disorder, bipolar disorder, substance-, alcohol- and nicotine-use disorders, suggests promising efficacy beyond the current FDA-approved indications (e.g., type 2 diabetes mellitus, obesity). The implicated brain regions of the aforementioned mental disorders contain glucagon-like peptide 1 (GLP-1) receptors associated with improving cognitive and behavioral functioning. Therefore, we aimed to systematically review the treatment effects of GLP-1RAs in various neurocognitive and psychiatric disorders. Online databases including PubMed, OVID, MEDLINE, Embase, PsycINFO and Google Scholar, were searched from inception until October 1, 2024. Additional studies were identified from the reference lists of the included articles. 22 studies were identified, with a total of 186,847 participants included. Results reported that GLP-1RAs meaningfully improved cognitive and affective functioning (e.g., memory), which in some cases was sustained beyond exposure to the agent. Separately, multiple epidemiological studies reported that GLP-1RAs have protective effects, with a suggestion of decrease in the incidence of mental disorders. These results provides the impetus for large, long-term, randomized controlled trials for GLP-1 RAs for the treatment of various mental disorders. This review is not registered in PROSPERO or any other registry.}, } @article {pmid41445644, year = {2025}, author = {Li, R and Langford, O and Insel, PS and Sperling, RA and Raman, R and Aisen, PS and Donohue, MC}, title = {Divergent latent classes of cognitive decline in the A4 and LEARN studies.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.15.25342305}, pmid = {41445644}, abstract = {IMPORTANCE: Alzheimer disease biomarkers in cognitively unimpaired older adults are associated with later cognitive and clinical decline, yet substantial heterogeneity in the timing and rate of decline remains insufficiently characterized.

OBJECTIVE: To identify subgroups of cognitive decline among biomarker-defined cognitively unimpaired adults and determine baseline predictors of heterogeneity in preclinical Alzheimer disease progression.

Longitudinal data were drawn from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study, which enrolled amyloid-positive participants, and the parallel LEARN Study, which enrolled amyloid-negative individuals meeting all other A4 criteria. Participants completed baseline amyloid PET, plasma P-tau217, structural MRI, and serial cognitive assessments. Latent Class Mixed-Effects Models (LCMMs) were used to identify distinct cognitive trajectory classes. Associations between class membership and demographic, clinical, and biomarker characteristics were evaluated.

MAIN OUTCOMES AND MEASURES: The primary outcome was longitudinal change in the Preclinical Alzheimer's Cognitive Composite (PACC).

RESULTS: Three cognitive trajectory classes were identified: stable, slow decliners, and fast decliners. Higher plasma P-tau217, smaller hippocampal volume, and elevated tau PET were associated with greater odds of belonging to declining classes. Among amyloid-positive individuals, approximately 70% were classified as stable over the observed follow-up interval.

CONCLUSIONS AND RELEVANCE: Latent class modeling reveals marked heterogeneity in preclinical cognitive trajectories, even among individuals with biomarker evidence of Alzheimer pathology. The high proportion of stable individuals is consistent with the long presymptomatic interval. Identifying subgroups of decline may improve prognostic modeling and guide enrichment strategies for precision secondary prevention trials.}, } @article {pmid41444683, year = {2025}, author = {Weissmann, C and Castellanos, LCS and Montes, MM and Uruk, G and Youssef, H and Reichard, RR and Gatto, RG and Josephs, KA}, title = {4R-tau isoform induction via TDP-43 in neurons in response to insulin: converging signaling pathways with implications for neurodegenerative disease.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {258}, pmid = {41444683}, issn = {2051-5960}, support = {PIP Grant No. 11220210100589CO//Consejo Nacional de Investigaciones Científicas y Técnicas/ ; UBACYT (Grant No. 20020220400291BA)//Universidad de Buenos Aires/ ; R01-AG37491//National Institute for Health Care Management Foundation/ ; R01 AG037491/AG/NIA NIH HHS/United States ; PICT 2020-01211//Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación/ ; }, mesh = {Animals ; *tau Proteins/metabolism ; *DNA-Binding Proteins/metabolism ; *Neurons/metabolism/drug effects ; Humans ; *Signal Transduction/drug effects/physiology ; *Insulin/pharmacology ; Protein Isoforms/metabolism ; HEK293 Cells ; Mice ; *Neurodegenerative Diseases/metabolism ; Phosphorylation/drug effects ; Cells, Cultured ; Cerebral Cortex/cytology/metabolism ; Mice, Inbred C57BL ; }, abstract = {Tau protein isoforms, regulated during development, are influenced by the nuclear factor TDP-43, which plays a crucial role in tau mRNA stability and exon 10 inclusion. Both tau and TDP-43 are prone to pathological phosphorylation and aggregation, with specific phosphorylated forms of TDP-43 linked to cytoplasmic mislocalization and alterations in the 3R/4R tau ratio as detected in different pathologies. In this study, we show that insulin treatment of embryonic mouse primary cortical neurons-cells that normally express only 3R-tau-induces the expression of 4R-tau, suggesting that metabolic signaling can influence tau isoform expression in a developmentally immature neuronal context. In addition, experiments in HEK293 cells revealed isoform-specific stabilization effects and showed that insulin promotes TDP-43 redistribution to the cytoplasm along with a phosphorylation pattern. These results underscore the complex interplay between TDP-43 and tau isoforms and metabolic signaling pathways that play a crucial role in their expression and localization with potential implications for understanding mechanisms of neurodegenerative disease onset and progression.}, } @article {pmid41444088, year = {2025}, author = {Lynch, S}, title = {Addressing Cognitive Dysfunction: Education, Diagnosis, and Practical Care.}, journal = {The Veterinary clinics of North America. Small animal practice}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cvsm.2025.09.030}, pmid = {41444088}, issn = {1878-1306}, abstract = {Cognitive dysfunction syndrome (CDS) is a common, yet underdiagnosed, neurobehavioral disease of domestic animals. Much like its human counterpart, Alzheimer's disease, CDS is the result of neuronal loss and inflammatory changes in the central nervous system; however, the specific pathophysiology of the disease continues to be researched in efforts to advance diagnostics, prognosis, and treatment. Diagnosis is typically conducted by ruling out possibilities and using assessment tools, including the Canine Dementia Scale and the Canine Cognitive Dysfunction Rating Scale. Treatment is often most successful when a tailored, multimodal approach is initiated early in the disease progression.}, } @article {pmid41442238, year = {2025}, author = {Periyakoil, VS and Von Gunten, C and Kraemer, H}, title = {Virtual, Nurse-Led Early Primary Palliative Care Intervention (ELICIT) for Community-Dwelling Older Adults With Cognitive Impairment: Protocol for a Randomized Controlled Trial.}, journal = {JMIR research protocols}, volume = {14}, number = {}, pages = {e75082}, pmid = {41442238}, issn = {1929-0748}, support = {R01 AG062239/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Cognitive Dysfunction/nursing/therapy ; *Palliative Care/methods ; Aged ; Independent Living ; Male ; Female ; Aged, 80 and over ; Quality of Life ; Randomized Controlled Trials as Topic ; Primary Health Care ; }, abstract = {BACKGROUND: Although dementia is a serious illness that progresses over many years, little is known about the primary palliative care needs of individuals who have it, especially those living in the community.

OBJECTIVE: This trial aims to test the impact of a virtual, nurse-led early primary palliative care intervention (ELICIT) on older adults living in the community who are chronically ill and have a diagnosis of cognitive impairment or are at risk of it.

METHODS: A total of 200 community-dwelling older adults who were chronically ill and had varying degrees of cognitive impairment were recruited and randomized to either usual care or usual care + a virtual, nurse-led ELICIT. For both arms, we will track the number of participants who (1) report supportive care needs to the blinded evaluators and (2) complete conversations on goals of care and document advance directives and the Physician Orders for Life-Sustaining Treatment form in the electronic health record. We will also track their end-of-life resource use and the percentage of participants who receive goal-concordant care. Changes in Edmonton Symptom Assessment Scale, Patient Activation Measure, and Quality of Life in Alzheimer's Disease scores will be tracked and analyzed.

RESULTS: As of October 2025, we have recruited 200 participants. We are following all study participants on an ongoing basis to determine whether they received goal-concordant care at the end of life and their resource use patterns. We hypothesize that, compared to the usual care arm, more participants in the intervention arm will (1) express supportive care needs to the blinded evaluators, (2) complete goals of care conversations, document advance care planning, and (3) have higher levels of goal-concordant care and lower end-of-life resource use.

CONCLUSIONS: The identification of the primary palliative care needs of community-dwelling older adults who are chronically ill and have various levels of cognitive impairment will help refine the intervention and enable trained nurses to provide virtual early primary palliative care within the scope of nursing.}, } @article {pmid41441957, year = {2025}, author = {Neve, V and Saqlain, S and Veeranjaneyulu, A and Karwa, P and Kapare, H and Yeralkar, K}, title = {Evaluation of the neuroprotective activity of Momordica dioica against aluminum chloride (AlCl3)-Induced alzheimer's disease in Wistar rats.}, journal = {Discover mental health}, volume = {5}, number = {1}, pages = {198}, pmid = {41441957}, issn = {2731-4383}, abstract = {Alzheimer's disease is a brain condition that slowly erodes a person's memory and cognitive abilities. It is caused by damage to brain cell, particularly in the hippocampus, a region crucial for memory. By 2050 worldwide no. of AD is going increases. Various therapeutic strategies have been explored for AD. The use of herbal products is one of the treatment regimens for AD. In this study, we examined how a herbal extract from Momordica dioica could potentially protect Wistar rats from AD caused by Aluminum chloride. Aluminum chloride (AlCl3) is widely used in preclinical studies to induce Alzheimer-like symptoms, as chronic exposure is known to promote oxidative stress, neuroinflammation, and cholinergic dysfunction-hallmarks of Alzheimer's disease pathology. A total of 86 Wistar rats were randomly assigned to nine experimental groups (n = 6-10 per group), including a normal control group and an Alzheimer's disease (AD) model group. One group treated with Donepezil (2.05 mg/kg), three groups treated with different doses of herbal extract of Momordica dioica (100, 200 and 400 mg/kg), and three groups treated with a combination of Donepezil and herbal extract of Momordica dioica (std + 100, std + 200 and std + 400 mg/kg). The aluminum chloride (17 mg/kg, p.o) was administered once daily for 7 days to induce AD. From the 8th day onward, the herbal extract of Momordica dioica was administered orally for 21 consecutive days at doses of 100, 200, and 400 mg/kg to groups 4, 5, and 6 respectively, as well as in combination with Donepezil (2.05 mg/kg) in groups 7, 8, and 9. This brought the total duration of the study to 28 days." Elevated Plus Maze and Forced Swim test was used for the behavioral assessment. After that, brain samples were collected for biochemical analysis. Herbal Extract significantly improved AlCl3-induced behavioral impairments and cognition deficits in Forced Swim Test, Elevated Plus Maze Test significantly with high dose. Then, herbal extract of Momordica dioica facilitated cholinergic activity via inhibiting acetylcholinesterase (AChE) activity. Besides, herbal extract of Momordica dioica decreased lipid peroxidation level & Nitrite level but enhanced levels of glutathione, Succinate dehydrogenase, Catalase and superoxide dismutase and results are more convincing with high dose. Histopathological analysis further confirmed reduced neuronal degeneration and better preservation of brain architecture, especially at higher doses of the herbal extract." The results suggested that herbal extract of Momordica dioica ameliorated AlCl3-induced cognitive and memory impairments, possibly through regulating AChE activity, suppressing oxidative stress. The herbal extract of Momordica dioica significantly improved behavioral impairments and cognition deficits, particularly at high doses. It facilitates cholinergic activity by inhibiting AChE activity and reduced oxidative stress. Overall, the conclusion states that the herbal extract may ameliorate and memory impairments associated with AD.}, } @article {pmid41441560, year = {2025}, author = {Clevenger, C and Jackson, WC and Stroud, J and Brubaker, M and Patel, M and Bucior, I and Bratlee-Whitaker, E and Brown, TM and Fehnel, S and Peschin, S and Cummings, J and Grossberg, G}, title = {Development and evaluation of the agitation in Alzheimer's screener for caregivers (AASC): a clinical tool to screen for agitation.}, journal = {Current medical research and opinion}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/03007995.2025.2606562}, pmid = {41441560}, issn = {1473-4877}, abstract = {OBJECTIVE: Although agitation is a common neuropsychiatric symptom in Alzheimer's dementia, it can be challenging to recognize and diagnose. Caregivers of individuals with Alzheimer's dementia are often the first to encounter agitation behaviors but may struggle to recognize and communicate symptoms to healthcare professionals (HCPs). Here, we describe the development and evaluation of the Agitation in Alzheimer's Screener for Caregivers (AASC), a practical screening tool to identify agitation symptoms and facilitate caregiver-HCP communication.

METHODS: The AASC was developed based on the International Psychogeriatric Association (IPA) criteria for agitation in cognitive disorders, input from multidisciplinary experts, and qualitative interviews with caregivers of patients with Alzheimer's dementia. Thereafter, a 2-phase quantitative evaluation study was conducted to refine the AASC and assess the predictive validity of the final tool against IPA criteria. Data were collected from caregiver-HCP dyads, where caregivers completed the AASC and HCPs used IPA criteria to inform their assessment of agitation.

RESULTS: A total of 226 caregiver-HCP dyads were quantitatively evaluated. The mean age of caregivers was 61 years; many were spouses/partners (46%), White (60%), and female (62%), providing an average of 60 h of care weekly (range: 9-168 h). Following initial assessment and refinement, the final AASC, evaluated in a subset of 105 dyads, showed a 73.3% agreement with IPA criteria, with sensitivity of 0.77, specificity of 0.70, and kappa and F1 scores of 0.47 and 0.71, respectively. Most patients were classified as having mild (41%) to moderate (37%) Alzheimer's dementia, while 22% had severe disease.

CONCLUSION: The AASC is a reliable, easy-to-use, 2-item screener for the presence and impact of agitation, in agreement with IPA criteria. The AASC supports caregivers and HCPs by providing an accessible framework for recognizing agitation throughout all stages of Alzheimer's dementia and prompting comprehensive assessment for diagnosis and appropriate treatment planning.}, } @article {pmid41440958, year = {2025}, author = {Rahmani, AR and Madani, SA and Aminov, E and Gogokhia, L and Bench, T and Kalogeropoulos, A}, title = {Heart Failure and Cognitive Impairment Through the Lens of the Gut Microbiome: A Narrative Review.}, journal = {Journal of personalized medicine}, volume = {15}, number = {12}, pages = {}, pmid = {41440958}, issn = {2075-4426}, abstract = {Heart failure (HF) affects over 55 million individuals globally, with prevalence projected to exceed 11 million in the United States by 2050 and is increasingly recognized as a systemic disorder extending beyond hemodynamic dysfunction to encompass profound alterations in neural and gut physiology. Cognitive impairment affects nearly half of HF patients and represents a major determinant of morbidity, self-care capacity, and mortality. Recent advances suggest that the gut microbiome serves as a pivotal intermediary in the heart-brain crosstalk, influencing neurocognitive outcomes through inflammatory, metabolic, and neurohumoral pathways. Dysbiosis in HF disrupts intestinal barrier integrity, facilitating translocation of endotoxins and microbial metabolites such as trimethylamine-N-oxide (TMAO), short-chain fatty acids (SCFAs), and bile acids, which in turn modulate neuroinflammation, cerebral perfusion, and neuronal signaling. The gut-heart-brain axis provides an integrative framework linking HF and cognitive impairment pathophysiology through dysbiosis-driven systemic inflammation and metabolite dysregulation. Gut-derived biomarkers and microbiome-targeted interventions represent promising strategies for detection of early alterations and precision treatment, highlighting the urge for prospective, multi-omics studies to establish causality and therapeutic efficacy. This review synthesizes current evidence connecting gut microbiome dysbiosis and metabolite alterations to both HF and cognitive impairment pathophysiology and proposes translational strategies for integrating microbiome-targeted therapies in HF patients with cognitive dysfunction.}, } @article {pmid41438688, year = {2026}, author = {Su, T and Li, Z and Yang, Y and Dai, Y and Li, Y and Zhao, H}, title = {In vitro 3D models of neuron-astrocyte interactions.}, journal = {Biochemistry and biophysics reports}, volume = {45}, number = {}, pages = {102400}, pmid = {41438688}, issn = {2405-5808}, abstract = {The pathological processes of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis) also include relationships between neuron and glia cells. Conventional two-dimensional (2D) cell cultures have limitations to mimic the microenvironment of cells inside living organisms because of flaws in intercellular relationships investigated using 2D cell cultures. Recent advances have introduced three-dimensional (3D) cell cultures that have the capability to create 3D cellular architecture to mimic advanced platforms for scientific inquiries into neurodegenerative diseases, simulating microenvironments inside living organisms.This review provides a brief overview of the development of in vitro 3D cell culture models of astrocytes and attempts to highlight the role of astrocytes in crucial pathophysiologic events occurring in 3D cultures. Studies have shown the use of in vitro 3D cultures to better represent the dual functions of astrocytes in neurodegenerative disorders. Looking ahead to the future, novel advances in microfluidics and multi-omics analysis promise to further improve 3D cultures and push forward new insights into neurological dysfunction to spark innovative advances for treatment strategies.}, } @article {pmid41437993, year = {2025}, author = {Fliri, A and Sostek, R and Kajiji, S}, title = {Protein swarm-based cause-effect analysis: effects of microRNAs on cooperation networks linking COVID-19 infections, atherosclerosis, and Alzheimer's disease.}, journal = {Frontiers in cardiovascular medicine}, volume = {12}, number = {}, pages = {1577844}, pmid = {41437993}, issn = {2297-055X}, abstract = {Well-being depends on the integrated operation of biological processes at all levels of system organization, from individual cells to tissues and organ systems, collectively sustaining homeostasis and optimal bodily functions. The regulation of cooperation among these processes is mediated by information flow within networks possessing diverse structural, functional, and temporal properties. Disruption in these networks is observed in conditions such as infections, inflammatory diseases, and cancer. To advance understanding of immune system roles and to elucidate mechanisms underlying health vulnerability during disease, we utilized proteomics data related to 4,800 diseases along with protein swarm-based cause-effect analyses to identify principles governing plasticity and self-organizing capabilities of immune systems. Our findings demonstrate that the precision of immune system functions is regulated by dynamic alterations in the topologies of cooperation networks that are partially modulated by microRNAs. Additionally, our analysis indicates that investigating the underlying causes of diseases through the study of cooperative network functions and their interactions with microRNAs-rather than concentrating exclusively on individual protein targets or microRNAs-provides significant insights for devising effective treatment strategies for infections, cardiovascular conditions, Alzheimer's disease, cancer, aging, and related health concerns.}, } @article {pmid41436813, year = {2025}, author = {Birnbaum, EM and Xie, L and Serrano, P and Rockwell, P and Figueiredo-Pereira, ME}, title = {BT-11 targets the LANCL2 pathway to attenuate cognitive deficits and hippocampal pathology in Alzheimer's transgenic rats.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-025-31514-z}, pmid = {41436813}, issn = {2045-2322}, support = {TL1-TR0002386//NIH Weill Cornell CTSC/ ; R01AG057555//NIH/NIA/ ; }, abstract = {Neuroinflammation is a key pathological hallmark of Alzheimer's disease (AD). Investigational and FDA approved drugs targeting inflammation already exist, thus drug repurposing for AD is a suitable approach. BT-11 is an investigational drug that reduces inflammation in the gut and improves cognitive function. BT-11 is orally active and binds to lanthionine synthetase C-like 2 (LANCL2), a glutathione-s-transferase, thus potentially reducing oxidative stress. We investigated the effects of BT-11 long-term treatment on the TgF344-AD rat model of AD. BT-11 (1) reduced spatial memory deficits, and hippocampal Abeta plaque load, and increased neuronal levels in males, and reduced microglia numbers in females, and (2) induced transcriptomic changes in signaling receptor, including G-protein coupled receptor pathways in both males and females, with changes in neurotrophic factors only in males. We detected LANCL2 in hippocampal nuclear and cytoplasmic fractions with potentially different post-translational modifications, suggesting distinct functions based on its subcellular localization. LANCL2 was present in oligodendrocytes, indicating a role in oligodendrocyte function. To our knowledge, these last two findings have not been reported. Overall, our data support that targeting LANCL2 with BT-11 improves cognition and reduces AD-like pathology potentially by modulating G-protein signaling. LANCL2's localization in oligodendrocytes suggest a possible role oligodendrocyte function that warrants further investigation. Our studies contribute to the field of new immunomodulatory AD therapeutics and establish LANCL2 as a promising therapeutic target meriting further mechanistic investigation.}, } @article {pmid41435831, year = {2025}, author = {Chaubey, K and Vázquez-Rosa, E and Tripathi, SJ and Shin, MK and Yu, Y and Dhar, M and Chakraborty, S and Yamakawa, M and Wang, X and Sridharan, PS and Miller, E and Bud, Z and Corella, SG and Barker, S and Caradonna, SG and Koh, Y and Franke, K and Cintrón-Pérez, CJ and Rose, S and Fang, H and Cintrón-Pérez, AA and Tomco, T and Zhu, X and Fujioka, H and Gefen, T and Flanagan, ME and Williams, NS and Wilson, BM and Chen, L and Dou, L and Cheng, F and Rexach, JE and Woo, JA and Kang, DE and Paul, BD and Pieper, AA}, title = {Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in human brain.}, journal = {Cell reports. Medicine}, volume = {}, number = {}, pages = {102535}, doi = {10.1016/j.xcrm.2025.102535}, pmid = {41435831}, issn = {2666-3791}, abstract = {Alzheimer's disease (AD) is traditionally considered irreversible. Here, however, we provide proof of principle for therapeutic reversibility of advanced AD. In advanced disease amyloid-driven 5xFAD mice, treatment with P7C3-A20, which restores nicotinamide adenine dinucleotide (NAD[+]) homeostasis, reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation and enhances hippocampal neurogenesis and synaptic plasticity, resulting in full cognitive recovery and reduction of plasma levels of the clinical AD biomarker p-tau217. P7C3-A20 also reverses advanced disease in tau-driven PS19 mice and protects human brain microvascular endothelial cells from oxidative stress. In humans and mice, pathology severity correlates with disruption of brain NAD[+] homeostasis, and the brains of nondemented people with Alzheimer's neuropathology exhibit gene expression patterns suggestive of preserved NAD[+] homeostasis. Forty-six proteins aberrantly expressed in advanced 5xFAD mouse brain and normalized by P7C3-A20 show similar alterations in human AD brain, revealing targets with potential for optimizing translation to patient care.}, } @article {pmid41433369, year = {2025}, author = {Alba, LO}, title = {Technology and Dementia Preconference.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21 Suppl 9}, number = {Suppl 9}, pages = {e110456}, doi = {10.1002/alz70863_110456}, pmid = {41433369}, issn = {1552-5279}, mesh = {Humans ; *Video Recording/standards ; *Social Media ; *Dementia ; Reproducibility of Results ; *Alzheimer Disease ; }, abstract = {BACKGROUND: Patients are increasingly using YouTube as a source of health-related information. This study assessed the quality and reliability of videos on Alzheimer's disease dementia (ADD) available on the platform.

METHOD: In October 2023, YouTube was systematically searched for ADD-related videos. Two independent physicians reviewed each video, scoring it using modified DISCERN (mDISCERN) for reliability and the Global Quality Scale (GQS) for content quality. Videos were categorized by goal and assessed for quality, accuracy, comprehensiveness, and specific content.

RESULT: There were 58 videos included in the study. Using the GQS, 16 videos (28%) were assessed as high quality, 32 videos (55%) as medium quality, and 10 videos (17%) as low quality. Using the mDISCERN scale, 48 videos (83%) were deemed reliable, while 10 videos (17%) were classified as unreliable. Videos from academic institutions and physicians exhibited higher mDISCERN and GQS scores compared to other groups (p = 0.004, p = 0.005, respectively), and a significant correlation was seen between mDISCERN and GQS (p < 0.001).

CONCLUSION: The majority of YouTube videos on ADD are good to fair quality, covering disease properties, treatment choices, and patient experiences. However, video popularity does not significantly correlate with content reliability and quality. Videos provided by academic institutions and healthcare professionals can help the general population to understand ADD.}, } @article {pmid41433362, year = {2025}, author = {Stothart, G and Alderman, S and Hermann, OP and Coulthard, E}, title = {Technology and Dementia Preconference.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21 Suppl 9}, number = {Suppl 9}, pages = {e110467}, doi = {10.1002/alz70863_110467}, pmid = {41433362}, issn = {1552-5279}, mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction/diagnosis/physiopathology ; Neuropsychological Tests ; *Electroencephalography/methods ; Middle Aged ; Reproducibility of Results ; *Dementia/diagnosis ; Aged, 80 and over ; }, abstract = {BACKGROUND: As viable pharmacotherapies and blood biomarkers emerge for dementia treatment and screening there remains a great need for accurate, sensitive biomarkers of cognitive function. We have previously demonstrated that Fastball, a new EEG method for the passive and objective measurement of recognition memory that requires no behavioural memory response or comprehension of the task, is sensitive to cognitive dysfunction in Alzheimer's disease. Here we present new evidence that Fastball is sensitive to amnestic dysfunction in an earlier stage of the dementia lifecourse, Mild Cognitive Impairment.

METHOD: 53 MCI patients and 54 healthy older adult controls completed a 3-minute Fastball task in which they passively viewed rapidly presented images while EEG captured their automatic ability to differentiate between images based on previous exposure. They also completed neuropsychological assessments of memory (DMS-48), sustained attention (Psychomotor Vigilance Task) and general cognitive function (ACE-iii). Participants were re-tested after one year to establish the test-retest reliability of Fastball in healthy older adults, and the sensitivity of Fastball to cognitive decline in MCI patients, over a one year period.

RESULTS: Amnestic MCI patients showed significantly reduced Fastball responses compared to non-amnestic MCI patients (p = 0.001, Cohen's d = 0.98). and healthy older adult controls (p = 0.005, Cohen's d = 0.64). Regression analyses showed that Fastball EEG responses were selectively predictive of neuropsychological measures of recognition memory and not attentional function. At year one follow-up Fastball showed moderate to good test-retest reliability in healthy older adult controls, and the six MCI-dementia converters showed a trend for lower Fastball responses at baseline which will be confirmed with further longitudinal assessment.

CONCLUSION: Fastball is further validated as a viable method for testing recognition memory in cognitively impaired populations. We have demonstrated that it is selectively predictive of memory dysfunction and not other cognitive functions such as attention. It is passive, non-invasive, quick to administer and uses cheap, scalable EEG technology. Fastball is a viable functional biomarker that can help to advance cognitive assessment in MCI.}, } @article {pmid41433361, year = {2025}, author = {Hoang, B and Pang, Y and Liang, S and Dodge, HH and Zhou, J}, title = {Technology and Dementia Preconference.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21 Suppl 9}, number = {Suppl 9}, pages = {e110588}, doi = {10.1002/alz70863_110588}, pmid = {41433361}, issn = {1552-5279}, mesh = {Aged ; Female ; Humans ; Male ; Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; *Dementia/diagnosis ; Early Diagnosis ; Language ; Linguistics ; }, abstract = {BACKGROUND: Mild Cognitive Impairment (MCI) is the prodromal stage of Alzheimer's disease. Early detection of MCI is essential for effective intervention and treatment. Recent studies have shown that linguistic marker is a promising and cost-effective approach to identify MCI. Existing studies aggregated multiple rounds of conversation and demonstrated their effectiveness, and yet the use of finer granularity of conversation is not widely studied. Intuitively, the time series of language markers reveal important dynamics that are easily wiped off by aggregation. Significant individual differences in speaking styles pose challenges for sequence models in capturing cognitive characteristics. We propose a novel temporal harmonization method that mitigates distributional differences in temporal language markers across subjects, enhancing the prediction.

METHOD: We utilized 6,771 conversations from 74 participants in Internet-Based Conversational Engagement Clinical Trial (I-CONECT) (NCT02871921). From each 30-minute conversation session, we extracted a 99-dimensional feature set including Linguistic Inquiry and Word Count, Syntactic Complexity, Lexical Diversity, and Response Length. For each subject, we have a sequence of feature vectors over time, up to 12 months. Our harmonization method leverages adversarial training via a min-max optimization framework with three components: Seq2Seq Harmonization, a Subject Classifier, and a Cognitive Classifier. The harmonization module learns to remove subject-specific components from temporal linguistic features, while the Subject Classifier infers subject identity. Finally, the Cognitive Classifier focuses on detecting MCI from the harmonized temporal features.

RESULT: We compared our approach with single-conversation input methods, where we trained neural networks to predict the outcome of individual conversations and used majority voting to determine the final output for each participant. Our results show that using temporal sequences improves detection performance compared to aggregated single-conversation outputs, both with and without harmonization. When applying temporal harmonization, the performance of subject classification significantly increases, achieving an AUC of 0.720 compared to 0.647 without harmonization.

CONCLUSION: Using only features extracted from semi-structured conversation, we achieved a reasonalbe AUC. Our study demonstrates the additional benefits of using temporal sequences of language markers to detect Mild Cognitive Impairment. Moreover, applying temporal harmonization helps remove subject-specific components in features and further enhances cognitive detection performance.}, } @article {pmid41433347, year = {2025}, author = {Bradbury, AR and Egleston, BL and Wood, E and Karlawish, J and Roberts, JS and Kim, S and Cacioppo, C and Eppelmann, L and Weinberg, M and Ofidis, D and Langlois, C and Reiman, EM and Tariot, PN and Langbaum, JB}, title = {Technology and Dementia Preconference.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21 Suppl 9}, number = {Suppl 9}, pages = {e110499}, doi = {10.1002/alz70863_110499}, pmid = {41433347}, issn = {1552-5279}, mesh = {Humans ; Female ; Male ; Aged ; Middle Aged ; *Apolipoprotein E4/genetics ; *Videoconferencing ; *Dementia/genetics ; Genotype ; *Genetic Counseling ; *Telephone ; *Alzheimer Disease/genetics/prevention & control ; Patient Reported Outcome Measures ; }, abstract = {BACKGROUND: APOE genotyping is increasingly important to identify candidates eligible for Alzheimer's prevention trials. Such testing is also now commonplace for patients considering new anti-amyloid treatments, given that APOE4 carriers are at elevated risk for treatment side effects. Data to inform best practices for sharing APOE results are needed.

METHOD: CONNECT4 is a multi-center, randomized trial (NCT02978729) comparing disclosure of APOE4 genotype by remote videoconference (VD) or telephone (TD) with a genetic counselor in cognitively unimpaired adults 60-75 YO. It was ancillary to the Generation 1 prevention trial, enrolling at 20 US sites. Patient-reported outcomes (PROs) were collected at 2-7 days (T1), 6 weeks (T2), and 6 months (T3) following APOE4 disclosure. Primary outcomes were change in genetic knowledge and disease-specific distress (T0-T1) and satisfaction (T1). We used T-tests and Fisher's exact tests to compare arms and carrier groups.

RESULT: 274 participants were randomized to TD and 267 to VD. Of those with complete data (n = 409, 76%), the mean age was 67.1 YO, 64.1% were female, 92.2% were white; 77.8% reported a family history of AD and 29.8% were APOE4 homozygotes, 40.4% were heterozygotes and 29.8% were noncarriers. There were no significant differences among arms in knowledge or distress, but slightly higher satisfaction with TD (Table 1). There were no significant differences in secondary PROs. By genotype, the only differences by arm included change in perceived lifetime numerical risk from T0-T1 among homozygotes (TD -5.19 v. VD +4.07, p = 0.018), and T0-T2 among noncarriers (TD -13.33 v. VD -22.28, p = 0.053) and satisfaction with genetic services among heterozygotes (TD 40.46 v VD 38.65, p = 0.01). In analyses evaluating moderators of PROs that adjusted for result, state anxiety increased under TD and decreased under VD for non-White participants (T0-T1), but declined by a similar amounts under both modalities for White participants (p = 0.039).

CONCLUSION: Both telephone and videoconference are reasonable options for disclosure of APOE results in cognitively unimpaired individuals across all genotypes. While satisfaction was slightly higher with TD, small differences in numerical perceived risk by genotype and reductions in state anxiety among non-white participants, suggest potential small benefits to VD for some subgroups.}, } @article {pmid41433296, year = {2025}, author = {Alba, LO}, title = {Technology and Dementia Preconference.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21 Suppl 9}, number = {Suppl 9}, pages = {e110890}, doi = {10.1002/alz70863_110890}, pmid = {41433296}, issn = {1552-5279}, mesh = {Humans ; *Video Recording/standards ; *Social Media ; *Dementia ; Reproducibility of Results ; *Alzheimer Disease ; }, abstract = {BACKGROUND: Patients are increasingly using YouTube as a source of health-related information. This study assessed the quality and reliability of videos on Alzheimer's disease dementia (ADD) available on the platform.

METHOD: In October 2023, YouTube was systematically searched for ADD-related videos. Two independent physicians reviewed each video, scoring it using modified DISCERN (mDISCERN) for reliability and the Global Quality Scale (GQS) for content quality. Videos were categorized by goal and assessed for quality, accuracy, comprehensiveness, and specific content.

RESULT: There were 58 videos included in the study. Using the GQS, 16 videos (28%) were assessed as high quality, 32 videos (55%) as medium quality, and 10 videos (17%) as low quality. Using the mDISCERN scale, 48 videos (83%) were deemed reliable, while 10 videos (17%) were classified as unreliable. Videos from academic institutions and physicians exhibited higher mDISCERN and GQS scores compared to other groups (p = 0.004, p = 0.005, respectively), and a significant correlation was seen between mDISCERN and GQS (p < 0.001).

CONCLUSION: The majority of YouTube videos on ADD are good to fair quality, covering disease properties, treatment choices, and patient experiences. However, video popularity does not significantly correlate with content reliability and quality. Videos provided by academic institutions and healthcare professionals can help the general population to understand ADD.}, } @article {pmid41433293, year = {2025}, author = {Mechanic-Hamilton, D and Humphreys, V and Hing, D and Schankel, L and Brown, CA and Wolk, DA}, title = {Technology and Dementia Preconference.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21 Suppl 9}, number = {Suppl 9}, pages = {e110613}, doi = {10.1002/alz70863_110613}, pmid = {41433293}, issn = {1552-5279}, mesh = {Humans ; Male ; Female ; Pilot Projects ; Aged ; *Cognitive Dysfunction/diagnosis ; Neuropsychological Tests ; *Mobile Applications ; *Alzheimer Disease/diagnosis ; *Dementia/diagnosis ; Middle Aged ; }, abstract = {BACKGROUND: Mobile, valid and engaging cognitive assessments are essential for detecting and tracking change in cognition. With the approval of anti-amyloid therapies (AATs), there is a need to monitor for both benefits and risks of these therapies. This pilot study aims to determine the feasibility and usability of an at-home, app-based cognitive assessment, the mobile cognitive app performance platform (mCAPP), to remotely collect cognitive performance data in a cohort of patients with Mild Cognitive Impairment (MCI) or mild dementia due to Alzheimer's disease (AD) undergoing AAT.

METHOD: mCAPP includes three gamified tasks (Figure 1). Eleven participants with MCI or mild dementia due to AD used mCAPP in the clinic and at home for up to three months while undergoing AAT treatment. They also completed paper and pencil neuropsychological tests and questionnaires about their use of technology and mCAPP usability. Participants included 7 women and 4 men with 15.1±2.6 years of education who were amyloid positive according to either Amyloid PET or cerebrospinal fluid results and deemed eligible for treatment by a multi-disciplinary AAT consensus panel at the University of Pennsylvania.

RESULT: Participants played the mCAPP tasks in-clinic and consistently engaged in 1-3 sessions per week for up to 3 months at-home. All participants used a smartphone in their daily lives. mCAPP usability rating was 7.1±1.2 (0-9 scale). Most participants rated the difficulty of the tasks as "just right" for Concentration (89%), Brick Drop (78%), and Space Imposters (78%) after playing the games one time. All tasks showed lower performance when comparing low and high cognitive load blocks (p's<.001). mCAPP measures correlated with some, but not all, paper and pencil measures from analogous domains. An example of one patient's performance during AAT treatment is shown in Figure 2.

CONCLUSION: This pilot study shows mCAPP's usability for both in-clinic and at-home use in a cohort of patients undergoing AAT. Performance across measures indicate initial reliability and validity of mCAPP. Future analyses will include the evaluation of mCAPP performance across multiple timepoints, practice effects compared to participants with unimpaired cognition, and longitudinal data analysis over the course of anti-amyloid treatment.}, } @article {pmid41433150, year = {2025}, author = {Hara, N and Kamada, M and Yamaguchi, H and Uenishi, T and Tanizawa, Y and Ueda, K and Osaga, S and Hatakeyama, N}, title = {Survey on family caregiver experiences before and after dementia diagnosis and support-related issues in Japan.}, journal = {Current medical research and opinion}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/03007995.2025.2603820}, pmid = {41433150}, issn = {1473-4877}, abstract = {OBJECTIVE: This study aimed to elucidate the experiences of family caregivers of people with dementia before and after diagnosis, including regarding medical treatment and support.

METHODS: We conducted a survey of 198 family caregivers of people with dementia in Japan to assess caregiver experiences regarding medical examination and diagnosis, patient functional status, and support resources.

RESULTS: The mean time from suspicion of dementia to the start of medical evaluation was 15.1 months, and the mean time from the start of medical evaluation to a confirmed diagnosis was 4.7 months. Time to the initial medical visit was significantly longer when the family caregiver was a child or daughter- or son-in-law, when dementia onset was younger, or when the first noticed symptom was forgetfulness (all p < 0.001). Family caregivers received dementia-related information from medical institutions and community comprehensive support centers, but satisfaction with these resources varied. Early diagnosis was valued for clarifying concerns about observed changes (62.1% of respondents), whereas uncertainty until diagnosis caused the greatest anxiety (34.3%), underscoring the need for coordinated support.

CONCLUSION: Family caregivers of people with dementia reported barriers to timely diagnosis and post-diagnosis support, highlighting the need for improved care pathways, enhanced collaboration between medical institutions and communities, and better access to support resources.}, } @article {pmid41433006, year = {2025}, author = {Uppuluri, CT and Prasad, YSKV and Asadi, K and Kumari, TP and Pelluri, R and Chakravarthi, G and Nalluri, BN and Gurram, PC}, title = {PDE5 Inhibitors as Modulators of Alzheimer's-Associated Inflammation and Oxidative Stress: A Meta-Analytical Assessment of Preclinical Studies.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {322}, pmid = {41433006}, issn = {1559-1182}, mesh = {*Alzheimer Disease/drug therapy/metabolism/complications ; *Oxidative Stress/drug effects ; Animals ; *Phosphodiesterase 5 Inhibitors/therapeutic use/pharmacology ; *Inflammation/drug therapy/metabolism ; Humans ; Antioxidants/pharmacology ; Biomarkers/metabolism ; Anti-Inflammatory Agents/pharmacology/therapeutic use ; }, abstract = {Neuroinflammation and oxidative stress contribute significantly to cognitive decline, a hallmark of neurodegenerative diseases such as Alzheimer's disease (AD). Addressing cognitive decline is a critical medical need, and phosphodiesterase-5 inhibitors (PDE5Is) may offer a promising solution. This meta-analysis highlights the anti-inflammatory and antioxidant actions of PDE5Is, which may help counter neuroinflammation and oxidative stress in neurodegenerative diseases including AD. We reviewed over 1,258 studies and considered 34 preclinical rodent studies of inflammation or oxidative stress. Quantitative data on biomarkers such as Tumor necrosis factor alpha (TNF-α), Interleukin 1 beta (IL-1β), IL-6, NF-κB, IL-10, Superoxide dismutase (SOD), Catalase (CAT), Glutathione peroxidase (GPx), Glutathione (GSH), Malondialdehyde (MDA), Myeloperoxidase (MPO), and caspase-3 was extracted and analyzed using a random-effects model. Study quality was evaluated with a modified CAMARADES checklist, and heterogeneity was assessed using the I[2] statistic. PDE5Is treatment significantly lowered pro-inflammatory cytokines and oxidative stress markers, while boosting the levels of critical anti-inflammatory and antioxidant molecules. The pooled standardized mean differences (SMDs) indicated treatment efficacy for nearly all biomarkers. Notably, the studies on Alzheimer's models confirmed similar therapeutic benefits in reducing amyloid burden and enhancing cognitive outcomes. With a strong safety profile and ability to modulate Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Nuclear erythroid-related factor 2 (Nrf2) pathways, PDE5Is offer promising neuroprotective potential. Thus, repurposing PDE5Is may develop new disease-modifying therapies for Alzheimer's, making clinical investigation crucial.}, } @article {pmid41432804, year = {2025}, author = {Orso, B and Bollack, A and Sheikh, ZH and Morbelli, S and Pardini, M and Farrar, G}, title = {Heterogeneity of dementia with lewy bodies: Insights from clinical presentations, neuropathology, and biomarkers.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {1}, pages = {31}, pmid = {41432804}, issn = {1590-3478}, mesh = {Humans ; *Lewy Body Disease/pathology/genetics/diagnosis/physiopathology/diagnostic imaging/metabolism ; Biomarkers/metabolism ; *Brain/pathology/diagnostic imaging ; }, abstract = {BACKGROUND: Dementia with Lewy Bodies (DLB) is a neurodegenerative disorder characterised by α-synuclein pathology, causing cognitive decline, motor and non-motor symptoms. This review explores the clinical and neuropathological heterogeneity of DLB, which complicates its early diagnosis, prognosis, and treatment. The staging of Lewy body (LB) pathology varies, with both brain-first and body-first hypotheses suggesting different origins and pathways for disease progression. Co-pathologies, such as amyloid-β plaques, tau tangles, and cerebrovascular changes, further influence the clinical presentation and rate of disease progression in DLB patients, contributing to significant variability. In this review, the role of genetic factors, particularly APOE ε4 and GBA mutations, in shaping DLB's clinical and pathological diversity is also emphasized. Heterogeneous manifestations, including REM sleep behavior disorder (RBD), mild cognitive impairment, and psychiatric-onset DLB, highlight the need for improved biomarkers to guide early diagnosis. Neuroimaging techniques such as [[18]F]FDG PET and [[123]I]FP-CIT SPECT help distinguish DLB from other dementias, like Alzheimer's disease (AD), though challenges remain in identifying co-pathologies with precision.

CONCLUSION: Overall, the paper explores the complexity of DLB's heterogeneous nature, advocating for deeper exploration of its diverse pathological pathways, genetic predispositions, and clinical profiles to improve diagnosis and treatment outcomes. Understanding this heterogeneity is crucial for the development of personalized therapeutic strategies and effective management of the disease.}, } @article {pmid41432779, year = {2025}, author = {Bergamin, E and Turco, F and Unti, E and Del Chicca, M and Ceravolo, R and Tognoni, G and Del Prete, E}, title = {Functional propriospinal myoclonus in Alzheimer's disease: coincidence or a new challenge?.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {47}, number = {1}, pages = {34}, pmid = {41432779}, issn = {1590-3478}, mesh = {Humans ; Female ; *Alzheimer Disease/complications/physiopathology ; Middle Aged ; *Myoclonus/physiopathology/complications/diagnosis/etiology ; Electroencephalography ; }, abstract = {Propriospinal myoclonus (PSM) is a rare hyperkinetic movement disorder characterized by involuntary and repetitive axial muscle contractions. Although traditionally classified as idiopathic or symptomatic, a functional etiology has often been described for PSM. Functional neurological disorders (FNDs), including functional PSM, are defined by symptoms inconsistent with other organic neurological conditions and often arise from brain circuit dysfunction affecting emotion processing, agency, attention, interoception, and predictive processing. Electrophysiological biomarkers such as Bereitschaftspotential (BP) and event-related desynchronization (ERD) offer diagnostic support, with ERD showing promise for functional PSM diagnosis. We report the first case of functional PSM in a 61-year-old woman with Alzheimer's Disease (AD). She presented with involuntary arrhythmic trunk movements, associated with anxiety and restlessness, resolving with distraction. Electrophysiological evaluation revealed ERD without BP, supporting a functional diagnosis. The coexistence of FMDs and neurodegenerative diseases like AD, though rare, underscores shared pathophysiological mechanisms, including disrupted agency and altered cortical processing. Treatment with Sertraline improved motor symptoms and anxiety, illustrating the importance of personalized management strategies in such cases. This report highlights the necessity for clinicians to recognize FMD in neurodegenerative diseases, promoting accurate diagnosis through biomarkers and integrated treatment approaches to improve patient outcomes. Further research is essential to refine diagnostic tools and therapeutic strategies for functional PSM in AD.}, } @article {pmid41432310, year = {2026}, author = {Krattli, RP and Markarian, M and Madan, S and Swami, D and McQuade, A and Baulch, JE and Blurton-Jones, M and Acharya, MM}, title = {Comparing Functional Consequences of Human iPSC-Microglia and Neural Stem Cell-Derived Extracellular Vesicles in Mitigating Cognitive Decline in Alzheimer's Disease.}, journal = {Aging cell}, volume = {25}, number = {1}, pages = {e70341}, pmid = {41432310}, issn = {1474-9726}, support = {DISC1-10079//California Institute for Regenerative Medicine/ ; DISC2-12400//California Institute for Regenerative Medicine/ ; //UC Irvine Sue and Bill Gross Stem Cell Research Center/ ; R01CA262213//U.S. National Institutes of Health (NIH)/ ; }, mesh = {*Alzheimer Disease/pathology/complications/therapy ; Humans ; *Extracellular Vesicles/metabolism/transplantation ; Animals ; *Microglia/metabolism ; *Induced Pluripotent Stem Cells/metabolism/cytology ; Mice ; *Neural Stem Cells/metabolism ; *Cognitive Dysfunction/therapy/pathology ; Disease Models, Animal ; }, abstract = {Stem cell-derived extracellular vesicles (EVs) show promise as a therapeutic approach for neurodegenerative diseases, particularly Alzheimer's Disease (AD), where traditional regenerative interventions have achieved limited success. Our previous research demonstrated the neuroprotective benefits of human neural stem cell (hNSC)-derived EVs in 2- and 6-month-old AD mice (5xFAD) that exibited improved cognitive function and reduced AD-related neuropathology. This study aimed to compare the neuroprotective efficacy of EVs derived from two human cell lines: hNSCs from H9 embryonic stem cells and human iPSC-derived microglia (iMGLs). Additionally, we investigated the efficacy of an expanded EV treatment paradigm at subsequently longer time points. Three-month-old 5xFAD mice received weekly retro-orbital vein injections of either hNSC- or iMGL-derived EVs for 4 weeks. Cognitive function testing revealed comparable cognitive improvements in both EV treatment groups compared to vehicle-injected AD mice. Both iMGL- and hNSC-derived EVs significantly reduced amyloid beta plaques, astrogliosis, and microglial activation, while restoring synaptophysin and postsynaptic density protein PSD-95 to control levels in AD brains. Gene expression analysis revealed significantly reduced neuroinflammation and elevated neuroprotective signatures following both EV treatments. MicroRNA analysis of the EV-derived cargo revealed unique and shared miRNA signatures associated with differentially expressed genes in both cell lines. These findings demonstrate the feasibility and neuroprotective benefits of recurrent systemic injections of EVs derived from human NSCs and differentiated human microglia lines in alleviating cognitive dysfunction and neuropathology in Alzheimer's disease.}, } @article {pmid41431971, year = {2026}, author = {Mohammed, AI and Mohammed, AI and Reynolds, E}, title = {Mind Your Mouth: Impact of Oral Bacteria on Alzheimer's Disease.}, journal = {Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology}, volume = {55}, number = {1}, pages = {1-6}, doi = {10.1111/jop.70111}, pmid = {41431971}, issn = {1600-0714}, mesh = {*Alzheimer Disease/microbiology/etiology ; Humans ; Porphyromonas gingivalis/pathogenicity ; *Periodontitis/microbiology/complications ; *Mouth/microbiology ; Risk Factors ; Cognitive Dysfunction/microbiology ; }, abstract = {BACKGROUND: Emerging evidence suggests a compelling nexus between periodontitis, a chronic inflammatory disease associated with an oral infection, and the development of Alzheimer's disease. Porphyromonas gingivalis , a keystone periodontal pathogen, has been detected in Alzheimer's disease-affected brain tissue and implicated in triggering neuroinflammation and promoting hallmark pathologies, including amyloid-beta accumulation and tau hyperphosphorylation, through virulence factors such as gingipains. With Alzheimer's disease posing a mounting global health challenge and periodontitis affecting a significant portion of the population, recognizing this link is both timely and critical.

METHODS: This editorial explores the biological and epidemiological evidence linking periodontal health to cognitive decline, evaluating studies on pathogen presence, inflammatory mechanisms, and associations between oral infection and neurodegeneration.

RESULTS: Evidence indicates that oral infections, particularly periodontitis, may play a more central role in neurodegeneration than previously acknowledged. Detection of periodontal pathogens in brain tissue, along with mechanistic studies demonstrating promotion of hallmark Alzheimer's pathologies, highlights the potential impact of chronic oral inflammation on cognitive decline.

CONCLUSION: An integrated healthcare approach uniting dentistry, neurology, and public health is needed to prioritize oral health as a modifiable risk factor for dementia. Early diagnosis and treatment of periodontitis may represent a promising and underutilized strategy to reduce systemic inflammation and mitigate the risk of Alzheimer's disease.}, } @article {pmid41431125, year = {2025}, author = {Pérez-Ruixo, C and Li, L and Galpern, WR and Perez-Ruixo, JJ}, title = {Mechanistic Population Pharmacokinetic-Pharmacodynamic Model of the Tau-Targeted Antibody Posdinemab in Healthy Participants and Participants with Alzheimer's Disease.}, journal = {Clinical pharmacology and therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1002/cpt.70173}, pmid = {41431125}, issn = {1532-6535}, abstract = {Disrupted homeostasis and transneuronal spread of hyperphosphorylated Tau protein (pTau) are hypothesized to be key pathogenic drivers of Alzheimer's disease (AD). Posdinemab (JNJ-63733657), a humanized IgG1/kappa monoclonal antibody that targets phosphorylated Tau protein at amino acid 217 (p217+tau), is currently in clinical development for the treatment of AD. In a first-in-human Phase 1 study (NCT03375697), posdinemab was well tolerated at doses up to 60 mg/kg, demonstrated linear pharmacokinetics (PK) in serum, and induced dose-dependent reductions in p217+tau levels in cerebrospinal fluid (CSF). The objective of the current analysis was to develop a mechanism-based population pharmacokinetic-pharmacodynamic (popPK-PD) model to guide the Phase 2 (Auτonomy) dose selection of posdinemab in participants with AD using the Phase 1 data from 69 adults. A two-compartment model was selected, which successfully described the available clinical PK-PD data and demonstrated that posdinemab PK in serum is linear, dose-proportional, and time-independent. Suppression of free p217+tau in CSF was used to reflect free antibody available to bind tau seeds in interstitial fluid (ISF). The PK-PD model-based simulations for fixed intravenous doses of 1,000 mg and 3,000 mg every 4 weeks predicted >90% reduction in tau seeds in ISF by Day 391 and Day 154, respectively, following treatment initiation. This model provides a physiologically relevant simulation-framework to investigate the impact of various posdinemab dose levels on PK-PD profiles, thereby supporting the clinical trial design of the Auτonomy study (NCT04619420).}, } @article {pmid41430548, year = {2025}, author = {Li, L and Kong, J and Fan, R and Yuan, Y and Zhu, L}, title = {Role of tRNA-Derived Fragments and Their Modifications in the Pathogenesis and Treatment of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {321}, pmid = {41430548}, issn = {1559-1182}, mesh = {*Alzheimer Disease/genetics/therapy/metabolism/pathology ; *RNA, Transfer/metabolism/genetics ; Humans ; Animals ; }, abstract = {Transfer RNAs (tRNAs), an essential class of noncoding RNAs, have recently emerged as a hotspot in the study of neurodegenerative diseases. The biological function of tRNA depends on precise processing and complex chemical modifications. During processing, tRNAs not only produce functional tRNAs used in protein synthesis but also generate tRNA-derived fragments (tRFs) that play roles in gene expression regulation. In addition, a series of chemical modifications, such as methylation, occur on the bases or phosphate backbone of tRNAs. In the progression of Alzheimer's disease (AD), researchers have observed significant changes in both the abundance and modification patterns of tRFs. This review summarizes the roles and regulatory mechanisms of tRFs and their chemical modifications in AD and integrates findings on potential tRF target genes to provide new insights into the pathogenesis of AD. Evidence suggests that distinct tRFs regulate gene expression through complementary interactions with specific targets. For example, AS-tDR-011389 upregulates CaMK2N1 expression by binding to its 3' untranslated region, suggesting that it may modulate calcium homeostasis in AD because CaMK2N1 is known to be involved in calcium signaling. Furthermore, tRF5-ProAGG was shown to target SV2B through predicted tRF5-mRNA pairing and qRT-PCR validation. Dysregulation of SV2B expression indicates that tRF5-ProAGG may influence synaptic vesicle trafficking and synaptic plasticity, thereby affecting neurotransmitter release and synaptic transmission in AD. Additionally, widespread reductions in cytoplasmic and mitochondrial tRNA methylation, accompanied by decreased expression of modification enzymes, have been observed in 5XFAD mice. These aberrant modifications may impair tRNA function, disrupt gene expression and protein translation, and ultimately contribute to AD progression.}, } @article {pmid41429557, year = {2025}, author = {Liu, HY and Lin, YL}, title = {[Advances in measurements and standardization of plasma phosphorylated tau217 as a biomarker for Alzheimer's disease].}, journal = {Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine]}, volume = {59}, number = {12}, pages = {2209-2215}, doi = {10.3760/cma.j.cn112150-20250331-00265}, pmid = {41429557}, issn = {0253-9624}, support = {320.6750.2024-03-38//Wu Jieping Medical Foundation "Reference Interval and Clinical Application of Plasma biomarkers p-Tau217 and NfL in Alzheimer's Disease"/ ; 2023A04J0439//School-enterprise Joint Project of Guangzhou Science and Technology Commission Institute "Molecular Markers of Genetic Susceptibility to Patients with Alzheimer's Disease"/ ; 2026C-TS046//Clinical Characteristic Project in Guangzhou "Combined Detection of Alzheimer's Disease Risk Genes and Pharmacogenomics Based on MALDI-TOF Mass Spectrometry"/ ; }, mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *tau Proteins/blood ; Biomarkers/blood ; Phosphorylation ; }, abstract = {With the approval of targeted drugs for modification therapy of Alzheimer's disease, the role of blood markers in the diagnosis and treatment of Alzheimer's disease is becoming more and more important. The economical and easily accessible plasma phosphorylated tau217 (p-tau217) is one of the most promising biomarkers for clinical application. Since it was first found in 2020, it has attracted wide attention in just a few years, rapidly becoming a research hotspot in this field, and is adopted as one of the core diagnostic biomarkers. This article reviewed the clinical measurements of plasma p-tau217 and the standardization of sample processing.}, } @article {pmid41429381, year = {2025}, author = {AmeliMojarad, M and AmeliMojarad, M}, title = {Antibody drug conjugates in Alzheimer's disease: emerging strategies and future directions.}, journal = {Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.neuroscience.2025.12.053}, pmid = {41429381}, issn = {1873-7544}, abstract = {Antibody-drug conjugates (ADCs) are emerging as a targeted therapeutic strategy for Alzheimer's disease (AD), offering precise delivery of disease modifying agents with reduced systemic toxicity. By linking monoclonal antibodies to small-molecule payloads, ADCs hold promise in overcoming key challenges in AD treatment, including poor blood-brain barrier (BBB) penetration and off-target effects. This review provides a critical synthesis of ADC strategies in neurodegeneration, with emphasis on molecular design, payload selection, and delivery mechanisms. Distinctively, we integrate lessons from oncology-based ADC development into the neurodegenerative context, highlighting how these cross disciplinary insights open new avenues for tackling multifactorial AD pathology, including amyloid-beta (Aβ) and tau-related mechanisms. By outlining translational progress, ongoing clinical efforts, and future directions, this review positions ADCs not only as a promising precision medicine approach but also as a novel framework for advancing therapeutic innovation in complex neurodegenerative disorders.}, } @article {pmid41429258, year = {2026}, author = {Zoroddu, S and Sedda, S and Mangoni, AA and Carru, C and Zinellu, A}, title = {Malondialdehyde in cognitive impairment: A systematic review and meta-analysis.}, journal = {Neuroscience and biobehavioral reviews}, volume = {181}, number = {}, pages = {106531}, doi = {10.1016/j.neubiorev.2025.106531}, pmid = {41429258}, issn = {1873-7528}, mesh = {Humans ; *Cognitive Dysfunction/blood ; *Malondialdehyde/blood ; *Alzheimer Disease/blood ; Biomarkers/blood ; Oxidative Stress/physiology ; }, abstract = {Malondialdehyde (MDA) is a marker of lipid peroxidation and oxidative stress, processes involved in neurodegeneration and cognitive decline. This systematic review and meta-analysis evaluated circulating MDA concentrations in individuals with Alzheimer's disease (AD) or mild cognitive impairment (MCI) compared to cognitively healthy controls. A systematic search of PubMed, Scopus, and Web of Science up to 18 July 2025 identified 36 studies (48 group comparators) including 2132 patients and 2169 controls. Pooled analysis revealed significantly higher MDA concentrations in cognitively impaired individuals (SMD = 1.46, 95 % CI 1.10-1.83; p < 0.001), with consistent increases in both AD (SMD = 0.82) and MCI (SMD = 1.24). Subgroup analyses showed comparable results across serum and plasma samples and across different geographical regions, while the analytical method influenced the effect size. Trim-and-fill analysis confirmed the robustness of findings despite publication bias. Circulating MDA is elevated in cognitive impairment, supporting its potential as a biomarker of early neurodegeneration and oxidative stress. Future studies should standardize measurement approaches and assess the utility of MDA for prognosis and treatment response.}, } @article {pmid41428961, year = {2025}, author = {Hasegawa, M and Kawaguchi, T and Kiyohara, H and Teratani, T and Nakamoto, N and Mikami, Y and Kanai, T}, title = {Neural regulation of gut inflammation via autonomic nerves: therapeutic implications for inflammatory bowel disease.}, journal = {Immunological medicine}, volume = {}, number = {}, pages = {1-24}, doi = {10.1080/25785826.2025.2604347}, pmid = {41428961}, issn = {2578-5826}, abstract = {Inflammatory bowel disease (IBD) is a debilitating and treatment-refractory condition with a complex and incompletely understood etiology. Recent advances in neuroimmunology have revealed that intestinal homeostasis is regulated by bidirectional communication between the autonomic nervous system and the immune system. In particular, vagus nerve-mediated cholinergic anti-inflammatory signaling plays a central role in modulating intestinal immune responses and represents a key mechanism linking neural regulation to IBD pathogenesis and therapy. In parallel, the gut-brain axis has emerged as a critical regulator of intestinal inflammation and systemic disease. Psychological stress alters gut immune function through mechanisms involving enteric glial activation and microbiota-derived metabolites, contributing to treatment-resistant depression via immune activation and changes in short-chain fatty acid profiles. Moreover, gut microbiota dysbiosis has been implicated in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, potentially preceding central pathology through vagal signaling and systemic inflammation. Together, these findings position the gut microbiota as an immunological and neurological hub connecting intestinal, systemic, and brain health. This review summarizes recent advances in gut-brain axis-mediated immune regulation in IBD and highlights emerging bioelectronic neuromodulation strategies targeting autonomic circuits as promising non-pharmacological approaches to restore gut immune balance.}, } @article {pmid41428676, year = {2025}, author = {Tang, P and Chen, X and Li, P and Zhang, L and Tang, B and Wen, J and Liu, Y and Kalsoom, I and Cheng, C}, title = {Discovery of F-18 labeled repurposed CNS drugs by computational strategy for effective tau imaging and alzheimer's diagnosis.}, journal = {PloS one}, volume = {20}, number = {12}, pages = {e0338901}, pmid = {41428676}, issn = {1932-6203}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis/metabolism/drug therapy ; *tau Proteins/metabolism ; Humans ; *Drug Repositioning/methods ; *Fluorine Radioisotopes/chemistry ; *Central Nervous System Agents/chemistry/pharmacology ; Positron-Emission Tomography/methods ; Blood-Brain Barrier/metabolism ; Algorithms ; Drug Discovery ; }, abstract = {Alzheimer's disease (AD) remains a significant challenge in diagnosis and treatment, with current methods insufficient for early detection. A major obstacle is the lack of effective imaging agents targeting the Tau protein, which plays a key role in AD pathology. To address this, we developed a computational methodology for selecting F-18 labeled drug candidates from a library of CNS-penetrant compounds curated from literature and databases. The library, consisting of 977 compounds, was evaluated based on clinical data, target proteins, pathways, toxicity, and other relevant factors. We implemented Python-based algorithms to select the top 39 compounds from virtual screening results, prioritizing those with optimal Tau binding affinity and BBB permeability. Additionally, we developed an algorithm to identify F-18 labeling candidates that maintain their biological activity post-labeling. We then performed virtual screening of an F-18 labeled drug library and selected the top 3 compounds based on stability and imaging potential. The selected compounds exhibited molecular weights of 350-520 Da, favorable logP values (2.05-2.72), and high BBB permeability. Our findings indicate that Drug 388 (BI-D1870), binds to Tau with a binding free energy of ΔG = -8.79 kcal/mol. Drug 416 (reported BRAF inhibitor, RG6344) shows a binding free energy of ΔG = -7.91 kcal/mol, while Drug 610 (Iloperidone/HP 873), a D2/5-HT2 receptor antagonist, exhibits a predicted binding free energy of ΔG = -6.88 kcal/mol with the target Tau protein respectively. Molecular dynamics simulations confirmed stable Tau-drugs interactions, with minimal RMSD fluctuations, indicating strong binding. The F-18 label enabled real-time PET imaging, allowing non-invasive tracking of the drug's binding to Tau in the brain. Our approach provides a comprehensive solution to the current limitations in Alzheimer's diagnosis by offering F-18 labeled drugs that effectively target Tau protein without compromising their biological activity, advancing both diagnostic and therapeutic strategies for AD.}, } @article {pmid41428481, year = {2025}, author = {Feng, T and Chen, W and Bian, Z and Sun, H and Shen, L}, title = {Protective effects of Dendrobium nobile Lindl. alkaloids in a novel mouse model of Alzheimer's disease with chronic cerebral hypoperfusion.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251406645}, doi = {10.1177/13872877251406645}, pmid = {41428481}, issn = {1875-8908}, abstract = {BackgroundIncreasing numbers of studies indicate that the pathophysiological progression of Alzheimer's disease (AD) could be accelerated by chronic cerebral hypoperfusion (CCH). These findings suggest that cerebrovascular dysfunction may induce cognitive impairment in AD by expediting neurodegeneration. Dendrobium nobile Lindl. alkaloids (DNLA), the primary active components of Dendrobium nobile Lindl., have been shown to enhance cognitive function and exhibit neuroprotective effects in AD animal models.ObjectiveHowever, the impact of DNLA on AD with CCH is still elusive.MethodsIn this study, we explored the therapeutic potential and underlying mechanisms of DNLA using a novel AD plus CCH mouse model.ResultsOur results demonstrate that DNLA significantly improved cerebral blood flow, attenuated motor and cognitive decline, reduced amyloid-β deposition, mitigated neuroinflammation, and alleviated neural oxidative stress in 12-month-old AD mice with CCH.ConclusionsOur study suggests that DNLA exerts multiple neuroprotective effects, effectively preserving motor and cognitive function in AD with CCH mice of 12 months. Thus, DNLA represents a promising therapeutic candidate for the prevention and treatment of AD plus CCH.}, } @article {pmid41428479, year = {2025}, author = {Ji, Y and Cui, X and Ding, Z and Wang, X and Wang, Y and Zhang, Y and Yuan, Z and Chang, Z and Liu, K and Liu, Y}, title = {Reveal the mechanism of action of donepezil combined with nimodipine in the treatment of Alzheimer's disease via metabolomics and lipidomics analyses in rats.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251407109}, doi = {10.1177/13872877251407109}, pmid = {41428479}, issn = {1875-8908}, abstract = {BackgroundWith the aging population, the number of Alzheimer's disease (AD) patients has been increasing annually, creating an urgent need for AD therapeutic drugs. Donepezil combined with nimodipine (DN) has demonstrated therapeutic potential in the treatment of AD, but its mechanism of action remains unclear.ObjectiveTo reveal the mechanism of DN in the treatment of AD rats.MethodsThe AD rat model was established and evaluated by behavioral experiments and pathology. The therapeutic mechanism of DN in AD treatment was investigated through lipidomics and hippocampal metabolomics analyses based on ultra-high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q-TOF/MS).ResultsThe learning and memory ability of AD rats can be improved after DN treatment. Significant changes were observed in 40 serum lipid metabolites and 19 hippocampal metabolites. These metabolites are mainly involved in glycerophospholipid metabolism, sphingolipid metabolism, amino acid metabolism, unsaturated fatty acid metabolism and other processes in AD rats.ConclusionsDN could improve cognitive function and nerve damage in AD rats. It may plays a therapeutic role in AD rats by regulating cholinergic damage, Ca[2+] overload, oxidative stress, neuroinflammation, and energy deficiency caused by metabolic disorders, which has practical significance for further research and clinical application of DN.}, } @article {pmid41428477, year = {2025}, author = {Solfrizzi, V and Imbimbo, BP}, title = {Comparing clinical effect sizes of Souvenaid[TM], lecanemab, and donanemab in early Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251406221}, doi = {10.1177/13872877251406221}, pmid = {41428477}, issn = {1875-8908}, abstract = {BackgroundLecanemab and donanemab are anti-amyloid-β monoclonal antibodies recently approved in the United States and Europe for the treatment of early Alzheimer's disease (AD). Their modest clinical benefit, safety profile, and cost raise debate about real-world applicability. Fortasyn Connect (Souvenaid[TM]), a multi-nutrient intervention, has shown potential clinical benefits in prodromal AD.ObjectiveTo compare the clinical effect sizes (Cohen's d) and estimated months of preserved independence in instrumental activities of daily living (IADLs) for lecanemab, donanemab, and Souvenaid™, based on published pivotal clinical trial data.MethodsCohen's d on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) was computed using standardized mean differences and 95% confidence intervals (CIs) derived from published trials. Times of functional independence were estimated using the Hartz approach.ResultsPoint estimates of Cohen's d effect sizes on CDR-SB were -0.34, -0.33, and -0.52 for lecanemab, donanemab, and Souvenaid™, respectively, with no statistically significant differences between drugs. Estimated gains in IADL independence were 10 months for lecanemab, 8 months for donanemab, and 27 months for Souvenaid™.ConclusionsDespite differences in study designs, Souvenaid[TM] demonstrated comparable clinical efficacy with superior safety, accessibility, and cost profile. These findings support further evaluation of Souvenaid[TM] as a non-invasive, scalable option in early AD management.}, } @article {pmid41428410, year = {2025}, author = {Gravelsins, L and Gervais, NJ and Brown, A and Ramana, S and Zhao, S and Nicoll, G and Bernardini, MQ and Jacobson, M and Einstein, G}, title = {Younger midlife females with bilateral salpingo-oophorectomy: respiratory disturbances during sleep.}, journal = {Climacteric : the journal of the International Menopause Society}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/13697137.2025.2595987}, pmid = {41428410}, issn = {1473-0804}, abstract = {OBJECTIVE: There are many menopauses; bilateral oophorectomy is associated with the worst cognitive outcomes. Compared to females with intact ovaries, females with bilateral oophorectomy experience early, abrupt ovarian hormone loss and are at increased risk for later-life Alzheimer's disease. They also have double the odds of developing later-life sleep disordered breathing (SDB) - a modifiable Alzheimer's risk factor. With respect to bilateral oophorectomy, it is unknown when respiratory disturbances occur or whether estradiol therapy (ET) ameliorates them. Also unknown is whether SDB influences cognition in this group.

METHOD: Females with risk-reducing bilateral salpingo-oophorectomy (BSO) taking ET (BSO+ET, n = 19) or not (BSO, n = 16) and premenopausal age-matched controls (AMC, n = 17) were assessed for SDB markers using take-home polysomnography and for working memory performance.

RESULTS: The BSO group showed signs of respiratory disturbance compared to the AMC group. Memory performance was uncorrelated with respiratory metrics. While the BSO+ET group showed an intermediate sleep phenotype, estrone glucuronide levels correlated with improved respiratory metrics.

CONCLUSION: The results suggest that respiratory disturbances manifest as early as 5 years post-BSO in younger females; ET offers some amelioration. The close relationship between sleep disruption and Alzheimer's risk emphasizes the importance of SDB screening post-BSO for early intervention.}, } @article {pmid41428270, year = {2025}, author = {Verma, S and Kumari, K and Kesharwani, P and Verma, K and Dwivedi, J and Paliwal, S and Sharma, S}, title = {Is the Era of One-Size-Fits-All Alzheimer's Treatment Officially Over?.}, journal = {Journal of molecular neuroscience : MN}, volume = {76}, number = {1}, pages = {3}, pmid = {41428270}, issn = {1559-1166}, mesh = {*Alzheimer Disease/drug therapy/therapy/metabolism ; Humans ; Animals ; Precision Medicine ; Biomarkers ; }, abstract = {Alzheimer's disease (AD) is prevalent in more than 55 million worldwide, a figure estimated to almost triple by 2050, highlighting the need for highly effective treatments. However, despite the large expenditure of research over several decades, over 90% of clinical trials-countless amyloid-β-targeted drugs among them-have failed, stressing the shortcomings of reductionist, one-target approaches. More and more, AD is viewed as a complex systems disorder, resulting from interlinked disruptions in proteostasis, neuroinflammation, vascular integrity, synaptic plasticity, and metabolic regulation. Such an understanding has transformed the therapeutic paradigm toward precision, multimodal treatment, integrating disease-modifying agents with biomarker-based diagnosis and patient stratification. Improved blood- and imaging-based biomarkers, new molecular targets, and drug-delivery technologies offer the hope for earlier intervention and more personalized treatment. Looking to the future, the way forward will rely on the integration of systems biology, computational modeling, and translational neuroscience into adaptive trial design able to tackle the heterogeneity of the disease. These developments combined constitute the progressive shift away from "one-size-fits-all" treatments towards a future of personalized, mechanism-based therapies in Alzheimer's disease.}, } @article {pmid41428168, year = {2025}, author = {Babu, PR and Turner, C and Ryznar, R}, title = {Cross-seeding of IAPP and Aβ42: A review of the molecular link between type 2 diabetes and Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {8}, pmid = {41428168}, issn = {1573-7365}, abstract = {UNLABELLED: Alzheimer’s Disease (AD) and Type 2 Diabetes Mellitus (T2DM) are interconnected conditions, both marked by the aggregation of amyloidogenic proteins: amyloid-β 42 (Aβ42) in AD and islet amyloid polypeptide (IAPP) in T2DM. Emerging evidence suggests that IAPP can cross the blood–brain barrier and interact with Aβ42, forming heterocomplexes that promote aggregation. This narrative review aims to describe the molecular mechanisms underlying IAPP and Aβ42 cross-seeding and evaluate its contribution to AD pathogenesis in the context of T2DM. A systematic search of PubMed was conducted using relevant MeSH terms. IAPP-Aβ42 cross-seeding enhances amyloid aggregation and cytotoxicity, but its impact on AD progression is best understood as part of a multifactorial process rather than a single driving cause. While preclinical models suggest amyloid-targeting approaches can reduce amyloid burden, clinical trials have largely failed to show cognitive benefits, likely due to late-stage intervention and the complex pathology of AD. Future research should focus on identifying early biomarkers for AD, clarifying IAPP-Aβ42 cross-seeding mechanisms, and exploring combination therapies targeting multiple pathological pathways. Early intervention may improve treatment efficacy, particularly in patients with comorbid T2DM.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11011-025-01767-8.}, } @article {pmid41427392, year = {2025}, author = {LaGrow, TJ and Itkyal, V and Watters, H and Jensen, KM and Ballem, R and Pan, WJ and Iraji, A and Calhoun, VD and Keilholz, S}, title = {Spatiotemporal Network Dynamics Reveal Alzheimer's Disease Progression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41427392}, issn = {2692-8205}, support = {R01 AG062581/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive disruptions in large-scale brain networks that precede cognitive decline, yet conventional functional connectivity analyses often fail to detect disruptions in coordination among large-scale brain networks that may be critical for early detection. This study leverages quasi periodic patterns (QPPs) and complex principal component analysis (cPCA) to characterize spatiotemporal network alterations across longitudinally stable (normal cognitive, mild cognitive impairment, dementia of Alzheimer's type) and transitioning (normal cognitive to mild cognitive impairment, mild cognitive impairment to dementia of Alzheimer's type) cohorts from the Alzheimer's Disease Neuroimaging Initiative using resting state fMRI. QPPs were used to derive recurrent spatiotemporal templates and network integrity measures at the intrinsic connectivity network level, while cPCA decomposed Hilbert transformed time series into complex valued patterns that capture amplitude and phase relationships. Nonparametric group comparisons revealed a structured trajectory in which limbic, subcortical, and higher cognition networks, including triple network components, are affected early, followed by progressive disruption in visual, cerebellar, sensorimotor, and additional triple network systems. Transitioning cohorts showed many of these alterations before formal diagnostic conversion, indicating that spatiotemporal signatures carry preclinical information. QPP based metrics were particularly sensitive to limbic and subcortical degradation, whereas cPCA emphasized changes in higher order, visual, and cerebellar patterns, revealing complementary aspects of the same underlying pathology. These findings extend prior QPP only work and highlight the utility of combining QPP and cPCA based measures as a dynamic, network-level biomarker framework for AD progression. with potential applications in early detection, characterizing disease trajectories, and treatment monitoring.}, } @article {pmid41427244, year = {2025}, author = {Balagurusamy, B and Ganesan, V and Gopi, V and Ilayaperumal, P}, title = {Liposomal and Nanomaterial-Based Strategies for Targeted Alzheimer's Disease Therapy.}, journal = {ACS omega}, volume = {10}, number = {49}, pages = {60004-60019}, pmid = {41427244}, issn = {2470-1343}, abstract = {Alzheimer's disease (AD) remains a major neurodegenerative disorder with limited therapeutic options. Liposomal drug delivery has emerged as a promising strategy to enhance drug bioavailability and targeted delivery across the blood-brain barrier. This review explores the role of liposomes and nanomaterials in AD therapy, focusing on their versatility for drug delivery, including intranasal formulations, gene therapy, and reactive oxygen species (ROS)-responsive systems. Various liposomal formulations, such as mannose-modified, antibody-targeted, exosome-like, and biomaterial-based carriers, have shown significant potential in improving therapeutic efficacy. Natural compound-loaded liposomes, including polyphenols, tannic acid, and plant extracts, offer neuroprotective benefits. Furthermore, the inhibition of amyloid-β (Aβ) aggregation, a key pathological feature of AD, is addressed through innovative liposomal approaches, including peptide-conjugated, chiral-modified, and transferrin-targeted liposomes. This review highlights the synergistic role of glymphatic clearance and microglial phagocytosis in reducing the amyloid burden. Liposomal-based strategies are promising for advancing AD treatment by improving drug stability, specificity, and brain-targeting efficiency.}, } @article {pmid41427231, year = {2025}, author = {Borrego-Sánchez, A and García-Frutos, EM and Darder, M and Sainz-Díaz, CI}, title = {Molecular Insights of 7‑Azaindole Drugs and Their Intercalation in the Confined Space of Montmorillonite.}, journal = {ACS omega}, volume = {10}, number = {49}, pages = {60287-60297}, pmid = {41427231}, issn = {2470-1343}, abstract = {Two derivatives of the group of 7-azaindoles, 1-benzyl-3-(piperidin-1-ylmethyl)-1H-pyrrolo [2,3-b] pyridine, and 1-benzyl-5-methoxy-3-(piperidin-1-ylmethyl)-1H-pyrrolo [2,3-b] pyridine as mono-oxalate salts are studied in this work as potential neuroprotective drugs for the treatment of Alzheimer's disease. Previously, we studied the use of a natural montmorillonite clay mineral as a candidate for a drug delivery system, finding that these drugs can be intercalated into the confined interlayer space of montmorillonite and subsequently released in a human medium for therapeutic use. However, some aspects of this study could not be explained. This work has studied this process at the atomic and molecular levels by using the Interface force field (FF). Initially, this methodology was validated in this work, reproducing the experimental crystal structure of these 7-azaindole drugs. Then, this FF was applied to calculate the intercalation of these drugs by cation exchange into montmorillonite according to the experimental results. Our calculations have reproduced this intercalation at the cation exchange capacity at the molecular level, finding that the experimental structure can only be justified with the intercalation of five drug molecules per 4 × 2 × 1 supercell of clay mineral inside the confined interlayer space. In addition, this intercalation does not produce a monolayer disposition postulated initially from experiments. On the contrary, our molecular dynamics simulations show that the intercalated molecules adopt a disordered disposition with a certain tendency to form a bilayer configuration in the confined interlayer space of montmorillonite. Besides, the spectroscopic infrared properties are useful for monitoring the preparation and encapsulation processes of pharmaceutical drugs. Then, these properties were studied experimentally and calculated theoretically. The calculated frequencies of the crystal structure of these 7-azaindole drugs allowed assignments of the experimental FT-IR spectra. This collaborative work with experimental and theoretical research enhances the knowledge for a promising drug delivery system for anti-Alzheimer therapy.}, } @article {pmid41426989, year = {2025}, author = {Sagaro, GG and Amenta, F}, title = {Comparison of the effects of choline alphoscerate and citicoline in patients with dementia disorders: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1649661}, pmid = {41426989}, issn = {1664-2295}, abstract = {BACKGROUND: Over 44 million people worldwide live with dementia, affecting their quality of life and well-being. Choline alphoscerate and citicoline supplements are commonly used to improve cognitive function in dementia patients. However, their efficacy remains inconsistent.

OBJECTIVE: This systematic review aimed to investigate and compare the effects of choline alphoscerate and citicoline on cognitive impairments, behavioural symptoms, and other clinical conditions in patients with dementia disorders.

METHODS: PubMed and Scopus were searched to identify relevant studies. We calculated weighted mean differences (WMD) or standardized mean differences (SMD) and 95% confidence intervals (CI) for continuous outcomes and odds ratios (OR) and 95% CI for binary outcomes.

RESULTS: This review included data from 358 participants across three randomized controlled trials (RCTs). As measured by the Sandoz Clinical Assessment for Geriatric Patients (SCAG), choline alphoscerate significantly improved clinical conditions in patients with dementia disorders compared with citicoline at the end of treatment [WMD: -3.92 (95% CI: -7.41 to -0.42)]. Specifically, our pooled analysis revealed that choline alphoscerate showed significant improvements in cognitive function, interpersonal relationships, affective disorders, apathy, and somatic functioning compared to citicoline at the end of treatment, as measured by the SCAG. However, there was no significant difference between the choline alphoscerate and citicoline treatment groups on memory or word fluency tests (WFT). Dropout rates for choline alphoscerate and citicoline were 9.4 and 6.7%, respectively [OR: 1.44 (95% CI: 0.66 to 3.13)], indicating no significant differences in acceptability.

CONCLUSION: Our findings indicate that choline alphoscerate is more effective than citicoline in improving the clinical conditions of dementia patients.

https://www.crd.york.ac.uk/PROSPERO/view/CRD42024626782, Identifier: CRD42024626782.}, } @article {pmid41426276, year = {2025}, author = {Sun, W and Bi, H and Qi, Z and Hu, M and Wang, W}, title = {Status and trends of transcranial magnetic stimulation research in Alzheimer's disease: A bibliometric and visual analysis.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251407542}, pmid = {41426276}, issn = {2542-4823}, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive memory loss and cognitive dysfunction and is the most common cause of dementia. In recent years, transcranial magnetic stimulation (TMS) has been widely used in the treatment of AD and has achieved better therapeutic results. In this study, from the perspective of bibliometrics, we used VOSviewer and CiteSpace software to visualize and analyze the research progress of TMS in AD in terms of scientific knowledge mapping, and to systematically review the current status and trend of the global research on TMS in the treatment of AD, in order to provide references and guides for future research in this field. Our bibliometric analysis of 605 publications (1999-2024) reveals three pivotal findings: The Italy dominate TMS-AD research output; repetitive transcranial magnetic stimulation (rTMS) targeting the precuneus and dorsolateral prefrontal cortex (DLPFC) shows consistent cognitive benefits; Emerging technologies are reshaping therapeutic precision. Intermittent theta burst stimulation as an emerging TMS stimulation mode is gradually becoming a future research direction. In the future, more attention will be paid to individualized therapeutic solutions and more precise stimulation with the help of neuronavigation to improve the therapeutic effect of TMS.}, } @article {pmid41425927, year = {2025}, author = {Qin, R and Li, C and Yuan, X and Chen, Y}, title = {Microbiome-targeted Alzheimer's interventions via gut-brain axis.}, journal = {Frontiers in microbiology}, volume = {16}, number = {}, pages = {1729708}, pmid = {41425927}, issn = {1664-302X}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options, underscoring the need for novel therapeutic targets. The gut-brain axis has emerged as a critical bidirectional communication system, with growing evidence establishing gut dysbiosis as a causal factor in AD pathogenesis. This dysbiosis, characterized by a reduction in beneficial microbes and an increase in pro-inflammatory taxa, compromises intestinal and blood-brain barrier integrity, promoting systemic inflammation and the translocation of neurotoxic agents like lipopolysaccharide (LPS). Consequently, the balance of key microbial metabolites is disrupted, reducing neuroprotective short-chain fatty acids (SCFAs) and indoles while elevating inflammatory mediators, which collectively exacerbate neuroinflammation, amyloid-β (Aβ) deposition, and tau pathology. This review evaluates promising interventions, including probiotics, anti-inflammatory diets, exercise, and phytochemicals that can restore microbial balance, enhance barrier function, and improve cognitive outcomes in preclinical and early clinical studies. However, clinical translation is hindered by an overreliance on animal models, short-term studies, and insufficient mechanistic insight. Future research must prioritize large-scale human trials, multi-omics integration to elucidate signaling pathways, and personalized approaches that account for host genetics and baseline microbiome composition to fully harness the therapeutic potential of the gut-brain axis for AD.}, } @article {pmid41425084, year = {2025}, author = {Pérez-Martínez, DA and Jarry, AC and Martino, G and Pesce, G and Pieniazek, I and Presto, J and Miernik, P and Casciano, R and Frederiksen, KS}, title = {Uncovering barriers to early diagnosis of Alzheimer's disease: a European perspective.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {4}, pages = {e70178}, pmid = {41425084}, issn = {2352-8737}, abstract = {INTRODUCTION: Timely and accurate diagnosis of early Alzheimer's disease (AD) is critical to maximizing the potential benefits of disease-modifying therapies; however, it remains a challenge in clinical practice.

METHODS: A double-blind survey was conducted among general practitioners (GPs; n = 52) and AD specialists (neurologists, psychiatrists, geriatricians, and others; n = 75) across five European countries to evaluate healthcare practitioners' (HCPs) perceptions of diagnosing AD. Data from all countries were pooled and presented overall.

RESULTS: GPs are usually the first point of contact for patients with mild cognitive impairment (MCI)/AD. Only 30% of patients received a formal diagnosis of AD during the MCI stage, and it took patients 15.2 months from symptom onset to their first primary care visit. The most common challenges identified by HCPs were referral times, lack of effective treatment, and resource and time constraints.

DISCUSSION: Systemic reforms are required to remove barriers in early AD diagnosis, including tailored training and coordinated care between GPs and AD specialists.

HIGHLIGHTS: Timely diagnosis of eAD remains a major challenge in clinical practice.Only one-third of patients received a formal diagnosis of AD during the MCI stage.It took patients 15.2 months from symptom onset to first primary care visit.Key diagnostic barriers include referral delays and lack of effective treatments.Addressing these issues may improve eAD diagnosis and timely intervention.}, } @article {pmid41424971, year = {2025}, author = {Zhao, J and Wang, X and Li, B}, title = {The Bidirectional Mechanism of Uric Acid Levels on Alzheimer's Disease: A Narrative Review.}, journal = {International journal of general medicine}, volume = {18}, number = {}, pages = {7639-7651}, pmid = {41424971}, issn = {1178-7074}, abstract = {Alzheimer's disease (AD) is a central nervous system disorder marked by the extracellular accumulation of β-amyloid (Aβ) plaques in the cerebral cortex and the intracellular aggregation of hyperphosphorylated tau protein, manifesting as progressive cognitive decline and neurodegeneration. The pathological mechanisms of AD are intricate, in clinical treatment, cholinesterase inhibitors have been widely used for many years as symptomatic therapy, alleviating symptoms by improving neurotransmitter levels, but they cannot halt disease progression. Anti-Aβ monoclonal antibodies belong to disease-modifying therapies, although they have achieved breakthrough advances in recent years, strict monitoring requirements must be followed. In recent years, numerous studies have revealed a "U-shaped" association between uric acid (UA) levels and AD risk, along with population heterogeneity. Furthermore, fluctuations in UA levels exert a "bidirectional effect" on AD. At physiological concentrations, UA may confer neuroprotective benefits through antioxidant activity, inhibition of neuroinflammation, preservation of the blood-brain barrier (BBB), regulation of autophagy, and promotion of the clearance of Aβ and tau proteins. Conversely, abnormal UA levels may accelerate AD progression by inducing oxidative stress, activating inflammatory responses, and compromising the BBB. We conducted a comprehensive literature review across multiple medical databases, including PubMed, Embase, Cochrane Library, Web of Science, Scopus, China National Knowledge Infrastructure (CNKI), and Wanfang Data. The selected articles underwent critical evaluation, summarization, and incorporation into this review to highlight research achievements in this domain. This narrative review summarizes current pharmacological treatments for AD and UA, encompassing traditional Chinese medicine (TCM) monomers, compounds, and Western medications. It also thoroughly explores and elucidates the complex mechanism underlying the "bidirectional effect" of UA levels and metabolic pathways on AD, offering insights and theoretical support for future AD drug development.}, } @article {pmid41424842, year = {2026}, author = {Lee, S and Kum, J and Kim, K and Park, TY and Ko, H and Na, DL and Kang, SY and Kim, H and Kim, Y and Kim, J}, title = {Clearance of amyloid plaque via focused ultrasonication in a mouse model of Alzheimer's disease.}, journal = {Theranostics}, volume = {16}, number = {5}, pages = {2310-2323}, pmid = {41424842}, issn = {1838-7640}, mesh = {Animals ; *Alzheimer Disease/therapy/pathology/metabolism ; *Plaque, Amyloid/therapy/pathology/metabolism ; Disease Models, Animal ; Mice ; Amyloid beta-Peptides/metabolism ; Humans ; Cell Line, Tumor ; Mice, Transgenic ; *Ultrasonic Therapy/methods ; Brain/pathology/metabolism ; Peptide Fragments/metabolism ; }, abstract = {Background: The success of anti-amyloid-β (Aβ) monoclonal antibodies in recent clinical trials validates the promising approach of clearing amyloid-β in Alzheimer's therapy. Building on these successes, focused ultrasound (FUS), a non-invasive therapeutic modality that delivers acoustic energy to targeted brain regions with high precision, has emerged as a potential technique to modulate Aβ pathology, either in combination with drugs or as a standalone treatment. This study focused on the standalone potential of FUS to reduce Aβ plaques without accompanying drugs. Methods: Synthetic Aβ42 aggregates were prepared and exposed to FUS. The changes in fibril and oligomer levels were analyzed using Thioflavin T (ThT) fluorescence, gel electrophoresis combined with photo-induced cross-linking of unmodified protein (PICUP) chemistry, transmission electron microscopy (TEM), and immunoblotting. The effect of FUS on Aβ42-induced cytotoxicity was evaluated in SH-SY5Y human neuroblastoma cells. FUS-mediated dissociation of Aβ plaques was performed by ex vivo and in vivo methods on the 5XFAD mouse model. In the ex vivo experiment, FUS was applied to brain slices, specifically targeting the hippocampal region. In the in vivo experiment, the left hippocampus of awake animals was sonicated in a transcranial manner ten times over two weeks using a miniature ultrasound transducer affixed to the skull. For both ex vivo and in vivo experiments, immunohistochemistry was performed on brain sections for measuring Aβ plaques after sonication. Blood was collected from animals before and after in vivo stimulation for plasma analysis. Results: In vitro, FUS treatment reduced the β-sheet structure of synthetic Aβ42 aggregates by up to 55.28% in the ThT assay, and fibrillar Aβ42 levels by up to 62.27% in the gel electrophoresis, as further confirmed by TEM imaging, which showed disrupted fibrillar structures. The level of oligomeric Aβ42 was also reduced by up to 65.02% following FUS exposure. SH-SY5Y cells treated with FUS-treated Aβ42 aggregates exhibited improved viability from 81.56% to 90.48%, showing a tendency of attenuated Aβ42-induced cytotoxicity by FUS. Ex vivo FUS stimulation significantly reduced the number of Aβ plaques in the hippocampal region compared to untreated brain slices. In vivo transcranial FUS reduced both the number and size of plaques in the FUS-treated hippocampal and thalamic region compared to the contralateral side. Plasma analysis with Aβ42 enzyme-linked immunosorbent assay revealed a 65.91% increase in Aβ levels following FUS treatment compared to pre-treatment levels, suggesting that Aβ plaques dissociated by FUS were released into the bloodstream. Conclusions: FUS exposure effectively reduced amyloid plaques in both ex vivo and in vivo models by disrupting fibrillar and oligomeric Aβ, demonstrating its potential as a non-invasive strategy for Aβ clearance.}, } @article {pmid41424797, year = {2025}, author = {Yang, H and Wang, Y and Xu, Y and Wang, C}, title = {CX3CR1: a potential microglia-specific PET imaging target in Alzheimer's and Parkinson's diseases.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1678159}, pmid = {41424797}, issn = {1663-9812}, abstract = {Microglia are the resident immune cells of the central nervous system (CNS), playing a crucial role in maintaining brain homeostasis and mediating neuroimmune responses. The chemokine receptor CX3CR1, predominantly expressed on microglia, regulates microglial function via interactions with its neuronal ligand CX3CL1. The CX3CR1-CX3CL1 signaling exhibits complex, context-dependent roles in neurodegenerative diseases. In Alzheimer's disease (AD) and Parkinson's disease (PD) animal models, CX3CR1 deficiency shows paradoxical outcomes, attenuating or exacerbating amyloid-β (Aβ) and tau pathologies in AD, while consistently worsening α-synuclein-induced neurodegeneration in PD. Although CX3CR1 emerges as a promising therapeutic and diagnostic target, its complex role in microglial dynamics remains incompletely understood. Positron emission tomography (PET) imaging provides a powerful, noninvasive method for investigating biological processes in vivo. There is an urgent need to develop and validate new PET tracers targeting microglial CX3CR1 in the CNS, further offering new opportunities for the diagnosis and treatment of neuroinflammation-associated neurodegenerative diseases.}, } @article {pmid41424796, year = {2025}, author = {Pirozhkov, SV and Vukolova, MN and Bulgakova, VV and Lutokhina, YA and Bolevich, SB and Sobolevsky, AI and Yelshanskaya, MV}, title = {Endothelium glutamate receptors in brain pathology.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1709274}, pmid = {41424796}, issn = {1663-9812}, abstract = {The endothelium in brain microcirculation functions not only as a barrier but also as a signal transduction component within a system that regulates multiple vascular processes, including muscle tone, permeability, and structural integrity. The control of local blood flow is vital to ensure adequate oxygen and nutrient supply, efficient removal of catabolic waste, and the maintenance of proper brain cell function. The role of endothelial glutamate receptors in brain pathology is an emerging area of research, particularly important for understanding how these receptors contribute to neurological diseases and disorders. Endothelial cells (ECs), which are considered active players in maintaining brain homeostasis, express glutamate receptors on their surface. Activation of these receptors can trigger a cascade of signaling events, including synthesis of nitric oxide (NO) and proinflammatory molecules. N-Methyl-D-Aspartate receptors (NMDARs) play a significant role in functional hyperemia, also known as neurovascular coupling (NVC), which is essential for maintaining the energy balance in brain cells. Growing evidence suggests that disturbance of this balance is implicated in several neurological diseases, such as Alzheimer's disease, stroke, and traumatic brain injury (TBI), where endothelial dysfunction may impair blood flow regulation, contributing to further neuronal damage and cognitive decline. This review focuses on the glutamate receptor-mediated alterations in endothelial permeability and the prevention of the brain pathology through direct modulation of these receptors. Notably, the metabotropic glutamate receptor mGluR1, along with NMDARs, may cause deleterious effects in brain ischemia, as their activation increases the permeability of the vessel wall. Stimulation of NMDARs may also lead to ferroptosis in ECs. EC dysfunction results in significant blood-brain barrier (BBB) disruption, allowing infiltration by inflammatory cells and the accumulation in brain of pathological proteins, such as amyloid-beta (Aβ) or autoantibodies. This contributes to neuronal dystrophy and apoptosis, as seen in Alzheimer's disease and autoimmune encephalopathy. Activated ECs generate proinflammatory mediators that attract leukocytes and sustain the neuroinflammatory response. Infiltrating peripheral white blood cells are key contributors to inflammatory damage following TBI. Regulation of ECs through glutamate receptors therefore represents a promising therapeutic strategy for treatment of neurodegenerative diseases, as well as ischemic and traumatic brain injuries.}, } @article {pmid41424575, year = {2026}, author = {Sharma, A and Sathiyanarayanan, L and Arulmozhi, S}, title = {Investigating the therapeutic potential of pinocembrin in Alzheimer's disease: insights from network pharmacology and molecular docking.}, journal = {In silico pharmacology}, volume = {14}, number = {1}, pages = {7}, pmid = {41424575}, issn = {2193-9616}, abstract = {The complicated neurodegenerative disease known as Alzheimer's disease (AD) is typified by neural malfunction, cognitive impairment, and gradual memory loss. Multi-target treatment approaches are desperately needed since AD etiology is complicated. Using network pharmacology, molecular docking, and in vitro experimental validation, this study explores the therapeutic potential of pinocembrin, a flavonoid recognized for its neuroprotective, antioxidant, and anti-inflammatory qualities. Network pharmacology study revealed nine important AD-associated targets of Pinocembrin, which are involved in neurotransmitter modulation, oxidative stress response, and neuronal protection. These targets include CA2, CYP1B1, CYP19A1, DPP4, ESR1, ESR2, HSP90AB1, MAOB, and SHBG. The relationship of these targets with important networks linked to AD, including PI3K-Akt signaling, estrogen signaling pathways, and neuroactive ligand-receptor interaction, was further validated by Gene Ontology (GO) and KEGG pathway enrichment analysis. According to ADMET study, Pinocembrin has good pharmacokinetic characteristics, such as low anticipated toxicity, intermediate blood-brain barrier permeability, and high gastrointestinal absorption. Strong and consistent binding affinities were shown by molecular docking studies, especially with CYP1B1 (-8.1 kcal/mol), DPP4 (-7.3 kcal/mol), and CA2 (-7.6 kcal/mol), indicating possible inhibitory effects on these targets. The compound's medicinal property was further supported by in vitro validation. Pinocembrin's safety profile was validated by the MTT assay, which demonstrated high cell survival (>90%) in PC12 neuronal cells at all tested dosages. In comparison to donepezil as a reference, pinocembrin also demonstrated moderate acetylcholinesterase (AChE) inhibitory action, with an IC50 of 50 µM. Furthermore, DPPH, ABTS, and H2O2 scavenging assays were used to indicate antioxidant activity. The IC50 values for these assays were 150 µg/mL, 78.6 µg/mL, respectively, and total reducing power was 46.5 mg EAA/g. All of these results point to the possibility of pinocembrin as a multi-target therapy drug for Alzheimer's disease. To verify its effectiveness and refine its pharmacological profile for therapeutic use, more in vivo research and molecular dynamics simulations are necessary.}, } @article {pmid41424454, year = {2025}, author = {Egba, SI and Edeh, MO and Uchenna, NO and Igwe, MC and Ogbodo, JO}, title = {Nasal Delivery of Phytochemicals Using Nanocarriers: Therapeutic Opportunities and Translational Challenges.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {15017-15041}, pmid = {41424454}, issn = {1178-2013}, mesh = {Humans ; *Phytochemicals/administration & dosage/pharmacokinetics/chemistry/therapeutic use ; Administration, Intranasal ; Animals ; *Nanoparticles/chemistry ; Nasal Mucosa/metabolism ; *Drug Carriers/chemistry ; Curcumin/administration & dosage/pharmacokinetics ; *Nanoparticle Drug Delivery System/chemistry ; *Drug Delivery Systems/methods ; Biological Availability ; Nanotechnology ; }, abstract = {The integration of phytochemicals with nanotechnology represents a promising approach to enhance nasal drug delivery, improving therapeutic efficacy and targeted brain delivery. This review explores recent advances in phytochemical-nanotechnology formulations and their applications in managing neurodegenerative diseases, respiratory disorders, and cancers. Phytochemicals such as curcumin, resveratrol, and quercetin exhibit potent pharmacological properties but suffer from poor solubility and limited bioavailability. Nanotechnology-based systems-including nanoparticles, liposomes, and nanoemulsions-overcome these drawbacks by improving stability, absorption, and controlled release. However, challenges such as nasal mucosa irritation, formulation complexity, regulatory barriers, and scalability still impede clinical translation. Notably, encapsulation of curcumin in polymeric nanoparticles has been shown to enhance its solubility and bioavailability, producing improved therapeutic outcomes in preclinical Alzheimer's models. Overall, this review underscores the synergistic potential of phytochemicals and nanotechnology in developing innovative nasal delivery platforms capable of providing targeted, effective, and patient-friendly treatment options for a range of medical conditions.}, } @article {pmid41423583, year = {2025}, author = {Katuwawala, K and Bharadwaj, P and Martins, I and De Silva, BGDNK and Ho, V and Dissanayake, A and Martins, RN and Fernando, WMADB}, title = {Unraveling the Significance of Fecal MicroRNA Profile in Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {319}, pmid = {41423583}, issn = {1559-1182}, mesh = {*Alzheimer Disease/genetics/diagnosis/metabolism/microbiology ; *MicroRNAs/genetics/metabolism ; Humans ; *Feces/chemistry ; Gastrointestinal Microbiome ; Animals ; }, abstract = {Alzheimer's disease (AD), a complex neurodegenerative disorder characterised by progressive cognitive decline, affects millions globally. With no current cure, treatment focuses on symptom management and slowing disease progression. Early identification is therefore crucial. Fecal microRNA (miRNA) analysis is emerging as a promising non-invasive diagnostic tool. Evidence suggests that miRNAs present in fecal samples may regulate gene expression linked to AD pathology, impacting cellular functions and disease progression. Dietary factors critically influence gut microbiota composition and diversity, affecting brain health via the gut brain axis. Macronutrients such as carbohydrates, proteins, and fats modulate miRNA expression and gut microbiota, influencing AD risk. High-fat diets can increase inflammation and contribute to AD. This review aims to provide a comprehensive overview of how diet-modulated fecal miRNAs and gut microbiota interplay may serve as novel, non-invasive indicators for early detection and intervention strategies in AD.}, } @article {pmid41423566, year = {2025}, author = {Kong, D and Zhang, T and Hou, G and Liu, G and Qi, X and Xing, H}, title = {A novel method for acoustic modeling of cranial bone based on the porosity index.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-025-33411-x}, pmid = {41423566}, issn = {2045-2322}, support = {2022YFS0048//Sichuan Science and Technology Program/ ; 82027808//National Natural Science Foundation of China/ ; 2020SCUNL210//Science Specialty Program of Sichuan University/ ; }, abstract = {Transcranial ultrasound stimulation (TUS) has emerged as a clinically validated neuromodulation technique. Particularly, phased array ultrasound can be applied in TUS to focus on the cortex or deep brain non-invasively, such as the ventral intermediate thalamic nucleus (VIM) and Precuneus (PCu) region for the treatment of essential tremor (ET) and Alzheimer Disease (AD). Current TUS treatment planning relies on computed tomography (CT)-derived skull porosity measurements, which involve patient radiation exposure and potential registration errors. This study proposes a Porosity Index (PI)-based method, derived from Ultrashort Echo Time (UTE) Magnetic Resonance (MR) images, for establishing skull acoustic models as a viable alternative, aiming to eliminate these limitations. Acoustic simulations using the K-Wave open-source platform were performed to validate the PI method's accuracy in predicting skull porosity and simulating focal distributions compared to CT. Focal spot characteristics were quantified using five metrics: peak intensity, target intensity, focal positioning error, Dice similarity coefficient, and Pearson correlation coefficient between CT- and PI-based simulation results. Statistical differences between these metrics were assessed using Tukey's multiple comparisons test. Quantitative comparisons against the gold-standard CT approach demonstrated comparable performance in peak focal intensity (deviation < 5%) and spatial pressure distribution patterns (Dice coefficient > 0.82). No significant differences (p > 0.05) were observed for any of the evaluated metrics. Our findings demonstrate that both the sound pressure distribution and prediction of the porosity are comparable with those from the reference CT. Using the PI to replace the traditional CT porosity has high feasibility and can achieve the purpose of reducing unnecessary radiation exposure and registration error for patients.}, } @article {pmid41423172, year = {2026}, author = {Luo, J and Tan, Z and Shang, P and Huang, S and Liu, Y and Wang, Y and Xie, H and Chen, Q}, title = {Accelerated intermittent theta burst stimulation combined with cognitive training modulates cortical plasticity and brain activation in patients with amnestic mild cognitive impairment.}, journal = {Experimental gerontology}, volume = {213}, number = {}, pages = {113009}, doi = {10.1016/j.exger.2025.113009}, pmid = {41423172}, issn = {1873-6815}, mesh = {Humans ; *Cognitive Dysfunction/therapy/physiopathology/psychology ; Male ; *Neuronal Plasticity ; Female ; Aged ; *Transcranial Magnetic Stimulation/methods ; Cognition ; Middle Aged ; Spectroscopy, Near-Infrared ; Theta Rhythm ; Dorsolateral Prefrontal Cortex/physiopathology ; *Amnesia/physiopathology/therapy ; Aged, 80 and over ; Cognitive Training ; }, abstract = {Amnestic mild cognitive impairment (aMCI) is the prodromal period of Alzheimer's disease without effective treatment. This research aimed to investigate the effects of accelerated intermittent theta burst stimulation (iTBS) combined with adaptive cognitive training (COG) on cognitive function in aMCI patients and explore the underlying neural mechanisms. Twenty-four aMCI patients participated in either the real (n = 12) or sham (n = 12) stimulation group. Both groups received adaptive COG, which comprised three sessions of real or sham iTBS delivered on the left dorsolateral prefrontal cortex (DLPFC) once a day for 14 days. The primary outcomes were the Montreal Cognitive Assessment (MoCA) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores. Secondary outcomes were changes in cortical plasticity measured by transcranial magnetic stimulation and brain activation monitored by functional near-infrared spectroscopy (fNIRS). Patients were evaluated before and after the intervention. Patients with aMCI who received iTBS combined with COG had a significant improvement in cognitive performance, as assessed by the ADAS-Cog and N-back. In the iTBS+COG group, cortical plasticity measured 30 min post-intervention correlated with ADAS-Cog changes (r = -0.59, p = 0.043). Furthermore, this plasticity was associated with 1-back activation (r = -0.58, p = 0.050), and 2-back activation correlated with ADAS-Cog changes (r = -0.59, p = 0.042). Accelerated iTBS targeted to the left DLPFC combined with adaptive COG promoted cognitive improvement in aMCI patients more effectively by modulating cortical plasticity and brain activation. Cortical plasticity and brain activation might be valuable measurements for understanding cognitive function (Chinese Clinical Trial Registry: ChiCTR2400087943).}, } @article {pmid41423157, year = {2026}, author = {Liu, J and Yang, J and Liu, S and Sun, W and Xu, B and Liu, J and Wei, F}, title = {Renshen Shouwu formula alleviates Alzheimer's disease pathology by modulating tryptophan metabolism and activating the SIRT1 signaling pathway.}, journal = {Journal of ethnopharmacology}, volume = {359}, number = {}, pages = {121073}, doi = {10.1016/j.jep.2025.121073}, pmid = {41423157}, issn = {1872-7573}, mesh = {Animals ; *Tryptophan/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Sirtuin 1/metabolism ; Mice ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Gastrointestinal Microbiome/drug effects ; Disease Models, Animal ; Male ; *Neuroprotective Agents/pharmacology ; Cerebral Cortex/drug effects/pathology/metabolism ; }, abstract = {The Renshen Shouwu is a traditional Chinese medicine formula, whose active components have neuroprotective and multiple pharmacological effects. However, Alzheimer's disease (AD) is a complex neurodegenerative disorder, and the exact mechanism of its treating AD remains to be elucidated, and more in - depth research is needed.

AIM OF THE STUDY: The aim of this study is to elucidate the protective effect and potential molecular mechanisms of Renshen Shouwu Formula (RSSW) on AD.

MATERIALS AND METHODS: Using senescence-accelerated mouse prone 8 (SAMP8) mice as an AD model, the cerebral cortex morphology was assessed by H&E staining. Non-targeted and targeted metabolomics, together with 16S rRNA sequencing, were performed to analyze the effects of RSSW on metabolic changes and gut microbiota in SAMP8 mice. Furthermore, potential therapeutic targets of RSSW were predicted by network pharmacology and validated via Western blot.

RESULTS: RSSW treatment significantly mitigated pathological damage in the cerebral cortex, and reduced pro-inflammatory cytokine levels in SAMP8 mice. Results of both non-targeted and targeted metabolomics analyses indicated that RSSW intervention could improve tryptophan metabolism in SAMP8 mice by elevating tryptophan levels, suppressing kynurenine pathway overactivation, and enhancing serotonin and indole derivative biosynthesis. Additionally, RSSW administration markedly increased the relative abundance of Lactobacillus in gut microbiota, which showed positive correlations with the levels of tryptophan, serotonin pathway metabolites, and neurotransmitters, and negatively with kynurenine pathway metabolites. Furthermore, network pharmacology identified that SIRT1 could serve as a potential target for RSSW in AD. Notably, RSSW upregulated SIRT1 protein levels and reduced levels of Ac-p53 and acetylated NF-κB proteins in the hippocampus of SAMP8 mice.

CONCLUSIONS: RSSW suppresses the progression of AD by regulating tryptophan metabolism, reshaping the gut microbiota, and activating SIRT1-mediated signaling pathways. These findings suggest that RSSW may be a promising therapeutic strategy for AD through multi-path action mechanisms.}, } @article {pmid41421725, year = {2026}, author = {Das, SK and Bashir, B and Kolekar, KA and Harish, V and Patle, D and Vishwas, S and Mittal, N and Jha, SK and Kumar, P and Gupta, G and Dureja, H and Dua, K and Chang, D and Kuppusamy, G and Singh, SK}, title = {Protein and peptide based nanotherapeutics for the management of Alzheimer's disease: Current insights and future directions.}, journal = {Ageing research reviews}, volume = {114}, number = {}, pages = {103000}, doi = {10.1016/j.arr.2025.103000}, pmid = {41421725}, issn = {1872-9649}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Animals ; *Peptides/administration & dosage/therapeutic use ; *Proteins/administration & dosage/therapeutic use ; Nanoparticles ; *Nanomedicine/methods/trends ; Drug Delivery Systems ; }, abstract = {Alzheimer's disease (AD) is the most chronic neurodegenerative disease. The pathological hallmark of AD includes the accumulation of amyloid-beta plaques (Aβ), oxidative stress as well as chronic inflammatory reactions. Current treatments, such as acetylcholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, and recently approved monoclonal antibodies, offer symptomatic relief or slightly slow down progression. However, they too are constrained by high cost, side effects and limited activity. Proteins and peptides are emerging focus of attention as promising therapeutics, due to their higher selectivity, participation in many pathological pathways, and are lesser toxicity than other therapies in recent years. These biomolecules mediate their effect by decreasing amyloid aggregation, preventing tau hyperphosphorylation, regulating oxidative damage and repairing synapses. Various proteins and peptides such as SS31, LPfFFD-PEG, SEN1576, α sheet peptides, D-(PGKLVYA), RI-OR2-TAT, TFP5, SEN304, PP-Leu, Ac-Leu-Pro-Phe-Phe-Asp-NH2 (iAb5p), and Cyclo (17, 21)- (Lys17, Asp21) Aβ (1-28) have been used in the treatment of AD. Nonetheless, these peptides have a limited clinical translatability due to their vulnerability to enzymatic degradation, systemic circulation instability, low bioavailability, and limited penetration across the blood-brain barrier (BBB). To overcome these challenges, nanotechnology-based treatments have become a revolutionary solution. Both functionalized and non-functionalized protein and peptide-loaded nanoparticles provide protection against degradation, cross the BBB, and allow sustained and targeted delivery of neuronal tissues. The ligand-functionalized nanoparticle systems increase the accumulation of therapeutics in the brain as they cross the blood-brain barrier more efficiently. These are also able to protect the circulatory proteins and peptides, and eventually lead to improved therapeutic results in preclinical models. The present review highlights the therapeutic and delivery potential of protein- and peptide-based nanocarriers as dual therapeutic and delivery vectors with disease-modifying capability and precision targeting. Together, these advances have placed nanotechnology-based protein and peptide therapeutics for better management of AD.}, } @article {pmid41421687, year = {2025}, author = {Lin, HW and Li, SP and Wen, JX and Zhang, JX and Zhang, BM and Wang, YJ and Cui, XJ and Yao, M}, title = {Multi-target neuroprotective effects of notoginsenoside R1 in neurodegenerative diseases: From pharmacokinetics to translational prospects.}, journal = {Pharmacological research}, volume = {}, number = {}, pages = {108074}, doi = {10.1016/j.phrs.2025.108074}, pmid = {41421687}, issn = {1096-1186}, abstract = {Neurodegenerative diseases impose a heavy social and economic burden, and effective therapeutic strategies are essential for slowing disease progression and improving patient quality of life. Notoginsenoside R1 (NGR1), a key saponin derived from Panax notoginseng (Burk. F.H. Chen), has been widely studied in experimental models of neurodegenerative diseases, such as stroke and Alzheimer's disease (AD). Based on a rigorous literature screening and a meta-analysis of animal studies, we confirmed that NGR1 significantly reduces infarct volumes in cerebral ischemia-reperfusion models and improves escape latency in AD mice. Mechanistically, NGR1 confers neuroprotection by attenuating oxidative stress, suppressing neuroinflammation, inhibiting apoptosis, and preserving the neurovascular unit. Furthermore, using network pharmacology, reverse virtual screening, and molecular docking, we preliminarily identified potential targets and signaling pathways, providing a theoretical basis for future studies. However, clinical translation of NGR1 remains limited due to poor oral bioavailability and restricted permeability across the blood-brain and blood-spinal cord barriers. To address these challenges, we summarized delivery strategies, including nanoparticle-based carriers, intranasal administration, and permeability enhancers, to facilitate NGR1 entry into the central nervous system. We also discussed additional potential approaches, such as structural modification and targeted delivery, analyzing their respective advantages and limitations. Collectively, these findings highlight NGR1 as a promising candidate for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid41421353, year = {2025}, author = {Sillau, SH and Coughlan, C and Ahmed, MM and Nair, K and Araya, P and Galbraith, MD and Ritchie, A and Ching-Jung Wang, A and Elos, MT and Bettcher, BM and Espinosa, JM and Chial, HJ and Epperson, N and Boyd, TD and Potter, H}, title = {Blood measure of neuronal death is exponentially higher with age, especially in females, and halted in Alzheimer's disease by GM-CSF treatment.}, journal = {Cell reports. Medicine}, volume = {}, number = {}, pages = {102525}, doi = {10.1016/j.xcrm.2025.102525}, pmid = {41421353}, issn = {2666-3791}, abstract = {Aging increases the risk of neurodegeneration, cognitive decline, and Alzheimer's disease (AD). We report that plasma concentrations of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and neurofilament light (NfL) become exponentially higher from ages 2 to 85 in cross-sectional samples, serving as neuronal death/damage biomarkers across the lifespan. UCH-L1 concentrations rise faster in females, who exhibit increased AD risk. Glial fibrillary acidic protein (GFAP) concentrations increase exponentially after age 40, especially in females. Age-adjusted UCH-L1, NfL, and GFAP plasma concentrations are greatly elevated in mildly cognitively impaired participants. Treatment of human AD trial participants with granulocyte-macrophage colony-stimulating factor (GM-CSF/sargramostim) apparently halts neuronal cell death: UCH-L1 biomarker concentrations are reduced to those of 5-year-old healthy controls. GM-CSF treatment also reduces neuronal apoptosis and astrogliosis in a rat model of AD. An exponential increase in neurodegeneration with age, accelerated by astrogliosis/inflammation, may underlie the contribution of aging to cognitive decline and AD and can be halted by GM-CSF/sargramostim treatment.}, } @article {pmid41421243, year = {2025}, author = {Keleş, T and Biyiklioglu, Z and Seyhan, G and Öz, E and Reis, R and Barut, B}, title = {Potential water-soluble metal phthalocyanine candidates for the treatment of Alzheimer's disease: Synthesis, cholinesterase enzyme inhibition, kinetic analysis and cytotoxicity against human neuroblastoma (SH-SY5Y).}, journal = {Journal of inorganic biochemistry}, volume = {276}, number = {}, pages = {113197}, doi = {10.1016/j.jinorgbio.2025.113197}, pmid = {41421243}, issn = {1873-3344}, abstract = {In this study, manganese (III), cobalt (II), copper (II) and zinc (II) phthalocyanines and their quaternized cationic derivatives bearing morpholine groups in the non-peripheral position were producedand characterized by various spectroscopic techniques such as UV-Vis, FT-IR, [1]H and [13]C NMR (only for Zn(II)), MALDI-TOF mass spectra. The inhibitory potential of new compounds on AChE and BuChE enzymes was investigated and IC50 values were determined. It was found that water-soluble derivatives showed stronger inhibitory properties. The most effective compounds in AChE inhibition were water-soluble zinc (II) phthalocyanine (ZT6Q) (IC50 = 0.85 ± 0.18 μM) and water-soluble manganese (III) phthalocyanine ZT3Q (IC50 = 2.26 ± 0.38 μM), while ZT6Q showed the strongest effect in BuChE inhibition (IC50 = 5.15 ± 0.48 μM). Lineweaver-Burk analyses revealed that these compounds inhibited both enzymes in a mixed manner. Ki and Kii values were also calculated. In cell viability tests against human neuroblastoma (SH-SY5Y), ZT6Q did not show cytotoxic effects up to 10 μM, on the contrary, they increased cell viability. However, ZT3Q exhibited higher cytotoxicity at 48 h exposure. The findings indicate that these compounds can be evaluated as potential therapeutic agents.}, } @article {pmid41420771, year = {2025}, author = {Hossain, A and Mia, E and Hasan, SA and Alshahrani, MY and Bristy, AH and Alam, S and Poly, IJ and Rakib, IH and Hossan, R and Hosen, SA and Akter, K and Khalipha, ABR}, title = {Piceatannol as a multi-target neuroprotective agent: mechanistic insights and therapeutic prospects in neurological disorders.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {6}, pmid = {41420771}, issn = {1573-7365}, mesh = {*Neuroprotective Agents/therapeutic use/pharmacology ; Humans ; Animals ; *Nervous System Diseases/drug therapy/metabolism ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; Stilbenes ; }, abstract = {Neurological disorders like Alzheimer's, Parkinson's, and stroke involve oxidative stress and inflammation. Current treatments mainly ease symptoms but have side effects. Piceatannol, a natural polyphenol, shows promise as a safer, multi-target neuroprotective agent. This review aims to compile and analyze preclinical evidence on PCN, elucidate its underlying mechanisms, and explore its therapeutic prospects in the management of neurological disorders. A comprehensive literature search was conducted using PubMed/MEDLINE and Google Scholar, incorporating in vitro and in vivo studies that evaluated PCN in relevant models. Findings indicate that PCN exerts neuroprotection through potent antioxidant effects, enhancing superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, and activating Nrf2 signaling while suppressing proinflammatory mediators via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathway inhibition. It also stabilizes mitochondrial function, prevents neuronal apoptosis by modulating Bcl-2/Bax balance and caspase activity, and mitigates ferroptosis. Furthermore, PCN reduces disease-specific pathological markers such as amyloid-β (Aβ) and acetylcholinesterase (AChE), improving memory, motor performance, and neurobehavioral outcomes. These effects are observed in diverse models, including cerebral ischemia-reperfusion injury (CIRI), subarachnoid hemorrhage (SAH), Alzheimer's disease, chronic unpredictable stress (CUS), and prion-related neurodegeneration. In conclusion, PCN's multi-target actions and safe clinical trial position make it a strong candidate for neurodegenerative disease therapy. While preclinical data are compelling, rigorous clinical trials are essential to validate efficacy, optimize dosage, and explore its potential as a standalone or adjunctive treatment for neurological disorders.}, } @article {pmid41420750, year = {2025}, author = {Motevalli, H and Mehrani, A and Zolfaghari, K and Khodaee, P and Yazdanpanah, N and Saleki, K and Rezaei, N}, title = {TLRs and NLRs modulate oral microbiome involvement in Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {7}, pmid = {41420750}, issn = {1573-7365}, mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology ; *Microbiota/physiology ; *Toll-Like Receptors/metabolism ; Animals ; *Mouth/microbiology ; Dysbiosis/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common and irreversible type of dementia, accounting for more than half of all dementia cases. Early diagnosis of AD plays a role in slowing the progression of the disease and also preserving the quality of life of patients. However, there is often a time lag of several decades between the biological onset of the disease and the time of clinical diagnosis. At the time of diagnosis, the patient often has noticeable cognitive decline, which reduces the effectiveness of available treatments. This diagnostic time lag from onset to the onset of symptoms highlights the need to identify accessible and cost-effective screening tools, such as biomarker-based diagnostic and screening methods. Studies have implicated disorders of the oral-brain axis in the pathogenesis of neurodegenerative diseases such as AD. Oral dysbiosis has been epidemiologically associated with an increased risk of cognitive decline and AD, making the oral microbiome a potential biomarker for screening and early diagnosis of AD. Oral dysbiosis also plays a role in the pathogenesis of AD by increasing systemic inflammation and neuroinflammation. TLR/NLR signaling has been identified as a key intrinsic pathway in the pathogenesis of these neuroinflammations and systemic inflammation, which may suggest the use of inhibitors such as TAK-242/MCC950 as a potential therapeutic approach in the treatment of AD, although preclinical and clinical evidence for the use of these inhibitors in the course of AD is still very limited. In this review, we discuss oral dysbiosis in AD and review studies investigating the mouth-brain axis as an effective pathway in AD from diagnosis to treatment.}, } @article {pmid41420698, year = {2025}, author = {Yan, Z and Yotsuya, Y and Hasegawa, Y}, title = {Neuroprotective Effect of Marine-Derived Nacre Extract against Aβ-Induced Toxicity via Preservation of Mitochondrial Function and Biogenesis.}, journal = {Neurochemical research}, volume = {51}, number = {1}, pages = {19}, pmid = {41420698}, issn = {1573-6903}, mesh = {Animals ; PC12 Cells ; *Amyloid beta-Peptides/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification ; Rats ; *Mitochondria/drug effects/metabolism ; Mice ; Male ; Membrane Potential, Mitochondrial/drug effects ; *Organelle Biogenesis ; Alzheimer Disease/drug therapy/metabolism ; Mice, Inbred C57BL ; }, abstract = {Pearls, formed from the nacreous layers of marine mollusks, have long been used in traditional medicine, yet the molecular basis of their bioactivity remains insufficiently characterized. Mitochondrial dysfunction is a central feature of Alzheimer's disease (AD) pathology and represents a critical therapeutic target. Although nacre extract has been reported to improve cognitive impairment, its effects on mitochondrial function and biogenesis under amyloid-β (Aβ)-induced toxicity remain unclear. In this study, we examined the impact of nacre extract on mitochondrial activity in PC12 cells and in an Aβ-injected mouse model. Treatment with nacre extract significantly alleviated Aβ-induced mitochondrial dysfunction in PC12 cells, restoring membrane potential, ATP production, and the expression of mitochondrial biogenesis-related genes, including PPARγ and Nrf1. MitoBright LT staining demonstrated recovery of mitochondrial mass following extract administration. In vivo, we first isolated and identified a sulfated polysaccharide fraction from nacre extract, which significantly improved Aβ-induced memory impairment. In parallel, this fraction preserved mitochondrial function in the brains of Aβ-injected mice, as evidenced by maintained membrane potential, ATP levels, and hippocampal succinate dehydrogenase expression. Together, these findings demonstrate that nacre extract exerts neuroprotective effects through its sulfated polysaccharide fraction, highlighting its potential as a marine-derived therapeutic resource against AD-related neurodegeneration.}, } @article {pmid41419667, year = {2025}, author = {Sabbagh, MN and Cummings, JL and Ballard, C and van der Flier, WM and Heneka, MT and Holst, JJ and Knudsen, LB and Salloway, S and Tansey, MG and Drucker, DJ}, title = {Repurposing glucagon-like peptide-1 receptor agonists for the treatment of neurodegenerative disorders.}, journal = {Nature aging}, volume = {}, number = {}, pages = {}, pmid = {41419667}, issn = {2662-8465}, abstract = {With therapeutic progress in Alzheimer's disease (AD), more molecular and mechanistic targets are coming into focus. Beyond amyloid, emerging targets include tau, neuroinflammation and neurotransmitters. Targeting neuroinflammation in neurodegenerative diseases has been explored using cyclooxygenase inhibitors, but it has mostly been unsuccessful. Among the drug classes under investigation for AD are the glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are approved for the treatment of type 2 diabetes (T2D), obesity and cardiovascular disease. GLP-1RAs are candidate treatments for AD based on several concepts. First, epidemiological data reveal that patients with T2D and cardiovascular disease receiving GLP-1RAs have substantial reductions in the risk of developing all-cause dementia. Second, GLP-1RAs reduce neuroinflammatory changes in preclinical models. Clinical trials have not yet shown that GLP-1RAs can slow the rate of cognitive decline in mild cognitive impairment and mild dementia due to AD. Here, we summarize data supporting the use of GLP-1RAs for the treatment of neurodegenerative diseases, with a focus on AD.}, } @article {pmid41419665, year = {2025}, author = {He, A and Wang, Y and Shen, Y and Dong, Z and Luo, L and Ge, X and Liu, X and Mao, Y and Zhang, T and Li, X and Li, H and Jing, W and Zhu, LQ and Zhang, Q and Lu, Y}, title = {Allosteric activation of a cell-type-specific GPR120 inhibits amyloid pathology of Alzheimer's disease.}, journal = {Nature aging}, volume = {}, number = {}, pages = {}, pmid = {41419665}, issn = {2662-8465}, support = {82430044//National Natural Science Foundation of China (National Science Foundation of China)/ ; 32421003//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82271486//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82325017//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {Black rice diets are enriched with unsaturated fatty acids that are thought to be beneficial for neurodegenerative disorders in aging. Here we find that α-linolenic acid (ALA) and 11,14-eicosadienoic acid (EDA), which are naturally enriched in black rice, inhibit amyloid pathology, rescue cognition and extend lifespan in mouse preclinical models of Alzheimer's disease via allosteric activation of G protein-coupled receptor 120 (GPR120) in plaque-associated macrophages and activated microglia. We generate the structures of GPR120 bound to ALA and EDA. We demonstrate that ALA and EDA allosterically modulate and synergistically activate GPR120 for macrophagic phagocytosis and clearance of β-amyloid aggregates in Alzheimer's disease mice. A cell-type-specific deletion of GPR120, or Gαi1, completely abrogates the therapeutic effects of ALA and EDA. This deletion can be rescued by a constitutive active Gαi1-Q204L. These findings show a cell-type-specific function of GPR120 in the brain and provide an enriched allosteric mechanism of GPR120 activation for the treatment of Alzheimer's disease.}, } @article {pmid41419043, year = {2026}, author = {Zheng, SG and Ye, RL and Huang, XN and Ye, WJ and Li, H and Zeng, NX}, title = {From medicinal herb to neuroprotective candidate: A review of curculigoside's potential in central nervous system disorders.}, journal = {Journal of ethnopharmacology}, volume = {359}, number = {}, pages = {121048}, doi = {10.1016/j.jep.2025.121048}, pmid = {41419043}, issn = {1872-7573}, mesh = {Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Glucosides/pharmacology/therapeutic use ; *Central Nervous System Diseases/drug therapy ; *Benzoates/pharmacology/therapeutic use ; Plants, Medicinal/chemistry ; Medicine, Chinese Traditional ; }, abstract = {UNLABELLED: Central nervous system disorders represent a major global cause of mortality and disability, with limited effective treatments available. Traditional Chinese Medicine theory posits a close link between kidney and brain function. Curculigoside, the primary bioactive phenolic glycoside and chemical marker of the kidney-tonifying herb Curculigo orchioides Gaertn, can cross the blood-brain barrier and demonstrates neuroprotective potential. However, to date, no comprehensive review has summarized its effects on central nervous system disorders. To our knowledge, this is the first comprehensive review to summarize and critically evaluate the therapeutic potential and mechanisms of curculigoside across a wide spectrum of central nervous system disorders.

AIM OF THE REVIEW: This study aimed to summarize the therapeutic effects and underlying mechanisms of curculigoside against various central nervous system disorders, evaluate its clinical translational potential, and provide new insights and strategies for clinical treatment.

METHOD: This study comprehensively searched PubMed, Web of Science, Google Scholar, China National Knowledge Infrastructure, and Wanfang Database for studies published before 31 May 2025.

RESULTS: Studies demonstrate curculigoside's efficacy in models of Alzheimer's disease, post-traumatic stress disorder, major depressive disorder, cerebral ischemic stroke, post-stroke depression, perioperative neurocognitive disorders, vascular dementia, and spinal cord injury. Its multifaceted mechanisms include enhancing neurotransmitter systems, reducing neurotoxic proteins, improving synaptic plasticity, and exerting anti-apoptotic, anti-inflammatory, antioxidant, and anti-ferroptotic effects, alongside promoting mitophagy, angiogenesis, oxidative phosphorylation, and neurogenesis/neural regeneration. Collectively, this evidence positions curculigoside as a multi-target neuroprotective agent with promising development prospects; however, its translational potential depends on future breakthroughs in addressing key challenges, including the conduct of large-scale clinical studies to verify its efficacy and safety, a deeper elucidation of its pharmacological mechanisms and toxicological profile, and the development of innovative strategies to improve its bioavailability, blood-brain barrier penetration, and retention in the brain.}, } @article {pmid41418600, year = {2025}, author = {Samir, M and Abo-Dya, NE and Elsherbiny, NM and Metwally, K and Abouleisa, RRE and Mohamed, TMA and Farraj, KA and Mohamed, ME and Elbadawi, MM and Elbastawesy, MAI and Badawi, WA}, title = {Design, synthesis, and biological evaluation of Benzimidazole-Aminopyrimidine hybrids as selective P38α MAPK inhibitors targeting Neuroinflammation in an AlCl3-induced rat model of Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {169}, number = {}, pages = {109391}, doi = {10.1016/j.bioorg.2025.109391}, pmid = {41418600}, issn = {1090-2120}, abstract = {p38α MAP kinase is a key driver of neuroinflammation in Alzheimer's disease (AD). It plays a crucial role in initiating the release of proinflammatory cytokines such as TNF-α and IL-1β. A novel series of benzimidazole-aminopyrimidine-hybrids (4a-m) was designed and synthesized as selective p38α inhibitors by combining two purine isosteric scaffolds with a flexible methyl thioether linker. Targets 4a-m were synthesized in good to excellent yields, characterized using NMR spectroscopy and mass spectrometry, and their purity was confirmed using elemental analysis. Docking and molecular dynamics studies suggested that several compounds bind strongly to p38α. Enzyme assays confirmed that four derivatives (4c, 4d, 4i, and 4j) inhibit p38α in the low-nanomolar range (IC50 ≈ 26-46 nM) with much weaker activity on p38β, p38γ, and p38δ, indicating an α-selective profile. Among them, 4i showed the lowest IC50 value (≈26 nM). Predicted blood-brain barrier (BBB) permeability parameters highlighted 4c and 4d as the best candidates for in vivo testing. Their neuroprotective effects were examined in an AlCl3-induced Alzheimer's-like rat model. Both compounds showed good in silico BBB permeability and were tested in an AlCl3-induced rat model of Alzheimer's disease. Treatment with 4c and 4d significantly decreased brain concentrations of NF-κB p65 by 35 % and 25 %, respectively, TNF-α (33 % and 20 %, respectively), and IL-1β (39 % and 20 %, respectively), along with notable histopathological improvement in cortical and hippocampal tissues. These findings collectively designate 4c as a robust, brain-penetrable p38α-targeting inhibitor that mitigates AD-associated neuroinflammation, signifying it as a promising candidate for subsequent development.}, } @article {pmid41418563, year = {2026}, author = {Valentino, K and Shen, B and Waisman, B and Le, GH and Ballum, H and Cheung, W and McIntyre, RS}, title = {Efficacy of xanomeline and xanomeline trospium in the treatment of cognitive impairment: A systematic review of preclinical and clinical trials.}, journal = {European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology}, volume = {103}, number = {}, pages = {112735}, doi = {10.1016/j.euroneuro.2025.11.012}, pmid = {41418563}, issn = {1873-7862}, mesh = {*Cognitive Dysfunction/drug therapy ; Humans ; Animals ; *Nortropanes/pharmacology/therapeutic use ; Drug Evaluation, Preclinical ; Clinical Trials as Topic ; *Benzilates/pharmacology/therapeutic use ; *Muscarinic Agonists/pharmacology/therapeutic use ; Treatment Outcome ; Pyridines ; Thiadiazoles ; }, abstract = {The high prevalence, persistence and clinical burden of cognitive impairment on health outcomes in persons with schizophrenia and bipolar disorder invites the need for innovative, mechanistically informed pharmacotherapeutic interventions. Evidence implicates dysregulation of muscarinic signalling as a mediator of cognitive dysfunction, identifying it as a potential therapeutic target. In accordance with the PRISMA guidelines, a systematic search was performed using the following electronic databases: PubMed, Medline, Cochrane Library, PsycInfo, Embase, Scopus, and Web of Science. Databases were searched from inception to May 1, 2025. Study screening and selection was performed by three reviewers (K.V., B.S., and B.W.). Included studies reported on the effects of xanomeline and/or xanomeline trospium on cognitive function. A total of 24 studies were included in this review. Preclinical and clinical studies consistently demonstrate that xanomeline trospium is well tolerated in both short and long-term evaluations. Furthermore, xanomeline trospium has been associated with cognitive improvements in both animal models and clinical populations (e.g., Alzheimer's disease (AD), schizophrenia), including improvements in verbal learning, delayed memory, and reaction time. Xanomeline trospium, an FDA approved muscarinic M1/M4 partial agonist with demonstrated safety, tolerability, and efficacy, represents a novel pharmacological intervention for the treatment of schizophrenia. The convergence of preclinical and clinical findings supports the hypothesis that xanomeline trospium exerts direct pro cognitive effects in persons with schizophrenia, bipolar disorder, and potentially other neuropsychiatric conditions (e.g., AD). Limitations of the current study include limited indications investigated and the absence of a comprehensive analysis of xanomeline's overall neurobiologic effects.}, } @article {pmid41418456, year = {2026}, author = {Gong, XN and Zhou, YX and Wang, CY and Wang, TT and Gao, ZY and Long, WC and Li, R and Cai, L}, title = {CPD47, a novel GSK-3β inhibitor, demonstrates antidepressant-like effects via the GSK-3β/β-catenin signaling pathway: Involvement of neurogenesis promotion and neuroinflammation inhibition.}, journal = {International immunopharmacology}, volume = {169}, number = {}, pages = {116065}, doi = {10.1016/j.intimp.2025.116065}, pmid = {41418456}, issn = {1878-1705}, mesh = {Animals ; Rats ; Neurogenesis/drug effects ; *Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism ; *Antidepressive Agents/pharmacology/therapeutic use ; PC12 Cells ; beta Catenin/metabolism ; Male ; *Depression/drug therapy ; Hippocampus/drug effects/pathology ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Behavior, Animal/drug effects ; Stress, Psychological/drug therapy ; Disease Models, Animal ; *Neuroinflammatory Diseases/drug therapy ; Corticosterone ; }, abstract = {The GSK-3β/β-catenin signaling axis is critically involved in the pathogenesis of depression. Targeted inhibition of GSK-3β to activate β-catenin signaling may provide a promising depression therapy. The novel GSK-3β inhibitor compound 47 (CPD47) has exhibited therapeutic promise in neurodegenerative disorders such as Alzheimer's disease, but its potential antidepressant effects and underlying mechanisms remain to be elucidated. This study assessed CPD47's protective effects against PC12 cell injury induced by corticosterone (CORT) and its antidepressant-like activity in rats exposed to chronic unpredictable mild stress (CUMS), with a special focus on the mechanisms involving the regulation of the GSK-3β/β-catenin signaling pathway. In this research, CPD47 treatment attenuated CORT-induced neurotoxicity in PC12 cells, as indicated by increased viability, decreased apoptosis, reduced oxidative stress, and suppressed inflammatory responses. In vivo, administration of CPD47 substantially alleviated depressive-like behaviors in CUMS rats, as indicated by behavioral improvements in sucrose preference, forced swim, sucrose splash, and open field tests. Additionally, CPD47 ameliorated hippocampal pathological damage and promoted hippocampal neurogenesis in CUMS rats. Notably, CPD47 markedly mitigated neuroinflammation in the hippocampus of CUMS rats. Mechanistically, CPD47 significantly inhibited GSK-3β activity and activated β-catenin signaling both in vitro and in vivo, with upregulated p-GSK-3β (Ser9) and β-catenin expression and decreased p-β-catenin. Importantly, GSK-3β overexpression abolished CPD47's benefits in CORT-stimulated PC12 cells, providing further evidence that GSK-3β is its crucial molecular target. Collectively, our findings indicate that CPD47 produces potent antidepressant-like effects through modulation of the GSK-3β/β-catenin axis, highlighting its promise as a candidate for depression therapy.}, } @article {pmid41417293, year = {2025}, author = {Sun, Y and Shao, M and Du, L and Gan, Y and Guan, Y and Cheng, G and Li, S and Jin, H and Li, B and Zhang, G and Yan, S and Xiao, X}, title = {Exploring neuroprotective effects of Chuanzhitongluo capsule on an alzheimer's disease rat model.}, journal = {Metabolic brain disease}, volume = {41}, number = {1}, pages = {5}, pmid = {41417293}, issn = {1573-7365}, support = {2021CXGCO10508//Major Scientific and Technological Innovation Project of Shandong Province/ ; 2019YFC1711205//National Key Research and Development Program of China/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Rats ; Male ; Disease Models, Animal ; Rats, Sprague-Dawley ; Oxidative Stress/drug effects ; Capsules ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) poses significant challenges to public health and well-being, with current treatments often providing limited efficacy. Chuanzhitongluo capsule (CZTL) has neuroprotective effects, and is expected to be used for the treatment of AD. In this study, the chemical composition, pharmacological effects and underlying mechanisms of CZTL against AD were systematically investigated. We identified the major components of CZTL through ultra-high-performance liquid chromatography coupled with a quadrupole time-of-flight mass spectrometer. AD rat model was established via scopolamine injection, followed by the administration of CZTL at various dosages, and pharmacological effects were then systematically evaluated. Furthermore, the potential mechanisms were explored using metabolomics and immunohistochemistry. Seventeen chemical constituents were identified from CZTL. Pretreatment with CZTL led to significant improvements in cognitive function and reductions in neuronal loss among AD rats. CZTL administration decreased abnormal protein aggregates (Aβ and Tau), along with markers of oxidative stress and inflammation. Metabolomic and immunohistochemical analyses indicated that CZTL modulated nicotinamide metabolism and impacted levels of NAD+, UMP, nitric oxide, and SIRT1 activity. These results suggest that CZTL effectively mitigates cognitive deficits and neuronal loss in AD by regulating nicotinamide and SIRT1, while inhibiting oxidative stress and inflammation. This study lies in their contribution to the development of novel anti-AD therapies derived from traditional Chinese medicine, paving the way for new approaches in managing neurodegenerative diseases.}, } @article {pmid41417196, year = {2025}, author = {Ding, Z and Hou, Q and Shao, N and Gao, W and Cai, B and Hu, S}, title = {Polydatin Attenuates Cognitive Deficits and Neuroinflammation by Inhibiting the P2X7/NLRP1 Inflammasome Pathway in APP/PS1 Mice and Aβ-Treated HT22 Cells.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {311}, pmid = {41417196}, issn = {1559-1182}, support = {2023AH050830//Scientific Research Foundation of Education Department of Anhui Province/ ; 2022rcyb017//the Talent Project of Anhui University of Chinese Medicine/ ; }, mesh = {Animals ; *Glucosides/pharmacology/therapeutic use ; *Amyloid beta-Peptides/toxicity ; *Inflammasomes/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology/complications ; Mice, Transgenic ; *Presenilin-1/metabolism ; *Stilbenes/pharmacology/therapeutic use ; *Receptors, Purinergic P2X7/metabolism ; *Signal Transduction/drug effects ; Hippocampus/pathology/drug effects/metabolism ; Mice ; *Adaptor Proteins, Signal Transducing/metabolism ; Cell Line ; *Apoptosis Regulatory Proteins/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; *Cognition Disorders/drug therapy/metabolism/pathology/complications ; Pyroptosis/drug effects ; Alzheimer Disease/drug therapy ; Peptide Fragments/toxicity ; Cognitive Dysfunction/drug therapy ; Male ; Oxidative Stress/drug effects ; }, abstract = {Aβ deposition is a central pathological hallmarks of Alzheimer's disease (AD), contributing to oxidative stress, neuroinflammation, and neuronal pyroptosis. Polydatin (PD) is a natural polyphenolic compound with known anti-inflammatory and antioxidant properties, has been rarely studied in the context of AD. This study aims to investigate the neuroprotective effects and underlying mechanisms of PD in APP/PS1 transgenic mice and Aβ25-35-treated HT22 cells. Spatial exploration experiments indicate that PD administration (200 mg/kg/day) attenuated cognitive deficits. Histopathological analyses, including hematoxylin-eosin staining and transmission electron microscopy, revealed that PD mitigated hippocampal structural damage in APP/PS1 mice. Western blot and RT-qPCR results showed that PD markedly reduced the expression of pyroptosis-related proteins, including P2X7, NLRP1, ASC, caspase-1, and GSDMD, as well as oxidative stress markers in the hippocampus. In vitro, Aβ25-35 exposure led to an increased expression of P2X7 and components of the NLRP1 inflammasome in HT22 cells, which was reversed by PD treatment. What's more, siRNA knockdown experiments revealed that silencing P2X7 significantly downregulated NLRP1, whereas siNLRP1 had no significant effect on P2X7 expression, suggesting that P2X7 functions upstream of NLRP1. These findings indicate that PD alleviates AD-like pathology by suppressing P2X7/NLRP1 inflammasome-mediated pyroptosis, highlighting its potential as a multi-target therapeutic candidate for AD intervention.}, } @article {pmid41417181, year = {2025}, author = {Zhang, R and Mu, S and Zhang, S and Qin, X and Du, G and Zhou, Y}, title = {Arctium lappa L. Leaves Alleviate Alzheimer's Disease-Like Pathologies by Modulating the Tricarboxylic Acid Cycle and Inhibiting STAT3/NF-кB Signaling.}, journal = {Plant foods for human nutrition (Dordrecht, Netherlands)}, volume = {81}, number = {1}, pages = {2}, pmid = {41417181}, issn = {1573-9104}, support = {No. 202403021212284//Fundamental Research Program of Shanxi Province/ ; No. 202403021211150//Fundamental Research Program of Shanxi Province/ ; No. 2024ZYY2A029//Shanxi Provincial Administration of Traditional Chinese Medicine research project/ ; No. 2024-021//Research Project Supported by Shanxi Scholarship Council of China/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; NF-kappa B/metabolism ; Plant Leaves/chemistry ; STAT3 Transcription Factor/metabolism ; Rats ; Signal Transduction/drug effects ; *Arctium/chemistry ; Male ; Hippocampus/drug effects/pathology ; Rats, Sprague-Dawley ; *Citric Acid Cycle/drug effects ; Disease Models, Animal ; *Plant Extracts/pharmacology ; Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; }, abstract = {Current drugs for Alzheimer's disease (AD) have limited efficacy and often cause adverse side effects. Burdock leaves, known for their heat-clearing and anti-inflammatory properties, can be consumed as a vegetable or brewed into tea. According to traditional Chinese medicine, heat-clearing and anti-inflammatory strategies are considered beneficial for the treatment of AD. Nevertheless, it remains unclear whether burdock leaves have neuroprotective effects or can alleviate neuroinflammation to delay AD progression. Herein, we found that the decline in learning and memory, as well as cognitive impairments in AD model rats, were significantly improved following burdock leaf intervention. Notably, the medium- and high-dose groups showed superior therapeutic outcomes compared to the low-dose group. Histopathological analysis of rat hippocampal tissue revealed that burdock leaves mitigated hippocampal lesions, neuronal loss, pathological amyloid β-protein accumulation, and abnormal phosphorylation of the microtubule-associated Tau protein. Metabolomics studies identified the tricarboxylic acid (TCA) cycle as a key metabolic pathway modulated by burdock leaves in AD regulation. Western blot analysis revealed that the therapeutic effects of burdock leaves may be mediated through the suppression of the STAT3/NF-κB signaling pathway and downregulation of inflammatory protein expression. Of note, the present study uncovered that burdock leaves could delay AD progression by ameliorating metabolic dysregulation and inhibiting STAT3/NF-κB-mediated inflammatory pathways, positioning them as a promising candidate for further exploration in AD therapeutics.}, } @article {pmid41416491, year = {2025}, author = {Janve, VA and Seto, M and Sperling, RA and Aisen, PS and Rissman, RA and Koran, MEI and Dumitrescu, L and Buckley, RF and Hohman, TJ and , }, title = {Blood gene expression network expression strongly relates to brain amyloid burden.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70982}, pmid = {41416491}, issn = {1552-5279}, support = {//Eli Lilly and Co./ ; /ALZ/Alzheimer's Association/United States ; //GHR Foundation/ ; //National Institutes of Health-National Institute on Aging/ ; //Accelerating Medicines Partnership/ ; }, mesh = {Humans ; Male ; Female ; *Brain/metabolism/diagnostic imaging/pathology ; *Alzheimer Disease/genetics/diagnostic imaging/blood ; Aged ; Positron-Emission Tomography ; *Gene Regulatory Networks ; Histones/genetics ; *Amyloid/metabolism ; *Amyloidosis/genetics ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Amyloid deposition occurs decades before symptoms emerge in Alzheimer's disease (AD). We leveraged blood transcriptomics and positron emission tomography (PET) measures of amyloidosis to identify gene networks in the blood that relate to amyloid burden in the brain.

METHODS: Whole-blood RNA sequencing and amyloid PET were leveraged from 1739 cognitively unimpaired participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. Linear regression related gene module expression to amyloid covarying for age, sex, education, and apolipoprotein E (APOE) ε2 and ε4 genotypes.

RESULTS: Of the 18 gene modules, one histone gene cluster module was associated with amyloid (β = -0.55, false discovery rate-adjusted p value = 0.029). We also observed nominal associations for the predicted proportion of activated natural killer (NK) cells (β = -0.454, p = 0.02) and CD4+ activated memory T cells (β = -0.169, p = 0.03) with amyloid deposition.

DISCUSSION: Our results implicate the histone gene cluster on chromosome 6 and immune cell proportions as blood correlates of brain amyloid deposition in preclinical AD.

HIGHLIGHTS: Higher expression of network module with histone gene cluster on chromosome 6 associated with lower amyloid levels. Four histone genes, H1-5, H3C3, H2BC3, H2AC14, and RRM2, emerged as key genes driving this association, where H1-5 emerged as a hub gene for this module. Pathways, including nucleosome assembly and DNA damage, were enriched in the histone module. A higher fraction of activated NK and activated CD4+ T cells was related to lower amyloid burden.}, } @article {pmid41415890, year = {2025}, author = {Jia, S and Li, Q and Rui, X and Qin, W and Zhang, W and Dou, J and Zhang, X}, title = {The ubiquitin-proteasome system in Alzheimer's disease: mechanism of action and current status of treatment.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1730206}, pmid = {41415890}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative disorders; current therapies can neither cure AD nor prevent its progression. The pathological hallmark of AD is the excessive deposition of abnormal proteins in the brain, primarily including β-amyloid (Aβ) and phosphorylated Tau proteins. The ubiquitin-proteasome system (UPS), a central intracellular protein degradation mechanism that removes misfolded proteins and maintains cellular homeostasis by inhibiting aberrant protein aggregation, plays an important role in the regulation of various physiological functions, as well as in the development of disease. Any abnormality in this process leads to protein misfolding and aggregation, and the accumulation and aggregation of ubiquitinated proteins is a common feature of many neurodegenerative diseases, including AD. A growing number of studies have confirmed the significance of UPS in the AD process, which may act in conjunction with other mechanisms leading to the development of AD, and may even be the direct cause of AD. UPS offers a whole new possibility for the development of drugs for AD prevention and treatment, as well as new strategies and approaches for the treatment of neurodegenerative diseases. Therefore, this review is based on UPS, describes the possible mechanisms of action of UPS in AD, and summarizes the preclinical studies of modulating UPS for the treatment of AD.}, } @article {pmid41415446, year = {2025}, author = {Linden, AK and Affaneh, A and Aylward, A and Wong, Y and Kessler, JA and Peng, CY}, title = {Differential Regulation of APOE4-Mediated Astrocytic Lipid Metabolism by BMP Signaling Exacerbates Alzheimer's Disease Pathologies in Neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.12.14.694212}, pmid = {41415446}, issn = {2692-8205}, abstract = {The two greatest risk factors for Alzheimer's Disease (AD) are aging and Apolipoprotein E4 (APOE4) polymorphism, yet how these factors interact remain unclear. In this study, we investigate how bone morphogenetic protein (BMP) signaling, which increases with age, contributes to APOE4-induced lipid metabolic dysfunctions using induced-pluripotent stem cell (iPSC)-derived astrocytes and cocultured neurons. Surprisingly, BMP signaling differentially altered lipid droplet formation, cholesterol synthesis and breakdown, and fatty acid-oxidation in APOE4 compared to APOE3 astrocytes, and increased secretion of oxidized LDL (oxLDL). Furthermore, neurons cocultured with BMP4-treated APOE4 astrocytes showed altered transcriptomic profiles based on scRNA-seq as well as increased tau phosphorylation (p-tau). oxLDL treatment similarly increased p-tau and reduced neuronal survival. Conversely, lipid uptake inhibition in neurons rescued the BMP4/APOE4 astrocyte-induced neuronal phenotype. These data demonstrate key interactions between APOE4 and aging-associated molecular signaling in AD pathogenesis and establish a causal linkage between astrocytic lipid metabolism and neuronal tau hyperphosphorylation.}, } @article {pmid41413577, year = {2025}, author = {Chu, C and Wang, Y and Ma, L and Ouyang, Y and Zisis, G and Masters, CL and Goudey, B and Jin, L and Pan, Y and , }, title = {Development and validation of an interpretable clinical scoring model to monitor the progression of preclinical Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {268}, pmid = {41413577}, issn = {1758-9193}, support = {GNT2007912//National Health and Medical Research Council/ ; 23AARF-1020292/ALZ/Alzheimer's Association/United States ; }, abstract = {BACKGROUND: Monitoring the progression of preclinical Alzheimer's disease (AD) is challenging due to the absence of obvious cognitive impairment, yet it's crucial for determining the optimal timing for disease-modifying treatments.

METHODS: This prognostic study used data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study. The development cohort included 412 participants from the placebo arm, and external validation was performed using 342 participants from the treatment arm. All participants had baseline brain amyloid-beta (Aβ) positron emission tomography (PET) standardized uptake value ratios (SUVR) below 1.4. Using the AutoScore machine learning framework, we developed two interpretable models: the AutoScore Amyloid-Beta (ASAB) model to predict Aβ accumulation (> 1.4 SUVR) and the AutoScore Phosphorylated Tau (ASPT) model to predict plasma phosphorylated tau-217 (pTau-217) elevation (> 0.3 pg/mL) over 4.5 years. Model performance was assessed using the area under the receiver operating characteristic curve (AUC-ROC) with 95% confidence intervals (CIs).

RESULTS: The ASAB model achieved an AUC-ROC of 0.87 (95% CI, 0.79–0.95), and the ASPT model achieved 0.86 (95% CI, 0.78–0.94). Modified models excluding baseline Aβ SUVR or pTau-217 values maintained a strong performance (AUC-ROC 0.76–0.82). External validation demonstrated a robust performance, with an AUC-ROC of 0.83 (95% CI, 0.78–0.87) for ASAB and 0.84 (95% CI, 0.80–0.89) for ASPT. Key predictors included baseline biomarker levels, cholesterol, platelet count, alanine transaminase, and creatine kinase.

CONCLUSIONS: The AutoScore-based models accurately predict longitudinal Aβ and pTau-217 levels using readily available clinical and laboratory data. These interpretable tools could help clinicians and researchers monitor preclinical AD progression and identify optimal windows for intervention.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01931-3.}, } @article {pmid41411709, year = {2026}, author = {Fisk, D and William, T and Spiwak, R and Modirrousta, M and Ko, JH and Sareen, J}, title = {Combining repetitive transcranial magnetic stimulation with transcranial direct current stimulation in treating psychiatric conditions: A systematic review.}, journal = {Psychiatry research}, volume = {356}, number = {}, pages = {116902}, doi = {10.1016/j.psychres.2025.116902}, pmid = {41411709}, issn = {1872-7123}, mesh = {Humans ; *Transcranial Direct Current Stimulation/methods ; *Transcranial Magnetic Stimulation/methods ; *Mental Disorders/therapy ; Combined Modality Therapy ; }, abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been thoroughly explored in the treatment of various psychiatric disorders and neuropsychiatric symptoms. However, whether combining rTMS and tDCS can safely and effectively treat psychiatric conditions remains unknown. In this systematic review, we seek to summarize all existing studies that have combined rTMS and tDCS to remedy psychiatric disorders and symptoms.

METHODS: We searched four databases in addition to grey literature to identify relevant studies. All abstracts and manuscripts were independently reviewed by two reviewers. For inclusion, studies necessarily consisted of those who received both rTMS and tDCS for a psychiatric condition or symptom.

RESULTS: Fourteen studies were reviewed, which had relevance to unipolar depression (five), bipolar disorder (two), obsessive-compulsive disorder (two), Alzheimer's Disease (one), chronic insomnia (two), depressive and anxiety symptoms (one) and stress (one). In three RCTs on unipolar depression, the group receiving both rTMS and tDCS experienced significant reductions in mean Hamilton Depression Rating Scale (HDRS) scores (by 18.22, 16.59 and 20.04) as well as response rates (83.33 % and 91.7 %) and remission rates (83.3 %) - all of which were generally superior compared to treatment with rTMS or tDCS alone. For chronic insomnia, one RCT noted greater improvements in sleep quality/efficiency and depressive symptoms compared to monotherapy. The type and frequency of side effects were comparable to monotherapy, and no significant adverse events were reported.

CONCLUSION: The existing evidence suggests that combining rTMS and tDCS alone yields greater symptomatic benefit for unipolar depression compared to either treatment alone. Further studies involving additional protocols and disorders could elucidate the utility of combined treatment.}, } @article {pmid41410987, year = {2025}, author = {Nakayama, Y and Chambers, JK and Uchida, K}, title = {Phosphorylated tau aggregation in the brains of aged Artiodactyla animals.}, journal = {Journal of neuropathology and experimental neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnen/nlaf139}, pmid = {41410987}, issn = {1554-6578}, support = {22KA3003//Japanese Ministry of Health and Welfare Sciences Research/ ; JPMJSP2108//JST SPRING/ ; }, abstract = {The aggregation of amyloid-β (Aβ) and phosphorylated tau (p-tau) in the human brain is associated with Alzheimer disease (AD). Although Aβ aggregation has been reported in various mammals, significant p-tau aggregation has been reported in only a few species. We examined Aβ and p-tau aggregation in the brains of 30 animals belonging to 12 artiodactyl species. Amyloid-β aggregates were observed in 2 animals (21 and 22 years old); p-tau aggregates were observed in all animals >9 years of age (n = 12). Regarding tau pathology, mildly affected animals exhibited neuropil threads (NTs), whereas severely affected animals exhibited NTs and neurofibrillary tangles. The most severe p-tau aggregation was observed in the parahippocampal gyrus, basal ganglia, hippocampus, and cerebral cortex. Proteinase K treatment resulted in high proteinase resistance for 4-repeat tau and low resistance for 3-repeat tau. These results suggest that p-tau aggregation occurs prior to Aβ aggregation in artiodactyls, which differs from other mammalian species and human AD. Regarding the distribution, p-tau aggregated in neurites and then in the neuronal cell soma of the parahippocampal gyrus and spread to associated regions of the brain. Moreover, 4-repeat tau was the main component of proteinase-resistant p-tau aggregates in the artiodactyl brains studied.}, } @article {pmid41410687, year = {2025}, author = {Steward, A and Dewenter, A and Hirsch, F and Roemer-Cassiano, SN and Zhu, Z and Dehsarvi, A and Biel, D and Klonowski, M and Frontzkowski, L and Palleis, C and Gnörich, J and Dichgans, M and Höglinger, G and Brendel, M and Franzmeier, N}, title = {ApoE4 lowers the ptau217 threshold for tau aggregation and spread in an allele dose-dependent manner.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf463}, pmid = {41410687}, issn = {1460-2156}, abstract = {In Alzheimer's disease, carriage of the ApoE4 risk allele is linked to faster tau accumulation at lower amyloid-PET levels, thereby accelerating disease progression. However, it remains unclear whether this ApoE4-facilitated transition from amyloidosis to tauopathy is mechanistically promoted by increased secretion of phosphorylated (p)tau, a key intermediate that drives the amyloid-to-tauopathy transition, or alternatively by increased ptau-driven tau aggregation. Therefore, we investigated where along the amyloid-to-tau axis ApoE4 accelerates tau aggregation and assessed i) whether ApoE4 increases ptau secretion or ii) whether ApoE4 increases ptau-associated tau aggregation. To this end, we analysed two large-scale APOE-genotyped cohorts covering the full Alzheimer's disease spectrum (ADNI: n=201) as well as a preclinical cohort (A4-LEARN: n=200), integrating baseline amyloid-PET, plasma ptau217 and CSF ptau181 with longitudinal tau-PET. Using linear regression, we tested whether ApoE4-carriage moderates i) amyloid-PET-associated plasma ptau217 increases or ii) ptau217-associated tau spreading from local epicentres across patient-tailored tau spreading stages. All analyses were independently validated across both cohorts, including an additional replication in an ADNI subset (n=115) with available CSF ptau181 measures as an alternative marker of ptau secretion. Finally, we used logistic regression to determine ApoE4 allele count-stratified plasma ptau217 thresholds marking early pathological tau-PET increases. We found that ApoE4 did not facilitate amyloid-PET-associated ptau increases, suggesting that amyloid-related ptau secretion is not altered by ApoE4-carriage. Contrastingly, we found that plasma ptau217 elevations were linked to faster tau-PET spread from local epicentres across connected brain regions in an ApoE4-allele dose-dependent manner, independent of amyloid (ADNI/A4-LEARN: mean β=0.44/0.56, p<0.001/<0.001). Lastly, we found that a higher ApoE4 allele count was linked to lower ptau217 thresholds marking transition to tauopathy, i.e. early abnormal tau-PET increases, consistently across both samples (ADNI: 0/1/2 ApoE4 alleles=0.62/0.34/0.15pg/ml, representing ∼45% and ∼76% reductions from non-carriers; Fujirebio ptau217 assay; A4/LEARN: 0/1/2 ApoE4 alleles=0.31/0.23/0.18pg/ml, representing ∼26% and ∼42% reductions; Eli Lilly ptau217 assay). These findings suggest that ApoE4, i.e. the key genetic risk factor for sporadic Alzheimer's disease, facilitates amyloid-dependent tau aggregation in an allele dose-dependent manner by enhancing the ptau-driven spread of fibrillar tau, leading to an earlier transition from amyloidosis to tauopathy at lower ptau217 levels. This has implications for plasma ptau-based screening approaches and therapeutic timing of anti-amyloid drugs in ApoE4 carriers: Specifically, ApoE4 carriers may require genotype-adjusted ptau thresholds to detect Alzheimer's disease pathophysiology, as well as anti-amyloid treatment at lower ptau levels to prevent the transition to tauopathy, which ultimately drives neurodegeneration and cognitive decline.}, } @article {pmid41410237, year = {2025}, author = {Kranz, DL and de Leon Velez, O and Ulupinar, E and Ozdinler, PH and Silverman, RB and Klein, WL}, title = {Identification of a glia-associated amyloid β oligomer subtype and the rescue from reactive astrogliosis by inhibitor NU-9.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70968}, pmid = {41410237}, issn = {1552-5279}, support = {//NIH/ ; AG061708//Foundation for the National Institutes of Health/ ; }, mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Gliosis/pathology/metabolism/drug therapy ; Mice ; *Alzheimer Disease/pathology/metabolism/drug therapy ; Mice, Transgenic ; Astrocytes/metabolism/drug effects/pathology ; *Neuroglia/metabolism/drug effects ; Disease Models, Animal ; Microglia/metabolism/drug effects ; Brain/pathology/metabolism/drug effects ; Humans ; Neurons/metabolism/pathology ; }, abstract = {INTRODUCTION: Neuronal degeneration and immune cell activation occur early in Alzheimer's disease (AD), but the responsible molecules remain undetermined. While exogenous amyloid beta oligomers (AβOs) induce neuronal death and gliosis, the role of endogenous AβOs is less defined.

METHODS: Brain sections from 1- to 12-month-old 5xFAD mice were immunolabeled for AβOs, activated glia, phosphorylated transactive response DNA-binding protein 43 kDa (pTDP-43), and other AD markers. Neuropathology was analyzed following 60-day oral treatment with NU-9, a small-molecule AβO inhibitor.

RESULTS: By 8 weeks, AβOs accumulated in the subiculum alongside early reactive astrocytes and activated microglia. Clinical-stage antibody ACU193 detected AβOs in early-stage degenerating neurons, while NU4-labeled denser deposits in late-stage degenerating neurons. ACU193[+] AβOs accumulated on reactive astrocyte surfaces, which also contained pTDP-43, and later emerged inside activated microglia. NU-9 reduced astrocyte-associated ACU193[+ ]AβOs, pTDP-43, and markedly diminished glial fibrillary acidic protein.

DISCUSSION: These findings demonstrate in vivo efficacy of NU-9 and support targeting ACU193[+ ]AβOs to mitigate AD progression.

HIGHLIGHTS: ACU193[+] AβOs accumulated as puncta in neurons at an early stage of degeneration, while NU4[+] AβOs appeared as dense deposits only in late-stage degenerating neurons. The onset and progression of ACU193[+] AβOs paralleled activated microglia and reactive astrocytes. ACU193[+] AβOs significantly increased on reactive astrocyte surfaces, as NU4[+] AβOs accumulated in halos around Thio-S[+] plaque cores. In older mice, the ACU193 signal decreased on astrocytes and was found inside activated microglia. Sixty-day oral NU-9 treatment significantly reduced astrocyte ACU193[+] AβOs and markedly decreased reactive astrogliosis.}, } @article {pmid41409874, year = {2025}, author = {Miyahara, R and Akiyama, O and Yoshida, N and Suzuki, M and Ashizawa, K and Kodama, T and Shimizu, Y and Kondo, A}, title = {A case of cerebral sparganosis diagnosed by surgical resection and molecular analysis.}, journal = {Surgical neurology international}, volume = {16}, number = {}, pages = {512}, pmid = {41409874}, issn = {2229-5097}, abstract = {BACKGROUND: Sparganosis is a rare parasitic infection caused by the plerocercoid larvae (spargana) of Spirometra species. Central nervous system (CNS) involvement is uncommon; cerebral sparganosis can be particularly challenging to diagnose because its clinical presentation and imaging features often mimic those of more common parasitic infections (e.g., neurocysticercosis) or neoplastic lesions.

CASE DESCRIPTION: A 74-year-old woman with slowly progressive Alzheimer's disease, who had undergone regular brain magnetic resonance imaging (MRI) examinations over the past three years, was incidentally found to have a slowly enlarging lesion with surrounding edema in the left frontal lobe on MRI of the brain. The lesion demonstrated calcification and radiological features atypical for a neoplastic process, thus prompting a left frontal craniotomy for diagnostic purposes. Intraoperatively, a whitish, linear structure was removed. Frozen section revealed granulomatous inflammation with parasitic structures. Molecular biological analysis identified the specimen as a Spirometra larva (Type I), confirming the diagnosis of cerebral sparganosis. Postoperatively, her baseline cognitive impairment persisted; however, follow-up MRI at 1 month demonstrated resolution of the enhancing lesion, and no new neurological deficits occurred.

CONCLUSION: Cerebral sparganosis should be considered in the differential diagnosis of intracranial mass lesions with a tumor-like appearance. Although the diagnosis remains challenging, molecular techniques permit definitive confirmation. Surgical resection serves a dual role, facilitating both accurate diagnosis and treatment.}, } @article {pmid41409674, year = {2025}, author = {Sai, I and Grill, JD and Younes, K and Winer, JR and Cody, KA and Sperling, R and Mormino, EC and Young, CB}, title = {Cognitive screening biases in a secondary prevention Alzheimer's disease clinical trial.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.64898/2025.11.28.25341235}, pmid = {41409674}, abstract = {INTRODUCTION: Alzheimer's disease (AD) prevention trials have multiple screening steps to identify cognitively unimpaired individuals with AD biomarker evidence. Cognitive/functional screening tests may be biased in underrepresented groups, thereby impacting trial eligibility.

METHODS: 6669 participants screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were grouped by ethnoracial background and testing language. Ethnoracial/language differences in ineligibility reason, cognitive/functional test performance, and amyloid positivity rates were examined.

RESULTS: Ethnoracial minorities were least likely to meet eligibility criteria. Patterns of incorrect Mini-Mental State Examination items and impaired Clinical Dementia Rating functional domains differed between groups excluded for impaired cognition/function, suggesting test biases. The Free and Cued Selective Reminding Test yielded more similar exclusion rates across groups than Logical Memory. Cognitive/functional screening biases may impact subsequent biomarker screening as amyloid positivity rates were lowest in ethnoracial minorities.

DISCUSSION: Biases in cognitive/functional screening tests may disproportionately exclude ethnoracial minorities in AD prevention trials.}, } @article {pmid41408986, year = {2025}, author = {Liu, C and Ene, J and Lu, W and Syed, F and Sun, L and Raulin, AC and Ren, Y and Wang, X and Kanekiyo, T and Li, Y}, title = {Immuno-Regulation of Brain Region-Specific Organoids Containing Isogenic Microglia-Like Cells.}, journal = {Advanced healthcare materials}, volume = {}, number = {}, pages = {e03579}, doi = {10.1002/adhm.202503579}, pmid = {41408986}, issn = {2192-2659}, support = {2017869//NSF/ ; R01NS125016//Foundation for the National Institutes of Health/ ; R21EB033495//Foundation for the National Institutes of Health/ ; }, abstract = {Most brain organoids derived from human induced pluripotent stem cells (iPSCs) lack microglia and thus immune function. Microglia-like cells (MGCs) can be differentiated from iPSCs, while the characteristics of isogenic MGC-containing brain organoids in modeling neurodegeneration and cell-cell communications have not been well investigated. In this study, iPSC-derived MGCs are co-cultured with isogenic forebrain cortical organoids (iFCo), which are stimulated with extracellular vesicles (EVs) of brain organoids differentiated from Alzheimer's disease (AD) patient-derived iPSCs (APOE ε4/ε4 and presenilin 1). The AD EV-stimulated co-culture organoids are treated with EVs from healthy MGCs or co-culture. Differential responses of the co-cultured organoids and the MGCs to AD EVs are demonstrated. The co-cultured organoids mitigated pro-inflammatory gene expressions. EVs from healthy MGCs or co-culture reduced the expression of IL-12β, iNOS, TREM2, and CASS4, which are associated with neural inflammation and degeneration, as well as showed regulation on genes involved in microglial activation and carbon metabolism. AD EV cargo analysis by proteomics and microRNA-sequencing revealed APOE and APP proteins and microRNAs regulated pathways such as mitophagy. This study paves the way for understanding the role of microglia and brain organoids in modeling neural degeneration and the development of EV-based cell-free therapeutics for AD treatment.}, } @article {pmid41408378, year = {2025}, author = {Neuharth, JI and Hernandez, KS and Bernholtz, J and Edwards, H and Stewart, A}, title = {Consideration of sex as a biological variable over the history of the 5xFAD Alzheimer's Disease mouse model.}, journal = {Biology of sex differences}, volume = {16}, number = {1}, pages = {105}, pmid = {41408378}, issn = {2042-6410}, support = {NIH T32NS007421/NH/NIH HHS/United States ; Lulu Merle Johnson Recruitment Fellowship//University of Iowa/ ; }, mesh = {Animals ; *Alzheimer Disease ; Disease Models, Animal ; Male ; Female ; Mice ; Mice, Transgenic ; *Sex Characteristics ; }, abstract = {BACKGROUND: Women are nearly twice as likely to be diagnosed with Alzheimer's Disease (AD) over their lifetime. However, historically, preclinical studies utilizing AD rodent models to define new therapeutic targets in AD treatment have neglected to consider the confounding influence of subject sex leading to a lack of mechanistic insight into the biological underpinnings of sex bias in AD.

METHODS: Here, we tracked choice of subject sex over the twenty-year history of the 5xFAD mouse, one of the most frequently cited pre-clinical AD models. We analyzed 1,330 primary research articles indexed on PubMed and recorded information provided regarding subject sex and/or as a rationale for not including datasets separated by sex, if noted. Trends were then plotted as a function of time ending in December 2024.

RESULTS: In the last 15 years, the number of published manuscripts on the 5xFAD model omitting information on subject sex has progressively declined. However, the proportion of studies utilizing either males only (29%) or combining data from both sexes (24%) far surpasses studies acknowledging sex as a biological variable (SABV) (< 12%) with no significant changes noted over time. On average, the ratio of male only: female only studies of 5xFAD mice hovered around 2:1. The most frequently cited reason for omitting sex-based analyses was either a lack of sex differences found (29%), accelerated development of plaque burden in 5xFAD females (17%), or the possibility of within- or between-sex variability (15%). Mention of SABV has steadily increased in studies utilizing 5xFAD mice peaking at ~ 30% of manuscripts published in 2024. However, two key confounds in the 5xFAD model, including the potential impact of an estrogen response element (ERE) and parental imprinting in the Thy1 promoter driving transgene expression, have been largely ignored.

CONCLUSIONS: The 5xFAD model represents a compelling example of how neglecting to recognize the impact of biological sex on neural function can compromise study design and data interpretation. Given sex-dependent Thy1 promoter regulation may skew phenotypic outcomes, investigators should judiciously interpret sex differences observed in any AD mouse utilizing the Thy1 promoter to drive transgene expression.}, } @article {pmid41408021, year = {2025}, author = {Kaur, K and Kulkarni, YA and Wairkar, S}, title = {Improved Oral Bioavailability and Brain Distribution of Hesperidin via Cochleate Formulation: Statistical Optimization and Pharmacokinetic Study.}, journal = {AAPS PharmSciTech}, volume = {27}, number = {1}, pages = {59}, pmid = {41408021}, issn = {1530-9932}, mesh = {*Hesperidin/pharmacokinetics/administration & dosage/chemistry ; Animals ; Biological Availability ; Rats, Wistar ; Administration, Oral ; Liposomes/chemistry ; Rats ; *Brain/metabolism ; Male ; Particle Size ; Chemistry, Pharmaceutical/methods ; Solubility ; Tissue Distribution ; Drug Liberation ; }, abstract = {Hesperidin, a flavanone, exhibits antioxidant, anti-inflammatory, and anti-amyloidogenic properties, making it a promising candidate for the treatment of Alzheimer's disease. The hesperidin possesses poor solubility, and its oral bioavailability is < 20%. Therefore, hesperidin cochleates (HC) were prepared using the trapping method of calcium ions into preformed liposomes to improve oral bioavailability. The HC formulation was statistically optimized by applying a 3-level factorial design. Optimum cochleates were observed, with an average particle size of 398.9 nm, a zeta potential of -39.1 mV, and an entrapment efficiency of 92.2%, respectively. The in vitro release of hesperidin from cochleates (Batch 15) was 97% in phosphate buffer at pH 7.4 after 24 h. The HC formulation exhibited a 1% release at a gastric pH of 1.2, indicating its stability in the stomach, allowing the formulation to reach the absorption site. In Wistar rats, a comparative pharmacokinetic study was conducted between hesperidin liposomes and HC. Hesperidin concentration was 2.21-fold higher in plasma and 1.2-fold higher in the brain after cochleates administration than in the liposomal formulation and more than 25-fold greater than plain API. Thus, cochleates may be superior oral carriers for hesperidin, improving its oral bioavailability for the treatment of Alzheimer's disease.}, } @article {pmid41407043, year = {2026}, author = {Fan, B and Liang, Y and Zhi, T and Wu, L and Wu, Y and Yang, Y and Xie, Z and Wu, X}, title = {GPR55 deficiency exacerbates cognitive impairments and Alzheimer's disease-like pathology in mice.}, journal = {Neurochemistry international}, volume = {192}, number = {}, pages = {106105}, doi = {10.1016/j.neuint.2025.106105}, pmid = {41407043}, issn = {1872-9754}, mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/genetics ; Mice ; *Cognitive Dysfunction/metabolism/pathology/genetics ; Hippocampus/metabolism/pathology ; Mice, Knockout ; Mice, Transgenic ; *Receptors, Cannabinoid/deficiency/genetics ; Mice, Inbred C57BL ; Male ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, characterized by progressive cognitive decline and neuronal damage. Although studies have indicated a link between G-protein coupled receptor 55 (GPR55) and AD-related cognitive impairment, the underlying mechanisms remain unclear. Here, we aim to further investigate the role of GPR55 in the pathogenesis of AD.

METHODS: We used viral vectors to knock down GPR55 expression in the hippocampus of normal mice. We also generated GPR55 knockout in AD mice by crossing GPR55[-/-] mice with APP/PS1 transgenic mice (APP/PS1; GPR55[-/-]). Behavioral tests were conducted to assess spatial memory deficits in 9-month-old APP/PS1; GPR55[-/-] mice. We also assessed the amyloid β (Aβ) deposition, glial cell activation, and synaptic protein expression in the hippocampus. In addition, we used AAV9 viruses to overexpress GPR55 in the hippocampus of APP/PS1; GPR55[-/-] mice to further observe its effect on cognitive function.

RESULTS: Knockdown of GPR55 in the hippocampus induces AD-like pathology, cognitive dysfunction, neuroinflammation, and synaptic plasticity damage in normal mice. This was evidenced by increased hippocampal levels of Aβ and p-Tau, enhanced glial cell activation accompanied by upregulation of proinflammatory cytokines, and aggravated synaptic plasticity damage in the normal mice. Furthermore, knockdown of GPR55 induced the reduction of P-AKT1/2/3/AKT1/2/3 and P-GSK3β/GSK3β, while increasing the expression of P-ERK1/2/ERK1/2 in the hippocampus of normal mice. In addition, GPR55 deficiency exacerbated AD-like pathology and spatial learning and memory deficits in APP/PS1 mice. Conversely, AAV9-mediated overexpression of GPR55 rescued spatial memory impairments in APP/PS1; GPR55[-/-] mice.

CONCLUSIONS: These findings underscore the critical role of GPR55 in AD progression and highlight its potential as a therapeutic target for AD treatment.}, } @article {pmid41406951, year = {2025}, author = {Fang, S and Cui, F and Drucker, DJ}, title = {Glucagon-like peptide-1 medicines in neurological and psychiatric disorders.}, journal = {Cell reports. Medicine}, volume = {6}, number = {12}, pages = {102511}, pmid = {41406951}, issn = {2666-3791}, mesh = {Humans ; *Glucagon-Like Peptide 1/therapeutic use/metabolism ; *Mental Disorders/drug therapy ; *Nervous System Diseases/drug therapy ; Diabetes Mellitus, Type 2/drug therapy ; }, abstract = {Glucagon-like peptide-1 (GLP-1) medicines are used for the treatment of type 2 diabetes (T2D) and obesity and reduce rates of cardiovascular disease, including stroke, in people with T2D. Substantial evidence from real-world data and clinical trials highlights the therapeutic potential of GLP-1 medicines for the treatment of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Similarly, there is growing evidence for the potential utility of using GLP-1 medicines to reduce rates of smoking, or use of alcohol, tobacco, cannabis, or cocaine in individuals with substance use disorders. More limited clinical data suggest utility for GLP-1 medicines in patients with migraine or intracranial hypertension. The available data suggest that the use of GLP-1 medicines exhibits an acceptable safety profile in most individuals with neuropsychiatric disorders. Here, we review recent clinical evidence and ongoing trials exploring the efficacy and safety of GLP-1 medicines across a broad range of neurological conditions.}, } @article {pmid41406583, year = {2025}, author = {Yıldızbaş, A and Taslimi, P and Tüzün, B and Sadeghian, N and Kurt, R and İstek, A}, title = {Chemical composition and bioactivity of Sideritis taurica Stephan ex Wild. (Lamiaceae) leaves: GC/MS analysis, antioxidant and enzyme inhibition activities, and in silico studies.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1270}, number = {}, pages = {124894}, doi = {10.1016/j.jchromb.2025.124894}, pmid = {41406583}, issn = {1873-376X}, abstract = {Since ancient times, Sideritis taurica and other Sideritis species have been used in traditional medicine in Türkiye and beyond for treating a variety of ailments, including coughs, sore throats, gastrointestinal, respiratory, and urogenital disorders, as well as wounds, colds, and flu, and are believed to possess numerous therapeutic properties such as antispasmodic, analgesic, antibacterial, anti-inflammatory, and antioxidant effects. This study aimed to evaluate the enzyme inhibition and antioxidant activities of various extracts from S. taurica leaves collected from Kurucaşile, Bartın, Türkiye. The extracts were prepared using ethanol, methanol, and hot/cold water extraction methods from leaves that were dried at room temperature and stored in a freezer. Enzyme inhibition activities were assessed against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-glucosidase, and α-amylase, with IC50 values calculated. Antioxidant activities were measured using DPPH, ABTS, and CUPRAC assays. Furthermore, ADME/T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) and molecular docking calculations were performed on the phytochemical components of S. taurica to investigate their effects and interactions with human metabolism. These calculations were performed on a number of proteins, including alpha-amylase protein (PDB ID: 1HNY), AChE protein (PDB ID: 4M0E), and BChE protein (PDB ID: 5NN0). The purpose of these calculations was to investigate the interaction between these substances and human metabolism. The results indicated that the ethanol and methanol extracts exhibited the highest inhibition on AChE and BChE (IC50 values of 73.99 μg/mL and 5.04 μg/mL, respectively). The methanol extracts also demonstrated potent inhibition against α-glucosidase (IC50 value of 25.81 μg/mL) and α-amylase (IC50 value of 70.42 μg/mL). Regarding antioxidant activity, the methanol extracts showed the highest radical scavenging activity in the DPPH (87.88 %) and ABTS (99.97 %) tests. Additionally, the methanol extracts stored in the freezer exhibited the best-reducing power in the CUPRAC assay (2.436 ± 0.1669). These findings underscore the potential of S. taurica as a source of natural antioxidants and enzyme inhibitors, suggesting its applicability in the treatment of neurodegenerative diseases such as Alzheimer's disease. In conclusion, extracts obtained from S. taurica leaves, particularly those derived from room temperature-dried leaves, demonstrate significant enzyme inhibition and antioxidant properties. Also, the findings support the consideration of S. taurica as a natural therapeutic source for neurodegenerative diseases and emphasize for further investigation into its active components and health benefits.}, } @article {pmid41405876, year = {2025}, author = {}, title = {Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: Research Summary.}, journal = {JAMA}, volume = {}, number = {}, pages = {e2522830}, doi = {10.1001/jama.2025.22830}, pmid = {41405876}, issn = {1538-3598}, } @article {pmid41405855, year = {2025}, author = {Devanand, DP and Wisniewski, T and Razlighi, Q and Qian, M and Wei, R and Andrews, HF and Acosta, EP and Bell, KL and Pelton, GH and Deliyannides, D and Perrin, AC and Caccappolo, E and Gershon, AA and Prasad, KM and Kreisl, WC and Mintz, A and Huey, ED}, title = {Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, pmid = {41405855}, issn = {1538-3598}, abstract = {IMPORTANCE: Neuroscientific, epidemiological, and electronic health record studies implicate herpes simplex virus (HSV) as potentially etiological for Alzheimer disease (AD).

OBJECTIVE: To compare the efficacy and adverse effects of valacyclovir vs placebo in participants with early symptomatic AD and HSV seropositivity (HSV-1 or HSV-2).

This randomized clinical trial included adults with a clinical diagnosis of probable AD or a clinical diagnosis of mild cognitive impairment with positive biomarkers for AD, a positive serum antibody test (IgG or IgM) for HSV-1 or HSV-2, and a Mini-Mental State Examination score of 18 to 28. The trial was conducted at 3 US outpatient clinics specializing in memory disorders. Recruitment occurred from January 2018 to May 2022; the last follow-up occurred in September 2024.

INTERVENTION: Either 4 g/d of valacyclovir (n = 60) or matching placebo (n = 60).

MAIN OUTCOMES AND MEASURES: The primary outcome was least-squares mean (LSM) change at 78 weeks in the 11-item Alzheimer's Disease Assessment Scale Cognitive (ADAS-Cognitive) Subscale score (range, 0-70; higher scores indicate greater impairment). The secondary outcomes were LSM change in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scale score; LSM change in the 18F-florbetapir amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR; higher scores indicate higher amyloid levels) for 6 brain regions (medial orbitofrontal, anterior cingulate, parietal lobe, posterior cingulate, temporal lobe, and precuneus); and LSM change in 18F-MK-6240 tau PET medial temporal SUVR (higher scores indicate higher tau levels) for 4 brain regions (amygdala, hippocampus, entorhinal, and parahippocampus). The frequency of adverse events was the safety outcome.

RESULTS: Of the 120 participants (mean age, 71.4 [SD, 8.6] years; 55% were female), 93 (77.5%) completed the trial. At 78 weeks, the LSM change in the 11-item ADAS-Cognitive Subscale score was 10.86 (95% CI, 8.80 to 12.91) in the valacyclovir group vs 6.92 (95% CI, 4.88 to 8.97) in the placebo group, indicating greater cognitive worsening with valacyclovir than placebo (between-group difference, 3.93 [95% CI, 1.03 to 6.83]; P = .01). The LSM change in the ADCS-ADL Scale score at 78 weeks was -13.78 (95% CI, -17.00 to -10.56) in the valacyclovir group vs -10.16 (95% CI, -13.37 to -6.96) in the placebo group (between-group difference, -3.62 [95% CI, -8.16 to 0.93]). At 78 weeks, the LSM change in the 18F-florbetapir amyloid PET SUVR was 0.03 (95% CI, -0.04 to 0.10) in the valacyclovir group vs 0.01 (95% CI, -0.06 to 0.08) in the placebo group (between-group difference, 0.02 [95% CI, -0.08 to 0.12]). The LSM change in the 18F-MK-6240 tau PET medial temporal SUVR at 78 weeks was 0.07 (95% CI, -0.06 to 0.19) in the valacyclovir group vs -0.04 (95% CI, -0.15 to 0.07) in the placebo group (between-group difference, 0.11 [95% CI, -0.06 to 0.28]). The most common adverse events were elevated serum creatinine level (5 participants [8.3%] in the valacyclovir group vs 2 participants [3.3%] in the placebo group) and COVID-19 infection (3 [5%] vs 2 [3.3%], respectively).

CONCLUSIONS AND RELEVANCE: Valacyclovir was not efficacious with cognitive worsening for the primary outcome and it is not recommended to treat individuals with early symptomatic AD and HSV seropositivity.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03282916.}, } @article {pmid41405805, year = {2025}, author = {Blair, HA}, title = {Sublingual Cyclobenzaprine: First Approval.}, journal = {Clinical drug investigation}, volume = {}, number = {}, pages = {}, pmid = {41405805}, issn = {1179-1918}, abstract = {TONMYA[™] is a sublingual eutectic formulation of cyclobenzaprine being developed by Tonix Pharmaceuticals for the treatment of various conditions, including fibromyalgia, post-traumatic stress disorder (PTSD), acute stress disorder, major depressive disorder, post-acute COVID-19 syndrome, alcohol use disorder, and agitation in Alzheimer's disease. The sublingual formulation was designed for rapid transmucosal absorption to produce diurnal variation in peak-to-trough drug concentrations, making it suitable for long-term bedtime use. On 15 August 2025, sublingual cyclobenzaprine was approved for the treatment of fibromyalgia in adults in the USA. This article summarizes the milestones in the development of sublingual cyclobenzaprine leading to this first approval for fibromyalgia.}, } @article {pmid41404527, year = {2025}, author = {Nestor, PJ and Pelekanos, M and Leinenga, G and Song, J and Lee, W and Richter-Stretton, G and McElligott, C and Fazlollahi, A and Mattingley, JB and Harris, A and Beale, H and Roberts, J and de Las Heras, R and Götz, J}, title = {A pilot safety and tolerability study of scanning ultrasound as a neuromodulation therapy in Alzheimer's disease.}, journal = {Brain communications}, volume = {7}, number = {6}, pages = {fcaf445}, pmid = {41404527}, issn = {2632-1297}, abstract = {Clearing amyloid-β pathology in Alzheimer's disease (AD) has been considered a prerequisite for restoring cognitive functions. Intriguingly, by application of a modality of scanning ultrasound (SUS) to mice that does not remove amyloid-β, we previously achieved significant cognitive improvements. This prompted us to explore SUS as a non-invasive brain stimulation strategy in an open-label safety trial in AD. We conducted a human pilot study in 12 participants with AD with the primary objective of determining feasibility, safety and tolerability. Exploratory secondary end-points were cognitive and behavioural measures, resting-state EEG and functional MRI. A portable device termed UltraThera[Pilot] was built under medical device standard guidelines, integrating a Brainsight image-guided neuronavigation system. A single-element 286-kHz transducer was programmed to deliver non-derated ultrasound doses of 2.6, 1.95 or 1.3 MPa. With four treatment sessions spaced fortnightly, four participants received 30 sonications per session (precuneus, ∼30 cm[3] brain tissue) and the remaining 8 received 100 sonications per session (bilateral precuneus and temporo-parietal association cortex, ∼100 cm[3]). Safety monitoring, EEG, MRI, cognitive and neuropsychiatric evaluations were performed. The treatment was fast, safe and well-tolerated at the 1.95 MPa dose. MRI showed no changes, whereas changes were observed in aperiodic EEG content. Cognitive performance did not change but statistically significant improvements in behavioural and psychological symptoms were found using the Neuropsychiatric Inventory test. In conclusion, this SUS safety trial met its primary and secondary end-points in biomarker-confirmed mild-to-moderate AD. It informs our future work in an upcoming efficacy trial in an AD population.}, } @article {pmid41404461, year = {2025}, author = {Li, W and Liu, X and Gao, C and Li, W and Liao, X}, title = {Network meta-analysis of the efficacy of pharmacological treatments for post-stroke cognitive impairment and vascular cognitive impairment.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1683496}, pmid = {41404461}, issn = {1664-2295}, abstract = {BACKGROUND: Based on recent reviews, vascular cognitive impairment (VCI) encompasses a spectrum of cognitive deficits caused by cerebrovascular disease and its risk factors, ranging from mild cognitive impairment to dementia, and often coexists with neurodegenerative conditions like Alzheimer's disease. VCI is categorized into four clinical-imaging subtypes, including post-stroke cognitive impairment (PSCI)-a common stroke complication and major VCI subtype. Current guidelines recommend cholinesterase inhibitors and NMDA receptor antagonists as first-line treatments for VCI, with expert consensus supporting donepezil and rivastigmine for PSCI. However, existing evidence primarily derives from placebo-controlled or head-to-head drug comparisons, lacking comprehensive evaluations of multiple cognitive enhancers. This study aims to systematically assess the efficacy and safety of cognitive-enhancing drugs in VCI, with a focused analysis on PSCI, to better inform clinical decision-making and improve patient outcomes.

METHODS: We systematically searched four databases using predefined search strategies. Eligible studies were selected based on predetermined criteria. The included studies were analyzed with StataSE 16.0, RevMan 5.3, and Grade software to compare the efficacy and safety of cognitive-enhancing drugs to identify the optimal treatment for VCI and PSCI.

RESULTS: Sixteen studies (5,599 participants) were included. In terms of cognitive outcomes, sailuotong was superior to placebo on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) (MD = -3.00, 95% CI: -4.50, -1.50) and ranked best (SUCRA 88.5%). Memantine was most effective on the Mini-Mental State Examination (MMSE) (MD = 1.23, 95% CI: 0.23-2.23; SUCRA 80.8%). For the secondary outcome, the MoCA assessment showed that Ginkgo biloba extract significantly improved Montreal Cognitive Assessment (MoCA) scores compared to placebo (MD = 1.29, 95% CI: 1.24, 1.35). Regarding safety, donepezil significantly increased the risk of overall adverse events compared to placebo (OR: 1.57; 95% CI: 1.19-2.06).

CONCLUSION: Our network meta-analysis suggests that memantine might have the best effect for PSCI, with sailuotong potentially serving as a secondary option. However, these estimates are based on a small randomized controlled trial and a sparse network. Therefore, the current evidence is limited, highlighting the need for more high-quality studies to robustly validate the therapeutic potential of these interventions for VCI and PSCI.

https://www.crd.york.ac.uk/PROSPERO/, identifier in PROSPERO (CRD420250627957).}, } @article {pmid41404160, year = {2025}, author = {Roche, S and Naran, N and Scholtz, J and Liu, KY and Reeves, S and Howard, R}, title = {Systematic review and meta-analysis of antipsychotic discontinuation in dementia.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {4}, pages = {e70188}, pmid = {41404160}, issn = {2352-8737}, abstract = {INTRODUCTION: Antipsychotics are used to treat behavioral and psychological symptoms of dementia (BPSD). However, treatment is associated with adverse outcomes. A 2018 Cochrane review found low-quality evidence that discontinuation may have little effect on BPSD by primarily comparing the difference in number of study non-completers between treatment groups and did not report a pooled effect size for relapse risk. We performed a meta-analysis of the pooled risk ratio (RR) of relapse of symptoms following antipsychotic medication discontinuation in people with dementia. We hypothesized that trial design (enriched responder samples vs long-term user withdrawal), treatment duration, length of follow-up, withdrawal speed, and sex of participants would affect relapse risk.

METHODS: We systematically searched PsycINFO, EMBASE, PubMed, and ClinicalTrials.gov databases for studies published between January 2018 and June 2024. The eight papers identified in the 2018 Cochrane review were also included in the meta-analysis. The study was registered with PROSPERO (CRD42024570329).

RESULTS: A total of nine studies were included, providing 682 observations with 135 events. Relapse definitions included participant removal due to worsening behavior or starting regular prescription of antipsychotic/rescue medication. A random-effects model found a pooled RR of relapse of 1.52 (95% CI: 1.18 to 1.95, p = 0.005) with stopping antipsychotics. Meta-regressions showed no effect of trial type, withdrawal speed, length of follow-up, or participant sex on RR.

DISCUSSION: While it is important to prescribe cautiously and to reduce and withdraw prescriptions in those who are considered to no longer need antipsychotics, there is a subgroup of patients for whom continuing medication is important. It was particularly surprising that the relative risk of relapse was unaffected by trial design, with similar effect sizes in both trials aiming to reduce prescription and prove efficacy. Further research is needed to identify factors associated with successful antipsychotic withdrawal.

HIGHLIGHTS: An updated meta-analysis of trials of withdrawal of antipsychotics in dementia.Relative risk of symptom relapse increased when stopping antipsychotics.Relapse risk was not affected by trial design or prior length of treatment.Relapse risk was not affected by length of follow-up, withdrawal speed, or sex.}, } @article {pmid41403906, year = {2025}, author = {Duan, Y and Han, C and Zheng, H and Yu, J and Luo, M}, title = {Global, regional, and national burden of Alzheimer's disease and other dementias from 1990 to 2021: findings from the Global Burden of Disease Study 2021.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1678212}, pmid = {41403906}, issn = {1663-4365}, abstract = {BACKGROUND: As the global population continues to age, the growing number of elderly individuals has contributed to an increase in age-related conditions and illnesses, such as dementia, which places considerable financial and emotional pressure on both families and society. Alzheimer's disease (AD), the most prevalent form of dementia among the elderly, significantly impacts their quality of life and ability to perform daily activities independently. Over the past three decades, the age-standardized mortality rate has declined and life expectancy has steadily increased worldwide. However, this long-term progress was disrupted by the COVID-19 pandemic, which reversed some of the gains made in life expectancy and contributed to a global decline. The pandemic has notably affected global health, exacerbating the prevalence of Alzheimer's disease and other dementias (ADOD).

METHODS: In line with the analytical approach used in the Global Burden of Disease Study (GBD) 2021, we examined the counts and age-standardized rates (ASR) for the prevalence, incidence, mortality, and Disability-Adjusted Life Years (DALYs) associated with ADOD, categorized by region, country, sex, and age from 1990 to 2021. To assess temporal patterns over the study period, we calculated the estimated annual percentage changes (EAPCs).

RESULTS: From 1990 to 2021, both the number and age-standardized rates (ASR) of prevalence, incidence, mortality, and DALYs associated with ADOD showed a significant increase globally. Regionally, high-middle SDI regions had the highest ASPR at 766.2 per 100,000 (95% UI: 659.8, 879.6), with the most considerable rise, reflected in an EAPC of 0.21 (95% CI: 0.17, 0.25). In East Asia, the highest age-standardized incidence rate (ASIR) was reported, at 149.6 (95% UI: 129.6, 171.1) per 100,000 people, along with the greatest increase in ASIR, at 0.4 (95% UI: 0.33, 0.47) among the 21 GBD regions. On a national level, China experienced the greatest burden of ADOD, with the highest ASPR of 900.8 (95% UI: 770.9, 1043.2) and the highest ASIR of 151.5 (95% UI: 131.2, 173.3) per 100,000 people. The 80-84 age group exhibited the highest rates of prevalence, incidence, and DALYs, whereas the number of deaths in the 85-89 age group surpassed those in other age categories. Throughout all age groups, females experienced a higher burden of ADOD than males, regardless of the time or geographical location. The burden of ADOD reached its lowest point in 2019 but has increased steadily since then.

CONCLUSION: In summary, this study highlights the global epidemiological trends of ADOD from 1990 to 2021, including the impact of the COVID-19 pandemic on it. As the population ages, ADOD has emerged as a significant public health concern worldwide. Although some regions have made progress in managing the burden of ADOD, most regions and countries still face a heavy disease burden. More effective prevention and treatment strategies are needed to alleviate the impact of ADOD. In particular, greater focus should be placed on women and the elderly.}, } @article {pmid41403678, year = {2025}, author = {Sinan Tokalı, F and Şenol, H and Demir, Y and Uluçay, O and Ameen, M and Shafiq, Z}, title = {New Mannich-type arylidenerhodanines as potent inhibitors of AChE and BChE: synthesis, biological evaluation, cytotoxicity and molecular modeling.}, journal = {RSC advances}, volume = {15}, number = {58}, pages = {50186-50205}, pmid = {41403678}, issn = {2046-2069}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with a gradual increase in severity. The underlying cause of the disease is the dysfunction of cholinergic neurotransmission affecting mainly the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Within the context of the present research, a new group of 3,5-disubstituted rhodanine derivatives containing tertiary amine groups has been prepared and their potency in the inhibition of AChE and BChE was assessed. Enzymatic assays demonstrated that compounds 6 and 11 exhibited exceptional inhibitory potency, with K i values of 13.61 nM and 12.70 nM against AChE, and 10.44 nM and 25.11 nM against BChE, respectively, surpassing the reference inhibitors tacrine (145.21 nM for AChE and 169.54 nM for BChE) and donepezil (67.41 nM for AChE and 62.44 nM for BChE). Cytotoxicity studies confirmed minimal toxicity in human umbilical vein endothelial cells (HUVEC) at concentrations several times higher than the effective inhibitory doses (IC50 = 79.13 µM for 6 and 69.14 µM for 11). The results from molecular docking and MM-GBSA calculations supported this presumption by foretelling strong binding affinities, where compound 11 was the one to show a free energy of -103.26 kcal mol[-1] for AChE and compound 6 -86.75 kcal mol[-1] for BChE. Moreover, the 250 ns molecular dynamics simulations gave a confirmation of the structural stability and the prolonged existence of the key interactions in the enzyme active sites during the entire time. The findings of this research emphasize compounds 6 and 11 as potential candidates for the creation of strong cholinesterase inhibitors for the treatment of Alzheimer's disease, thus encouraging additional studies.}, } @article {pmid41403033, year = {2026}, author = {Berthier, ML and Sosa-Welford, A and Orozco-Arroyave, JR and López-Barroso, D and Torres-Prioris, MJ and Dávila, G and García, AM}, title = {Speech and language outcome measures in clinical trials of Alzheimer's and Parkinson's diseases.}, journal = {Expert review of neurotherapeutics}, volume = {26}, number = {1}, pages = {15-34}, doi = {10.1080/14737175.2025.2600616}, pmid = {41403033}, issn = {1744-8360}, mesh = {Humans ; *Alzheimer Disease/complications/diagnosis/therapy ; *Parkinson Disease/complications/diagnosis/therapy ; Clinical Trials as Topic ; *Outcome Assessment, Health Care ; *Language Disorders/diagnosis/etiology ; }, abstract = {INTRODUCTION: Alongside core diagnostic symptoms, Alzheimer's disease (AD) and Parkinson's disease (PD) involve early and pervasive speech-language impairments (SLI), often appearing in preclinical stages and capturing disease severity. However, speech language outcome measures are under-represented in clinical trials, missing out on critical clinical outcome assessments (COAs).

AREAS COVERED: The purpose of this review is to survey the findings from classical (analogical) and novel (digital) speech-language measures as pathways toward more precise diagnosis and response to treatment indices in interventional clinical trials. This narrative review covers two main areas; first, it examines the strengths and limitations of SL measures in traditional cognitive testing scales to identify adequate COAs for AD and PD. Second, it overviews findings on classical and digital COAs that hold great promise despite their widespread absence in clinical trials.

EXPERT OPINION: Incorporating strategic SL COAs in clinical trials may identify early, severity-sensitive deficits and enhance the clinical insights thus obtained. The modification of clinical trial designs will nevertheless be required to increase sensitivity to identify meaningful clinical outcomes.}, } @article {pmid41402453, year = {2025}, author = {Rasà, DM and Stanga, S and Santonicola, P and Mazzarella, N and Camera, A and Matino, I and Zampi, G and Boido, M and Di Schiavi, E and Vercelli, A}, title = {10H-phenothiazine exerts beneficial effects in spinal muscular atrophy in vitro and in vivo models.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {45757}, pmid = {41402453}, issn = {2045-2322}, support = {Department of Excellence//Ministry of University and Research (MUR)/ ; 24401//AFM-Telethon/ ; P40 OD010440/OD/NIH HHS/United States ; Mission M4C2I1.3, PRR.AP015.118//National Recovery and Resilience Plan (NRRP)/ ; GGP16203//Italian Telethon Foundation/ ; }, mesh = {Animals ; *Muscular Atrophy, Spinal/drug therapy/pathology/metabolism/genetics ; Mice ; Disease Models, Animal ; *Phenothiazines/pharmacology/therapeutic use ; Motor Neurons/drug effects/metabolism/pathology ; Survival of Motor Neuron 1 Protein/genetics/metabolism ; Cells, Cultured ; *Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; Drug Repositioning ; }, abstract = {Spinal Muscular Atrophy (SMA) is a neurodegenerative disorder affecting lower motor neurons (MNs) and leading to muscle atrophy, due to mutation of the SMN1 gene, which encodes SMN protein. Experimental studies also demonstrated the upper MN impairment. The available approved drugs for SMA increase the SMN protein production. Although effective, outcomes are dependent upon treatment timing and disease severity. Drug repositioning may represent a valid strategy to identify new treatments by repurposing FDA/EMA-approved drugs that, combined with the available ones, could delay neurodegeneration. To this aim, for the first time we used primary cortical neurons derived from the SMNΔ7 mice as defective in vitro disease model, to preliminary assess drug efficacy on neuronal survival and morphology. Under basal conditions, SMA cortical neurons showed significantly reduced vitality and altered morphology compared to WT neurons. All the parameters were rescued after treatment with known compounds (Valproic Acid, 4-aminopyridine and N-acetylcysteine), already tested in either preclinical or clinical context for SMA. We then investigated for the first time in SMA pathology the efficacy of 10H-phenothiazine (10H-PTZ), known to exert neuroprotection and to target altered mechanisms in Parkinson's and Alzheimer's disease. Its administration to SMA cortical neurons induced significant protective effects on both neuronal survival and morphology that were further confirmed in vivo, in a C. elegans SMA model. Overall, our results provide valuable insights, both in vitro and in vivo, into the potential of 10 H-PTZ repurposing for SMA, although additional functional studies will be required.}, } @article {pmid41401902, year = {2025}, author = {Li, HR and Shi, JZ and Zhang, MJ and Yun, LY and Zhou, YF and He, YY and Li, X and Du, GH and Pang, XB and Wang, MW and Xie, XM and Kou, JJ}, title = {Cftr nominates a novel therapeutic target for Alzheimer's disease: Evidence from integrative omics and in vitro validation.}, journal = {Neuropharmacology}, volume = {286}, number = {}, pages = {110808}, doi = {10.1016/j.neuropharm.2025.110808}, pmid = {41401902}, issn = {1873-7064}, abstract = {Alzheimer's disease (AD), among the most prevalent neurodegenerative disorders, poses substantial challenges for therapeutic development due to its complex pathophysiology, necessitating novel treatment strategies. This study applied an integrated transcriptomics and untargeted metabolomics approach to hippocampal tissues from wild-type and 3 × Tg-AD mice to identify AD-associated molecular alterations and key pathways. KEGG pathway enrichment analysis of significantly differentially expressed genes and metabolites identified several core candidate genes, including C5ar1, Gabrg1, Ptger1, Tac1, Lpar2, Pnp2, Cftr, and Sstr3. PCR-based validation in both in vivo and in vitro models confirmed Cftr as the most promising candidate for further investigation. In Aβ25-35-induced cellular AD models, Cftr knockdown or pharmacological inhibition activated the NLRP3 inflammasome pathway, exacerbating neuroinflammation and oxidative stress, whereas enhancing Cftr activity attenuated these pathological processes. These results establish Cftr as a potential therapeutic target for AD and reveal that its modulation of NLRP3 inflammasome signaling represents a strategic avenue for mitigating neuroinflammation and oxidative stress, suggesting a promising direction for intervening in AD progression.}, } @article {pmid41401892, year = {2025}, author = {Jogeshwar, BK and Lu, S and Nephew, BC}, title = {Neuroanatomical-based machine learning prediction of Alzheimer's Disease across sex and age.}, journal = {Neuroscience}, volume = {594}, number = {}, pages = {95-112}, doi = {10.1016/j.neuroscience.2025.12.030}, pmid = {41401892}, issn = {1873-7544}, abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. In 2024 it affected approximately 1 in 9 people aged 65 and older in the U.S., 6.9 million individuals. Early detection and accurate AD diagnosis are crucial for improving patient outcomes. Magnetic resonance imaging (MRI) has emerged as a valuable tool for examining brain structure and identifying potential AD biomarkers. This study performs predictive analyses by employing machine learning techniques to identify key brain regions associated with AD using numerical data derived from anatomical MRI scans, going beyond standard statistical methods. Using the Random Forest Algorithm, we achieved 92.87 % accuracy in detecting AD from Mild Cognitive Impairment and Cognitive Normals. Subgroup analyses across nine sex- and age-based cohorts (69-76 years, 77-84 years, and unified 69-84 years) revealed the hippocampus, amygdala, and entorhinal cortex as con- sistent top-rank predictors. These regions showed distinct volume reductions across age and sex groups, reflecting distinct age- and sex-related neuroanatomical patterns. Younger males and females (aged 69-76) exhibited volume decreases in the right hippocampus, suggesting its importance in the early stages of AD. Older males (77-84) showed substantial volume decreases in the left inferior temporal cortex. The left middle temporal cortex showed decreased volume in females, suggesting a potential female-specific influence, while the right entorhinal cortex may have a male-specific impact. These age-specific sex differences could inform clinical research and treatment strategies, aiding in identifying neuroanatomical markers and therapeutic targets for future clinical interventions.}, } @article {pmid41401852, year = {2026}, author = {Huang, YW and Chan, HC and Khoo, JY and Chan, ML and Bender, D and Ponnusamy, VK and Belaidi, AA and Ke, LY}, title = {Assessing the critical role of ceramide in the pathogenesis of Alzheimer's disease and its clinical significance.}, journal = {Neurochemistry international}, volume = {192}, number = {}, pages = {106104}, doi = {10.1016/j.neuint.2025.106104}, pmid = {41401852}, issn = {1872-9754}, mesh = {*Alzheimer Disease/metabolism/pathology/drug therapy ; Humans ; *Ceramides/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/pathology ; Clinical Relevance ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, and synaptic loss. Emerging evidence indicates that apolipoprotein E (APOE) polymorphism and dysregulated ceramide metabolism are critical links among these pathogenic processes. Ceramide accumulation in the brain contributes to Aβ generation, tau phosphorylation, and neuronal apoptosis. Elevated ceramide levels have been observed in plasma, cerebrospinal fluid, and peripheral organs such as the liver, reflecting systemic lipid dysregulation. Lipoproteins-particularly low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL)-transport ceramide across the blood-brain barrier, while apoE4 isoforms exacerbate this process by disrupting vascular integrity and lipid homeostasis. In addition, hepatic and gut-derived ceramides may influence neurodegeneration through the liver-gut-brain axis. Therapeutic interventions targeting ceramide synthesis (serine palmitoyltransferase inhibitors), production (neutral sphingomyelinase inhibitors), and the ceramide/sphingosine-1-phosphate (S1P) balance show potential in preclinical models for reducing Aβ pathology, tau aggregation, and neuroinflammation. These findings position ceramide metabolism as a critical mediator of AD pathogenesis and a promising target for diagnosis and treatment. Modulating ceramide and S1P signaling could complement current amyloid- and tau-directed therapies, offering new opportunities for disease modification and early intervention.}, } @article {pmid41400820, year = {2025}, author = {Al-Mayahi, S and Andersson, ML and Mo, M and Garcia-Ptacek, S and Xu, H and Wikström, E and Eriksdotter, M}, title = {Increased mortality in dementia patients using inhaled anticholinergics: A nationwide register study from the Swedish registry on dementia/cognitive disorders, SveDem.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251406309}, doi = {10.1177/13872877251406309}, pmid = {41400820}, issn = {1875-8908}, abstract = {BackgroundPatients with chronic obstructive pulmonary disease (COPD) face increased risks of cognitive impairment and mortality compared with the general population. Inhaled anticholinergics (LAMA/SAMA) are central in COPD treatment. The link between COPD and dementia is well studied, while effects of COPD medications on survival in dementia patients, have received limited attention.ObjectiveDescribe dementia patients using LAMA/SAMA in the Swedish Dementia Registry (SveDem) and compare survival between users (exposed) and non-users (unexposed).MethodsThis register-based study used data from SveDem and the Swedish Prescribed Drug Register to identify dementia patients using inhaled anticholinergics. All patients diagnosed with dementia between 2008-01-01 and 2017-12-31 were included. Exposed patients had at least one LAMA/SAMA dispensation per year in the two years prior the index date or more than one in the year before. Standardized-mortality-rates (SMR) were calculated, and survival analysed using Kaplan-Meier and Cox regression.ResultsA total of 74,018 dementia patients were included, of whom 3.5% had used inhaled anticholinergics. Alzheimer's disease was the most common dementia type. SMR was higher in exposed patients across all age groups: 8.21 versus 4.08 (ages 61-75) and 2.94 versus 1.84 (ages 75-90). Exposed had a higher risk of death (crude HR 1.73, 95% CI: 1.62-1.86) compared to unexposed.ConclusionsIn this register-based study we observed an association between inhaled anticholinergic use and reduced survival in dementia patients. This association is thought to be mainly driven by the underlying disease, COPD. Further studies are needed to clarify effects of inhaled anticholinergics on survival.}, } @article {pmid41400119, year = {2026}, author = {Basak, S and Colafrancesco, AM and Hernandez, RD and Wei, X and McMeekin, LJ and Dang, D and Simmons, M and Browning, JL and Noel, K and Zhou, F and Lund, FE and Saad, JS and Watsen, SG and Pickrell, AM and Cowell, RM and Olsen, ML}, title = {Novel Roles for the Ectoenzyme CD38 in the Maintenance of Transcriptional and Metabolic Homeostasis in Astrocytes.}, journal = {Glia}, volume = {74}, number = {2}, pages = {e70112}, pmid = {41400119}, issn = {1098-1136}, support = {R01NS124037/NH/NIH HHS/United States ; T32NS09.5775/NH/NIH HHS/United States ; 1S10RR026478/NH/NIH HHS/United States ; P30 CA013148/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Astrocytes/metabolism ; *ADP-ribosyl Cyclase 1/metabolism/genetics/deficiency ; *Homeostasis/physiology ; Mice ; Mice, Knockout ; Mice, Inbred C57BL ; NAD/metabolism ; Male ; *Membrane Glycoproteins/metabolism/genetics ; Brain/metabolism ; Mesencephalon/metabolism ; }, abstract = {CD38 is an ectoenzyme that converts NAD+ to NAM to help maintain bioenergetic homeostasis. CD38 dysregulation and gene variation is reported in neurodegenerative conditions such as Parkinson's disease (PD) and Alzheimer's disease (AD), highlighting the need to better understand CD38 biology within the brain. Here, we demonstrate enrichment of Cd38 in midbrain astrocytes and describe how CD38 deficiency influences brain metabolism, astrocytic gene expression, and bioenergetics. We demonstrate increased NAD content, decreased NAM content, and increased NAD/NAM in the midbrain and striatum of CD38-deficient (Cd38[-/-]) mice, indicating the dependence on CD38 for NAD to NAM conversion in the brain. RNA-sequencing of isolated astrocytes revealed numerous differentially expressed genes in Cd38[+/-] and Cd38[-/-] mice, with alterations in mitochondrial, metabolic, senescence-related, astrocyte reactivity, and other genes involved in PD and AD etiology. Furthermore, functional metabolic analysis of midbrain revealed changes in pyruvate oxidation, age-dependent increase of citrate synthase (CS) activity, and reduction of cytochrome c oxidase-to-CS ratio in Cd38 deficiency. These findings identify a novel role for astrocytes in the regulation of CD38-dependent NAD/NAM homeostasis in the brain and provide a framework for future studies evaluating the relationship between CD38 dysfunction, aging, and vulnerability of neuronal populations in neurodegenerative disease. Importantly, these studies underscore the necessity to better resolve the impact of CD38 deficiency on brain metabolism, considering ongoing clinical trials and discussions related to the use of CD38 modulators for the treatment of cancers, age-related decline, and neurodegenerative disease.}, } @article {pmid41399980, year = {2025}, author = {Chu, F and Zhou, X and Ma, R and Liu, R and Liu, X and Zhu, K and Wang, Y and Wang, X and Li, Y and Zhang, S and Yin, T and Liu, Z}, title = {Piezo1-Targeted Magnetoacoustic Nanobubbles Rescue Alzheimer's Pathology by Electromechanical Neuromodulation and Amyloid-β Clearance.}, journal = {ACS nano}, volume = {}, number = {}, pages = {}, doi = {10.1021/acsnano.5c13702}, pmid = {41399980}, issn = {1936-086X}, abstract = {Amyloid-β (Aβ) is considered a core pathological feature of Alzheimer's disease (AD), and its clearance efficiency is highly dependent on the function of the Piezo1 channel in microglia. However, the activity of Piezo1 is impaired under the pathological conditions of AD, and existing pharmacological strategies struggle to achieve precise targeted intervention in deep brain regions. To address these concerns, our research proposes a synergistic therapeutic paradigm leveraging transcranial magneto-acoustic stimulation (TMAS) to actuate microglial-Piezo1-targeted magnetic nanobubbles (PT-MNBs) for AD treatment. TMAS noninvasively focuses physical energy into deep brain lesion areas through a magnetoacoustic coupling field and drives PT-MNBs to generate responsive mechanical and electrical stimulation signals. PT-MNBs achieve microglia-specific anchoring through surface-modified phosphatidylserine, while conjugated anti-Piezo1 antibodies precisely deliver mechano-electrical stimulation signals to antibody-functionalized Piezo1 ion channels in microglial populations. This synchronously activates the mechanical- and voltage- sensitive domains of Piezo1 to recruit microglia to areas of inflammation and increase Aβ clearance, ameliorating synaptic plasticity impairment and ultimately reversing the pathological progression of AD. This dual-action mechanism achieves spatially precise manipulation of cellular mechanical and electrical activity in deep brain regions of AD mice and enhances Piezo1 function through precise energy delivery, enhancing their ability to clear Aβ plaques, opening an avenue for a noninvasive, deep-targeted physical stimulation-mediated nanoparticle synergistic therapy for AD.}, } @article {pmid41399798, year = {2025}, author = {Ghosh, S and Debnath, I and Bhunia, S and Nandi, S and Ashique, S and Nayak, A and Mallick, S and Basak, S}, title = {Decoding natural products for neuroprotection: Pathway networks and structural insights for drug development.}, journal = {Chinese herbal medicines}, volume = {17}, number = {4}, pages = {643-672}, pmid = {41399798}, issn = {2589-3610}, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis, are progressive disorders marked by neuronal dysfunction and death, driven by pathological mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, and protein misfolding. Despite scientific advances, current treatments remain largely palliative, underscoring the need for multitargeted therapeutic strategies. This narrative review synthesizes preclinical and clinical evidence to explore the neuroprotective potential of natural products, with a focus on their ability to modulate key molecular pathways implicated in NDs. A comprehensive literature search across Scopus, ScienceDirect, PubMed, MDPI, and Web of Science identified relevant studies. Bioactive compounds such as curcumin, resveratrol, ginsenosides, quercetin, and marine-derived molecules like fucoxanthin and phlorotannin demonstrated antioxidant, anti-inflammatory, anti-amyloidogenic, and mitochondrial-protective effects by modulating pathways including PI3K/Akt, NF-κB, and Nrf2/ARE, thereby mitigating neuronal damage and promoting cell survival. Natural products from diverse sources, including honey, ginseng, marine macroalgae, and cyanobacteria, exhibited broad-spectrum neuroprotective properties, with advances in nano-formulations improving bioavailability and brain penetration. Furthermore, emerging approaches such as gene-drug interaction studies and scaffold-based drug design offer promising avenues for enhancing clinical translation. While natural products provide a holistic, multitargeted approach to combat NDs, challenges related to bioavailability and therapeutic translation persist, necessitating future research that integrates advanced drug delivery systems, precision medicine, and synthetic modifications to develop innovative and effective treatment paradigms.}, } @article {pmid41399730, year = {2025}, author = {Zhang, Y and Chen, S and Yan, G and Zhang, Z and Amina, and Wang, T and Wang, S and Zhang, C and Sun, Y}, title = {MAPT mutation-induced behavioral variant frontotemporal dementia in an Asian patient: a multimodal biomarker case report resolving diagnostic challenges with Alzheimer's disease.}, journal = {Frontiers in genetics}, volume = {16}, number = {}, pages = {1645068}, pmid = {41399730}, issn = {1664-8021}, abstract = {BACKGROUND: The clinical phenotypic overlap between frontotemporal dementia (FTD) and Alzheimer's disease (AD) frequently leads to misdiagnosis, while biomarkers (e.g., Aβ-PET) and genetic testing provide critical differential diagnostic evidence. Although MAPT gene mutations represent common genetic etiologies of FTD, their occurrence in Asian populations remains underreported. Specifically, FTD caused by the MAPT IVS10 + 16C>T mutation shows limited documentation in Asian populations, with its phenotypic heterogeneity and treatment responses remaining poorly characterized.

METHODS: We present a case of FTD manifesting progressive memory decline, compulsive behaviors, and apathy. MRI revealed bilateral frontoparietotemporal atrophy with prominent medial temporal lobe and hippocampal involvement, initially misdiagnosed as AD. Subsequent Aβ-PET negativity emerged as a pivotal diagnostic turning point, and identification of a heterozygous MAPT mutation (IVS10 + 16C>T) confirmed behavioral variant FTD (bvFTD) diagnosis. Partial improvement in compulsive behaviors and verbal fluency was observed following memantine treatment. A literature review summarizes clinical characteristics of FTD associated with IVS10 + 16C>T mutations.

RESULTS: Comprehensive neuropsychological assessment, cranial MRI, and negative Aβ-PET excluded AD pathology. Genetic confirmation of MAPT IVS10 + 16C>T mutation established bvFTD diagnosis. Three-month memantine treatment reduced compulsive behaviors without cognitive improvement. Literature analysis indicates this mutation's rarity in Asian populations, typically presenting with behavioral abnormalities frequently misdiagnosed as AD.

CONCLUSION: This study rectified misdiagnosis of MAPT IVS10 + 16C>T-associated bvFTD through multimodal diagnostics, emphasizing the synergistic value of genetic testing and neuroimaging. Memantine's partial behavioral symptom alleviation suggests potential mutation-specific therapeutic efficacy requiring further validation. Future directions should optimize diagnostic protocols (e.g., cost-effective genetic screening) and address barriers to early diagnosis in Asian populations.}, } @article {pmid41399578, year = {2025}, author = {Gassull, A}, title = {Ethical Challenges in Managing a Displaced Neer III Humeral Head Fracture in an Undocumented Immigrant With Early Alzheimer's Disease: A Case Report.}, journal = {Cureus}, volume = {17}, number = {11}, pages = {e96805}, pmid = {41399578}, issn = {2168-8184}, abstract = {This report describes an 82-year-old undocumented Peruvian female immigrant presenting to the ED with right elbow pain and limited shoulder mobility, diagnosed with a displaced Neer III right humeral head fracture sustained two days prior. She had not clearly communicated shoulder pain to her family for two days post-injury, possibly due to early Alzheimer's disease, which may have impaired her ability to recognize or articulate the severity of her injury, illustrating the clinical-ethical intersection. Radiographic imaging confirmed the fracture with medial displacement, necessitating surgical intervention. Due to her undocumented status and lack of health insurance, she was required to pay the full cost of a reverse shoulder prosthesis (€24,000), which she could not afford. Her Alzheimer's-related dependency and absence of family support in Peru prevented seeking treatment abroad, resulting in discharge with a sling. Comprehensive blood tests ruled out metabolic contributors to her fall. This case highlights ethical challenges in healthcare access for undocumented immigrants, compounded by Alzheimer's-related communication and dependency issues, underscoring disparities and the need for equitable care. This case exemplifies how clinical vulnerability and legal status can intersect to create barriers in emergency and trauma care.}, } @article {pmid41399419, year = {2025}, author = {Chen, HW}, title = {Axial Spinal Traction as a Potential Modulator of Cerebrospinal and Glymphatic Circulation in Neurodegenerative Diseases: A Technical Report and Biomechanical Hypothesis.}, journal = {Cureus}, volume = {17}, number = {12}, pages = {e99153}, pmid = {41399419}, issn = {2168-8184}, abstract = {Impairment of glymphatic function contributes to the accumulation of metabolic and proteinaceous waste products implicated in neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and certain spinocerebellar ataxias. Pelvis-stabilized axial spinal traction (PSAST) is a biomechanical technique designed to produce brief, controlled cranio-caudal elongation of the vertebral column and spinal dural sac, potentially generating transient pressure gradients capable of influencing cerebrospinal fluid (CSF) dynamics and glymphatic circulation. The technique has been applied in the author's musculoskeletal practice for more than eight years without observed persistent or treatment-related adverse effects, although such practice-based experience does not constitute a formal safety evaluation. Improved sleep quality has been the most consistently reported patient-perceived response to PSAST, a clinically notable observation given the dependence of glymphatic function on consolidated slow-wave sleep. These practice-based observations provide preliminary, hypothesis-generating support for exploring whether controlled axial elongation may modulate cerebrospinal and glymphatic physiology. To the best of the author's knowledge, this report presents the first peer-reviewed technical description of a reproducible, whole-axis axial spinal traction procedure with defined force parameters intended to examine potential modulation of CSF and glymphatic circulation. The report outlines the PSAST protocol and its biomechanical rationale and safety considerations and proposes its potential relevance as a noninvasive, investigational approach for conditions associated with impaired glymphatic function.}, } @article {pmid41399037, year = {2025}, author = {Di Donna, MG and Motta, C and Bonomi, CG and Bernocchi, F and Ricci, F and Poli, M and Koch, G and Martorana, A}, title = {Reframing TDP-43 in Alzheimer's disease: From co-pathology to neurovascular culprit.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70988}, pmid = {41399037}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; *DNA-Binding Proteins/metabolism ; *Blood-Brain Barrier/metabolism/pathology ; Astrocytes/metabolism/pathology ; Endothelial Cells/metabolism/pathology ; *Brain/pathology/metabolism ; }, abstract = {Alzheimer's disease (AD) is widely recognized as a multifactorial disorder involving neurovascular and glial dysfunction beyond amyloid-β and tau pathology. In this Perspective, we synthesize recent evidence to propose a conceptual framework linking transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) to neurovascular unit (NVU) disruption in AD. Traditionally considered a neuronal co-pathology, TDP-43 also aggregates in astrocytes and endothelial cells, impairing blood-brain barrier (BBB) integrity, glymphatic clearance, and metabolic homeostasis. Endothelial TDP-43 loss disrupts β-catenin signaling and fibronectin, triggering vascular breakdown and neuroinflammation. Astrocytic perivascular aggregates correlate with reduced aquaporin-4 (AQP4) and CD146, further compromising clearance pathways. These vascular-glial mechanisms may accelerate AD progression and help explain clinical heterogeneity and limited therapeutic response in TDP-43-positive patients. We argue for the reclassification of TDP-43 as a potential upstream driver of disease progression. Such a shift would support the development of integrative biomarkers and precision treatment strategies targeting NVU dysfunction. HIGHLIGHTS: Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) may act as a driver of neurovascular dysfunction in Alzheimer's disease (AD). We propose reclassifying TDP-43 from co-pathology to upstream contributor. TDP-43 affects endothelial cells and astrocytes, disrupting blood-brain barrier (BBB) and clearance. Neurovascular unit (NVU) dysfunction links TDP-43 to inflammation, hypoperfusion, and cognitive decline. A vascular-glial model of AD opens new therapeutic and biomarker opportunities.}, } @article {pmid41398677, year = {2025}, author = {Wang, B and Wang, Y and Yang, F and Han, F and Li, K and Sun, K and Liang, P}, title = {The effect of repetitive transcranial magnetic stimulation on immediate and long-term cognitive functions in Alzheimer's dementia and mild cognitive impairment: a meta-analysis.}, journal = {Journal of neuroengineering and rehabilitation}, volume = {22}, number = {1}, pages = {262}, pmid = {41398677}, issn = {1743-0003}, support = {LGKCYLWS2022034//Key Project of Medical and health technology of Longgang District, Shenzhen/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Cognitive Dysfunction/therapy/psychology ; *Transcranial Magnetic Stimulation/methods ; *Cognition/physiology ; Randomized Controlled Trials as Topic ; Neuropsychological Tests ; Treatment Outcome ; Aged ; }, abstract = {BACKGROUND: Alzheimer's dementia (AD) and mild cognitive impairment (MCI) are characterized by progressive cognitive decline. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technology, has been widely used to improve cognition in AD and MCI. However, the impact of rTMS on immediate and long-term cognitive functions in AD and MCI, as well as the optimal stimulating parameters, need further clarification.

METHOD: Thirty-one randomized controlled trials were included to examine the effects of rTMS on immediate cognition (post-treatment cognition), while nine trials were specifically used to assess its impact on long-term cognition (follow-up cognition). All participants were tested on at least one of the neuropsychological scales of the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Alzheimer's disease Assessment Scale-Cognitive Section (ADAS-Cog) to evaluate global cognitive outcomes of rTMS. The study followed the guidelines for meta-analysis of intervention studies and assessed the risk of bias of the included studies. Moderator analysis was used to examine factors that might affect treatment effect. Sensitivity analysis was used to evaluate stability of results. Meta-regression analysis was used to assess the interpretability of heterogeneity. Begg's and Egger's test and funnel plot were applied to assess publication bias.

RESULTS: The results demonstrated that rTMS significantly improved immediate cognition (SMD = 0.93, 95% CI = 0.64 to 1.22, p < 0.001) and long-term cognition (SMD = 0.42, 95% CI = 0.13 to 0.70, p = 0.004) across all patients (including AD and MCI). Moderator analysis revealed that targeting dorsolateral prefrontal cortex (DLPFC), using intensities of 80% or less of the motor threshold, total time of 800 min or more and stimulation sessions greater than 20 significantly enhanced immediate cognitive performance than their counterparts. In contrast, stimulation frequency, duration/session and patient type showed no significant impact on immediate cognition. For long-term cognition, differences in stimulation protocols had no influence on treatment effect for all patients.

CONCLUSION: rTMS had a positive effect on immediate and long-term cognition in AD and MCI, stimulation region, intensity, total time and number of sessions significantly improve immediate cognition. These findings suggest that rTMS has potential as a promising adjunctive treatment for AD and MCI.}, } @article {pmid41398371, year = {2025}, author = {Yoon, J and Ha, H and Lee, HW and Kim, S and Yu, YM and Chun, H}, title = {Potential beneficial effects of PD-1/PD-L1 blockade in Alzheimer's disease: a systematic review and meta-analysis of preclinical and clinical studies.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {41398371}, issn = {1476-5578}, abstract = {BACKGROUND: Programmed cell death protein 1 (PD-1) and its ligand (PD-L1) are crucial in cancer immune evasion and in modulating neuroinflammation. Although PD-1/PD-L1 signaling is believed to modulate immune and neuronal responses, its role in AD pathophysiology remains unclear, with existing studies reporting inconsistent findings.

METHOD: This systematic review and meta-analysis investigated the effects of PD-1/PD-L1 blockade on AD-related pathology and cognitive behavior in preclinical studies. Additionally, we evaluated the impact of PD-1/PD-L1 inhibitors on cognitive outcomes in clinical studies involving cancer patients. Relevant research was systematically identified using the MEDLINE, Embase, CENTRAL, and Web of Science databases from their inception until July 31, 2025. Overall, 40 studies were included in this meta-analysis, conducted using R software.

RESULTS: Preclinical studies revealed that blockade of PD-1 signaling reduces amyloid-beta plaque burden, tau phosphorylation, and astrocyte reactivity in AD mouse models. These pathological improvements were accompanied by enhanced cognitive performance, whereas wild-type mice showed no significant cognitive changes under the same treatment, whereas wild-type mice showed no significant cognitive changes under the same treatment. Furthermore, clinical studies demonstrated the beneficial effect of PD-1 signaling inhibitors on cognitive function in patients with cancer.

CONCLUSIONS: PD-1/PD-L1 inhibition impacts AD pathology and cognitive function, suggesting its potential as a therapeutic development strategy for AD. Further studies are warranted to clarify the exact mechanisms, opening avenues for future therapies that modulate the PD-1/PD-L1 pathway for AD.}, } @article {pmid41398125, year = {2025}, author = {Huang, FW and Bello, ST}, title = {Role of Neuronal Cholecystokinin Receptor: An Emerging Therapeutic Target for Ameliorating Neurological Diseases.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {296}, pmid = {41398125}, issn = {1559-1182}, support = {11103220, 11101521, 11102422//Hong Kong Research Grants Council/ ; }, mesh = {Animals ; Humans ; *Receptors, Cholecystokinin/metabolism/antagonists & inhibitors ; *Nervous System Diseases/metabolism/drug therapy ; *Neurons/metabolism ; Cholecystokinin/metabolism ; }, abstract = {Neuronal cholecystokinin (CCK) is the most abundant neuropeptide in the mammalian brain and serves as a critical neuromodulator regulating the physiological states of animals. Previous research on CCK primarily focused on its roles in digestive function, satiety regulation, and emotional modulation, while its involvement in the development of brain diseases remains largely unexplored. Interestingly, recent studies have revealed that CCK-2 receptor antagonists have significant effects on neural modulation, suggesting a potential strategy for the treatment of brain disorders such as Alzheimer's disease, depression, and motor neuron disease, among others. To elucidate the neural effects of CCK on the progression of neurological disorders, we review the available evidence on the neuropeptide CCK in brain diseases at multiple levels and propose novel and complementary approaches to the treatment of brain diseases based on recent developments.}, } @article {pmid41398046, year = {2025}, author = {Heron, R and Amato, C and Monteiro-Black, B and Williams, RJ and Wood, W}, title = {Amyloid-beta induces distinct forms of cell death in different neuronal populations.}, journal = {Cell death and differentiation}, volume = {}, number = {}, pages = {}, pmid = {41398046}, issn = {1476-5403}, support = {22460/Z/21/Z//Wellcome Trust (Wellcome)/ ; 218627/Z/19/Z//Wellcome Trust (Wellcome)/ ; 218627/Z/19/Z//Wellcome Trust (Wellcome)/ ; MR/W019264/1//RCUK | Medical Research Council (MRC)/ ; 894935//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions)/ ; }, abstract = {Recent FDA approval for treating Alzheimer's disease (AD) with amyloid-beta (Aβ) immunotherapy is a historic breakthrough, which has rekindled widespread interest in understanding the molecular basis of Aβ toxicity. In this study, we developed a novel Drosophila model to investigate Aβ42-induced pathologies in vivo and in real time. Strikingly, we unveiled compelling evidence that secreted Aβ42 affects different neurons in distinct ways-both in susceptibility to Aβ42 deposition and in the mode of cell death triggered. Additionally, we observed altered larval crawling behaviour which-remarkably-could be recovered by inhibiting ferroptotic cell death with small molecule inhibitors. Collectively these findings showcase this as a powerful new model for investigating Aβ toxicity in AD and identifying novel treatment strategies.}, } @article {pmid41397735, year = {2025}, author = {Zong, G and Li, R and Jiang, Y and Chen, Z and Yan, S and Yi, Z and Ren, X and Jia, B}, title = {[Two cases of urinary retention in patients with Alzheimer's disease with agitation treated by acupuncture].}, journal = {Zhongguo zhen jiu = Chinese acupuncture & moxibustion}, volume = {45}, number = {12}, pages = {1822-1824}, doi = {10.13703/j.0255-2930.20250804-k0002}, pmid = {41397735}, issn = {0255-2930}, mesh = {Aged ; Humans ; Acupuncture Points ; *Acupuncture Therapy ; *Alzheimer Disease/complications/therapy/psychology ; *Psychomotor Agitation/therapy/complications ; *Urinary Retention/therapy/etiology ; }, abstract = {This article reports 2 cases of urinary retention in Alzheimer's disease with agitation treated by acupuncture. Based on patients' clinical symptoms, the etiology and pathogenesis were determined, and acupuncture was applied to Baihui (GV20), Sishencong (EX-HN1), Shenting (GV24), and bilateral Ciliao (BL32), Zhongliao (BL33), Fengchi (GB20), Taiyang (EX-HN5), etc. to regulate the mind and promote water metabolism. The positive and negative electrodes of the SDZ-Ⅴ type electroacupuncture device were attached to ipsilateral Ciliao (BL32), Zhongliao (BL33) respectively, with continuous wave, at the frequency of 15 Hz, and the current of 3 to 10 mA, depending on patients' tolerance. The needles were retained for 20 min. The treatment was delivered once every other day, 3 interventions a week and 12 interventions as 1 course. Both patients reported the micturition desire after 1 intervention with acupuncture and the catheter was removed on the same day. The urination was ameliorated without dysuresia after 1-2 courses of treatment, and the agitated behavior was alleviated. It can be the reference for the clinical treatment of urinary retention in patients with Alzheimer's disease with agitation.}, } @article {pmid41397578, year = {2026}, author = {Wang, X and Wang, X and Zhao, C and Zhao, H and Wang, P and Song, T}, title = {Enhancement of cognitive behavior and hippocampal neural oscillations by rhythmic unipolar pulsed magnetic stimulation in 5xFAD Alzheimer's disease mice.}, journal = {Behavioural brain research}, volume = {500}, number = {}, pages = {115995}, doi = {10.1016/j.bbr.2025.115995}, pmid = {41397578}, issn = {1872-7549}, mesh = {Animals ; *Alzheimer Disease/therapy/physiopathology ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Gamma Rhythm/physiology ; *Magnetic Field Therapy/methods ; Theta Rhythm/physiology ; Male ; *CA1 Region, Hippocampal/physiopathology ; *Behavior, Animal/physiology ; *Hippocampus/physiopathology ; Cognitive Dysfunction/therapy/physiopathology ; *Cognition/physiology ; }, abstract = {Alzheimer's disease (AD) imposes a heavy burden on families and society. Rhythmic magnetic stimulation has emerged as a promising non-invasive therapy to mitigate AD-related cognitive decline. In this study, we applied a rhythmic unipolar compound pulsed magnetic field (cPMF; carrier frequency: 40 Hz, repetition rate: 5 Hz, magnetic flux density: 0-20 mT) incorporating both theta and gamma rhythms to evaluate its effects on behavior and neural oscillations in AD mice and to explore the underlying mechanisms. 5xFAD mice received unipolar cPMF stimulation for 1 h/d over 8 consecutive weeks. Learning and memory were assessed using the novel object recognition (NOR) and the Morris water maze (MWM) tests. In NOR test, unipolar cPMF-treated mice showed a higher cognitive index in test phase 2, and in MWM test, exhibited shorter escape latencies in the training trial and spent less time to first cross the precise former platform location with a higher crossing frequency over this target area in the probe trial. Local field potentials (LFPs) in the hippocampal CA1 area were recorded via in vivo electrophysiology. LFP analysis showed that unipolar cPMF treatment enhanced power of cognitive-related neural oscillations and strengthened theta-gamma phase-amplitude coupling. RNA sequencing analysis further indicated that unipolar cPMF-treated mice exhibited differential gene expression in molecular function and multiple neurotransmitter synaptic signaling pathways. In conclusion, unipolar cPMF might improve cognitive function in 5xFAD mice by modulating cognitive-related neural oscillations. These findings could provide experimental support for the low-intensity pulsed magnetic stimulation as a potential therapeutic strategy for AD.}, } @article {pmid41397211, year = {2026}, author = {Satyadev, N and Piura, YD and Tipton, PW and Dunham, SR and Morris, JC and Geschwind, MD and Brier, M and Graff-Radford, NR and Day, GS}, title = {Standardizing "Rapid": Applying the Clinical Dementia Rating to Define Rapidly Progressive Dementia.}, journal = {Neurology}, volume = {106}, number = {1}, pages = {e214439}, doi = {10.1212/WNL.0000000000214439}, pmid = {41397211}, issn = {1526-632X}, mesh = {Humans ; Female ; Male ; Disease Progression ; Aged ; *Dementia/diagnosis ; Aged, 80 and over ; Retrospective Studies ; Middle Aged ; *Mental Status and Dementia Tests/standards ; }, abstract = {BACKGROUND AND OBJECTIVES: Rapidly progressive dementia (RPD) accounts for 3%-4% of dementia cases yet presents a disproportionate clinical challenge given the wide differential diagnosis and the need to quickly identify potentially treatment-responsive causes. The lack of a standardized definition of RPD challenges generalization of published findings and precludes multisite studies. We sought to determine whether a standardized definition, based on the Clinical Dementia Rating (CDR), could reliably distinguish individuals with a broad spectrum of causes of RPD early in the symptomatic course.

METHODS: RPD was defined as dementia (global CDR ≥1) developing within 1 year or incapacitation (global CDR ≥2) within 2 years of symptom onset. Patients with suspected RPD were referred from inpatient and outpatient settings at Mayo Clinic in Florida (Jacksonville, FL) and Washington University in St. Louis (Saint Louis, MO) and prospectively evaluated (RaPID cohort). Retrospective data from participants assessed across 46 research centers were also analyzed (National Alzheimer's Coordinating Center [NACC] data set). Characteristics and rates of progression (main outcome) were compared between typically progressive and RPD. Univariable and multivariable analyses were performed using Mann-Whitney U/Kruskal-Wallis (continuous) and Fisher exact/χ[2] tests (binary), respectively. Our definition of RPD was compared against definitions identified through a scoping review conducted using a validated 6-stage approach.

RESULTS: In the RaPID cohort, 185 of 248 (74.6%) patients met our CDR-based RPD definition (median [range] age-at-symptom onset: 68.8 years [22.0-90.7]; 45.4% female). Autoimmune (55/185, 29.7%), neurodegenerative (51/185, 27.6%), and prion diseases (35/185, 18.9%) predominated. Among 20,418 NACC participants with cognitive impairment, 836 (4.1%) met our RPD definition (median [range] age-at-symptom onset: 74 years [24-103]; 57.1% female). Neurodegenerative diseases predominated, especially Alzheimer disease (485/836, 58.0%). Individuals with RPD declined substantially faster (ΔCDR sum-of-boxes/year: RaPID, 14.4 ± 5.3 vs 4.3 ± 4.3, p < 0.001; NACC, 6.7 ± 3.1 vs 1.7 ± 1.4, p < 0.001). Our scoping review identified 22 studies that applied 10 distinct definitions of RPD. Uniquely, our CDR-based definition clearly distinguished individuals with a broad spectrum of causes of RPD, assessed across multiple sites/settings, supporting early diagnosis with minimal resource requirements.

DISCUSSION: The CDR-based definition of RPD effectively identified individuals with a broad spectrum of causes of RPD early in the symptomatic course. The need for training and time to reliably administer the CDR may limit application of the proposed definition of RPD. Validation in additional cohorts is required to support generalizability.}, } @article {pmid41396874, year = {2025}, author = {Zu, J and Li, C and Cui, M and Liu, X and Pan, Z and Li, X and Zhang, F and Gentz, J and Mitteregger-Kretzschmar, G and Herms, J and Shi, Y}, title = {Pioglitazone attenuates complement-mediated microglial synaptic engulfment in an Alzheimer's disease model.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf462}, pmid = {41396874}, issn = {1460-2156}, abstract = {Synaptic loss is an early hallmark of Alzheimer's disease (AD), predominantly driven by aberrant microglial reactivity. Pioglitazone, a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist with anti-diabetic properties, has been shown to suppress microglial activity and improve cognitive performance in both AD models and clinical studies. However, whether its neuroprotective effects involve direct modulation of synaptic architecture remains unclear. Here, using longitudinal in vivo two-photon imaging, multi-channel immunohistochemistry, super-resolution confocal microscopy, and 3D reconstruction techniques in an AD mouse model, we analysed synaptic and microglial interactions. We show that a 4-week pioglitazone treatment preserves dendritic spine density and enhances spine stability over time. Mechanistically, pioglitazone reduces synaptic C1q deposition, thereby limiting complement-mediated microglial synaptic engulfment and attenuating synapse loss. These findings identify pioglitazone as a modulator of complement-dependent microglial synaptic pruning and support its therapeutic potential in preserving synaptic integrity during early AD pathogenesis.}, } @article {pmid41396614, year = {2025}, author = {Brown, CA and Mundada, NS and Cousins, KAQ and Sadeghpour, N and Lyu, X and McGrew, E and Korecka, M and Chen-Plotkin, A and Xie, L and Wisse, LEM and Detre, JA and McMillan, CT and Lee, EB and Nasrallah, IM and Das, SR and Mechanic-Hamilton, D and Yushkevich, PA and Shaw, LM and Wolk, DA and , }, title = {Evaluation of Copathology and Clinical Trajectories in Individuals With Tau-Clinical Mismatch.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {41396614}, issn = {2168-6157}, abstract = {IMPORTANCE: Even within individuals who are amyloid positive, clinical symptoms can be impacted by Alzheimer pathology, other pathologic proteins, and cognitive reserve or resilience. Understanding how each of these factors contributes to a patient's clinical presentation is crucial for prognosis and treatment decisions in the era of disease-modifying therapies.

OBJECTIVE: To evaluate tau-clinical mismatch as a means to identify those more likely to harbor copathology and/or exhibit resilience to Alzheimer pathology.

This was a longitudinal, observational cohort study conducted from 2004 to 2024. The setting included multiple academic medical centers in the US participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI) or Penn Alzheimer's Disease Research Center (Penn-ADRC). Included in the analysis were individuals with clinical assessment and measures of either tau positron emission tomography (tau-PET) or phosphorylated tau 217 (p-tau217) who were selected from individuals positive for amyloid β (Aβ+) in the ADNI cohort (aged 55-95 years) and the Penn-ADRC cohort (aged 54-92 years).

EXPOSURES: Clinical assessment (Clinical Dementia Rating Sum of Boxes [CDR-SB]) and tau burden (tau-PET or p-tau217) for mismatch group classification.

MAIN OUTCOMES AND MEASURES: Cross-sectional measures of neurodegeneration (medial temporal lobe volume and thickness, cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature), α-synuclein cerebrospinal fluid seed-amplification assay, and longitudinal CDR-SB.

RESULTS: A total of 365 participants (mean [SD] age, 75.4 [7.9] years; 192 female [52.6%]) in the ADNI tau-PET group and 524 participants (mean [SD] age, 77.1 [7.9] years; 268 male [51.1%]) in the ADNI p-tau217 group were selected from the 998 individuals who were Aβ+ in the ADNI cohort and used to generate tau-clinical mismatch models with 55.6% to 57.1% classified as canonical (CDR-SB commensurate to tau), 23.7% to 24.7% as resilient (CDR-SB < tau), and 19.3% to 19.7% as vulnerable (CDR-SB > tau). Vulnerable groups had evidence of greater likelihood of copathology, with TDP-43 neurodegeneration patterns and α-synuclein positivity. Mismatch groups showed diverging clinical trajectories with earlier cognitive impairment in vulnerable groups and later impairment in resilient individuals. Similar findings were seen when applied to an independent dataset of 244 individuals (mean [SD] age, 73.7 [6.8] years; 139 female [57.0%]) of the 248 who were Aβ+ in Penn-ADRC cohort. Finally, these models were applied to a cohort receiving antiamyloid therapy to show the utility of this method for predicting individual cognitive trajectories during therapy.

CONCLUSION AND RELEVANCE: Results of this cohort study suggest that tau-clinical mismatch identified individuals more likely to have an accelerated disease course due to the presence of copathology and those exhibiting greater cognitive resilience to disease pathology. These models provide an important tool that can be implemented in clinical practice to provide improved individualized prognosis and, potentially, monitoring of response to disease-modifying therapy.}, } @article {pmid41396413, year = {2025}, author = {Zuliani, G and Brombo, G and Romagnoli, T and Polastri, M and Dario, FDP and Zuin, M}, title = {Effectiveness of acetylcholinesterase inhibitors and memantine in patients affected by severe dementia.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {41396413}, issn = {2509-2723}, abstract = {The efficacy of acetylcholinesterase inhibitors (AChEI) and memantine (ME) in severe dementia remains uncertain, and real world data are limited. We evaluated the progression of cognitive decline and mortality rates in a cohort of outpatients with severe dementia treated with AChEI and/or ME or not treated, from the National Alzheimer's Coordinating Center Uniform Data Set (NACC-UDS). Overall, 703 patients (mean age:78.3 ± 7.2 years; females:56.1%) with severe dementia (Mini-Mental State Examination-MMSE ≤ 10/30) were included [407 late-onset Alzheimer's disease (LOAD), 126 Lewy body dementia (LBD), 170 vascular dementia (VD)]. Patients were grouped by treatment status: untreated (AChEI - /ME - ; n.70), AChEI only (AChEI + ; n.294), ME only (ME + ; n.215), combined therapy (AChEI + /ME + ; n.124). During follow-up (mean:1.7 ± 0.3 years; range:0.2-2.9 years) the mean MMSE scores declined by - 1.7 points (Standard Deviation: -1.55 to -1.9) in AChEI - /ME - (p for trend:0.001), - 1.5 points (-1.55 to -1.9) in AChEI + (p:0.001), - 0.7 points (-0.5 to -0.9) in ME + (p:0.09), while it increased by + 0.7 points (+ 0.4 to + 1.0) in AChEI + /ME + (p:0.001). Survival rates were 8% in AChEI - /ME - , 10% in AChEI + , 28% in ME + , and 49% in AChEI + /ME + . In Cox proportional hazards analysis (age and sex adjusted), AChEI + /ME + exhibited a 39% reduction in total mortality compared with no treatment (HR:0.61; 95%CI:0.49-0.77; p < 0.001), ME + displayed a 22% reduction (HR:0.78; 95%CI:0.65-0.94; p:0.007), while AChEI + showed no association (HR:0.97; 95%CI:0.80-1.18; p:0.75). When the Cox proportional hazards models were stratified by dementia subtype, consistent significant patterns were observed in LOAD and LBD. In this real-world cohort of older adults with severe dementia, the combination therapy (ME + AchEI) seems to be associated with the best outcomes, including a stabilization of cognitive function and reduced total mortality.}, } @article {pmid41396167, year = {2026}, author = {Robinson, L and Bray, J and Melis, V and Harrington, CR and Wischik, CM and Riedel, G}, title = {Effects of hydromethylthionine mesylate and rivastigmine in a pharmacological mouse model of Alzheimer's disease.}, journal = {Behavioural pharmacology}, volume = {37}, number = {1}, pages = {64-69}, pmid = {41396167}, issn = {1473-5849}, support = {PAR 1577//WisTa Laboratories Ltd/ ; }, mesh = {Animals ; *Rivastigmine/pharmacology ; *Alzheimer Disease/drug therapy/physiopathology ; Mice ; Scopolamine/pharmacology ; Disease Models, Animal ; Female ; Maze Learning/drug effects ; Cholinesterase Inhibitors/pharmacology/administration & dosage ; *Tacrine/analogs & derivatives/pharmacology ; Memory/drug effects ; }, abstract = {The results from clinical trials have indicated that the tau aggregation inhibitor hydromethylthionine mesylate (HMTM) produces disease-modifying effects in Alzheimer's disease (AD) patients when administered alone, but less of an effect when administered in conjunction with cholinesterase inhibitors (ChEIs). The use of ChEIs for AD has been supported by their ability to reverse scopolamine-induced cognitive impairments in rodents reminiscent of those seen in AD patients. We have previously shown that another tau aggregation inhibitor, methylthionine chloride (MTC), is able to reverse scopolamine-induced deficits in spatial learning and memory. The objective here was to determine the symptomatic efficacy of HMTM and rivastigmine, alone or in combination, in a scopolamine model of AD. Female NMRI mice were treated systemically with scopolamine (0.5 mg/kg) or vehicle in combination with ChEI rivastigmine (0.5 mg/kg) or HMTM (5 or 15 mg/kg) daily before assessment of spatial learning and memory performance in a reference memory task in the water maze. Systemic administration of scopolamine induced significant impairments in the spatial learning of the mice compared to vehicle treatment. These deficits were reversed by treatment with HMTM at both doses and with rivastigmine when given alone. Furthermore, coadministration of rivastigmine with HMTM ameliorated the impairments induced by scopolamine. These findings extend our previous observations with MTC and confirm that HMTM also has a dual mode of action, disease modification through tau aggregation inhibition, but also having symptomatic effects through its normalisation of cholinergic activity.}, } @article {pmid41396015, year = {2025}, author = {Leng, L and Liao, Z and Lu, P and Sun, Y and Weng, Q and Fan, W and Zhu, H and Wu, W and Liu, P and Liu, X and Zhang, K and Wang, W and Luo, B and Wang, Z and Peng, G}, title = {Real-world experience with baseline characteristics and safety of lecanemab for Alzheimer's disease in Eastern China.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251406619}, doi = {10.1177/13872877251406619}, pmid = {41396015}, issn = {1875-8908}, abstract = {BackgroundLecanemab reduces amyloid levels and modestly slows cognitive decline in a large cohort of early Alzheimer's disease (AD) but lacks real-world safety data in Chinese population.ObjectiveThe real-world study aims to analyze baseline characteristics and preliminary safety of lecanemab for AD in Zhejiang Province, and to evaluate the efficacy of plasma biomarkers for patient screening.MethodsThis multi-center study included 190 patients with AD in Zhejiang Province, who completed baseline assessments and received lecanemab treatment with follow-up.ResultsThe study included 176 participants with early AD and 14 moderate. In the early AD (mean age 68.04 years, Mini-Mental State Examination 20.03 and Montreal Cognitive Assessment 14.93), 124 (70.5%) participants were female, and 127 (72.1%) were junior high school education level or less. APOE4 heterozygote was predominant (48.9%). Logistic regression for distinguishing early AD from the Aβ negative cognitively unimpaired populations showed that p-Tau 217 independently provided better classification efficacy (area under the curve = 0.9983, p < 0.0001). In the early AD, 29 (16.5%) participants experienced infusion-related reactions (IRR) after the first-dose lecanemab, and amyloid-related imaging abnormalities (ARIA) were identified in 17 patients (9.7%), while 3 (21.4%) with IRR and none ARIA observed in the moderate AD.ConclusionsThe real-world lecanemab cohort had more females, lower educational level, and higher disease burden compared with the clinical trial cohort. Overall lecanemab exhibited a manageable short-term safety profile with no measurable cognitive efficacy. Extensive monitoring and management are required for ARIA of clinically importance. The plasma p-Tau 217 showed high accuracy for early AD screening.}, } @article {pmid41394556, year = {2025}, author = {Seto, M and Klinger, HM and Clifton, M and Janve, VA and Brown, JA and Birkenbihl, C and Coughlan, G and Townsend, DL and Wang, TC and Properzi, M and Hanseeuw, B and Chhatwal, J and Yang, HS and Rissman, RA and Aisen, P and Cuppels, M and Donohue, MC and Raman, R and Johnson, KA and Sperling, RA and Dumitrescu, L and Hohman, TJ and Buckley, RF}, title = {Blood-based Transcriptomics Reveal Sex- and Amyloid-Modulated Biology of Plasma pTau217 in Preclinical Alzheimer's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394556}, issn = {2692-8205}, support = {DP2 AG082342/AG/NIA NIH HHS/United States ; R01 AG063689/AG/NIA NIH HHS/United States ; U19 AG010483/AG/NIA NIH HHS/United States ; }, abstract = {Plasma pTau217, an emerging Alzheimer's disease (AD) biomarker, may reflect a synaptic response to β-amyloid (Aβ) plaques before cortical tangle formation, but the broader biological processes at play remain unclear. Using whole blood RNAseq, we sought to identify gene expression associated with plasma pTau217 and to determine whether APOEε4, sex, and neocortical Aβ-PET burden further amplify these associations in 724 participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Studies. 1,540 genes were moderated by Aβ-PET, and 772 genes were moderated by both Aβ-PET and sex. Our findings include genes previously associated with AD (e.g., TREML2) and implicate biological functions such as chromatin remodeling, lipid signaling, and RNA processing that interact with Aβ-PET and sex to impact plasma pTau217. Our results underscore the complexity of molecular mechanisms that can be linked to plasma pTau217, particularly in the context of elevated Aβ-PET.}, } @article {pmid41394158, year = {2025}, author = {Li, Y and Zhang, Y and Liu, M and Dawuti, T and Chen, X and Xiao, H}, title = {Polyphenol-rich Morus nigra L. extract mitigates neuroinflammation and cognitive impairment through gut-brain axis modulation in an Alzheimer's disease rat model.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1695768}, pmid = {41394158}, issn = {1663-9812}, abstract = {BACKGROUND: The gut-brain axis (GBA) has emerged as a critical pathway in the pathogenesis of Alzheimer's disease (AD), offering a potential target for dietary interventions. This study aimed to explore the neuroprotective effects of a polyphenol-enriched extract from Morus nigra L. fruits (MMF) in an AD rat model, focusing on gut-brain communication.

METHODS: AD-like pathology was induced in rats using a combination of D-galactose and aluminum chloride, followed by a 10-week MMF treatment. Cognitive performance was evaluated using the Morris water maze, and brain Aβ1-42 accumulation and neuroinflammation (Iba1, GFAP) were assessed. Multi-omics approaches, including 16S rDNA sequencing and untargeted colonic metabolomics, were applied.

RESULTS: MMF treatment significantly enhanced spatial memory, reduced hippocampal Aβ burden, and attenuated glial activation. Furthermore, MMF restored gut microbial diversity and increased the abundance of short-chain fatty acid-producing Firmicutes taxa, which were inversely correlated with inflammation. Metabolomics analysis revealed that MMF modulated bile acid and lipid metabolic pathways, with β-muricholic acid, DHA, and ergosterol identified as key effectors.

CONCLUSION: MMF alleviates AD pathology through modulation of the gut microbiota and metabolic reprogramming, suggesting a promising microbiota-targeted strategy for AD prevention.}, } @article {pmid41394066, year = {2025}, author = {Rubiño-Díaz, JÁ and Zapata-Moreno, M}, title = {Highly sensitive early-onset Alzheimer's disease: a case report.}, journal = {Frontiers in psychology}, volume = {16}, number = {}, pages = {1688924}, pmid = {41394066}, issn = {1664-1078}, abstract = {BACKGROUND: Early-onset Alzheimer's disease (EOAD) is an atypical syndrome that can be confused with other neurodegenerative diseases. This disease presents before the age of 65, with symptoms that generally affect executive functions, praxis, and visuoperceptual abilities, as opposed to episodic memory. Highly sensitive individuals present the temperament trait of sensory processing sensitivity, which is characterized by a differential susceptibility compared to other individuals. Neuropsychological evaluation should involve a holistic and integrative person-centered care approach for optimal treatment and disease progression.

CASE SUMMARY: A highly sensitive 54-year-old individual was diagnosed with EOAD at age 47 in 2017. Neuropsychological follow-up was conducted for 6 years. Initial neuropsychological testing revealed a cognitive pattern with impairments in executive functions, attention, and visual perception, the advancement of which led to a progressive deterioration in daily, occupational, and social functioning. During this period, he received psychotherapy from a psychologist specializing in neuropsychology and high sensitivity, using a holistic and integrative approach. Initially, sessions were held twice a week throughout the first year of consultation and, subsequently, continued at the patient's home and in his usual context, using a completely ecological perspective and consisting of person-centered care. In 2022, the patient, aged 59, was admitted to a nursing home. This situation, outside his usual environment, without autobiographical references and his own life story, led to accelerated deterioration, with the patient ultimately dying at age 60, in 2023.

CONCLUSION: The patient with highly sensitive EOAD was followed for 6 years by a psychologist specializing in neuropsychology and high sensitivity. Neuropsychological intervention was maintained with a holistic and integrative person-centered approach using the unmet needs model to address cognitive, psychological, and functional levels. Follow-up with this approach could be key to slowing the disease and ensuring patient satisfaction throughout the entire progression of the illness. Greater visibility into unusual cases like this will enable psychology professionals to be vigilant for timely differential and diagnostic testing, which will significantly impact the treatment and progression of the illness, ultimately influencing quality of life and well-being through an optimal neuropsychological approach.}, } @article {pmid41393110, year = {2025}, author = {Kim, EH and Lee, YJ and Moon, YS and Kwon, OD and Kwon, DR}, title = {Evaluation of microcurrent as an adjunct to donepezil therapy in an Alzheimer's disease mouse model: a pilot study.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1689593}, pmid = {41393110}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder due to Aβ plaque accumulation, followed by loss of synapses and decline in cognitive abilities. Donepezil is currently one of the standard pharmacological treatments for Alzheimer's disease. Recently, microcurrent (MC) therapy has emerged as a non-pharmacological adjunct for AD management. Recently, microcurrent therapy emerged as a non-pharmacological alternative to treat AD.

OBJECTIVE: The study investigates the therapeutic outcomes of the MC as an adjuvant to donepezil in mitigating cognitive dysfunction in the transgenic mouse model (5XFAD).

METHODS: Transgenic 5xFAD mice were assigned to the control, donepezil, MC, or MC + donepezil (combination) groups. Behavioral performance was assessed using the novel object recognition (NOR) and radial arm maze (RAM) tests. Amyloid burden, glial activation, cytokine expression, apoptotic signaling, and intracellular pathways (PI3K-AKT, AMPK, and JAK2/3) were analyzed by immunohistochemistry and Western blotting.

RESULTS: Combined treatment with donepezil and microcurrent showed a trend toward improved cognitive performance and reduced pathology compared to donepezil alone, although these differences were not statistically significant. Aβ plaque burden in the cortex and the hippocampus was reduced by approximately 68%, thereby exceeding reductions observed with either treatment alone. Microglial and astroglial activation (Iba1, GFAP, and CD68) and pro-inflammatory cytokines (TNF-α and IL-1β) were reduced in both the donepezil and combination groups compared with untreated 5xFAD mice, with no significant difference between 5xD and 5xD + MC. Apoptotic markers (cleaved caspase-3 and cleaved PARP) were significantly reduced in both treatment groups compared with untreated controls but not significantly different between donepezil and combination therapy. At the molecular level, both donepezil and combination therapy activated PI3K-AKT and AMPK signaling and increased inhibitory phosphorylation of GSK-3β compared with untreated 5xFAD mice; no significant difference was observed between the two treatment groups.

CONCLUSION: Donepezil combined with microcurrent therapy showed comparable efficacy to donepezil alone, with numerical trends toward further improvement in cognitive function and pathology, but without statistically significant differences. Both treatments reduced Aβ burden, attenuated glial activation, and modulated survival-related pathways to a similar extent. These findings support a multi-target therapeutic strategy and highlight the translational potential of integrating microcurrent therapy with standard pharmacological treatment for AD.}, } @article {pmid41392105, year = {2025}, author = {Barani, M and Zargari, F and Mirinejad, S and Madani, F and Hajinezhad, MR and Sargazi, S}, title = {Ginsenoside Rg3-encapsulated pegylated niosomes exhibit multimodal therapeutic potential in Alzheimer's disease.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-025-32528-3}, pmid = {41392105}, issn = {2045-2322}, support = {4021411//National Institute for Medical Research Development/ ; }, abstract = {Ginsenoside Rg3 (GRg3), a bioactive compound extracted from ginseng, has demonstrated the ability to inhibit Aβ production and deposition. In this study, PEGylated GRg3-loaded niosomes were developed and characterized for potential AD treatment. Their efficacy was assessed using in vitro and in vivo models, as well as molecular dynamics simulations of self-assembly. Our formulation achieved a relatively high encapsulation efficiency of 83.02% and a controlled release profile, with 75.73% of the drug released over 48 h. In vitro, co-administration of Aβ with free or PEGylated GRg3-loaded niosomes markedly reduced the levels of Total Antioxidant Capacity, Malondialdehyde (MDA), and caspase-3 gene expression compared to the Aβ-only group. In vivo evaluations revealed that treatment with the niosomal formulation did not significantly alter behavioral parameters, MDA levels, or Superoxide Dismutase activity. However, catalase activity was significantly higher than in the control group. Histopathological and immunohistochemical analyses showed reduced neurovascular damage and preservation of blood-brain barrier (BBB) and hippocampal integrity in the treated group. MD simulations confirmed the spontaneous self-assembly of surfactant molecules into a bilayer structure with successful incorporation of GRg3. Our findings underscore the potential of PEGylated niosomes as efficient nanocarriers for GRg3 delivery in the AD treatment.}, } @article {pmid41391900, year = {2026}, author = {Ehret, F and Rogers, CL and Fontanesi, J and Wilson, GD and Chitti, BS and Starner, J and Sidiqi, B and Goenka, A and Schulder, M and Bruynzeel, AME and Verhoeff, JJC and MacDonagh, AC and Park, HI and Shih, HA and Kleinberg, L}, title = {Radiation Therapy for Non-Malignant Central Nervous System Tumors, Disorders, and Illnesses - Current Applications and Future Directions.}, journal = {Seminars in radiation oncology}, volume = {36}, number = {}, pages = {77-94}, doi = {10.1016/j.semradonc.2025.08.005}, pmid = {41391900}, issn = {1532-9461}, mesh = {Humans ; *Central Nervous System Neoplasms/radiotherapy ; *Mental Disorders ; }, abstract = {Radiation therapy has a central role in the treatment of various malignant central nervous system tumors, including gliomas, high-grade meningiomas, and brain metastases. This also applies to a plethora of non-malignant central nervous system lesions, such as vestibular schwannomas and arteriovenous malformations, and, in specific situations, for selected functional and psychiatric disorders. In patients with these conditions, the goal of radiation therapy is generally to preserve and stabilize function. In addition, as these illnesses, with some exceptions such as arteriovenous malformations, are rarely life-threatening, the risks of radiation therapy must be interpreted in a different context than for patients with malignancy. Given the continuous and growing interest in the use of radiation therapy for non-malignant tumors and functional conditions, this review summarizes the current and future directions in central nervous system applications, addressing its use for the management of vestibular schwannomas, arteriovenous malformations, trigeminal neuralgia, tremor, Alzheimer's disease, and other psychiatric conditions, such as obsessive-compulsive disorder, addiction, and eating disorders.}, } @article {pmid41391736, year = {2025}, author = {Chen, H and Zhang, Z and Yi, W and Wang, N and Dong, X and Xing, Y and Liu, Q and Wu, Y and Ma, X}, title = {Bone-brain crosstalk: emerging roles of osteocalcin in central nervous system disorders.}, journal = {Neuroscience}, volume = {595}, number = {}, pages = {1-8}, doi = {10.1016/j.neuroscience.2025.12.028}, pmid = {41391736}, issn = {1873-7544}, abstract = {Despite significant advancements in understanding the pathogenesis of various central nervous system (CNS) disorders, challenges remain in the early intervention and targeted therapies for common neurodegenerative and psychiatric conditions such as Parkinson's disease (PD), Alzheimer's disease (AD), anxiety, depression, and strokes. Recent studies have increasingly focused on the interaction between the peripheral and central nervous systems, emphasizing the regulatory influence of peripheral mechanisms on CNS disorders. This evolving perspective paves the way for innovative treatment strategies for CNS diseases, with the bone-brain axis emerging as a key regulatory pathway. This axis was first systematically proposed to highlight the role of bone-derived hormones in brain function. Importantly, bone tissue extends its functions beyond mere structural support and movement; it secretes molecules like osteocalcin (OCN) that influence neuronal and glial cell activities. This interaction is vital for regulating multiple CNS processes, including mood, cognition, inflammation, and the formation and differentiation of myelin. Upon release from bone tissue, OCN enters the bloodstream and affects peripheral organs via the Gprc6a receptor, while also crossing the blood-brain barrier to interact with receptors such as Gpr158 and Gpr37 in specific brain areas. This intra-brain interaction significantly impacts the progression and prognosis of various CNS disorders. This article undertakes a comprehensive analysis of OCN modulation in CNS disorders and its underlying mechanisms, laying the groundwork for further exploration of its clinical applications and suggesting new research avenues and therapeutic strategies for CNS diseases.}, } @article {pmid41391511, year = {2026}, author = {Gawai, M and Nistane, N and Tatode, AA and Qutub, M and Umekar, MJ and Premchandani, T and Taksande, JB}, title = {Transforming anti-Alzheimer's therapy by targeting endogenous receptorrial system through ligand-conjugated nanoformulations.}, journal = {Ageing research reviews}, volume = {114}, number = {}, pages = {102994}, doi = {10.1016/j.arr.2025.102994}, pmid = {41391511}, issn = {1872-9649}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Ligands ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; *Drug Delivery Systems/methods ; *Nanoparticles/administration & dosage ; Brain/metabolism/drug effects ; }, abstract = {Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder, contributing to the majority of dementia cases in the elderly globally. Characterized by progressive cognitive decline, AD is associated with complex neuropathological changes, including the accumulation of amyloid-beta (Aβ) plaques and tau tangles, synaptic loss, and neuroinflammation. One of the significant challenges in treating AD is the blood-brain barrier (BBB), which prevents many therapeutic agents from reaching the brain. Despite advancements in understanding AD's pathology, limited treatment options are available, largely due to the inability of conventional drugs to effectively target the brain. Ligand-conjugated nanoparticles (NPs) are promising for targeted drug delivery to the brain. These NPs, engineered with ligands that can bind to specific receptors or transporters on the BBB, facilitate the crossing of the barrier via receptor-mediated endocytosis or adsorptive-mediated transcytosis. This strategy enhances therapeutic agents' bioavailability and cellular uptake, offering a potential solution to overcome current limitations in AD treatment. Using nanotechnology to design ligand-conjugated NPs for targeted and sustained drug delivery could significantly improve therapeutic outcomes for AD patients by addressing key pathological processes in the brain.}, } @article {pmid41391505, year = {2025}, author = {Liu, Y and Zhang, J and Li, W and Qu, Q and Shan, Z and Liu, C and Jiao, K and Hou, X}, title = {Osthole ameliorates cognitive impairment in ovariectomized rats via estrogen-mediated enhancement of cholinergic function and regulation of neurotransmitter homeostasis.}, journal = {Neuropharmacology}, volume = {286}, number = {}, pages = {110806}, doi = {10.1016/j.neuropharm.2025.110806}, pmid = {41391505}, issn = {1873-7064}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive dysfunction that is closely associated with cholinergic system damage. Estrogen deficiency is a well-established risk factor for AD in women. Osthole (OST), a phytoestrogen with mild, bidirectional regulatory properties, has been proposed as a potential estrogen replacement. This study aimed to investigate the mechanisms by which OST ameliorates cognitive impairment. Cognitive deficits were induced in female Sprague-Dawley rats by bilateral ovariectomy (OVX), and OST was subsequently administered by oral gavage. Behavioral tests revealed that OST significantly improved learning and memory and reduced anxiety-like and depression-like behaviors in OVX rats. H&E staining and Nissl staining demonstrated that OST reversed neuronal damage in the hippocampus and cortex. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment restored the estrogen-cholinergic-NGF axis: E2, ERα, and ERβ expression were upregulated; Ach, ChAT, NGF, and TrkA levels were increased, whereas AChE activity was decreased. Moreover, OST inhibited neuronal apoptosis by elevating Bcl-2 and reducing Bax expression, enhanced the expression of markers of synaptic plasticity (PSD95, SYN, and BDNF), and modulated neurotransmitter release (GABA and E). Collectively, these multi-target effects identify OST as a promising candidate for treating AD in women.}, } @article {pmid41390238, year = {2025}, author = {Mummery, CJ and Rasmussen, J and Blackburn, D and Coulthard, E and Davies, RR and Dorsey, R and Fox, NC and Hosseini, AA and Ivenso, C and Jones, M and Kennelly, SP and Kipps, C and Lashley, D and Mackay, G and Negi, R and Nilforooshan, R and Passmore, PA and Perry, R and Raymont, V and Rowe, JB and Russ, TC and Taylor, JP and Burns, A}, title = {Lecanemab appropriate use recommendations for clinical practice in the UK.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2025-336597}, pmid = {41390238}, issn = {1468-330X}, abstract = {Lecanemab is an anti-amyloid monoclonal antibody, recently approved in the UK as a treatment for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD) in adults who are apolipoprotein E ε4 gene (APOE4) heterozygotes or non-carriers.A group of UK neurologists, old age psychiatrists and geriatricians with expertise in AD convened to agree appropriate use recommendations for lecanemab in UK clinical practice. The primary focus of these recommendations is safety.Eligibility criteria for lecanemab in the UK include (a) a clinical diagnosis of MCI or mild dementia due to AD, (b) the presence of amyloid-β pathology, confirmed using approved methods (ie, an amyloid positron emission tomography scan or cerebrospinal fluid assay) and (c) APOE4 heterozygous or non-carrier status. Eligibility screening should be conducted in secondary care and those identified as being potentially eligible for lecanemab should be referred to a specialist centre for confirmation of the likely pathological diagnosis, APOE4 counselling and testing and a multidisciplinary consensus decision regarding treatment eligibility. Lecanemab is administered as an intravenous infusion every 2 weeks, and those eligible for treatment should have brain magnetic resonance imaging (MRI) scans prior to the 1st, 5th, 7th and 14th infusions. Specific guidance is provided for safety monitoring and management of potential adverse reactions, including amyloid-related imaging abnormalities and infusion-related reactions.The introduction of lecanemab into UK clinical practice provides an important opportunity to improve services for all people living with dementia, not just those eligible for lecanemab treatment.}, } @article {pmid41390089, year = {2025}, author = {Sheng, J and Wang, L and Zhang, Q and Chien Chou, JT and Zhang, R and Li, T and Lu, Y}, title = {Integrating multimodal data to identify single nucleotide polymorphism-related biomarkers and regulatory mechanisms in Alzheimer's disease.}, journal = {Neuroscience}, volume = {593}, number = {}, pages = {141-159}, doi = {10.1016/j.neuroscience.2025.12.022}, pmid = {41390089}, issn = {1873-7544}, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease with unclear regulatory mechanisms at the cell-type level. A multi-omics model called single nucleotide polymorphisms (SNPs)-transcriptomic-single-nucleus ribonucleic acid sequencing (snRNA-seq) integration (STSNI) is proposed to identify SNPs-related biomarkers and regulatory mechanisms in AD. Differential expression analysis identified differentially expressed genes (DEGs) between AD patients and healthy controls (HCs) in the GSE118553 dataset. Cell-type annotation in the GSE138852 dataset revealed several cell subclusters, and DEGs were identified within these subclusters. Intersection analysis among DEGs from the GSE118553 dataset, cell-subcluster-specific DEGs from the GSE138852 dataset, and SNP-associated genes from the ADNI2 dataset yielded 14 overlapping genes. Using the least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) algorithms, six biomarkers were identified. Functional enrichment and gene set enrichment analysis (GSEA) linked these biomarkers to pathways such as carboxylic acid catabolic process, exocytic vesicle membrane, and carbon metabolism. Meanwhile, six cell types were identified, including astrocytes, endothelial cells, oligodendrocytes, oligodendrocyte progenitor cells (OPCs), microglia, and neurons. The biomarker-transcription factor (TF) network indicated that Cispb M4676 regulates IQGAP2, NRXN1, GRIA3 and FGF14. Overall, our study identified six SNP-related biomarkers (IQGAP2, HHAT, FGF14, CTNNA3, GRIA3, and NRXN1) associated with AD. The STSNI framework provided novel insights into the cellular and molecular mechanisms underlying AD. Significance Statement: As the global population continues to age, Alzheimer's disease (AD) has emerged as a major public health concern. The pathological changes associated with AD include the formation of extracellular amyloid plaques, intracellular neurofibrillary tangles, and neuronal loss with gliosis proliferation. Bioinformatics methods are used to explore the immune infiltration characteristics, biological pathways and regulatory mechanisms of single nucleotide polymorphisms (SNPs) related key genes in AD. The pathogenesis of AD from the overall level and single-cell level is explored based on SNPs-related genes, combined with snRNA-seq data and transcriptome data. This study provides an opportunity for the discovery of novel diagnostic molecular markers and potential treatment targets to serve as the foundation for the development of more effective management techniques for AD.}, } @article {pmid41389844, year = {2026}, author = {Shi, H and Zhao, Y}, title = {Astaxanthin inhibits the aggregation and cytotoxicity of tau4RDΔK280 via possible interaction with the aggregation-prone segments.}, journal = {Neurochemistry international}, volume = {192}, number = {}, pages = {106103}, doi = {10.1016/j.neuint.2025.106103}, pmid = {41389844}, issn = {1872-9754}, mesh = {*tau Proteins/metabolism/genetics/antagonists & inhibitors ; Xanthophylls/pharmacology ; Animals ; Mice ; Tauopathies/metabolism/drug therapy/genetics ; *Protein Aggregates/drug effects/physiology ; Humans ; *Protein Aggregation, Pathological/metabolism/drug therapy ; Cell Survival/drug effects/physiology ; Neuroprotective Agents/pharmacology ; Molecular Docking Simulation/methods ; }, abstract = {Tauopathies are a group of neurodegenerative disorders characterized by the presence of abnormal aggregates of microtubule associated protein tau in the brain. In the most common tauopathy, Alzheimer's disease (AD), the aggregation of tau is closely linked with synaptic dysfunction and neuronal death, while targeting the aggregation of tau has been demonstrated to have therapeutic potential. Astaxanthin is a carotenoid with neuroprotective function, which has been shown to inhibit Aβ-induced pathology in AD animal and cell models. However, the effects of astaxanthin on tau aggregation and toxicity are much less explored. In this study, we generated a cell model of tauopathy overexpressing the amyloidogenic pro-aggregant tau repeat domains carrying the FTDP-17 mutation ΔK280 in N2a cells (N2a-tau4RDΔK280). It was found that astaxanthin treatment alleviated the cytotoxicity of N2a-tau4RDΔK280 cells while reducing the amount of tau4RDΔK280 aggregates in the cells. Results from the thioflavin T aggregation assay demonstrated that astaxanthin inhibited the aggregation of tau4RDΔK280 in vitro. Further analyses with transmission electron microscopy confirmed that astaxanthin reduced the formation of amyloid fibril structures of tau4RDΔK280 in vitro. Thus, astaxanthin might inhibit the cytotoxicity of N2a-tau4RDΔK280 cells by preventing the formation of tau4RDΔK280 aggregates. Molecular docking simulation analyses revealed that astaxanthin was able to directly interact with tau4RDΔK280 as well as several key aggregation-prone segments of tau protein. In conclusion, our results demonstrated that astaxanthin might exert neuroprotection by inhibiting the formation of tau aggregates via direct interaction with the key aggregation-prone segments.}, } @article {pmid41389629, year = {2026}, author = {Ruiz de Martín Esteban, S and Grande, MT and Martínez-Relimpio, AM and Herráez-Aguilar, D and Mostany, R and Hillard, CJ and Hind, WH and Romero, J}, title = {Treatment with a botanical mixture of cannabidiol:Δ[9]-tetrahydrocannabinol enhances microglial phagocytosis and shapes amyloid plaques in a mouse model of Alzheimer's disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {194}, number = {}, pages = {118902}, doi = {10.1016/j.biopha.2025.118902}, pmid = {41389629}, issn = {1950-6007}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Dronabinol/pharmacology/therapeutic use ; *Cannabidiol/pharmacology/therapeutic use ; *Microglia/drug effects/pathology/metabolism ; Male ; *Phagocytosis/drug effects ; Disease Models, Animal ; Mice ; *Plaque, Amyloid/pathology/drug therapy/metabolism ; Mice, Transgenic ; Behavior, Animal/drug effects ; Anxiety ; Motor Activity/drug effects ; }, abstract = {The potential use of phytocannabinoids in neurodegenerative disorders is currently under intense investigation based on their potential anti-inflammatory, antioxidant, and neuroprotective effects. Here, we tested the effects of chronic (28 days) treatment with a complex botanical mixture of purified cannabidiol:Δ[9]-tetrahydrocannabinol (CBD:THC, 99:1) in male 5xFAD mice, a murine model of Alzheimer's disease that recapitulates amyloid pathology. Effects of exposure to this cannabinoid mixture were evaluated using behavioral tests (elevated plus maze for anxiety, tail suspension for depression-like behavior, rotarod for motor coordination, open field for locomotor activity, and novel object recognition for memory), quantification of protein expression (IL-1β, CD40, TREM2, COX2), assessment of functional parameters (microglial phagocytic activity by flow cytometry), and in vivo multiphoton microscopy (time-course of changes of neuritic plaque structural features). Twice daily dosing with 50 mg/kg subcutaneously (s.c.) significantly reduced locomotion, increased anxiety- and depression-like behaviors and had no effect on memory and motor coordination. In vivo imaging experiments suggest that the CBD:THC treatment enhanced microglial phagocytic activity on amyloid plaques; this effect was observed both in plaque features (multiphoton microscopy measurements) as well as in microglia (flow cytometry data). Exposure to CBD:THC induced significant changes in in vivo microglia-amyloid interactions, increasing phagocytic activity and reducing the amyloid peptide accumulation in the neuritic plaques. Thus, CBD:THC (99:1) may be a promising treatment to reduce amyloid pathology, though caution should be noted due to the behavioral alterations observed, i.e., increased anxiety- and depression-like behaviors as well as decreased locomotion.}, } @article {pmid41389410, year = {2026}, author = {Li, X and Yan, S and Li, M and Liu, R and Lu, Q and Lu, M and Bai, F and Shen, QD}, title = {Piezoelectric nanoparticle-driven rhythmic ultrasound neuromodulation for treatment of early-stage Alzheimer's disease.}, journal = {Biomaterials}, volume = {328}, number = {}, pages = {123905}, doi = {10.1016/j.biomaterials.2025.123905}, pmid = {41389410}, issn = {1878-5905}, mesh = {Animals ; *Alzheimer Disease/therapy/pathology/physiopathology ; *Nanoparticles/chemistry ; Mice ; Male ; Ultrasonic Waves ; Hippocampus ; Disease Models, Animal ; Neuronal Plasticity ; Mice, Inbred C57BL ; Humans ; Mice, Transgenic ; }, abstract = {Synaptic dysfunction and loss are central drivers of cognitive decline in Alzheimer's disease (AD), yet current therapeutic approaches targeting amyloid-β or tau pathology have largely failed to rescue synaptic function. Neural oscillations and synaptic plasticity are tightly coupled and underpin functional brain networks, suggesting that modulating oscillatory dynamics may offer new therapeutic avenues. Here, we developed a strategy for precise, non-genetic neuromodulation using focused ultrasound and piezoelectric Ba0.85Ca0.15Zr0.1Ti0.9O3 (BCZT) nanoparticles to generate targeted, gamma-frequency electromagnetic fields in the hippocampal CA3 subregion of early-stage AD mouse models. This rhythmic stimulation effectively restored impaired gamma oscillations, enhanced synaptic plasticity, and remodeled memory-related network connectivity, as validated by local field potential recordings, patch-clamp electrophysiology, and functional MRI. Mechanistically, we demonstrate that NF-κB transcription factor activation during rhythmic stimulation regulates AMPAR trafficking by balancing synaptic internalization and delivery, with concurrent upregulation of P300-mediated histone acetylation. Our findings establish a novel paradigm for spatially precise, periodic neuromodulation that restores hippocampal information processing and network function in early AD, highlighting the therapeutic potential of piezoelectric nanomaterials for neural circuit repair in AD and other neurodegenerative diseases characterized by impaired neural rhythms.}, } @article {pmid41389269, year = {2025}, author = {Isaković, J and Athanassiadis, A and Khubeis, M}, title = {Stem cells strike back: advancements in Alzheimer's and Parkinson's disease treatment and modeling efforts from 2019 to 2024.}, journal = {Journal of molecular medicine (Berlin, Germany)}, volume = {104}, number = {1}, pages = {2}, pmid = {41389269}, issn = {1432-1440}, mesh = {Humans ; *Alzheimer Disease/therapy ; *Parkinson Disease/therapy ; *Stem Cell Transplantation/methods ; Animals ; Clinical Trials as Topic ; *Stem Cells/cytology/metabolism ; Cell Differentiation ; }, abstract = {This review critically evaluates the current state of stem cell therapy (SCT) for treating and modeling of Alzheimer's (AD) and Parkinson's disease (PD). It includes an in-depth analysis of both preclinical and clinical studies, with a particular focus on clinical trials conducted between 2019 and 2024, reflecting recent advancements in the field. Preclinical studies were examined to elucidate the molecular mechanisms underlying SCT and identify developments that could be translated into clinical practice. Within these studies, stem cells, including embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs), have shown high differentiation and proliferation abilities. These properties, along with their capacity to inhibit inflammation, prevent apoptosis, and stimulate angiogenesis, make them promising candidates for treating AD and PD. Over the past 15 years, 76 SCT-based trials have been conducted-27 for AD and 48 for PD-with more than half occurring in the past 5 years. Despite the promise of SCT, the field faces challenges such as ethical concerns regarding the use of ESCs, heterogeneity of isolated cultures, and inconsistent results across preclinical trials. Novel materials and electromagnetic fields (EMFs) offer potential solutions to these issues. While bioengineering approaches can enhance the successful engraftment of transplanted stem cells, EMFs can direct the cells' migration and differentiation. In conclusion, although significant progress has been made in SCT, ongoing efforts are needed to address existing challenges. Nevertheless, SCT holds considerable promise for the future, offering potential breakthroughs in the treatment of neurodegenerative diseases.}, } @article {pmid41388533, year = {2025}, author = {Khan, AR and Makhoul, GW and Raji, MA}, title = {Mirtazapine for gastrointestinal side effects of glucagon-like peptide-1 receptor agonist therapy in older adults.}, journal = {Endocrine regulations}, volume = {59}, number = {1}, pages = {260-264}, doi = {10.2478/enr-2025-0030}, pmid = {41388533}, issn = {1336-0329}, mesh = {Humans ; Aged ; Female ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Diabetes Mellitus, Type 2/drug therapy ; *Mirtazapine/therapeutic use ; *Hypoglycemic Agents/adverse effects ; Glucagon-Like Peptides/adverse effects ; *Gastrointestinal Diseases/chemically induced/drug therapy ; Nausea/chemically induced/drug therapy ; Vomiting/chemically induced/drug therapy ; Glucagon-Like Peptide 1 ; }, abstract = {Objective. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) play a role in management of type 2 diabetes (T2D) and obesity by promoting glycemic control and weight reduction. Beyond these benefits, GLP-1 RAs have demonstrated positive effects on cardiovascular, renal, and neurological health, with emerging evidence supporting their therapeutic potential in conditions such as chronic kidney disease, asthma, obstructive sleep apnea, Parkinson's disease, and Alzheimer's disease. However, their widespread clinical use is often hindered by gastrointestinal side effects including nausea, anorexia, vomiting, and diarrhea that limit adherence and dose titration. Effective management of these adverse effects is essential to optimize treatment outcomes and maintain long-term therapy. Case report. A 72-year-old woman with a history of cognitive impairment, T2D, atrial fibrillation, obesity, and mood disorders presented with persistent gastrointestinal symptoms while receiving semaglutide. Dose escalation was restricted due to severe nausea, vomiting, and diarrhea, which markedly affected her quality of life. To manage these symptoms, mirtazapine was initiated. Following its introduction, the patient reported significant improvement in gastrointestinal tolerance enabling continued semaglutide therapy and successful dose advancement. Additional benefits included enhanced mood, better sleep, and overall well-being. No adverse effects related to mirtazapine were observed throughout the treatment. Conclusion. This case suggests that mirtazapine may be beneficial in mitigating GLP-1 RA-induced gastrointestinal side effects, thereby improving adherence and therapeutic efficacy. Further research is needed to evaluate the safety, mechanism, and generalizability of this approach in broader clinical practice.}, } @article {pmid41388352, year = {2026}, author = {Akinluyi, ET and Takahashi-Yamashiro, K and Connolly, MG and Poon, WW and Macauley, MS}, title = {Interplay between CD33 and TREM2 in Alzheimer's Disease: Potential Mechanistic Insights into Microglial Function in Amyloid Pathology.}, journal = {ACS chemical neuroscience}, volume = {17}, number = {1}, pages = {62-76}, doi = {10.1021/acschemneuro.5c00805}, pmid = {41388352}, issn = {1948-7193}, mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *Microglia/metabolism ; *Sialic Acid Binding Ig-like Lectin 3/metabolism ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism ; Plaque, Amyloid/metabolism/pathology ; Brain/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, tau neurofibrillary tangles, and progressive neuronal loss leading to cognitive decline. With millions affected worldwide, there remains an urgent need for innovative treatment strategies to combat this disease. Genome-wide association studies (GWAS) have identified genes expressed in microglia, the resident immune cells of the brain, as key mediators of AD susceptibility. Among microglial risk genes, CD33 and TREM2 stand out for their contrasting roles in AD risk. Accumulating evidence indicates that these receptors converge on overlapping signaling pathways to regulate microglial activation and Aβ clearance. Here, we review the current understanding of CD33 and TREM2 biology in AD, with a focus on their potential crosstalk and functional antagonism. We propose potential mechanistic models by which human CD33 isoforms regulate TREM2 activity in either the absence or presence of Aβ pathology and discuss therapeutic strategies targeting this axis. Together, these insights suggest new avenues for microglia-targeted interventions in AD.}, } @article {pmid41387197, year = {2026}, author = {Fredriksen-Goldsen, KI and Teri, L and Kim, HJ and Jones-Cobb, B and LaFazia, D and McKenzie, G and Petros, R and Jung, H and Oswald, AG and Hoy-Ellis, C and Emlet, C}, title = {Innovations in Dementia Empowerment and Action: RCT for Underserved Communities.}, journal = {Journal of the American Geriatrics Society}, volume = {74}, number = {1}, pages = {119-131}, doi = {10.1111/jgs.70189}, pmid = {41387197}, issn = {1532-5415}, support = {R01AG055488//National Institute on Aging of the National Institutes of Health/ ; }, mesh = {Humans ; Male ; Female ; Aged ; Single-Blind Method ; Quality of Life ; *Dementia/therapy/psychology ; *Empowerment ; *Cognitive Behavioral Therapy/methods ; Medically Underserved Area ; Aged, 80 and over ; Caregivers/psychology ; Social Stigma ; Exercise ; *Vulnerable Populations/psychology ; Middle Aged ; }, abstract = {BACKGROUND: Research has revealed dementia disparities among underserved older adults. Built upon standard-Reducing Disability in Alzheimer's Disease (s-RDAD), Innovations in Dementia Empowerment and Action (IDEA) is designed and culturally tailored for underserved communities through an empowerment stigma-reduction cognitive-behavioral intervention and tested with sexual and gender minority (SGM) adults and care partners.

METHODS: The study is a 2-arm (IDEA and s-RDAD), single-blind, randomized controlled trial (RCT) with a staggered multiple baseline design. With 161 dyads (person living with dementia/care partner), the aim of the study is to compare the two arms via between and within group differences on primary (physical activity) and secondary outcomes (e.g., quality of life, physical functioning, and resource literacy) at post-treatment, and 30 and 56 week follow-up.

RESULTS: When comparing the two arm between-group differences, the IDEA care partners' community resource literacy was significantly higher at 30-week follow-up than for s-RDAD (contrast = 0.10, p = 0.005). While both intervention arms demonstrated efficacy with significant improvement in physical activity (contrastIDEA = 0.10, p = 0.010; contrasts-RDAD = 0.14, p < 0.001) and quality of life (contrastIDEA = 0.06, p < 0.001; contrasts-RDAD = 0.03, p = 0.035) for the person with dementia at post-treatment, positive treatment effects on physical activity (contrastIDEA = 0.09, p = 0.032) and quality of life (contrastIDEA = 0.03, p = 0.040) persisted at 30 weeks for IDEA but not for s-RDAD.

CONCLUSION: While both intervention arms were efficacious, IDEA demonstrated sustained efficacy. The cultural tailoring of interventions is promising to address disparities in dementia care and interventions in underserved communities. Future research is needed for the translation of this efficacious intervention to the larger community.

CLINICALTRIALS: gov identifier: NCT03550131.}, } @article {pmid41385058, year = {2025}, author = {Jiang, H and Escamilla, S and Beestrum, M and Salas-Lucia, F}, title = {Cost-effectiveness of testing biofluid biomarkers to diagnose Alzheimer's disease: a systematic review.}, journal = {The European journal of health economics : HEPAC : health economics in prevention and care}, volume = {}, number = {}, pages = {}, pmid = {41385058}, issn = {1618-7601}, abstract = {BACKGROUND: Alzheimer's disease (AD) affects tens of millions of individuals and their families in the world. As AD progresses, the effectiveness of treatment declines, making a timely diagnosis crucial. One promising approach for timely diagnosis is testing biofluid biomarkers in patients' blood and cerebrospinal fluid (CSF). However, a comprehensive evaluation of whether these tests are cost-effective is missing. Here, we conducted a systematic review to assess the cost-effectiveness of testing biofluid biomarkers to diagnose AD.

METHOD: We searched PubMed, Embase, Cochrane Library, and Web of Science for studies published until October 2024. Studies were included if published in English, conducted an economic evaluation of CSF or blood biomarker testing to diagnose AD, and provided economic outcomes. We assessed the quality of studies using the CHEERS 2022 criteria.

RESULTS: Nine studies were included: six evaluated CSF biomarker tests and three on blood biomarker tests. All studies used model-based simulations (decision trees or Markov models) rather than trial-based evaluations. CSF biomarker tests were mostly cost-effective compared to neurocognitive assessments or neuroimaging, while blood biomarker tests showed mixed results. Key cost-effectiveness contributors included AD prevalence, diagnostic accuracy, and treatment effectiveness. Studies met ~ 80% of the CHEERS criteria, with missing information on patient engagement.

CONCLUSION: Our review supports that biofluid biomarker testing could be cost-effective to diagnose AD. Given the lack of trial-based economic evaluations, model-based studies are a valuable starting point. Future evaluations should incorporate patient-centered outcomes and consider the emotional value and other socio-economic factors that affect patients and families suffering from AD.}, } @article {pmid41384832, year = {2025}, author = {Villarejo Galende, A and González-Sánchez, M and Hilario, A and Llamas-Velasco, S and Morenas-Rodríguez, E and Muñoz-García, MI and Ramos-González, A and Pérez-Martínez, DA and Blanco-Palmero, VA}, title = {Severe symptomatic amyloid-related imaging abnormalities in Alzheimer's disease: Two case reports and systematic review of reported cases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251404505}, doi = {10.1177/13872877251404505}, pmid = {41384832}, issn = {1875-8908}, abstract = {BackgroundAmyloid-related imaging abnormalities (ARIA) are a recognized complication of anti-amyloid monoclonal antibodies for Alzheimer's disease (AD). While typically asymptomatic, a subset of patients develops severe clinical symptoms and radiological findings requiring intensive management. Data on their presentation, treatment, and outcomes remain limited.ObjectiveWe report two cases and analyze the clinical features of all published cases of severe symptomatic ARIA, with a focus on associated risk factors, therapeutic approaches, and patient outcomes.MethodsWe report two cases of severe symptomatic ARIA in patients treated with gantenerumab. A systematic review was conducted following PRISMA guidelines using MEDLINE, Web of Science, and manual reference screening. We included case reports and series providing individual-level data on symptomatic ARIA episodes classified as severe by clinical criteria. Demographic, genetic, clinical, radiological, therapeutic, and outcome data were extracted.ResultsThirty-six cases were included (2 new and 34 from 21 publications). Fifteen cases were associated with lecanemab, 10 with gantenerumab, 6 with donanemab, and 5 with other antibodies. APOE ε4 was present in 62.5%, including 10 ε4/ε4 homozygotes. Baseline MRI showed hemorrhagic markers in 10 cases, including superficial siderosis in 2 of the 5 patients with isolated macrohemorrhages. Most episodes occurred within 6 months of treatment. Symptoms included altered consciousness (75%), focal deficits (66.7%), seizures (38.9%), and headache (36.1%). ARIA-E resolved in all non-fatal cases. Corticosteroids were used in 72%. Among the patients whose outcome data were available, 15 patients recovered completely, 10 had persistent deficits, and 10 died.ConclusionsSevere symptomatic ARIA is a rare but serious adverse effect of anti-amyloid therapy. Standardized diagnostic and therapeutic guidelines are needed to minimize ARIA-related morbidity and mortality.PROSPERO registration no. CRD420251055067.}, } @article {pmid41383948, year = {2025}, author = {Mu, L and Wang, Y}, title = {The role of gut microbiota-derived metabolites in neuroinflammation.}, journal = {Neuroprotection (Chichester, England)}, volume = {3}, number = {2}, pages = {131-144}, pmid = {41383948}, issn = {2770-730X}, abstract = {Neuroinflammation, a key defense mechanism of the nervous system, is associated with changes in inflammatory markers and stimulation of neuroimmune cells such as microglia and astrocytes. Growing evidence indicates that the gut microbiota and its metabolites directly or indirectly regulate host health. According to recent studies, bacterial dysbiosis in the gut is closely linked to several central nervous system disorders that cause neuroinflammation, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, sepsis-associated encephalopathy, and ischemic stroke. Recent findings indicate a bidirectional communication network between the gut microbiota and central nervous system that influences neuroinflammation and cognitive function. Dysregulation of this system can affect the generation of cytotoxic metabolites, promote neuroinflammation, and impair cognition. This review explores the lesser-studied microbiota-derived metabolites involved in neuroinflammation-bile acids, trimethylamine-N-oxide, and indole derivatives-as targets for creating new treatment tools for neuroinflammatory illnesses, as well as possible biomarkers for early diagnosis and prognosis.}, } @article {pmid41383947, year = {2025}, author = {Schwartz, SS and Rhea, EM and Banks, WA and Herman, ME}, title = {Beta cells to brain cells: The pivotal role of insulin and glucose metabolism in Alzheimer's disease.}, journal = {Neuroprotection (Chichester, England)}, volume = {3}, number = {2}, pages = {145-164}, pmid = {41383947}, issn = {2770-730X}, abstract = {The risk factors and neuropathologies of cognitive decline and the onset and progression of dementia-related disorders were, until recently, obtuse. A critical predisposing factor to Alzheimer's disease (AD) that has emerged is glucose dysmetabolism. It is now understood that energy imbalances or excess nutrient intake sit in the crosshairs of neurodegeneration. Within the brain, the regulation of glucose operates semiautonomously from the periphery to ensure a defended, uninterrupted supply of glucose for neuronal processes. In this localized brain energetic milieu, hyperglycemia, hyperinsulinemia, and insulin resistance constitute independent risk factors for AD. Disturbances in the blood‒brain barrier (BBB) and brain insulin resistance are two newly understood insults connecting glucose metabolism with AD. This dysglycemia waylays insulin signaling, an otherwise potentially protective mechanism against AD plaques. In parallel, studies in the clinical setting demonstrate that glucose-lowering in patients with type 2 diabetes (T2D) reduces the risk of AD. The American Diabetes Association (ADA) elevated its guidelines to include cognitive issues (or risk) as a comorbidity in T2D patient treatment plans. Choice of antidiabetes therapy is imperative: evidence supports the use of metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor analogs, and sodium glucose cotransporter 2 inhibitors to help prevent and mitigate cognitive outcomes and AD. Sulfonylureas, on the other hand, may actually worsen cognitive deficits and integrity. We are at a fascinating juncture: preclinical research is at a stage to inform the development of rational previously unexplored targets. Simultaneously, current clinical evidence is translatable now into real-world strategies to reduce the incidence and severity of comorbid AD in our aging population.}, } @article {pmid41383815, year = {2025}, author = {Zhang, R and Liu, YY and Xia, X and Li, X}, title = {Unvalidated efficacy and significant risks hinder clinical use of deep cervical lymphatic-venous anastomosis for Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1671741}, pmid = {41383815}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and the pathological accumulation of amyloid-beta (Aβ) plaques and tau tangles. Recent studies suggest that dysfunction of the cerebral lymphatic clearance system may contribute to the progression of AD. This review critically examines the potential of deep cervical lymphatic-venous anastomosis (LVA) as a treatment for enhancing brain protein clearance and reducing cognitive decline in AD patients. Although animal models indicate that improving lymphatic drainage could facilitate Aβ clearance, clinical evidence is still insufficient. Current studies often have small sample sizes, short follow-up periods, and methodological weaknesses. Despite preliminary reports of cognitive improvements in small-scale clinical trials, the efficacy of LVA remains unproven, making widespread clinical adoption premature. Ethical concerns and technical challenges also pose significant barriers to clinical implementation. Rigorous randomized controlled trials (RCTs) are necessary to assess the long-term safety and efficacy of LVA for treating AD. Furthermore, the establishment of clear ethical and regulatory frameworks is essential before clinical use.}, } @article {pmid41383524, year = {2025}, author = {Zhang, X and Zhong, M and Li, Y and Wang, H and Xi, G and Wang, F and Cheng, C and Shi, Y}, title = {Oral microbiota and central nervous system diseases: A review.}, journal = {Neuroprotection (Chichester, England)}, volume = {3}, number = {1}, pages = {79-94}, pmid = {41383524}, issn = {2770-730X}, abstract = {Oral microbiota is the second largest microbial colony in the body and forms a complex ecological community that influences oral and brain health. Impaired homeostasis of the oral microbiota can lead to pathological changes, resulting in central nervous system (CNS) diseases. However, the mechanisms and clinical value of how the oral microbiome influences the brain remain unclear. This review summarizes recent clinical findings on the role of the oral microbiota in CNS diseases and proposes potential approaches to understand the way the oral microbiota and brain communicate. We propose three underlying patterns involving neuroinflammation, neuroendocrine regulation, and CNS signaling between oral microbiota and CNS diseases. We also summarize the clinical characteristics and potential utilization of the oral microbiota in ischemic stroke, Alzheimer's and Parkinson's disease, intracranial aneurysms, and mental disorders. Although the current findings are preliminary and clinical evidence is incomplete, oral microbiota is a potential biomarker for the clinical diagnosis and treatment of CNS diseases.}, } @article {pmid41383520, year = {2025}, author = {Saxena, SK and Sharma, D and Kumar, S and Maurya, VK and Ansari, S and Malhotra, HS and Singh, A}, title = {Decoding the role of large heat shock proteins in the progression of neuroinflammation-mediated neurodegenerative disorders.}, journal = {Neuroprotection (Chichester, England)}, volume = {3}, number = {1}, pages = {48-62}, pmid = {41383520}, issn = {2770-730X}, abstract = {Chronic neuroinflammation and protein aggregation are the fundamental events mainly responsible for the progression of neurodegenerative diseases (NDs). Potential neurotoxic changes in the intra- and extracellular environment are typical hallmarks of many NDs. Treatment of ND is challenging, as the symptoms in these patients arises when a significant numbers of neurons have already been destroyed. Heat shock proteins (HSPs) can bind to recipient cells that are susceptible to stress, such as neurons, in the extracellular environment, therefore enhancing stress resistance. Among all, HSP60, HSP70, and HSP90 are highly conserved molecular chaperones involved in protein folding and assembly, maintaining cellular homeostasis in the central nervous system. Notably, α-synuclein accumulation is a major pathophysiology in Parkinson's disease, where HSP90 modulates the assembly of α-synuclein in vesicles to prevent its accumulation. Moreover, HSP90 regulates the activity of the glycogen synthase kinase-3β protein, which is crucial in diabetes mellitus-associated neurocognitive disorder. Therefore, understanding the molecular mechanism by which HSPs facilitate protein aggregation and respond to inflammatory stimuli, including metabolic disease such as diabetes, is essential for understanding the significance of HSPs in NDs. This review emphasizes the role of various HSPs in the progression of NDs such as Alzheimer's, Parkinson's, multiple sclerosis, and Huntington's disease, including diabetes, which is one of the major risk factors for neurodegeneration.}, } @article {pmid41383377, year = {2024}, author = {Hanumanthappa, R and Parthasarathy, A and Heggannavar, GB and Pc, K and Nanjaiah, H and Kumbhar, R and Devaraju, KS}, title = {Recent advances in therapeutic strategies for Alzheimer's and Parkinson's disease using protein/peptide co-modified polymer nanoparticles.}, journal = {Neuroprotection (Chichester, England)}, volume = {2}, number = {4}, pages = {255-275}, pmid = {41383377}, issn = {2770-730X}, abstract = {The blood-brain barrier (BBB), which protects the brain from foreign molecules, makes delivery of drugs to the central nervous system is challenging. Nanoparticles (NPs) have been used over the past decade as drug delivery systems for the treatment of many disorders with great results. However, the effectiveness of NPs in delivering drugs to the brain for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD) is limited by the BBB. A recent breakthrough in nanotechnology delivery systems involves the use of surface-modified polymer NPs that enhance drug absorption and transport across the BBB; however, the technology still has some limitations. Studies conducted over the past few years have demonstrated that NPs modified with peptides or proteins can effectively cross the BBB via specific receptors, thus enhancing their delivery efficiency. In this review, we explore the use of polymer NPs combined with peptides and proteins for the treatment of AD and PD. This discussion focuses on the pathophysiology of these diseases, the BBB, and the potential of therapeutics based on co-modifying NPs with peptides and proteins. Additionally, we outline future directions for the use of polymer NPs conjugated with these biomolecules.}, } @article {pmid41382294, year = {2025}, author = {Su, X and Takayanagi, R and Maeda, H and Saido, TC and Ohshima, T}, title = {Sex-related upregulation of bone morphogenetic protein signaling inhibits adult neurogenesis in APP[NL-G-F] alzheimer's disease model mice.}, journal = {Biology of sex differences}, volume = {16}, number = {1}, pages = {103}, pmid = {41382294}, issn = {2042-6410}, support = {JP22K06464//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Neurogenesis/physiology ; Female ; Male ; Up-Regulation ; Mice, Transgenic ; Disease Models, Animal ; Signal Transduction ; Mice, Inbred C57BL ; *Bone Morphogenetic Proteins/metabolism ; *Sex Characteristics ; Hippocampus/metabolism ; Mice ; Neural Stem Cells ; Estrogens/pharmacology ; }, abstract = {BACKGROUND: Bone morphogenetic proteins (BMPs) have been reported in many studies to be related to adult neurogenesis. Neurogenic impairment is a hallmark of Alzheimer's disease (AD), while the involvement of BMPs remains unclear.

METHODS: AD models were established using APP[NL-G-F] transgenic mice and C57BL/6 mice subjected to intracerebral injection of Aβ(25-35) peptide. Female APP[NL-G-F] mice received pharmacological inhibitor treatment, whereas Neuro2a cells were exposed to estrogen stimulation in vitro. Immunofluorescence staining was conducted to evaluate hippocampal neural stem cell proliferation. The hippocampus and cellular pellets were isolated, and quantitative PCR (qPCR) was employed to determine mRNA expression levels.

RESULTS: Our study revealed that APP[NL-G-F] mice and Aβ-injected mice exhibited impaired neurogenesis in the brain, with a clear sex-dependent difference only in APP mice. Several BMPs were markedly upregulated in the hippocampus of AD model mice, with significantly higher expression in females than in males. BMP inhibitor attenuated neural stem cell proliferation deficits in female APP[NL-G-F] mice. Estrogen stimulation robustly enhanced BMP6 expression in Neuro2a cells.

CONCLUSIONS: Our findings reveal a sex-dependent impairment of neurogenesis in APP[NL-G-F] mice driven by BMP signaling. Blocking BMP signaling enhances adult neural stem cell proliferation in female APP[NL-G-F] mice, providing a potential therapeutic target for AD.}, } @article {pmid41382170, year = {2025}, author = {Jannati, A and Thompson, K and Toro-Serey, C and Gomes-Osman, J and Banks, RE and Higgins, C and Showalter, J and Bates, D and Tobyne, S and Pascual-Leone, A}, title = {Concurrent detection of cognitive impairment and amyloid positivity with a multimodal machine learning-enabled digital cognitive assessment.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {261}, pmid = {41382170}, issn = {1758-9193}, mesh = {Humans ; *Machine Learning ; *Cognitive Dysfunction/diagnosis/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; Aged ; Neuropsychological Tests ; *Alzheimer Disease/diagnosis ; Biomarkers/blood ; Aged, 80 and over ; tau Proteins/metabolism ; Brain/metabolism/diagnostic imaging ; Middle Aged ; }, abstract = {BACKGROUND: Early identification of cognitive impairment and brain pathology associated with Alzheimer's disease (AD) is essential to maximize benefits from lifestyle interventions and emerging pharmacologic disease-modifying treatments (DMT). Digital cognitive assessments (DCAs) can quickly capture an array of metrics that can be used to train machine-learning (ML) models to concurrently evaluate different outcomes. DCAs have the potential to optimize clinical workflows and enable efficient assessment of cognitive function and the likelihood of a given underlying pathology.

METHODS: We assessed the ability of a multimodal ML-enabled DCA, the Digital Clock and Recall (DCR), to concurrently estimate brain amyloid-beta (Aβ) status and detect cognitive impairment, as compared with traditional cognitive assessments, including the MMSE, RAVLT, a DCA, Cognivue[®], and blood-based biomarkers in 930 participants from the Bio-Hermes-001 clinical study.

RESULTS: Aβ42/40, p-tau181, APS, and p-tau217 poorly classified cognitive impairment (AUCs: 0.61; 0.63; 0.63; 0.70, respectively), but accurately classified Aβ status (AUCs: 0.81; 0.78; 0.85, 0.89, respectively). MMSE, RAVLT, and Cognivue poorly classified Aβ status (AUCs: 0.70, 0.73, 0.70, respectively). However, separate multimodal, DCR-based ML classification models, run in parallel, accurately classified both cognitive impairment (AUC = 0.83) and Aβ-PET status (AUC = 0.81).

CONCLUSIONS: DCAs that leverage digital technologies to generate advanced metrics, such as the DCR, enable accurate and efficient detection of cognitive impairment associated with AD pathology. They have the potential to empower health systems and primary care providers to help their patients make timely treatment decisions.}, } @article {pmid41381656, year = {2025}, author = {Riley, S and Nguyen, V and Bhattacharjee, R and Ng, PQ and Ritchie, T and Kamath, KS and Fisk, I and Gecz, J and Kumar, R and Searle, IR}, title = {TMT-based quantitative proteomic assessment of Vicia sativa induced neurotoxicity by β-cyano-L-alanine and γ-glutamyl-β-cyano-L-alanine in SH-SY5Y cells.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {510}, pmid = {41381656}, issn = {2045-2322}, support = {LP200200957//Australian Research Council/ ; UA720//South Australian Grains and Industry Trust/ ; BB/V018108/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; }, mesh = {Humans ; *Proteomics/methods ; Cell Line, Tumor ; Tandem Mass Spectrometry ; *Proteome ; *Dipeptides/toxicity ; Apoptosis/drug effects ; Oxidative Stress/drug effects ; *Alanine/analogs & derivatives/toxicity ; }, abstract = {β-cyano-L-alanine (BCA) and γ-glutamyl-β-cyano-L-alanine (GBCA) are the primary antinutritional compounds in Vicia sativa, a high-protein, drought-tolerant legume. While their neurotoxicity in monogastric animals has been reported, the molecular basis remains largely unknown. In this study, we optimised a rapid in vitro assay using retinoic acid-differentiated SH-SY5Y human neuroblastoma cells to assess BCA and GBCA toxicity, and then applied Tandem mass tags (TMT)-mass spectrometry (MS)-based quantitative proteomics to identify dysregulated proteins. BCA treatment dysregulated the proteins involved in DNA damage, translation, and oxidative stress, many of which are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease, as well as various cancers. In contrast, GBCA impacted the proteins linked to mitosis, cell cycle regulation, and apoptosis pathways. Interestingly, the absence of overlapping dysregulated proteins between BCA- and GBCA-treated cells suggested that the two toxins likely induce neurotoxicity via distinct mechanisms. These findings offer new insights into the molecular and cellular alterations caused by V. sativa toxins and their implications for animal feed safety.}, } @article {pmid41381439, year = {2025}, author = {Ang, S and Zhang, X and Hong, J and Xue, K and Li, J and Du, X and Gao, Y and Wang, X and Li, X and Chen, B and Li, Y and Zhang, J and Liu, S}, title = {The safety and efficacy of gamma frequency auditory and visual stimulation in the treatment of alzheimer's disease: a systematic review and meta-analysis.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {523}, pmid = {41381439}, issn = {2158-3188}, support = {82271546//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2025-ZZ-004//National Clinical Key Specialty Construction Program - Independent Research Project/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy ; *Cognitive Dysfunction/therapy ; *Acoustic Stimulation/methods/adverse effects ; *Photic Stimulation/methods/adverse effects ; *Gamma Rhythm ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline and significant global health burden. Current treatments offer limited benefits, highlighting the need for novel therapies. Gamma-frequency auditory and visual stimulation (GFAVS), utilizing 40 Hz neuromodulation, has gained attention as a non-invasive treatment for cognitive deficits and underlying pathophysiology in AD.

OBJECTIVE: This systematic review and meta-analysis aimed to assess the safety and efficacy of GFAVS in treating Alzheimer's disease (AD) and mild cognitive impairment (MCI).

METHODS: A comprehensive literature search across multiple databases (PubMed, Cochrane Library, MEDLINE, Web of Science, and Embase) was performed up to November 2025. Controlled trials involving adults (≥50 years) with AD or MCI, using GFAVS, were included. Meta-analyses assessed adverse events, cognitive function, and brain changes.

RESULTS: Eleven studies (341 participants) were included. GFAVS was safe, with no significant increase in overall adverse events (RR = 0.99, P = 0.93; RD = -0.01, P = 0.93). However, GFAVS significantly increased the risk of tinnitus (RR = 6.46, P = 0.08; RD = 0.16, P = 0.01). GFAVS significantly improved structural brain changes (SMD = 1.74, P = 0.02), especially in mixed AD and MCI populations (SMD = 3.05, P < 0.00001). Nevertheless, no significant improvements were observed in cognitive function (SMD = 0.16, 95% CI [-0.36 to 0.68], P = 0.55) or activities of daily living (SMD = 0.53, 95% CI [-1.26 to 2.33], P = 0.56), despite the observed structural brain changes. High heterogeneity was observed.

CONCLUSION: GFAVS appears to be well tolerated and may induce structural brain alterations in individuals with Alzheimer's disease or mild cognitive impairment; however, its impact on cognition or daily functioning remains to be established. Large-scale, rigorously designed trials are required to clarify optimal protocols and address the observed heterogeneity.}, } @article {pmid41379906, year = {2025}, author = {Zhang, L and Li, L and Cao, P and Yang, J and Zaiane, OR and Wang, F}, title = {An Efficient Transfer Learning With Prompt Learning for Brain Disorders Diagnosis.}, journal = {IEEE journal of biomedical and health informatics}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/JBHI.2025.3625375}, pmid = {41379906}, issn = {2168-2208}, abstract = {The limited availability of training data significantly restricts the performance of deep supervised models for brain disease diagnosis. It is crucial to develop a learning framework through cross-disease transfer learning that can extract more information from the limited data. To address this challenge, we concentrate on prompt learning and endeavor to extend its application to the brain networks. Specifically, we propose a novel prompt learning framework called BPformer, which integrates knowledge transferred across diseases via specific prompts while keeping the original architecture of BPformer unchanged. The specific prompts incorporate 1) a mask prompt to determine whether the edges are noisy or discriminating, 2) disorder prompts for modeling consistent and disorder-specific knowledge, and 3) adaptive instance-level prompts to account for inter-individual variations. We evaluate BPformer on the private center Nanjing Medical University dataset, the public Autism Brain Imaging Data Exchange dataset, and the public Alzheimer's Disease Neuroimaging Initiative dataset. We demonstrate the effectiveness of the proposed model across various disease classification tasks, including major depressive disorder, bipolar disorder, alzheimer's disease, and autism spectrum disorder diagnoses. In addition, the proposed method enables disease interpretability and subtype analysis, empowering physicians to provide patients with more accurate and fine-grained treatment plans.}, } @article {pmid41379352, year = {2025}, author = {Mohanty, R and Wheatley, S and Chiotis, K and Marseglia, A and Westman, E and , }, title = {Distinct cerebrovascular pathways underlying Alzheimer's disease-related neurodegeneration.}, journal = {Acta neuropathologica}, volume = {150}, number = {1}, pages = {64}, pmid = {41379352}, issn = {1432-0533}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/complications ; Female ; Male ; Aged, 80 and over ; Aged ; *Brain/pathology/diagnostic imaging ; *Cerebrovascular Disorders/pathology/diagnostic imaging ; White Matter/pathology ; Cerebrovascular Circulation/physiology ; Neuroimaging ; Cerebral Amyloid Angiopathy/pathology ; Arteriolosclerosis/pathology ; }, abstract = {The etiology of cerebrovascular pathology is heterogeneous. Independent or synergistic role of this pathology relative to Alzheimer's disease (AD) pathology is necessary to clarify distinct neurodegenerative pathways. We evaluated the interplay of various cerebrovascular markers postmortem and their in vivo neuroimaging, clinical and neuropathologic correlates using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In 109 individuals, postmortem cerebrovascular pathology (atherosclerosis of the circle of Willis, cerebral amyloid angiopathy [CAA], arteriolosclerosis, white matter rarefaction, old infarcts, microinfarcts, hemorrhages, other ischemic/vascular changes) was characterized. Additionally, we assessed in vivo neuroimaging (cortical thickness, subcortical volume, white matter lesion burden, glucose standardized uptake value ratio, fractional anisotropy of white matter tracts, cerebral blood flow), cognitive, and neuropathologic measures (atrophy, AD pathology and copathologies including Lewy body, TDP-43, hippocampal sclerosis). The study sample had mean (standard deviation) age of 82.9 (7.2) years and included 29 women (27%) and 84 (77%) with intermediate/high AD neuropathologic change. Arteriolosclerosis and CAA emerged as dominant cerebrovascular markers using multiple correspondence analysis. More severe arteriolosclerosis was explained by higher white matter lesion burden and greater postmortem hippocampal atrophy (β = 143.2, 95% CI 63.9 to 230.1, p = 0.0003), but not AD pathology. More severe CAA was explained by fractional anisotropy (β = - 20, 95% CI - 41.5 to -3.1, p = 0.02) adjusted for AD pathology and reduced integrity of superior cerebellar peduncle, posterior thalamic radiation, and sagittal stratum tracts (rho < - 0.6, false discovery rate corrected p < 0.05). More severe CAA was also explained by cortical atrophy and AD pathology (β = 0.6, 95% CI 0.2 to 1.2, p = 0.007), and associated with poorer memory (β = - 0.2, 95% CI - 0.3 to -0.09, p = 0.0009). Results demonstrate two dominant cerebrovascular pathways. An arteriolosclerosis-driven pathway is unspecific to AD pathology, whereas a CAA-driven pathway is specific to AD pathology. Cerebrovascular pathology is associated with AD pathology in an etiology-dependent manner which may influence eligibility for treatment or treatment-emergent adverse events in disease-modifying therapies for AD.}, } @article {pmid41379219, year = {2025}, author = {Taylor, LW and Simzer, EM and Young, LFP and Holt, K and Spires-Jones, TL and Durrant, CS}, title = {Confirmation of p-tau Ser356's association with Alzheimer's disease pathology and lowering in response to WZ4003 treatment in brain slice cultures. Reply to: "Phospho-tau Ser356 is mostly confined to pre-NFT neurons in Alzheimer's pathology".}, journal = {Acta neuropathologica}, volume = {150}, number = {1}, pages = {63}, pmid = {41379219}, issn = {1432-0533}, support = {UKDRI-Edin005//UK Dementia Research Institute/ ; RADF-2019a-001//Race Against Dementia/ ; AS-PG-21-006/ALZS_/Alzheimer's Society/United Kingdom ; }, } @article {pmid41378779, year = {2025}, author = {Begines, P and Fernández-Bolaños, JG and López, Ó}, title = {An updated patent review of acetylcholinesterase inhibitors for the treatment of Alzheimer's disease (2021-present).}, journal = {Expert opinion on therapeutic patents}, volume = {}, number = {}, pages = {1-32}, doi = {10.1080/13543776.2025.2602702}, pmid = {41378779}, issn = {1744-7674}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with a complex and not fully elucidated etiology. An exponential rise in its incidence underscores the urgent need for effective therapeutic strategies. AD imposes a significant economic burden on public healthcare systems and on patient's families.

AREAS COVERED: This manuscript focuses on the review of potent acetylcholinesterase (AChE) inhibitors, either through chemical synthesis or isolation from natural sources, aimed at restoring acetylcholine levels. Most of the compounds discussed act as multitarget agents and are categorized into four groups: drug derivatives (9 patents), heterocyclic scaffolds (16 patents), natural products from plant extracts (12 patents), and synthetic compounds inspired by natural templates (18 patents).

EXPERT OPINION: AChE inhibition remains a compelling target in AD drug design, as it enhances acetylcholine levels and can alleviate cognitive decline. Furthermore, inhibitors that interact with the peripheral anionic site (PAS) of AChE may reduce β-amyloid self-aggregation, thereby preventing the deposition of neurotoxic peptides in the brain. However, targeting AChE alone is insufficient for the development of effective therapeutics. A multitarget approach, combining AChE inhibition with pharmacophores addressing β-amyloid aggregation, neuroinflammation, oxidative stress, and other pathological hallmarks, holds greater promise for the development of more efficient anti-Alzheimer's agents.}, } @article {pmid41378217, year = {2025}, author = {Li, W and Huang, W and Zhou, P and Yao, Y and Cai, B and Ye, S}, title = {Sporoderm-removed ganoderma lucidum spore powder (S-GLSP) alleviates neuroinflammation injury by regulating microglial polarization through inhibition of NLRP3 inflammasome activation.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1690192}, pmid = {41378217}, issn = {1663-9812}, abstract = {INTRODUCTION: Sporoderm-Removed Ganoderma lucidum Spore Powder (S-GLSP), derived from the spores of the medically valued fungus Ganoderma lucidum, exhibits diverse pharmacological activities and shows considerable potential in the treatment of Alzheimer's disease (AD). However, its underlying mechanisms of action remain incompletely elucidated. This study aims to investigate the protective effects of S-GLSP against AD and to explore the molecular mechanisms involved.

MATERIALS AND METHODS: The chemical profile of S-GLSP extract was characterized using LC-MS/MS. Alzheimer's disease models were established both in vivo and in vitro: a rat model was induced by D-galactose combined with intracerebroventricular injection of Aβ, while a cellular model was stimulated with LPS. The neuroprotective effects of S-GLSP were assessed through behavioral tests and hematoxylin-eosin (HE) staining. Immunofluorescence staining, Western blot (WB), RT-qPCR, and ELISA were employed to evaluate microglial polarization and NLRP3 inflammasome activation. Cell viability was measured using MTT and EdU assays. Finally, NLRP3 knockdown was performed to verify whether S-GLSP modulates microglial polarization via regulation of the NLRP3 inflammasome.

RESULTS: A total of 42 chemical compounds were identified in S-GLSP, including flavonoids, alkaloids, terpenoids, saccharides, phenolics, fatty acids, nucleosides, amino acids, and other. S-GLSP treatment alleviated neuronal damage, improved learning and memory deficits, and reduced the expression of phosphorylated tau (p-tau) in AD model rats. Further experiments in vitro and in vivo showed that S-GLSP downregulated M1 phenotypic markers (CD86, iNOS, TNF-α) and upregulated M2 markers (CD206, Arg-1, IL-10). Moreover, S-GLSP inhibited NLRP3 inflammasome activation and regulated the secretion of IL-1β and IL-18, effects that were consistent with those observed following NLRP3 knockdown.

CONCLUSION: Our findings demonstrate that S-GLSP alleviates Alzheimer's disease pathology by inhibiting NLRP3 inflammasome activation, promoting a shift in microglial polarization from the M1 to the M2 phenotype, and modulating the release of inflammatory cytokines. This study provides novel mechanistic insights into the therapeutic potential of S-GLSP for AD.}, } @article {pmid41377997, year = {2025}, author = {Monteiro, R and Dunn, JT and Rodriguez, G and Fisher, DW and Dong, H}, title = {Targeting central immune signaling enhances the effects of methylphenidate in alleviating apathy-like behavior in 5xFAD mice.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41377997}, issn = {2693-5015}, support = {R01 AG062249/AG/NIA NIH HHS/United States ; R01 AG079989/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is frequently accompanied by neuropsychiatric symptoms (NPS), among which apathy, one of the most prevalent and burdensome, accelerates cognitive decline and disease progression, yet its molecular underpinnings remain unclear. Our previous RNA-sequencing of AD subjects revealed abnormal immune gene expression uniquely associated with apathy. In this study, we investigated whether these changes are also linked to apathy-like behavior in 5xFAD mice, and whether administration of C3a receptor antagonist SB290157, alone or with methylphenidate, modifies these behaviors. We first validated the expression of apathy-related immune hub genes identified in human AD in the prefrontal cortex (PFC) of 16-month-old 5xFAD mice using RT-qPCR. Separate cohorts of similarly aged 5xFAD and WT mice then received SB290157 and/or methylphenidate for two weeks. Results indicate that increased immune-related genes, including Tyrobp, C3, C3ar, C1qa, C1qb, and C1qc expression, were strongly correlated with apathy-like behavior in 5xFAD mice. Combined SB290157 and methylphenidate treatment significantly improved nest-building behavior, reduced C3 and C3ar protein expression, as well as restored dendritic spine density in the PFC. Our results confirm complement-mediated immune dysregulation is linked to apathy and suggest that co-targeting complement and catecholaminergic pathways may offer a novel therapeutic strategy for alleviating apathy in AD.}, } @article {pmid41377219, year = {2025}, author = {Pandey, P and Rajput, S and Gaur, T and Khandia, R and Gurjar, P}, title = {Animal models in human surgery and implant innovation: ethical considerations and scientific advancements.}, journal = {Annals of medicine and surgery (2012)}, volume = {87}, number = {12}, pages = {8291-8303}, pmid = {41377219}, issn = {2049-0801}, abstract = {The main aim of biological research is to bridge the gap between preclinical findings and clinical applications so that human health can be improved. Animal models are beneficial in replicating disease mechanisms, facilitating diagnosis, and assessing treatment efficacy for any disease. They play a vital role in drug discovery, toxicological assessments, dosage determination, and the evaluation of side effects, all while adhering to the ethical guidelines. These models are effectively used to treat a wide range of human diseases, including autoimmune disorders, rheumatoid arthritis, epilepsy, Alzheimer's disease, cardiovascular conditions, atherosclerosis, severe acute respiratory syndrome/Coronavirus disease 2019 (SARS/COVID-19), and diabetes. In disease modeling, they significantly contribute to drug development, medical device testing, tissue engineering, wound healing, and bone and cartilage regeneration. One cannot deny the fact that there are major significances of small and large animal models in scientific studies, apart from various advantages and challenges. Animal Models play an essential role in pharmaceutical research, biomedical research, genome editing, transgenic studies, and surgical applications. These models enable scientists and researchers to perform experiments that would be ethically or practically impossible in humans. In recent years, various animal species have been widely used to study health problems, including the 2019 Coronavirus pandemic, diabetes, and obesity. Mice, pigs, rabbits, rats, murine, primate, porcine, and aquatic models have played a crucial role in understanding the neurological, behavioral, cardiovascular, and oncological disorders while contributing to the development of innovative therapeutic approaches for their treatment. The studies in which pain is inflicted on animals must follow strict ethical standards. Whereas research involving painless animal death is often more accepted because of the fact that animals have limited awareness of their future. This review highlights the use of animal models in indispensable contributions to modern medicine and underscores their relevance in disease research, treatment development, and ethical considerations in experimental studies and their scientific advancements.}, } @article {pmid41376208, year = {2025}, author = {Li, X and Gao, W and Ye, Q and Li, H}, title = {The Role and Therapeutic Potential of the cGAS-STING Signaling Pathway in Alzheimer's Disease.}, journal = {Brain and behavior}, volume = {15}, number = {12}, pages = {e71130}, pmid = {41376208}, issn = {2162-3279}, support = {LH2023H064// Natural Science Foundation of Heilongjiang Province of China/ ; 82105035//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Nucleotidyltransferases/metabolism ; *Signal Transduction/physiology ; *Membrane Proteins/metabolism ; Animals ; Autophagy/physiology ; }, abstract = {PURPOSE: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, posing a significant challenge to global public health. As a core signaling pathway in the mammalian innate immune system, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a pivotal role in maintaining intracellular homeostasis. This review aims to systematically elucidate the role and therapeutic potential of the cGAS-STING signaling pathway in AD, focusing on its involvement in key pathological processes and its relevance to AD risk factors.

METHOD: Through literature search, we summarized the molecular mechanisms of the cGAS-STING pathway and its dysregulation in AD, emphasizing the integrated evidence linking cGAS-STING to neuroinflammation, autophagy impairment, and neuronal death, as well as its interactions with aging, obesity, cardiovascular disease, and diabetes.

FINDINGS: The cGAS-STING pathway is critically involved in AD pathogenesis, contributing to neuroinflammation, defective autophagy, and neuronal loss. Its activation is associated with multiple AD risk factors, suggesting a broad influence on disease progression. Pharmacological inhibition of cGAS-STING shows promise in attenuating these pathological features in preclinical models.

CONCLUSION: The cGAS-STING signaling pathway plays a central regulatory role in the central nervous system, and its dysregulation promotes neuroinflammation and is closely associated with AD. This pathway forms a vicious cycle by integrating multiple pathological signals, including mitochondrial dysfunction and endoplasmic reticulum stress. Small-molecule inhibitors and natural products targeting this pathway have demonstrated significant efficacy in preclinical studies, providing a basis for developing disease-modifying therapies for AD. Future efforts should focus on multi-target combination strategies (e.g., STING inhibitors co-administered with Aβ/tau drugs) and dynamically deciphering pathway alterations across AD stages to advance personalized treatment approaches.}, } @article {pmid41375579, year = {2025}, author = {O'Donnell, AJ and Zhao, X and Parr, A and Aspinall, S and Anderson, TS}, title = {Early Outcomes of Lecanemab for Alzheimer's Disease in the Veterans Health Administration.}, journal = {Journal of clinical medicine}, volume = {14}, number = {23}, pages = {}, pmid = {41375579}, issn = {2077-0383}, support = {N/A//Technology Enhancing Cognition and Health - Geriatric Research Education and Clinical Center (TECH-GRECC), VA Pittsburgh Healthcare System/ ; }, abstract = {Background/Objectives: While lecanemab (Leqembi) and several amyloid targeting therapies were approved for Alzheimer's disease, questions remain on real-world implementation, safety, and effectiveness. The objective of this study was to describe the uptake and early outcomes of Veterans initiating lecanemab. Methods: This retrospective cohort study included Veterans who initiated lecanemab in the Veteran's Health Administration (VHA) between October 2023 and July 2024. Treatment persistence and monitoring, change in Montreal Cognitive Assessment (MoCA) score, incidence of adverse events, including amyloid-related imaging abnormalities (ARIA), and healthcare utilization were analyzed at 7 months. Results: Overall, 32 Veterans (mean [SD] age 75.3 [6.0] years, 100% male, 97% white, 84% urban dwelling) initiated lecanemab. Seventeen patients (53%) had mild cognitive impairment, 15 (47%) had mild dementia; mean baseline MoCA score was 21.3 (SD 3.4). At 7 months following treatment initiation, we assessed process, safety, and effectiveness outcomes. Process outcomes: In all, 25 patients (78%) were persistent with treatment. Safety outcomes: Three patients (9%) experienced a stroke, and 7 (22%) experienced ARIA. Effectiveness outcomes: Only 12 (38%) patients had a MoCA completed by 7 months, and the mean change in MoCA was 0.0 (SD 3.7, p = 1.0). A follow-up amyloid positron emission tomography (PET) scan was completed by 9 (28%) patients, and 5 had reductions in amyloid. Conclusions: Initial observations in a small VHA cohort suggest that uptake of lecanemab was limited, and the finding that nearly 30% of patients experienced ARIA or stroke within 7 months of initiation underscores the importance of monitoring the lecanemab safety and effectiveness long-term. These early findings should be interpreted cautiously given the limited sample size and very limited follow-up MoCA data.}, } @article {pmid41375185, year = {2025}, author = {Vieira, RC and Nascimento, LA and Nascimento, AA and Alves, NRM and Nascimento, ÉCM and Martins, JBL}, title = {NCIVISION: A Siamese Neural Network for Molecular Similarity Prediction MEP and RDG Images.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {23}, pages = {}, pmid = {41375185}, issn = {1420-3049}, support = {306682/2021-4 and 308419/2025-1//National Council for Scientific and Technological Development/ ; 00193-00000869/2021-31//Foundation for Research Support of the Federal District/ ; }, mesh = {*Neural Networks, Computer ; Static Electricity ; *Drug Discovery/methods ; Humans ; Cholinesterase Inhibitors/chemistry/pharmacology ; Protein Kinase Inhibitors/chemistry/pharmacology ; }, abstract = {Artificial neural networks in drug discovery have shown remarkable potential in various areas, including molecular similarity assessment and virtual screening. This study presents a novel multimodal Siamese neural network architecture. The aim was to join molecular electrostatic potential (MEP) images with the texture features derived from reduced density gradient (RDG) diagrams for enhanced molecular similarity prediction. On one side, the proposed model is combined with a convolutional neural network (CNN) for processing MEP visual information. This data is added to the multilayer perceptron (MLP) that extracts texture features from gray-level co-occurrence matrices (GLCM) computed from RDG diagrams. Both representations converge through a multimodal projector into a shared embedding space, which was trained using triplet loss to learn similarity and dissimilarity patterns. Limitations associated with the use of purely structural descriptors were overcome by incorporating non-covalent interaction information through RDG profiles, which enables the identification of bioisosteric relationships needed for rational drug design. Three datasets were used to evaluate the performance of the developed model: tyrosine kinase inhibitors (TKIs) targeting the mutant T315I BCR-ABL receptor for the treatment of chronic myeloid leukemia, acetylcholinesterase inhibitors (AChEIs) for Alzheimer's disease therapy, and heterodimeric AChEI candidates for cross-validation. The visual and texture features of the Siamese architecture help in the capture of molecular similarities based on electrostatic and non-covalent interaction profiles. Therefore, the developed protocol offers a suitable approach in computational drug discovery, being a promising framework for virtual screening, drug repositioning, and the identification of novel therapeutic candidates.}, } @article {pmid41375178, year = {2025}, author = {Tsopka, IC and Pontiki, E and Sigala, I and Nikolakaki, E and Prousis, KC and Hadjipavlou-Litina, D}, title = {Design, Synthesis, Biological Evaluation, and In Silico Studies of Novel Multitarget Cinnamic Acid Hybrids.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {23}, pages = {}, pmid = {41375178}, issn = {1420-3049}, mesh = {*Cinnamates/chemistry/pharmacology/chemical synthesis ; Humans ; *Drug Design ; Antioxidants/pharmacology/chemistry/chemical synthesis ; Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry ; Lipoxygenase Inhibitors/pharmacology/chemical synthesis/chemistry ; Lipid Peroxidation/drug effects ; Molecular Docking Simulation ; Cyclooxygenase Inhibitors/pharmacology/chemical synthesis/chemistry ; Computer Simulation ; Structure-Activity Relationship ; Nitric Oxide Donors/chemistry/pharmacology/chemical synthesis ; Nitric Oxide ; Lipoxygenase/metabolism ; Molecular Structure ; Cell Line, Tumor ; Cyclooxygenase 2/metabolism/chemistry ; }, abstract = {Chronic inflammation is implicated in the development of various multifactorial diseases, including cancer, diabetes, arthritis, cardiovascular disorders, Alzheimer's disease, and autoimmune diseases. The enzymes that play a key role in the onset of the inflammation are cyclooxygenases (COXs) and lipoxygenases (LOXs). In recent years, cinnamic acid hybrid molecules, particularly those incorporating a nitric oxide (NO) donor moiety, have attracted considerable attention as potential pharmacological agents for the treatment of multifactorial diseases. In the present study, novel cinnamic acid-nitric oxide (NO) donor hybrids were synthesized as multitarget agents and evaluated for their antioxidant, anti-inflammatory, and cytotoxic properties. In particular, hybrids 5a-i, 6a-i, 9a-i, and 11 were synthesized and evaluated as lipid peroxidation and LOX inhibitors, while selected molecules were further tested as COX-1 and COX-2 inhibitors. Hybrids 6a-i, 9a-i, and 11 that contain a NO donor moiety, were additionally tested as albumin denaturation inhibitors and for their ability to release NO. The results indicated that compound 9a is a promising multitarget agent, exhibiting the lowest IC50 for LOX inhibition, significant antioxidant activity, and the highest NO donor potency. Furthermore, compound 9e demonstrated significant inhibitory activity against both COX-2 and LOX, suggesting its potential as a dual COX-LOX inhibitor. Additionally, compound 6i exhibited the strongest cytotoxic activity among the tested compounds, with EC50 values ranging from 36 to 45 μM across multiple cancer cell lines. All synthesized compounds were also evaluated through in silico studies.}, } @article {pmid41374080, year = {2025}, author = {Kimble, R and Shannon, OM}, title = {Can Beetroot (Beta vulgaris) Support Brain Health? A Perspective Review on Alzheimer's Disease.}, journal = {Nutrients}, volume = {17}, number = {23}, pages = {}, pmid = {41374080}, issn = {2072-6643}, mesh = {Humans ; *Alzheimer Disease/prevention & control ; *Beta vulgaris/chemistry ; *Brain/drug effects ; Antioxidants/pharmacology ; Nitrates/pharmacology ; Oxidative Stress/drug effects ; Neuroprotective Agents/pharmacology ; Animals ; Polyphenols/pharmacology ; Betalains/pharmacology ; }, abstract = {Alzheimer's disease (AD), the leading cause of dementia, has limited treatment options despite extensive pharmacological research. This has increased interest in dietary strategies that act across multiple pathological mechanisms. Beetroot (Beta vulgaris), known for its cardiovascular and metabolic benefits, contains a distinctive combination of bioactive compounds including inorganic nitrate, betalains, and polyphenols. Together these constituents influence vascular function, oxidative stress, mitochondrial efficiency, inflammation, and the microbiota. Previous reviews have typically focused on dietary nitrate in dementia prevention or have examined nitrate and betalains separately. In contrast, this review synthesises evidence on beetroot as a combined neuroprotective food. Preclinical data indicate that beetroot and its key constituents enhance antioxidant defences, support neuronal bioenergetics, and modulate cholinergic and inflammatory pathways. Human studies further suggest that nitrate-rich beetroot can improve cerebral blood flow and vascular responsiveness, and that higher intakes of plant-derived nitrate are associated with reduced cognitive decline. However, findings are inconsistent, most trials are small and short in duration, and research directly involving people with AD is scarce. By integrating vascular, antioxidant, and microbiome perspectives, this review identifies beetroot as a promising yet underexplored dietary candidate for AD management. Further mechanistic studies and multidomain approaches combining metagenomics, biomarkers, neuroimaging, and cognitive outcomes are needed.}, } @article {pmid41374061, year = {2025}, author = {Calzoni, E and Cusumano, G and Bertoldi, A and Alabed, HBR and Pellegrino, RM and Buratta, S and Urbanelli, L and Zengin, G and Emiliani, C}, title = {Rhubarb-Derived Extracellular Vesicles Mitigate Oxidative Stress and Metabolic Dysfunction in an Alzheimer's Cellular Model.}, journal = {Nutrients}, volume = {17}, number = {23}, pages = {}, pmid = {41374061}, issn = {2072-6643}, support = {CUP J97G22000170005//National Innovation Ecosystem grant ECS00000041/ ; }, mesh = {*Oxidative Stress/drug effects ; *Rheum/chemistry ; *Alzheimer Disease/metabolism ; Humans ; *Extracellular Vesicles/metabolism ; *Antioxidants/pharmacology ; Energy Metabolism/drug effects ; Reactive Oxygen Species/metabolism ; }, abstract = {Background/Objectives: Extracellular vesicles derived from edible plants have emerged as bioactive nanostructures with potential therapeutic and nutraceutical properties and are currently being investigated as natural carriers for the treatment of oxidative stress-induced damage and oxidative stress-related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). Recent studies suggest that PDEVs exhibit high stability within the gastrointestinal tract and selective tissue-targeting abilities, facilitating the efficient delivery of bioactive molecules. Methods: This study investigates the antioxidant effects of Rheum rhabarbarum-derived EVs by assessing the antioxidant activity through different in vitro assays and their effects on oxidative stress and energy metabolism in the cellular model of Alzheimer's disease. Results: Rhubarb-derived EVs showed measurable antioxidant capacity in chemical assays and were non-toxic under the tested conditions. Treatment reduced intracellular ROS levels and modulated oxidative stress-related proteins, suggesting a potential protective effect against oxidative damage. Moreover, metabolic analysis revealed a decrease in glycolytic activity, indicating a potential restoration of cellular bioenergetic homeostasis. Conclusions: These results provide preliminary evidence supporting the nutraceutical interest of rhubarb-derived EVs in counteracting oxidative stress, while further studies will be needed to confirm their biological relevance and therapeutic potential.}, } @article {pmid41373689, year = {2025}, author = {Brehar, FM and Costea, D and Tataru, CP and Rădoi, MP and Ciurea, AV and Munteanu, O and Tulin, A}, title = {The Fluidic Connectome in Brain Disease: Integrating Aquaporin-4 Polarity with Multisystem Pathways in Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373689}, issn = {1422-0067}, mesh = {*Aquaporin 4/metabolism ; Humans ; Animals ; Blood-Brain Barrier/metabolism ; *Brain Diseases/metabolism/pathology ; *Connectome/methods ; Astrocytes/metabolism ; *Neurodegenerative Diseases/metabolism/pathology ; Glymphatic System/metabolism ; }, abstract = {The way in which Aquaporin-4 (AQP4) is localized on the astrocytes' surface-i.e., with AQP4 channels predominantly located on the endfeet of astrocytes near the blood vessels-represents an important structural element for maintaining brain fluid homeostasis. In addition to this structural function, AQP4 polarity also facilitates glymphatic transport, the maintenance of the blood-brain barrier (BBB) functions, ion buffering, and neurotransmitter removal, and helps regulate neurovascular communications. The growing body of literature suggests that the loss of AQP4 polarity-a loss in the organization of AQP4 channels to the perivascular membrane-is associated with increased vascular, inflammatory, and metabolic disturbances in the context of many neurological diseases. As a result, this review attempts to synthesize both experimental and clinical studies to highlight that AQP4 depolarization often occurs in conjunction with early signs of neurodegeneration and neuroinflammation; however, we are aware that the loss of AQP4 polarity is only one factor in a complex pathophysiological environment. This review examines the molecular structure responsible for maintaining the polarity of AQP4-such as dystrophin-syntrophin complexes, orthogonal particle arrays, lipid microdomains, trafficking pathways, and transcriptional regulators-and describes how the vulnerability of these systems to various types of vascular stress, inflammatory signals, energy deficits, and mechanical injury can lead to a loss of AQP4 polarity. Furthermore, we will explore how a loss of AQP4 polarity can lead to the disruption of perivascular fluid movement, changes in blood-brain barrier morphology, enhanced neuroimmune activity, changes in ionic and metabolic balance, and disruptions in the global neural network synchronization. Importantly, we recognize that each of these disruptions will likely occur in concert with other disease-specific mechanisms. Alterations in AQP4 polarity have been observed in a variety of neurological disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, traumatic brain injury, and glioma; however, we also observe that the same alterations in fluid regulation occur across all of these different diseases, but that no single upstream event accounts for the alteration in polarity. Ultimately, we will outline emerging therapeutic avenues to restore perivascular fluid transport, and will include molecular-based therapeutic agents designed to modify the anchoring of AQP4, methods designed to modulate the state of astrocytes, biomaterials-based drug delivery systems, and therapeutic methods that leverage dynamic modulation of the neurovascular interface. Future advances in multi-omic profiling, spatial proteomics, glymphatic imaging, and artificial intelligence will allow for earlier identification of AQP4 polarity disturbances and potentially allow for the development of more personalized treatment plans. Ultimately, by linking these concepts together, this review aims to frame AQP4 polarity as a modifiable aspect of the "fluidic connectome", and highlight its importance in maintaining overall brain health across disease states.}, } @article {pmid41373648, year = {2025}, author = {Ishikawa, K and Fujikawa, R and Okita, K and Kimura, F and Watanabe, T and Katsurabayashi, S and Iwasaki, K}, title = {Microglia in Brain Aging and Age-Related Diseases: Friends or Foes?.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373648}, issn = {1422-0067}, support = {24K18288 (R.F.), 23K27496 (S.K.) and 24H02336 (S.K.)//JSPS KAKENHI/ ; }, mesh = {Humans ; *Microglia/metabolism/pathology ; *Aging/pathology ; *Brain/pathology/metabolism ; Animals ; *Neurodegenerative Diseases/pathology/metabolism ; }, abstract = {With the global rise in population aging, establishing effective strategies for the prevention and treatment of age-related neurodegenerative diseases, as well as their prodromal stage of cognitive frailty, has become an urgent challenge. Recent studies have revealed that the neural basis of both frailty and age-related disorders is closely associated with chronic neuroinflammation and impaired clearance of cellular debris, processes that are primarily regulated by microglia, the resident immune cells of the brain. As aging progresses, microglia exhibit reduced surveillance and motility, diminished phagocytic efficiency, and transition into a proinflammatory, hyperresponsive state. Such maladaptive microglia contribute to synaptic loss, white matter deterioration, and the spread of neurodegenerative pathology. Conversely, single-cell transcriptomic studies have identified distinct microglial subsets, including CD11c[+] microglia, which show upregulation of lysosomal and lipid metabolism pathways, enhanced debris clearance, and elevated neurotrophic factor expression. These features suggest that certain microglial populations adopt protective or adaptive phenotypes that preserve neural integrity. However, under chronic inflammation or pathological conditions, even protective microglia may become inflammation-promoting. This review summarizes current evidence on microglial changes in aging, frailty, and neurodegeneration, emphasizing their dual roles and discussing strategies that modulate microglial function to maintain brain health and prevent or treat frailty and age-related diseases.}, } @article {pmid41373506, year = {2025}, author = {Muzaffar, S and Tyagi, A and Pugazhenthi, S}, title = {Therapeutic Potential of Irisin in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373506}, issn = {1422-0067}, support = {NEUD-004-07F//United States Department of Veterans Affairs/ ; }, mesh = {Humans ; *Fibronectins/metabolism/therapeutic use/genetics ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Exercise ; }, abstract = {Irisin is a myokine secreted by muscle in response to exercise. It is derived from a transmembrane protein called fibronectin type III domain-containing protein 5 (FNDC5). The Fndc5 gene is expressed in several tissues, including skeletal muscle, brain, adipose tissue, heart, kidney, and lung. Irisin is cleaved from FNDC5 protein by the enzyme furin and released into circulation. In addition to exercise, several drugs have been shown to increase the production of irisin. Administration of exogenous irisin mimics the beneficial actions of exercise. Irisin can cross the blood-brain barrier and exert neuroprotective actions in the brain. It has been shown to reverse Alzheimer's pathologies in clinical and animal studies. Irisin also exerts protective effects against obesity, diabetes, and cardiovascular disease, diseases that often coexist with aging AD patients. Multiple approaches have been taken to suggest that exercise may act through irisin. Studies have provided direct evidence linking the two using Fndc5 gene deletion and irisin antibodies. Irisin binds to αVβ1/β5 integrins to mediate the activation of integrin-FAK pathways. While exercise as a lifestyle modification for healthy aging is well recognized, it may present limitations in some aging populations, especially those with disease conditions, including Parkinson's disease. Administration of exogenous irisin or small molecules that increase the expression of endogenous irisin or facilitate its actions are some alternate approaches that can mimic the beneficial actions of exercise. This review discusses the therapeutic potential of irisin in the treatment of neurodegenerative and other aging-associated diseases.}, } @article {pmid41373466, year = {2025}, author = {Adamski, P and Szeleszczuk, Ł and Gackowski, M and Grodner, B}, title = {Creatine and Taurine as Novel Competitive Inhibitors of Acetylcholinesterase: A Biochemical Basis for Nutritional Modulation of Brain Function.}, journal = {International journal of molecular sciences}, volume = {26}, number = {23}, pages = {}, pmid = {41373466}, issn = {1422-0067}, mesh = {*Taurine/pharmacology/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemistry ; *Acetylcholinesterase/metabolism/chemistry ; Molecular Docking Simulation ; Humans ; *Creatine/pharmacology/chemistry ; *Brain/drug effects/physiology/metabolism ; Kinetics ; }, abstract = {Acetylcholinesterase (AChE) is a key enzyme responsible for terminating cholinergic neurotransmission by hydrolyzing acetylcholine. While clinically approved AChE inhibitors such as donepezil, rivastigmine, and galantamine are used in the symptomatic treatment of Alzheimer's disease and related dementias, little is known about the modulatory effects of common dietary compounds on AChE activity. In this study, we investigated the influence of creatine (CR) and taurine (TA)-two widely consumed nutritional supplements with reported neuroprotective and cognitive-enhancing properties-on AChE. Enzyme kinetics were evaluated using a modified Ellman's method, and Lineweaver-Burk analyses revealed that both CR and TA act as competitive inhibitors. Calculated parameters (Km, Vmax), inhibition constants (Ki), and half maximal inhibitory concentrations (IC50) consistently indicated stronger potency for CR (IC50 = 0.0056 ± 0.00018 mM) compared to TA (IC50 = 0.0097 ± 0.00035 mM). To complement the experimental data, molecular docking was performed using two crystal structures of human AChE. Docking confirmed that both ligands preferentially occupy the active-site region in a manner consistent with competitive inhibition, with CR showing more favorable binding scores than TA. Although markedly weaker than clinical drugs, these findings provide the first biochemical and in silico evidence that CR and TA directly interact with AChE, suggesting subtle cholinergic modulation relevant to cognitive function and neuroprotection.}, } @article {pmid41372777, year = {2025}, author = {Mi, F and Li, H and Pan, D and Yu, C}, title = {Effect of organismal rhythmic activity on Aβ clearance by the glymphatic system.}, journal = {European journal of medical research}, volume = {}, number = {}, pages = {}, doi = {10.1186/s40001-025-03646-5}, pmid = {41372777}, issn = {2047-783X}, abstract = {Abnormal deposition of β-amyloid (Aβ) is a significant pathological feature of neurodegenerative diseases, particularly Alzheimer's disease (AD). The glymphatic system (GS) plays a crucial role in Aβ clearance. Various rhythmic activities of the organism dynamically influence Aβ clearance by modulating GS function. In this paper, we systematically review the mechanisms linking cardiovascular rhythms, respiratory rhythms, neural rhythms, circadian rhythms, and exercise patterns to Aβ clearance via the GS. Cardiovascular rhythms affect cerebral perfusion pressure and vascular pulsation to regulate GS transport efficiency; respiratory rhythms modulate intracranial pressure and cerebrospinal fluid (CSF) circulation through thoracic pressure variations; neural rhythms (including delta waves during non-rapid eye movement (NREM) sleep and neurovascular coupling) synchronize neuro-glial-vascular interactions to enhance GS clearance. Circadian rhythms coordinate these primary rhythms by regulating melatonin levels and cerebral blood flow, while exercise patterns adjust GS function via aquaporin-4 (AQP4) polarization. Additionally, we elaborate on the cascade effect of AD resulting from rhythmic dysregulation. A thorough understanding of how rhythmic activities impact Aβ clearance by the GS may offer new perspectives and potential intervention strategies for the prevention and treatment of AD through the concept of "synchronized multiple rhythms"-a novel framework that integrates multi-rhythm synergy. Clinically, this work provides a theoretical basis for developing targeted interventions, such as personalized exercise timing regimens, respiratory rhythm training, and closed-loop neurovascular feedback devices, to restore GS function in AD patients.}, } @article {pmid41372196, year = {2025}, author = {Du, M and Li, N and Li, T and Zhao, Z and Liu, H and Li, X and Gong, N and Duan, B and Wang, W and Jian, Y and Ma, W and Zhang, X and Wang, Y and Zhang, Z and Bai, Y and Wang, X and Wang, C and Liu, J and Guan, X and Zhou, F and Wang, W and Li, L and Zhu, X and Lei, Y and Duan, Y and Han, G and Wei, P and Gao, S and Wang, S and Chen, A and Huang, Y and Yang, H and Xue, X and Zhang, H}, title = {Chimeras co-targeting antigens and FcγRIIb trigger degradation of extracellular soluble proteins and pathological aggregates.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-025-67207-4}, pmid = {41372196}, issn = {2041-1723}, support = {82261138553//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82373898//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {While the clinical utility of conventional antibody therapies is undeniable, their therapeutic potential is often constrained high antigen loads and the recycling of antibody-antigen complexes via neonatal Fc receptor (FcRn). Here, we present a platform, based on a design similar to bispecific antibodies, FcγRIIb-Targeting Chimeras (FcRTAC). These constructs recognise antigens with one arm and bind FcγRIIb with the other arm to harness the unique endocytic properties of FcγRIIb to direct the recognized pathogenic antigens to lysosomes for irreversible degradation. The FcRTAC platform demonstrates broad therapeutic potential across multiple disease-relevant targets, including IgE, proprotein convertase subtilisin/kexin type 9 (PCSK9) and amyloid-β (Aβ). Notably, a single intravenous administration of blood brain barrier (BBB)-penetrating adeno-associated viral vector (AAV) encoding an Aβ-targeting FcRTAC construct achieves sustained therapeutic effects, establishing proof-of-concept for AAV-mediated delivery of an Aβ degrader as a strategy for Alzheimer's disease treatment. Our comprehensive investigation of binding properties of FcRTACs reveals critical molecular determinants of function and enables development of optimized engineering approaches. In summary, our approach represents a versatile therapeutic platform for treating diverse diseases ranging from autoimmune disorders to neurodegenerative conditions, while simultaneously serving as a user-friendly, plug-and-play research tool for extracellular protein knockout in basic biological research.}, } @article {pmid41371839, year = {2026}, author = {Kubohira, Y and Okano, N and Taharabaru, T and Ishimatsu, A and Era, T and Yanagihara, K and Ishikura, K and Nakagawa, Y and Higashi, T and Motoyama, K}, title = {A water-soluble β-cyclodextrin polymer reduces cholesterol accumulation and autophagy dysfunction in vitro and in Niemann-Pick type C disease model mice.}, journal = {Carbohydrate polymers}, volume = {374}, number = {}, pages = {124676}, doi = {10.1016/j.carbpol.2025.124676}, pmid = {41371839}, issn = {1879-1344}, mesh = {Animals ; *Cholesterol/metabolism ; *Niemann-Pick Disease, Type C/drug therapy/metabolism/pathology ; *Autophagy/drug effects ; Mice ; Humans ; *beta-Cyclodextrins/chemistry/pharmacology ; Disease Models, Animal ; *Cyclodextrins/chemistry/pharmacology ; Water/chemistry ; Cell Line, Tumor ; Solubility ; Cellulose ; }, abstract = {Niemann-Pick disease type C (NPC) and Alzheimer's disease (AD) are characterised by cognitive dysfunction and neurological impairment. In both diseases, the abnormal accumulation and disruption of cholesterol homeostasis in the brain may contribute to the pathogenesis and exacerbation of symptoms. Cyclodextrins (CDs) are attracting attention as therapeutic agents that can reduce free cholesterol in the brain. A water-soluble β-CD polymer (β-CDP) consisting of multiple β-CDs cross-linked by epichlorohydrin was recently developed and reportedly has improved safety and higher circulation time in the bloodstream. In this study, we evaluated the potential of β-CDP as a promising therapeutic agent for NPC and AD. β-CDP lowered free cholesterol levels and reversed autophagy dysfunction in cholesterol-accumulated human neuroblastoma cells. Longer circulation time in the bloodstream and reduced cholesterol accumulation in NPC mice were also observed after its subcutaneous administration. These results suggest that β-CDP may be a safe therapeutic agent in the treatment of NPC and AD.}, } @article {pmid41371570, year = {2026}, author = {Supasai, S and Suntaratti, P and Odton, M and Longji, T and Karananan, T and Yasom, S and Ampawong, S and Limpanont, Y and Mutirangura, A}, title = {HMGB1 Box A gene therapy reverses cognitive and neuropathological features in AlCl3/D-galactose rat model of Alzheimer's disease.}, journal = {Experimental neurology}, volume = {397}, number = {}, pages = {115583}, doi = {10.1016/j.expneurol.2025.115583}, pmid = {41371570}, issn = {1090-2430}, mesh = {Animals ; *Alzheimer Disease/therapy/chemically induced/pathology/genetics ; Rats ; *HMGB1 Protein/genetics/therapeutic use ; Aluminum Chloride/toxicity ; *Genetic Therapy/methods ; Male ; Disease Models, Animal ; Galactose/toxicity ; Rats, Sprague-Dawley ; Hippocampus/pathology/metabolism ; Maze Learning/physiology/drug effects ; }, abstract = {Alzheimer's disease (AD), the leading cause of dementia, is pathologically defined by the accumulation of amyloid-β and tau pathology, resulting in progressive cognitive decline. Our previous work demonstrated that high mobility group box 1 (HMGB1) Box A plasmids alleviated cellular senescence and restored cognitive performance in aged rat models, supporting their therapeutic potential for neurodegenerative disorders such as AD. In this study, we investigated the efficacy of HMGB1 Box A gene therapy in an AD-like rat model chronically induced by AlCl3 and D-galactose. Following the onset of AD pathology, Box A plasmids were administered weekly at varying doses over eight weeks. Box A treatment significantly improved behavioral outcomes, including responsiveness, locomotor activity, and learning and memory performance. At the neuropathological level, Box A reduced hippocampal Aβ accumulation and tau pathology, restored neuronal density, and attenuated synaptic degeneration. Moreover, it suppressed hippocampal microgliosis, astrogliosis, and the expression of proinflammatory mediators. Box A also diminished markers of cellular senescence in the hippocampus. These findings demonstrate that HMGB1 Box A gene therapy confers multi-level neuroprotective effects in AD, from molecular and cellular restoration to behavioral recovery. This strategy holds strong promise as a disease-modifying treatment for AD, contributing to improved well-being by advancing therapeutic innovation to promote healthy aging and combat age-related neurodegenerative diseases.}, } @article {pmid41370943, year = {2026}, author = {Xu, J and He, Z and Pan, Y and Cao, B and Chen, G}, title = {Nanotherapeutic potential of Baicalein-encapsulated hUC-MSC exosomes in Alzheimer's disease: Modulating oxidative stress and neuroinflammation.}, journal = {Biomaterials advances}, volume = {181}, number = {}, pages = {214619}, doi = {10.1016/j.bioadv.2025.214619}, pmid = {41370943}, issn = {2772-9508}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Oxidative Stress/drug effects ; *Flavanones/pharmacology/therapeutic use/administration & dosage/chemistry ; *Exosomes/chemistry/metabolism ; Humans ; Rats ; Male ; *Mesenchymal Stem Cells/cytology/metabolism ; Amyloid beta-Peptides/metabolism ; Rats, Sprague-Dawley ; *Neuroprotective Agents/pharmacology/therapeutic use/administration & dosage ; Antioxidants/pharmacology ; *Neuroinflammatory Diseases/drug therapy ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) accumulation, neuroinflammation, and oxidative stress. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSC@Exo) represent promising nanoscale carriers for targeted drug delivery. In this study, Baicalein (Bac), a potent antioxidant and anti-inflammatory flavonoid, was encapsulated into hUC-MSC-derived exosomes (Exo@Bac) to enhance its therapeutic efficacy. The neuroprotective potential of Exo@Bac was evaluated in a rat model of Aβ1-42-induced AD. Rats received intraperitoneal injections of Bac, hUC-MSC@Exo, or Exo@Bac, and cognitive performance was assessed using the passive avoidance test and Morris water maze. Exo@Bac treatment significantly improved memory deficits and elevated brain-derived neurotrophic factor (BDNF) expression compared to controls. Histopathological analyses revealed reduced neuronal damage and apoptosis, alongside decreased Aβ1-42 deposition in Exo@Bac-treated rats. Furthermore, Exo@Bac enhanced antioxidant defense (increased SOD), attenuated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and lowered lipid peroxidation (MDA). Mechanistically, Exo@Bac promoted AMPK phosphorylation while suppressing NF-κB p65 signaling, indicating modulation of both oxidative stress and neuroinflammatory pathways. These findings demonstrate that Exo@Bac acts as a nanotherapeutic agent capable of mitigating AD pathology, highlighting its potential as a novel strategy for Alzheimer's disease therapy.}, } @article {pmid41369702, year = {2025}, author = {Hooshmandi, E and Rafiei, E and Owjfard, M and Mohammadi, Y and Koohpeyma, F and Simani, L and Safari, MS and Rai, SN and Ashjazadeh, N and Pandamooz, S and Bayat, M and Salehi, MS}, title = {Neuroprotective and Immunomodulatory effects of human hair follicle stem cells on streptozotocin-induced memory impairment in rats: insights into inflammation and neurotrophic mechanisms.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {178}, pmid = {41369702}, issn = {1573-4978}, support = {29005//Vice-Chancellor for Research, Shiraz University of Medical Sciences/ ; }, mesh = {Animals ; Male ; Rats ; Rats, Sprague-Dawley ; Streptozocin ; Humans ; *Memory Disorders/chemically induced/therapy/metabolism ; *Hair Follicle/cytology ; Hippocampus/metabolism ; Inflammation ; Stem Cell Transplantation/methods ; Alzheimer Disease/therapy ; Disease Models, Animal ; *Stem Cells/cytology/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Neuroinflammatory Diseases ; Neuroprotective Agents/pharmacology ; }, abstract = {BACKGROUND/OBJECTIVE: Alzheimer's disease (AD), a primary cause of dementia, involves cognitive decline and neuroinflammation. Human hair follicle stem cells (hHFSCs) have shown neuroprotective potential, but their effects on immune modulation, especially in xenogeneic transplantation, remain unclear. This study aimed to investigate the therapeutic potential of hHFSCs against memory impairment and neuroinflammation induced by streptozotocin (STZ) in male rats.

METHODS: Adult male Sprague-Dawley rats were intracerebroventricularly injected with STZ (3 mg/kg) to induce AD-like cognitive deficits. hHFSC transplantation (1 × 10[6]) was done on days 4, 14, and 21 post-surgery. Y-maze and Passive avoidance were used to assess memory. Hippocampal tissue was analyzed for mRNA expression of pro/anti-inflammatory factors and neurotrophic markers using quantitative RT-PCR. Histological evaluation quantified hippocampal pyramidal neurons and volume.

RESULTS: STZ significantly impaired memory in passive avoidance test, but not Y-maze. hHFSC significantly improved memory performance. mRNA analysis revealed elevated BDNF, TGFβ, and GFAP levels in the STZ group. The increased TGFβ and GFAP levels continued following hHFSC treatment, indicating a compensatory response. Moreover, pro-inflammatory factors (IL-1β, IL-6, and TNFα) were upregulated following hHFSC therapy, suggesting persistent neuroinflammation. hHFSC led to anti-inflammatory effects through the elevation of IL-10. In addition, hHFSCs significantly reduced hippocampal atrophy and neuronal loss induced by STZ.

CONCLUSION: hHFSCs exhibit partial neuroprotective effects against STZ-induced memory impairment. The simultaneous upregulation of pro- and anti-inflammatory markers underscores the complexity of the inflammatory response in this xenogeneic model. Future investigations should consider immunocompromised models or immunosuppressive protocols better to isolate the therapeutic effects of hHFSCs from immune responses.}, } @article {pmid41369361, year = {2025}, author = {Yu, SP and Gu, X and Jiang, MQ and Sastry, A and Wu, L and Li, Y and Wei, L}, title = {Combined Preventive and Preconditioning Treatments for the Comorbidity of Alzheimer's Disease and Ischemic Stroke in a GluN3A Knockout Mouse and a 5xFAD Mouse.}, journal = {Cells}, volume = {14}, number = {23}, pages = {}, pmid = {41369361}, issn = {2073-4409}, support = {AG067473, NS114221; RX001473 (VA); RX003865 (VA)//National Instutute of Health, USA, VA Research Administration, USA/ ; }, mesh = {Animals ; *Alzheimer Disease/prevention & control/complications ; *Ischemic Stroke/prevention & control/complications ; Mice ; *Receptors, N-Methyl-D-Aspartate/metabolism/genetics/deficiency ; Mice, Knockout ; Disease Models, Animal ; Memantine/pharmacology/therapeutic use ; Male ; Comorbidity ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) and stroke have been identified as risk factors for each other. More than half of AD patients suffer stroke attacks and worse ischemic injuries. There has been a lack of research focus and clinical treatment for the comorbidity of these neurological disorders. AD and ischemic stroke share characteristic pathophysiology, including hyperactivities of excitatory neurons and NMDA receptors (NMDARs), excitotoxicity, and synapse/neurovascular destruction. Our recent investigations identified the deficiency of the NMDAR regulatory GluN3A (NR3A) subunit as a novel pathogenesis of sporadic AD. The present investigation tested a preemptive treatment to prevent AD development in two AD models and, in the meantime, to prime the susceptible brain against upcoming ischemic attacks. In the preclinical stage of 3-month-old GluN3A KO mice, an NMDAR-mediated sporadic AD model, and 5xFAD mice, an amyloid-based familial AD model, treatments with memantine (MEM), an NMDAR antagonist (10 mg/kg/day in drinking water) and a drug-free control were started when cognition of these mice was generally normal. Three months later, the mice were subjected to focal cerebral ischemic surgery, followed by continued 1.5-2.0 months of MEM or vehicle control. Morphological, pathological, and functional assessments were performed and compared at different time points. In both AD models, the early MEM treatment confined AD progression before and after stroke, reduced ischemia-induced brain injury, suppressed neuroinflammation, and improved locomotion, sensorimotor, psychological, and cognitive functions. This is the first report endorsing a shared mechanism of NMDAR hyperactivity in AD and stroke in AD models with distinctive risk factors. The dual therapeutic effects of the preemptive MEM treatment provide a disease-modifying possibility for individuals who are susceptible to sporadic or familial AD as well as ischemic stroke.}, } @article {pmid41368712, year = {2025}, author = {He, Q and Xia, Y and Shen, Q and Huang, C and Nie, X and Hu, X and Tang, X}, title = {Relationships between sarcopenia and Alzheimer's disease: screening for mitochondria-related biomarkers.}, journal = {Computer methods in biomechanics and biomedical engineering}, volume = {}, number = {}, pages = {1-22}, doi = {10.1080/10255842.2025.2598656}, pmid = {41368712}, issn = {1476-8259}, abstract = {This study aims to identify mitochondrial-related biomarkers for sarcopenia and Alzheimer's disease (AD). Through the GEO database and machine learning algorithms, three diagnostic biomarkers (FKBP5, PRKAG1, and FBP2) were identified, and the constructed models showed good diagnostic accuracy in both internal and external datasets. Furthermore, multiple analyses such as GSEA, immune infiltration, and drug prediction were conducted. These findings provide new insights into shared pathological mechanisms and clinical diagnosis and treatment of sarcopenia and AD. Further clinical and experimental studies are needed to validate these results.}, } @article {pmid41368444, year = {2025}, author = {Pang, R and Jia, Q and Ma, C and Li, T and Bi, W and Wang, H and Liu, R and Chen, P and Lee, ES and Jiang, HB}, title = {Alzheimer's Disease: The Current and Emerging Treatment Approaches.}, journal = {Behavioural neurology}, volume = {2025}, number = {}, pages = {9627699}, pmid = {41368444}, issn = {1875-8584}, mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; Genetic Therapy/methods ; Amyloid beta-Peptides/metabolism ; Animals ; Plaque, Amyloid ; Neurofibrillary Tangles/pathology ; Plant Extracts/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease characterized by amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs) as its main pathological features. It mainly manifests as cognitive dysfunction, and its pathological process may occur before symptom onset. However, the current drugs and methods for treating AD have unsatisfactory therapeutic outcomes. Therefore, finding a treatment that can inhibit the progression of AD by targeting its pathological features is an urgent need. This review summarizes the current traditional drugs that can delay the progression of AD and new drugs that act on the pathological characteristics of AD and highlights the potential value of related plant extracts. In addition, this review explores the application of different vectors, such as viral vectors and nanoparticles, in gene therapy and drug delivery. These data will provide novel ideas for new drug development and the search for new therapeutic mechanisms.}, } @article {pmid41368288, year = {2025}, author = {Wang, X and Yang, F and Chen, P and Yang, M and Deng, Y and Zhan, Z}, title = {Mesenchymal Stem Cell-Derived Extracellular Vesicles in Alzheimer's Disease: A Novel Cell-Free Therapeutic Strategy and Diagnostic Biomarker.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {14375-14391}, pmid = {41368288}, issn = {1178-2013}, mesh = {*Alzheimer Disease/therapy/diagnosis ; *Extracellular Vesicles/metabolism/transplantation ; Humans ; *Mesenchymal Stem Cells/cytology/metabolism ; Biomarkers/metabolism/analysis ; Animals ; }, abstract = {With the ongoing trend of population aging worldwide, the incidence of Alzheimer's disease (AD) is steadily increasing. In the absence of effective therapeutic options for atypical forms of AD, reducing its prevalence and improving treatment outcomes have become pressing priorities. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have attracted growing attention as a new cell-free therapeutic approach for AD due to their high stability, low immunogenicity, and minimal tumorigenic risk. This review provides a comprehensive overview of the pathological mechanisms underlying AD, highlights the diagnostic potential of MSC-EVs, and elaborates on their therapeutic advantages and mechanisms of action. Furthermore, it addresses the key challenges and considerations associated with the clinical translation of MSC-EVs.}, } @article {pmid41367378, year = {2025}, author = {Toyli, A and Shaik, A and Zhao, C and Chen, QH and Sha, Q and Zhou, W}, title = {The heart-brain axis: unraveling the interconnections between cardiovascular and Alzheimer's diseases.}, journal = {Frontiers in cardiovascular medicine}, volume = {12}, number = {}, pages = {1685461}, pmid = {41367378}, issn = {2297-055X}, abstract = {Cardiovascular disease (CVD) and Alzheimer's disease (AD) are leading causes of death and disability worldwide, and recent research has increasingly illuminated a complex, bidirectional relationship between the two. This review synthesizes epidemiological, mechanistic, imaging, and genetic evidence linking CVD and AD through the heart-brain axis-a network of interrelated physiological and demographic pathways. We detail how cerebral hypoperfusion, inflammation, blood-brain barrier dysfunction, imbalance of the autonomic nervous system, and systemic amyloidosis contribute to shared neurodegenerative and cardiovascular outcomes. Multi-organ imaging studies, including MRI and PET, reveal that dysfunction of the cardiovascular system correlates with brain atrophy, white matter lesions, glymphatic impairment, and accumulation of AD-related proteinopathies. Genetic analyses further support overlapping risk architectures, particularly involving APOE and loci associated with lipid metabolism, vascular integrity, and inflammation. Age and sex are critical modifiers, with midlife CVD exerting the strongest influence on later cognitive decline, and sex-specific physiological responses shaping disease susceptibility. Finally, we explore how modifiable lifestyle factors, pharmacologic interventions, and precision medicine approaches targeting inflammatory and vascular pathways can jointly reduce the burden of both CVD and AD. Multidisciplinary collaboration to understand the interconnected biology of the heart and brain is essential for advancing integrated prevention and treatment strategies in aging populations.}, } @article {pmid41367129, year = {2025}, author = {Yang, C and Li, B and Yang, S and Wang, X and Zhu, G and Wang, J}, title = {Electroacupuncture Prevents Against AD-Like Phenotypes in APP/PS1 Mice: Investigation of the Mechanisms From Cerebral Microangiopathy.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {12}, pages = {e70696}, pmid = {41367129}, issn = {1755-5949}, support = {2023CXMMTCM013//Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM/ ; 2023CXMMTCM021//Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM/ ; 82474633//National Natural Science Foundation of China/ ; 202304295107020105//Anhui Provincial Key R&D Programme/ ; 2208085MH282//Anhui Natural Science Foundation/ ; 2508085MH226//Anhui Natural Science Foundation/ ; 2024AH051045//The Key project of Anhui Natural Science Research/ ; ZYJCLLYB-11//Open Fund for Key Disciplines of Basic Theory of Traditional Chinese Medicine/ ; }, mesh = {Animals ; *Electroacupuncture/methods ; Mice ; *Alzheimer Disease/prevention & control/genetics/pathology/therapy ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; Phenotype ; Cerebrovascular Circulation/physiology ; Disease Models, Animal ; Hippocampus ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Electroacupuncture (EA) has been widely used in Alzheimer's disease (AD) treatment. However, its underlying mechanisms remain poorly elucidated.

PURPOSE: This study aimed to investigate the effects of EA on AD-like phenotypes and explore the mechanisms.

METHODS: We first evaluated AD-like behaviors and cerebral blood flow (CBF) changes in APPswe/PS1dE9 (APP/PS1) mice at different ages. Subsequently, the therapeutic effects of EA at acupoints Baihui (GV20), Guanyuan (CV4), and Zusanli (ST36), as well as sunitinib, a PDGFRβ-specific inhibitor, on AD-like phenotypes in APP/PS1 mice were investigated. CBF was monitored by laser speckle imaging, and hippocampal synaptic ultrastructure and microvascular morphology were examined by transmission electron microscopy (TEM). Western blot was performed to measure related protein expression. Finally, functional ultrasound (fUS) imaging was used to assess changes in brain-wide functional connectivity.

RESULTS: Compared with age-matched wild-type (WT) mice, 6- and 9-month-old APP/PS1 mice exhibited significant cognitive decline, while all age groups (3-, 6-, and 9-month-old) of APP/PS1 mice showed significantly reduced CBF. APP/PS1 mice showed elevated expression of microvascular markers in both the hippocampus and cortex. EA significantly ameliorated AD-like behaviors and prevented CBF reduction as well as microvascular deformation in 6-month-old APP/PS1 mice compared with non-treatment group. TEM and western blot analysis revealed damaged synaptic structure and reduced synaptic proteins in APP/PS1 mice, all of which were markedly alleviated by EA treatment. In addition, EA treatment downregulated the aberrantly elevated expression of PDGFRβ and CD31, enhanced the levels of tight junction proteins (Occludin, Claudin-5, and ZO-1) and glucose transporter 1 (GLUT1), and suppressed the expression of inflammatory proteins. Of note, intervention with sunitinib also improved AD-like behaviors in APP/PS1 mice. Remarkably, fUS imaging results showed that EA enhanced the functional connection between hippocampal regions of APP/PS1 mice.

CONCLUSION: Our data demonstrates that EA ameliorates AD-like phenotypes, potentially through preventing microangiopathy.}, } @article {pmid41366853, year = {2025}, author = {Lin, Z and Hong, Y and Hu, Y and Xiao, Q and Peng, SL and Wu, D and Guo, T and Jiang, D}, title = {White matter hyperintensity modulates the amyloid-tau-cognition association and anti-amyloid treatment efficacy in asymptomatic older adults.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70990}, pmid = {41366853}, issn = {1552-5279}, support = {//National Institutes of Health-National Institute on Aging/ ; //Eli Lilly and Company/ ; /ALZ/Alzheimer's Association/United States ; //Accelerating Medicines Partnership/ ; //GHR Foundation/ ; 82302144//National Natural Science Foundation of China/ ; 62401363//National Natural Science Foundation of China/ ; 24PJA047//Shanghai Pujiang Program/ ; //Xiaomi Young Scholar Program/ ; }, mesh = {Humans ; *White Matter/pathology/diagnostic imaging ; Male ; Female ; Aged ; *tau Proteins/metabolism ; *Cognitive Dysfunction/pathology/diagnostic imaging/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/drug therapy/pathology/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; Aged, 80 and over ; *Cognition ; Treatment Outcome ; }, abstract = {INTRODUCTION: White matter hyperintensities (WMH), a key imaging biomarker of small vessel injury, may play a complex role in Alzheimer's disease (AD). We hypothesize that WMH not only directly contributes to cognitive decline but also moderates the relationship among AD pathology, treatment, and cognitive decline.

METHODS: A total of 1169 participants with 240-week follow-up in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were analyzed. Linear regression models examined WMH's contribution to cognitive decline, its interaction with Aβ on p-Tau217 level, and its interaction with anti-amyloid treatment on cognitive decline.

RESULTS: Increase in WMH volume independently contributed to cognitive decline (p = 0.0028). Baseline WMH significantly moderated the relationship between Aβ change and p-Tau217 change (p = 0.0035). Specifically, Aβ accumulation correlated with p-Tau217 increase only in participants with low baseline WMH. WMH growth was associated with cognitive decline only in the treatment group (p < 0.0001).

DISCUSSION: WMH modulates the interplay of pathologies, emphasizing the need for comprehensive treatment approaches targeting multiple pathways.

HIGHLIGHTS: White matter hyperintensity (WMH) independently contributed to cognitive decline. WMH modulated the longitudinal relationship between Aβ and p-Tau217. WMH interacted with anti-amyloid treatment on longitudinal cognitive decline.}, } @article {pmid41366831, year = {2025}, author = {Moretti, DV and Kuhn, E and Dubbelmann, MA and Sikkes, SAM and Castilhos, RM and Chapman, S and Gifford, KA and Butterbrod, E and Nosheny, RL and , }, title = {Clinical definition, biological characterization, and detection guidelines of subjective cognitive decline due to Alzheimer's disease and related dementia: A position paper from ISTAART SCD PIA.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70847}, pmid = {41366831}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease/diagnosis/complications/psychology ; Biomarkers ; *Cognitive Dysfunction/diagnosis/etiology/psychology ; Neuropsychological Tests ; }, abstract = {Subjective cognitive decline (SCD)-self-perceived cognitive worsening without objective deficits-has emerged as a clinically meaningful, potential early manifestation of Alzheimer's disease (AD). Positioned at the intersection of normal aging, neuropsychiatric symptoms, and preclinical neurodegeneration, SCD offers a unique window for early detection and intervention. However, detection heterogeneity, variable prognostic trajectories, and limited equity in assessment hinder its full clinical utility. This position paper synthesizes current evidence on SCD's diagnostic complexity, neurobiological underpinnings, and modifiable influences. We highlight the need for harmonized assessment frameworks, scalable digital tools, inclusive research, and ethically grounded biomarker disclosure practices. Importantly, we advocate for personalized, (non-)pharmacological interventions targeting this early phase. By refining the conceptualization and operationalization of SCD, we can better identify individuals at heightened AD risk and deliver timely, equitable, and meaningful prevention strategies. SCD represents a pivotal inflection point in the dementia continuum-and a call to shift toward proactive brain health. HIGHLIGHTS: Subjective cognitive decline (SCD) may signal early-stage Alzheimer's despite normal test performance. Diagnostic heterogeneity limits current clinical and research utility. Biomarkers and digital tools could enhance risk stratification in SCD. Mental health and social context shape symptom reporting and outcomes. SCD offers a window for tailored (non-drug) preventive interventions.}, } @article {pmid41366707, year = {2025}, author = {Feng, Y and Wang, S and Xia, H and Jiang, X and Wu, M and Pan, S and Song, W}, title = {Meningeal lymphatics as a therapeutic target for neurodegenerative disorders.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {65}, pmid = {41366707}, issn = {2047-9158}, support = {82230043//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Meninges/immunology/pathology ; *Neurodegenerative Diseases/immunology/therapy/drug therapy/pathology ; *Lymphatic Vessels/immunology/pathology ; Animals ; Brain ; Glymphatic System ; }, abstract = {Advancements in visualization methods have brought the meningeal lymphatic system (MLS) into the spotlight. The meningeal lymphatic vessels (mLVs) play a vital role in draining cerebrospinal fluid and immune cells, acting as a central hub for immune surveillance in the brain. Age-related morphological and functional declines of mLVs suggest their involvement in the pathogenesis of neurodegenerative disorders (NDDs). In this article, we summarize key discoveries about the MLS over the past decade, highlight the neuro-immune crosstalk in the meninges, and discuss the role of mLVs in both brain homeostasis and neurodegeneration. As a critical regulator of brain function and a potential therapeutic target, the MLS offers a promising avenue for the diagnosis and treatment of NDDs, particularly Alzheimer's Disease.}, } @article {pmid41366593, year = {2025}, author = {Lee, WJ and Cho, K and Lee, D and Lee, S and Kim, GW}, title = {Therapeutic Efficacy of Autologous Blood-Derived Stem Cells with Growth Factors in Moderate to Severe Alzheimer's Disease: A Clinical Trial.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {277}, pmid = {41366593}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/therapy/diagnostic imaging ; Male ; Female ; Aged ; Treatment Outcome ; *Intercellular Signaling Peptides and Proteins/therapeutic use ; Transplantation, Autologous ; Brain/diagnostic imaging/metabolism/pathology ; *Stem Cell Transplantation/methods ; *Severity of Illness Index ; *Stem Cells/cytology ; Cognition ; Aged, 80 and over ; }, abstract = {Alzheimer's disease (AD) is characterized by cognitive decline, memory loss, and a gradual loss of daily functioning. Unfortunately, despite extensive research, effective treatments for AD remain limited. Of these, stem cell-based therapies show promise for their regenerative potential and ability to modulate pathological processes. Autologous blood-derived stem cells (ABSCs), which are isolated from a patient's own blood, have demonstrated therapeutic efficacy in AD. This clinical study evaluated the safety and efficacy of ABSCs on patients with AD and investigated the changing levels of growth factors derived from ABSCs treatment. The efficacy of the treatment on cognitive function was assessed using the Mini-Mental State Examination, Clinical Dementia Rating, and AD Assessment Scale-Cognitive Subscale, all widely used tools to assess cognitive function in patients with AD. The neuroimaging and molecular mechanisms were the secondary outcomes. The neuroimaging examinations performed included PET-CT with amyloid imaging, for assessing amyloid plaque deposition in the brain at baseline and at 3 and 6 months after treatment; FDG-PET, for measuring brain glucose metabolism and acquiring insights into neuronal activity and overall brain function; and MRI, performed at baseline and follow-up, for assessing structural brain changes. ABSCs treatment resulted in notable improvements in cognitive function, reductions in amyloid plaque burden, and improved neuroimaging outcomes. Autologous stem cell therapy also reduced the risk of immune rejection, offering a safety advantage over allogeneic stem cell therapies. Furthermore, the use of growth factors to enhance stem cell efficacy aligns with existing research demonstrating improvements in stem cell limitations. This study provides compelling evidence that ABSCs combined with growth factors exhibit significant therapeutic potential for patients with moderate to severe AD. Our findings indicate that our current combination treatment may offer a multi-target approach to addressing the complex pathogenesis of neurodegenerative diseases and is thereby a potentially sustainable therapeutic strategy for AD. Furthermore, the combination of ABSCs with growth factors can potentially provide a much-needed therapeutic alternative for AD.}, } @article {pmid41365480, year = {2026}, author = {Majumder, M and Dutta, D and Paidi, RK and Pahan, K}, title = {Activation of PPARα by gemfibrozil lowers tau-associated neuropathology in the MAPT mouse model of Alzheimer's disease.}, journal = {Brain research}, volume = {1873}, number = {}, pages = {150089}, doi = {10.1016/j.brainres.2025.150089}, pmid = {41365480}, issn = {1872-6240}, mesh = {Animals ; *Gemfibrozil/pharmacology ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *tau Proteins/metabolism/genetics ; *PPAR alpha/metabolism/genetics/agonists ; Disease Models, Animal ; Mice, Transgenic ; Mice ; Hippocampus/metabolism/drug effects/pathology ; Neurons/metabolism/drug effects/pathology ; Tauopathies/metabolism/drug therapy/pathology ; Gliosis ; Male ; Humans ; Phosphorylation/drug effects ; }, abstract = {The current dogma states that inhibiting tau accumulation and its associated neuropathologies might be a relevant strategy to prevent neuronal loss and cognitive dysfunction in Alzheimer's disease (AD). The present study demonstrates the therapeutic potential of an FDA-approved lipid lowering drug and an agonist of peroxisome proliferator and activated receptor α (PPARα), called gemfibrozil, in reducing tau accumulation and associated neuropathologies in the MAPT (PS19) mouse model of AD, expressing P301S mutated form of human tau protein in neurons. Daily oral treatment of gemfibrozil in MAPT mice reduced total tau and phosphorylated form of tau in the hippocampal subregions including CA1 and DG. Concurrently, gemfibrozil treatment upregulated PPARα level in the hippocampus and that was accompanied with inhibition of microgliosis and astrogliosis. Gemfibrozil also attenuated the loss of synaptic plasticity as determined by the expression of post-synaptic protein, PSD95, and calcium influx in the hippocampal tissue. The instrumental role of PPARα in gemfibrozil-mediated reduction of tauopathy was confirmed as PPARα deficiency in MAPT mice significantly augmented tau and phospho-tau accumulation in the hippocampus and gemfibrozil treatment failed to reverse tau pathology and gliosis in the brain of PPARα deficient MAPT mice. Lastly, gemfibrozil improved the cognitive function of MAPT mice during the symptomatic phase of disease progression, but it failed to reverse cognitive impairment in the PPARα deficient MAPT mice. These data suggest that neuroprotective effects of gemfibrozil in MAPT mice is mediated by PPARα. Moreover, targeting PPARα by small molecules like gemfibrozil may hold translational potential against tauopathy.}, } @article {pmid41365196, year = {2025}, author = {Zhang, X and Yang, J and Xiao, M and Zhang, J and Cai, C and Wei, W and Fang, S and Ren, X and Guo, K and Yang, P and Wang, W and Hu, Y and Fang, J}, title = {Yangxue Qingnao Wan ameliorates cognitive impairment in scopolamine-induced AD mice via modulating neuropeptide signaling pathways and suppressing neuroinflammation.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {150}, number = {}, pages = {157602}, doi = {10.1016/j.phymed.2025.157602}, pmid = {41365196}, issn = {1618-095X}, abstract = {BACKGROUND: Alzheimer's disease (AD), a fatal neurodegenerative disorder with increasing incidence worldwide, remains a significant therapeutic challenge. Yangxue Qingnao Wan (YXQNW), a traditional Chinese medicine, has shown promise in AD treatment. However, its intricate mechanism of action necessitates further investigation. Clarifying YXQNW's active components and molecular targets could advance novel therapeutic strategies for AD.

PURPOSE: This research aimed to identify anti-AD bioactive compounds in YXQNW and investigate their mechanisms using transcriptomic profiling and network proximity analysis.

METHODS: The neuroprotective effects of YXQNW were evaluated in scopolamine (SCOP)-induced AD mice through behavioral tests, histopathological assessments, and biochemical analyses (acetylcholinesterase activity, oxidative stress markers and pro-inflammatory cytokines). Transcriptomic analysis was employed to explore YXQNW's regulatory targets and pathways. Key targets were validated by RT-qPCR, immunofluorescence (IF) and Western blot. Network proximity was used to predict anti-AD components, followed by in vitro mechanism validation in SCOP-induced HT22 cells using Gpr139 agonist and antagonist.

RESULTS: YXQNW ameliorated spatial memory deficits, cholinergic dysfunction, oxidative stress, and neuroinflammation in vivo. Transcriptomics analysis uncovered significantly modulation of neuropeptide signaling pathways, including upregulation of Gpr139 and downregulation of Gal/Galr1, mitigating cognitive impairment. Network proximity identified 8 anti-AD components, with Palmatine, Ligustilide, and Obtusifolin demonstrating efficacy in reducing oxidative stress, inflammation, and neuronal damage in vitro, and could also regulate the expression of neuropeptides. Moreover, Palmatine inhibits neuroinflammation via regulating Gpr139 protein expression.

CONCLUSIONS: YXQNW alleviates AD-like pathology by restoring cholinergic homeostasis, suppressing oxidative stress and neuroinflammation, and regulating neuropeptide signaling. And its active ingredient (Palmatine) can inhibit inflammatory response by regulating the expression of Gpr139 protein. This study supports YXQNW's clinical application and provides novel insights for AD drug discovery.}, } @article {pmid41365116, year = {2025}, author = {Taj, T and Kaushik, M and Islam, A and Das, J and Kumar, B and Hussain, MS and Ramzan, M and Ashique, S and Tariq, M and Sridhar, SB and Yasmin, S and Panigrahy, UP and Malik, T and Ansari, MY}, title = {Microbiota-brain interaction: The role of gut-derived proteins in addressing various neurological disorders including Parkinson's (PD) and Alzheimer's diseases (AD).}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {193}, number = {}, pages = {118861}, doi = {10.1016/j.biopha.2025.118861}, pmid = {41365116}, issn = {1950-6007}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Brain/metabolism/physiopathology ; Animals ; *Parkinson Disease/microbiology/metabolism/physiopathology ; *Alzheimer Disease/microbiology/metabolism/physiopathology ; Probiotics ; Dysbiosis ; *Nervous System Diseases/microbiology ; }, abstract = {The microbiota-brain interaction is a complex network connecting gut microbiota to the enteric nervous system (ENS) and the central nervous system (CNS) that are crucial for neurotransmission and neurological health. Metabolites such as short-chain fatty acids (SCFA), neurotransmitters, and neuromodulators from the gut microbiota influence behavior and brain function. This review focuses on the study related with gut bacteria, including Bifidobacterium infantis and Lactobacillus species, producing various metabolites in gut including bile acids, SCFA, histamine, and others to communicate with the brain or CNS. Dysbiosis can lead to neurological conditions such as anxiety, depression, PD, and AD. SCFAs from gut bacteria bind to the free fatty acid receptors of intestinal epithelial cells (IECs), affecting neurones and influencing neuroactivity. Gut bacteria also produce neurotransmitters that regulate growth hormone release through interactions with the CNS and endocrine systems. Brain signals interact directly with the pituitary and adrenal glands through the hypothalamic-pituitary-adrenal (HPA) axis, which in turn communicates with enteroendocrine cells (EECs). Investigating probiotics, prebiotics, and dietary changes could open new avenues for treatment for mental and neurological problems.}, } @article {pmid41365088, year = {2026}, author = {Shi, Y and Zhang, H and Cong, S and Zhu, X and Liu, Y and Li, J and Tang, K and Xue, R and Liu, X and Tan, Z and Chen, J and Deng, Y}, title = {Benzylpiperidine-pyridazin-3(2H)-one derivatives as potential multifunctional agents against Alzheimer's disease.}, journal = {European journal of medicinal chemistry}, volume = {303}, number = {}, pages = {118437}, doi = {10.1016/j.ejmech.2025.118437}, pmid = {41365088}, issn = {1768-3254}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Animals ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; Structure-Activity Relationship ; Humans ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Mice ; *Piperidines/chemistry/pharmacology/chemical synthesis ; *Pyridazines/chemistry/pharmacology/chemical synthesis ; *Antioxidants/pharmacology/chemistry/chemical synthesis ; Molecular Structure ; Acetylcholinesterase/metabolism ; Dose-Response Relationship, Drug ; Peptide Fragments/antagonists & inhibitors/metabolism ; Male ; Protein Aggregates/drug effects ; }, abstract = {Based on multitarget-directed-ligands (MTDLs) strategy, a series of benzylpiperidine-pyridazin-3(2H)-ones were designed, synthesized and evaluated as innovative multifunctional agents for Alzheimer's disease (AD). Biological evaluation revealed that most compounds exhibited excellent acetylcholinesterase (AChE) inhibition, potent antioxidant activity and moderate β-amyloid (Aβ1-42) aggregation inhibition. Among them, compound 7a emerged as a synergistic multifunctional agent with significant inhibition of AChE (EeAChE: IC50 = 0.21 μM; HsAChE: IC50 = 13 nM) and anti-Aβ activity (IC50 = 2.92 μM for self-induced Aβ1-42 aggregation; IC50 = 1.28 μM for disaggregation of Aβ1-42 fibrils; IC50 = 3.72 μM for Cu[2+]-induced Aβ1-42 aggregation; IC50 = 2.16 μM for disaggregation of Cu[2+]-induced Aβ1-42 fibrils). In addition, 7a was endowed with the potential to serve as antioxidant (2.88 Trolox equivalents), metals chelator and anti-neuroinflammatory agent for synergistic treatment. Moreover, 7a exhibited pronounced neuroprotective effects across multiple cellular models. Pharmacokinetically, 7a displayed favorable brain penetration (AUCbrain/plasma = 0.77) and sustained exposure. In vivo evaluation demonstrated that 7a effectively ameliorated scopolamine-induced cognitive impairment in the Morris water maze, which was associated with restored cholinergic function and mitigated oxidative stress in mice. The synergistic multi-target efficacy combined with favorable pharmacokinetic properties underscores its potential as a disease-modifying therapeutic agent for AD.}, } @article {pmid41364547, year = {2026}, author = {Kim, SR and Kim, SK and Kobayashi, H and Nishikawa, H}, title = {Efficacy of MR Imaging Findings in Clinical Management of Hepatic Encephalopathy and Alzheimer's Disease.}, journal = {Hepatology research : the official journal of the Japan Society of Hepatology}, volume = {56}, number = {1}, pages = {11-20}, doi = {10.1111/hepr.70091}, pmid = {41364547}, issn = {1386-6346}, abstract = {In the aging society, distinguishing hepatic encephalopathy (HE) from Alzheimer's disease (AD) poses significant clinical challenges attributed to overlapping neuropsychiatric symptoms including memory loss, disorientation, and impaired daily functioning. Traditional diagnostic approaches relying on clinical assessment and biochemical markers often prove insufficient, necessitating advanced neuroimaging techniques for differential diagnosis. This review examines magnetic resonance imaging (MRI) techniques for differential diagnosis of HE and AD, focusing on T1-weighted imaging findings characteristic of HE, and voxel-based specific regional analysis system (VSRAD) applications in AD diagnosis. Analysis of the literature encompassed peer-reviewed articles examining neuroimaging patterns, diagnostic accuracy, and clinical correlations in both HE and AD. T1-weighted MRI displays bilateral symmetric hyperintensity at the globus pallidus in 70%-90% of HE patients attributed to manganese deposition secondary to impaired hepatic clearance, and provides evidence of HE-related brain changes independent of ammonia levels. VSRAD analysis reveals characteristic medial temporal lobe atrophy patterns in AD, with diagnostic accuracy rates of 91.6% for very mild, 95.8% for mild, and 98.2% for moderate-to-severe AD. Clinical studies demonstrate that brain atrophy detected by VSRAD correlates significantly with functional impairment in activities of daily living, independent of conventional liver function parameters. The integration of T1-weighted MRI and VSRAD analysis provides enhanced diagnostic accuracy for differentiating HE-associated cognitive impairment from primary neurodegenerative conditions, offering valuable prognostic information regarding functional capacity and cognitive trajectory. This systematic neuroimaging approach enables more precise therapeutic decision-making, signals treatment expectations, and directs rehabilitation planning and long-term care strategies in an aging population with increasing prevalence of both hepatic and neurodegenerative disorders.}, } @article {pmid41364455, year = {2025}, author = {Nakamura, Y and Kurokawa, T and Terashima, S and Nishimura, A}, title = {Efficacy and safety of a novel, extended-release rivastigmine transdermal patch (TW-4752N) in patients with Alzheimer's disease: A 24-week randomized, double-blind trial with a 28-week open-label extension.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251401601}, doi = {10.1177/13872877251401601}, pmid = {41364455}, issn = {1875-8908}, abstract = {BackgroundRivastigmine may offer greater efficacy and convenience of use with a novel formulation than previously reported.ObjectiveTo evaluate the efficacy and safety of a novel, twice-weekly rivastigmine patch (TW-4752N) (TW) in Alzheimer's disease (AD) patients with mild to moderate dementia.MethodsThis was a multicenter, phase III, double-blind study comparing TW and an existing rivastigmine transdermal patch (RT) with an open-label extension. The primary endpoint was the change in ADAS-Jcog total score at week 24 from baseline. Secondary endpoints included the ADAS-Jcog total score at weeks 8, 16, and 24.ResultsA total of 354 and 362 patients were available for efficacy and safety analysis, respectively. Changes in ADAS-Jcog total score at week 24 from baseline were similar between the two groups in the full analysis set with an intergroup difference of -0.84 ± 0.44 (95% CI, -1.695 to 0.016) and with the upper limit of the 95% CI being below the non-inferiority margin of 1.1, demonstrating the non-inferiority of TW. However, analysis of the per-protocol set demonstrated a significant intergroup difference in favor of TW likely suggesting a greater treatment effect with TW than with RT (p = 0.032). Adverse events (AEs) reported in ≥3% of patients were similar between the groups, with the only AE with an intergroup difference of ≥10% in incidence being application site pruritus (TW/RT, 27.6%/17.1%).ConclusionsTW represents a viable alternative option of interest to patients with AD, providing comparable or potentially greater efficacy than RT and comparable safety, as well as greater convenience of use.}, } @article {pmid41362973, year = {2025}, author = {Burd, SG and Bogolepova, AN and Lebedeva, AV and Rubleva, YV and Kovalenko, EA and Makhnovich, EV and Osinovskaya, NA and Gileva, EA and Pantina, NV and Kovaleva, II and Efimenko, AP and Bokitko, TA and Alekseeva, GA}, title = {[Epileptic seizures in patients with Alzheimer's disease].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {125}, number = {11}, pages = {36-43}, doi = {10.17116/jnevro202512511136}, pmid = {41362973}, issn = {1997-7298}, mesh = {Humans ; *Alzheimer Disease/complications/epidemiology ; *Epilepsy/epidemiology/etiology/diagnosis/drug therapy ; Risk Factors ; Prevalence ; }, abstract = {Neurodegenerative diseases are one of the leading causes of epileptic seizures with onset in later life. Particular attention is paid to Alzheimer's disease (AD), as a disease that accounts for up to 70% of cases of all types of dementia, and, according to the literature, shares genetic and pathophysiological mechanisms with epilepsy. This paper reviews the literature on the prevalence of epilepsy in AD patients. The reasons for the widely varying data (ranging from 0.5 to 64%) depending on the selected population, the reliability of the established diagnosis, the form and genetic characteristics of the disease, as well as the examination methods used, are considered. The main risk factors for the development of AD and epilepsy, semiotics and features of seizures in patients with AD, as well as approaches to the treatment of such patients, are also covered.}, } @article {pmid41362151, year = {2025}, author = {Jafari, EA and Alshahawey, M and Zaman, MA and Smith, SM and Gong, Y and Smith, GE and McDonough, CW}, title = {Characterizing Alzheimer's Disease and Related Dementia in a Hypertension Population Within the State of Florida Using Electronic Health Record-Based Data.}, journal = {Clinical pharmacology and therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1002/cpt.70150}, pmid = {41362151}, issn = {1532-6535}, support = {NIH P30 AG066506//1Florida Alzheimer's Disease Research Center/ ; K01 HL141690/GF/NIH HHS/United States ; R03 HL172123/GF/NIH HHS/United States ; R03 HL172987/GF/NIH HHS/United States ; AG066506/GF/NIH HHS/United States ; CDRN-1501-26692/PCORI/Patient-Centered Outcomes Research Institute/United States ; RI-CRN-2020-005/PCORI/Patient-Centered Outcomes Research Institute/United States ; RI-FLORIDA-01-PS1/PCORI/Patient-Centered Outcomes Research Institute/United States ; UL1TR001427//NIH National Center for Advancing Translational Sciences/ ; UL1TR000064//NIH National Center for Advancing Translational Sciences/ ; }, abstract = {Hypertension is a known modifiable risk factor for Alzheimer's disease and related dementia (ADRD). However, it is unknown how variance in hypertension control, antihypertensive medications, and social determinants of health, such as social deprivation index (SDI), influence the risk of developing ADRD. Validated hypertension computable phenotype algorithms were applied to electronic health record data from the OneFlorida Data Trust (1/1/2013-12/31/2016), to identify apparent treatment-resistant hypertension (aTRH), and hypertension-control levels (well-controlled hypertension, intermediate-controlled hypertension, uncontrolled hypertension). The primary outcome was a new ADRD diagnosis using validated ICD-9/10 codes. Multiple adjusted stepwise logistic regression models were used to identify factors associated with ADRD development. ADRD cumulative hazard incidence per hypertension control levels was assessed using the Nelson-Aalen estimator and log-rank test. A total of 57,273 hypertension patients with 6401 (11%) incident ADRD cases were included in the analysis. The average age was 67 years, with 57% females and 32% identifying as Black or African American. aTRH was a significant ADRD predictor (OR: 1.327, 95% CI: 1.234-1.427), compared to other hypertension phenotypes. aTRH was also significantly associated with a higher incidence of ADRD over time (P < 0.0001). Patients prescribed thiazide diuretics (OR: 0.894, 95% CI: 0.837-0.956) and fixed-dose combination medications (OR: 0.804, 95% CI: 0.732-0.882) had a lower risk of ADRD. A linear relationship between SDI quartiles and ADRD risk was found. aTRH was significantly associated with the development of ADRD. Our study also highlights the importance of comprehensive hypertension control and socioeconomic interventions in preventing or reducing ADRD risk in hypertension patients.}, } @article {pmid41360503, year = {2025}, author = {Li, G and Li, P and Huang, L and Zhu, J and Qin, X and Lu, Y}, title = {[Protective effects of quercetin, the key component of Zuo Gui Wan, against Alzheimer's disease via the PI3K/AKT pathway: insights from network pharmacology, molecular docking, and cell experiments].}, journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences}, volume = {}, number = {}, pages = {1-12}, doi = {10.3724/zdxbyxb-2025-0661}, pmid = {41360503}, issn = {1008-9292}, abstract = {OBJECTIVES: To investigate the protective mechanism of quercetin, the core component of Zuo Gui Wan, against Alzheimer's disease through the PI3K/AKT signaling pathway, based on network pharmacology, molecular docking, and cell experi-ments.

METHODS: The active components of Zuo Gui Wan were identified by searching TCMSP, PubChem, Swiss Target Prediction, and BATMAN-TCM databases, and their potential targets were predicted. The target information was standardized using Uniprot, and Alzheimer's disease-related target genes were obtained from Drugbank, GeneCards, and OMIM. The intersection of these datasets was used to identify the potential targets of Zuo Gui Wan for treating Alzheimer's disease. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. The protein-protein interaction (PPI) network of potential targets was visualized using Cytoscape 3.10.1 software and the STRING database. The key active compounds and core potential targets for treating Alzheimer's disease with Zuo Gui Wan were identified through calculation. Based on the enrichment analysis results and literature, quercetin and the PI3K/AKT pathway were selected for verification. Molecular docking and binding ability prediction between quercetin and the core target AKT were performed using CB-Dock2, and visualization was conducted with AutoDock and PyMOL software. Finally, Aβ1-42-induced HT-22 mouse hippocampal neuronal cells were used to construct an Alzheimer's disease cell model. Quercetin, the PI3K inhibitor LY294002, and the activator EGF were used as interventions. The groups were divided as follows: Control, Aβ1-42, Aβ1-42+Quercetin 2.5 μM, Aβ1-42+Quercetin 5 μM, Aβ1-42+Quercetin 10 μM, Aβ1-42+EGF, and the PI3K/AKT modulation group: Control, LY294002, LY294002+Quercetin 10 μM, LY294002+EGF. CCK-8 assays were performed to detect cell viability, while JC-1, Calcein AM-PI, and Hoechst staining were used to assess cell apoptosis. Western blotting was employed to detect the expression of relevant target proteins.

RESULTS: Network pharmacology and cell experiments collectively demonstrate that the key active ingredient of Zuo Gui Wan, quercetin, targets core proteins such as AKT1 and GSK3β through a network-based approach, significantly enriching the PI3K/AKT pathway. Molecular docking results indicate that quercetin has a strong binding affinity with AKT. Experimental validation in the Aβ1-42 oligomer-induced HT-22 model reveals that quercetin significantly activates the PI3K/AKT signaling pathway, which is inhibited by Aβ1-42 oligomers, as well as Bcl-2 protein expression. It also suppresses the expression of Cleaved Caspase 3/Caspase 3, BAX, and Cytochrome C proteins. JC-1, Hoechst 33342, and Calcein AM-PI staining results further show that quercetin can significantly alleviate apoptosis induced by Aβ1-42 oligomers in HT-22 cells. Treatment with the PI3K inhibitor LY294002 in HT-22 cells leads to reduced cell viability and decreased expression of p-AKT/AKT and Bcl-2 proteins, while increasing the expression of Cleaved Caspase 3/Caspase 3, BAX, and Cytochrome C proteins. Additionally, apoptosis levels increase as observed in JC-1, Hoechst 33342, and Calcein AM-PI staining, all of which can be reversed by quercetin and the PI3K agonist EGF.

CONCLUSIONS: Quercetin, the key active ingredient of Zuo Gui Wan, exerts its protective effects against Alzheimer's disease by regulating the PI3K/AKT signaling pathway, inhibiting neuronal cell damage and apoptosis.}, } @article {pmid41360445, year = {2025}, author = {Menczel Schrire, Z and Mitchell, HF and Low, LF and Espinosa, N and Eames, P and Toltz, J and Walsh, P and Mowszowski, L and Espinoza, D and Lin, CS and Peres Da Costa, N and Naismith, SL}, title = {NeuroMusic: protocol for a randomised-controlled trial of keyboard and singing music training programmes for older adults with mild cognitive impairment.}, journal = {BMJ open}, volume = {15}, number = {12}, pages = {e104158}, pmid = {41360445}, issn = {2044-6055}, mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Music Therapy/methods ; Aged ; Single-Blind Method ; *Singing ; Randomized Controlled Trials as Topic ; *Music ; Cognition ; Neuronal Plasticity ; Australia ; Female ; Male ; }, abstract = {INTRODUCTION: Music-based training programmes, such as learning how to play an instrument or sing in a choir, have been suggested as potential interventions for promoting healthy brain ageing in older adults at risk of cognitive decline because of their ability to enhance cognitive functions and potentially promote neuroplasticity. However, there is limited empirical evidence in older adults at risk of dementia, especially that evaluates both piano and singing interventions and their effects on cognition and neuroplasticity. In this protocol, we outline a study to assess the efficacy of keyboard and singing music training programmes on reducing cognitive decline and other outcomes in older adults with Mild Cognitive Impairment (MCI).

METHODS AND ANALYSIS: This randomised, single-blind, controlled, parallel-group trial aims to enrol 432 individuals with MCI from the community in Sydney, Australia. Participants are randomly allocated to participate in either keyboard lessons, singing lessons or a film discussion control group once a week for 3 months. The primary objective is to assess the effectiveness of two music training programmes (keyboard and choral singing) for enhancing verbal memory after 3 months compared with control. Additionally, we will examine how these music-based interventions affect other aspects of cognition, mood, sleep, overall well-being, markers of brain plasticity and blood biomarkers of Alzheimer's disease and neurodegeneration. Tertiary objectives are to identify factors that impact the success of the interventions, such as participation rates, engagement levels and key demographic and clinical features. Outcomes are collected at baseline and at 3 and 9 months. The primary endpoint analysis will include all randomised participants to estimate the treatment effect using intention-to-treat principles. Primary and secondary outcomes will be analysed using linear mixed models and effect size measures will be calculated.This study will be the first robust, randomised controlled trial to assess the potential and relative value of music engagement for cognitive decline in high-risk MCI individuals, as well as broader effects on other markers of mental health, well-being and neurodegeneration. Co-designed with implementation in mind, the music interventions can potentially be delivered within memory clinic or community settings.

ETHICS AND DISSEMINATION: The Sydney University Human Research Ethics Committee (2023-026) has approved this protocol. The trial findings will be shared through conferences, publications and media.

TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12623000407695), Registered 21/04/2023 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385552 PROTOCOL VERSION: 2.02 29/11/2024.}, } @article {pmid41359976, year = {2025}, author = {Pan, L and Song, X and Su, G and Gandy, LA and Fang, B and Buttaci, M and Gibson, J and Xia, K and Zhang, F and Liu, J and Wang, L and Temple, S and Wang, C}, title = {N-Sulfated Heparan Sulfate Promotes Reelin Signaling as a Co-receptor.}, journal = {Journal of the American Chemical Society}, volume = {147}, number = {51}, pages = {46773-46779}, pmid = {41359976}, issn = {1520-5126}, mesh = {Reelin Protein ; *Heparitin Sulfate/metabolism/chemistry ; *Cell Adhesion Molecules, Neuronal/metabolism/chemistry ; *Serine Endopeptidases/metabolism/chemistry ; *Extracellular Matrix Proteins/metabolism/chemistry ; *Nerve Tissue Proteins/metabolism/chemistry ; Humans ; *Signal Transduction ; HEK293 Cells ; Animals ; }, abstract = {Heparan sulfate (HS) plays a central role in signal transduction, while Reelin is an essential signaling protein in both the developing and adult brain. A Reelin COLBOS variant was recently discovered with enhanced HS binding and resilience against autosomal dominant Alzheimer's disease (ADAD), underscoring the importance of Reelin-HS interactions. However, the glycan determinants of Reelin-HS interactions have not been well-characterized, which we systematically investigated here. Surface plasmon resonance (SPR) showed that full length Reelin binds HS with high affinity (KD = 17 ± 5 nM), which is enhanced by the COLBOS variant (KD = 10 ± 2 nM). Competition SPR and glycan array studies further revealed that HS N-sulfation is critical for Reelin-HS binding, consistent with Haddock modeling. In cell surface binding assays, heparinase treatment, which degrades HS, or the knockout of a key HS N-sulfation enzyme (NDST1) significantly reduced Reelin attachment. Functionally, a cellular split-luciferase assay showed that heparinase treatment or adding heparin in culture medium reduces Reelin-induced ApoER2 dimerization, demonstrating that HS is a coreceptor for Reelin receptor activation. In contrast, N-desulfated heparin does not inhibit Reelin receptor dimerization. Our work establishes HS as a coreceptor for Reelin signaling and N-sulfation as a key glycan determinant of Reelin-HS recognition. Our work provides mechanistic insights into diverse neurodevelopmental and neurodegenerative diseases associated with Reelin signaling and suggests novel therapeutic strategies targeting HS sulfation.}, } @article {pmid41359335, year = {2025}, author = {Cantoni, V and Casula, EP and Tarantino, B and Cupidi, C and Huber, N and Altomare, D and Premi, E and Zummo, E and Esposito, R and Leonardi, C and Herukka, SK and Solje, E and Ferrari, A and Cotelli, MS and Gasparotti, R and Martorana, A and Fracassi, C and Santarnecchi, E and Koch, G and Haapasalo, A and Grassi, M and Benussi, A and Borroni, B}, title = {Home-Based Gamma Transcranial Alternating Current Stimulation in Patients With Alzheimer Disease: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {8}, number = {12}, pages = {e2546556}, pmid = {41359335}, issn = {2574-3805}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology ; Male ; Female ; *Transcranial Direct Current Stimulation/methods ; Aged ; Double-Blind Method ; Middle Aged ; Feasibility Studies ; Treatment Outcome ; Italy ; Electroencephalography ; Aged, 80 and over ; }, abstract = {IMPORTANCE: Alzheimer disease (AD) is characterized by dysregulated gamma brain oscillations. Transcranial alternating current stimulation (tACS) is a novel, noninvasive brain stimulation technique capable of entraining cerebral oscillations at targeted frequencies.

OBJECTIVE: To assess the safety, feasibility, and efficacy of home-based gamma tACS applied over the precuneus in patients with prodromal and mild AD.

This double-blind, randomized, sham-controlled clinical trial with an open-label extension phase was conducted at a tertiary AD research clinic in Italy from December 10, 2022, to October 15, 2024. Patients with a diagnosis of AD were eligible to participate.

INTERVENTION: Participants were randomized to receive either home-based gamma tACS (5 sessions/wk, 60 minutes each) or sham stimulation for 8 weeks (double-blind phase). All participants subsequently received gamma tACS for an additional 8 weeks (open-label phase) and an 8-week follow-up.

MAIN OUTCOMES AND MEASURES: The primary end points were safety, feasibility, and clinical efficacy. Secondary end points included measures of biological efficacy, including gamma band power via electroencephalography, cholinergic neurotransmission, AD plasma biomarker levels, and brain connectivity as assessed via magnetic resonance imaging.

RESULTS: Sixty consecutive patients with prodromal or mild AD were screened; 50 were randomized to gamma or sham tACS (mean [SD] age, 67.3 [7.8] years; 25 [50.0%] female and 25 [50.0%] male). Home-based gamma tACS was safe and well-tolerated. A significant enhancement in global cognitive functions, activities of daily living, and associative memory performances was observed. Marginal mean differences between the sham vs gamma tACS groups were significant for the Clinical Dementia Rating sum of boxes (0.35; 95% CI, 0.10-0.61; P = .007), Alzheimer Disease Assessment Scale-cognitive subscale (0.93; 95% CI, 0.50-1.36; P = .001), Alzheimer Disease Cooperative Study-Activities of Daily Living (-0.55; 95% CI, -0.89 to -0.21; P = .02), and Face-Name Association Test (-1.14; 95% CI, -1.66 to -0.61; P ≤ .001). During the open-label phase, a significant marginal mean difference was observed for Alzheimer Disease Assessment Scale-cognitive subscale (-0.59; 95% CI, -1.02 to -0.16; P = .007), Alzheimer Disease Cooperative Study-Activities of Daily Living (0.41; 95% CI, 0.04-0.08; P = .02), and Face-Name Association Test (1.04; 95% CI, 0.50-1.57; P = .003). Neurophysiological measures showed an increase in cholinergic transmission, coinciding with an increase in gamma power following gamma tACS, effects not seen with sham stimulation. No changes of plasma biomarkers were observed. No add-on effect was observed after 2 repeated treatments with gamma tACS, suggesting that 8 rather than 16 weeks of treatment represents the ideal duration.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, home-based gamma tACS was feasible and improved clinical outcomes in AD, with neurophysiological evidence of brain engagement. These findings support further investigation of gamma tACS as a potential therapeutic intervention for AD.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05643326.}, } @article {pmid41359327, year = {2025}, author = {Gotlieb, E and Joseph, B and Blank, L and Jetté, N}, title = {Barriers and Consequences of Prior Authorization for Neurologic Medications: A Scoping Review.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2025.4560}, pmid = {41359327}, issn = {2168-6157}, abstract = {IMPORTANCE: Prior authorization (PA) is widely used by insurers to control health care costs and promote high-value care, but it can create significant barriers to accessing medications. This is particularly concerning in neurology, where timely treatment is critical to avoid disease progression and optimize patient outcomes.

OBJECTIVE: To assess the consequences, barriers, and facilitators of PA policies affecting access to pharmacologic treatment in 6 common neurologic conditions-Alzheimer disease, Parkinson disease, multiple sclerosis, migraine, cerebrovascular disease, and epilepsy-with focus on impacts on patients, clinicians, and administrators.

EVIDENCE REVIEW: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines for scoping reviews were followed, and the study protocol was registered on Open Science Framework. MEDLINE and Embase were searched up to November 1, 2024, using Ovid for studies that assessed the role of PA as a primary or secondary outcome for the 6 included neurologic conditions, or for neurology broadly if strongly applicable to the study aim, after the signage of the Affordable Care Act in March 2010. Abstract screening and full-text review were done in duplicate. Key information was charted in extraction, including study characteristics, demographics, methods, results, and implications for relevant stakeholders. The results were aggregated and thematically analyzed.

FINDINGS: A total of 364 studies were identified using our search strategy on Ovid, 278 records were screened, and 20 studies were included in this review. The most frequently identified consequences for patients were delays in care (60%) and increase in disease activity (25%). The most frequently identified consequence for clinicians (35%) and administrators (15%) was time burden. The most common facilitators were the use of clinical pharmacists or technicians (20%) and health system specialty pharmacies (15%).

CONCLUSIONS AND RELEVANCE: According to the results of this scoping review, PA can contribute to significant access barriers for people with neurological conditions and is associated with burden for all stakeholders involved. Reforms to PA can work towards more equitable access to medications for patients.}, } @article {pmid41358721, year = {2026}, author = {Ke, S and Chen, Z and Qi, Y and Zhang, J and Chen, Q and Chen, J and Bo, H}, title = {Heyndrickxia coagulans as a next-generation probiotic: current evidence and future perspectives.}, journal = {Food & function}, volume = {17}, number = {1}, pages = {15-40}, doi = {10.1039/d5fo03559g}, pmid = {41358721}, issn = {2042-650X}, mesh = {*Probiotics/therapeutic use ; Humans ; Animals ; *Lactobacillaceae/physiology ; }, abstract = {Heyndrickxia coagulans, a spore-forming probiotic, has garnered significant attention due to its exceptional tolerance to gastric acid and heat, alongside its multifaceted therapeutic potential. This review systematically delineates the unique biological characteristics of this bacterium, which include high survivability mediated by its spore form (retaining 73% viability after microwave treatment at 260 °C), dual lactate fermentation pathways, and plasticity in ATP synthesis that depends on pH and growth rate. Clinical evidence supports its efficacy in managing metabolic disorders (e.g., type 2 diabetes and non-alcoholic fatty liver disease), gastrointestinal conditions (e.g., constipation and irritable bowel syndrome), and neuropsychiatric disorders (e.g., depression and Alzheimer's disease). The underlying mechanisms involve the production of short-chain fatty acids (SCFAs), modulation of the TLR4/MyD88/NF-κB signaling pathway, and suppression of oxidative stress. Notably, therapeutic effects are strain-specific: H. coagulans MTCC 5856 (2 × 10[10] CFU day[-1]) significantly reduces abdominal distension (P < 0.01), while the strain Unique IS-2 alleviates anxiety-like behaviors by upregulating hippocampal BDNF. Although toxicological assessments establish a no observed adverse effect level (NOAEL) of >1000 mg kg[-1] in rodent models, its limited capacity for intestinal colonization presents a clinical challenge. Future research should prioritize large-scale clinical trials, multi-omics mechanistic investigations, and the development of synbiotic formulations to fully realize its potential as a next-generation therapeutic agent.}, } @article {pmid41358632, year = {2025}, author = {Zhang, S and Wang, T and Xue, G and Zheng, R and Ding, N and Yang, J and Zhang, M}, title = {Dysregulated mTOR signaling in Alzheimer's disease: Linking pathogenic mechanisms to emerging therapeutic strategies.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251400667}, doi = {10.1177/13872877251400667}, pmid = {41358632}, issn = {1875-8908}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and multifaceted pathogenic mechanisms (including amyloid-β [Aβ] plaques, tau neurofibrillary tangles, synaptic dysfunction, and neuroinflammation). Importantly, no effective disease-modifying treatment is currently available for AD. Emerging evidence implicates dysregulated mammalian target of rapamycin (mTOR) signaling as a key contributor to AD pathogenesis. This review analyzes how aberrant mTOR signaling influences major aspects of AD pathology, including Aβ production and clearance, tau protein hyperphosphorylation, autophagy dysfunction, synaptic plasticity impairments, neuroinflammation, and oxidative stress. Notably, hyperactivated mTOR accelerates AD progression through multiple mechanisms. It promotes Aβ accumulation and tau pathology, suppresses autophagic clearance of toxic aggregates, and disrupts neuronal homeostasis, thereby exacerbating cognitive decline. Consequently, mTOR has gained attention as a therapeutic target. This review evaluates the therapeutic potential of various mTOR-targeted interventions, such as the mTORC1 inhibitor rapamycin and its analogues (rapalogs), second-generation ATP-competitive mTOR inhibitors, and certain natural compounds and traditional Chinese medicine approaches. These strategies have demonstrated promise in mitigating AD-related pathology by enhancing autophagy, reducing Aβ/tau burden, and preserving synaptic and cognitive function in preclinical studies. However, the clinical translation of mTOR-targeted therapies faces key challenges, including poor blood-brain barrier penetration of many mTOR inhibitors, potential systemic side effects, and limited clinical validation to date. Further research is needed to optimize brain delivery, dosing regimens, and target specificity to fully realize the therapeutic potential of mTOR modulation in AD.}, } @article {pmid41358629, year = {2025}, author = {Kandeel, M and Mahmoud, M}, title = {Comparative efficacy and safety of different brexpiprazole doses for agitation in Alzheimer's disease: A systematic review and network meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251404500}, doi = {10.1177/13872877251404500}, pmid = {41358629}, issn = {1875-8908}, abstract = {BackgroundAgitation in Alzheimer's disease significantly impacts patient outcomes and caregiver burden. Brexpiprazole has emerged as a promising treatment option, but optimal dosing remains unclear.ObjectiveTo evaluate the comparative efficacy and safety of different brexpiprazole doses in treating agitation associated with Alzheimer's disease through a systematic review and network meta-analysis (NMA).MethodsFollowing PRISMA guidelines, we searched PubMed, Embase, Web of Science, and Scopus through January 2025. Four randomized controlled trials (N = 1451) comparing various brexpiprazole doses (0.5-3 mg/day) with placebo were included. Primary outcomes included changes in the Cohen-Mansfield Agitation Inventory (CMAI), the Clinical Global Impression-Severity Scale (CGI-S), and the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) scores, alongside safety measures.ResultsBrexpiprazole 2 mg demonstrated significant improvement in CMAI scores versus placebo (mean difference [MD]: -5.88; 95% CI: -8.13 to -3.63) and CGI-S scores (MD: -0.48; 95% CI: -0.95 to -0.01). Multiple doses showed significant NPI-NH improvements, with 2-3 mg showing the strongest effect (MD: -4.60; 95% CI: -7.54 to -1.66). Higher doses (2-3 mg) increased treatment-emergent adverse events (risk ratio [RR]: 1.20-1.33) but showed no significant difference in serious adverse events compared to placebo.ConclusionsBrexpiprazole 2 mg provides optimal therapeutic benefit while maintaining a favorable safety profile. The findings support initiating treatment at lower doses with careful titration to 2 mg based on individual response and tolerability. Future research should focus on long-term outcomes and real-world effectiveness.}, } @article {pmid41358624, year = {2025}, author = {Seixas-Lima, B and Rosa-Neto, P and Phillips, NA and Borrie, M and Roncero, CT and Lahiri, D and Dori, D and Eintracht, S and Chertkow, H}, title = {Peripheral inflammation in a Canadian cohort of neurodegenerative conditions: Occurrence, determinants, and impact.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251401611}, doi = {10.1177/13872877251401611}, pmid = {41358624}, issn = {1875-8908}, abstract = {Background"Inflammaging" describes chronic low-grade inflammation observed in aging individuals. It may play a major role in neurodegeneration.ObjectiveTo assess blood inflammatory markers in older adults. We hypothesized that elevated inflammation would be found in some cognitively normal older adults but would be more prevalent in individuals with cognitive impairment.MethodsInterleukin-6 (IL-6) and C-reactive protein (CRP) were assessed in 514 Canadian individuals in COMPASS-ND, a detailed study of cognitive impairment in the elderly. Cumulative link model (CLM) was used to investigate the relationship between inflammation status (low, medium, or high tertiles) and demographic and lifestyle factors along with cognitive function and cognitive diagnoses.ResultsWe found that 12% of cognitively normal older adults had IL-6 levels in the highest tertile, but this increased in cognitively impaired cohorts-36% in Alzheimer's disease, 55% mixed dementia, 30% mild cognitive impairment, and 39% vascular mild cognitive impairment. We found that 36% of cognitively unimpaired older individuals display "elevated" IL-6 (middle and high tertile values), while approximately 70% of those with cognitive impairment also do so. Inflammation markers increased most robustly in association with age, higher body mass index, and higher Fazekas (MRI white matter hyperintensity) score. There were also weaker associations with female sex, nutrition, number of comorbidities, and poor sleep.ConclusionsPeripheral low-grade inflammation was common, particularly in individuals with cognitive impairment; and obesity and age were the main drivers. It remains unclear whether treatment targeting such inflammation might have a therapeutic role in dementia prevention.}, } @article {pmid41357417, year = {2025}, author = {Roy, A and Kumar, D and Bhattacharya, P and Borah, A}, title = {In silico decoding strategic pathways inhibition by coptisine for halting Alzheimer's pathology: a mechanistic insight.}, journal = {In silico pharmacology}, volume = {13}, number = {3}, pages = {202}, pmid = {41357417}, issn = {2193-9616}, abstract = {Alzheimer's Disease (AD) is a brain disorder with various neuropathological hallmarks and has become a major concern globally due to limited therapeutic options. Cholinergic dysfunction due to the depletion of acetylcholine (ACh) levels in the synapse caused by increased acetylcholinesterase (AChE) activity is one of the major factors that drives AD progression. AChE also accelerates amyloid beta (Aβ) formation and leads to amyloid plaque deposition in the brain. Production of Aβ from amyloid precursor protein (APP) with sequential cleavage by β-secretase (BACE1) and γ-secretase causes severe brain damage due to plaque toxicity. Neurofibrillary tangles (NFTs), a neuronal catastrophe resulting from hyperphosphorylation of tau protein due to upregulation of glycogen synthase kinase 3 beta (GSK3β) and downregulation of Wnt signaling because of Dickkopf-1 and low density lipoprotein receptor-related protein 6 (DKK1-LRP6) interaction, are a major pathogenic event in AD. Recent research has increasingly focused on targeting amyloidopathy, tauopathy, and cholinergic pathways as therapeutic strategies for mitigating AD pathology. Coptisine, a bioactive alkaloid having enormous pharmacological properties, including neuroprotective action, is considered in our in-silico investigation. Collective inhibition of key targets in AD pathogenesis, like AChE, β-secretase (BACE1), γ-secretase, GSK3β, and DKK1-LRP6 interaction, could be a positive approach in the arsenal of Alzheimer's treatment. In this article, we report that coptisine can inhibit these five major targets as evident from our molecular docking study, and propose it as a potential multi-target drug to play a key role in halting AD pathology. Further, comparative analysis based on predicted values of cheminformatics and pharmacokinetic profiling of coptisine and known inhibitors increases its possibility to ameliorate AD. However, robust research, including a preclinical and clinical study on coptisine for its safety and efficacy assessment against AD pathology, is warranted for its validation as an anti-AD drug.}, } @article {pmid41357230, year = {2025}, author = {Xu Lou, I and Zhou, H and Wan, H}, title = {The critical role of Th17 cells and IL-17A in autoimmune and inflammation-associated neurological diseases: mechanisms and therapeutic perspectives.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1656422}, pmid = {41357230}, issn = {1664-3224}, mesh = {Humans ; *Th17 Cells/immunology/metabolism ; *Interleukin-17/immunology/metabolism ; Animals ; Inflammation/immunology ; *Autoimmune Diseases/immunology/therapy ; *Nervous System Diseases/immunology/therapy/etiology/metabolism ; *Neuroinflammatory Diseases/immunology/therapy ; }, abstract = {Helper T cells 17 (Th17) and their effector cytokine, interleukin-17A (IL-17A), play a dual role in immune homeostasis. On one hand, they are essential in defense against extracellular pathogens, such as bacteria and fungi, by inducing chemokine production and recruiting neutrophils. On the other hand, their dysregulated activity is strongly linked to autoimmune and inflammatory disorders, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and others. This article reviews the molecular mechanisms regulating Th17 differentiation and function, emphasizing the role of transcription factors like RORγt and RORα, as well as the influence of cytokines such as IL-6, IL-23, and TGF-β. Additionally, it explores the imbalance between pro-inflammatory Th17 cells and regulatory T cells (Tregs), a critical axis in the pathogenesis of autoimmune and neuroinflammatory diseases. In the context of neurological disorders, Th17 cells can infiltrate the central nervous system (CNS), where they contribute to neuroinflammation by activating microglia and astrocytes, exacerbating damage in conditions such as multiple sclerosis, traumatic brain injury, and neurodegenerative diseases. Emerging therapies, including anti-IL-17 monoclonal antibodies and natural modulators, are discussed as potential strategies to restore the Th17/Treg balance without compromising protective immunity. Finally, the need for further research is highlighted to elucidate the specific mechanisms of Th17 infiltration into the CNS, their interaction with the gut microbiota, and the development of personalized therapies. The integration of immunological, metabolic, and environmental approaches offers promising perspectives for the treatment of Th17/IL-17-mediated diseases.}, } @article {pmid41357129, year = {2025}, author = {Rananaware, P and Singh, S and Brahmkhatri, VP}, title = {Scavenging of reactive oxygen and nitrogen species using nanoparticles and their applications in disease management.}, journal = {RSC advances}, volume = {15}, number = {56}, pages = {47955-47980}, pmid = {41357129}, issn = {2046-2069}, abstract = {Nanomaterials constitute a new trend of disease management that is associated with advanced nanotechnology and bioengineered materials, presenting new solutions for various diseases that were previously problematic to handle with traditional chemical drugs or natural materials. Due to their high surface area, charge, variable size, and other properties, nanomaterials have been broadly used to manage several diseases. Specifically, nanomaterials have appeared with a significant ability to act as RONS scavengers for treatment and disease management. This is a result of their versatility in various applications, controlled release, enhanced reactivity, and unique biochemical properties. Recently, specific nanomaterials for treatment and disease management have been effectively developed into clinical tests. This review article focuses on the different types of nanomaterials that are effective for RONS scavenging and are used for different biomedical applications associated with excessive RONS generation. Nanoparticle-based systems have gained significant attention in recent years for their potential applications in scavenging reactive oxygen and nitrogen species (RONS) as part of disease management strategies. These nanoparticles can be designed to enhance the delivery, stability, and efficacy of antioxidants or other scavenging agents. The current review article provides a complete overview of the anti-inflammatory nature and use of nanoparticle systems by examining the molecular and pathological mechanisms of oxidative stress and the function of this stress in both cell and tissue damage. However, it is important to consider the biocompatibility, stability, and potential toxicity of these nanoparticle systems for therapeutic applications. Additionally, targeted delivery and controlled release mechanisms can enhance their efficacy in scavenging RONS at specific disease sites. RONS play a dual role in biological systems-they are essential for various physiological processes, such as cell signalling and host defence, but their overproduction can lead to oxidative and nitrosative stress, contributing to the development and progression of several diseases. Managing RONS is a key aspect of disease prevention and treatment. This article focuses on the use of nanomaterials for the treatment of various cancers, and in other areas such as tissue engineering, wound healing, osteoclast genesis, inflammation, and neurodegenerative disorders, such as Parkinson's and Alzheimer's disease, through RONS scavenging.}, } @article {pmid41356945, year = {2025}, author = {Kumar, P and Bhat, A and Goel, D and Mittal, M}, title = {Clinico-Etiological Profile of Young-Onset Dementia From a Tertiary Care Center in Northern India.}, journal = {Cureus}, volume = {17}, number = {11}, pages = {e96203}, pmid = {41356945}, issn = {2168-8184}, abstract = {BACKGROUND: This study examines young-onset dementia (YOD). Young-onset dementia refers to cases of dementia that manifest earlier in life and often pose unique clinical and management challenges. Despite its significant impact, data on YOD in northern India remain limited.

OBJECTIVE: To evaluate the clinico-etiological profile and cognitive characteristics of young-onset dementia patients presenting to a tertiary care center in Uttarakhand, India.

METHODS: This is a longitudinal follow-up study that was conducted over 1.5 years in the Department of Neurology. A total of 37 patients under 65 years of age out of 40 selected, diagnosed with major neurocognitive disorder (DSM-5), were included. Comprehensive clinical assessments, brain imaging, and cognitive evaluations were conducted. Data were analyzed using IBM Corp. Released 2018. IBM SPSS Statistics for Windows, Version 24. Armonk, NY: IBM Corp., with chi-square tests, analysis of variance (ANOVA), and Bonferroni corrections, with significance set at p<0.05.

RESULTS: The majority of patients were males (65%) and aged 56 to 65 years (50%). Vascular dementia was the most common cause (37.8%), followed by Alzheimer's disease (18.9%) and frontotemporal dementia (13.5%). Based on the verbal-language/orientation-memory (VLOM) ratio, 27.5% had frontotemporal-type dementia and 7.5% had Alzheimer-type dementia. Significant cognitive decline (p < 0.05) in MMSE and ACE-III scores was observed in Alzheimer's disease and frontotemporal dementia. Vitamin B12 deficiency showed 13.5% improvement with treatment. VLOM ratios effectively differentiated frontotemporal dementia (FTD) from AD.

CONCLUSION: This study concluded that vascular dementia is the leading cause of YOD in this region, reflecting a high burden of modifiable vascular risk factors. The VLOM ratio offers diagnostic value in distinguishing dementia subtypes. Early identification and intervention are essential to address the functional burden of YOD.}, } @article {pmid41356558, year = {2025}, author = {Wang, H and Yang, F and Gao, Z and Cheng, Z and Liang, X}, title = {The gut-brain axis in Alzheimer's disease: how gut microbiota modulate microglial function.}, journal = {Frontiers in aging}, volume = {6}, number = {}, pages = {1704047}, pmid = {41356558}, issn = {2673-6217}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder that can be caused by multiple factors, such as abnormal amyloid-beta (Aβ) deposition, pathological changes in Tau protein, lipid metabolism disorders, and oxidative stress. Recent studies have revealed the potential link between gut microbiota and AD, particularly the impact of gut microbiota and its derivatives on microglia. As immune cells in the central nervous system (CNS), microglia are involved in neuroinflammation and the regulation of cognitive function. Research indicates that the dysregulation of gut microbiota may affect the phenotype and function of microglia through various mechanisms, including direct metabolite action and indirect immune and neurotransmitter regulation. This article reviews the direct and indirect effects of gut microbiota and its derivatives on microglia, explores their role in the pathogenesis of AD, and discusses therapeutic strategies based on gut microbiota, such as dietary regulation, probiotics, fecal microbiota transplantation, and traditional Chinese medicine. Although existing studies have shown the potential of these interventions, further research is needed to completely understand their application in the treatment of AD.}, } @article {pmid41355970, year = {2026}, author = {Park, A and Hong, SM and Lee, Y and Lee, J and Jeon, S and Seo, SY and Lee, J and Kim, SH and Ko, EJ and Lee, HR and Jung, SH and Bae, M and Kang, MC and Park, MG and Nam, S and Kim, SY}, title = {Deep learning identifies TP-41 for methylglyoxal scavenging in Alzheimer's treatment.}, journal = {Theranostics}, volume = {16}, number = {3}, pages = {1103-1122}, pmid = {41355970}, issn = {1838-7640}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Pyruvaldehyde/metabolism ; Animals ; *Deep Learning ; Mice ; Disease Models, Animal ; Glycation End Products, Advanced/metabolism ; Humans ; Male ; Memory Disorders/drug therapy ; Mice, Inbred C57BL ; }, abstract = {Rationale: Increased levels of advanced glycation end products (AGEs) have been observed in the brain tissues of patients with Alzheimer's disease (AD). Methylglyoxal (MGO) is a potent precursor of AGEs. To date, there have been no reports of utilizing deep learning (DL) technologies to target MGO scavengers for the development of AD therapeutics. Therefore, DL-driven approaches may play a crucial role in identifying potential MGO scavengers and candidates for Alzheimer's treatment. Methods: We developed "DeepMGO," a novel DL-based MGO scavenging activity prediction model, trained on 2,262 MGO scavenging activity assays from 660 compounds. Using this approach, we identified and validated TP-41 as a potential MGO scavenger in a mouse model of memory impairment. Results: DeepMGO demonstrated robust predictive performance and identified novel compounds with high MGO scavenging activity. TP-41 ameliorated depression symptoms and memory deficits in mouse models. Conclusions: Using DeepMGO, we identified TP-41 as a potential therapeutic agent for AD.}, } @article {pmid41355958, year = {2026}, author = {Wu, Y and Fan, Y and Bao, S and Song, Y and Wang, R and Wu, J and Liu, X and Jin, J and Kong, L and Hou, B and Liang, P and Chen, T and Liu, W and Peng, B and He, F and Zhou, Y and Xu, J and Chen, Y and Han, S and Yin, J and He, X}, title = {Mertk promotes early microglial-mediated synaptic engulfment in Alzheimer's disease.}, journal = {Theranostics}, volume = {16}, number = {3}, pages = {1238-1261}, pmid = {41355958}, issn = {1838-7640}, mesh = {*Microglia/metabolism ; *Alzheimer Disease/metabolism/pathology/genetics ; *c-Mer Tyrosine Kinase/metabolism/genetics ; Animals ; Mice ; *Synapses/metabolism/pathology ; Disease Models, Animal ; Phagocytosis ; Hippocampus/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; PPAR gamma/metabolism ; Mice, Knockout ; Mice, Inbred C57BL ; Humans ; Mice, Transgenic ; Male ; }, abstract = {Rationale: Synaptic deficits occur prior to the emergence of Aβ plaques and tau pathology in Alzheimer's disease (AD). Dysregulated microglia excessively prune synapses, leading to synaptic loss. While microglia phagocytic receptor Mertk participates in synaptic pruning, the role of Mertk in driving early synaptic loss in AD remains elusive. Methods: Single-cell RNA sequencing (scRNA-seq) was used to analyze transcriptional changes of microglia in early stage of AD mice. Mertk-mediated synaptic engulfment was investigated both in vivo and in vitro. Results: Phagocytic-associated microglia with upregulated Mertk were identified in the early stage of AD mice. Dysregulated synaptic pruning by microglia caused hippocampal synaptic loss and memory deficits in two AD mouse models. Notably, Mertk knockout or antagonist treatment reversed excessive synapse elimination by microglia. Mechanistically, Aβo-induced PPARγ promoted Mertk transcription, mediating microglial phagocytosis of synapses. Conclusions: Collectively, our findings suggest that PPARγ-regulated, Mertk-mediated microglial synaptic engulfment contributes to early synaptic loss in AD, highlighting microglial Mertk as a potential therapeutic target for AD.}, } @article {pmid41355756, year = {2025}, author = {Liu, F and Tang, YL and Zhang, ZB and Tan, YH and Lin, SH and Wang, NY and Li, JN and Pan, ZJ and Li, JF and Huang, JF and Ding, YQ and Guo, CM and Xu, L and Peng, C and Zhou, QX}, title = {Modifying Glucose Metabolism Reverses Memory Defects of Alzheimer's Disease Model at Late Stages.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e06695}, doi = {10.1002/advs.202506695}, pmid = {41355756}, issn = {2198-3844}, support = {2022ZD0204900//National Program of Brain Science and Brain-Inspired Intelligence Technology 2030/ ; 32271080//National Natural Science Foundation of China/ ; 32071029//National Natural Science Foundation of China/ ; 82473909//National Natural Science Foundation of China/ ; 32170662//National Natural Science Foundation of China/ ; 32070818//National Natural Science Foundation of China/ ; 202401AS070131//Yunnan Fundamental Research Project/ ; 202402AA310014//Yunnan Provincial Science and Technology Department/ ; LG-QS-202205-05//The Lingang Laboratory/ ; 202001BB050005//Natural Science Foundation of Yunnan Province/ ; //Xingdian talent program of Yunnan Province/ ; }, abstract = {Significant efforts have harvested a sophisticated understanding of Alzheimer's disease (AD) including amyloid beta (Aβ) cascade mechanisms, although effective treatment for reversing or stopping AD progression is not available. This study reports that ferul enanthate (SL), a novel derivative of active agents targeting brain microvessels, oxidative phosphorylation, and ATP generation can reverse the hippocampus-dependent spatial memory defects and reduce Aβ plaques in AD model mice (APP/PS1) at advanced stages. Spatial transcriptomics discovers that SL endows a cluster of genes expressing in Aging-AD-Rescue (AAR) pattern, which is prominent in hippocampal dendritic region where Aβ plaques are densely deposited. Furthermore, this AAR rule covers hippocampal Glut1 (glucose transporter 1) expression and ATP generation, which are further confirmed by immunoblotting or immunofluorescence studies. Our data demonstrate that SL can still reverse memory defects at advanced stages of AD mice by modifying aging-dependent multiple pathologies of AD, particularly promoting Glut1 expression and ATP generation.}, } @article {pmid41355547, year = {2025}, author = {Lu, Q and Di, X and Guo, X}, title = {Comprehensive Review on the Protective Effects of Lycium barbarum Polysaccharide on Neurodegenerative Diseases.}, journal = {Endocrine, metabolic & immune disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715303393082251027072838}, pmid = {41355547}, issn = {2212-3873}, abstract = {Neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, ischemic stroke, and other related conditions, significantly impact the quality of life, particularly in low-income nations. The pathogenesis of these diseases is driven by neuroinflammation, oxidative stress, apoptosis, mitochondrial dysfunction, and regulation of autophagy. To date, no therapies or medications can fully reverse the progression of these diseases. Natural polysaccharides have demonstrated significant therapeutic potential in the treatment of neurodegenerative diseases. Lycium barbarum polysaccharide, derived from the traditional Chinese medicine Lycium barbarum L., has attracted considerable attentionfor its diverse biological activities, biodegradability, ease of modification, and low toxicity. This review aims to systematically evaluate the neuroprotective effects of Lycium barbarumpolysaccharides and their mechanisms in various neurodegenerative disease models. For this study, we used multiple scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar. We verified the correct plant name through the website plantlist.org. The search results were interpreted and documented based on the retrieved bibliographic information. Lycium barbarum polysaccharide has shown significant therapeutic potential for the treatment of neurodegenerative diseases. Experimental evidence reveals its neuroprotective effects through various mechanisms, including reducing neuroinflammation, alleviating oxidative stress, inhibiting apoptosis, improving mitochondrial function, and regulating autophagy. The current review established that Lycium barbarum polysaccharide holds promise as a therapeutic agent for neurodegenerative diseases. However, further research is required to address the limitations identified in previous studies and to guide future experimental investigations and clinical applications.}, } @article {pmid41355080, year = {2025}, author = {van Dyck, CH and Sperling, R and Johnson, K and Dhadda, S and Kanekiyo, M and Li, D and Gee, M and Hersch, S and Irizarry, M and Kramer, L}, title = {Long-term safety and efficacy of lecanemab in early Alzheimer's disease: Results from the clarity AD open-label extension study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70905}, pmid = {41355080}, issn = {1552-5279}, support = {//Eisai Inc. and Biogen/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology ; Female ; Male ; Aged ; Quality of Life ; Treatment Outcome ; Disease Progression ; Amyloid beta-Peptides ; Aged, 80 and over ; }, abstract = {INTRODUCTION: In Clarity AD, lecanemab reduced markers of amyloid in early symptomatic Alzheimer's disease and slowed cognitive and functional decline at 18 months. Herein, we report 36-month data from the ongoing open-label extension (OLE).

METHODS: Clarity AD is an 18-month, randomized study (Core), with an OLE where participants received open-label lecanemab. Clinical and health-related quality-of-life (HRQoL) outcomes were evaluated overall and by examining "delayed-start" and "early-start" cohorts. Low pathology (i.e., low baseline amyloid or tau) subgroups were analyzed.

RESULTS: ARIA rates were low after 6 months and not associated with long-term progression. Across clinical and HRQoL endpoints, lecanemab-treated participants continued to benefit through 36 months. Separation between early and delayed start was maintained between 18 and 36 months. The low pathology subgroup showed stability or improvement over 18-36 months.

DISCUSSION: Benefit continued to accrue with ongoing lecanemab treatment through 36 months. Results in the low pathology subgroup support early initiation of lecanemab treatment.

HIGHLIGHTS: This research evaluated the long-term efficacy, safety, and HRQoL results from an ongoing extension of the phase 3 Clarity AD, which included open-label lecanemab treatment for up to 36 months. Overall, the results show participants continue to accrue a lecanemab treatment benefit up to 36 months and highlight the importance of continued long-term lecanemab treatment. Results presented in our paper demonstrate that lecanemab continued suppression of amyloid plaque levels and significantly slowed clinical decline on multiple measures of cognition, function, and quality of life in early AD at 18 months and continued for 36 months to date. No new safety signals were observed with continued lecanemab treatment. After the first 6 months, ARIA rates were low and similar to ARIA rates on placebo, with no association between ARIA occurrence and accelerated long-term clinical progression. Taken together with existing data, these results provide a clear rationale and a demonstration of the disease modification effects of long-term lecanemab therapy.}, } @article {pmid41354641, year = {2025}, author = {Feyzbakhsh, H}, title = {Nanoparticle-based strategies for overcoming the blood-brain barrier in CNS disorders and brain cancer: precision diagnostics and therapeutics for Alzheimer's, Parkinson's, multiple sclerosis, and glioblastoma.}, journal = {Tissue barriers}, volume = {}, number = {}, pages = {2599564}, doi = {10.1080/21688370.2025.2599564}, pmid = {41354641}, issn = {2168-8370}, abstract = {Nanoparticle (NP)-based technologies are transforming the management of central nervous system (CNS) disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and brain cancer (BC), glioblastoma, by surpassing the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). This review integrates NP approaches, comprising organic (e.g. liposomes, polymeric NPs), inorganic (e.g. gold, iron oxide), carbon-based, and hybrid systems, to overcome disease-specific barriers. In AD, superparamagnetic iron oxide NPs (SPIONs) and gold NPs (AuNPs) improve amyloid-beta plaque and tau protein detection, while liposomes precisely deliver anti-amyloid drugs. For PD, dopamine-loaded liposomes and cerium oxide NPs reinstate dopaminergic function and decrease oxidative stress, with improved motor outcomes. In MS, PEGylated liposomes and PLGA NPs regulate autoimmune responses, inducing remyelination and attenuating neuroinflammation. For BC, dendrimers and magnetic NPs facilitate targeted chemotherapy delivery across the BBB/BBTB, improving glioblastoma treatment outcomes. We compare NP types critically based on physicochemical characteristics, efficacy, toxicity, and clinical translation potential, highlighting gaps in long-term safety and scalability. Challenges like NP toxicity and regulatory complexities are discussed, suggesting biocompatible designs and standardized FDA/EMA pathways. By consolidating diagnostic and therapeutic innovations, this review outlines a roadmap for NP-based precision medicine, paving the way for clinical translation and better patient outcomes in CNS disorders and brain cancer.}, } @article {pmid41354326, year = {2025}, author = {Wiredu, K and Gowda, P and Rhee, J and Mueller, A and Simon, C and Kelly Graves, O and Qu, JZ and Spite, M and McKay, TB and Akeju, O}, title = {Long-chain polyunsaturated fatty acid lipid and oxylipin alterations in postoperative delirium after cardiac surgery.}, journal = {Journal of lipid research}, volume = {67}, number = {1}, pages = {100959}, doi = {10.1016/j.jlr.2025.100959}, pmid = {41354326}, issn = {1539-7262}, abstract = {Lipids play a crucial role in signaling, membrane dynamics, and inflammatory regulation, yet their involvement in postoperative delirium pathogenesis remains unclear. This study examined serum lipidomic alterations in postoperative delirium and assessed the effects of dexmedetomidine treatment on these changes. Lipidomic profiling was conducted at baseline and postoperative day 1 in two independent cohorts of cardiac surgery patients. Mass spectrometry-based shotgun lipidomics and targeted lipid analyses were used to assess lipidomes and oxylipins, respectively. Cardiac surgery was associated with decreased serum lysophospholipids. Postoperative delirium was associated with increased long-chain polyunsaturated fatty acid phospholipids, particularly phosphatidylethanolamines, and elevated oxylipins. Dexmedetomidine, a potential delirium-mitigating medication, reduced long-chain polyunsaturated fatty acid phospholipids. These findings highlight lipid modulation as a potential target for postoperative delirium prevention.}, } @article {pmid41353845, year = {2026}, author = {Azadmaleki, H and Zolnour, A and Rashidi, S and Noble, JM and Hirschberg, J and Esmaeili, E and Morovati, T and Zolnoori, M}, title = {TransformerCARE: A novel speech analysis pipeline using transformer-based models and audio augmentation techniques for cognitive impairment detection.}, journal = {International journal of medical informatics}, volume = {207}, number = {}, pages = {106208}, doi = {10.1016/j.ijmedinf.2025.106208}, pmid = {41353845}, issn = {1872-8243}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; Female ; Male ; Aged ; *Speech ; Algorithms ; }, abstract = {OBJECTIVE: Early diagnosis of cognitive impairment, including Alzheimer's and other dementias, is critical for effective treatment and slowing disease progression. However, over 50% of cases remain undiagnosed until advanced stages due to limitations in current methods. Recognizing speech impairments as early markers of cognitive decline, this study evaluated the utility of speech analysis as a technique for early detection. We introduce TransformerCARE, a speech processing pipeline utilizing advanced speech transformer models.

METHODS: TransformerCARE incorporated a series of key steps, including preprocessing, speech segmentation, transformer fine-tuning, segment aggregation, performance evaluation, and data augmentation. In the fine-tuning step, we evaluated the performance of four state-of-the-art speech transformer models: Wav2vec 2.0, HuBERT, WavLM, and DistilHuBERT. For data augmentation, we adopted multiple techniques, with particular emphasis on frequency masking due to its ability to preserve subtle acoustic cues associated with cognitive impairment. We measured the performance of TransformerCARE on the ADReSSo Challenge dataset from DementiaBank, comprising 237 subjects (122 cognitively impaired and 115 cognitively normal).

RESULTS: TransformerCARE demonstrated its highest performance with HuBERT, achieving an AUC of 81.80 (F1-score = 79.31) using an aggregation technique that averaged embeddings of 14-second speech segments. Augmenting the training data with frequency masking improved performance by 5 %, resulting in an AUC of 86.11 (F1-score = 84.63). We also demonstrated that incorporating clinicians' speech during patient interactions can improve the performance of the pipeline. Our error analysis revealed significant differences between the acoustic patterns of correctly identified negative cases (true negatives) and those incorrectly identified as positive (false positives), as well as between correctly identified positive cases (true positives) and those incorrectly identified as negative (false negatives). This indicates specific deviations in speech characteristics among inaccurately diagnosed subjects.

CONCLUSION: In summary, TransformerCARE demonstrates strong potential for integration into clinical workflows as a screening tool for cognitive impairment, aiding in the timely and appropriate care of affected patients.}, } @article {pmid41353509, year = {2025}, author = {Kolouei, A and Barati, M and Abbas-Mohammadi, M}, title = {Investigating the binding potential of the Melissa officinalis oil against Alzheimer's targets by molecular docking and in vitro evaluations.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {736}, pmid = {41353509}, issn = {2045-2322}, mesh = {*Molecular Docking Simulation ; *Alzheimer Disease/drug therapy/metabolism ; *Melissa/chemistry ; PC12 Cells ; Animals ; Rats ; Antioxidants/pharmacology/chemistry ; Amyloid Precursor Protein Secretases/metabolism/chemistry ; *Oils, Volatile/pharmacology/chemistry ; Amyloid beta-Peptides/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; *Plant Oils/pharmacology/chemistry ; Cell Survival/drug effects ; Humans ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with limited treatment options. Melissa officinalis (M. officinalis), traditionally used for its medicinal properties, contains compounds that may offer therapeutic benefits for AD. We extracted essential oils from M. officinalis using supercritical CO2 and identified 31 compounds via GC-MS, supplemented by 20 non-volatile compounds from the Dictionary of Natural Products. Molecular docking was performed against five AD-related targets: β-Secretase, γ-Secretase, amyloid-β) A(, neprilysin, and acetylcholinesterase. The oil's antioxidant capacity and cytotoxicity on PC12 cells were evaluated using DPPH and MTT assays, respectively. Docking analysis revealed that sajerinic acid had the highest affinity for acetylcholinesterase, neprilysin, and γ-Secretase. Aβ and β-Secretase were most affected by 3',4',5,7-tetrahydroxyflavone, 3'-O-β-D-glucuronopyranoside, γ-O-β-D-glucopyranoside and 2,3,19,23-tetrahydroxy-12-ursen-28-oic acid-23-sulfate, 28-O-β-D-glucopyranosyl ester, respectively. Among oil compounds, triethyl citrate showed the highest affinity for β-Secretase, neprilysin, and γ-Secretase, while 2,2-dimethoxybutane exhibited the highest potential for interaction with Aβ and acetylcholinesterase. The oil reduced PC12 cell survival in a dose-dependent manner. The extract also displayed significant antioxidant activity, suggesting a potential to reduce oxidative stress. These findings suggest that M. officinalis contains compounds with potential anti-Alzheimer's properties, warranting further investigation. The identified compounds could serve as leads for developing novel therapeutics, and the antioxidant activity of the extract supports its traditional use in managing neurodegenerative conditions. Further studies are needed to validate these findings in vivo and explore the therapeutic potential of M. officinalis in AD.}, } @article {pmid41352683, year = {2026}, author = {Shim, GH and Lau, ECY and Huynh, ALH and Lu, CY and Tan, ECK}, title = {Influence of patient characteristics on efficacy and safety of anti-amyloid monoclonal antibodies in Alzheimer's disease: A systematic review and meta-analysis.}, journal = {Ageing research reviews}, volume = {114}, number = {}, pages = {102981}, doi = {10.1016/j.arr.2025.102981}, pmid = {41352683}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Treatment Outcome ; *Amyloid beta-Peptides/antagonists & inhibitors/immunology ; }, abstract = {BACKGROUND: Lecanemab and donanemab are the first anti-amyloid monoclonal antibodies (mAbs) clinically available as disease-modifying therapies for Alzheimer's disease (AD). However, it remains unclear whether their treatment effects differ across demographic, clinical, or genetic subgroups.

OBJECTIVE: This systematic review aimed to explore how patient characteristics modify the efficacy, safety and humanistic outcomes of anti-amyloid mAbs lecanemab and donanemab in patients with early AD.

METHODS: A systematic search of MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library was conducted from database inception to July 30th, 2025, using a combination of keywords and Medical Subject Heading terms relating to lecanemab and donanemab. Meta-analyses were conducted for safety outcomes where sufficient data was available.

RESULTS: Sixteen studies representing six randomised clinical trials (total N = 5633) were included. Both lecanemab and donanemab showed the greatest slowing of cognitive decline in White/Caucasian patients and apolipoprotein E4 (ApoE4) non-carriers. Amyloid-related imaging abnormalities with edema/effusion (ARIA-E) and microhemorrhages (ARIA-H) were more prevalent in ApoE4 carriers. The risk of ARIA-E was 2.19 times higher (95 %CI:1.91-2.50) and ARIA-H was 3.45 times higher (95 %CI:1.35-8.72) in ApoE4 carriers versus non-carriers. Statistically significant improvements in health-related quality of life were observed with lecanemab in ApoE4 heterozygous participants and in those aged 65-74 years.

CONCLUSIONS: The efficacy and safety of anti-amyloid mAbs in AD may differ based on patients' demographic and genetic factors. These findings highlight the potential for personalised treatment strategies and inform national drug policies. Further research is needed to evaluate long-term outcomes and address under-studied patient populations.

SUMMARY: The efficacy and safety of lecanemab and donanemab varied across patient subgroups, including age, sex, race/ethnicity and genetic factors such as ApoE4 genotype status. The risk of ARIA was higher in ApoE4 carriers, particularly the homozygous.}, } @article {pmid41352634, year = {2025}, author = {Geleta, LA and Doyle, C and Garton, FC and Fowler, M and Carr, JM and Akkari, PA and McRae, AF and Rogers, ML and Madakkatel, I and Benyamin, B}, title = {The roles of human endogenous retrovirus in neurodegenerative diseases: A systematic review.}, journal = {Brain, behavior, and immunity}, volume = {132}, number = {}, pages = {106201}, doi = {10.1016/j.bbi.2025.106201}, pmid = {41352634}, issn = {1090-2139}, abstract = {BACKGROUND: Human endogenous retroviruses (HERVs) constitute ∼8 % of the human genome, far exceeding the 2 % occupied by protein-coding genes. Although most HERV sequences are inactive, some HERV elements can be reactivated under certain conditions and may contribute to neurodegenerative diseases (NDDs). However, the findings vary across different HERV families, disease models, and detection methods. Here, we systematically review and synthesize the available evidence on the role of HERVs in human NDDs and reconcile inconsistencies in the literature.

METHODS: We systematically searched MEDLINE, EMBASE, Cochrane Library, PsycINFO, Scopus, Web of Science, CINAHL, and Emcare to identify relevant studies. Two independent reviewers screened studies, assessed quality, and extracted data. Qualitative synthesis was conducted for all included NDDs, specifically Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson's disease (PD), and due to data availability, meta-analysis was used to assess the impact of HERVs antibodies on ALS only.

RESULTS: Twenty-six studies (N ranges: 6-485) met the inclusion criteria, with majority focusing on HERV-K and ALS. Across studies, the association between HERV expression and NDDs was inconsistent, particularly for ALS, PD, and FTD, whereas investigations in AD showed a more consistent upregulation of specific HERVs. Studies relying on polymerase chain reaction (PCR) (typically smaller) showed inconsistent associations (21 studies), while RNA sequencing studies reported consistent associations (9 studies). A preliminary meta-analysis revealed a fivefold increase [OR: 5.83; 95 % CI: 4.14, 8.18] in ALS risk among participants with positive HERV antibodies.

CONCLUSIONS: The inconsistencies in HERV involvement across NDDs highlight the need for further studies employing standardized methodologies. RNAseq findings on the association of HERVs expression and NDDs support the need for large-scale RNA sequencing studies (rather than small, PCR studies) and careful tissue selection to clarify HERVs' role in NDDs. The association of HERV-K antibodies with ALS risk and prognosis suggests a significant role in disease, which could help detect biomarkers and used as a target for treatment.}, } @article {pmid41351718, year = {2025}, author = {Krishnan, M and Kumaresan, M and Ravi, S and Martin, LC and Manikandan, B and Raman, T and Ramar, M}, title = {Bornyl Acetate and Menthol Provide Neuroprotection Against Lipopolysaccharide-Induced Alzheimer's Disease-Like Condition in C57BL/6 Mice by Downregulating NARC-1 Lipid Antagonist.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {262}, pmid = {41351718}, issn = {1559-1182}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology/prevention & control ; Mice, Inbred C57BL ; Lipopolysaccharides ; *Menthol/pharmacology/therapeutic use ; *Down-Regulation/drug effects ; Male ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; *Neuroprotection/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurological illness that causes Aβ deposition and cognitive impairments. Anti-cholinesterase and anti-depressant drugs are used as medications; however, their side effects spotlight the need for alternate treatments. Bornyl acetate and menthol are monoterpenes with bioactive potential investigated against inflammation induced by lipopolysaccharide (LPS) in C57BL/6 mice. In our study, we analysed various behavioural changes along with memory activities as well as assessed neuronal damage, acetylcholinesterase activity, amyloid deposition, mitochondrial membrane integrity, calcium deposition and oxidation derivatives. In addition, we also examined gene and protein expression associated with lipid dysfunction in neuroinflammation. Our findings revealed that monoterpenes such as bornyl acetate and menthol potentially improved LPS-induced behaviour changes and cognitive activities. In addition, these compounds have the potential effects against amyloid plaque formation, calcium build-up, mitochondrial membrane damage and oxidative markers (malondialdehyde, protein carbonyls and advanced glycation end products) in the LPS-injected C57BL/6 mice. Treatment with bornyl acetate and menthol also inhibited neural apoptosis-regulated convertase (NARC-1)/proprotein convertase subtilisin/kexin type 9 (PCSK-9) by upregulating low-density lipoprotein receptor-related protein (LRP)-1 protein expression. Cholesterol oxidation genes, including 11β-hydroxysteroid dehydrogenase 1 & 2, as well as proinflammatory microglial, apoptotic and amyloidogenic protein and gene expression, were decreased respectively when treated with monoterpenes while promoting the upregulation of anti-inflammatory. Based on the results, we concluded that these compounds can potentially target and prevent neuroinflammation, including Alzheimer's disease.}, } @article {pmid41351658, year = {2025}, author = {Singh, I and Singh, AK}, title = {Senolytics as Modulators of Critical Signaling Pathways: a Promising Strategy to Combat Brain Aging and Neurodegenerative Disorders.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {261}, pmid = {41351658}, issn = {1559-1182}, support = {CRG/2022/006612//Anusandhan National Research Foundation/ ; }, mesh = {Humans ; *Aging/drug effects/metabolism/pathology ; *Signal Transduction/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Brain/drug effects/metabolism/pathology ; Animals ; *Senotherapeutics/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; }, abstract = {Aging of the brain, an intricate process, is a significant risk factor for neurodegenerative disorders (NDDs), such as Alzheimer's disease and Parkinson's disease. Senescent cell accumulation is an important hallmark of brain aging. These cells resist apoptotic cell death, produce proinflammatory cytokines, increase oxidative stress, and store toxic proteins that exacerbate neurodegeneration. These senescent cells cause neuroinflammation and dysfunction of the neuronal microenvironment by transmitting senescent phenotypes to neighboring healthy cells. Senolytics have become a viable treatment option to reduce the effects of brain aging since they specifically target and destroy senescent cells. Numerous senolytic compounds, such as dasatinib, fisetin, and quercetin, effectively eliminate senescent cells and reduce the accumulation of harmful substances, including misfolded toxic protein aggregates and reactive oxygen species, thereby helping to maintain tissue homeostasis. These medications aid in reducing oxidative stress and inflammation, two significant factors in brain aging and NDDs, by encouraging the removal of senescent cells. The key molecules involved in this process are mTOR, Nrf2-Keap1, AMPK, and Sirtuin 1 (SIRT1). The modulation of the mTOR and AMPK pathways affects autophagy and cellular metabolism, facilitating the elimination of harmful accumulations and damaged cell organelles. In addition, cellular repair and improved antioxidant defense are encouraged by the activation of the SIRT1 and Nrf2 pathways. The combination of senolytic therapy with these signaling pathways provides a novel approach to attack the cellular and molecular foundations of brain aging and neurodegenerative disorders.}, } @article {pmid41350983, year = {2025}, author = {Deng, H and Lee, TA and Gaber, CE and Kim, K and Crawford, SY and Bayliss, EA and Singh, S and Young, JG and Toh, S and Li, X}, title = {Treatment patterns of symptomatic treatments for Alzheimer's disease and related dementias.}, journal = {BMC geriatrics}, volume = {26}, number = {1}, pages = {39}, pmid = {41350983}, issn = {1471-2318}, } @article {pmid41350761, year = {2025}, author = {He, H and Razlighi, QR and Gazes, Y and Habeck, C and Stern, Y and , }, title = {Integrating individualized connectome with amyloid pathology improves predictive modeling of future cognitive decline.}, journal = {Communications medicine}, volume = {5}, number = {1}, pages = {515}, pmid = {41350761}, issn = {2730-664X}, support = {R01 AG026158/AG/NIA NIH HHS/United States ; R01 AG038465/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: The deposition of amyloid-β (Aβ) in the human brain is a hallmark of Alzheimer's disease and is associated with cognitive decline. Aβ pathology is traditionally assessed at the whole-brain level across neocortical regions using positron emission tomography (PET). However, these measures often show weak associations with future cognitive impairment. A more sensitive pathology metric is needed to quantify early Aβ burden and better predict cognitive decline. Here, we aim to develop a network-based metric of Aβ burden to improve early prediction of cognitive decline in aging populations.

METHODS: We integrated subject-specific brain connectome information with Aβ-PET measures to construct a network-based metric of Aβ burden. Cross-validated predictive modeling was used to evaluate the performance of this metric in predicting longitudinal cognitive decline. Furthermore, we identified a neuropathological signature pattern linked to future cognitive decline, and we validated this pattern in an independent cohort.

RESULTS: Our results demonstrate that incorporating individualized structural connectome, but not functional connectome, information into Aβ measures enhances predictive performance for prospective cognitive decline. The identified neuropathological signature pattern is reproducible across cohorts.

CONCLUSION: These findings advance our understanding of the spatial patterns of Aβ pathology and its relationship to brain networks, highlighting the potential of connectome-informed network-based metrics for Aβ-PET imaging in identifying individuals at higher risk of cognitive decline.}, } @article {pmid41350438, year = {2025}, author = {Liu, D and Li, X and Shi, P and Hong, W and Huang, J and Hou, M and Ma, L and Liao, Q and Yang, H and Fu, X and Zhou, H and Lu, J and Liu, Y and Feng, X and Wang, D and Zhou, R}, title = {7,8-Dihydroxyflavone ameliorates bone loss by regulating TRKB/AKT/FOXO3a pathway in a mouse model of alzheimer's disease.}, journal = {Psychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {41350438}, issn = {1432-2072}, support = {81972112//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: The incidence of osteoporosis is increased in Alzheimer's disease (AD). The pathogenesis of AD with osteoporosis is still unknown, there is no ideal treatment as yet for it. 7,8-Dihydroxyflavone (7,8-DHF), a functional brain-derived neurotrophic factor (BDNF) mimetic, shows therapeutic potential for neurological and orthopedic disorders.

OBJECTIVES: This research investigated the molecular mechanisms by which 7,8-DHF mitigates bone loss and cognitive dysfunction in osteoporotic AD mice.

METHODS: Micro-CT analysis quantified bone loss in AD mice. The Morris water maze (MWM) assessed mouse cognitive function, and immunohistochemical analysis measured Aβ plaque deposition. qPCR and Western blotting measured expression levels of APP, Aβ42, TRKB, and FOXO3a in osteoblasts isolated from femoral bone marrow mesenchymal stem cells (BMSCs) and brain tissue. ELISA determined the levels of IL-1β, IL-6, osteocalcin (OCN), fibroblast growth factor 23 (FGF23) and sclerostin. For in vitro experiments, osteoblast differentiation was monitored in MC3T3-E1 cells co-cultured with Aβ42, with concurrent measurement of TRKB, AKT, and FOXO3a expression. The efficacy of 7,8-DHF against bone loss and osteoblast differentiation was systematically evaluated.

RESULTS: Cognitive impairment and bone loss manifested in APP/PS1 mice. 7,8-DHF treatment ameliorated bone mass reduction, decreased Aβ42 expression in bone tissue, and enhanced TRKB expression. Concurrently, 7,8-DHF improved cognitive function and accelerated clearance of [¹²⁵I]-Aβ42 from the brain. In in-vitro, Aβ42 increased inflammatory cytokine levels, suppressed TRKB expression, and impaired osteoblast differentiation. 7,8-DHF reduced the levels of AKT and pFOXO3a by TRKB.

CONCLUSION: 7,8-DHF could alleviate bone mass loss in AD mice by regulating the TRKB/AKT/FOXO3a pathway. This finding provides new ideas for the treatment strategy of AD with osteoporosis and is beneficial to the health of the elderly.}, } @article {pmid41350162, year = {2026}, author = {Rosenberg, PB and Amjad, H and Burhanullah, H and Nowrangi, M and Vandrey, R and Pierre, MJ and Outen, JD and Schultz, M and Marano, C and Agronin, M and Wilkins, JM and Harper, D and Laffaye, T and Reardon, E and Turner, K and Ozonsi, R and Drury, M and Nguyen, A and Hasoğlu, T and Cromwell, J and Leoutsakos, JM and Forester, BP}, title = {A Randomized Controlled Trial of the Safety and Efficacy of Dronabinol for Agitation in Alzheimer's Disease.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {34}, number = {2}, pages = {167-179}, pmid = {41350162}, issn = {1545-7214}, support = {K23 AG064036/AG/NIA NIH HHS/United States ; R01 AG050515/AG/NIA NIH HHS/United States ; R03 AG063237/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Dronabinol/adverse effects/therapeutic use/administration & dosage/pharmacology ; Female ; *Alzheimer Disease/complications/drug therapy ; *Psychomotor Agitation/drug therapy/etiology ; Male ; Double-Blind Method ; Aged ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {IMPORTANCE: Agitation in Alzheimer's disease (AD) is a great source of distress for patients and caregivers and a major public health burden. Current treatments are only modestly effective and many have safety issues including mortality risk. Novel therapeutic options are needed. There is preliminary evidence for the safety and efficacy of dronabinol (tetrahydrocannabinol, THC) for agitation in AD.

OBJECTIVE: Assess the safety and efficacy of dronabinol (THC) to decrease agitation in AD.

DESIGN: THC-AD was a 3-week randomized parallel double-blind placebo-controlled clinical trial, conducted between 2017 and 2024.

SETTING: 5 inpatient and outpatient academic clinical research centers in the Eastern U.S.

PARTICIPANTS: Volunteer sample of 75 participants meeting inclusion criteria for agitation of AD (International Psychogeriatric Association Provision Criteria) with Neuropsychiatric Inventory Clinician Version Agitation or Aggression (NPI-C A/A) domains total score of 4 or greater. Major exclusion criteria included seizure disorder, delirium, and non-AD dementia.

INTERVENTIONS: 3 weeks dronabinol vs. placebo titrated up to target dose of 10 mg daily in divided twice-daily.

MAIN OUTCOMES AND MEASURES: Prespecified co-primary agitation outcomes were the Pittsburgh Agitation Scale (PAS) and NPI-C A/A total score.

RESULTS: The majority of participants were female and were taking concomitant psychotropic medications (antidepressants and antipsychotics) at baseline. Study participants were moderately agitated at baseline, were diverse in ethnic background (9% Black, 11% Hispanic/Latina/Latino), and had severe cognitive impairment evidenced by MMSE or SIB-8. 84% completed the 3-week trial. Dronabinol decreased agitation on both primary outcomes greater than placebo to a clinically relevant extent. The fitted between-arm difference in PAS decline/week was -0.74 (SE 0.3, p = 0.015, effect size = 0.53) and for NPI-C A/A the decline was not significant at -1.26 (SE 0.67, p = 0.094, effect size = 0.36). No secondary outcomes differed between treatment arms including sleep, activities of daily living, Cohen-Mansfield Agitation Inventory (CMAI), cognition, intoxication, or use of 'as-needed' lorazepam or trazodone. Dronabinol treatment was not associated with greater intoxication nor with other adverse events (AEs) except for somnolence.

CONCLUSIONS AND RELEVANCE: Adjunctive dronabinol treatment was safe and effective for treating agitation in AD.

CLINICAL TRIALS REGISTRATION: NCT02792257.}, } @article {pmid41349452, year = {2026}, author = {Rossiter, K}, title = {Despite all our rage: An autoethnographic analysis on the role of shared affect in dementia caregiving relationships.}, journal = {Social science & medicine (1982)}, volume = {389}, number = {}, pages = {118802}, doi = {10.1016/j.socscimed.2025.118802}, pmid = {41349452}, issn = {1873-5347}, mesh = {Humans ; *Caregivers/psychology ; *Dementia/psychology ; Female ; Anthropology, Cultural ; Male ; *Rage ; Aged ; Middle Aged ; Interpersonal Relations ; *Alzheimer Disease/psychology ; }, abstract = {Using an autoethnographic approach, this paper explores the phenomenon of shared rage between Alzheimer's patients and their informal family caregivers. Unlike previous analyses regarding dementia care, this work understands that rage within caregiving relationships is both dynamic and productive. Drawing broadly from social scientific studies regarding emotional labour and "feeling work," this work argues that Alzheimer's sufferers and their informal caregivers form two halves of a dyad, each of whom may use rage as a form of protection against loss of relational identity and pursuant grief, and to demand humane and dignified treatment from broken formal care systems. This individual rage simultaneously offers a point of connection between both halves of the caregiving dyad, which is otherwise torn asunder by interpersonal manifestations of the disease. Ultimately this paper argues for a brave, curious and compassionate response to caregiving dyads in which experiences of rage are not stigmatized, minimized or medicalized. Rather, this analysis suggests that experiences of anger are recognized as an often-excruciating form of emotional labour necessitated by an insidious disease and inadequate formal care systems.}, } @article {pmid41349262, year = {2025}, author = {Qi, L and Lin, L and Zheng, J and Liu, X and Liu, X and Chen, Z and Liu, L}, title = {Liraglutide improves cognitive function by reducing amyloid-beta peptide accumulation and inhibiting inflammation in 5 × FAD mice.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1093/gerona/glaf265}, pmid = {41349262}, issn = {1758-535X}, abstract = {Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by progressive memory decline. The increasing prevalence of AD has attracted considerable attention globally. The glucagon-like peptide-1 analog, liraglutide, a drug widely used in the treatment of type 2 diabetes, has shown promising neuroprotective effects in AD, including enhancing neuronal survival, reducing amyloid beta protein accumulation, improving synaptic plasticity, and reducing tau protein hyperphosphorylation. However, its potential impact on cognitive function remains unclear. We evaluated the effects of liraglutide (25 nmol/day for 8 weeks) on the cognitive ability of 12-month-old 5 × familial Alzheimer's disease (FAD) mice. The Morris water maze test was used to evaluate the spatial learning ability of mice. Histological evaluations were performed by Nissl staining and transmission electron microscopy. Neuroinflammation was detected by double immunofluorescence staining and enzyme-linked immunosorbent assay. Protein expression in the cortex and hippocampal was detected by immunohistochemistry and Western blotting. The spatial cognitive ability improved in 5 × FAD mice after liraglutide administration and was associated with an increased number of pyramidal cells in the cortex and hippocampus. Liraglutide also alleviated ultrastructural changes in the chemical synapses and reduced both local and systemic inflammation in AD mice. Furthermore, liraglutide reduced amyloid β protein expression, which may be associated with the regulation of nuclear factor kappa B/beta-secretase 1 pathways in AD mice. The potential of liraglutide to improve the cognitive function in AD mice offers an effective pharmacological approach for treating neurodegenerative diseases.}, } @article {pmid41347369, year = {2026}, author = {Yang, J and Deng, Y and Qin, S and Chen, Z and Lu, Y and Ji, S and Hang, T and Song, M}, title = {An aggregation-induced emission-active theranostic agent for selectively detecting and intervening pathological Tau protein.}, journal = {Journal of materials chemistry. B}, volume = {14}, number = {1}, pages = {261-272}, doi = {10.1039/d5tb01783a}, pmid = {41347369}, issn = {2050-7518}, mesh = {*tau Proteins/metabolism/analysis ; Humans ; *Fluorescent Dyes/chemistry/chemical synthesis/pharmacology ; *Theranostic Nanomedicine ; Stilbenes/chemistry ; Optical Imaging ; }, abstract = {The accumulation of Tau aggregates is commonly linked with various neurodegenerative diseases, such as Alzheimer's disease, Pick's disease, and corticobasal degeneration. Notwithstanding substantial investments in the development of clinical strategies for effective intervention, traditional design paradigms are predominantly confined to molecules featuring either a solitary function or single-dimensional mode of intervention, ignoring the necessity of personalized and precise medicine. Herein, we design and synthesize a dual-functional aggregation-induced emission-active agent to serve as both a fluorescent probe for the imaging of pathological Tau and a modulator for intervention. This amphiphilic theranostic agent, named TPE-P9, is prepared via a one-pot Michael reaction between hydrophobic maleimide-modified tetraphenylethylene (TPE-Mal) and a hydrophilic cysteine-modified Tau-targeting peptide (CKVQIINKK). Microscale thermophoresis measurement and in vitro fluorescence analysis demonstrate that TPE-P9 exhibits specific binding affinity (Kd = 4.46 µM) and high selectivity towards Tau fibrils, featuring a pronounced low background interference, which is superior to the classical amyloid protein probe thioflavin T (ThT). At the living cellular level, TPE-P9 is capable of readily imaging endogenic pathological Tau to distinguish normal neurons from the lesional neurons in situ, and the staining consequence is almost consistent with that of ThT. On the other hand, as a modulator, TPE-P9 can potently protect neurons from cytotoxic Tau-induced apoptosis both by inhibiting aberrant post-translational modification-induced Tau self-assembly and by blocking the produced pathological Tau propagation, enhancing cell viability by 35.4%. These findings offer valuable insights for the development of innovative image-guided therapeutic strategies for targeted tauopathies treatment.}, } @article {pmid41346709, year = {2026}, author = {Liu, S and Semyachkina-Glushkovskaya, O and Yu, T and Ilukov, E and Rafailov, E and Sokolovski, S and Kurths, J and Zhu, D}, title = {Neuro-lymphaphotonics opens new horizons of the future technologies for the therapy of brain diseases.}, journal = {Theranostics}, volume = {16}, number = {2}, pages = {776-793}, pmid = {41346709}, issn = {1838-7640}, mesh = {Humans ; *Brain Diseases/therapy ; Animals ; Brain ; *Low-Level Light Therapy/methods ; *Lymphatic Vessels/radiation effects ; Blood-Brain Barrier ; }, abstract = {Pharmacological treatment of brain diseases is hampered by the blood-brain barrier that prevents the vast majority of drugs from entering the brain. For this reason, the pharmaceutical industry is reluctant to invest in the development of new neurotropic drugs. Even if effective pharmacological strategies for the treatment of brain diseases will be found, it will take 10-15 years between the emergence of an idea and the introduction of a drug to the market. This creates priority for the development of neuro-lymphaphotonics based on the development of promising non-pharmacological strategies for managing functions of the meningeal lymphatic vessels (MLVs). MLVs play a crucial role in the removal of toxins and metabolites from brain as well as in regulation of brain homeostasis and its immunity. Since MLVs are located on the brain surface, light penetrating the skull easily reaches MLVs and affects their functions. Therefore, MLVs are an ideal target for photobiomodulation (PBM). The pioneering studies have shown that PBM of MLVs is a promising strategy for the treatment of a wide range of neuropathology, including Alzheimer's or age-related brain diseases, brain tumor, intracranial hemorrhage, brain damages caused by diabetes. It has recently been discovered that sleep enhances the therapeutic effects of PBM and is a "therapeutic window" in overcoming the limitations of PBM in the elderly. Considering that the PBM technologies are non-invasive and safe with commercially viable possibilities (portability and low cost), neuro-lymphaphotonics open up promising prospects for the development of future technologies for the effective therapy of brain diseases.}, } @article {pmid41345983, year = {2025}, author = {Abi-Ghanem, C and Opiela, AK and Paul, AS and Comito, ML and Hao, L and Martino, G and Kyaw, NR and Salinero, AE and Mansour, FM and Kelly, RD and Mutahi, AM and Sura, A and Thrasher, CA and Groom, EA and Batchelder, MR and Zuloaga, KL}, title = {Loss of ovarian hormones is detrimental in early disease stages of mouse models of Alzheimer's disease and multi-etiology dementia.}, journal = {Biology of sex differences}, volume = {17}, number = {1}, pages = {4}, pmid = {41345983}, issn = {2042-6410}, support = {A2022001F//Bright-Focus Foundation/ ; 908878//American Heart Association/ ; 25PRE1374600//American Heart Association/ ; R01 NS110749/NS/NINDS NIH HHS/United States ; U01 AG072464/AG/NIA NIH HHS/United States ; R01 NS110749/NS/NINDS NIH HHS/United States ; U01 AG072464/AG/NIA NIH HHS/United States ; AARG-21-849204/ALZ/Alzheimer's Association/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology/pathology ; Female ; Disease Models, Animal ; Ovariectomy ; Mice ; Mice, Transgenic ; *Estradiol ; *Dementia/etiology ; }, abstract = {BACKGROUND: Up to 80% of Alzheimer's disease (AD) patients suffer from brain vascular damage resulting in multi-etiology dementia (MED). Sex is a well-known risk factor for dementia; out of three AD patients two are women. 17β-estradiol, a predominant ovarian hormone in woman before menopause, is known to have beneficial effects on the cerebrovasculature, neuroinflammation and neuroprotection. Here, we investigated the consequences of the loss of ovarian hormones caused by surgical menopause (ovariectomy) on AD and MED.

METHODS: The App[NL-F] knock-in mice were used to model AD. At about 5.5 months of age, a stage corresponding to early disease pathology, female App[NL-F] mice were subjected to ovariectomy (OVX) or sham surgery (Intact) and left to recover for 3 weeks to clear any endogenous gonadal hormones. In half of the mice from each group, MED was modeled using chronic cerebral hypoperfusion (unilateral carotid artery occlusion), a model of vascular contributions to cognitive impairment and dementia (VCID). Control animals (AD only model) received sham surgery. Mice were then subjected to a battery of behavioral tests before being euthanized and brains were collected to assess pathology.

RESULTS: We found that loss of ovarian hormones impairs spatial learning and memory, impairs activities of daily living, and affects underlying pathology including compromising microglial response. Some of these effects were exacerbated by cerebral hypoperfusion (VCID).

CONCLUSIONS: These results shed light on the effects of ovarian hormone loss after surgical menopause in female mouse model of AD and MED in order to better understand sex-specific risk factors.}, } @article {pmid41345807, year = {2025}, author = {Lawrence, JM and Dampier, W and Mell, JC and De Souza, DR and Schardien, K and Yeakle, K and Barnett, RJ and Sen, B and Ahmed, A and Bouchard, M and Wigdahl, B and Nonnemacher, MR}, title = {Inflammatory microglia signals drive A1-like polarization of astrocytes even in the presence of HIV-1 Tat.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {251}, pmid = {41345807}, issn = {1559-1182}, support = {R01 NS089435/NS/NINDS NIH HHS/United States ; T32 MH079785/MH/NIMH NIH HHS/United States ; MH079785/MH/NIMH NIH HHS/United States ; NS089435/NS/NINDS NIH HHS/United States ; }, mesh = {*Astrocytes/metabolism/pathology/drug effects ; Humans ; *Microglia/metabolism/pathology/drug effects ; *tat Gene Products, Human Immunodeficiency Virus/metabolism/pharmacology ; *Inflammation/pathology/metabolism ; Blood-Brain Barrier/metabolism/pathology/drug effects ; *Signal Transduction/drug effects ; *Cell Polarity/drug effects ; *HIV-1/metabolism ; Endothelial Cells/metabolism/drug effects ; Cells, Cultured ; }, abstract = {In the context of neurodegeneration, activated microglia facilitate inflammation via secretion of TNF-α, IL-1α, and C1q. Astrocytes exposed to this signaling array polarize to a reactive inflammatory phenotype, termed A1 or A1-like. Astrocytes are essential for neuronal survival, synaptic support, and blood-brain barrier (BBB) function, but A1-like astrocytes upregulate inflammatory gene expression, downregulate neurotrophic factors, and secrete neurotoxic signals. The consequences of A1-like polarization on BBB function are unknown but may have etiological implications for some diseases. Frequently identified by upregulation of complement component 3 (C3), A1-like astrocytes have been characterized in neurodegenerative disorders like Alzheimer's disease, with polarization correlated with disease progression and severity. However, the role of A1-like astrocytes in neurodegeneration associated with chronic viral infections, like HIV-1-associated neurocognitive disorder (HAND), remains unclear. An in vitro system using primary human astrocytes, as well as a BBB model featuring primary human brain microvascular endothelial cells (BMECs) co-cultured with astrocytes, was used to elucidate cellular and molecular consequences of chronic astrocyte activation. As measured by whole transcriptome analysis and protein expression assays, repeated treatment with TNF-α, IL-1α, and C1q induced A1-like polarization of astrocytes both in monoculture and in a BBB model, resulting in increased secretion of pro-inflammatory signals. No substantial change to BBB permeability was observed. In contrast, exposure to HIV-1 viral protein Tat did not independently induce A1-like polarization. Ongoing investigations into the effect of astrocyte polarization on BBB integrity and treatment with pathogenic proteins may provide insights into the role of neurotoxic astrocytes in neurovirologic pathologies.}, } @article {pmid41345718, year = {2025}, author = {Platen, M and Gläser, E and Dahling, V and Gesell, D and Hauptmann, M and Horenkamp-Sonntag, D and Koller, D and Kubat, D and Marschall, U and Riederer, C and Scheibner, H and Schroth, J and Swart, E and Michalowsky, B}, title = {Regional disparities of antidementia drug treatment in Germany: what can we learn for the new generation of Alzheimer's therapies.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {259}, pmid = {41345718}, issn = {1758-9193}, mesh = {Humans ; Germany/epidemiology ; *Alzheimer Disease/drug therapy/epidemiology ; Male ; Female ; Aged ; *Healthcare Disparities/statistics & numerical data ; Aged, 80 and over ; Rural Population ; *Nootropic Agents/therapeutic use ; Socioeconomic Factors ; Middle Aged ; }, abstract = {BACKGROUND: Current antidementia drugs can temporarily slow cognitive decline in Alzheimer's disease but are underused. Regional and socioeconomic disparities, including limited specialist access in rural or deprived areas, may exacerbate inequities and challenge the rollout of emerging disease-modifying therapies. This study aimed to evaluate associations between regional contextual factors and antidementia drug prescription (AD-Rx) among newly diagnosed people living with Alzheimer's disease (PlwAD) in Germany and to identify spatial clustering of prescribing patterns.

METHODS: This study analyzed anonymized claims data from three statutory health insurers for 53,753 PlwAD who received their first diagnosis between January 2020 and December 2022. Regions, defined by three-digit postal codes (ZIP3, n = 576), were categorized by the German Index of Socioeconomic Deprivation (GISD) quintiles and Degree of Urbanization (urban, suburban, rural). Multilevel logistic regression with random intercepts for ZIP3 was used to assess associations between receiving AD-Rx (dichotomous) and urbanization and deprivation, adjusting for age, sex, the Charlson Comorbidity Index, the long-term care level and the year of diagnosis. Global Moran's I was used to evaluate large-scale spatial clustering, and regional Moran's I was calculated to detect regional hotspots and coldspots.

RESULTS: Overall, 64% of PlwAD received at least one AD-Rx. Rural residency was associated with slightly lower odds of receiving AD-Rx compared to urban areas (OR 0.92; 95%CI 0.87-0.98; p = 0.010), whereas deprivation was not. Interaction models demonstrated that an increased deprivation further reduced AD-Rx odds in rural areas (OR per GISD unit = 0.98; 95% CI 0.96-0.99; p = 0.024). Global Moran's I revealed no significant large-scale clustering (I = 0.011; p = 0.613), but regional analysis identified several regional hotspots (high-high clusters) predominantly in moderately deprived urban areas and coldspots (low-low clusters) in highly deprived or rural areas.

CONCLUSION: Alzheimer's patients in rural and high-deprivation regions face limited access to recommended antidementia medications. Targeted interventions, such as teleconsultations, expanding specialist outreach, and collaborative care models in underserved areas, as well as regional dementia networks and national registries, could promote the equitable delivery of current and future Alzheimer's antibody therapies. However, further qualitative and quantitative research is needed to identify the underlying regional causes of these treatment disparities.

TRIAL REGISTRATION: DRKS00031944.}, } @article {pmid41345521, year = {2025}, author = {Elnemais Fawzy, M and Wang, S and Palmer, P and Gatchel, J and Marshall, GA and Gagliardi, G and Vannini, P and , }, title = {Association between anosognosia and neuropsychiatric symptoms in Alzheimer's disease dementia patients.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {316}, pmid = {41345521}, issn = {2045-2322}, support = {R01 AG061083/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; AG061083/NH/NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/psychology/complications/diagnostic imaging ; Male ; Female ; Aged ; *Agnosia/psychology/complications/epidemiology ; Aged, 80 and over ; Neuropsychological Tests ; Positron-Emission Tomography ; }, abstract = {Anosognosia, the lack of awareness of memory decline, and Neuropsychiatric Symptoms (NPS) are prevalent and debilitating symptoms in Alzheimer's disease (AD) dementia. Understanding the coexistence of these symptoms may help guide clinical interventions and treatment strategies. This study aimed to compare NPS prevalence in patients with and without anosognosia at baseline and to assess the association between anosognosia and NPS over time. We examined patients with AD dementia enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI). To be included in the current study, patients had to have undergone baseline assessments and at least one subsequent follow-up evaluation. Furthermore, all patients had to have amyloid (as assessed using Positron Emission Tomography, PET), Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), and Everyday Cognition (ECog) variables available throughout the study. Anosognosia, our exposure of interest, was determined using Ecog scores from patients and study partners. Study partners evaluated the presence or absence of 12 NPS (our outcomes of interest) using the NPI. Cox proportional hazards models, excluding patients who had any symptoms of NPS at baseline, were used to evaluate NPS onset by group (anosognosia/no anosognosia) while adjusting for age, sex, years of education, and MMSE. 112 patients with follow-up data (mean = 1 year) were included in this study. Of these, 47.3% (n = 53) had anosognosia, while 52.7% (n = 59) did not. In those with anosognosia at baseline, we observed a trend toward greater prevalence of agitation and motor symptoms. Exploratory time-to-event analysis demonstrated that the patients with anosognosia had a faster onset of apathy (HR: 2.78, 95% CI: 1.37-5.62, p = 0.01) compared to the patients without anosognosia. In this exploratory study, while there were no significant differences in frequency of NPS at baseline between the groups, patients with anosognosia demonstrated faster onset of apathy as compared to patients without anosognosia. These findings underscore the importance of longitudinal assessments and tailored interventions targeting the management of NPS in AD dementia patients with anosognosia. Further research is warranted to explain the underlying mechanisms driving these associations and to inform the development of targeted therapeutic strategies aimed at improving patient outcomes in this population.}, } @article {pmid41344886, year = {2025}, author = {Perovnik, M and Simončič, U and Jamšek, J and Gregorič Kramberger, M and Brumberg, J and Meyer, PT and Perani, D and Caminiti, SP and Brendel, M and Stockbauer, AC and Camacho, V and Alcolea, D and Vandenberghe, R and Van Laere, K and Ko, JH and Lee, CS and Pardini, M and Lombardo, L and Padovani, A and Pilotto, A and Ochoa-Figueroa, MA and Davidsson, A and Cháfer-Pericás, C and Álvarez-Sánchez, L and Garibotto, V and Lemstra, AW and Ferreira, D and Morbelli, SD and Tang, CC and Eidelberg, D and Trošt, M and , }, title = {Metabolic brain networks in dementia with Lewy bodies: from prodromal to manifest disease stages.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2025-336935}, pmid = {41344886}, issn = {1468-330X}, abstract = {BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, yet it remains under-recognised and misdiagnosed, which delays treatment, causes inaccurate prognosis and limits research opportunities. Imaging with 2-[[18]F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is a supportive DLB biomarker. We evaluated a multivariate, quantifiable metabolic network biomarker, termed DLB-related pattern (DLBRP), for its further clinical translation across centres and disease stages.

METHODS: We analysed demographic, clinical and FDG PET imaging data of 1180 participants from 14 tertiary centres and two multicentre datasets. We included 379 DLB, 28 mild cognitive impairment-LB (MCI-LB), 195 dementia due to Alzheimer's disease (ADD), 172 MCI-AD without α-synuclein co-pathology (MCI-AD-S-), and 73 MCI-AD with α-synuclein co-pathology (S+) patients, along with a comparative group of 333 normal controls (NCs). From the scans, we calculated the expression of DLBRP, AD-related pattern (ADRP) and Parkinson's disease-related pattern (PDRP) and compared them across groups. DLBRP scores were correlated with clinical measurements.

RESULTS: Across independent cohorts, DLBRP robustly distinguished DLB from NCs (sensitivity >89%, specificity >90%), and scores correlated with Unified Parkinson's Disease Rating Scale Part III and independently predicted Mini-Mental State Examination. DLBRP was elevated already in MCI-LB. In a small longitudinal dataset, we observed steady increases in DLBRP expression with scores exceeding the diagnostic threshold prior to dementia onset. DLBRP and PDRP discriminated DLB from ADD (sensitivity, 74%-90%; specificity, 80%). In MCI-AD groups, ADRP was expressed, whereas DLBRP and PDRP were increased only in MCI-AD-S+, although comparatively less than in MCI-LB.

CONCLUSIONS: This study demonstrates the value of DLBRP in diagnosing prodromal and manifest DLB and distinguishing them from their AD counterparts. While overlap between patterns may reflect actual co-pathology, this possibility cannot be accepted without thorough pathological confirmation. The current findings support the use of DLBRP in patient evaluation and in future trial design.}, } @article {pmid41344825, year = {2025}, author = {Johnson, SL and Gibbons, SR and Nielsen, CJ}, title = {Theranostics Beyond Oncology: Emerging Applications.}, journal = {Journal of nuclear medicine technology}, volume = {53}, number = {Suppl 1}, pages = {141S-143S}, doi = {10.2967/jnmt.125.271192}, pmid = {41344825}, issn = {1535-5675}, mesh = {Humans ; *Theranostic Nanomedicine/methods ; }, abstract = {Theranostics, the combination of targeted diagnostic imaging and treatment, is rapidly expanding its role beyond oncology into various noncancerous diseases. Recent advances in radiopharmaceuticals, molecular imaging, and nanoparticle-based technologies are enabling the detection and treatment of conditions in cardiology, neurology, autoimmune, and bone marrow disorders. These innovations include targeted imaging and therapy for atherosclerosis and cardiac amyloidosis, as well as neurodegenerative disorders such as Alzheimer disease. Additionally, they encompass biomarkers such as fibroblast activation protein inhibitor and radiolabeled glucocorticoids in autoimmune and inflammatory diseases, as well as the selective ablation of diseased tissue in bone marrow conditioning. Despite the promise of these developments, several challenges must be considered, including the integration of theranostic strategies into standard practice and establishing their efficacy through robust clinical trials. This review examines the emerging nononcologic applications of theranostics, highlighting current research and future potential.}, } @article {pmid41341968, year = {2026}, author = {Hong, J and An, HK and Nam, H and Choi, J and Yu, SW}, title = {Presenilin 2 regulates corticosterone-induced autophagic death of adult hippocampal neural stem cells.}, journal = {Animal cells and systems}, volume = {30}, number = {1}, pages = {35-46}, pmid = {41341968}, issn = {1976-8354}, abstract = {Chronic psychological stress is a well-known risk factor for neurodegenerative diseases including Alzheimer disease (AD), yet the underlying mechanisms remain unclear. We previously showed that chronic stress impairs adult hippocampal neurogenesis by triggering autophagic cell death of adult hippocampal neural stem (HCN) cells. Impairment of adult hippocampal neurogenesis is widely observed in the brains of human AD patients and animal models. However, it remains unknown whether stress-induced death of HCN cells is related to the pathogenesis of AD. In this study, we investigated whether the stress hormone, corticosterone (CORT) induces HCN cell death through presenilin 2 (Psen2), a gene associated with familial AD. Using CRISPR/Cas9-based knockout models and in vitro CORT treatment, we found that Psen2 expression is upregulated by CORT and Psen2 deletion prevents CORT-induced death in HCN cells. However, the Psen2 N141I mutation, despite its pathogenicity in AD, did not exacerbate CORT-induced cell death in vitro and hippocampus-dependent behavioral deficits in vivo. These findings indicate that while Psen2 is essential for stress-induced death of HCN cells, the Psen2 N141I mutation alone may not be sufficient to link chronic stress to AD pathogenesis.}, } @article {pmid41341510, year = {2025}, author = {Yang, J and Yang, F and Chen, G and Liu, M and Yuan, S and Zhang, TE}, title = {Receptor-mediated mitophagy: a new target of neurodegenerative diseases.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1665315}, pmid = {41341510}, issn = {1664-2295}, abstract = {Neurodegenerative diseases are a category of neurological conditions with high prevalence that pose major treatment challenges. Common pathologies involve protein accumulation and mitochondrial damage. Mitophagy maintains cellular homeostasis by removing defective mitochondria, which are associated with the pathogenesis of neurodegenerative diseases. Although the ubiquitin-dependent mitophagy mediated by the PINK1-Parkin pathway has been extensively studied, growing evidence indicates that receptor-mediated mitophagy plays a crucial compensatory role in neurons, particularly when the PINK1-Parkin pathway is impaired. This review focuses on the emerging field of receptor-mediated mitophagy, systematically elaborating its role as a key homeostatic mechanism operating independently of the canonical PINK1/Parkin pathway. It provides a focused analysis of the specific functions and activation mechanisms of key receptors-including BNIP3, NIX, FUNDC1, and AMBRA1-in models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, this review explores the clinical potential of targeting these specific receptors for precise intervention, aiming to provide a new theoretical foundation and direction for developing therapeutic strategies against neurodegenerative diseases.}, } @article {pmid41341242, year = {2024}, author = {Gutman, B and Shmilovitch, AH and Aran, D and Shelly, S}, title = {Twenty-Five Years of AI in Neurology: The Journey of Predictive Medicine and Biological Breakthroughs.}, journal = {JMIR neurotechnology}, volume = {3}, number = {}, pages = {e59556}, pmid = {41341242}, issn = {2817-092X}, abstract = {Neurological disorders are the leading cause of physical and cognitive disability across the globe, currently affecting up to 15% of the world population, with the burden of chronic neurodegenerative diseases having doubled over the last 2 decades. Two decades ago, neurologists relying solely on clinical signs and basic imaging faced challenges in diagnosis and treatment. Today, the integration of artificial intelligence (AI) and bioinformatic methods is changing this landscape. This paper explores this transformative journey, emphasizing the critical role of AI in neurology, aiming to integrate a multitude of methods and thereby enhance the field of neurology. Over the past 25 years, integrating biomedical data science into medicine, particularly neurology, has fundamentally transformed how we understand, diagnose, and treat neurological diseases. Advances in genomics sequencing, the introduction of new imaging methods, the discovery of novel molecular biomarkers for nervous system function, a comprehensive understanding of immunology and neuroimmunology shaping disease subtypes, and the advent of advanced electrophysiological recording methods, alongside the digitalization of medical records and the rise of AI, all led to an unparalleled surge in data within neurology. In addition, telemedicine and web-based interactive health platforms, accelerated by the COVID-19 pandemic, have become integral to neurology practice. The real-world impact of these advancements is evident, with AI-driven analysis of imaging and genetic data leading to earlier and more accurate diagnoses of conditions such as multiple sclerosis, Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease, and more. Neuroinformatics is the key component connecting all these advances. By harnessing the power of IT and computational methods to efficiently organize, analyze, and interpret vast datasets, we can extract meaningful insights from complex neurological data, contributing to a deeper understanding of the intricate workings of the brain. In this paper, we describe the large-scale datasets that have emerged in neurology over the last 25 years and showcase the major advancements made by integrating these datasets with advanced neuroinformatic approaches for the diagnosis and treatment of neurological disorders. We further discuss challenges in integrating AI into neurology, including ethical considerations in data use, the need for further personalization of treatment, and embracing new emerging technologies like quantum computing. These developments are shaping a future where neurological care is more precise, accessible, and tailored to individual patient needs. We believe further advancements in AI will bridge traditional medical disciplines and cutting-edge technology, navigating the complexities of neurological data and steering medicine toward a future of more precise, accessible, and patient-centric health care.}, } @article {pmid41339994, year = {2025}, author = {Sivalingam, AM and Sureshkumar, DD}, title = {The Central Role of m6A as Epigenetic Regulator in Metabolic Disorders of Therapeutic Potential and Clinical Implications.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {247}, pmid = {41339994}, issn = {1559-1182}, mesh = {Humans ; *Epigenesis, Genetic ; *Metabolic Diseases/genetics/therapy/metabolism ; *Adenosine/analogs & derivatives/metabolism/genetics ; Animals ; Aging/genetics ; }, abstract = {N6-methyladenosine (m6A) is the most common reversible mRNA modification, regulating fundamental cellular processes. It plays a vital role in aging and age-related diseases by influencing gene expression, RNA splicing, and stability. Growing evidence suggests that m6A modifications orchestrate key hallmarks of aging, including cellular senescence, stem cell exhaustion, and chronic inflammation factors that contribute to neurodegeneration, cardiovascular disease, and cancer. The intricate crosstalk between m6A and chromatin modifications is now recognized as a fundamental mechanism shaping age-associated epigenetic landscapes and influencing disease susceptibility. Core m6A regulators, such as METTL3, FTO, and ALKBH5, are implicated in age-related metabolic decline, neurodegeneration, and impaired tissue regeneration, making them promising therapeutic targets. Dysregulated m6A patterns are linked to aberrant RNA metabolism, protein aggregation, and synaptic dysfunction in Alzheimer's and Parkinson's diseases, while in cardiovascular and metabolic disorders, m6A modifications contribute to endothelial dysfunction, inflammation, and oxidative stress. Recent breakthroughs in computational modeling and RNA-editing technologies have revolutionized m6A research. High-precision deep-learning models (e.g., m6A-DCR) and CRISPR-based m6A editing tools provide powerful platforms to decode m6A's role in aging and disease progression. These advances pave the way for novel therapeutic strategies, offering opportunities for early diagnostics, precision medicine, and personalized interventions. Despite these promising developments, challenges remain in translating m6A-targeted therapies into clinical applications. Future research must enhance treatment specificity, minimize off-target effects, and elucidate the broader implications of m6A in aging. Advancing our understanding of m6A's functional landscape is essential for developing next-generation RNA-based therapeutics to combat aging and its associated diseases.}, } @article {pmid41338979, year = {2025}, author = {Nakamura, K and Kanou, M and Ito, S and Jimbo, T and Kouzaki, K and Nakazato, K and Nakamjima, R and Yamanouchi, K and Ueda, H and Yamana, K}, title = {Beta-nicotinamide mononucleotide attenuates creatine kinase release in Duchenne muscular dystrophy model rats.}, journal = {The Journal of veterinary medical science}, volume = {}, number = {}, pages = {}, doi = {10.1292/jvms.25-0258}, pmid = {41338979}, issn = {1347-7439}, abstract = {Beta-nicotinamide mononucleotide (beta-NMN) is a direct precursor of nicotinamide adenine dinucleotide (NAD[+]), a coenzyme essential for maintaining homeostasis in living organisms. NMN administration has attracted attention as a potential treatment for aging and age-related conditions, including diabetes, Alzheimer's disease, and chronic kidney disease. Duchenne muscular dystrophy (DMD) is a progressive, degenerative muscle disease caused by X-linked frameshift mutations in the Dmd gene. NAD[+] levels in skeletal muscle decline in DMD pathology. In this study, we explored the therapeutic potential of NMN as an NAD[+] booster for muscular dystrophy by administering NMN to DMD rats, which exhibit severe phenotypes comparable to those of human DMD patients, for 2 months. Although NMN administration did not improve muscle function in DMD rats, it did reduce the release of creatine kinase in their blood. RNA-seq analysis revealed that NMN administration could reverse DMD-related gene expression changes associated with skeletal muscle homeostasis. These results suggest that NMN can protect skeletal muscle against degeneration in DMD and may hold therapeutic potential for DMD patients.}, } @article {pmid41338440, year = {2025}, author = {Zarei, O and Talebi Moghaddam, M and Moradi Vastegani, S}, title = {Machine learning and deep learning in clinical practice: Advancing neurodegenerative disease diagnosis with multimodal markers.}, journal = {Brain research bulletin}, volume = {234}, number = {}, pages = {111667}, doi = {10.1016/j.brainresbull.2025.111667}, pmid = {41338440}, issn = {1873-2747}, abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis, present major global health challenges due to their progressive and incurable nature. Early and accurate diagnosis is critical to slow disease progression and optimize therapeutic interventions, yet conventional diagnostic approaches, such as neuroimaging, cerebrospinal fluid biomarker analysis, and clinical evaluation are often inadequate at the prodromal stage. Recent advances in artificial intelligence, particularly machine learning (ML), have provided new opportunities for precision diagnosis and treatment in neurology, using large data and multimodal biomarkers. Applications of ML to data from neuroimaging, electrophysiology, behavioral functions, speech and handwriting analysis, and molecular biomarkers have shown promising improvements in diagnostic accuracy, patient classification, and therapeutic recommendations. However, significant challenges remain, including data heterogeneity, model interpretability, population diversity, and ethical concerns surrounding patients' privacy. The purpose of this review is to examine current applications of ML in the diagnosis and management of neurodegenerative diseases through various data, highlight its strengths and limitations, and discuss future directions for using these approaches in clinical practice. We also outline emerging directions, including multimodal fusion with longitudinal data, federated and privacy-preserving learning, and the potential of explainable AI (XAI) and large language models (LLMs) in clinical decision support.}, } @article {pmid41338169, year = {2026}, author = {Li, S and Li, X and Li, S and Chen, D and Xia, C}, title = {Discovery of novel hybrids of coumarin and quinoline as potential anti-Alzheimer's disease agent.}, journal = {Bioorganic & medicinal chemistry}, volume = {133}, number = {}, pages = {118499}, doi = {10.1016/j.bmc.2025.118499}, pmid = {41338169}, issn = {1464-3391}, mesh = {*Coumarins/chemistry/pharmacology/therapeutic use ; *Quinolines/chemistry/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; Humans ; Mice ; Structure-Activity Relationship ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis/therapeutic use ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Molecular Structure ; *Drug Discovery ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Oxidative Stress/drug effects ; Dose-Response Relationship, Drug ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Blood-Brain Barrier/metabolism ; Cell Line, Tumor ; }, abstract = {The multifaceted nature of Alzheimer's disease (AD) spurred growing interest in developing multi-target-directed ligands (MTDLs) for its prevention and treatment. Coumarin and quinoline scaffolds, recognized for their broad spectrum of AD-related biological activities including amyloid-β (Aβ) aggregation regulation, cholinesterase (ChE) inhibition, β-secretase 1 (BACE1) inhibition and neuroprotection, were identified as potential building blocks. Here in this study, 24 novel coumarin-quinoline hybrid compounds were rationally designed and synthesized. Inhibition studies targeting Aβ, ChE and BACE1 identified compound B8 as a promising lead compound. B8 exhibited effective binding to Aβ, and significantly attenuated Aβ-induced SH-SY5Y cell death by lowering oxidative stress and decreasing cellular apoptosis. Crucially, B8 demonstrated excellent blood-brain barrier (BBB) permeability, and intragastric administration of B8 to 7-month-old APP/PS1 transgenic mice resulted in improved cognitive function. This improvement was supported by the protection of hippocampal and cortical neurons from necrosis, attenuation of oxidative stress and inflammation in these brain regions, as well as a reduction in Aβ deposition. These findings highlight the potential of coumarin-quinoline hybrids as a novel class of AD therapeutics, with B8 emerging as a promising lead candidate warranting further investigation.}, } @article {pmid41338025, year = {2026}, author = {Wagdy, M and Ibrahim, AA and Yahia, AM and Maher, RM and Abo-Elwafa, AH and Salah, A and Heikal, YM}, title = {Neurobiotech innovative strategies targeting Alzheimer's disease through therapeutic micro and macroalgae potentials.}, journal = {Journal of neuroimmunology}, volume = {411}, number = {}, pages = {578821}, doi = {10.1016/j.jneuroim.2025.578821}, pmid = {41338025}, issn = {1872-8421}, mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; *Seaweed ; Animals ; *Microalgae ; Antioxidants/therapeutic use ; *Neuroprotective Agents/therapeutic use ; Anti-Inflammatory Agents/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder identified by cognitive decline, memory loss, and behavioral changes, affecting approximately 50 million people worldwide. Genetic predisposition, environmental variables, and aging all play a role in the development of AD. Current therapeutic approaches primarily focus on alleviating symptoms through drugs such as donepezil and memantine. However, these treatments offer limited efficacy and may be accompanied by adverse effects. In contrast, natural therapies derived from algae present a promising alternative. Microalgae, including Chlorella and Spirulina, and macroalgae such as Fucus vesiculosus, Ecklonia cava, Sargassum, Laminaria japonica, and Fucus species, are rich in bioactive molecules having antioxidant and anti-inflammatory characteristics. These substances demonstrated potential in addressing the pathological features of AD, such as oxidative stress and neuroinflammation. Furthermore, advances in biotechnological tools like CRISPR-Cas9 gene editing are poised to enhance the efficacy of these natural therapies by targeting and modifying disease-associated genes. This review aims to bridge the fields of neurobiotechnology and marine bioresources by examining the synergistic potential of algal compounds and gene-editing strategies in combating Alzheimer's disease. Algal-derived compounds are utilized in pharmaceuticals, nutraceuticals, and dietary supplements, and may offer neuroprotective benefits that could aid in the prevention or treatment of AD.By integrating insights from molecular biology, pharmacology, and genomics, we seek to illuminate a novel, multidisciplinary framework for future therapeutic innovation.}, } @article {pmid41337426, year = {2025}, author = {Li, J and Gao, Y and Yang, P and Guan, Z and Wang, T and Ma, G and Lei, B}, title = {Multi-Modal Feature Fusion Using Transformer for Early Alzheimer's Disease Diagnosis.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-4}, doi = {10.1109/EMBC58623.2025.11253151}, pmid = {41337426}, issn = {2694-0604}, mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; Deep Learning ; Algorithms ; Early Diagnosis ; }, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder. Early and accurate diagnosis of AD is essential for effective treatment. However, due to the class imbalance problem, there is a significant data gap between different categories. Moreover,the data feature differences of AD are relatively small, which poses challenges for its application in the early diagnosis of AD. To tackle these problems, we propose an intelligent early AD diagnosis model based on Transformer. The deep learning diagnosis model utilizes Transformer to integrate image features and non-image features. Furthermore, it incorporates a class imbalance loss function to optimize the performance of early AD diagnosis, thereby enhancing the model's ability to recognize underrepresented classes. In order to alleviate the problem of class imbalance and test the model performance, we used stratified 5-fold cross validation to verify the model effect.Experimental results demonstrate that our model can significantly improve the accuracy of AD diagnosis, which is markedly better than traditional methods. Additionally, loss function we used more effectively mitigates the problem of class imbalance. We believe this work can effectively reduce the burden on medical staff to diagnose early AD.}, } @article {pmid41337360, year = {2025}, author = {Lee, HP and Arginteanu, T and Kudela, P and Wyse-Sookoo, K and Anderson, WS and Salimpour, Y}, title = {Phase-Dependent Neuromodulation in a Computational Hippocampal Model.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-4}, doi = {10.1109/EMBC58623.2025.11254724}, pmid = {41337360}, issn = {2694-0604}, mesh = {*Hippocampus/physiology ; Humans ; *Models, Neurological ; Computer Simulation ; Theta Rhythm/physiology ; Neurons/physiology ; Animals ; }, abstract = {The critical role of phase-amplitude coupling (PAC) between oscillations of differing frequencies highlights the promise of phase-dependent neuromodulation as a therapeutic strategy for various neurological conditions. In the hippocampus, theta-gamma PAC is linked to key memory processes and information transfer. Computational models avoid technical challenges in in vivo and in vitro experiments and offer a practical alternative for exploring the mechanisms behind phase-dependent effects. In this study, we built on a published CA3 hippocampal computational model implemented in the NEURON-Python environment. We used a closed-loop autoregressive (AR) forward prediction model that sampled the network's local field potential (LFP) to achieve real-time calculation of stimulus time points locked to a target phase of the theta oscillation. Our approach enabled the delivery of current injections to all neuronal populations at either the peak or the trough of the theta rhythm. Analysis of the resulting network LFP showed distinct phase-dependent changes in the theta band during stimulation. The peak-phase stimulation significantly enhanced theta-gamma coupling. Further study on a large-scale human-based model is needed to better capture these phase-dependent effects. Overall, the results underscored the importance of closed-loop stimulation systems and the potential of phase-targeted neuromodulation to influence PAC. These findings offer new avenues for treating disorders marked by disrupted oscillations, including Alzheimer's disease and other memory disorders.Clinical Relevance- This study provides investigations of the origins of neuronal oscillations and the development of a brain stimulation technique for modulating the level of oscillations, possibly contributing to the development of novel treatment methods for neurological disorders associated with abnormal oscillations..}, } @article {pmid41337282, year = {2025}, author = {Uhm, J and Kim, HY and Choe, B and Agrawal, H and Yoon, S and Yun, JH}, title = {Smartphone Keystroke-based Cognitive Impairment Diagnostic Methodology.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-7}, doi = {10.1109/EMBC58623.2025.11253467}, pmid = {41337282}, issn = {2694-0604}, mesh = {Humans ; *Smartphone ; *Cognitive Dysfunction/diagnosis ; Male ; Aged ; Female ; }, abstract = {With the global population rapidly aging, dementia has emerged as a major public health concern. Significant efforts are being made to address the health and other problems associated with dementia. Although several advances have been made in the diagnosis and treatment of dementia, many challenges remain unresolved. Existing dementia diagnostic methods are often not performed in a timely manner due to poor accessibility, leading to delays in initiation of treatment. In this study, we propose a smartphone keystroke-based diagnostic method as a solution to overcome the limitations associated with the early diagnosis and treatment of dementia. As compared to other existing methods, the proposed diagnostic method is easier to develop and maintain, promoting commercialization and widespread use. The diagnostic method has been designed to extract language-agnostic keystroke data features from smartphone keyboard input logs. Rather than simply extracting features assessing motor skills from keystroke data or features demonstrating language usage patterns from text, this study focused on features that can assess cognitive abilities without using linguistic characteristics. Clinical trials were conducted in patients with mild cognitive impairment and early Alzheimer's dementia were conducted, and a series of experiments and validation tests were performed using the trial data. The results demonstrated that the proposed smartphone keystroke-based diagnostic method is effective in diagnosing cognitive impairment. The proposed method does not require the use of any special equipment except smartphones, which facilitates low-cost commercialization. This study presents a diagnostic method that addresses the problem of people who avoid tests for the diagnosis of dementia due to economic and psychological burdens.Clinical RelevanceThis study provides an approach for early detection of dementia using ordinary smartphone keystroke logs. The proposed method has the potential to improve the quality of life of patients with dementia. Following large-scale clinical research and the integration of more digital biomarkers, the methodology proposed in this study can potentially facilitate the development of an early diagnostic platform for dementia.}, } @article {pmid41336985, year = {2025}, author = {Salinas-Medina, A and Gonzalez-Mitjans, A and Toussaint, PJ and Liu, X and Evans, A}, title = {HISRON: AI-Driven GPU-Accelerated Framework for Scalable High-Resolution Neuroimaging Analysis.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-7}, doi = {10.1109/EMBC58623.2025.11253703}, pmid = {41336985}, issn = {2694-0604}, mesh = {Humans ; *Neuroimaging/methods ; *Image Processing, Computer-Assisted/methods ; *Computer Graphics ; Algorithms ; *Artificial Intelligence ; Brain/diagnostic imaging ; }, abstract = {Ultra-high-resolution imaging, particularly cellular neuroimaging, poses challenges from terabyte-scale data and computational complexity. We present HISRON (High-Resolution Scalable Neuroimaging) a GPU-accelerated framework enabling scalable multidimensional analysis, combining unsupervised learning for adaptive feature extraction, benchmarked anisotropic diffusion for noise reduction, and promptable segmentation models with a zero-shot generalization feature. Dynamic overlap-aware tiling maximizes parallelization while preserving spatial context, enabling real-time processing of complex structures. Built on NVIDIA CUDA and CuPy, the framework achieves transformative efficiency: 10x faster noise reduction and detection of 200,000 neuron centroids in 30 seconds (40% pipeline improvement). This advances integration with AI-driven segmentation/classification pipelines, overcoming bottlenecks in high-dimensional computer vision. By emphasizing scalability, our method accelerates analysis of biomedical imaging data, directly supporting translational healthcare innovations in neuroscience. The tool's adaptability underscores its potential for clinical research, enhancing precision in neuroanatomical studies and fostering discoveries in brain function and pathology.Clinical relevance-The proposed framework directly addresses critical challenges in modern clinical neuroimaging, where the analysis of high-resolution data is essential for diagnosing and monitoring neurological disorders such as Alzheimer's, Parkinson's diseases, and epilepsy. By enabling real-time processing of terabyte-scale datasets, this technology reduces delays in image interpretation, facilitating faster decision-making in time-sensitive scenarios, such as intraoperative imaging during neurosurgery or stroke assessment. The zero-shot segmentation model's adaptability ensures robust performance across heterogeneous imaging protocols, which is vital for multicenter clinical studies and personalized treatment planning. Additionally, the framework's efficiency in detecting neuron populations at scale supports large-scale neuroanatomical studies, enhancing our understanding of brain connectivity abnormalities in psychiatric and neurodegenerative conditions. By lowering computational barriers, this tool democratizes access to advanced imaging analytics, empowering clinics with limited resources to adopt precision medicine approaches. These advancements align with the growing demand for AI-driven scalable solutions to improve diagnostic accuracy, accelerate therapeutic discovery, and optimize patient outcomes in neurology and neurorehabilitation.}, } @article {pmid41336397, year = {2025}, author = {Seo, K and Hwang, J and Kim, K and Argrawal, H and Yun, JH and Yoon Kim, H}, title = {End-to-End Classification of Cognitive Impairment Using Daily-Life Gait Data.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-7}, doi = {10.1109/EMBC58623.2025.11254035}, pmid = {41336397}, issn = {2694-0604}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis/physiopathology/classification ; *Gait ; Aged ; Male ; Female ; Middle Aged ; Smartphone ; Accelerometry ; *Activities of Daily Living ; Alzheimer Disease/diagnosis/physiopathology ; Wearable Electronic Devices ; }, abstract = {We investigated the feasibility of using commercial smart devices to prescreen cognitive impairments for timely intervention. A total of 125 individuals aged 50 and older were recruited from a local clinic and categorized into groups based on cognitive diagnosis: Mild Alzheimer's Disease (AD), Mild Cognitive Impairment (MCI), and Subjective Cognitive Decline (SCD).This study focused on distinguishing individuals requiring treatment (AD and MCI) from those without cognitive impairment (SCD) using gait-related data collected from daily life. This classification task was particularly challenging, as the SCD group shares cognitive symptoms with MCI and the data was collected in non-controlled, real-world conditions.Participants used smartphones and smartwatches for one month to collect accelerometer and gyroscope data during daily activities. We preprocessed walking segments and trained a deep learning classifier to differentiate between the two groups. The model achieved an area under the curve (AUC) of 0.70, demonstrating the potential of wearable-based gait analysis for cognitive impairment detection. A sensor ablation study revealed that wrist-worn gyroscope data alone achieved a comparable AUC of 0.70, suggesting a moderate association between arm motion and cognitive impairment. The results further indicated that integrating smartphone accelerometers and smartwatch gyroscopes enhanced classification performance.This study is part of a broader multimodal research initiative that integrates gait analysis with voice recordings, phone usage patterns, and other behavioral data to improve cognitive impairment classification. Future work will explore multi-modal fusion techniques to enhance accuracy and reliability, with the long-term goal of developing accessible, real-world screening tools for early detection.}, } @article {pmid41336106, year = {2025}, author = {Shanmugasundaram, S and K, GG and Sinha, N}, title = {EEG Complexity Measures for Alzheimer's and Frontotemporal Dementia Classification Using Explainable Machine Learning.}, journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference}, volume = {2025}, number = {}, pages = {1-7}, doi = {10.1109/EMBC58623.2025.11253046}, pmid = {41336106}, issn = {2694-0604}, mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology/classification ; *Electroencephalography/methods ; *Frontotemporal Dementia/diagnosis/physiopathology/classification ; *Machine Learning ; Male ; Female ; Aged ; Signal Processing, Computer-Assisted ; Middle Aged ; }, abstract = {This study aimed to classify patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) from healthy controls (CN) using non-linear EEG features. We explored various classification tasks, including binary classifications (CN vs. AD, CN vs. FTD, FTD vs. AD) and multi-class classifications, employing machine learning models such as XGBoost, multi-layer perceptron, k-nearest neighbors, and support vector machines. To understand the model's decision-making process, we employed explainable AI (XAI) using SHAP (SHapley Additive exPlanations) analysis. An EEG dataset of 88 subjects: 36 with AD, 29 controls, and 23 with FTD, was used. The occipital electrode O2 played a crucial role in differentiating AD from controls. In both FTD vs. AD and CN vs. FTD classifications, features from the frontal and temporal electrodes exhibited the highest importance. The results showed that XGB and MLP perform best across all classification tasks, with 100% accuracy achieved in CN vs. AD classification and area under the curve values of 0.99 for most classifiers. Distinguishing unhealthy patients (AD and FTD) from healthy controls yielded lower performance, potentially due to the differential EEG signal alterations in these conditions. The multi-class classification of AD, FTD, and controls achieved accuracy of 82%, lower than the binary classification tasks. The study proposed a novel methodology combining non-linear EEG features and machine learning models, offering the potential for improved disease detection.Clinical relevance- This study offers the potential to provide a non-invasive, efficient method for early detection and differentiation of AD and FTD from healthy controls. The ability to classify these neurodegenerative diseases using EEG, a widely accessible and cost-effective tool, could significantly aid in the timely diagnosis and monitoring of disease progression. This could lead to more personalized treatment plans and improved patient care.}, } @article {pmid41335145, year = {2025}, author = {Banu, Z and Das, NR}, title = {Protective effects of alkaloidal fraction of Elaeocarpus angustifolius Blume against AlCl3-evoked neurotoxicity: insights from an in vivo model of Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {8}, pages = {330}, pmid = {41335145}, issn = {1573-7365}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Aluminum Chloride/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; Male ; *Plant Extracts/pharmacology/therapeutic use ; Disease Models, Animal ; *Alkaloids/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism/pathology ; Oxidative Stress/drug effects ; Maze Learning/drug effects ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and neuronal degeneration. Current treatments offer limited efficacy. Elaeocarpus angustifolius Blume (Rudraksha), used traditionally in Ayurveda for neurological disorders, has shown potential for cognitive health, warranting investigation in AD models. This study aimed to evaluate the neuroprotective efficacy of an alkaloid-rich fraction of E. angustifolius (EAF) in an AlCl3-induced rat model of AD. AD-like symptoms were induced by oral administration of AlCl3 (100 mg/kg) for 60 days, followed by a 30-day oral treatment with EAF (200 and 400 mg/kg). Cognitive performance was assessed using the Morris water maze, elevated plus maze, novel object recognition, and locomotor activity tests. Biochemical and molecular markers were analysed, and hippocampal histopathology was conducted. AlCl3 exposure caused significant cognitive and motor deficits, elevated Aβ1-42 and phosphorylated tau, decreased acetylcholine and dopamine, increased glutamate and NF-κB, and reduced NRF-2 expression, indicating oxidative stress and neuroinflammation. EAF treatment significantly improved behavioral outcomes, reduced Aβ1-42 and tau levels, restored neurotransmitter balance, enhanced antioxidant markers (GSH, SOD, CAT), and reduced MDA. It suppressed NF-κB and upregulated NRF-2, suggesting antioxidant and anti-inflammatory effects. Histopathological analysis confirmed hippocampal neuroprotection. EAF exhibited significant neuroprotective effects by mitigating oxidative stress, neuroinflammation, and AD-related pathologies, including amyloid accumulation and cholinergic dysfunction. These findings support the potential of EAF as a therapeutic candidate for AD prevention and management.}, } @article {pmid41333818, year = {2025}, author = {An, L and Zhang, J and Wang, X and Ge, Y and Sun, K and Dong, J and Wang, P and Li, W and Li, M and Hu, X and Wang, B and Yu, XA}, title = {Nanocarriers based therapy and diagnosis of brain diseases: cross the blood-brain barrier.}, journal = {Science and technology of advanced materials}, volume = {26}, number = {1}, pages = {2554048}, pmid = {41333818}, issn = {1468-6996}, abstract = {The blood-brain barrier (BBB) is the protective interface that isolates the central nervous system from circulating blood, which restricts approximately 98% of small molecule drugs and nearly all large molecules from entering the brain. Current methods to bypass the BBB, such as laser-guided interstitial thermal therapy and magnetic resonance guided focused ultrasound, are fraught with risks like impairing BBB integrity and brain damage, and are not suitable for long-term treatment. Nanocarriers have emerged as promising tools due to their ability to enhance drug delivery across the BBB while minimizing systemic toxicity. These nanocarriers leverage mechanisms including receptor-mediated, carrier-mediated, cell mediated and extra-stimuli mediated transport to improve BBB traverse and brain targeting. The review evaluates these strategies separately, discussing their potential and limitations for clinical application, and highlights recent advancements in integrating and optimizing nanocarriers utilizing synergistic strategies for the treatment and diagnosis of neurological disorders, including tumors, Alzheimer's disease, Parkinson's disease, and brain infections.}, } @article {pmid41332987, year = {2025}, author = {Huai, JX and Chang, EE and Zhu, YR and Ma, WL and Lv, TS and Sun, J and Zhou, XQ}, title = {Diabetic encephalopathy: metabolic reprogramming as a potential driver of accelerated brain aging and cognitive decline.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1701406}, pmid = {41332987}, issn = {2296-634X}, abstract = {Diabetic encephalopathy (DE) is a serious neurological complication of diabetes and is expressed as progressive decline in cognitive function, emotional disorders, and changes in brain structure. This review brings together the relevant evidence and demonstrates that metabolic reprogramming, the adaptive reconfiguration of the core metabolic pathway in response to hyperglycemia, is a potential driver of accelerated brain aging in DE. The main pathological characteristics are: abnormal brain insulin signaling, resulting in a decrease in neuronal glucose intake and a decrease in mitochondrial oxidative phosphorylation, oxidative stress and neuroinflammation caused by high blood sugar, in which excess reactive oxygen species (ROS), impairs mitochondrial integrity and leads to activation of microglia cells. The impaired mitophagy and the macrophages remove defects and cause the accumulation and energy collapse of the dysfunctional organelles. In addition, it promotes excessive glycolytic flux, lipolysis disorder, lactic acid accumulation, and ceramide-dependent synaptic damage. We further examine shared metabolic mechanisms between DE and neurodegenerative diseases such as alzheimer's disease (AD) and treatment strategies for pathological metabolic reprogramming including GLP-1 receptor agonists, NAD[+] boosters, and AMPK activators. This analysis laid the foundation for new intervention measures against the development of DE.}, } @article {pmid41332414, year = {2025}, author = {Zhao, X and Xu, Z and Wang, D and Li, T and Xu, L and Li, Z and Bai, X and Zhu, H and Liu, Y and Wang, Y}, title = {Nanotechnology-based targeted regulation of NLRP3 Inflammasome: therapeutic strategies and clinical application prospects in inflammatory diseases.}, journal = {Drug delivery}, volume = {32}, number = {1}, pages = {2580730}, pmid = {41332414}, issn = {1521-0464}, mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; Humans ; *Inflammasomes/metabolism ; Animals ; *Inflammation/drug therapy/metabolism ; Drug Delivery Systems/methods ; Nanotechnology/methods ; *Anti-Inflammatory Agents/administration & dosage/pharmacology ; Reactive Oxygen Species/metabolism ; Nanoparticles ; Nanomedicine/methods ; }, abstract = {The NLRP3 inflammasome plays a critical role in the onset and progression of various inflammatory diseases, making targeting its activation an important research direction for treating these conditions. Nanotechnology can effectively inhibit the activation of the NLRP3 inflammasome through several mechanisms, such as scavenging reactive oxygen species (ROS), regulating calcium ion flux, and stabilizing mitochondrial function, thereby alleviating inflammation and promoting tissue repair. Studies have demonstrated that nanomaterials exhibit promising anti-inflammatory effects in animal models, showing broad application potential, particularly in the treatment of conditions such as atherosclerosis, diabetes, and Alzheimer's disease. However, the clinical translation of nanotherapy still faces numerous challenges, including issues related to material biocompatibility, long-term safety, targeting efficiency, and controlled drug delivery. Future research should integrate targeting ligands, responsive materials, and multifunctional nanoplatforms to enhance the specificity and efficacy of treatments while minimizing side effects. Additionally, the prospects of nanotechnology in personalized treatment and clinical applications are substantial, necessitating further integration of basic research with clinical validation to expedite the clinical translation of NLRP3-targeted nanomedicines.}, } @article {pmid41331838, year = {2025}, author = {Kumar, N and Jangid, K and Kumar, V and Devi, B and Arora, T and Mishra, J and Kumar, V and Dwivedi, AR and Parkash, J and Bhatti, JS and Kumar, V}, title = {Investigations of 3-Hydroxy Chromone Derivatives as Multipotent Therapeutics for the Treatment of Alzheimer's Disease: In Silico and In Vitro Interventions and Fluorescence Studies.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {24}, pages = {4751-4768}, doi = {10.1021/acschemneuro.5c00847}, pmid = {41331838}, issn = {1948-7193}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Cholinesterase Inhibitors/pharmacology/chemistry ; Monoamine Oxidase/metabolism ; Monoamine Oxidase Inhibitors/pharmacology/chemistry ; *Chromones/pharmacology/chemistry ; Amyloid beta-Peptides/metabolism ; Acetylcholinesterase/metabolism ; *Neuroprotective Agents/pharmacology/chemistry ; Cell Line, Tumor ; Antioxidants/pharmacology ; Reactive Oxygen Species/metabolism ; Molecular Docking Simulation ; }, abstract = {Chromone-based small organic molecules are designed and synthesized as putative multipotent ligands to intervene in several interlinked pathological pathways of Alzheimer's disease. The synthesized compounds were evaluated as acetylcholinesterase, monoamine oxidase, and amyloid β aggregation inhibitors using biochemical assays. Most of the compounds were found to inhibit the enzymes in a lower micromolar concentration range. In the series, two compounds, i.e., NSS-16 and NSS-18, displayed a balanced activity profile with the IC50 values of 1.77 and 1.53 μM against AChE and 2.06 and 1.51 μM against MAO-B. NSS-16 and NSS-18 showed moderate inhibitory activity against the self-induced Aβ aggregation with inhibition percentages of 17.8 and 24.0%, respectively. These compounds also showed potent antioxidant activity and formed metal chelates. In addition, the compounds were tested against SH-SY5Y neuronal cells and found to be neuroprotective and noncytotoxic. Moreover, the compounds inhibited reactive oxygen species (ROS) production up to 70% and exhibited a mixed type of inhibition in enzyme kinetic studies of AChE. These chromone derivatives showed a strong fluorescence intensity with a quantum yield of 30-50% and can be utilized in various biological studies including in vitro and in vivo assessments. Computational studies showed that the lead compounds fit well in the active cavity of enzymes and displayed thermodynamic stability for a time interval of 100 ns. Thus, these compounds displayed a multipotent activity profile and have the potential to be developed as potential therapeutics for AD.}, } @article {pmid41330788, year = {2025}, author = {Zimmer, JA and Sims, JR and Evans, CD and Nery, ESM and Wang, H and Wessels, AM and Tronchin, G and Sato, S and Raket, LL and Andersen, SW and Sapin, C and Paget, MA and Gueorguieva, I and Ardayfio, P and Khanna, R and Brooks, DA and Matthews, BR and Mintun, MA and , }, title = {Donanemab in early symptomatic Alzheimer's disease: results from the TRAILBLAZER-ALZ 2 long-term extension.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100446}, doi = {10.1016/j.tjpad.2025.100446}, pmid = {41330788}, issn = {2426-0266}, abstract = {BACKGROUND: Donanemab significantly slowed clinical progression in participants with early symptomatic Alzheimer's disease (AD) during the 76-week placebo-controlled period of TRAILBLAZER-ALZ 2.

METHODS: Participants who completed the placebo-controlled period were eligible for the 78-week, double-blind, long-term extension (LTE). Early-start participants were randomized to donanemab in the placebo-controlled period. Delayed-start participants (randomized to placebo) started donanemab in the LTE. Participants who met amyloid treatment course completion criteria were switched to placebo. An external control cohort comprised participants from the AD Neuroimaging Initiative (ADNI).

RESULTS: At 3 years, donanemab slowed disease progression on the Clinical Dementia Rating Scale (CDR)-Sum of Boxes (CDR-SB) in early-start participants versus a weighted ADNI control (-1.2 points; 95 % confidence interval [CI], -1.7, -0.7). Seventy-six weeks after initiating donanemab, delayed-start participants also demonstrated slower CDR-SB progression versus a weighted ADNI control (-0.8 points; 95 % CI, -1.3, -0.3). Participants who completed treatment by 52 weeks demonstrated similar slowing of CDR-SB progression at 3 years. Compared with delayed-start participants, early-start participants demonstrated a significantly lower risk of disease progression on the CDR-Global over 3 years (hazard ratio=0.73; p < 0.001). In both groups, >75 % of participants assessed by positron emission tomography 76 weeks after starting donanemab achieved amyloid clearance (<24.1 Centiloids). The addition of LTE data to prior modeling predicted a median reaccumulation rate of 2.4 Centiloids/year. No new safety signals were observed compared to the established donanemab safety profile.

CONCLUSIONS: Over 3 years, donanemab-treated participants with early symptomatic AD demonstrated increasing clinical benefits and a consistent safety profile, with limited-duration dosing.

TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04437511.}, } @article {pmid41330635, year = {2025}, author = {Crowe, A and Yao, Y and Newman, M and Hoxha, K and Baffic, T and Brunden, KR}, title = {HDAC6 Inhibition Reduces Seeded Tau and α-Synuclein Pathologies in Primary Neuron Cultures and Wild-type Mice.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {}, number = {}, pages = {}, doi = {10.1523/JNEUROSCI.1092-25.2025}, pmid = {41330635}, issn = {1529-2401}, abstract = {A previous compound screen identified two molecules with histone deacetylase 6 (HDAC6) inhibitory activity that reduced Alzheimer's disease (AD)-like tau inclusions in a primary rat cortical neuron model seeded with AD-brain derived tau fibrils. Testing here of additional HDAC6-selective inhibitors confirmed that compounds of this type decreased neuronal tau inclusions. Moreover, HDAC6 inhibitors also reduced Parkinson's disease (PD)-like α-synuclein aggregates in primary neurons seeded with recombinant α-synuclein fibrils. Knockdown of HDAC6 expression through treatment of seeded neuron cultures with AAV harboring HDAC6-specific shRNA also resulted in a reduction of tau and α-synuclein inclusions. Multiple compounds were evaluated for their ability to inhibit brain HDAC6 in mice, and ACY-738 was found to effectively inhibit brain HDAC6 activity upon oral dosing. ACY-738 was utilized in an efficacy study in which tau and α-synuclein pathologies were induced in wild-type mice through intracerebral injections of AD-brain derived tau and α-synuclein fibrils. Groups of male and female mice first received ACY-738 in drinking water one day prior to (pre-seeding) or one week after (post-seeding) brain injections of fibrils, followed by continued dosing for an additional 3 months. A control group of fibril-injected mice received water without ACY-738. Immunohistochemical evaluations revealed that ACY-738 administration resulted in significant reductions of tau pathology in both dosing schemes. Moreover, α-synuclein pathology was significantly reduced in mice with pre-seeding ACY-738 administration, with a strong trend toward reduction after post-seeding dosing. These results suggest that HDAC6 inhibitors have potential for the treatment of AD, PD and related diseases.Significance Statement The spread and abundance of brain tau pathology correlate with AD patient cognitive status, and there are presently no approved drugs that target tau. We demonstrate that HDAC6 inhibition or knockdown reduce both tau and α-synuclein inclusions that develop in wild-type rodent neuron models. A preferred HDAC6 inhibitor, ACY-738, was identified that inhibits brain HDAC6 when administered orally to mice. This compound was examined in a wild-type mouse model that develops concurrent seeded tau and α-synuclein brain inclusions. Significant reductions of both tau and α-synuclein inclusions were observed in mice dosed with ACY-738, suggesting that HDAC6 inhibition may be a therapeutic strategy for AD, PD and related diseases.}, } @article {pmid41330156, year = {2026}, author = {Costa, A and Provensi, G and Titi, C and Leri, M and Bucciantini, M and Ferraroni, M and Keeton, AB and Moore, AM and Piazza, GA and Abadi, AH and Angeli, A and Supuran, CT}, title = {Exploring dual inhibitors Carbonic Anhydrases and Phosphodiesterase 5 as potential agents for treatment Alzheimer's disease.}, journal = {European journal of medicinal chemistry}, volume = {303}, number = {}, pages = {118404}, doi = {10.1016/j.ejmech.2025.118404}, pmid = {41330156}, issn = {1768-3254}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Carbonic Anhydrase Inhibitors/pharmacology/chemistry/chemical synthesis/therapeutic use ; Animals ; Mice ; *Phosphodiesterase 5 Inhibitors/pharmacology/chemistry/chemical synthesis/therapeutic use ; Structure-Activity Relationship ; Molecular Structure ; *Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism ; Dose-Response Relationship, Drug ; *Carbonic Anhydrases/metabolism ; Cell Survival/drug effects ; Amyloid beta-Peptides/antagonists & inhibitors ; Cell Line, Tumor ; Male ; Crystallography, X-Ray ; }, abstract = {In this study, we report for the first time the design and evaluation of a series of compounds with potential therapeutic relevance for Alzheimer's disease (AD), able to inhibit both human Carbonic Anhydrase (hCA) isoforms most involved in this disease as well as Phosphodiesterase 5 (PDE5), using sildenafil as the structural scaffold. A total of 19 new dual-target molecules were synthesized and biologically assessed, leading to the identification of compound 8a as the most promising candidate, exhibiting potent inhibition toward both enzymatic targets. The binding interactions of three selected derivatives (6, 8a, and 10d) with hCA II were elucidated by X-ray crystallography experiments. Moreover, compound 8a demonstrated a favourable safety profile, as it did not markedly impair cell viability on differentiated SH-SY5Y at concentrations up to 100 μM and conferred protection against Aβ-induced cytotoxicity showing superior efficacy compared to the single-target reference agents acetazolamide (AAZ) and sildenafil in mitigating oxidative stress. In vivo, chronic administration of compound 8a prevented deficits in both recognition and working memory in Aβ1-42-infused mice, outperforming vehicle-treated controls. Collectively, these findings highlight the potential of dual CA/PDE5 inhibition as a novel therapeutic strategy for Alzheimer's disease.}, } @article {pmid41329964, year = {2025}, author = {Chen, M and Tang, G and Zhang, Y and Qian, ZJ}, title = {Exploring the Protective Effects of Two Alkaloids 1 and 2 from Aspergillus terreus C23-3 on Neuronal Cells by Combining Bioinformatics Prediction and Experimental Verification.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {24}, pages = {4700-4710}, doi = {10.1021/acschemneuro.5c00739}, pmid = {41329964}, issn = {1948-7193}, mesh = {*Aspergillus/chemistry ; *Alkaloids/pharmacology ; *Neurons/drug effects/metabolism ; Animals ; *Neuroprotective Agents/pharmacology ; Molecular Docking Simulation ; Apoptosis/drug effects ; Mice ; Glycogen Synthase Kinase 3 beta/metabolism ; Computational Biology/methods ; Phosphorylation/drug effects ; Cell Line ; Cell Survival/drug effects ; }, abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease that can lead to brain cell death and brain atrophy, manifested as memory loss, cognitive decline, and behavioral abnormalities. Its mechanism is complex, and there is currently no effective treatment method. The search for new therapies and natural drug candidates has become the focus of research. In recent years, marine-derived strains of Aspergillus terreus have become an important research direction for treating AD due to the unique structure and biological activity of their secondary metabolites. In this study, we investigated the potential of two alkaloids from Aspergillus terreus C23-3 in the treatment of AD through bioinformatics analysis and experimental validation. Bioinformatics analyses showed that the two alkaloids may act by modulating key targets associated with AD, especially alkaloid 2, which may exert significant therapeutic effects on AD by inhibiting glycogen synthase kinase-3β (GSK-3β) activity and reducing the level of hyperphosphorylation of Tau proteins. Molecular docking experiments showed that alkaloids 1 and 2 formed stable complexes with GSK-3β with a high affinity. Cellular experiments showed that alkaloids 1 and 2 could effectively inhibit apoptosis and injury in HT-22 cells. Further studies showed that alkaloid 2 reduced the phosphorylation level of Tau protein and attenuated oxidative-stress-induced neurological injury by inhibiting GSK-3β and its related pathways. These results suggest that alkaloid 2 has significant potential for AD therapy.}, } @article {pmid41328628, year = {2026}, author = {Ren, S and Singh, J and Gsteiger, S and Cogley, C and Reed, B and Abrams, KR and Dawoud, D and Owen, RK and Tappenden, P and Quinn, TJ and Bujkiewicz, S}, title = {Evaluating amyloid-beta as a surrogate endpoint in trials of anti-amyloid-beta drugs in Alzheimer's disease: a Bayesian meta-analysis.}, journal = {Journal of comparative effectiveness research}, volume = {15}, number = {1}, pages = {e250095}, pmid = {41328628}, issn = {2042-6313}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Bayes Theorem ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Biomarkers/metabolism ; Randomized Controlled Trials as Topic ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Antibodies, Monoclonal/therapeutic use ; }, abstract = {Aim: The use of amyloid-beta (Aβ) clearance to support regulatory approvals of drugs in Alzheimer's disease (AD) remains controversial. We evaluate Aβ as a potential trial-level surrogate endpoint for clinical function in AD. Materials & methods: Data on the effectiveness of anti-Aβ monoclonal antibodies (MABs) on Aβ and multiple clinical outcomes were identified from randomized controlled trials through a literature review. A Bayesian bivariate meta-analysis was used to evaluate Aβ as a surrogate endpoint for clinical function across all MABs and for each individual anti-Aβ MAB. The analysis for individual therapies was conducted in subgroups of treatments and by applying Bayesian hierarchical models to borrow information across treatments. Results: We identified 23 randomized controlled trials with 39 treatment contrasts for seven MABs. The surrogate relationship between treatment effects on Aβ and Clinical Dementia Rating-Sum of Boxes (CDR-SOB) across all MABs was strong: with a meaningful slope of 1.41 (0.60, 2.21) and small variance of 0.02 (0.00, 0.05). For individual treatments, the surrogate relationships were suboptimal, displaying large uncertainty. Sharing information across treatments considerably reduced the uncertainty, resulting in moderate surrogate relationships for aducanumab and lecanemab. No meaningful association was detected for other clinical outcomes, including Mini Mental State Examination and Alzheimer's Disease Assessment Scale-Cognitive Subscale. Conclusion: Although our results from the analysis of data across all MABs suggested that Aβ was a potential surrogate endpoint for CDR-SOB, individually the surrogacy patterns varied across treatments and showed no evidence of association. Bayesian information-sharing revealed moderate surrogate relationship only for aducanumab and lecanemab.}, } @article {pmid41328259, year = {2025}, author = {Shan, G and Cummings, J}, title = {Assessing safety and efficacy in subpopulations in Alzheimer's disease clinical trials: contextualizing representativeness.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {4}, pages = {e70186}, pmid = {41328259}, issn = {2352-8737}, abstract = {UNLABELLED: Efficacy outcomes in clinical trials are based on well-powered analyes of the entire participating population. Trial populations will comprise many types of demographic and biological subgroups, including individuals of different sexes, groups of older and younger individuals, participants with or without the apolipoprotein E ε4 (APOE) genotype, ethnoracial groups, participants from urban versus rural communities, participants with lower and higher educational levels, or individuals who have or have not undergone previous therapies such as anti-amyloid monoclonal antibodies (MABs). Each subgroups is underpowered to draw definitive outcomes, and analyses can lead to inaccurate conclusions. Disciplined subgroup analysis can be hypothesis generating and can help guide drug development decision-making. The risks associated with subgroup analysis can be mitigated by using standard terminology, prespecifying outcomes of interest, stratifying randomization, conducting interaction analyses to identify confounds, and limiting the number of subgroup comparisons. Alternative efficacy and safety analyses such as the interaction test and non-inferiority analyses may yield important insights. Together, these design and analytic straegies may allow trialists to avoid spurious interpretations and derive more informative conclusions regarding the impact of therapy on subgroups in Alzheimer's disease (AD) clinical trials. Greater understanding of safety and efficacy in the subgroups participating in trials is crtically important for indicating what conclusions can be generalized if the candidate therapy is approved.

HIGHLIGHTS: Clinical trials are sized to allow well-powered conclusions based on analysis of the entire participating population.Trial populations geared to be representative of the subgroups of the older population with AD are underpowered to allow drawing confident conclusions about efficacy or safety in subgroups.Strategies such as non-inferiority analysis combined with transparent reporting of the analytic framework may facilitate understanding treatment efficacy and safety in subgroups.}, } @article {pmid41327837, year = {2025}, author = {Padture, A and Gupta, S and Sivaram, A and Swamy, KV}, title = {Repurposing of Potential Curcumin Derivatives Against Cyclooxygenase-2 Using In Silico Methods and Its Implications in Neurological Disorders.}, journal = {Biotechnology and applied biochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1002/bab.70106}, pmid = {41327837}, issn = {1470-8744}, abstract = {Cyclooxygenase-2 (COX-2) plays a crucial role in inflammatory responses and has been implicated in neuroinflammatory processes associated with neurological disorders such as Alzheimer's disease. While selective COX-2 inhibitors (coxib class of drugs) have been developed, their use is limited by adverse effects, necessitating the exploration of alternative therapeutic approaches. This study investigates the potential of curcumin derivatives as COX-2 inhibitors and their possible therapeutic applications in neurological disorders. Previous in silico studies show various amino acids interacting with naturally occurring curcumin derivatives. We explored the potential of 2561 curcumin derivatives as COX-2 enzyme inhibitors by examining their binding affinity to the protein. Using molecular docking, we assessed their interactions with two regions of COX-2, identifying five standout compounds with powerful binding affinities. The binding energies of these compounds lie around -10.7 and -10.6 kcal/mol. To better understand how these top candidates behave in a dynamic biological environment, we ran molecular dynamics simulations focusing on their interactions with one part of the enzyme. These simulations revealed that the compounds formed stable complexes with COX-2, maintaining consistent hydrogen bonds and hydrophobic contacts throughout. RMSD and RMSF graphs exhibit greater stability of these compounds as compared to the control molecule. Finally, energy calculations confirmed that these interactions were not only stable but also energetically favorable, suggesting that several curcumin derivatives could be promising COX-2 inhibitors. This study provides valuable insights into the potential of curcumin derivatives as COX-2 inhibitors and their possible therapeutic applications in neurological disorders. The identified compounds warrant further investigation through in vitro and in vivo studies to validate their efficacy and safety as potential alternatives to current selective COX-2 inhibitors in the treatment of neuroinflammatory conditions.}, } @article {pmid41327376, year = {2025}, author = {Liu, LR and Li, L and Lu, LL and Fan, SJ and Liu, LZ and He, RB and Li, H and Xian, XH and Li, WB}, title = {Ceftriaxone alleviates mitochondrial damage through the inhibition of extrasynaptic NMDA receptor-mediated changes in intracellular calcium levels to improve cognitive deficits in APP/PS1 mice.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {253}, pmid = {41327376}, issn = {1758-9193}, support = {H2024206387//Natural Science Foundation of Hebei Province/ ; 81971007//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Ceftriaxone/pharmacology/therapeutic use ; *Mitochondria/drug effects/metabolism ; Mice ; *Calcium/metabolism ; *Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; *Cognitive Dysfunction/drug therapy/metabolism ; Mice, Transgenic ; Mice, Inbred C57BL ; Presenilin-1/genetics ; Male ; Amyloid beta-Protein Precursor/genetics ; Disease Models, Animal ; Alzheimer Disease/metabolism ; Hippocampus/drug effects/metabolism ; Excitatory Amino Acid Transporter 2/metabolism/genetics ; }, abstract = {BACKGROUND: Mitochondrial dysfunction and dysregulated calcium homeostasis contribute to Alzheimer's disease (AD) pathogenesis. The extrasynaptic N-methyl-D-aspartic acid (NMDA) receptor (eNMDAR) plays a crucial role in calcium influx and subsequent signaling cascades. In individuals with AD, the reduced expression and function of glutamate transporter-1 (GLT-1) result in glutamate spillover from the synaptic clefts to the extrasynaptic region, thereby activating eNMDAR and inducing mitochondrial damage. Ceftriaxone (Cef) has been reported to ameliorate cognitive deficits in APPswe/PS1dE9 (APP/PS1) mice by upregulating GLT-1. This study aimed to explore whether Cef alleviates mitochondrial dysfunction to improve cognitive impairment and the roles of GLT-1 and eNMDAR, particularly the participation of eNMDAR-induced intracellular calcium signaling in this process.

METHODS: C57BL/6J, APP/PS1, and GLT-1-knockdown APP/PS1 mice were used. NMDA (1 mM, 2 µL per ventricle) was injected cerebroventricularly into APP/PS1 mice once to activate eNMDAR. Cef (200 mg/kg) was intraperitoneally administered for 14 days. Cognitive function was evaluated by novel object recognition, novel location recognition and Morris water maze tests. Hippocampal mitochondrial ultrastructure was observed using transmission electron microscopy. Hippocampal mitochondrial membrane potential (MMP) was detected using JC-1 staining. The expression of eNMDAR and proteins related to mitochondrial biogenesis and dynamics was evaluated by western blot. A neuron‒astrocyte coculture derived from the cerebral cortex of embryonic mice was used to evaluate the effects of Cef on eNMDAR-induced neuronal calcium influx, mitochondrial calcium accumulation and MMP loss using live-cell imaging.

RESULTS: Cef treatment attenuated hippocampal mitochondrial dysfunction, including ultrastructural damage, reduced aspect ratio, dysregulation of MMP, impaired biogenesis and dynamics, and cognitive deficits, and prevented the upregulation of eNMDAR expression in APP/PS1 mice in a GLT-1-dependent manner. These protective effects on hippocampal mitochondrial dysfunction and cognitive deficits were counteracted by eNMDAR activation. Furthermore, Cef incubation inhibited eNMDAR-mediated calcium influx in a GLT-1-dependent way and reduced MMP in primary cortical neurons. Notably, Cef incubation significantly suppressed mitochondrial calcium overload, which was mechanistically linked to the observed decline in MMP.

CONCLUSIONS: Cef treatment prevented the upregulation of eNMDAR expression and the subsequent extracellular calcium influx in a GLT-1-dependent manner, thereby reducing mitochondrial calcium loading and ultimately mitigating mitochondrial damage and cognitive deficits in APP/PS1 mice.}, } @article {pmid41327179, year = {2025}, author = {Eshak, D and Arumugam, M}, title = {Nanomaterials: an overview of current trends and future prospects in neurological disorder treatment.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {1366}, pmid = {41327179}, issn = {1479-5876}, mesh = {Humans ; *Nervous System Diseases/therapy/drug therapy ; *Nanostructures/therapeutic use/chemistry ; Animals ; Blood-Brain Barrier ; }, abstract = {The World Health Organization (WHO) has identified neurological disorders (NDs) as one of the major health concerns worldwide, resulting in high mortality rates. NDs are conditions affecting the central and peripheral nervous systems, including the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, neuromuscular junctions, and muscles. These neurological diseases include Alzheimer's disease, Parkinson's disease, glioma/brain cancer, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, neuroinfections, ischemic stroke, trauma, hypoxia/anoxia, and depression. Unfortunately, these disorders remain difficult to treat due to the limited ability of conventional drugs to cross the blood-brain barrier (BBB) and achieve significant pharmacological effects in the brain. There is an urgent need to develop methods that can enhance drug efficacy and bypass the BBB. The application of various nanomaterials represents a promising approach to address these neurological disorders. Drugs incorporated with nanomaterials help improve therapeutic outcomes, reduce toxicity, provide better stability, enable targeted delivery, and enhance drug loading capacity. Numerous types and morphologies of inorganic and organic nanomaterials are increasingly employed for treating NDs, including quantum dots, dendrimers, metal nanoparticles, polymeric nanoparticles, liposomes, carbon nanotubes, metal oxide nanoparticles, and micelles. Their exceptional properties such as sensitivity, selectivity, and potential to bypass the BBB make them suitable for both diagnosis and treatment of NDs. In this review article, we briefly summarize the etiology and pathophysiology of various NDs along with current literature highlighting the use of nanomaterials for treating neurological disorders.}, } @article {pmid41326296, year = {2025}, author = {Welchman, AE and Kourtzi, Z}, title = {Solving the 'Goldilocks problem' in dementia clinical trials with multimodal AI.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100397}, doi = {10.1016/j.tjpad.2025.100397}, pmid = {41326296}, issn = {2426-0266}, abstract = {The development of effective therapeutics for Alzheimer's Disease and related dementias (ADRD) has been hindered by patient heterogeneity and the limitations of current diagnostic tools. New treatments have no chance of working if given to patients who cannot benefit from them. This perspective explores how advances in Artificial Intelligence (AI), particularly multimodal machine learning, can solve the 'Goldilocks problem' of identifying patients for inclusion in clinical trials and support precision treatment in real-world healthcare settings. We examine the challenges of patient stratification, grounded by a conceptual framework of identifying each person's stage and subtype of dementia. We review data from several clinical trials of Alzheimer's disease therapeutics, to explore how AI-guided patient stratification can improve trial outcomes, reduce costs and improve recruitment. Further, we discuss the integration of AI into clinical workflows, the importance of model interpretability and generalizability, and ethical imperative to address algorithmic bias. By combining AI with scientific insight, clinical expertise, and patient experience, we argue that intelligent analytics can accelerate the discovery and delivery of new diagnostics and therapeutics, ultimately transforming dementia care and improving outcomes for patients around the globe.}, } @article {pmid41326295, year = {2025}, author = {Au, R and Popp, Z and Low, S and Ashton, NJ and Zetterberg, H}, title = {Reinventing "N" in the A/T/N framework: The case for digital.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {}, number = {}, pages = {100395}, doi = {10.1016/j.tjpad.2025.100395}, pmid = {41326295}, issn = {2426-0266}, abstract = {Breakthroughs in biomarkers for amyloid (A), tau (T), and neurodegeneration (N) have advanced the prospects of accurate Alzheimer's disease (AD) diagnosis. However, presence of pathology does not always translate into clinical expression and there are still clear knowledge gaps as to whether someone with AD biological indicators will lead to clinically apparent disease necessary to warrant drug treatments that carry toxicity risk. Reliance on decades-old assessment tools inhibits detection and monitoring at preclinical and early disease stages when new treatments could prove most effective. Evidence has accumulated that digital measures provide accurate detection of disease at early stages. We call for a re-evaluation of the A/T/N diagnostic framework, with digital evaluation measures complementing non-AD specific neurodegeneration markers, and even potentially replacing those non-specific to AD, to provide a clinically relevant feature critical to clinical trial advances and treatment decisions. Achieving this will only be possible if further research into novel digital evaluation tools is pursued with the same support and consideration as amyloid and tau.}, } @article {pmid41325816, year = {2026}, author = {Farhana, F and Sultana, MA and Hia, RA and Hegde, V}, title = {Postmenopausal sarcopenia and Alzheimer's disease: The interplay of mitochondria, insulin resistance, and myokines.}, journal = {Neuroscience and biobehavioral reviews}, volume = {180}, number = {}, pages = {106501}, doi = {10.1016/j.neubiorev.2025.106501}, pmid = {41325816}, issn = {1873-7528}, mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology ; *Sarcopenia/metabolism/physiopathology ; *Insulin Resistance/physiology ; *Postmenopause/metabolism ; Female ; *Mitochondria/metabolism ; Animals ; Muscle, Skeletal/metabolism ; Myokines ; }, abstract = {As life expectancy increases, cognitive impairments such as Alzheimer's disease (AD) create serious problems for older adults. Women regardless of ethnicity and age group, are disproportionately affected, accounting for two-thirds of AD cases, with post-menopausal women representing over 60 % of those affected. Sarcopenia, defined by gradual reduction of skeletal muscle mass, strength, and activities, is increasingly correlated with an elevated risk of cognitive decline in post-menopausal women. Menopause-related hormonal decline (particularly estrogen loss) and aging contribute to sarcopenia, characterized by muscle mitochondrial dysfunction, oxidative stress, and insulin resistance. This sarcopenia-driven reduction in muscle mass and functional capacity further reduces the production of myokines (e.g., BDNF, irisin), impairing neuronal proliferation, adult neurogenesis, and spatial learning/memory. These pathophysiological changes show a contributing link between sarcopenia and AD progression in post-menopausal women. This review is unique in that it discusses the triangular interplay between menopause, sarcopenia, and AD, offering an integrated mechanistic framework that links hormonal decline, muscle loss, and neurodegeneration. We aim to clarify the pathophysiological causes behind the muscle-brain axis and suggest viable treatment approaches to slow down sarcopenia and cognitive deterioration in postmenopausal women based on current evidence. The formulation of targeted strategies for enhancing the quality of life and lessening healthcare expenditures in this expanding population depends on the advancement of understanding this complex interconnection between menopause, sarcopenia and cognition.}, } @article {pmid41325201, year = {2025}, author = {Zhao, N and Wang, Y and Yang, S and Guo, W and Li, Z and Cao, H and Zhang, Z and Li, Y and Chen, D and Xia, S and Xie, Z and Qu, Y and Wu, Y and Li, J and Yi, L and Wang, G and Guo, M}, title = {Surgical Protocols for Deep Cervical Lymphovenous Anastomosis in a Rat Model: Lymph Node and Lymphatic Vessel Anastomoses.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {225}, pages = {}, doi = {10.3791/69201}, pmid = {41325201}, issn = {1940-087X}, mesh = {Animals ; *Lymphatic Vessels/surgery ; *Anastomosis, Surgical/methods ; Rats ; *Lymph Nodes/surgery ; Neck/surgery ; *Veins/surgery ; Female ; }, abstract = {Deep cervical lymphovenous anastomosis (dcLVA) has become a promising treatment strategy for Alzheimer's disease (AD), offering significant improvements compared to the current limited treatment options. However, the underlying mechanism of dcLVA remains unclear. Although clinical trials are ongoing, animal models simulating dcLVA provide a valuable tool for exploring its mechanism. This study aims to develop a standardized protocol for creating dcLVA models in animals to facilitate basic research and address clinical challenges. We describe the surgical procedures and key steps for anastomosing the deep cervical lymph node (dcLN) and its afferent lymphatic vessel (ALV) with the posterior facial vein (PFV), detailing these two distinct surgical methods: deep cervical lymph node-vein anastomosis (dcLnVA) and deep cervical lymphatic vessel-vein anastomosis (dcLaVA). Beyond promoting lymphatic drainage, the comparison of these two surgical methods also helps us to understand and explore the role of the deep cervical lymph node and deep cervical lymphatic system in the pathogenesis of AD. Overall, the complete and clear presentation of the surgical procedure and key anatomical landmarks in the rat helps to standardize the surgical protocol, which can minimize confounding factors and reduce inter-experimental variability, thus laying a solid methodological foundation for a deeper understanding of the mechanisms involved.}, } @article {pmid41324859, year = {2025}, author = {Shi, C and Dong, J and Hui, X and Xu, Z and Zhao, Z and Dong, L}, title = {Production, Mechanisms, and Therapeutic Strategies of Tryptophan Metabolites in CNS Diseases.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {226}, pmid = {41324859}, issn = {1559-1182}, support = {22XYJ0002//Xi'an Innovation Capability Strong Foundation Plan/ ; }, mesh = {Humans ; *Tryptophan/metabolism ; Animals ; *Central Nervous System Diseases/metabolism/therapy/drug therapy ; Gastrointestinal Microbiome/physiology ; }, abstract = {Tryptophan (TRP) metabolites, which are produced from TRP via three pathways-kynurenine, 5-hydroxytryptamine, and indole-are key signaling molecules of the gut-brain axis and are involved in a variety of central nervous system (CNS) disease processes, such as Alzheimer's disease, depression, and schizophrenia by orchestrating inflammatory responses, redox imbalances, neurotransmitter dynamics, mitochondrial dysfunction, and apoptotic/autophagic pathways. However, TRP metabolites exhibit bidirectional modulatory effects, combining different neuroprotective and neurotoxic substances, depending on their metabolic environment and concentration thresholds, posing significant challenges for therapeutic strategies. Therefore, it is important to modulate TRP metabolite production factors, including the regulation of key enzymes in metabolic pathways, the gut microbiota, hormones, and the disease pathology microenvironment, to promote the production of neuroprotective metabolites and inhibit neurotoxic metabolite production. In this review, we detail the influencing factors affecting TRP metabolite production, the regulatory role of TRP metabolites in CNS disorders, and therapeutic strategies related to TRP metabolites for CNS disorders. Targeting TRP metabolizing enzymes or remodeling the ecology of the gut microbiota could be a new strategy for the treatment of CNS diseases, providing a theoretical basis for future precision intervention in CNS diseases.}, } @article {pmid41323809, year = {2025}, author = {Horgan, NG and Djurovic-Topalovic, A and Ademoye, TA and Reyes-Charles, HI and Kobayashi, N and Plascencia-Villa, G and Perry, G and Murakami, T and Fortin, JS}, title = {Epigallocatechin-3-Gallate: A potential amyloid Fibril Disaggregator of Serum amyloid A1.}, journal = {Biochemistry and biophysics reports}, volume = {44}, number = {}, pages = {102365}, pmid = {41323809}, issn = {2405-5808}, abstract = {Serum amyloid A1 (SAA1) is a 122-amino acid protein that, after cleavage, matures into a 104-amino acid form. Its N-terminus is responsible for binding high-density lipoprotein (HDL), while the C-terminus maintains its structural integrity. As an acute-phase protein, SAA1 is produced by the liver in response to acute inflammation. SAA1 is also a precursor to amyloid A (AA), and its accumulation can lead to AA amyloidosis-a condition secondary to chronic inflammation that causes tissue damage and organ dysfunction. Our study explores methods to disaggregate SAA1 fibrils isolated from the cat spleen, chicken liver, and cow liver. Specifically, we investigate the use of epigallocatechin-3-gallate (EGCG), a polyphenolic flavonoid extracted from green tea known for its anti-inflammatory and antioxidant properties, to disaggregate these fibrils. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) were used to analyze these fibrils after treatment with 1 % DMSO and 400 μM of EGCG in 10 mM PBS (pH 7.4). The results demonstrated that EGCG effectively reduced fibril size, as confirmed by DLS characterization, with the disappearance or diminished prominence of the 10[3-4] nm peak. Additional TEM results confirmed that EGCG disaggregated amyloid-beta fibrils isolated from Alzheimer's disease brains. These findings suggest that compounds like EGCG could be valuable in treating inflammatory and neurodegenerative conditions by disaggregating amyloid fibrils.}, } @article {pmid41323723, year = {2025}, author = {Dewangan, B and Swain, P and Patra, S and Bodhe, PR and Kulkarni, N and Sahu, B}, title = {Synthesis and evaluation of HFIP bearing triazolo-amides as amyloid-β aggregation inhibitors and suppressors of aggregation induced neuroinflammation.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {41323723}, issn = {2632-8682}, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease with biological signatures of amyloid beta (Aβ) aggregated plaques and increased levels of bio-metals like copper (Cu), zinc (Zn), and iron (Fe). Aβ-induced lysosomal membrane permeabilization is a key event in neuronal injury in AD. Aβ aggregation also modulates mitochondria membrane potential (MMP), activates interleukin 1β and NLRP3 inflammasome eventually leading to increased reactive oxygen species (ROS) production, neuronal apoptosis and mitochondrial dysfunction. Here, we report a multi-functional compound (2f) identified through structure-activity relationship study from a series of polyfluorinated triazole compounds. Compound 2f suppressed metal induced aggregation, downregulated NLRP3 inflammasome and IL-1β expression. It has maintained the lysosomal acidic pH and restored mitochondrial membrane potential. HFIP bearing triazolo amide (2f) was found to chelate with Cu(ii) and Zn(ii) selectively in the presence of a range of other physiologically relevant metals. Further, a molecular dynamics (MD) simulation study revealed 2f disrupted the aggregation via interacting with chain A of pentameric Aβ. Therefore the HFIP bearing triazole amides may serve as potential scaffolds for drug development towards the treatment of AD.}, } @article {pmid41322563, year = {2025}, author = {Dias, AJ and Sena Oliveira, A and Silva, AC and Braga, AL}, title = {Rational Design and Greener Synthesis of Selenylated Indolamides as Potential Anti-Alzheimer's Agents.}, journal = {ACS omega}, volume = {10}, number = {46}, pages = {56334-56348}, pmid = {41322563}, issn = {2470-1343}, abstract = {This study presents the rational design and sustainable synthesis of selenylated indolamides as potential therapeutic agents for Alzheimer's disease. Through computational approaches, including molecular docking and pharmacokinetic analyses, we identified key structural modifications that improve acetylcholinesterase inhibition, a critical target for AD treatment. We employed an environmentally benign I2/DMSO oxidation system to optimize the synthetic protocol, enabling the efficient selenylation of 27 indolamide derivatives (5a-6a) via a straightforward and practical transformation, delivering high yields of up to 99%. Importantly, the methodology proved scalable, delivering an 88% yield on a gram-scale reaction. In silico ADMET predictions using the pkCSM platform indicated that C2-selenylated indolamides possess an improved safety profile and promising pharmacokinetic properties, suggesting their potential for further drug development. In particular, compounds 5a and 5y demonstrated the best balance between reaction yield and docking score (94% and 86.17; 98% and 93.71, respectively). These findings highlight the significance of incorporating green chemistry principles alongside advanced in silico methodologies to drive innovation in drug discovery.}, } @article {pmid41322352, year = {2025}, author = {Liu, S and Zhao, M and Liu, Y and Yang, X and Yan, H and Xu, H and Wu, Y and Xu, Y}, title = {Comparative efficacy and safety of symptomatic therapy and disease-modifying therapy for Alzheimer's disease: a systematic review and network meta-analysis.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1656906}, pmid = {41322352}, issn = {1662-4548}, abstract = {BACKGROUND: The management of Alzheimer's disease has shifted toward disease-modifying therapies aimed at delaying disease progression rather than focusing solely on symptomatic treatment. This study summarizes the latest evidence regarding the benefits and harms of anti-Alzheimer's disease drugs.

METHODS: We conducted a comprehensive review of randomized controlled trials from PubMed, Embase, Cochrane Library, Web of Science databases, and other sources up to April 2025. Two researchers independently reviewed the literature and analyzed the data. A network meta-analysis was performed using Review Manager version 5.3 and Stata version 18.0 to calculate mean differences (MDs) and 95% confidence intervals (CIs) for direct and indirect comparisons. Treatment efficacy was evaluated using the Surface Under the Cumulative Ranking Curve (SUCRA). Bias was assessed using the Revised Cochrane Risk of Bias Tool version 2.0, and publication bias was analyzed with funnel plots.

RESULTS: The network meta-analysis included 23 randomized controlled trials with 16,010 participants, evaluating nine pharmacological interventions ranging from traditional symptomatic therapies to four United States Food and Drug Administration- and National Medical Products Administration-approved disease-modifying therapies, notably anti-amyloid beta monoclonal antibodies. Aducanumab significantly improved ADAS-cog scores compared with placebo (MD -5.97, 95%CI -10.33, -1.61; SUCRA: 93.0%) and demonstrated notable improvements in ADCS-ADL scores (MD 4.99, 95%CI 2.27, 7.72; SUCRA: 98.6%). Memantine ranked highest for neuropsychiatric symptoms (SUCRA: 80.8%). Aducanumab also had the highest SUCRA for CDR-SB (91.5%) and showed moderate superiority in MMSE scores (MD 3.55, 95%CI 1.35, 5.75; SUCRA: 98.2%).

CONCLUSION: Symptomatic treatments, especially memantine for neuropsychiatric symptoms, remain effective. However, the network meta-analysis indicates that, for patients with mild cognitive impairment or mild Alzheimer's disease, aducanumab demonstrates the greatest potential for cognitive and clinical improvement (MMSE, ADAS-cog, ADCS-ADL), despite associated risks such as adverse events and amyloid-related imaging abnormalities linked to disease-modifying therapies. Lecanemab provides moderate benefits, while donanemab appears less effective. Thus, clinicians should apply disease-modifying therapies cautiously and individually, carefully balancing potential risks and benefits for each patient.

PROSPERO [CRD42025637730], https://www.crd.york.ac.uk/PROSPERO/.}, } @article {pmid41322300, year = {2025}, author = {Domínguez-Fernández, C and Kumar, A and Kumar, R and Darreh-Shori, T}, title = {From heart to brain: cognitive potential of propranolol and diltiazem through cholinergic enhancement via butyrylcholinesterase inhibition.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1694610}, pmid = {41322300}, issn = {1663-9812}, abstract = {BACKGROUND: Butyrylcholinesterase (BChE) has emerged as a promising therapeutic target in the treatment of Alzheimer's disease (AD), particularly in its later stages when acetylcholinesterase (AChE) activity declines. Drug repurposing offers a strategic approach to identify novel BChE inhibitors among existing FDA-approved compounds.

OBJECTIVE: This study aimed to evaluate the cholinesterase inhibitory potential of propranolol and diltiazem-two widely used cardiovascular drugs-through in silico modelling and in vitro and ex vivo enzyme-inhibition kinetic.

METHODS: Molecular docking was performed using AutoDock Vina to assess the binding affinity of propranolol and diltiazem to AChE and BChE. In vitro screening and inhibition were measured using a modified Ellman's assay with human recombinant AChE and plasma-derived BChE. Ex-vivo IC50 and Ki values were determined through kinetic analyses in pooled plasma samples, and inhibition modes were characterized using nonlinear regression models.

RESULTS: Both propranolol and diltiazem selectively inhibited BChE, with minimal activity against AChE. At 100 μM, BChE inhibition exceeded 80% for both compounds, while AChE inhibition was limited to 18% (propranolol) and 2% (diltiazem). Propranolol exhibited a Ki of 0.19 µM, comparable to the selective BChE inhibitor ethopropazine (Ki = 0.15 µM), and acted as a competitive inhibitor. Diltiazem exhibited a higher Ki of 2.3 µM. These effects were observed at concentrations within or near reported brain levels for propranolol, suggesting potential in vivo relevance.

CONCLUSION: Propranolol and diltiazem demonstrate selective BChE inhibition, with propranolol showing potency comparable to established potent BChE inhibitors. Given their established safety profiles and CNS activity, these compounds represent promising candidates for repurposing in the treatment of AD and other cognitive disorders. Further in vivo studies are warranted to explore their therapeutic potential.}, } @article {pmid41321177, year = {2025}, author = {Sahakian, BJ}, title = {The role of psychopharmacology and cognitive neuroscience in understanding the brain in the treatment of psychiatric disorders and neurological diseases for the benefit of society.}, journal = {Journal of psychopharmacology (Oxford, England)}, volume = {}, number = {}, pages = {2698811251397329}, doi = {10.1177/02698811251397329}, pmid = {41321177}, issn = {1461-7285}, abstract = {This perspectives piece reflects on some of the major scientific contributions in psychopharmacology, cognitive neuroscience, and public policy of Professor Barbara J. Sahakian, Commander of the Most Excellent Order of the British Empire (CBE). Her pioneering research has advanced the understanding of brain mechanisms, including neurotransmitter modulation, and psychological processes involved in cognition, emotion, and motivation, leading to novel treatments for disorders such as Alzheimer's disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. She has also contributed to a better understanding of brain mechanisms underlying and psychological processes involved in these disorders. She has championed early detection of Alzheimer's disease through neuropsychological tools, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning (PAL) test and contributed to identifying cognitive and neural changes in Huntington's disease gene carriers. Beyond clinical research, Sahakian has influenced public health policy through initiatives such as the UK Government Foresight Project on Mental Capital and Wellbeing and the National Institute for Health and Care Excellence guidelines on gambling-related harms. She has also led efforts in neuroethics and public engagement, co-authoring accessible science books and participating in global forums. Recent research emphasises preventative psychiatry, including lifestyle interventions, such as diet, sleep, social connection, and lifelong learning as preventive strategies for cognitive decline and mental health problems. Through interdisciplinary collaborations and mentorship, Sahakian continues to inspire the next generation of scientists to pursue innovative research for societal benefit in neuropsychopharmacology and cognitive neuroscience.}, } @article {pmid41320930, year = {2026}, author = {Suthar, T and Maurya, R and Sonwani, A and Upadhayay, P and Datusalia, AK and Naqvi, S and Jain, K}, title = {Nose-to-Brain Delivery of Donepezil Hydrochloride via Oleic Acid-Conjugated PAMAM G4 Dendrimers for the Treatment of Alzheimer's-Like Dementia.}, journal = {Molecular pharmaceutics}, volume = {23}, number = {1}, pages = {177-195}, doi = {10.1021/acs.molpharmaceut.5c00761}, pmid = {41320930}, issn = {1543-8392}, mesh = {*Dendrimers/chemistry ; *Donepezil/administration & dosage/pharmacokinetics/chemistry ; *Alzheimer Disease/drug therapy ; Animals ; *Brain/metabolism/drug effects ; *Oleic Acid/chemistry ; Administration, Intranasal ; Cholinesterase Inhibitors/administration & dosage/pharmacokinetics ; Humans ; Rats ; Drug Liberation ; Drug Delivery Systems/methods ; Male ; Drug Carriers/chemistry ; Cell Line, Tumor ; }, abstract = {Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder characterized by dementia and cognitive impairments. Acetylcholinesterase (AChE) inhibitors are generally prescribed for clinical management of AD symptoms. Donepezil hydrochloride (DPZ) is a reversible, selective, and noncompetitive inhibitor of AChE recommended for the treatment of mild-to-moderate AD. However, a higher dose of this drug must be administered to achieve adequate therapeutic concentrations in the brain, leading to peripheral side effects. In the present research work, oleic acid (OA) conjugated PAMAM G4 dendrimers (OA-G4) are explored for delivering DPZ to the brain. OA was conjugated to PAMAM G4 dendrimers using EDC conjugation chemistry, and the conjugation was confirmed by nuclear magnetic resonance (NMR) and Fourier-transform infrared (FTIR) spectroscopy. DPZ was successfully loaded on the OA-G4 conjugate, and the loading and entrapment efficiency were found to be 78.59% ± 5.52% and 62.12% ± 0.67%, respectively. The drug release studies showed a faster release of DPZ from the DPZ-OA-G4 conjugate for the initial 6 h, followed by a sustained release, with 68.44% ± 1.88% of the drug released in 24 h. Cytotoxicity studies in SH-SY5Y cells demonstrated the safety and cytocompatibility of the conjugate at a wide range of concentrations. Cell internalization study revealed deep localization of the dendrimeric nanoconjugate in SH-SY5Y cells. Biodistribution studies of the OA-G4 conjugate through the intranasal route, using an IVIS whole-body live imaging system, demonstrated abundant fluorescence in the brain, indicating efficient brain targeting via nose-to-brain delivery. Neurobehavior studies in male SD rats suggested significant attenuation of AlCl3-induced cognitive decline in DPZ-OA-G4 treated animals, which was further confirmed with biochemical and histological evaluations. In conclusion, this study provides proof of concept that DPZ can be successfully targeted to the brain using ligand-conjugated dendrimeric systems via intranasal administration, a noninvasive route that enables direct nose-to-brain delivery, bypasses the blood-brain barrier, and minimizes systemic side effects.}, } @article {pmid41319675, year = {2025}, author = {Langbaum, JB and Bradbury, AR and Egleston, BL and McCarty Wood, E and Langlois, CM and Largent, EA and Harkins, K and Erickson, CM and Stites, SD and Oyen, E and Riviere, ME and Liu, F and Graf, A and Kim, SYH and Grill, JD and Reiman, EM and Tariot, PN and Roberts, JS and Karlawish, J}, title = {Impact of learning APOE genotype on cognitively unimpaired adults: a pre-screening cohort study of the Alzheimer's Prevention Initiative Generation Study 1.}, journal = {The lancet. Healthy longevity}, volume = {6}, number = {11}, pages = {100778}, pmid = {41319675}, issn = {2666-7568}, support = {P30 AG072980/AG/NIA NIH HHS/United States ; UF1 AG046150/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Middle Aged ; *Alzheimer Disease/genetics/prevention & control/psychology ; Aged ; *Apolipoproteins E/genetics ; Genotype ; Depression ; Anxiety ; Apolipoprotein E4/genetics ; Cohort Studies ; Cognition ; Genetic Predisposition to Disease ; }, abstract = {BACKGROUND: The apolipoprotein E (APOE) gene is the best established genetic risk factor for Alzheimer's disease in later life, with the ε4 allele conferring higher risk. APOE disclosure is becoming increasingly common in the clinical care of people with Alzheimer's disease and in cognitively unimpaired adults. In this study, we aimed to describe changes in measures of genetic disease knowledge and psychiatric symptoms following APOE disclosure to cognitively unimpaired adults.

METHODS: Data were collected as part of the screening phase of the global, multicentre, Alzheimer's Prevention Initiative Generation Study 1 (NCT02565511). Eligible individuals were cognitively unimpaired (Mini-Mental State Exam total score ≥24), aged 60-75 years, and psychologically pre-screened for readiness (by measures of depressive symptoms and anxiety) to receive their APOE genotype from a health-care provider. Participants were assessed before disclosure, and 2-7 days, 6 weeks, 6 months, and 12 months after disclosure. Multivariable linear and ordinal logistic regressions were used to compare changes in genetic disease knowledge, anxiety, depression, and distress by APOE4 genotype status, adjusting for key covariates, with a focus on 2-7 days after disclosure. Multiple imputation by chained equations methods was used to account for missing outcome data.

FINDINGS: The trial took place between Nov 30, 2015, and Sept 23, 2019. In total, 9496 participants (including 790 APOE4 homozygotes, 4869 heterozygotes, and 3837 non-carriers) learned their APOE genotype from a health-care provider as part of Generation Study 1 screening. 4038 (42·5%) participants were in the 65-69-year age group, 5790 (61·0%) were female, 3706 (39·0%) were male, and 8862 (93·3%) self-identified as White. Increase in genetic disease knowledge 2-7 days after disclosure was greater in APOE4 homozygotes (mean 1·19 [SD 3·95]) than in heterozygotes (0·78 [3·95], p=0·042) and non-carriers (0·29 [3·96], p=0·0002). Disease-specific distress 2-7 days after disclosure increased more in homozygotes (2·25 [6·42]) than in heterozygotes (0·53 [5·08], p<0·0001) and non-carriers (0·79 [4·95], p<0·0001). Levels of anxiety 2-7 days after disclosure increased in homozygotes (0·17 [2·95]) but decreased in heterozygotes (-0·67 [2·68], p<0·0001) and non-carriers (-0·66 [2·67], p<0·0001). There were no significant changes in depressive symptoms following disclosure for any APOE4 group. Notably, for all APOE4 groups, increases in distress and anxiety were small and did not reach predefined levels of clinical concern.

INTERPRETATION: In cognitively unimpaired, psychologically pre-screened adults, APOE disclosure by a trained health-care provider was generally safe and well tolerated, consistent with results from previous studies. To our knowledge, this is the largest study experience of APOE disclosure to date, especially for homozygotes, and is notable for the older age of participants compared with previous research. These results are timely and important given anticipated increases in APOE disclosure to guide clinical decision making once an Alzheimer's disease prevention treatment is approved for cognitively unimpaired adults or if patients' family members are interested in genetic testing. Scalable approaches for returning Alzheimer's disease risk information are critical to meeting anticipated demand. Results from this study may be useful to bolster clinical translatability of disclosure programmes.

FUNDING: The National Institute on Aging, Alzheimer's Association, Banner Alzheimer's Foundation, GHR Foundation, F-Prime Biomedical Research Initiative (FBRI), and Novartis Pharma.}, } @article {pmid41319153, year = {2025}, author = {Wu, CY and Chen, L and Fatima, H and Gatchel, J and Das, S and Kivisäkk, P and Arnold, SE and Dodge, HH}, title = {Combined use of plasma p-tau217, NfL, and GFAP predicts domain-specific cognitive decline in cognitively unimpaired and MCI individuals.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {12}, pages = {e70934}, pmid = {41319153}, issn = {1552-5279}, support = {P30AG062421/GF/NIH HHS/United States ; R01AG051628/GF/NIH HHS/United States ; R01AG056102/GF/NIH HHS/United States ; K01AG088184/GF/NIH HHS/United States ; }, mesh = {Humans ; *tau Proteins/blood ; Male ; Female ; *Cognitive Dysfunction/blood/diagnosis ; *Glial Fibrillary Acidic Protein/blood ; *Neurofilament Proteins/blood ; Biomarkers/blood ; Aged ; Phosphorylation ; Neuropsychological Tests ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Accurate identification of individuals at risk for cognitive decline is critical for treatment planning and trial enrichment strategies. We evaluated the combined utility of plasma phosphorylated tau at threonine 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in predicting domain-specific cognitive decline.

METHODS: Participants (n = 523; 40.9% cognitively unimpaired [CU]; 59.1% mild cognitive impairment [MCI]) were from the Massachusetts Alzheimer's Disease Research Center. Cognition was assessed using the National Alzheimer's Coordinating Center Uniform Data Set. Participants were classified as high(+)/low(-) for each biomarker using Gaussian mixture models.

RESULTS: Among all participants, high p-tau217 alone [p-tau217(+)NfL(-)GFAP(-)] was associated with a steeper decline in episodic/semantic memory and processing speed compared to the all-low group (p ≤ 0.02). With the addition of high GFAP [p-tau217(+)NfL(-)GFAP(+)], steeper decline extended to most cognitive domains, including global cognition and executive function, compared to the all-low group. In CU, faster decline in global cognition and executive function was seen when all biomarkers were elevated ([p-tau217(+)NfL(+)GFAP(+)]; p ≤ 0.04).

DISCUSSION: Combined plasma biomarkers predict decline in cognitive domains vulnerable to early disease.

HIGHLIGHTS: High phosphorylated tau at threonine 217 (p-tau217) alone was associated with declines in semantic/episodic memory, whereas its combination with elevated glial fibrillary acidic protein (GFAP) predicted declines in a wider range of cognitive domains. Elevated neurofilament light chain (NfL) amplifies the cognitive decline already driven by p-tau217 and GFAP. In cognitively unimpaired individuals, subtle domain-specific cognitive declines can be detected when both core and non-core Alzheimer's disease biomarkers are used. Our finding highlights the importance of focusing on vulnerable cognitive domains during early disease where global cognition may appear stable but specific impairments can be masked within composite scores.}, } @article {pmid41318982, year = {2025}, author = {Huang, Y and Guo, Y and Zhang, H and Deng, J and Huang, Z and Chen, A and Wu, X and Lin, D and Ye, P and Chen, X and Zheng, X}, title = {Repeated Exposure to Lidocaine Induces Alzheimer's‐Like Cognitive Impairment and Neuropathology in Aged Mice Through BDNF‐Regulated Autophagy.}, journal = {Journal of cellular and molecular medicine}, volume = {29}, number = {23}, pages = {e70970}, pmid = {41318982}, issn = {1582-4934}, support = {82171186//National Natural Science Foundation of China/ ; 82471278//National Natural Science Foundation of China/ ; 2023Y9282//The Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2023Y9315//The Joint Funds for the Innovation of Science and Technology of Fujian Province/ ; 2021QH1307//Startup Fund for scientific research, Fujian Medical University/ ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; *Autophagy/drug effects ; Mice ; *Lidocaine/adverse effects ; *Cognitive Dysfunction/pathology/metabolism/chemically induced ; *Alzheimer Disease/pathology/metabolism/chemically induced ; Hippocampus/pathology/metabolism/drug effects ; Male ; Signal Transduction/drug effects ; Receptor, trkB/metabolism ; Astrocytes/metabolism/drug effects/pathology ; Disease Models, Animal ; TOR Serine-Threonine Kinases/metabolism ; *Aging/pathology ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; }, abstract = {Lidocaine is widely used for perioperative pain management, but repeated exposure may cause neurotoxicity, including neurological deficits. This study investigates mechanisms underlying cognitive decline induced by repeated lidocaine exposure. Eighteen-month-old mice received repeated clinically relevant lidocaine infusions over 3 days. Cognitive function was assessed by Morris water maze, Y-maze and open field tests. Hippocampal pathology was examined via TEM, Nissl staining, immunofluorescence for astrocyte polarisation and Aβ deposition, and western blot for tau, BDNF, TrkB, mTOR and autophagy proteins. The TrkB agonist 7,8-DHF was used to modulate BDNF/TrkB/mTOR signalling. Repeated lidocaine exposure impaired cognition and induced Alzheimer's-like hippocampal pathology, as evidenced by increased accumulation of Aβ and tau toxic proteins, along with neuronal death. It reduced BDNF expression, inhibited TrkB phosphorylation, and activated mTOR signalling, leading to autophagy inhibition and pathological protein accumulation. Lidocaine shifted astrocytes towards the neurotoxic A1 phenotype, decreasing neuroprotective A2 astrocytes and BDNF synthesis. TrkB agonist treatment restored signalling, enhanced autophagy and improved cognitive deficits and pathology. Repeated lidocaine exposure promotes A1 astrocyte increase and A2 decrease, inhibiting autophagy via the BDNF/TrkB/mTOR pathway, resulting in toxic protein deposition and Alzheimer's-like cognitive impairment.}, } @article {pmid41318018, year = {2025}, author = {de Souza, PC and Bezerra, TPW and de Melo Rêgo, MJB and da Rosa, MM}, title = {Advances in neurological therapies: A review of clinical trials in Alzheimer's, Parkinson's, and multiple sclerosis.}, journal = {The American journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.amjmed.2025.11.025}, pmid = {41318018}, issn = {1555-7162}, abstract = {The period from 2020 to 2025 marked a pivotal juncture in the treatment of major neurological diseases, with Phase II-IV trials delivering the first compelling evidence for disease-modifying interventions in Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This narrative review provides a critical analysis of this evolving therapeutic landscape, focusing on efficacy, safety, and practical implications. Our analysis reveals unprecedented yet heterogeneous progress. In Alzheimer's disease, anti-amyloid monoclonal antibodies (donanemab, lecanemab) achieved regulatory approval, establishing a new treatment paradigm despite modest efficacy and risks of amyloid-related imaging abnormalities (ARIA). In Parkinson's disease, GLP-1 receptor agonists (lixisenatide) demonstrated the first convincing disease modification signals in Phase II trials. For multiple sclerosis, the failure of Bruton's tyrosine kinase (BTK) inhibitors contrasted with the consolidation of anti-CD20 therapies as the therapeutic standard, refined by innovations in dosing and delivery. Collectively, these findings herald a new era of disease-modifying therapy in neurology, though current gains remain limited and dependent on biomarker stratification and safety monitoring. The challenge ahead is translating these successes into accessible, sustainable clinical benefits.}, } @article {pmid41317176, year = {2025}, author = {Pour, FT and Saadatpour, F and Salari, A}, title = {Comprehensive and In-Depth Molecular and Pathway Studies of the Hippocampus in Alzheimer's Disease.}, journal = {Cellular and molecular neurobiology}, volume = {45}, number = {1}, pages = {110}, pmid = {41317176}, issn = {1573-6830}, support = {CSBI14011102//Cognitive Science and Biology Institute (CSBI)/ ; SBNGC14011101//Systems Biology and Next Generation Company (SBNGC)/ ; }, mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; Humans ; *Hippocampus/metabolism/pathology ; Protein Interaction Maps/genetics ; *Signal Transduction/genetics ; Gene Regulatory Networks ; Gene Expression Profiling ; Male ; Gene Expression Regulation ; Female ; }, abstract = {Alzheimer's disease (AD) still lacks a conclusive treatment, largely due to an incomplete understanding of the molecular mechanisms involved. To enhance our knowledge of AD pathogenesis and identify potential therapeutic targets, this study integrates differential gene expression analysis, pathway enrichment, hub gene discovery, protein-protein interaction (PPI) clustering, and transcription factor/protein kinase regulation into a single, cohesive pipeline. This comprehensive systems-level approach moves beyond single-gene analyses to offer a broader, mechanistically focused insight into AD biology. Using RNA-seq data from the CA1 region of the hippocampus-a subregion selectively affected in early AD-we identified 1,104 differentially expressed genes (DEGs). Among the enriched pathways, "7-alpha-hydroxycholesterol" was upregulated, while "vacuolar organization" was downregulated in AD samples. Furthermore, five novel hub genes (MRPS7, RPL5, GFM1, RAD51, and ASPM) were identified within the PPI network. The first three-MRPS7, RPL5, and GFM1-along with ACO2 and MT-ATP6, are potentially linked to hereditary forms of AD due to their roles in mitochondrial function. We also discovered four collaborative clusters within the network that notably associated with the "inflammatory response", "7-alpha-hydroxycholesterol", "Mitochondrial dysfunction" and "Oxidative phosphorylation" pathways, making them promising candidates for therapeutic and diagnostic investigation due their behavioral information members. Additionally, we identified ten transcription factors (GATA2, CHD1, THRA, IRF7, ZBTB48, POLE4, ZNF219, SLC2A4RG, NR1D1, and RXRA) and one protein kinase (PRKCZ) as potential regulatory elements in AD. This study broadens our understanding of Alzheimer's disease by identifying five candidate hub genes, two functional PPI clusters, two signaling pathways, and eleven regulatory proteins, thereby laying the groundwork for future therapeutic and diagnostic developments in molecular AD research.}, } @article {pmid41316284, year = {2025}, author = {Chen, C and Mo, M and Åkerman, M and Garcia-Ptacek, S and Xu, H and Eriksdotter, M}, title = {Dynamic associations of cholinesterase inhibitors and memantine with cognitive trajectories in individuals with Alzheimer's or mixed dementia: a real-world analysis using the quality registry SveDem.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {256}, pmid = {41316284}, issn = {1758-9193}, abstract = {BACKGROUND: Alzheimer’s disease (AD) and mixed dementia (MxD) represent major public health concerns, yet there is limited real-world evidence on the long-term associations of commonly prescribed pharmacological treatments, particularly cholinesterase inhibitors (ChEIs) and their combination with memantine. This study aims to evaluate the long-term, time-varying associations of ChEIs and memantine on cognitive decline in a large, nationwide cohort of individuals diagnosed with AD or MxD.

METHODS: This observational study utilized data from the Swedish registry for cognitive/dementia disorders (SveDem), analyzing 32,282 individuals diagnosed with AD or MxD between 2007 and 2022. Patients were followed for up to 11 years to track treatment patterns and cognitive trajectories. Initiation of ChEIs (donepezil, galantamine, or rivastigmine) or memantine within six months after an AD or MxD diagnosis and then the time-varying medications (ChEIs alone, memantine alone or memantine added on to ChEIs) within six months after each follow-up were analyzed. Linear mixed-effects model was used to assess cognitive decline measured by Mini-Mental State Examination (MMSE) score trajectories.

RESULTS: Of the 32,282 participants (mean age 78.4 years; 61% women), 78.4% initiated treatment with ChEIs alone, and 21.6% with memantine alone. Over time, prescription patterns shifted from monotherapy to combination therapy, with donepezil and galantamine more likely to achieve 1 Defined Daily Dosages (DDD) than rivastigmine users. Memantine alone users experienced a yearly cognitive decline of 1.79 MMSE points (95% CI: −1.85, −1.73). Compared with memantine users, patients on ChEIs alone declined 0.65 points less per year (95% CI: −0.59, −0.72), while those on combination therapy declined 0.19 points less per year (95% CI: −0.10, −0.28). Among ChEIs, donepezil users experienced an annual decline of 1.02 points (95% CI: −1.06, −0.98). In comparison, galantamine users declined an additional 0.05 points per year (95% CI: −0.11, 0.01), and rivastigmine users declined an additional 0.17 points per year (95% CI: −0.24, −0.11), relative to donepezil.

CONCLUSIONS: In this large cohort of patients with AD or MxD, ChEIs users alone, particularly donepezil and galantamine, showed slower cognitive decline compared to users of memantine or combination therapy users. While differences were modest, the results contribute to a better understanding of treatment trajectories in routine clinical practice.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01918-0.}, } @article {pmid41315790, year = {2025}, author = {Dong, D and Ahmed, W and Sagar, R and Boyd, RJ and Mahairaki, V}, title = {Mapping key mitochondrial genes in Alzheimer's disease through human tissue and iPSC derived neurons.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {42766}, pmid = {41315790}, issn = {2045-2322}, support = {RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; RF190106435;DFD-18159;T32AG0585279;//NIA;The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease at Johns Hopkins;National Institutes of Health/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Neurons/metabolism/pathology ; *Mitochondria/genetics/metabolism ; *Genes, Mitochondrial ; Oxidative Stress/genetics ; Gene Expression Profiling ; Gene Ontology ; Brain/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition that has become a global health challenge due to an aging world population and no available effective treatment. Mitochondrial dysfunction plays a crucial role in the development of AD due to its critical role in neuronal survival and function. However, the specific mitochondrial genes and pathways involved in AD pathogenesis remain poorly defined. In this study, we incorporated seven AD human postmortem and three AD iPSC-derived neurons (iNs) gene expression datasets to identify mitochondria-related Differentially Expressed Genes (mitoDEGs) between AD and control. The Gene Ontology (GO) analysis is conducted to investigate the AD biological mechanisms, and a random forest model is developed to assess how well the key mitoDEGs differentiate AD and control groups. Through our analysis, we identified fourteen key mitochondria related genes that show significant dysregulation in both postmortem brain tissues and iNs derived from AD patients. These genes have strong connections to oxidative stress, indicating mitochondrial dysfunction plays a crucial role in Alzheimer's disease pathology. Our study identified the key genes and pathways as promising targets for future research and therapeutic interventions, highlighting the importance of mitigating oxidative stress and restoring mitochondrial function in AD.}, } @article {pmid41314754, year = {2025}, author = {Jana, MK and Swarup, V and Tripathy, S and Gupta, NM and Chatla, SS and Joshi, D and Mandal, S and Giri, A and Jana, S and Narayan, M and Maiti, SB and Das, S}, title = {Future horizons: Innovation, aging, and equity.}, journal = {Progress in brain research}, volume = {297}, number = {}, pages = {427-468}, doi = {10.1016/bs.pbr.2025.08.010}, pmid = {41314754}, issn = {1875-7855}, mesh = {Humans ; *Aging ; *Precision Medicine/trends/methods ; *Neurodegenerative Diseases/therapy/diagnosis ; Artificial Intelligence ; }, abstract = {Precision medicine is on the verge of transforming the treatment of neurodegenerative diseases (NDDs) like Alzheimer's disease (AD) and Parkinson's disease (PD), in response to the intricate interactions of genetic, epigenetic, environmental, and lifestyle factors underlying disease heterogeneity. As the world's aging populations grow, with dementia cases expected to double by 2040 and the costs amounting to over €130 billion a year in Europe alone, there is an urgent need for novel strategies to stem the socioeconomic costs of NDDs. Conventional "one-drug-fits-all" strategies that depend on late-stage symptom treatment are progressively insufficient for disorders that are marked by heterogeneous molecular pathways and unpredictable clinical courses. Recent improvements in artificial intelligence (AI), multi-omics integration, and biomarker research now allow patients to be stratified into subpopulations following their genetic risk profiles, neuroimaging signatures, and fluid biomarkers (e.g., amyloid-beta, tau, α-synuclein), enabling early diagnosis and focused treatments. For example, artificial intelligence platforms such as the IHI-PROMINENT project are creating forecasting algorithms to chart disease progression and tailor treatment outcomes, and gene therapy and antisense oligonucleotides (ASOs) address precise mutations in familial AD and PD. These advances are supported by pharmacogenomics, which individualizes drug regimens according to metabolic profiles to reduce side effects and maximize efficacy. Still, translating these advances into practice has major barriers to overcome, such as large-scale biomarker validation, multi-omics standardization, and incorporating real-world evidence from digital health technologies. Aging populations only add complexity to this environment, as comorbidities like diabetes and cardiovascular diseases interact with neurodegenerative pathways, requiring system-based, holistic approaches to care. Equity is still a key challenge: differences in access to sophisticated diagnostics (e.g., PET scans, CSF examination) and expensive therapies (e.g., monoclonal antibodies, CAR-T cell therapy) threaten to worsen global health disparities. In retaliation, initiatives such as the JPND research paradigm advance remote clinical trials and telemedicine platforms for the diverse community in decentralized settings, and policies target reducing financial disincentives through risk-sharing strategies and public-private partnerships. Precision medicine in the treatment of NDDs depends on an integrated network among academia, clinics, and industry, by taking advantage of communal biobanks and AI-enabled big data analysis, for refining the drug development process and validating new targets, e.g., neuroinflammatory signaling and gut-brain axis dysfunction. Innovations, like CRISPR-mediated editing and ambient neuroimaging, have innate or potential power to personalize treatment by identifying early-stage and even pre-symptomatic patients and modulating one's lifestyle in light of genetic risk. However ethical considerations around data privacy, algorithmic bias, and informed consent for Sustained therapeutic interventions over a lifetime should guide, not lag, the transformation. With the drive toward preventive rather than delayed care, precision medicine represents a revolutionary paradigm shift in health care, and a possibility to convert NDDs from devastatingly fatal diagnoses to easily managed chronic diseases and render equitable access to innovations possible for the masses. Success will require consistent investment in translational studies, interdisciplinary training, and global regulatory harmonization to translate the promise of precision medicine into tangible improvements in the quality of life for the millions of individuals afflicted with neurodegenerative disorders.}, } @article {pmid41314753, year = {2025}, author = {Jana, MK and Mukherjee, P and Chatla, SS and Sharma, P and Mistry, J and Swarup, V and Srivastava, AK and Das, S and Gupta, NM and Ahuja, A and Samanta, S and Narayan, M}, title = {Global case studies and collaborative frameworks.}, journal = {Progress in brain research}, volume = {297}, number = {}, pages = {377-426}, doi = {10.1016/bs.pbr.2025.08.013}, pmid = {41314753}, issn = {1875-7855}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/diagnosis ; *Biomedical Research ; *International Cooperation ; }, abstract = {As neurodegenerative diseases (NDDs) like Alzheimer's and Parkinson's continue to rise globally, the need for cross-border collaboration in research and treatment has never been more critical. This chapter explores prominent global case studies and collaborative frameworks that exemplify how united efforts are transforming the landscape of NDD research. By pooling expertise, data, and resources, international initiatives are accelerating discoveries in early diagnosis, biomarker identification, and personalized therapies. Highlighting landmark consortia such as the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n.d.), Parkinson's Progression Markers Initiative (PPMI), and emerging multi-omics collaborations, the chapter illustrates how these partnerships overcome the complexity and heterogeneity of NDDs. It delves into technological innovations like artificial intelligence, blockchain data sharing, and real-time patient monitoring, which empower researchers and clinicians to connect genetic, environmental, and lifestyle factors in a holistic manner. Ethical considerations and data privacy frameworks are underscored as pivotal to fostering trust among participants and bridging disparities between regions with varying access to precision medicine. The chapter also sheds light on successful public-private partnerships and patient-focused global networks that place individuals at the center of discovery and care. Challenges such as standardizing protocols across countries, navigating legal frameworks, and securing sustainable funding are discussed alongside future directions for expanding collaborative reach. Ultimately, this comprehensive overview conveys the unprecedented promise held by global cooperation in combating neurodegenerative diseases-offering hope for improved diagnostics, innovative treatments, and enhanced quality of life for millions worldwide.}, } @article {pmid41314749, year = {2025}, author = {Priyanka, S and Manjari, T and Hemalatha, S and Ambika, S and Yılmaz, B and Aktürk, B and Arısan, ED and Kumari, A and Manojkumar, Y}, title = {Precision therapeutics for Alzheimer's disease.}, journal = {Progress in brain research}, volume = {297}, number = {}, pages = {247-276}, doi = {10.1016/bs.pbr.2025.08.011}, pmid = {41314749}, issn = {1875-7855}, mesh = {Humans ; *Alzheimer Disease/therapy/genetics/drug therapy ; *Precision Medicine/methods ; Animals ; }, abstract = {Despite extensive research, Alzheimer's disease (AD) a progressive neurodegenerative disorder marked by cognitive decline, neuronal loss, and the build-up of amyloid-beta plaques and tau tangles continues to lack effective treatments. Precision medicine presents a promising shift by customizing interventions to an individual's genetic, molecular, and lifestyle profile. This chapter explores key advancements in precision therapeutics for AD, including biomarker-driven therapies, pharmacogenomics, and targeted disease-modifying agents such as monoclonal antibodies. Recent innovations, including RNA-based therapeutics, stem cell approaches, and CRISPR-mediated gene editing, are also discussed. While precision medicine holds immense promise, challenges in clinical translation, patient stratification, and regulatory pathways must be addressed. By bridging cutting-edge research with clinical applications, this chapter provides insights into the evolving landscape of individualized treatment strategies for AD.}, } @article {pmid41314745, year = {2025}, author = {Fatima, S and Tiwari, S and Siddiqi, B and Quadri, SN and Abdin, MZ}, title = {Biomarkers: From early detection to treatment personalization.}, journal = {Progress in brain research}, volume = {297}, number = {}, pages = {131-153}, doi = {10.1016/bs.pbr.2025.08.008}, pmid = {41314745}, issn = {1875-7855}, mesh = {Humans ; *Biomarkers/metabolism ; *Neurodegenerative Diseases/diagnosis/therapy/metabolism ; *Precision Medicine/methods ; Early Diagnosis ; }, abstract = {Neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), present increasing issues associated with the unavoidable aging of the world's population. These challenges are further highlighted by the socioeconomic consequences of these diseases. The identification and use of biomarkers for prompt diagnosis, careful observation, and efficient treatment approaches is essential to overcoming these obstacles. The primary methods for diagnosing neurodegenerative illnesses are invasive procedures like lumbar punctures to measure CSF fluid or functional brain imaging methods. Biomarkers for underlying proteinopathy in blood serum and cerebral fluid have been the focus of recent biological research, particularly in vivo. With their ability to provide novel pathways for early detection, illness progression tracking, and individualized treatment plans, biomarkers have become essential instruments in precision medicine. The classification of biomarkers including fluid, digital imaging, and molecular biomarkers is examined in this chapter, with an emphasis on their function in neurodegenerative diseases. In neurodegenerative illnesses and the aging brain, tau, amyloid-β, α-synuclein, and TDP-43 are commonly seen to be deposited together rather than separately. These may be disregarded, and it might be challenging to determine their clinicopathological significance. An overview of illness pathophysiology, diagnostic implications, and the most recent molecular and ultrastructural categories for neurodegenerative disorders are given in this chapter. Addressing these issues through interdisciplinary research and technological advancements will be crucial for the future of biomarker-driven precision medicine. This chapter provides an in-depth overview of the evolving landscape of biomarkers and their transformative impact on the early detection and personalized treatment of neurodegenerative diseases.}, } @article {pmid41314744, year = {2025}, author = {Gunasekaran, B and Arifin, AH and Yu, WH and Hanafi, S and Rao, KDK and Salvamani, S}, title = {Precision medicine in neurodegenerative diseases: From research to clinical practice.}, journal = {Progress in brain research}, volume = {297}, number = {}, pages = {1-52}, doi = {10.1016/bs.pbr.2025.08.006}, pmid = {41314744}, issn = {1875-7855}, mesh = {Humans ; *Precision Medicine/methods ; *Neurodegenerative Diseases/therapy/genetics/diagnosis ; Biomarkers ; }, abstract = {The chapter outlines how precision medicine is reshaping the way neurodegenerative diseases (NDs) which includes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) are understood, diagnosed, and treated. It discusses the limitations of current therapies, which mainly address symptoms without altering disease progression. Genetic and molecular factors that influence disease development are described, including distinctions between familial and sporadic forms. The chapter also covers the roles of epigenetic changes, gene expression, protein dysfunction, mitochondrial DNA, and non-coding RNAs in NDs. Biomarkers in blood and cerebrospinal fluid, along with imaging techniques and digital tools, are presented as key elements in early diagnosis and disease monitoring. Patient stratification based on clinical features, molecular profiles, and biomarkers helps guide treatment decisions and improve outcomes. The chapter reviews ongoing developments in genotype-based drug design, gene therapy, pharmacogenomics, and personalized lifestyle strategies. Clinical case studies show how these approaches are being used in practice. The chapter also discusses challenges in applying precision medicine, such as trial design, data integration, unequal access, and regulatory hurdles. Finally, it highlights the future tools like single-cell transcriptomics, digital twins, and global research collaborations that aim to bring precision approaches into everyday care.}, } @article {pmid41314580, year = {2026}, author = {Wang, X and Wang, D and Liu, J and Han, F and Liang, P and Yang, J and Xu, W and Ma, J and Wu, Y and An, X and Xue, Y and Chen, H and Zeng, L and Qu, Y and Ai, J}, title = {Systemic delivery of liposome-loaded microRNA-195 ameliorates spatial memory impairment in a rat model of chronic cerebral hypoperfusion.}, journal = {International journal of biological macromolecules}, volume = {336}, number = {}, pages = {149290}, doi = {10.1016/j.ijbiomac.2025.149290}, pmid = {41314580}, issn = {1879-0003}, mesh = {Animals ; *MicroRNAs/administration & dosage/genetics/chemistry/pharmacology ; Rats ; *Liposomes/chemistry ; Disease Models, Animal ; Male ; *Spatial Memory/drug effects ; Cognitive Dysfunction/drug therapy ; Blood-Brain Barrier/metabolism ; *Memory Disorders/drug therapy ; Rats, Sprague-Dawley ; }, abstract = {Chronic cerebral hypoperfusion (CCH), a subclinical state underlying mild cognitive impairment (MCI), triggers multiple pathological changes associated with Alzheimer's disease (AD) and vascular dementia (VaD), including amyloid-β (Aβ) deposition, tau phosphorylation, microglial activation and neural circuit dysfunction. Developing multitarget therapeutics to effectively prevent the transition from MCI to AD and/or VaD remains an urgent challenge. Herein, we engineered a brain-targeted dual-modified PEGylated nanoliposome (LipTM@miR-195), incorporating mannose (MAN) and the trans-activating protein of HIV type 1 (TAT), which encapsulates polyethyleneimine (PEI) complesed microRNA-195 (miR-195). In a CCH rat model, tail-vein administration of LipTM@miR-195 (0.112 mg/kg) efficiently crossed the blood-brain barrier (BBB) without detectable side effects. Treatment reversed CCH-induced spatial learning and memory deficits, rescued neural circuit dysfunction, and suppressed elevated APP, BACE1, AT8 and CD68 levels. Collectively, these findings provide compelling evidence that LipTM@miR-195 nanoliposome holds therapeutic potential for CCH-induced cognitive impairment, thereby preventing the progression from MCI to AD and/or VaD.}, } @article {pmid41314098, year = {2025}, author = {Ye, M and Kim, JS and Shim, I}, title = {CB1 receptor activation and inhibition differentially modulate cognitive deficits and neuropathology in 3xTg-AD mice.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {193}, number = {}, pages = {118818}, doi = {10.1016/j.biopha.2025.118818}, pmid = {41314098}, issn = {1950-6007}, mesh = {Animals ; *Receptor, Cannabinoid, CB1/metabolism/agonists/antagonists & inhibitors ; Mice ; *Alzheimer Disease/metabolism/pathology/drug therapy/psychology ; *Piperidines/pharmacology ; Mice, Transgenic ; tau Proteins/metabolism ; Hippocampus/metabolism/drug effects/pathology ; Male ; *Pyrazoles/pharmacology ; Oxidative Stress/drug effects ; Disease Models, Animal ; *Cognitive Dysfunction/metabolism/drug therapy/pathology ; Amyloid beta-Peptides/metabolism ; Phosphorylation ; Maze Learning/drug effects ; Arachidonic Acids ; }, abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and progressive neuronal loss. The endocannabinoid system regulates synaptic function, inflammation, and redox homeostasis through cannabinoid receptor type 1 (CB1). This study aimed to determine whether pharmacological activation or inhibition of the CB1 receptor differentially modulates Alzheimer's disease-related pathology. 3xTg-AD mice received weekly intraperitoneal injections of the CB1 agonist ACEA (1 mg/kg) or the inverse agonist AM251 (1 mg/kg) from 6 to 12 months of age. Cognitive function was assessed using the Morris Water Maze (MWM) and Y-maze, while hippocampal tissues were analyzed for Aβ, p-Tau, glial markers (GFAP, Iba-1), cytokines (IL-1β, IL-10), oxidative stress markers (SOD, GSH, MDA), and neuronal viability (NeuN). Cerebral glucose metabolism was evaluated using [1] [8]F-FDG positron emission tomography (PET). ACEA administration reduced tau phosphorylation, glial activation, IL-1β expression, and oxidative stress, while increasing IL-10 levels, neuronal preservation, and cerebral glucose metabolism. AM251 treatment aggravated tau pathology, neuroinflammation, oxidative imbalance, and cognitive impairment. Double immunofluorescence demonstrated CB1 receptor colocalization with both Iba-1-positive microglia and GFAP-positive astrocytes, with CB1 predominantly localized to microglia, suggesting a microglia-dependent mechanism underlying CB1-mediated neuroprotection. Aβ levels were not affected by either treatment. Chronic CB1 receptor activation attenuates tau-associated pathology and metabolic dysfunction in 3xTg-AD mice, indicating the therapeutic relevance of CB1 signaling modulation in neurodegenerative disorders.}, } @article {pmid41313999, year = {2026}, author = {Pei, Z and Zhu, L and Ren, H and Liu, Y and Shi, X and Lin, Y and Wang, J and Li, P and Wang, P and Ji, Y and Zhou, Y and Tang, X and Jiang, X and Tong, X and Guo, Y}, title = {EEG-based stratification in Alzheimer's disease: Cognitive progression, pathological marker associations, and therapeutic interventions.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {182}, number = {}, pages = {2111440}, doi = {10.1016/j.clinph.2025.2111440}, pmid = {41313999}, issn = {1872-8952}, mesh = {Humans ; *Alzheimer Disease/physiopathology/therapy/diagnosis/psychology ; Male ; Aged ; Female ; *Electroencephalography/methods ; Transcranial Magnetic Stimulation/methods ; Disease Progression ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; *Cognitive Dysfunction/physiopathology/therapy ; Parkinson Disease/physiopathology/therapy ; *Cognition/physiology ; Biomarkers ; *Brain/physiopathology ; }, abstract = {OBJECTIVE: Clinical cognitive and pathological marker stratification systems have evolved separately, causing mismatches that limit their clinical use. This study retrospectively validated the link between EEG and clinical symptoms, pathological markers, and the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS).

METHODS: This multicenter study involved 308 Alzheimer's patients (AD), 176 with Parkinson's (PD), and 181 normal controls. Resting-state EEG were analyzed to identify four oscillation modes. An EEG-based cognitive risk system was created and validated, also evaluating its effect on rTMS therapy effectiveness.

RESULTS: EEG oscillation changes correlated with cognitive decline, revealing distinct brain network disruptions in AD and PD. These oscillation changes were associated with AD biomarkers, particularly tau hyperphosphorylation. Multicenter validation showed an 83% concordance with the Clinical Dementia Rating Scale, and EEG stratification enhanced rTMS therapeutic efficacy.

CONCLUSIONS: This study showed that EEG-based stratification can assess cognitive function, track disease progression, identify key intervention periods, and improve patient selection for better treatment outcomes in clinical settings.

SIGNIFICANCE: This study demonstrates that EEG can connect disease processes to clinical symptoms at a molecular level, offering a unified framework for improved dementia management. This method allows for dynamic monitoring and precise neuromodulation, enhancing personalized care for neurodegenerative diseases.}, } @article {pmid41313889, year = {2026}, author = {Jelčić, A and Talić, S and Odak, I and Mlakić, M and Lasić, Z and Roca, S and Šagud, I and Bruketa, T and Bosnar, M and Barić, D and Škorić, I}, title = {Exploring the selective butyrylcholinesterase inhibition potential of phenol carbamates: Experimental and computational study.}, journal = {European journal of medicinal chemistry}, volume = {302}, number = {Pt 3}, pages = {118375}, doi = {10.1016/j.ejmech.2025.118375}, pmid = {41313889}, issn = {1768-3254}, mesh = {*Butyrylcholinesterase/metabolism ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Carbamates/pharmacology/chemistry/chemical synthesis ; Humans ; Structure-Activity Relationship ; Molecular Docking Simulation ; Molecular Structure ; Dose-Response Relationship, Drug ; Acetylcholinesterase/metabolism ; Hep G2 Cells ; *Phenols/chemistry/pharmacology/chemical synthesis ; *Phenol/chemistry/pharmacology ; }, abstract = {A series of fourteen novel phenol carbamates was synthesized and evaluated as potential selective butyrylcholinesterase (BChE) inhibitors targeting cholinergic dysfunction in Alzheimer's disease (AD). The compounds were prepared efficiently from resveratrol analogs via a Wittig reaction followed by carbamoylation, and their structures were confirmed by NMR, MS, and HRMS analyses. All derivatives were screened for inhibitory activity against acetylcholinesterase (AChE) and BChE using a modified Ellman method. None of the compounds inhibited AChE, whereas all selectively inhibited BChE, with IC50 values ranging from 0.045 to 6.840 μM. The most potent inhibitor, compound 13, bearing a pyrrolidine moiety, exhibited an IC50 value of 0.045 μM, outperforming the reference drug galantamine by more than two orders of magnitude. Molecular docking and dynamics simulations confirmed strong π-π and alkyl-π interactions between the ligands and the enzyme's active site, accounting for their high affinity and selectivity. In silico ADME(T) analysis predicted excellent intestinal absorption, blood-brain barrier penetration, and low cytotoxicity, while minor genotoxicity alerts were observed for a few derivatives. In vitro cytotoxicity assays in HepG2 cells confirmed the absence of toxicity at concentrations up to 30 μM. These results highlight methoxy-substituted phenol carbamates, particularly compound 13, as promising lead structures for the design of selective BChE inhibitors and potential therapeutic agents for the treatment of AD.}, } @article {pmid41313642, year = {2025}, author = {Mangalmurti, A and Zengeler, KE and Hollis, A and Golden, E and Riddlemoser, G and Lukens, JR}, title = {Microglial CLEC7A restrains amyloid beta plaque pathology in a mouse model of Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70943}, pmid = {41313642}, issn = {1552-5279}, support = {ADSF-21-816651/ALZ/Alzheimer's Association/United States ; /NH/NIH HHS/United States ; R01AG071996/AG/NIA NIH HHS/United States ; R01AG087406/AG/NIA NIH HHS/United States ; RF1AG078684/AG/NIA NIH HHS/United States ; //Cure Alzheimer's Fund/ ; //The Steven A Newman AD Award/ ; //Rick Sharp Foundation/ ; //Harrison Family Foundation/ ; T32GM007267//Medical Scientist Training Program/ ; T32AI007496//Immunology Training Program/ ; T32AI007496//National Institute of Allergy and Infectious Diseases/ ; T32GM156694/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/genetics ; *Plaque, Amyloid/pathology/metabolism ; Disease Models, Animal ; *Microglia/metabolism/pathology ; *Lectins, C-Type/metabolism/genetics ; Mice ; Mice, Transgenic ; Mice, Knockout ; Macrophages/metabolism ; Amyloid beta-Peptides/metabolism ; Humans ; Brain/pathology/metabolism ; }, abstract = {INTRODUCTION: CLEC7A is a surface receptor that is highly upregulated on microglia in many Alzheimer's disease (AD) models. Little is known about the role that microglial CLEC7A signaling plays in AD-related pathogenesis.

METHODS: We utilized an inducible, central nervous system (CNS) macrophage-specific knockout of Clec7a to evaluate the role of CLEC7A in the 5xFAD mouse model of AD at 5 months of age. We used immunofluorescence microscopy, single-nuclei RNA sequencing, along with biochemical assays, to evaluate plaque burden, microglial activity, and neuronal health.

RESULTS: CNS macrophage-targeted deletion of CLEC7A in 5xFAD mice led to a twofold increase in plaque burden, exacerbated neuritic dystrophy, and altered the expression of neuronal health genes, but did not appreciably impact microglial activation, plaque engulfment, or disease-associated microglia acquisition.

DISCUSSION: These findings identify protective roles for CLEC7A in AD-related amyloidosis and suggest that CLEC7A-targeting therapeutics may offer promising strategies for treatment of AD.

HIGHLIGHTS: Conditional loss of CLEC7A in central nervous system (CNS) macrophages of 5xFAD mice results in increased amyloid beta deposition. Loss of CLEC7A does not alter the disease-associated microglia transcriptional program or affect the recruitment of microglia to plaque surfaces. Exacerbation of amyloid deposition with loss of CNS-macrophage CLEC7A is associated with worsened neuronal health highlighted by increased neuritic dystrophy.}, } @article {pmid41312814, year = {2026}, author = {Akpınar, O and Nazıroğlu, M}, title = {Glutathione and TRPM2 Inhibition Reduce Amyloid-Beta and Lipopolysaccharide-Induced Apoptosis, Inflammation, and Oxidative Stress in Microglial Cells.}, journal = {Cell biology international}, volume = {50}, number = {1}, pages = {e70109}, doi = {10.1002/cbin.70109}, pmid = {41312814}, issn = {1095-8355}, support = {//This study was supported by the Scientific Research Projects Coordination Unit (BAP) of Süleyman Demirel University (project number: TDK-2021-8387). Project owner was Mustafa Nazıroğlu./ ; }, mesh = {*TRPM Cation Channels/antagonists & inhibitors/metabolism ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; Lipopolysaccharides/pharmacology ; *Microglia/metabolism/drug effects ; *Amyloid beta-Peptides/metabolism/pharmacology ; *Inflammation/metabolism ; *Glutathione/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Animals ; Mice ; Cell Line ; Calcium/metabolism ; }, abstract = {Microglia cells impacted by inflammation and Alzheimer's disease produce toxic reactive oxygen species (ROS), emit signaling molecules, and death as a result of microglia being active due to excessive Ca[2+] entering the cells. The TRPM2 channel plays a crucial role in Ca[2+] permeability, inflammation, ROS, and apoptosis changes in the BV2 microglia cells, while glutathione (GSH) treatment reduces the changes through TRPM2 inhibition. However, the effect of TRPM2 inhibitors and GSH treatment on oxidative stress, inflammation, and apoptotic values in BV2 microglia cells activated with LPS and amyloid-beta (Aβ) has not been investigated yet. The study aimed to assess the effects of TRPM2 inhibition and GSH treatment on the values in BV2 cells activated with LPS and Aβ. BV2 cells were divided into five groups: control (CNT), LPS, Aβ, Aβ + LPS, and Aβ + LPS + GSH. Increased levels of inflammation biomarkers (TNF-α, IL-1β, and IL-6), intracellular Ca[2+] level, cytosolic ROS, mitochondrial membrane dysfunction, cell death, apoptosis, caspases (caspase-3, -8, and -9), and TRPM2 current density were observed in the cells stimulated with LPS and Aβ. These values increased more when LPS and Aβ were incubated together. However, these apoptotic, inflammatory, and oxidant levels decreased in cells treated with GSH and TRPM2 blockers. In conclusion, the involvement of TRPM2 stimulation was demonstrated on Aβ and LPS-induced Ca[2+] entry, oxidative stress, inflammation, and apoptosis parameters in microglia cells. TRPM2 inhibition by GSH treatment seems to be a potential source for the prevention of Aβ and LPS-induced oxidative stress, apoptosis, and inflammation.}, } @article {pmid41312794, year = {2025}, author = {Healy, M and Thomas, S and Brodtmann, A}, title = {Magnetic resonance imaging eligibility for anti-amyloid monoclonal antibody treatment for Alzheimer disease: a single-centre retrospective review for service planning.}, journal = {Internal medicine journal}, volume = {}, number = {}, pages = {}, doi = {10.1111/imj.70254}, pmid = {41312794}, issn = {1445-5994}, } @article {pmid41312566, year = {2025}, author = {Kwinta, R and Morawiec, N and Bączyk, J and Kubicka-Bączyk, K and Adamczyk-Sowa, M}, title = {Aging immunity - the role of T and B cells in neurological disorders among older adults.}, journal = {Neurologia i neurochirurgia polska}, volume = {}, number = {}, pages = {}, doi = {10.5603/pjnns.106498}, pmid = {41312566}, issn = {0028-3843}, abstract = {INTRODUCTION: Immunosenescence is a natural process of immune system aging, which leads to significant changes in the functioning of both innate and adaptive immunity. Alterations in T and B lymphocytes can significantly impact the progression of neurological diseases including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

STATE OF THE ART: Immunosenescence affects T and B cell subsets, reducing their proliferative capacity and altering cytokine profiles. In MS, these changes promote disease progression and diminish responses to immunomodulatory therapies. In AD and PD, dysfunctional T and B cells contribute to sustained neuroinflammation, exacerbating neurodegeneration. ALS is similarly associated with altered adaptive immunity.

CLINICAL IMPLICATIONS: Recognizing how immunosenescent T and B cells contribute to disease in older adults is crucial for refining treatment strategies. These age-related immune changes may explain varied responses to therapies and highlight the need for novel approaches targeting the aged immune system in neurodegenerative diseases.

FUTURE DIRECTIONS: Future research should focus on identifying the mechanisms by which immunosenescent lymphocytes modulate neuroinflammation and neurodegeneration in aging populations. Novel biomarkers and immunomodulatory therapies tailored to older adults could significantly improve outcomes in patients with neurological diseases.}, } @article {pmid41311387, year = {2025}, author = {Zhou, Y and Wang, Y and Yang, H and Zhang, C and Meng, J and Zhang, L and Li, K and Huang, LL and Zhang, X and Luo, H and Zhang, Y}, title = {Sorafenib promotes the E3 ubiquitin ligase FBXW7 to increase tau degradation and ameliorate tauopathies.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {11}, pages = {5817-5831}, pmid = {41311387}, issn = {2211-3835}, abstract = {Tauopathies, including Alzheimer's disease (AD), are a series of neurodegenerative diseases characterized by pathological accumulation of the microtubule-associated protein tau. Since the abnormal modification and deposition of tau in nerve cells are crucial for tauopathy etiology, methods for reducing tau levels, such as promoting tau degradation, may become effective strategies for disease treatment. Herein, we identified that sorafenib significantly reduced total tau and phosphorylated tau levels through screening FDA-approved drugs. We showed that sorafenib treatment attenuated cognitive deficits and tau pathologies in PS19 tauopathy model mice. Mechanistically, we found that sorafenib inhibited multiple kinases involved in tau phosphorylation and promoted autophagy. Importantly, we further demonstrated that sorafenib also promoted the expression of the E3 ubiquitin ligase FBXW7, which could bind tau and mediate tau degradation through the ubiquitin-proteasome pathway. Finally, we showed that FBXW7 expression decreased in the brains of AD patients and tauopathy model mice, and that overexpression of FBXW7 in the hippocampus attenuated cognitive deficits and tau pathologies in PS19 mice. These results suggest that sorafenib may be a promising treatment option for tauopathies by promoting tau degradation and reducing tau phosphorylation, and that targeting FBXW7 could also serve as an alternative therapeutic strategy for tauopathies.}, } @article {pmid41311386, year = {2025}, author = {Zhao, Y and Liu, X and Yang, S and Wang, J and Wu, D and Bu, Y and Xie, X}, title = {Electrochemical biosensors with right-side-out-oriented cell membrane coating for the evaluation of AChE inhibitors as potential anti-Alzheimer's disease agents.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {11}, pages = {5988-6000}, pmid = {41311386}, issn = {2211-3835}, abstract = {Biosensors based on acetylcholinesterase (AChE) are crucial for early diagnosis, less invasive treatment, and drug evaluation of Alzheimer's disease (AD). However, existing technologies often suffer from enzyme conformational changes, leading to altered activity and loss and reduced sensor efficacy. To address this challenge, we developed a novel right-side-out-oriented red blood cell membrane-coated electrochemical biosensors (ROCMCBs) to evaluate AChE inhibitors from traditional Chinese medicines (TCMs) as potential anti-AD agents. The developed right-side-out-oriented coating based on immunoaffinity not only fully exposed the binding sites of AChE on the cell membrane but also ensured its conformation and stability as a peripheral membrane-anchoring protein, which was conducive to maintaining its biological activity and producing optimal interaction with drugs. At the same time, the biosensors exhibited a satisfactory sensitivity (limit of detection = 0.41 pmol/L). Ultimately, six potentially active compounds against AD (baicalin, geniposide, gastrodin, berberine, rhynchophylline, and senkyunolide A) were rapidly identified and evaluated from TCMs. This project provides a promising strategy for developing cell membrane-coated electrochemical biosensors. The application of cell membrane-coated electrochemical biosensors with well-defined cell membrane orientation further expands new perspectives and methods for AChE-targeted anti-AD research.}, } @article {pmid41311299, year = {2025}, author = {Pini, L and Allali, G and Imbimbo, BP and Germani, M and Corbetta, M}, title = {Brain connectivity as a new target for Alzheimer's disease therapy?.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf404}, pmid = {41311299}, issn = {1460-2156}, abstract = {The recent introduction of immunotherapeutic agents targeting amyloid-β (Aβ) has advanced the pharmacological treatment of Alzheimer's disease (AD). Although several anti-Aβ antibodies have dramatically reduced cerebral amyloid plaques, this has not translated into major cognitive or clinical benefits, thus questioning the clinical relevance of these biomarker changes. Indeed, there is an ongoing debate over whether amyloid reduction alone constitutes sufficient evidence of disease modification to justify regulatory approval. Against this backdrop, we propose a third pathway that transcends the binary framework of molecular versus clinical end points by positioning brain connectivity as a system-level intermediate phenotype. This approach is supported by a growing body of evidence. Alterations in brain networks are early, sensitive, and modifiable markers of AD pathology. Connectivity metrics capture the dynamic interplay between genetic and environmental factors, offering a unified model of disease. Advances in precision medicine, such as individualized connectivity 'fingerprints' and the emergence of digital twins, further position brain connectivity as a powerful platform for therapeutic innovation. We argue that adopting brain network analysis as a key outcome measure enables a shift beyond isolated biomarker achievements toward a more integrated, biologically grounded, and clinically meaningful framework for disease modification in AD, bridging the gap between molecular advances and real-world impact.}, } @article {pmid41311279, year = {2025}, author = {Garland, H and Jacobson, M and Xu, S and Zissimopoulos, J}, title = {A scoping review of population-based dementia registries: advancing research, care, and policy.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70938}, pmid = {41311279}, issn = {1552-5279}, mesh = {Humans ; *Registries ; *Dementia/therapy/epidemiology ; *Health Policy ; }, abstract = {Despite their value for public health, research, and care, population-based registries for Alzheimer's disease and related dementias (ADRD) remain limited. We conducted a scoping review of dementia registry studies through December 2023 and identified population-based dementia registries in Organisation for Economic Co-operation and Development countries. We characterized their structure and scope, assessed key themes, and developed recommendations for registry development. We identified 21 population-based dementia registries from a review of 235 publications. These registries help fill gaps in dementia research by providing longitudinal data, improving case identification, and standardizing outcomes for clinical and policy use. However, many registries lack data on healthcare use and caregiving and have limited geographical coverage, thereby reducing their ability to inform research and public health efforts to address dementia burden in an era of rapidly evolving dementia diagnostics and treatments. As dementia cases rise and advancements in prevention, detection, and treatment accelerate, population-based registries are essential for generating real-world evidence to improve dementia care, policy, and outcomes. HIGHLIGHTS: This scoping review identified 21 population-based dementia registries across OECD countries, highlighting the current landscape and structural gaps. Registries provide critical longitudinal data and standardization for research and policy but often lack information on healthcare use, caregiving, and broad geographic representation. With rising dementia rates and evolving treatments, population-based registries are essential for producing real-world evidence to strengthen care, research, and public health planning.}, } @article {pmid41311076, year = {2025}, author = {Li, X and Zhang, Y and Gu, Y and Chen, N and Qian, X and Zhang, P and Hao, J and Wang, F}, title = {[Association between Tau protein deposition and brain metabolites: N-acetylaspartate and creatine as potential biomarkers for advanced Alzheimer's disease].}, journal = {Nan fang yi ke da xue xue bao = Journal of Southern Medical University}, volume = {45}, number = {11}, pages = {2350-2357}, pmid = {41311076}, issn = {1673-4254}, mesh = {Humans ; *Alzheimer Disease/metabolism/diagnostic imaging ; *Aspartic Acid/analogs & derivatives/metabolism ; *tau Proteins/metabolism ; *Creatine/metabolism ; *Brain/metabolism ; Biomarkers/metabolism ; Positron-Emission Tomography ; Male ; Female ; Proton Magnetic Resonance Spectroscopy ; Choline/metabolism ; Aged ; Middle Aged ; }, abstract = {OBJECTIVES: To investigate the associations between Tau protein deposition and brain biochemical metabolites detected by proton magnetic resonance spectroscopy ([1]H-MRS) in patients with advanced Alzheimer's disease (AD).

METHODS: From April, 2022 to December, 2024, 64 Tau-positive AD patients and 29 healthy individuals underwent [18]F-APN-1607 PET/MR and simultaneously acquired multi-voxel [1]H-MRS in the Department of Nuclear Medicine, Nanjing First Hospital. Visual analysis and voxel-based analysis of PET/MR data were performed to investigate the Tau protein deposition patterns in AD patients. Valid voxels within the [1]H-MRS field of view were selected, and their standardized uptake value ratio (SUVr) in PET and metabolite levels of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), NAA/Cr, and Cho/Cr were recorded. The Tau-positive (Tau[+]) voxels and Tau-negative (Tau[-]) voxels of the AD patients were compared for PET and [1]H-MRS parameters, and the correlations between the metabolites and Tau PET SUVr within Tau[+] voxels were analyzed.

RESULTS: Significant Tau protein deposition were observed in the AD patients, involving mainly the bilateral frontal lobes (30.07%), parietal lobes (29.96%), temporal lobes (21.07%), and occipital lobes (15.89%). A total of 1422 valid voxels in AD group (including 994 Tau[+] and 428 Tau[-] voxels) and 814 voxels in the control group were selected. The AD patients showed significantly decreased NAA level and increased SUVr compared with the control group (P<0.05). Subgroup analyses revealed that Tau[+] voxels had higher SUVr and lower Cr and Cho/Cr than Tau[-] voxels (P<0.05). Compared with the control group, Tau[+] voxels exhibited higher SUVr and lower Cr (P<0.05), while Tau[-] voxels showed lower NAA (P=0.004). No significant differences were found in Cho or NAA/Cr among the subgroups (P>0.05). Within Tau[+] voxels, NAA, Cho, and Cr were negatively correlated with SUVr (P<0.001).

CONCLUSIONS: The patients with progressive AD have significant Tau protein deposition in the brain, which is correlated with alterations in metabolite levels. Decreased NAA is more prominent in early or pre-tau deposition stages, while Cr changes is more significant in the regions with Tau protein deposition, suggesting the potential of NAA and Cr as biomarkers for Tau protein deposition in AD for disease monitoring and treatment evaluation.}, } @article {pmid41309432, year = {2026}, author = {Bai, N and Liu, S and Wei, J and Zheng, B and Wang, W and Li, X and Yang, J and Song, X and Wang, L and Yi, F and Cao, L}, title = {Sirtuins in Alzheimer's disease: mechanistic insights and therapeutic opportunities.}, journal = {Trends in pharmacological sciences}, volume = {47}, number = {1}, pages = {100-119}, doi = {10.1016/j.tips.2025.10.016}, pmid = {41309432}, issn = {1873-3735}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Sirtuins/metabolism/antagonists & inhibitors ; }, abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterized by progressive cognitive decline and complex neuropathology. Its main features include amyloid-β (Aβ) plaques, tau neurofibrillary tangles (NFTs), and neuroinflammation. Current therapies provide only limited symptomatic relief and cannot stop disease progression, highlighting the urgent need for disease-modifying strategies. Recent research has revealed multiple roles of sirtuins in AD pathology, positioning them as promising therapeutic targets. Studies using small-molecule compounds to target sirtuins, in both cellular and animal models and clinical analyses of AD patients, demonstrate their therapeutic potential. This review discusses the distinct roles of individual sirtuin isoforms in AD pathogenesis and evaluates the therapeutic evidence for small-molecule sirtuin modulators.}, } @article {pmid41309190, year = {2025}, author = {Shah, A and Karthikeyan, T and Hashem, S and Kumar, R and Bhat, AA and Macha, MA}, title = {Protein misfolding and neurodegeneration: Mechanisms, implications, and therapeutic strategies.}, journal = {Advances in protein chemistry and structural biology}, volume = {148}, number = {}, pages = {135-177}, doi = {10.1016/bs.apcsb.2025.08.012}, pmid = {41309190}, issn = {1876-1631}, mesh = {Humans ; *Protein Folding ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy/therapy ; *Proteostasis Deficiencies/metabolism/pathology/therapy ; Animals ; Proteostasis ; }, abstract = {Protein misfolding and aggregation play a pivotal role in the development of neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's disease, and other related disorders. Proper protein folding is essential for cellular function, but due to the complexity of the folding process and external factors like genetic mutations, oxidative stress, and aging, misfolding is inevitable. These misfolded proteins often aggregate into toxic forms that disrupt cellular processes, leading to neuronal damage and cognitive decline. This chapter provides a comprehensive overview of molecular mechanisms behind protein misfolding, highlighting how these abnormal structures contribute to neurodegeneration. It also explores the role of the proteostasis network and its therapeutic potential in alleviating these processes. Focusing on multitarget therapeutic strategies, the chapter offers insights into promising approaches for addressing the root causes of neurodegenerative diseases while identifying key research gaps that could shape future treatment developments. By blending current knowledge with emerging therapeutic directions, this chapter provides a comprehensive and engaging perspective on combating the challenges of protein misfolding in neurodegeneration.}, } @article {pmid41307609, year = {2025}, author = {Katayama, S and Tsujimoto, M and Suzuki, K and Ueda, K and Shimoura, K and Suo, S and Hatakeyama, N}, title = {Care Partners' Perceptions of Amyloid-Targeting Therapy and Treat‑to‑Clearance for Alzheimer's Disease in Japan: A Qualitative Study.}, journal = {Neurology and therapy}, volume = {}, number = {}, pages = {}, pmid = {41307609}, issn = {2193-8253}, abstract = {INTRODUCTION: Donanemab has been developed as an amyloid-targeting therapy (ATT) for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD). In registration trials involving donanemab, a treat‑to‑clearance approach was used, in which patients discontinued ATT when amyloid plaque levels decreased below a predefined threshold, which differs from previously available symptomatic treatments for AD. Our study explored care partners' perceptions regarding ATT and treat‑to‑clearance.

METHODS: This was a cross-sectional, qualitative interview study. Care partners of individuals with MCI or mild dementia due to AD participated in online semi-structured interviews about their perceptions regarding the impact of MCI or mild dementia diagnoses due to AD, the burden of supporting, and use/cessation of ATT. The qualitative data from the interviews were analyzed using a thematic approach.

RESULTS: The participants were 22 care partners (5 male/17 female), and their median age was 59 (range 35-81) years. The most common relationships between care partners and the individuals with AD were child (50.0%) and spouse/partner (45.5%); 68.2% of the care partners lived with the individuals with AD. Thematic analysis identified three major classifications (Thoughts regarding therapy; Treat‑to‑clearance; and Burdens of support), along with 15 themes and five sub-themes. Care partners expressed experiencing mental burden and time constraints, while treat‑to‑clearance could save care partners' time by reducing hospital waiting time and alleviating financial burden. Confirming the clearance of amyloid β plaques provided care partners with a sense of relief, while they remained concerned about the potential progression of AD symptoms and sought follow-up care after stopping treatment.

CONCLUSIONS: These results suggest that providing clear explanations and facilitating shared decision-making when introducing ATT, as well as introducing follow-up care and long-term evidence after stopping treatment, are needed.}, } @article {pmid41307478, year = {2025}, author = {Wang, X and Chen, L and Qiu, J and Wang, K and Xi, P and Cheng, X and He, Z and Jiang, H}, title = {Dipeptidyl Peptidase 4 Mediated Caspase-8 Affects Cognitive Impairment in Mice With Alzheimer's Disease.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {39}, number = {23}, pages = {e71264}, doi = {10.1096/fj.202501322RR}, pmid = {41307478}, issn = {1530-6860}, support = {82204837//MOST | NSFC | National Natural Science Foundation of China-Zhejiang Joint Fund for the Integration of Industrialization and Informatization (NSFC-Zhejiang Joint Fund)/ ; 81760207//MOST | NSFC | National Natural Science Foundation of China-Zhejiang Joint Fund for the Integration of Industrialization and Informatization (NSFC-Zhejiang Joint Fund)/ ; LQ23H290004//Zhejiang Provincial Natural Science Foundation of China/ ; 2024AY10021//Jiaxing Science and Technology Plan Project‌/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism ; Male ; Mice ; *Dipeptidyl Peptidase 4/metabolism/genetics ; Mice, Inbred C57BL ; *Caspase 8/metabolism/genetics ; *Cognitive Dysfunction/metabolism ; Mice, Knockout ; Amyloid beta-Peptides/toxicity ; Disease Models, Animal ; Pyroptosis ; Dipeptidyl-Peptidase IV Inhibitors/pharmacology ; Maze Learning ; Hippocampus/metabolism ; Neurons/metabolism ; }, abstract = {To investigate the effect of dipeptidyl peptidase 4 (DPP4) on cognitive impairment in Alzheimer's disease (AD), the present study used seven-week-old male C57BL/6J and DPP4 knockout mice. The AD model was induced by microinjection of Aβ25-35 into the lateral ventricle. Morris water maze test showed that DPP4 knockout significantly improved the spatial learning and memory abilities of AD mice. Western blot results showed that DPP4 knockout increased the expression levels of BDNF, CREB and Bcl-2 in the hippocampus of AD mice while the expression levels of Caspase-8, pyroptosis-related proteins NLRP3, Caspase-1, GSDMD, IL-118, IL-1β, and apoptosis-related proteins Caspase-3 and Bax were decreased. Similar results were observed after HT22 neurons were treated with Aβ25-35 and the DPP4 inhibitor sitagliptin (Sit). Moreover, the treatment with a Caspase-8 inhibitor (Z-LETD-FMK) showed that the inhibition of Caspase-8 inhibited the expression of NLRP3 and Caspase-1 in the AD model cells, but had no further inhibitory effect under the treatment of Sit. Our results suggest that DPP4 knockout may ameliorate learning and memory dysfunction in AD model mice by regulating pyroptosis and apoptosis pathways through Caspase-8.}, } @article {pmid41307069, year = {2025}, author = {Zhang, Y and Qiu, J and Shang, Y and Zhao, X and Yang, S and Chen, Y and Dai, S and Ai, M and Huang, W and Zhang, J and Liu, X}, title = {Impact of DL-3-n-Butylphthalide on Progression in Alzheimer's Disease: A Retrospective Cohort Analysis.}, journal = {Neuropsychiatric disease and treatment}, volume = {21}, number = {}, pages = {2495-2511}, pmid = {41307069}, issn = {1176-6328}, abstract = {OBJECTIVE: To evaluate the efficacy of DL-3-n-butylphthalide (NBP), a synthetic compound that has shown neuroprotective effects, on cognitive function, psychiatric-behavioral symptoms, and daily activities in patients with Alzheimer's disease (AD).

METHODS: This retrospective cohort study included patients with AD treated with or without NBP. Disease deterioration and decline were defined by changes in Clinical Dementia Rating-Sum of Boxes (CDR-SB) over six months. Multivariate logistic regression, inverse probability of treatment weighting (IPTW) and overlap-weighted propensity score matching (PSM) were used to adjust for confounding.

RESULTS: Totally 100 were included in this study, with 39 classified as the NBP group and 61 as the non-NBP group. NBP was associated with lower odds of deterioration (adjusted odds ratio [OR] = 0.19, 95% confidence interval [CI]: 0.04-0.88, p = 0.034) and decline (adjusted OR = 0.10, 95% CI: 0.03-0.49, p = 0.001). In IPTW and PSM analyses, deterioration occurred in 4.31% vs 22.10% and 4.06% vs 24.27%, and decline in 4.31% vs 39.38% and 4.06% vs 44.28% for the NBP and non-NBP groups, respectively.

CONCLUSION: NBP was associated with reduced risks of clinical worsening and helped preserve cognitive and behavioral functions in patients with AD. These results highlight the potential of NBP as a promising therapeutic option in AD management. Future randomized controlled trials are necessary to validate these findings and assess the long-term efficacy of NBP in clinical settings.

SIGNIFICANCE: This real-world study suggests that NBP may slow disease progression and preserve cognitive and behavioral function in AD.}, } @article {pmid41306895, year = {2025}, author = {Duncan, GB and Dickson, SP and Kaplan, JM and Johnson, SB and Duke, TM and Dayley, CW and Hendrix, SB and Altstiel, LD and Mallinckrodt, CH}, title = {Leveraging recent advances in plasma biomarkers to optimize early proof of concept trials in Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {4}, pages = {e70183}, pmid = {41306895}, issn = {2352-8737}, abstract = {INTRODUCTION: The importance of biomarkers as a primary outcome or as supportive evidence of clinical effect is rising as the field shifts toward disease-modifying treatments and earlier intervention, because they have lower variability and can indicate disease progression earlier than clinical outcomes. This study assessed the performance of plasma pTau 181 and 217 as a predictive biomarker and potential primary endpoint in early-phase Alzheimer's disease (AD) trials.

METHODS: Summary data from recent monoclonal antibody (mAb) trials including plasma pTau 181 and 217 were analyzed to evaluate associations between plasma pTau 181/217 and clinical outcomes. The suitability of plasma pTau 181/217 as a surrogate endpoint for internal decision making was assessed using Prentice criteria. Simulations were conducted to explore the statistical power of using plasma pTau 181/217 as a primary outcome in dose-escalation, proof-of-concept (POC) trial designs. Additional criteria for biomarker validation were applied to simulated data.

RESULTS: A strong group-level correlation (r = 0.781) was observed between treatment effects on plasma pTau 181/217 and Clinical Dementia Rating scale - Sum of Boxes (CDR-SB). Mean change in plasma pTau 181/217 significantly predicted mean change in CDR-SB (p = 0.013). The treatment effect on pTau 181/217 was ∼2.6 times greater than on CDR-SB. Prentice Criteria 1, 2, and 4 were met or reasonably met; Criterion 3 is not applicable in the POC setting.

CONCLUSION: Plasma pTau 181/217 at 6 months shows future promise to reasonably likely predict clinical benefit for drugs that reduce pTau 181/217 levels, supporting its use as a primary endpoint in early-phase trials. With effect sizes similar to those seen with donanemab, adequately powered trials may require as few as 100 participants. Such trials should include prespecified analyses to evaluate individual-level Prentice criteria, and pTau 181/217 results can be used to predict potential Phase 3 clinical outcomes.

HIGHLIGHTS: The group-level correlation between a biomarker treatment effect and clinical endpoint treatment effect is a measurement of the biomarker's ability to predict clinical outcome.The correlation of group level plasma pT217 or pT181 effect size at 6 months with clinical outcome Clinical Dementia Rating scale - Sum of Boxes (CDR-SB) effect size at 12 months was approximately 0.781 with p values of 0.013.Cohen's d effect size of plasma pTau as an outcome was 2.6 times greater than the Cohen's d of CDR-SB, leading to higher power or lower sample sizes.As a primary endpoint, plasma pTau meets or reasonably meets Prentice Criteria 1, 2, and 4, while Criterion 3 was deemed not applicable in the proof-of-concept study setting.}, } @article {pmid41306402, year = {2025}, author = {Riberas-Sánchez, A and García-Brito, S and Vila-Solés, L and Aldavert-Vera, L and Segura-Torres, P and Huguet, G and Carreras-Badosa, G and Kádár, E}, title = {Intracranial self-stimulation mitigates spatial task deficits, modifies miR-146a and miR-495 serum levels and restores hippocampal NRF2 levels in a rat model of sporadic Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1671196}, pmid = {41306402}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease associated with aging. While deep brain stimulation (DBS) shows therapeutic promise, the long-term persistence of its effects remains understudied. Expression patterns of circulating miRNAs, proposed diagnostic biomarkers, and their modulation by DBS are still poorly characterized in longitudinal studies. This study investigates the effect of a 13-week prolonged ICSS treatment on spatial memory and serum miRNA expression in a male rat model of sporadic AD (SAD) by intracerebroventricular injection of streptozotocin (STZ).

METHODS: Morris water maze (MWM) tasks were conducted at 1 and 5 months post-STZ. Serum miRNA levels were quantified by qRT-PCR at 29 (Ser0), 73 (Ser1) and 136 (Ser2) days after STZ administration. Corpus callosum thickness and NRF2 protein levels in the hippocampal CA1 region were assessed using Nissl staining and immunohistochemistry, respectively. Target validation of miR-495 was performed via transfection assays in the human neuroblastoma SH-SY5Y cell line.

RESULTS: MFB-ICSS treatment significantly reduced escape latency in the MWM task in the STZ + ICSS group compared to untreated STZ rats at 5 months post-STZ. At Ser0, levels of miR-16, miR-30c, miR-181, miR-191 and miR-196a were significantly increased in STZ group. In STZ rats, miR-146a and miR-495 levels increased from Ser1 to Ser2, an effect not observed in the Control or STZ + ICSS groups. In SH-SY5Y cells, miR-495 overexpression significantly downregulated both NRF2 mRNA and protein levels. Moreover, STZ exposure increased miR-495 and reduced NRF2 protein levels. MFB-ICSS also reversed the STZ-induced reductions in both CA1 NRF2 levels and corpus callosum thickness.

CONCLUSION: Prolonged MFB-ICSS treatment mitigates cognitive deficits, modulates circulating levels of miRNA-495 and miR-146a, restores hippocampal NRF2 levels, and preserves corpus callosum integrity in the SAD rat model by STZ injection. These findings highlight the therapeutic potential of MFB-ICSS as a non-pharmacological intervention in AD. Furthermore, this study confirms NRF2 as a target of miR-495 in the context of AD.}, } @article {pmid41306115, year = {2025}, author = {Li, G and Cobb, B and Nelson, TM and Devanarayan, V and Borentain, S and Mielke, MM and Galvin, JE and Kivipelto, M and Tkatch, R and De Santi, S and Frech, F and Vandercappellen, J and Nakamura, Y and Crislip, R and Meyerhoff, J and Mattke, S and Hampel, H}, title = {Risk prediction of mild cognitive impairment using electronic health record data.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {4}, pages = {e70209}, pmid = {41306115}, issn = {2352-8729}, abstract = {INTRODUCTION: Mild cognitive impairment (MCI) is underdiagnosed by primary care providers (PCPs), with detection rates as low as 6%-15%. Predictive models support the identification of individuals at risk, enabling timely intervention.

METHODS: This retrospective study was conducted on 271,054 cognitively unimpaired and 14,501 confirmed MCI cohorts from electronic health records. A machine learning model was developed with a data-driven variable selection approach based on demographics and comorbidities.

RESULTS: From 101 variables, 26 were chosen for the final model, achieving an overall area under the curve (AUC) of 86%. Age-stratified AUCs were 79.1% (40-49), 77.0% (50-64), 76.9% (65-79), and 74.4% (≥80), showing the highest predictive performance in younger age groups.

DISCUSSION: Demographic factors and comorbidities can serve as effective predictors for the risk of MCI. The model demonstrates strong predictive performance and assists as a triage tool for PCPs, facilitating the identification of individuals with MCI for early treatment.

HIGHLIGHTS: Predictive algorithms using electronic health records (EHRs) are useful for identifying individuals at risk for mild cognitive impairment (MCI) to triage for further clinical evaluation.A machine learning model was developed using EHR data to predict those at risk for MCI.The model identified 26 variables that were able to distinguish the MCI from non-MCI cohorts.The model accurately detected MCI across the cohort (area under the curve [AUC] = 86%) and trended best for younger age groups (AUC was 77%, 77%, and 74% in 50-64, 65-79, and ≥80 age groups, respectively).Implementation of a triage tool could be used to detect MCI across aging patient populations sooner, leading to a timelier diagnosis, intervention, and treatment management.}, } @article {pmid41304967, year = {2025}, author = {Akantibila, M and Carabetta, VJ}, title = {Sirtuins as Therapeutic Targets for Treating Cancer, Metabolic Diseases, and Neurodegenerative Diseases.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {11}, pages = {}, pmid = {41304967}, issn = {1424-8247}, support = {R35GM138303/GM/NIGMS NIH HHS/United States ; }, abstract = {Sirtuins are NAD[+]-dependent enzymes that are conserved in all domains of life, including mammals, metazoans, plasmodia, yeast, bacteria, and archaea. In humans, there are seven isoforms (SIRT1 to 7), and they function in cellular homeostasis, aging, DNA repair, survival, metabolism, and stress responses. Recent advances highlight the diverse functions of sirtuins in the pathogenesis and progression of cancer, metabolic diseases, and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). To date, there is evidence that all seven isoforms contribute to cancer development, while SIRT1-3 and 6 contribute to metabolic and neurodegenerative diseases. Modulators of sirtuin activity are being actively explored to understand their biological and molecular mechanisms and potential for the treatment of various diseases. In this review, we begin with a broad discussion of post-translational modifications, protein deacetylation, and the mechanism of action of sirtuins. Next, we discuss the role of sirtuins in cancer, including inhibitors and activators of sirtuin activity as cancer therapies. In addition, we discuss the relationship of sirtuins to metabolic diseases and as possible treatment targets. Finally, we discuss the role of sirtuins in AD, PD, and HD, and sirtuin modulators for treating neurodegenerative diseases.}, } @article {pmid41304930, year = {2025}, author = {Almaghrabi, M}, title = {Multitarget-Directed Ligands for Alzheimer's Disease: Recent Novel MTDLs and Mechanistic Insights.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {11}, pages = {}, pmid = {41304930}, issn = {1424-8247}, support = {447-13-1011//Taibah University/ ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, affecting millions of people and challenging the public health framework globally. While the definitive cause of AD remains unclear, researchers are concentrating their efforts on several prominent theories. Currently, there are very few FDA-approved medications for AD, and these primarily alleviate symptoms rather than alter the disease's progression. In response, research efforts focus on developing new medicines that address the complex nature of AD through multi-targeted approaches. Multitarget-directed ligands (MTDLs) are a promising treatment strategy for AD, despite the significant challenges they pose. This review examines recent advancements in designing prospective targeted MTDLs to combat AD, with a focus on categorizing the lead generation process and investigating the integration methods of key pharmacophores within the 2024-2025 timeframe. The review highlights numerous examples of novel MTDLs that address various AD hallmarks, demonstrating their broad therapeutic potential. These targets and activities include cholinesterase (AChE and/or BuChE) inhibition, monoamine oxidase (MAO-A and/or MAO-B) inhibition, antioxidant activity, amyloid-beta (Aβ) aggregation inhibition, tau protein aggregation inhibition, glycogen synthase kinase 3β (GSK-3β) inhibition, calcium channel blockade, anti-inflammatory activity, and other hallmarks.}, } @article {pmid41304419, year = {2025}, author = {Ezzaki, C and Chaari, A and Al-Othman, A}, title = {Recent Advances on Chitosan-Based Nanoparticles for Brain Drug Delivery.}, journal = {Polymers}, volume = {17}, number = {22}, pages = {}, pmid = {41304419}, issn = {2073-4360}, abstract = {The blood-brain barrier (BBB) represents a major challenge in effective drug delivery systems intended for treating neurological disorders. It restricts the transport of therapeutic agents to the brain. Chitosan-based nanoparticles (CNPs) can be used for brain drug delivery because of their biocompatibility, biodegradability, and ability to enhance drug permeability across the BBB. This review article discusses the design and application of CNPs for brain-targeted drug delivery, exploring their mechanisms of action, including adsorptive-mediated and receptor-mediated endocytosis. Surface modifications with ligands such as chlorotoxin are discussed for improving specificity and therapeutic results. Findings show that CNPs allow controlled drug release, enhance stability, and reduce side effects, which make them effective for treating multiple neurological conditions, including Alzheimer's disease, Parkinson's disease, brain tumors, and ischemic stroke. CNPs can encapsulate multiple therapeutic agents, such as anti-inflammatory drugs, cytotoxic agents, and genetic materials, and maintain stability under different physiological conditions. Intranasal delivery routes are mainly discussed in this paper for their ability to bypass systemic circulation and achieve direct brain targeting. This review also addresses challenges such as cytotoxicity and the need for optimizing nanoparticle size, charge, and surface properties to improve the therapy results. While CNPs are suitable for brain drug delivery, there is a research gap, which is the lack of systematic studies evaluating their long-term effects on brain tissue and health. Most studies focus on acute therapeutic outcomes and in vitro or short-term in vivo analysis, which do not address some questions about the chronic exposure risks, biodistribution, and clearance pathways of CNPs. This review also explores the use of chitosan-based nanoparticles to deliver drugs to the brain for the treatment of multiple neurological disorders.}, } @article {pmid41303831, year = {2025}, author = {Uehara, MA and Kalia, S and Garcia Campuzano, M and Moussavi, Z}, title = {ADAS-Cog Trajectories Differ from Expected Decline in Dementia Following Repeated Non-Invasive Interventions over 3 Years.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {11}, pages = {}, pmid = {41303831}, issn = {1648-9144}, support = {RGPIN-2023-04308//Natural Sciences and Engineering Research Council of Canada/ ; IT43832//Mitacs/ ; }, mesh = {Humans ; Male ; Female ; Aged ; *Dementia/therapy/psychology ; Aged, 80 and over ; Transcranial Magnetic Stimulation/methods ; *Cognitive Dysfunction/therapy ; Disease Progression ; Alzheimer Disease/therapy/psychology ; Longitudinal Studies ; Neuropsychological Tests ; Middle Aged ; Mental Status and Dementia Tests ; }, abstract = {Background and Objectives: Non-pharmaceutical interventions such as cognitive training, transcranial electrical stimulation (tES), and repetitive transcranial magnetic stimulation (rTMS) have shown promise in improving cognitive outcomes in Alzheimer's disease (AD) and dementia. However, the long-term effects of repeated non-invasive interventions remain unknown. This study investigated whether repeated non-invasive interventions administered over a span of 1 to 3 years were associated with slower cognitive decline compared to typical AD progression, and whether longer no-treatment intervals between treatments predicted greater post-treatment decline. Materials and Methods: Seventy-three participants living with dementia or AD received 2 to 9 blocks of non-invasive treatments (including tES, rTMS, cognitive training). Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores were collected longitudinally up to 3 years (36 months), across multiple intervention and assessment sessions. A mixed-effects model was used to estimate the rate of cognitive decline, adjusting for baseline age, sex, and baseline cognition (MoCA) with participants being the random effect. The observed rate of change was compared to a meta-analysis estimate of AD progression. Additionally, a linear mixed-effects model using robust sandwich estimation of standard errors was employed to assess whether the no-treatment interval was associated with changes in ADAS-Cog scores. Results: Participants showed a significantly slower rate of cognitive decline than expected from the AD reference rate (p < 0.001), with many demonstrating stabilized ADAS-Cog scores during their respective treatment periods, ranging from 1 to 3 years. Medication analyses revealed no significant effect of AD medications, antidepressants, antihypertensives, or cholesterol-lowering agents on cognitive outcomes. Furthermore, longer no-treatment intervals were significantly associated with greater post-treatment decline (p < 0.001). Conclusions: Repeated non-invasive treatments seem to slow the rate of cognitive decline in individuals living with dementia when administered over a prolonged period. This study provides evidence supporting the feasibility and effects of personalized long-term non-invasive treatment strategies for dementia.}, } @article {pmid41303478, year = {2025}, author = {Polishchuk, H and Guzik, K and Kantyka, T}, title = {Beyond Hunger: The Structure, Signaling, and Systemic Roles of Ghrelin.}, journal = {International journal of molecular sciences}, volume = {26}, number = {22}, pages = {}, pmid = {41303478}, issn = {1422-0067}, support = {UMO-2016/22/E/NZ5/00332//National Science Centre/ ; }, mesh = {*Ghrelin/metabolism/chemistry ; Humans ; *Signal Transduction ; Animals ; *Receptors, Ghrelin/metabolism/chemistry ; *Hunger/physiology ; }, abstract = {Our understanding of Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor 1a (GHSR1a), has expanded from considering it to be a "hunger hormone" to a pleiotropic regulator of whole-body physiology. This review synthesizes the current advances spanning ghrelin biogenesis, signaling, and systems biology. Physiologically, preproghrelin processing and O-acylation by ghrelin O-acyltransferase (GOAT) generate acyl-ghrelin, a high-potency GHSR1a agonist; des-acyl ghrelin predominates in circulation and exerts context-dependent, GHSR1a-independent, or low-potency effects, while truncated "mini-ghrelins" can act as competitive antagonists. The emergence of synthetic ligands, agonists, antagonists, and reverse-agonists has provided the necessary tools to decipher GHSR1a activity. Recent cryo-EM structures of GHSR1a with peptide and small-molecule ligands reveal a bipartite binding pocket and provide a framework for biased signaling, constitutive activity, and receptor partner selectivity. Beyond the regulation of feeding and growth-hormone release, ghrelin modulates glucose homeostasis, gastric secretion and motility, cardiovascular tone, bone remodeling, renal hemodynamics, and innate immunity. Ghrelin broadly dampens pro-inflammatory responses and promotes reparative macrophage phenotypes. In the emerging scholarship on ghrelin's activity in the central nervous system, ghrelin has been found to influence neuroprotection, stress reactivity, and sleep architecture, and has also been implicated in depression, Alzheimer's disease, and substance-abuse disorders. Practical and transitional aspects are also highlighted in the literature: approaches for ghrelin stabilization; recent GHSR1a agonists/antagonists and inverse agonists findings; LEAP-2-based strategies; and emerging GOAT inhibitors. Together, structural insights and pathway selectivity position the ghrelin system as a druggable axis for the management of inflammatory diseases, neuropsychiatric and addiction conditions, and for obesity treatment in the post-GLP-1 receptor agonist era.}, } @article {pmid41303365, year = {2025}, author = {Faa, G and Meloni, C and Lastretti, M and Pinna, M and Manchia, M and Paribello, P}, title = {Perturbations of Zinc Homeostasis and Onset of Neuropsychiatric Disorders.}, journal = {International journal of molecular sciences}, volume = {26}, number = {22}, pages = {}, pmid = {41303365}, issn = {1422-0067}, mesh = {Humans ; *Zinc/metabolism ; *Homeostasis ; *Mental Disorders/metabolism/etiology ; Attention Deficit Disorder with Hyperactivity/metabolism ; Animals ; Schizophrenia/metabolism ; Depressive Disorder, Major/metabolism ; Alzheimer Disease/metabolism ; Autism Spectrum Disorder/metabolism ; Parkinson Disease/metabolism ; Bipolar Disorder/metabolism ; }, abstract = {Zinc (Zn[2+]) is a trace element essential for its catalytic, antioxidant, and immunomodulatory roles extending to synaptic signalling in the central nervous system. In this narrative review, we aim to offer the reader evidence linking perturbations of the Zn[2+] homeostasis, including deficiency, excess, or transportation anomalies, to neuropsychiatric conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BD). A targeted, unsystematic PubMed search followed by an extensive pearl-growing strategy was applied to further augment study selection based on the extensive expertise of study authors. Overall, most of the evidence currently available suggests a modest benefit for a Zn[2+] supplement of around 25-30 mg/day as an augmentation to MDD treatment, with potential benefits of smaller magnitude in paediatric ADHD. Evidence for perturbations of Zn[2+] as a biomarker of risk for these neuropsychiatric disorders remains unconvincing. The role of Zn[2+] supplements in the treatment of the selected conditions remains largely unknown due to the lack of specific, randomised controlled trials conducted to explore their efficacy. The long-term safety, optimal doses for specific applications, and the exploration of possible biomarkers to stratify patient selection to identify the optimal candidate for Zn[2+] supplements remain unanswered questions.}, } @article {pmid41303334, year = {2025}, author = {Pecoraro, M and Serra, A and Lamberti, MJ and Pascale, M and Franceschelli, S}, title = {New Role of Protein Misfolding Corrector in the ER Stress-Inflammation Axis: Possible Therapeutic Indication in Neuronal and Epithelial Tumor Cells.}, journal = {International journal of molecular sciences}, volume = {26}, number = {22}, pages = {}, pmid = {41303334}, issn = {1422-0067}, support = {ORSA231580//University of Salerno/ ; }, mesh = {Humans ; *Endoplasmic Reticulum Stress/drug effects ; *Inflammation/metabolism/drug therapy ; *Neurons/metabolism/drug effects/pathology ; Protein Folding/drug effects ; Calcium/metabolism ; Cell Line, Tumor ; Thapsigargin/pharmacology ; A549 Cells ; Epithelial Cells/metabolism/drug effects ; Proteostasis Deficiencies/drug therapy/metabolism ; }, abstract = {Protein misfolding diseases are characterized by structurally abnormal proteins that lose their functionality, resulting in cellular and tissue dysfunction. Neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease, share a common etiopathogenesis characterize by the accumulation of misfolded proteins. These proteins autonomously aggregate within neuronal cells, triggering inflammation and cell death. The accumulation of misfolded proteins triggers endoplasmic reticulum (ER) stress, leading to alter Ca[2+] homeostasis. This prolonged stress condition induces the cleavage of procaspase 4 which is resident in ER and activates NF-kB pathway activation, leading to inflammatory responses and cell death. In this study, the efficacy of the drug Vx-445 (Elexacaftor), used in the pharmacological treatment of cystic fibrosis, was assessed in human adenocarcinomic basal alveolar epithelial (A549) and neuronal (SH-SY5Y) cell lines, where ER stress was induced by Thapsigargin. The aim was to assess whether the corrector was able to reduce ER stress by restoring cellular homeostasis and, probably, the proper folding of misfolded proteins and reducing the inflammatory response triggered by these events. Therefore, protein levels of IkBα, p-STAT 3 and COXII were analyzed by flow cytofluorimetry, while Ca[2+] content was measured by spectrofluorimetry. The results obtained suggest a significant effect of Vx-445 in restoring cellular homeostasis, leading to reduced expression of inflammation-related proteins, such as IL-6, tested by ELISA. Although preliminary, these results encourage further studies to explore the potential repurpose of Vx-445 as a therapeutic candidate for conditions involving ER stress and chronic inflammatory diseases associated with protein misfolding, beyond its current use in cystic fibrosis.}, } @article {pmid41301832, year = {2025}, author = {Christodoulou, RC and Papageorgiou, PS and Sarquis, MD and Rivera, L and Morales Gonzalez, C and Eller, D and Rivera, G and Petrou, V and Vamvouras, G and Vassiliou, E and Papageorgiou, SG and Georgiou, MF}, title = {From Lesion to Decision: AI for ARIA Detection and Predictive Imaging in Alzheimer's Disease.}, journal = {Biomedicines}, volume = {13}, number = {11}, pages = {}, pmid = {41301832}, issn = {2227-9059}, abstract = {Background: Alzheimer's disease (AD) remains the leading cause of dementia worldwide, with anti-amyloid monoclonal antibodies (MABs) marking a significant advance as the first disease-modifying therapies. Their use, however, is limited by amyloid-related imaging abnormalities (ARIA), which appear as vasogenic edema or effusion (ARIA-E) and hemosiderin-related changes (ARIA-H) on MRI. Variability in imaging protocols, subtle early findings, and the lack of standardized risk models challenge detection and management. Methods: This narrative review summarizes current artificial intelligence (AI) applications for ARIA detection and risk prediction. A comprehensive literature search across PubMed, Embase, and Scopus identified studies focusing on MRI-based AI analysis, lesion quantification, and predictive modeling. Results: The evidence is organized into six thematic domains: ARIA definitions, imaging challenges, foundations of AI in neuroimaging, detection tools, predictive frameworks, and future perspectives. Conclusions: AI offers promising avenues to standardize ARIA evaluation, improve lesion quantification, and enable individualized risk prediction. Progress will depend on multicenter datasets, shared frameworks, and prospective validation. Ultimately, AI-driven neuroimaging may transform how treatment-related complications are monitored in the era of anti-amyloid therapy.}, } @article {pmid41301782, year = {2025}, author = {Christodoulou, RC and Vamvouras, G and Papageorgiou, PS and Sarquis, MD and Petrou, V and Rivera, L and Morales, C and Rivera, G and Papageorgiou, SG and Vassiliou, E}, title = {Interpretable Machine Learning for Risk Stratification of Hippocampal Atrophy in Alzheimer's Disease Using CSF Erythrocyte Load and Clinical Data.}, journal = {Biomedicines}, volume = {13}, number = {11}, pages = {}, pmid = {41301782}, issn = {2227-9059}, abstract = {Background/Objectives: Hippocampal atrophy indicates Alzheimer's disease (AD) progression and guides follow-up and trial enrichment. Identifying high-risk patients is crucial for optimizing care, but accessible, interpretable machine-learning models (ML) are limited. We developed an explainable ML model using clinical data and CSF erythrocyte load (CTRED) to classify adults with AD as high- or low-risk based on hippocampal volume decline. Methods: Included ADNI participants with ≥2 MRIs, baseline lumbar puncture, and vital signs within 6 months of MRI (n = 26). The outcome was the Annual Percentage Change (APC) in hippocampal volume, classified as low or high risk. Predictors were standardized; models included SVM, logistic regression, and Ridge Classifier, tuned and tested on a set (n = 6). Thresholds were based on out-of-fold predictions under a 10-90% positive rate. Explainability used PFI and SHAP for per-patient contributions. Results: All models gave identical classifications, but discrimination varied: Ridge AUC = 1.00, logistic = 0.889, and SVM = 0.667. PFI highlighted MAPres and sex as main signals; CTRED contributed, and age had a minor impact. Conclusions: The explainable ML model with clinical data and CTRED can stratify AD patients by hippocampal atrophy risk, aiding follow-up and vascular assessment planning rather than treatment decisions. Validation in larger cohorts is needed. This is the first ML study to use CSF erythrocyte load to predict hippocampal atrophy risk in AD.}, } @article {pmid41301520, year = {2025}, author = {Lope-Piedrafita, S and Serra-Mir, G and Melón, P and Bonaterra, A and Hernández-Guillamon, M and Villegas, S}, title = {ScFv-h3D6 Prevents Bapineuzumab-Induced Hemorrhagic Events in the APP23 Mouse Model of Alzheimer's Disease.}, journal = {Biomolecules}, volume = {15}, number = {11}, pages = {}, pmid = {41301520}, issn = {2218-273X}, support = {SAF2017-89613R//Ministerio de Economía y Empresa, Spain/ ; PI17-00275//Instituto de Salud Carlos III/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism/genetics/diagnostic imaging ; *Single-Chain Antibodies/pharmacology ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Antibodies, Monoclonal, Humanized/adverse effects ; Humans ; Amyloid beta-Peptides/metabolism ; Cerebral Amyloid Angiopathy/drug therapy ; Magnetic Resonance Imaging ; Amyloid beta-Protein Precursor/genetics ; }, abstract = {The occurrence of amyloid-related imaging abnormalities (ARIAs), found in clinical trials for Aβ-immunotherapy, has been related to the antibody's effector function on glial activation by the Fc portion of the antibody. The use of single-chain variable fragments (scFv) has been proposed as a safer therapeutic strategy. Here, the effects of the mice format of bapineuzumap (mAb-m3D6) and its scFv (scFv-h3D6) on the occurrence of ARIAs in the APP23 mouse model of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) have been addressed by magnetic resonance imaging (MRI). Results are supported by histological and/or biochemical determinations. Aged APP23 mice showed a significantly higher number of microhemorrhages than non-transgenic mice. mAb-m3D6 produced an increase in the number of new hemorrhagic events, mainly in the cortex, whereas scFv-h3D6 did not. Both mAb-m3D6 and scFv-h3D6 reduced Aβ levels by the same extent. Axonal/myelin damage was found in the frontal corpus callosum of APP23 mice, which did not recover after treatment. In conclusion, the scFv-h3D6 format appears safer than the full-length mAb in the APP23 model of AD and CAA. This finding is highly relevant in light of the new FDA- and EMA-approved mAbs, which exclude APOEε4 allele carriers due to the occurrence of hemorrhages.}, } @article {pmid41301403, year = {2025}, author = {Zhang, S and Liu, X and Xu, S and Li, W and Song, J and Tian, Q and Du, Y}, title = {Multi-Omics Integration Reveals Electroacupuncture Ameliorates Cognitive Impairment in Alzheimer's Disease via Gut-Brain Axis.}, journal = {Biomolecules}, volume = {15}, number = {11}, pages = {}, pmid = {41301403}, issn = {2218-273X}, support = {82374564//National Natural Science Foundation of China/ ; 81873380//National Natural Science Foundation of China/ ; 82074566//National Natural Science Foundation of China/ ; 2025AFD596//Hubei Provincial Joint Fund Project/ ; }, mesh = {Animals ; *Electroacupuncture/methods ; *Alzheimer Disease/therapy/metabolism/microbiology ; Mice ; *Gastrointestinal Microbiome ; *Cognitive Dysfunction/therapy/metabolism ; Male ; *Brain/metabolism ; Disease Models, Animal ; Metabolomics ; RNA, Ribosomal, 16S/genetics ; Metabolome ; *Brain-Gut Axis ; Multiomics ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) lacks effective therapeutic strategies. Electroacupuncture (EA) offers promising neuroprotective effects, but its underlying mechanisms remain unclear.

OBJECTIVE: To explore the mechanisms of EA's neuroprotective effects on AD via microbiome and metabolome integration.

METHODS: Utilizing a well-established model of AD, Senescence-Accelerated Mouse Prone 8 (SAMP8), EA intervention was performed. 16S ribosomal RNA (rRNA) sequencing and serum metabolomics were conducted on SAMP8 mice, SAMP8 mice after EA intervention, and their normal control group Senescence-Accelerated Mouse Resistant 1 (SAMR1) mice.

RESULTS: SAMP8 mice were subjected to electroacupuncture (EA) treatment at the Baihui (GV20) and Shenshu (BL23) acupoints for 15 min daily over a period of four weeks. EA enhanced cognitive function and reduced neuronal damage in AD models. The treatment lowered pro-inflammatory cytokines (TNF-α, IL-1β) and AD-related pathologies (tau, Aβ1-42). EA also rebalanced gut microbiota by increasing beneficial Gastranaerophilales while decreasing harmful Proteobacteria. Additionally, it restored purine and phenylpropanoid metabolism by regulating key metabolites. Importantly, EA reduced levels of specific metabolites linked to pro-inflammatory bacteria (Sphingomonas, Massilia, Escherichia-Shigella), simultaneously decreasing their abundance. These findings highlight EA's multi-target effects on neuroinflammation, gut microbiota, and metabolic pathways in AD. Notably, the interactions between EA-regulated key metabolites and AD-related targets, predicted via PubChem and ChEMBL databases, remain computational and have not been validated by experimental studies.

CONCLUSIONS: EA exerts neuroprotective effects in AD via modulation of gut microbiota and metabolic pathways, representing a novel non-pharmacological therapeutic strategy.}, } @article {pmid41301354, year = {2025}, author = {Gao, J and Liu, L and Yang, Z and Fan, J and For The Alzheimer's Disease Neuroimaging Initiative, }, title = {Predictors of Transition from Mild Cognitive Impairment to Normal Cognition and Dementia.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {15}, number = {11}, pages = {}, pmid = {41301354}, issn = {2076-328X}, support = {2024-BS-160//Natural Science Foundation of Liaoning Province/ ; LJ212410165004//Education Department Project of Liaoning Province/ ; 2024BSL004//Ph.D. Start-up Project of Liaoning Normal University/ ; }, abstract = {Mild cognitive impairment (MCI) represents a heterogeneous state between normal aging and dementia, with varied transition pathways. While factors influencing MCI progression are known, their role in cognitive reversal is unclear. This study analyzed 756 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, classified as progressive MCI (pMCI, N = 272, mean age = 75.10 ± 7.34 years), reversible MCI (rMCI, N = 52, mean age = 69.94 ± 7.98 years) and stable MCI (sMCI, N = 432, mean age = 73.34 ± 7.44 years) based on 36-month follow-up. We compared demographic, lifestyle, clinical, cognitive, neuroimaging, and biomarker data across groups and developed a prediction model. Patients in the rMCI group were significantly younger and had a higher level of education compared with those in the pMCI group. Memory, general cognition, daily functional activities, and hippocampal volume effectively distinguished all three groups. In contrast, Aβ, tau, and other brain regions were able to distinguish only between progressive and non-progressive cases. Informant-reported Everyday Cognition (Ecog) scales outperformed self-reported Ecog scales in differentiating subtypes and predicting progression. Multinomial regression revealed that higher education, larger hippocampal volume, and lower daily functional impairment were associated with reversion, whereas APOE ε4, poorer memory, and greater brain atrophy predicted progression (model accuracy: 78%). The results confirm the significant utility of hippocampal volume, education level, and daily functional activities for assessing baseline disparities and predicting reversion. This study highlights the differential contributions of cognitive abilities and brain regions on MCI reversal, advancing understanding of MCI heterogeneity and providing evidence for precise diagnosis and treatment in early MCI.}, } @article {pmid41300531, year = {2025}, author = {Valle, ML and Getaneh, B and William, C and Ghiso, J and Rostagno, A}, title = {Antioxidants Trolox and Methazolamide Protect Microvascular Endothelial Cells from Oxidative Damage Induced by Sporadic and Familial Forms of Oligomeric Amyloid-β.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {11}, pages = {}, pmid = {41300531}, issn = {2076-3921}, support = {AG065651//National Institute of Health/ ; }, abstract = {Cerebral amyloid angiopathy (CAA), present in more than 90% of Alzheimer's disease (AD) cases, associates with focal ischemia and neurovascular dysfunction. Genetic variants at positions 21-23 of amyloid beta (Aβ), among them the Dutch mutation (AβE22Q), are primarily linked to CAA and the development of cerebral hemorrhages. An important contributor to CAA pathogenesis is the dysregulation of mitochondria-mediated pathways with concomitant induction of oxidative stress. Using biochemical assays and immunofluorescence microscopy, this work demonstrates the exacerbated formation of reactive oxygen species (ROS) in human brain microvascular endothelial cells after short exposure to soluble oligomers of synthetic homologues of Aβ1-42 and the Dutch variant, inducing lipid peroxidation and protein carbonylation, both markers of oxidative stress. The heterogeneity of the soluble oligomeric assemblies inducing this oxidative response was highlighted by their reactivity with two conformational antibodies recognizing specific and mutually exclusive epitopes associated with either soluble prefibrillar oligomers or soluble fibrillar oligomers. Treatment with the multitarget antioxidants Trolox and methazolamide significantly attenuated the Aβ-mediated ROS production and reduced oxidative stress markers to basal levels. Our data highlight the damaging role of heterogeneous Aβ oligomers and the preventing effect of antioxidants, suggesting ROS modulation as a complementary therapeutic strategy to preserve neurovascular unit integrity.}, } @article {pmid41300478, year = {2025}, author = {Fu, Y and Zhang, X and Li, L and Jiang, H and Ren, Q and Yi, T and Zhang, Y and Lu, Y}, title = {PPARα-Mediated Fatty Acid Catabolism in Astrocytes Was Involved in Improvement of Cognitive Dysfunction by Phlorizin in APP/PS1 Mice.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {11}, pages = {}, pmid = {41300478}, issn = {2076-3921}, support = {7252230//Yi Lu/ ; }, abstract = {Central lipid metabolism disorders are crucial for the development of Alzheimer's disease (AD). Phlorizin (PHZ) improved lipid metabolism abnormalities in AD nematodes, but its mechanism of action in improving AD-related symptoms and whether it can alleviate AD cognitive impairment remain unclear. To elucidate the effects and mechanisms of PHZ on lipid metabolism disorders in an AD model, gavage administration of PHZ for 8 weeks improved cognitive dysfunction and lipid disorders in APPswe/PSEN1dE9 (APP/PS1) mice. Concurrently, in astrocytes induced by palmitic acid (PA)- mediated lipid metabolic disorder, PHZ treatment improved astrocytic lipid accumulation by upregulating the target peroxisome proliferator-activated receptor α (PPARα) and its downstream pathways, thereby promoting astrocytic fatty acid oxidation. We validated PHZ's strong in vitro binding affinity with PPARα. Co-culture systems of lipid-metabolically disordered astrocytes and neurons further demonstrated that PHZ significantly improved neuronal cell viability and reduced intracellular lipid accumulation, thereby decreasing the expression of enzymes associated with β-amyloid protein (Aβ) production. This study demonstrates that gavage administration of PHZ for 2 months improves cognitive deficits and pathological markers in AD mice. Furthermore, at the cellular level, PHZ may exert its effects by enhancing astrocytic lipid metabolism, thereby preventing neuronal lipotoxicity and mitigating AD progression.}, } @article {pmid41300346, year = {2025}, author = {Yeasmin, A and Torrente, MP}, title = {Histone Post-Translational Modifications and DNA Double-Strand Break Repair in Neurodegenerative Diseases: An Epigenetic Perspective.}, journal = {Biology}, volume = {14}, number = {11}, pages = {}, pmid = {41300346}, issn = {2079-7737}, support = {1R15NS125394-01/NH/NIH HHS/United States ; }, abstract = {DNA damage is a hallmark of the fatal process of neurodegeneration in the central nervous system (CNS). As neurons are terminally differentiated, they accumulate metabolic and oxidative burdens over their whole life span. Unrepaired DNA develops into DNA double-strand breaks (DSBs), which are repaired through homologous recombination (HR) or non-homologous end joining (NHEJ). Being post-mitotic and unable to normally undergo HR, damage and defective repair is especially burdensome to CNS neurons. Current research has not produced treatment to prevent and halt progression of neurodegeneration. Hence, novel targeting strategies are desperately needed. Recent investigations in histone post-translational modifications (PTMs) reveal new mechanistic insight and highlight unexplored targets to ameliorate neurodegeneration. As various histone PTMs dictate and facilitate DSB repair, they represent an underexploited area in investigating DNA damage and incorrect repair aiding neurodegeneration. Here, we review the histone PTM alterations in several neurodegenerative diseases: Amyotrophic Lateral Sclerosis/Frontotemporal Dementia, Parkinson's Disease, Alzheimer's Diseases, Multiple Sclerosis, and Huntington's Disease. These findings emphasize that histone PTM alterations can enable an aberrant DNA damage response (DDR) leading to neurodegeneration. Further research into the connections between histone PTMs and DNA damage in decaying neurons will illuminate novel targets to dampen the aberrant DDR and promote neuronal survival.}, } @article {pmid41300191, year = {2025}, author = {Kishimoto, Y and Kubota, T and Nakashima, K and Kirino, Y}, title = {rTg4510 Tauopathy Mice Exhibit Non-Spatial Memory Deficits Prevented by Doxycycline Treatment.}, journal = {Brain sciences}, volume = {15}, number = {11}, pages = {}, pmid = {41300191}, issn = {2076-3425}, support = {20790084//Japan Society for the Promotion of Science/ ; 24590133//Japan Society for the Promotion of Science/ ; 16K08215//Japan Society for the Promotion of Science/ ; }, abstract = {Background: Hyperphosphorylated tau accumulation and neurofibrillary tangles (NFTs) are hallmarks of tauopathies, including Alzheimer's disease (AD), and are strongly associated with cognitive decline. The rTg4510 mouse model, which expresses mutant human tau (P301L), develops progressive tauopathy in the absence of amyloid-β pathology, providing a valuable tool for investigating tau-driven neurodegeneration. Previous studies have demonstrated spatial and object-recognition memory deficits at six months of age, which can be prevented by doxycycline (DOX)-mediated suppression of tau expression. However, it remained unclear whether non-spatial hippocampal learning, particularly temporal associative learning, would be similarly affected. Methods: We evaluated six-month-old rTg4510 mice with or without DOX treatment. To control for potential motor confounds, we first assessed spontaneous home cage activity. We then tested hippocampus-dependent non-spatial learning using two paradigms: trace eyeblink conditioning (500-ms trace interval) and contextual fear conditioning. Results: General motor function remained intact; however, rTg4510 mice without DOX treatment exhibited increased rearing behavior. These mice demonstrated significant deficits in trace eyeblink conditioning acquisition, with particularly clear impairment on the final day of training. Contextual fear conditioning showed milder deficits. Analysis of response peak latency revealed subtle temporal processing abnormalities during early learning. Two months of DOX treatment initiated at four months of age prevented these learning deficits, confirming their association with tau overexpression. Conclusions: Our findings demonstrate that rTg4510 mice exhibit deficits in non-spatial temporal associative learning alongside previously reported spatial and object-recognition impairments. Trace eyeblink conditioning serves as a sensitive behavioral assay for detecting tau-related hippocampal dysfunction, and the prevention of learning deficits by DOX treatment highlights its potential utility as a translational biomarker for evaluating tau-targeted interventions.}, } @article {pmid41300171, year = {2025}, author = {Costa, ACS and Brandão, AC and Leiva, V and Taylor, HG and Johnson, MW and Salmona, P and Abreu-Silveira, G and Scheidemantel, T and Roizen, NJ and Ruedrich, S and Boada, R}, title = {Baseline Neuropsychological Characteristics of Adolescents and Young Adults with Down Syndrome Who Participated in Two Clinical Trials of the Drug Memantine.}, journal = {Brain sciences}, volume = {15}, number = {11}, pages = {}, pmid = {41300171}, issn = {2076-3425}, support = {R03AG086928/AG/NIA NIH HHS/United States ; 100.10500.100.0001C//University Hospitals Cleveland's Center for Neurodegenerative Disorders/ ; 3U24AG057437//University Hospitals Cleveland's Center/ ; }, abstract = {BACKGROUND/OBJECTIVES: Down syndrome (DS) is a neurodevelopmental and neurodegenerative disorder typically caused by trisomy 21. We recently concluded a two-site (Ohio, USA and São Paulo, Brazil), phase-2, randomized trial to evaluate the efficacy, tolerability, and safety of the drug memantine in enhancing cognitive abilities of adolescents and young adults with DS. This trial was a follow-up study to a pilot trial performed in Colorado, USA. Results of these two clinical trials have been published elsewhere. Here, we present a comparative analysis of the baseline neuropsychological assessments at the three sites of these two studies, including their psychometric properties, and an account of the considerations involved in the test battery design. We compared test results in the different sites as a way of evaluating the replicability and generalizability of the test results. The distribution of the test results at each site was analyzed and combined when no differences were detected between the mean values of these results. We used post-treatment data from the placebo arms of these studies to quantify test-retest reliability.

RESULTS: Most measures had comparable mean values across test sites, and had good-to-excellent feasibility, few floor effects, and good-to-excellent test-retest reliability. A few measures, however, were deemed unsuitable for use in future studies.

CONCLUSIONS: This study demonstrated remarkable consistency of results across studies in two countries with significantly different cultures and levels of socioeconomic development, which provides supporting evidence for the future design and implementation of similar multicenter, international clinical studies involving participants with DS.}, } @article {pmid41299730, year = {2025}, author = {Seong, WJ and An, SJ and Gim, J and Gupta, DP and Park, J and Kang, S and Lee, KH and Song, GJ}, title = {Adenylate kinase 5, a novel genetic risk factor for Alzheimer's disease, regulates microglial inflammatory activation.}, journal = {Molecular brain}, volume = {18}, number = {1}, pages = {89}, pmid = {41299730}, issn = {1756-6606}, support = {NRF-2022R1A4A1018963//National Research Foundation of Korea/ ; HU23C0199//Korea Dementia Research Center/ ; }, mesh = {*Alzheimer Disease/genetics/enzymology/pathology ; *Microglia/pathology/enzymology/metabolism/drug effects ; Animals ; Humans ; *Adenylate Kinase/genetics/metabolism ; Polymorphism, Single Nucleotide/genetics ; *Inflammation/pathology/genetics/enzymology ; *Genetic Predisposition to Disease ; Risk Factors ; Mice, Inbred C57BL ; Male ; Lipopolysaccharides ; Mice ; Female ; Genome-Wide Association Study ; Phagocytosis/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and neuroinflammation, primarily mediated by microglia. In this study, we investigate the role of adenylate kinase 5 (AK5) in microglial function and its association with AD-related pathology. Analysis of brain tissues from AD patients and AD model mice revealed a significant reduction in AK5 expression. In vitro knockdown of AK5 in microglial cells attenuated lipopolysaccharide-induced pro-inflammatory responses, including decreased nitric oxide and tumor necrosis factor-alpha production, while enhancing phagocytic activity. Moreover, AK5 silencing induced metabolic reprogramming, evidenced by reduced lipid droplet accumulation and adipose triglyceride lipase mRNA levels, alongside increased farnesoid X receptor mRNA expression. Genome-wide association studies further identified two AK5 single nucleotide polymorphisms (SNPs), rs59556669 and rs75224576, significantly associated with hippocampal and amygdala atrophy as well as increased AD risk. Notably, these SNPs were not in linkage disequilibrium with the apolipoprotein E (APOE) locus, suggesting that AK5 may represent an independent genetic risk factor for AD. Collectively, our findings identify AK5 as a key regulator of microglial immune and metabolic function. The presence of AK5 variants may contribute to AD susceptibility, and AK5 expression or genetic status could serve as a potential biomarker for early risk assessment. Further exploration of AK5-targeted interventions may provide new therapeutic avenues for AD prevention or treatment.}, } @article {pmid41299186, year = {2025}, author = {Targett, IL and Pring, K and Valiente, AIM and Qualtrough, D and Conway, ME and Crompton, LA and Craig, TJ}, title = {Chronic Fatty Acid Exposure Disrupts SH-SY5Y and Neuronal Differentiation and Is a Potential Link Between Type-2 Diabetes and Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {183}, pmid = {41299186}, issn = {1559-1182}, mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/complications ; *Diabetes Mellitus, Type 2/pathology/metabolism ; *Neurons/drug effects/pathology/metabolism ; *Cell Differentiation/drug effects ; Cell Line, Tumor ; *Fatty Acids/toxicity/pharmacology ; Glycogen Synthase Kinase 3 beta/metabolism ; Neurogenesis/drug effects ; Insulin/metabolism ; Signal Transduction/drug effects ; Phosphorylation/drug effects ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia, for which there is no curative treatment and few disease-modifying therapies. The vast majority of AD is late onset (LOAD) without a specific genetic cause, although many genetic and non-genetic risk factors have been identified. One of the most significant modifiable risk factors is diet/lifestyle, with type-2 diabetes mellitus (T2DM) increasing LOAD risk by over 50%. Despite the epidemiological data, the reasons for this link are not understood. Here, we investigated whether altered free fatty acid (FFA) levels seen in T2DM can adversely affect neuronal differentiation, a crucial stage in adult hippocampal neurogenesis (AHN), which is defective in LOAD. We show that chronic exposure of the neuroblastoma cell line, SH-SY5Y to T2DM-relevant levels of the FFAs, oleate and palmitate, profoundly affects the differentiation of these cells. This effect is particularly pronounced for the saturated FFA, palmitate, resulting in neuronal cells of altered morphology, lacking expression of key synaptic markers. We further demonstrate that this exposure dysregulates insulin signalling, GSK3β activity, CDK5 levels and CREB phosphorylation. Crucially, these effects were only observed on exposure during differentiation and can be partially replicated in hiPSC-derived forebrain neurones. Although APP expression is increased by palmitate exposure, there was no increase in secreted or intracellular Aβ, and tau phosphorylation was reduced, implying that these defects are separate from the classical hallmarks of AD. We conclude that long-term, chronic exposure of differentiating neurones induces pathological changes that may explain the link between T2DM and LOAD.}, } @article {pmid41299145, year = {2025}, author = {Hosseini, E and Sahraian, MA and Negah, SS}, title = {Unlocking the Therapeutic Potential of RGMa: A New Frontier in Neurological Disorder Treatment.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {186}, pmid = {41299145}, issn = {1559-1182}, mesh = {Humans ; Animals ; *Nervous System Diseases/metabolism/drug therapy/therapy ; *Nerve Tissue Proteins/metabolism ; GPI-Linked Proteins/metabolism ; }, abstract = {Finding new biomolecules to target upstream signaling in neurological disorders is a state-of-the-art research strategy. Axon guidance molecules (AGMs) play vital roles in development; however, evidence suggests that these molecules are involved in the pathogenesis of several neurological diseases. Recent studies have shown that repulsive guidance molecule A (RGMa), a member of AGMs, can be targeted as a novel therapeutic option. This molecule has been implicated in several diseases, and inhibiting it improves the outcomes. For example, in various pathological conditions such as multiple sclerosis, neuromyelitis optica, optic nerve crush model, focal cerebral ischemia, traumatic brain injury, and vascular dementia the expression of RGMa is significantly elevated. RGMa has been detected on amyloid plaques and in the glial scar in brains impacted by Alzheimer's disease. Furthermore, RGMa is elevated by activated astrocytes after exposure to TGFβ. Since the role of RGMa in the development of neurological disorders is crucial, inhibiting RGMa can lead to positive outcomes such as axonal regeneration, neuronal repair, and behavioral improvement. Our review explores the impact of RGMa and outlines the positive results achieved by targeting it in preclinical studies. Based on this information, it is clear that RGMa has significant potential as both a predictive biomarker and a therapeutic option.}, } @article {pmid41298976, year = {2025}, author = {Alqahtani, SM and Al-Kuraishy, HM and Al-Gareeb, AI and Albuhadily, AK and Shokr, MM and Alexiou, A and Papadakis, M and Batiha, GE}, title = {Pharmacological modulation of the PI3K/AKT/GSK3β axis: a new frontier in Alzheimer's disease treatment.}, journal = {Inflammopharmacology}, volume = {}, number = {}, pages = {}, pmid = {41298976}, issn = {1568-5608}, abstract = {Amyloid-beta (Aβ) plaques and the intracellular buildup of hyperphosphorylated tau protein are hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative disease that causes synaptic dysfunction and neuronal death. Glycogen synthase kinase 3 beta (GSK3β), protein kinase B (AKT), and phosphatidylinositol 3-kinase all have aberrant signaling pathways that contribute to the pathophysiology of AD. The PI3K/AKT neuroprotective pathway is seriously inhibited in AD, which leads to brain insulin resistance (BIR) and neurodegeneration. However, AD leads to hyperactivation of GSK3β, which in turn produces tau hyperphosphorylation, Aβ accumulation, and cognitive impairment. BIR and PI3K/AKT/GSK3β signaling in AD have a complicated interaction that is covered in this article. The pathway has both neuroprotective and pathogenic functions. The therapeutic use of GSK3β inhibitors and PI3K/AKT activators to decrease AD pathogenesis is also discussed. Changing these pathways can improve cognitive function, reduce tau and Aβ pathology, and restore insulin signaling, according to preclinical and clinical research. Finding highly specialized treatments with minimal side effects remains a challenge. More research is required to thoroughly assess the safety and efficacy of medications that target specific pathways and to clarify the molecular mechanisms underlying PI3K/AKT/GSK3β dysregulation in AD in order to create novel and effective treatment alternatives.}, } @article {pmid41298245, year = {2025}, author = {La Joie, R and Cummings, JL and Dage, JL and Galasko, D and Ikonomovic, MD and Karikari, TK and Landau, SM and Llibre-Guerra, JJ and Mummery, CJ and Ossenkoppele, R and Price, JC and Risacher, SL and Smith, R and van Dyck, CH and Carrillo, MC}, title = {Treatment-related amyloid clearance (TRAC): a framework to characterize patients in the era of anti-amyloid therapies.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70997}, pmid = {41298245}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/diagnostic imaging ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; *Brain/metabolism/diagnostic imaging/drug effects ; }, abstract = {Following regulatory approval of anti-amyloid beta (Aβ) therapies, a better characterization of patients receiving these treatments is needed to guide clinical management and inclusion in future trials. This Alzheimer's Association-convened workgroup proposes a terminology, treatment-related amyloid clearance (TRAC), to reflect alterations in disease pathophysiology based on biomarker evidence for clearance of Aβ deposits. TRAC designates biomarker-defined pharmacodynamic changes, rather than direct neuropathological evidence, and applies to individuals with (1) pretreatment biomarker confirmation of cerebral Aβ deposition, (2) treatment with an Aβ-targeting therapy, and (3) a follow-up biomarker test indicative of partial or full clearance of Aβ deposits. The workgroup currently recommends defining TRAC using amyloid-positron emission tomography (PET) and emphasizes the role of quantitative measurements for defining the degree of clearance. This framework is expected to be adapted over time in response to rapidly evolving biomarker and clinical advances and with the accumulation of real-world data on patients receiving anti-Aβ therapies. Highlights TRAC identifies patients with biomarker evidence for clearance of amyloid deposits. TRAC is currently defined using amyloid-PET. Full TRAC means that PET levels dropped below predetermined positivity threshold. Partial TRAC means that PET levels dropped significantly but remain above threshold. This framework is meant to guide future research on patients receiving treatment.}, } @article {pmid41297852, year = {2026}, author = {Adeyemi, O and Christina, W and Arcila-Mesa, M and Dickson, VV and Ferris, R and Tarpey, T and Fletcher, J and Blaum, C and Chodosh, J}, title = {Enhanced quality in primary care for elders with diabetes and dementia: Protocol for a multisite randomized controlled trial.}, journal = {Contemporary clinical trials}, volume = {160}, number = {}, pages = {108165}, pmid = {41297852}, issn = {1559-2030}, support = {R33 AG057291/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Primary Health Care/standards/organization & administration ; Aged ; *Quality Improvement/organization & administration ; *Dementia/therapy ; *Alzheimer Disease/therapy ; Glycated Hemoglobin ; Randomized Controlled Trials as Topic ; Multicenter Studies as Topic ; *Diabetes Mellitus/therapy ; Female ; Male ; Pragmatic Clinical Trials as Topic ; Aged, 80 and over ; }, abstract = {BACKGROUND: The Enhanced Quality in Primary Care for Elders with Diabetes-ADRD (EQUIPED-ADRD) is a quality improvement and pragmatic cluster-randomized controlled trial that uses clinical decision guidelines to streamline the care of older adults with diabetes mellitus and Alzheimer's disease/Alzheimer's disease-related Dementia (DM-AD/ADRD). This study tests whether the EQUIPED-ADRD intervention will increase the proportion of older adults with DM and AD/ADRD with desirable glycemic ranges, and reduce treatment burden, dementia severity, and healthcare utilization among participants and their care partners in the intervention arm compared to those in the control arm.

METHODS: We will recruit older adults (≥65 years) with both DM and AD/ADRD diagnoses, who have care partners, and receive care at the enrolled New York University clinics. The intervention involves the use of panel managers to streamline the integration of clinical decision guidelines among primary care providers and improve the experiences of care partners and patients. Those in the control arm will have no panel management. We will conduct surveys and interviews, and extract data from EMR and Medicare claims to assess the association between the intervention and primary and secondary outcomes. The primary outcome is achieving within-range HbA1c, while the secondary outcomes include measures of healthcare utilization. Patient and care partner treatment burden, dementia symptoms, and care partner diabetes care distress.

CONCLUSIONS: The EQUIPED-ADRD intervention (implemented between 2018 and 2021) will assess the effect of an institutional guideline on the quality of life and health outcomes of older adults with DM-AD/ADRD and their care partners. Clinical Trial NumberNCT03723707.}, } @article {pmid41297835, year = {2026}, author = {Zhang, X and Dong, Y and Zou, Z and Chen, L and Li, W and Wang, L and Li, K and He, J and Shi, Q}, title = {Association of human plasma and cerebrospinal fluid metabolomes with vascular dementia and its subtypes: A Mendelian randomization study.}, journal = {Brain research}, volume = {1871}, number = {}, pages = {150060}, doi = {10.1016/j.brainres.2025.150060}, pmid = {41297835}, issn = {1872-6240}, mesh = {Humans ; *Dementia, Vascular/cerebrospinal fluid/blood/genetics/metabolism ; Mendelian Randomization Analysis/methods ; *Metabolome/genetics/physiology ; Genome-Wide Association Study ; Male ; Female ; Biomarkers/cerebrospinal fluid/blood ; Aged ; }, abstract = {BACKGROUND AND OBJECTIVE: Vascular dementia (VaD) is one of the most common subtypes of dementia after Alzheimer's disease. Investigating body fluid metabolites is critical for understanding VaD pathophysiology and identifying potential therapeutic targets. This study employs Mendelian randomization (MR) analysis to explore the causal relationship between body fluid metabolites and VaD.

METHODS: Data for VaD were retrieved from the FinnGen database. 1,400 plasma metabolites were collected from the GWAS Catalog. 338 cerebrospinal fluid (CSF) metabolites data were obtained from a subset of participants in the WADRC and WRAP studies. The inverse-variance weighted (IVW) method was used to explore causal relationships between plasma/CSF metabolites and VaD, with supplementary analyses using Weighted mode, MR-Egger, and Weighted median methods. Multiple sensitivity analyses were conducted for robustness.

RESULTS: Following strict validation and FDR correction, significant associations (p_fdr < 0.05) were identified exclusively in plasma metabolites. The most significant metabolite was N-acetyl-aspartyl-glutamate (NAAG), with higher NAAG levels linked to reduced risks of VaD of acute onset and SVaD. Metabolonic lactone sulfate also showed significant associations across multiple disease groups, with elevated levels associated with lower disease risk, supported by FDR correction and sensitivity analyses. No significant CSF metabolites were identified after FDR correction. Disparities between CSF and plasma metabolites in disease-risk expression were observed, with only partial overlap in causal relationships (IVW, p < 0.05).

CONCLUSION: This study identified fluid metabolite biomarkers associated with VaD through Mendelian randomization, offering new insights and strategies for the prediction and treatment of VaD.}, } @article {pmid41296223, year = {2025}, author = {Bharath, HC and Pradeep, N and Shashidhar, R and Nanjappa, Y}, title = {Synergistic medical genetic evolutionary optimization and deep convolutional generative augmentation with SHAP-driven interpretability for precise Alzheimer's disease severity grading.}, journal = {Brain informatics}, volume = {12}, number = {1}, pages = {31}, pmid = {41296223}, issn = {2198-4018}, abstract = {Alzheimer's disease (AD) diagnosis at an early yet accurate stage is critical to support effective treatment or intervention. Still it is not very feasible due to the presence of image data class imbalance, low interpretability of models, and a high computational cost. This research proposes a novel, end-to-end diagnostic framework that considers a Medical Genetic Algorithm (MedGA)-optimized Convolutional Neural Network (CNN) with a Deep Convolutional Generative Adversarial Network (DCGAN) to generate synthetic MRIs and SHapley Additive Explanations (SHAP) to analyse and interpret the model. The given methodology is trained and tested on the Open Access Series of Imaging Studies (OASIS) dataset. The DCGAN component introduces 700 structurally coherent synthetic images (SSIM = 0.92) into the underrepresented Moderate Dementia class, improving the overall recall by 10% and balancing the dataset. MedGA succeeds in optimizing CNN hyperparameters and resulting in complexity reduction (20%) in networks without loss of testing accuracy (97%) at the four demonstrated stages of AD: Non-Demented, Very Mild Demented, Mild Demented, and Moderate Demented. SHAP analysis emphasises the role of key brain areas, the hippocampus and the amygdala in the results of classification accuracy, leading to 25% greater interpretability and clinician confidence. Comparative evaluation shows that the current framework is exceptionally better in terms of predictive performance and explainability than current state-of-the-art approaches. This combined method provides a powerful and adaptable device to categorize AD at an early age, with promising outcomes in precise diagnosis in health facilities.}, } @article {pmid41296218, year = {2025}, author = {Vaz, M and Soares Martins, T and Trigo, D and da Cruz E Silva, OAB and Amado, F and Vitorino, R and Henriques, AG}, title = {Aβ Modulates Extracellular Vesicles Proteomic Profile Impacting Phosphorylation Mediators.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {179}, pmid = {41296218}, issn = {1559-1182}, mesh = {*Extracellular Vesicles/metabolism/drug effects ; *Amyloid beta-Peptides/pharmacology ; Phosphorylation/drug effects ; *Proteomics/methods ; Animals ; Mice ; *Proteome/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Cell Line, Tumor ; Alzheimer Disease/metabolism ; Humans ; Protein Interaction Maps/drug effects ; }, abstract = {Alzheimer's disease (AD) is characterized by the formation of senile plaques and neurofibrillary tangles, mainly composed of amyloid-β (Aβ) peptide aggregates and hyperphosphorylated tau protein, respectively. AD pathophysiology is highly complex, involving multiple abnormal cellular pathways linked to disease progression. Recently, extracellular vesicles (EVs) have emerged as potential contributors to disease development. Thus, this study explored the proteome of neuronal EVs under conditions that mimic Alzheimer's disease by employing mass spectrometry in EVs isolated from N2a cells treated with Aβ. Bioinformatic analysis revealed proteins involved in signal transduction, post-translational protein modification, translation, and proteolysis. Furthermore, Aβ treatment led to either an enrichment or scarcity of proteins related to cytoskeletal and mitochondrial dynamics, calcium-dependent signalling, phosphorylation, as well as proteins involved in Aβ production and aggregation. Overlap between EVs' proteome upon Aβ treatment and key AD-related proteins identified glycogen synthase kinase 3β (GSK3β) as a central node in the resulting protein interaction network. Additionally, the GSK3β interactome, derived from the EVs' proteome, highlighted protein phosphatases as relevant EVs' cargo under Alzheimer's disease mimicking conditions. The activity of GSK3β and protein phosphatases in EVs was monitored, revealing significant differences between control and Aβ-treated conditions. These findings support not only that EVs carry key proteins involved in phosphorylation dynamics but also that Aβ treatment alters EVs' proteomic profile, potentially impacting AD development. Proteomic changes in EVs may provide valuable insights into the mechanisms underlying AD and also contribute to the identification of novel potential therapeutic targets.}, } @article {pmid41296090, year = {2025}, author = {Wang, M and Zeng, Y and Jin, Y and Wu, J and Li, J}, title = {Progress and Perspectives on the Estrogen-Microbiota-Brain Axis in Alzheimer's Disease.}, journal = {Neurochemical research}, volume = {51}, number = {1}, pages = {3}, pmid = {41296090}, issn = {1573-6903}, support = {No. QKHJC-ZK[2022]-260//Guizhou Provincial Science and Technology Projects/ ; NO.gzwjrs2023-005//Guizhou Provincial High level Innovative Talent Fund/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/microbiology ; *Estrogens/metabolism ; *Gastrointestinal Microbiome/physiology ; *Brain/metabolism/drug effects ; Animals ; Dysbiosis/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder shaped by genetic, metabolic, environmental, and sex-specific factors. Emerging evidence highlights the estrogen-gut microbiota-brain (EGMB) axis as a critical framework linking endocrine regulation, microbial activity, and cognitive outcomes. Estrogen exerts neuroprotective effects by modulating synaptic plasticity, oxidative stress, amyloid and tau pathology, and neuroinflammation, while its decline during menopause increases AD vulnerability. Parallel to this, gut dysbiosis and altered microbial metabolites, particularly short-chain fatty acids (SCFAs) and secondary bile acids (sBAs), contribute to barrier dysfunction, chronic inflammation, and synaptic impairment. Importantly, estrogen remodels microbial composition and metabolite profiles, whereas microbial β-glucuronidase (β-GUS) activity sustains estrogen bioavailability, establishing a reciprocal regulatory loop. Preclinical studies demonstrate that depletion of gut microbiota diminishes estrogen's protective effects, underscoring the central role of microbial metabolites as signaling bridges.Therapeutically, these insights support the integration of hormone replacement therapy with microbiota-targeted interventions such as probiotics, prebiotics, and fecal microbiota transplantation. Such combined strategies may synergistically enhance neuroprotection, though their efficacy depends on timing, dosage, and individual variability. Future precision approaches integrating multi-omics profiling and sex-specific stratification hold promise for identifying predictive biomarkers and optimizing treatment windows. In summary, the EGMB axis offers a mechanistic foundation for understanding sex differences in AD and a translational framework for developing individualized, multidimensional strategies for early diagnosis, prevention, and therapy.}, } @article {pmid41295439, year = {2025}, author = {Zachara, R and Gendosz de Carrillo, D and Wlaszczuk, A and Gorzkowska, A and Mazur, W and Jedrzejowska-Szypulka, H}, title = {The Cognitive Changes Among Patients over 65 Years of Age in a Rural Area-The Preliminary Report of Protective and Predisposing Factors.}, journal = {Neurology international}, volume = {17}, number = {11}, pages = {}, pmid = {41295439}, issn = {2035-8385}, support = {PCN-2-042/N/2/I//Medical University of Silesia/ ; }, abstract = {Background: Aβ1-42 and APOE concentrations, as well as Aβ42/40 ratio, may be considered as a link between hypertension (HTN) or diabetes mellitus (DM), brain amyloidosis, and dementia. HTN and DM are associated with cognitive impairment and may contribute to the development of Alzheimer's disease (AD). This preliminary study aimed to evaluate the impact of vascular risk factors on the concentration of biochemical AD markers and cognitive state. As it is a cross-sectional study in nature, causal relationships cannot be established. Methods: The study was conducted in the south of Poland among a rural population over 65 years of age. A total of 58 patients qualified into the study were divided into groups according to the presence of HTN (n = 18) or HTN coexisting with DM (n = 40). A healthy control group was also formed (n = 20), resulting in 78 study participants. The study population was also divided based on M-ACE results, forming a normal cognition group (NC) and a deteriorated cognition group (DC). Biochemical tests, neurological scales assessments, and ultrasound examinations were conducted. Results: Patients who scored in the normal range on the M-ACE had higher Aβ1-42 (median 38.52 vs. 27.35 pg/mL, p = 0.02) and apoE concentrations (median 125.0 vs. 65.73 μg/mL, p = 0.002), and a higher Aβ42/40 ratio (median 0.39 vs. 0.29 p < 0.000) compared to the DC group. Considering the study groups, the highest Aβ42/40 ratio was found among the HC group (median 0.47). The median score for the M-ACE scale was 3 points lower when HTN and DM coexisted, compared to the sole diagnosis of HTN (25 points and 28 points, respectively). A higher number of years of education correlated with better M-ACE results. Lipid and uric acid concentrations were not related to M-ACE or MMSE scores. An inverse relationship connected Aβ1-40 and Aβ1-42 to BMI, the duration of HTN treatment, and glycated hemoglobin. Conclusions: Aβ1-42, APOE, and Aβ42/40 are not only correlated with cognition but also related to patient's disease profile. The coexistence of DM and HTN was associated with the most significant decline in cognitive functioning. However, a higher number of years of education may protect against the development of dementia in old age. The roles of cholesterol and uric acid in cognitive decline are still inconclusive.}, } @article {pmid41295407, year = {2025}, author = {Dimitrova, D and Kehayova, G and Dimitrova, S and Dragomanova, S}, title = {Marine-Derived Natural Substances with Anticholinesterase Activity.}, journal = {Marine drugs}, volume = {23}, number = {11}, pages = {}, pmid = {41295407}, issn = {1660-3397}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; *Biological Products/pharmacology/chemistry/isolation & purification/therapeutic use ; Humans ; *Aquatic Organisms/chemistry ; Animals ; Alzheimer Disease/drug therapy ; Butyrylcholinesterase/metabolism ; Neuroprotective Agents/pharmacology/chemistry/isolation & purification ; Acetylcholinesterase/metabolism ; }, abstract = {Alzheimer's disease continues to be one of the most urgent neurodegenerative conditions, with acetylcholinesterase (AChE) inhibitors serving as a fundamental component of contemporary treatment approaches. Growing evidence underscores that marine ecosystems are a rich source of structurally varied and biologically active natural products exhibiting anticholinesterase properties. This review presents a thorough synthesis of marine-derived metabolites-including those sourced from bacteria, fungi, sponges, algae, and other marine life-that demonstrate inhibitory effects against AChE and butyrylcholinesterase (BuChE). Numerous compounds, such as meroterpenoids, alkaloids, peptides, and phlorotannins, not only show nanomolar to micromolar inhibitory activity but also reveal additional neuroprotective characteristics, including antioxidant effects, anti-amyloid properties, and modulation of neuronal survival pathways. Despite these encouraging findings, the transition to clinical applications is hindered by a lack of comprehensive pharmacokinetic, toxicity, and long-term efficacy studies. The structural variety of marine metabolites provides valuable frameworks for the development of next-generation cholinesterase inhibitors. Further interdisciplinary research is essential to enhance their therapeutic potential and facilitate their incorporation into strategies for addressing Alzheimer's disease and related conditions.}, } @article {pmid41294911, year = {2025}, author = {Abreu, MM and Hosseine-Farid, M and Silverman, DG}, title = {Total Reversal of ALS Confirmed by EMG Normalization, Structural Reconstitution, and Neuromuscular-Molecular Restoration Achieved Through Computerized Brain-Guided Reengineering of the 1927 Nobel Prize Fever Therapy: A Case Report.}, journal = {Diseases (Basel, Switzerland)}, volume = {13}, number = {11}, pages = {}, pmid = {41294911}, issn = {2079-9721}, abstract = {BACKGROUND: Neurological disorders are the leading cause of disability, affecting over three billion people worldwide. Amyotrophic lateral sclerosis (ALS) is among the most feared and uniformly fatal neurodegenerative diseases, with no therapy capable of restoring lost function.

METHODS: We report the first application of therapeutic fever to ALS using Computerized Brain-Guided Intelligent Thermofebrile Therapy (CBIT[2]). This fully noninvasive treatment, delivered through an FDA-approved computerized platform, digitally reengineers the 1927 Nobel Prize-recognized malarial fever therapy into a modern treatment guided by the Brain-Eyelid Thermoregulatory Tunnel. CBIT[2] induces therapeutic fever through synchronized hypothalamic feedback, activating heat shock proteins, which are known to restore proteostasis and neuronal function.

CASE PRESENTATION: A 56-year-old woman was diagnosed with progressive ALS at the Mayo Clinic, with electromyography (EMG) demonstrating fibrillation and fasciculation indicative of denervation corroborated by neurological and MRI findings; the patient was informed that she had an expected survival of three to five years. A neurologist from Northwestern University confirmed the diagnosis and thus maintained the patient on FDA-approved ALS drugs (riluzole and edaravone). Her condition rapidly worsened despite pharmacological treatment, and she underwent CBIT[2], resulting in (i) electrophysiological reversal with complete disappearance of denervation; (ii) biomarker correction, including reductions in neurofilament and homocysteine, IL-10 normalization (previously linked to mortality), and robust HSP70 induction; (iii) restoration of gait, swallowing, respiration, speech, and cognition; (iv) reconstitution of tongue structure; and (v) return to complex motor tasks, including golf, pickleball, and swimming.

DISCUSSION: This case provides the first documented evidence that ALS can be reversed through digitally reengineered fever therapy aligned with thermoregulation, which induces heat shock response and upregulates heat shock proteins, resulting in the patient no longer meeting diagnostic criteria for ALS and discontinuation of ALS-specific medications. Beyond ALS, shared protein-misfolding pathology suggests that CBIT[2] may extend to Alzheimer's, Parkinson's, and related disorders. By modernizing this Nobel Prize-recognized therapeutic principle with computerized precision, CBIT[2] establishes a framework for large-scale clinical trials. A century after fever therapy restored lost brain function and so decisively reversed dementia paralytica such that it earned the 1927 Nobel Prize in Medicine, CBIT[2] now safely harnesses the therapeutic power of fever through noninvasive, intelligent, brain-guided thermal modulation. Amid a global brain health crisis, fever-based therapies may offer a path to preserve thought, memory, movement, and independence for the more than one-third of humanity currently affected by neurological disorders.}, } @article {pmid41294858, year = {2025}, author = {Thiyagarajan, S and Leclerc, E and Vetter, SW}, title = {The Receptor for Advanced Glycation End-Products (RAGE) Regulates Cell Adhesion Through Upregulation of ITGA8.}, journal = {Cells}, volume = {14}, number = {22}, pages = {}, pmid = {41294858}, issn = {2073-4409}, support = {U54 GM128729/GM/NIGMS NIH HHS/United States ; 1U54GM128729-20/NH/NIH HHS/United States ; }, mesh = {Humans ; *Cell Adhesion ; *Receptor for Advanced Glycation End Products/metabolism/chemistry/genetics ; *Up-Regulation ; }, abstract = {The Receptor for Advanced Glycation End-Products (RAGE) is a cell surface receptor of the immunoglobulin-like receptor superfamily. RAGE is a pattern-recognition, multi-ligand receptor that binds glycated proteins, specific non-glycated proteins, and nucleic acids. RAGE ligands are typically part of the group of damage-associated molecular patterns (DAMPs) or alarmins. As such, RAGE is a receptor for molecular products of cellular stress, abnormal metabolism, and inflammation. Activation of RAGE by its ligands leads to pro-inflammatory signaling, often resulting in persistent RAGE activation in various disease states. Consequently, RAGE has been investigated as a potential drug target in the treatment of diabetic complications, vascular disease, Alzheimer's disease, and multiple types of cancer. An underexplored aspect of RAGE is its role in cell adhesion. Structural comparison of the extracellular domain of RAGE has revealed structural similarity to the activated leukocyte cell adhesion molecule (ALCAM). The present study reveals the role and mechanism of RAGE in regulating cell adhesion. We investigated the role of individual RAGE domains in cell adhesion to extracellular matrix proteins and the changes in protein expression resulting from RAGE upregulation. Key findings include that RAGE displays substrate-specific adhesion to extracellular matrix proteins, that the intracellular domain of RAGE is required for modulating cell spreading, and that regulation of ITGA8 depends on the cytoplasmic domain of RAGE.}, } @article {pmid41294748, year = {2025}, author = {Ki, MR and Kim, DH and Abdelhamid, MAA and Pack, SP}, title = {Cancer and Aging Biomarkers: Classification, Early Detection Technologies and Emerging Research Trends.}, journal = {Biosensors}, volume = {15}, number = {11}, pages = {}, pmid = {41294748}, issn = {2079-6374}, support = {RS2021NR060107//the National Research Foundation of Korea/ ; the National Research Foundation of Korea//the National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neoplasms/diagnosis ; *Biomarkers, Tumor ; *Aging ; *Early Detection of Cancer ; Biomarkers ; Biosensing Techniques ; Artificial Intelligence ; }, abstract = {Cancer and aging are two distinct biological processes with shared cellular pathways, such as cellular senescence, DNA damage repair, and metabolic reprogramming. However, the outcomes of these processes differ in terms of proliferation. Understanding biomarkers related to aging and cancer opens a pathway for therapeutic interventions and more effective prevention, detection, and treatment strategies. Biomarkers, ranging from molecular to phenotypic indicators, play an important role in early detection, risk assessment, and prognosis in this endeavor. This review comprehensively examines key biomarkers associated with cancer and aging, highlighting their importance in early diagnostic strategies. The review discusses recent advances in biomarker-based diagnostic technologies, such as liquid biopsy, multi-omics integration, and artificial intelligence, and emphasizes their novel potential for early detection, accurate risk assessment, and personalized therapeutic interventions in cancer and aging science. We also explore the current state of biosensor development and clinical application cases. Finally, we discuss the limitations of current early diagnostic methods and propose future research directions to enhance biomarker-based diagnostic technologies.}, } @article {pmid41294271, year = {2025}, author = {Gupta, R and Lin, S and DiStefano, MJ and Woo, HYJ and Mao, E and Wilson, R and Amjad, H and Drabo, EF and Segal, JB}, title = {Patient Preferences for Dementia Interventions: A Scoping Review With a Systematic Review of Medications and Choice-Based Methods.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.70209}, pmid = {41294271}, issn = {1532-5415}, support = {1R61AG088961-01/AG/NIA NIH HHS/United States ; K23AG064036/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Despite emerging treatment options for Alzheimer's disease and related dementias (ADRD), patient preferences for treatment and care remain poorly understood.

METHODS: We searched PubMed, PsycINFO, CINAHL, and EMBASE through November 12, 2024 for studies reporting stated preferences for dementia treatment- and care-related interventions. We synthesized key findings from studies using choice-based preference elicitation methods and those addressing medication preferences.

RESULTS: We screened 8300 abstracts and 82 studies published between 1996 and 2024 were included. Most evaluated preferences for non-pharmacological interventions. Studies were experimental (37; 45.1%), observational (36; 43.9%), and qualitative (21; 25.6%). Six studies used choice-based preference elicitation methods and five assessed preferences for medications. Patients valued memory improvement and emotional or social support, despite highly heterogeneous data.

CONCLUSIONS: This review highlights significant gaps in the literature on treatment preferences-particularly for medications-among older adults with cognitive impairment, underscoring the need for further research, development of validated clinical tools, and appropriate methods to elicit preferences to better align interventions with patient values.}, } @article {pmid41292987, year = {2025}, author = {Gogola, JV and Wee, SWS and Garcia, AJ}, title = {Repeat Opioid Use Modulates Microglia Activity and Amyloid Beta Clearance in a Mouse Model of Alzheimer's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41292987}, issn = {2692-8205}, support = {R01 DA061412/DA/NIDA NIH HHS/United States ; R01 HL163965/HL/NHLBI NIH HHS/United States ; R01 HL169679/HL/NHLBI NIH HHS/United States ; }, abstract = {In addition to driving dependency and overdose, illicit use of opioids, such as fentanyl, is linked to the risk for cognitive decline and dementia. Growing evidence also indicates that opioid use is associated with pathological features, paralleled early in Alzheimer's disease (AD), which raises the possibility of the involvement of mechanistic interactions between opioid use and AD progression. Here, we investigate how chronic fentanyl use (i.e., 20 days) influences the neuroimmune state, microglial activity, and amyloid burden in wildtype and APPPS1-21 mice, a transgenic model of AD. In wild-type mice, fentanyl use promoted a pro-inflammatory state without increasing the incidence of disease-associated microglia. In APPPS1-21 mice, chronic fentanyl use led to a shift favoring an anti-inflammatory state, which was associated with increased microglia clustering and activation at Aβ plaques, increased Aβ internalization in plaque-associated activated microglia, decreased soluble Aβ, and decreased plaque burden. Our findings indicate that chronic fentanyl use fundamentally changes the trajectory of neuroimmune activity and features characteristic of early AD by enabling microglia to enhance Aβ clearance. The interactions demonstrate how substance use can reshape the neuroimmune landscape in neurodegenerative disease, emphasizing the importance of tailored treatment strategies.}, } @article {pmid41292940, year = {2025}, author = {Mayeri, Z and Woods, G and Rane, A and Kifle, A and Chamoli, M and Shukla, S and Walton, CC and Andersen, JK}, title = {A Compound Enhancing Lysosomal Function Reduces Tau Pathology, Microglial Reactivity and Rescues Working Memory in 3xTg AD Mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41292940}, issn = {2692-8205}, support = {R01 AG067325/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Recent advancements in Alzheimer's disease (AD) therapeutics have validated the use of amyloid beta (Aβ)-clearing antibodies, which reduce Aβ pathology but leave other disease hallmarks largely unaddressed. Since AD involves multiple pathological processes, additional strategies are needed to target complementary mechanisms. One such target is autophagy, a lysosomal mediated degradation pathway essential for cellular homeostasis that removes toxic protein aggregates and damaged organelles. This process is implicated in AD, as impaired lysosomal function promotes Aβ and tau accumulation. Our laboratory recently identified a novel natural mitophagy-inducing compound (MIC) that may serve as a therapeutic intervention for AD.

METHODS: We evaluated the effects of MIC in aged 3xTgAD mice, a transgenic model displaying both Aβ and tau pathology. Mice received either standard diet or diet containing MIC beginning at age 4 months until 20 months on alternating weeks. Age-matched non-transgenic (NonTg) controls were included under standard and MIC-supplemented diets to assess compound effects during normal aging. Neuropathological changes were assessed using immunohistochemistry (IHC) for Aβ, phosphorylated tau (pTau), and microglial reactivity. Cognitive performance was evaluated using the Morris Water Maze (MWM) to assess spatial learning and memory and the Y-maze to measure working memory.

RESULTS: At 20 months of age, our neuropathological assessment showed that 3xTgAD mice fed an MIC-supplemented diet had a significant reduction in pTau accumulation and microglial reactivity, although Aβ burden remained unchanged. At 15 months, MIC diet also improved spatial learning and memory in aged NonTg controls but not in 3xTgAD mice. However, in younger 8-month-old 3xTgAD mice, MIC restored working memory performance to NonTg levels, indicating an age-dependent therapeutic response.

CONCLUSION: MIC emerges as a potential modulator of tau pathology and neuroinflammation. As a naturally derived compound, MIC offers potential for combination therapy with FDA-approved Aβ-clearing antibodies, enabling a multimodal approach to AD treatment that addresses amyloid, tau, and microglia-related pathology.}, } @article {pmid41292809, year = {2025}, author = {Steigmeyer, AD and Battison, AS and Liebman, IR and van Dyck, CH and Slusher, BS and Arnsten, AFT and Malaker, SA and Datta, D}, title = {Region-specific proteomic analysis of aging rhesus macaques following chronic glutamate-carboxypeptidase-II (GCPII) inhibition elucidates potential treatment strategies for sporadic Alzheimer's disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41292809}, issn = {2692-8205}, support = {R01 AG061190/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; T32 GM067543/GM/NIGMS NIH HHS/United States ; R21 AG079145/AG/NIA NIH HHS/United States ; KL2 TR001862/TR/NCATS NIH HHS/United States ; }, abstract = {Sporadic Alzheimer's disease (sAD) lacks effective preventive therapies, underscoring the need to target pathogenic drivers. Aberrant calcium signaling is an established early event in sAD pathogenesis that is closely linked to neuroinflammation. Aged rhesus macaques are predominantly APOE-ε4 homozygotes and naturally exhibit cognitive decline, calcium dysregulation, amyloid deposition, and tau pathology, which allows for a translationally relevant animal model. We previously identified an evolutionarily expanded role for postsynaptic type 3 metabotropic glutamate receptors (mGluR3) in dorsolateral prefrontal and entorhinal cortex, where they regulate cAMP-calcium opening of K[+] channels to sustain neuronal firing and working memory. mGluR3 signaling is driven by N-acetylaspartylglutamate (NAAG) and constrained by glutamate carboxypeptidase II (GCPII), whose expression rises with age and inflammation. In prior work, chronic inhibition of GCPII with the orally bioavailable inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) improved neuronal firing, working memory, and reduced pT217Tau pathology in aged macaques. Here, we employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to define the proteomic consequences of chronic 2-MPPA treatment in vulnerable (entorhinal cortex, dorsolateral prefrontal cortex) versus resilient (primary visual cortex) regions. We identified >2,400 proteins across experimental conditions, and label-free quantification revealed region-specific differential expression patterns paralleling known vulnerability gradients in sAD. Gene ontology enrichment of vulnerable regions implicated pathways governing protein deneddylation, amyloid and tau-associated processes, synaptic plasticity, mitochondrial homeostasis, and oxidative stress, revealing putative targets for therapeutic intervention in sAD. These findings demonstrate that GCPII inhibition engages distinct, region-selective molecular programs in the aging primate cortex, consistent with the protection of circuits most vulnerable to sAD. By mapping the proteomic shifts that occur with treatment, we reveal molecular signatures that not only serve as candidate biomarkers but also highlight novel mechanistic pathways contributing to calcium-driven degeneration in sAD. As such, more focused investigations into these pathways of therapeutic interest are warranted, in addition to the analysis of key post-translational modifications and their potential roles in sAD.}, } @article {pmid41292786, year = {2025}, author = {Dong, Y and Watson, DJ}, title = {Thyrotropin-releasing hormone protects hippocampal neurons against glutamate toxicity via phosphatidylinositol 3-kinase/AKT pathway and new protein synthesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.11.11.687668}, pmid = {41292786}, issn = {2692-8205}, abstract = {UNLABELLED: Thyrotropin-releasing hormone is best known as a neuropeptide that stimulates the release of thyroid-stimulating hormone and prolactin in hypothalamic-pituitary-thyroid (HPT) axis. Independent from its activity in the HPT axis, TRH also exerts strong neuroprotective activity against neurodegenerative diseases such as Alzheimer's disease, epilepsy and traumatic brain injury. Although multiple factors have been linked to its neuroprotective action, the cellular mechanism of TRH neuroprotection is still not clear. Here we show that TRH protects hippocampal neurons against glutamate toxicity via phosphatidylinositol 3-kinase (PI3K)/AKT pathway and new protein synthesis. Both adeno-associated virus (AAV) mediated TRH transduction and TRH peptide given exogenously over 24 hours period of time inhibit glutamate-induced lactate dehydrogenase (LDH) release. This effect is not mediated by the decreased intracellular calcium response as TRH treatment (24 hours) has no effect on glutamate-induced increase in intracellular calcium nor the calpain activity. While TRH treatment (10 minutes) significantly inhibits glutamate-induced increase in intracellular calcium, no protective effect is observed when TRH is applied 30 minutes before or after glutamate stimulation. Instead, PI3K inhibitor LY294002 but not mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated kinase (ERK)1/2 inhibitor U0126 completely inhibits the protective effect of TRH. LY294002 also blocks TRH induced AKT activation. In addition, protein synthesis inhibitor cycloheximide inhibits the protective effect of TRH. Taken together, these results suggest PI3K/AKT signaling pathway and new protein synthesis are involved in the protective effect of TRH against glutamate toxicity, thereby providing mechanistic support for its action in neurodegenerative diseases.

HIGHLIGHTS: TRH has strong neuroprotective activity against neurodegenerative diseases such as traumatic brain injury and Alzheimer's disease. Understanding the cellular mechanism for TRH neuroprotection might aid developing novel treatment strategy. In the present study we demonstrate that TRH neuroprotection is mediated via PI3K/AKT signaling pathway and new protein synthesis. This finding provides mechanistic support for the action of TRH in traumatic brain injury and other neurodegenerative diseases.}, } @article {pmid41292642, year = {2025}, author = {Jiang, C and Krivinko, J and Yu, Z and Sweet, RA and Zeng, L and Wang, H and Ding, Y and Zeng, Z and Kofler, J and Wang, L}, title = {Comparative Mortality Risk of Aripiprazole, Olanzapine, Quetiapine and Risperidone in Alzheimer's Disease: A Real World Cohort Study with Treatment Effect Heterogeneity Analysis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41292642}, support = {P30 AG066468/AG/NIA NIH HHS/United States ; R01 MH116046/MH/NIMH NIH HHS/United States ; S10 OD028483/OD/NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND: Second-generation antipsychotics (SGAs) are frequently used off-label to manage behavioral symptoms in Alzheimer's disease (AD), despite ongoing concerns about their safety. Comparative evidence on mortality risk across specific SGAs remains limited.

OBJECTIVE: To compare all-cause mortality among AD patients treated with commonly prescribed SGAs and to explore treatment effect heterogeneity using causal machine learning.

METHODS: We conducted a retrospective cohort study using de-identified electronic health records from the Truveta platform (2018-2024). Patients with incident AD initiating treatment with aripiprazole, risperidone, quetiapine, or olanzapine were identified using an active-comparator, new-user design. Drug exposure was modeled as a time-varying covariate in Cox proportional hazards models, with propensity score matching applied to control for confounding. Causal tree and targeted maximum likelihood estimation (TMLE) were used to identify subgroups with heterogeneous treatment effects.

RESULTS: Among 17,004 AD patients, aripiprazole was associated with significantly lower mortality than olanzapine (HR = 0.667, 95% CI: 0.472-0.941) and quetiapine (HR = 0.677, 95% CI: 0.462-0.990). Quetiapine was also associated with lower mortality than olanzapine (HR = 0.833, 95% CI: 0.702-0.990) and risperidone (HR = 0.830, 95% CI: 0.705-0.978). Causal tree analysis revealed treatment effect heterogeneity by clinical characteristics, particularly among patients using type 2 diabetes (T2DM) medications. In subgroup analyses, aripiprazole remained protective in T2DM users (HR = 0.604 vs. quetiapine and risperidone, p = 0.002).

CONCLUSIONS: Mortality risks vary substantially across SGAs in AD patients. Aripiprazole and quetiapine were associated with lower mortality compared to olanzapine and risperidone. Treatment effect heterogeneity suggests the need for individualized prescribing based on patient characteristics such as comorbid T2DM.}, } @article {pmid41292493, year = {2025}, author = {Li, Y and Liu, W and Wang, X and Qin, W and Liu, Z and Lyu, D and Li, Y and Li, B and Xu, L and Cao, S and , and Chong, JRF and Lai, MKP and Chen, CLH and Jia, J}, title = {Effect of SSRIs on clinical progression in amnestic mild cognitive impairment stratified by Alzheimer's disease pathology.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70946}, pmid = {41292493}, issn = {1552-5279}, support = {2021ZD0201802//STI2030-Major Projects/ ; Z201100005520016//Beijing Municipal Science & Technology Commission/ ; Z201100005520017//Beijing Municipal Science & Technology Commission/ ; CX23YZ15//Chinese Institutes for Medical Research/ ; 31627803//National Key Scientific Instrument and Equipment Development Project/ ; U20A20354//Key Project of the National Natural Science Foundation of China/ ; 81530036//Key Project of the National Natural Science Foundation of China/ ; NMRC/CG/NUHS/2010//National Medical Research Council/ ; NMRC/CG/013/2013//National Medical Research Council/ ; NMRC/CIRG/1485/2018//National Medical Research Council/ ; CG21APR2010//National Medical Research Council/ ; MOH-000707//National Medical Research Council/ ; 2024KCJY0104//Key Project of the Science and Technology Innovation Elite Program/ ; GZC20240164//Postdoctoral Fellowship Program (Grade C) of China Postdoctoral Science Foundation/ ; 2024M750266//China Postdoctoral Science Foundation/ ; }, mesh = {Humans ; *Cognitive Dysfunction/pathology/drug therapy/diagnostic imaging ; *Selective Serotonin Reuptake Inhibitors/therapeutic use ; *Alzheimer Disease/pathology/drug therapy ; Male ; Female ; Disease Progression ; Aged ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; *Amnesia/pathology ; Aged, 80 and over ; tau Proteins/metabolism ; Longitudinal Studies ; }, abstract = {INTRODUCTION: This study examined whether selective serotonin reuptake inhibitors (SSRIs) treatment influenced cognitive trajectory and progression to Alzheimer's disease (AD) dementia in amnestic mild cognitive impairment (MCI) patients, stratified by AD pathology.

METHODS: Four hundred fifty-seven amnestic MCI participants in the ADNI database were analyzed. AD pathology was determined by baseline amyloid beta (Aβ) and tau positron emission tomography. Kaplan-Meier survival analysis and Cox proportional hazards models evaluated MCI-to-AD progression. Linear mixed models analyzed longitudinal cognitive trajectories, amyloid accumulation, and cortical thickness.

RESULTS: SSRI treatment showed no significant effect on AD dementia progression (hazard ratio = 1.64, 95% confidence interval: 0.61 to 4.38) or cognitive trajectories, regardless of AD pathology. No significant differences in Aβ accumulation or cortical thickness were observed between SSRI users and non-users. External validation confirmed no significant SSRI effect on AD progression or cognitive decline.

DISCUSSION: SSRI treatment was not associated with long-term cognitive effects in amnestic MCI, irrespective of underlying AD pathology.

HIGHLIGHTS: SSRI treatment was not associated with long-term AD dementia risk in MCI. SSRI treatment had no impact on long-term cognitive performance changes in MCI. SSRI treatment did not affect Aβ accumulation or cortical thickness in MCI. SSRIs had no effect on MCI progression, regardless of underlying AD pathology.}, } @article {pmid41291954, year = {2025}, author = {Xiao, L and Sharma, P and Yang, X and Abebe, D and Loh, YP}, title = {Neurotrophic factor-α1/carboxypeptidase E regulates critical protein networks to rescue neurodegeneration, defective synaptogenesis and impaired autophagy in Alzheimer's disease mice.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {59}, pmid = {41291954}, issn = {2047-9158}, support = {Intramural research grant//National Institute of Child Health and Human Development/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics/therapy ; Mice ; *Autophagy/physiology ; *Synapses/metabolism/pathology ; Male ; Mice, Transgenic ; *Carboxypeptidase H/genetics/metabolism ; Hippocampus/metabolism/pathology ; Humans ; Disease Models, Animal ; Genetic Therapy/methods ; Proteomics ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: The global aging population is increasingly inflicted with Alzheimer's disease (AD), but a cure is still unavailable. Neurotrophic factor-α1/carboxypeptidase E (NF-α1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology in AD mouse models. However, the mechanisms of action of NF-α1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.

METHODS: AAV-human NF-α1/CPE or a non-enzymatic form, NF-α1/CPE-E342Q, was delivered into the hippocampus of 3 × Tg-AD male mice. The effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of the hippocampus was carried out.

RESULTS: Hippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss, neurodegeneration and microglial activation in 3 × Tg-AD mice, indicating that the action is independent of its enzymatic activity. Quantitative proteomic analysis of the hippocampus of 3 × Tg-AD mice revealed differential expression of > 2000 proteins involving many metabolic pathways after NF-α1/CPE gene therapy. Of these, two new proteins, Snx4 and Trim28, which increase Aβ production and tau levels, respectively, were down-regulated by NF-α1/CPE. Western blot analysis verified their reduction in AAV-NF-α1/CPE-treated 3 × Tg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as the top signaling pathway altered in response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3 × Tg-AD mice and were restored with AAV-NF-α1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple protein markers of autophagy were down-regulated in 3 × Tg-AD mice, accounting for impaired autophagy. NF-α1/CPE gene therapy upregulated the levels of these proteins in 3 × Tg-AD mice, thereby reversing autophagic impairment.

CONCLUSIONS: This study uncovered vast actions of NF-α1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival, synaptogenesis and autophagy, while down-regulating many proteins that promote tau and Aβ accumulation to reverse memory loss and AD pathology in 3 × Tg-AD mice. AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment (Graphical Abstract).}, } @article {pmid41291841, year = {2025}, author = {Li, L and Xu, F and Duan, H and Qi, J and Zhang, J and Ma, K}, title = {Identification and validation of PANoptosis-related biomarkers in Alzheimer's disease via single-cell RNA sequencing and machine learning.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {1170}, pmid = {41291841}, issn = {2047-783X}, support = {QNYJ2023001//Henan Academy of Medical Sciences/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Machine Learning ; Biomarkers/metabolism ; *Single-Cell Analysis/methods ; Sequence Analysis, RNA/methods ; Gene Regulatory Networks ; Gene Expression Profiling ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with complex underlying mechanisms. PANoptosis, a newly defined form of programmed cell death that integrates pyroptosis, apoptosis, and necroptosis, may play a crucial role in AD pathogenesis. However, the involvement of PANoptosis-related genes in AD remains unclear.

METHODS: We analyzed single-cell RNA-seq data (GSE181279) to identify differentially expressed genes (scDEGs) between AD patients and normal controls. PANoptosis-associated genes (PAGs), curated from published studies, were intersected with differentially expressed genes (DEGs) from GSE85426 to identify differentially expressed PAGs (DE-PAGs). Weighted gene co-expression network analysis was performed to identify key gene modules. Candidate genes were identified by overlapping scDEGs, DEGs, and module genes. Hub genes were screened via three machine learning algorithms: least absolute shrinkage and selection operator (LASSO), support vector machine (SVM), and random forest (RF). Genes with consistent expression across GSE85426 and GSE48350 were considered potential biomarkers. These were evaluated by receiver operating characteristic analysis and incorporated into a nomogram. Gene set enrichment analysis was used to explore associated pathways. Immune infiltration analysis was used to assess the biomarkers' roles in the immune microenvironment and identify potential therapeutic targets. Finally, qRT-PCR was performed to validate biomarker expression in clinical samples.

RESULTS: Overlapping 987 scDEGs, 991 DEGs, and 5327 module genes yielded 27 candidate genes. LASSO, SVM, and RF analyses identified eight hub genes, among which five (BACH2, CKAP4, DDIT4, GGNBP2, and ZFP36L2) were ultimately validated as biomarkers. A nomogram based on these genes showed good predictive performance (area under the curve (AUC) = 0.779). Seven immune cell types differed significantly between the AD and control groups, with T follicular helper cells strongly correlated with most biomarkers except CKAP4 (cor > 0.36, p < 0.001). Several Aβ- and tau-related genes and immune factors also showed significant associations (|cor|> 0.3, p < 0.05). These biomarkers were further linked to AD and other functional pathways. qRT-PCR was used to validate the transcriptomic findings, with the exception of BACH2.

CONCLUSIONS: This study identified five novel PANoptosis-related biomarkers with diagnostic and therapeutic potential in AD. These findings provide a theoretical basis for future clinical research and may contribute to improved AD diagnosis and treatment strategies.}, } @article {pmid41291238, year = {2025}, author = {Li, H and Yu, C and Markovic, T and Nestler, EJ and Dong, Y}, title = {Chemical strategies for brain delivery of genomic therapy.}, journal = {Nature reviews. Chemistry}, volume = {9}, number = {12}, pages = {841-854}, pmid = {41291238}, issn = {2397-3358}, support = {R35 GM144117/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Genetic Therapy/methods ; *Brain/metabolism ; Animals ; Nanoparticles/chemistry ; *Drug Delivery Systems/methods ; Lipids/chemistry ; Polymers/chemistry ; Oligonucleotides/chemistry ; *Gene Transfer Techniques ; }, abstract = {Genomic therapy has emerged as a transformative strategy for the prevention, diagnosis and treatment of a wide array of diseases, including Alzheimer's disease, amyotrophic lateral sclerosis and other CNS-related diseases. Recent developments in chemical strategies and delivery platforms have enhanced the potential of genomic therapies for brain disorders. In this Review, we summarize such strategies, focusing on advances in delivery platforms such as lipid nanoparticles, polymers and oligonucleotide conjugates to facilitate the brain delivery of DNA-based or RNA-based therapeutics into the CNS. We present an overview of the chemical structures and functional moieties of lipids, polymers and oligonucleotides used in these platforms. Lastly, we provide an outlook on future chemical directions to further improve the delivery of genomic medicines to the brain.}, } @article {pmid41290974, year = {2025}, author = {Salmani, M and Anoush, M and Kalantari-Hesari, A and Jahani-Maleki, A and Nouri, F and Hosseini, MJ and Mohammadi, M}, title = {Protective role of fucoidan against cognitive deficits and redox imbalance in a scopolamine-induced Alzheimer's disease model in rats.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {41813}, pmid = {41290974}, issn = {2045-2322}, mesh = {Animals ; *Polysaccharides/pharmacology ; *Scopolamine/toxicity/adverse effects ; *Alzheimer Disease/chemically induced/drug therapy/metabolism ; Male ; Rats ; Disease Models, Animal ; Oxidative Stress/drug effects ; Rats, Wistar ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; *Neuroprotective Agents/pharmacology ; Hippocampus/drug effects/metabolism ; Oxidation-Reduction/drug effects ; Donepezil/pharmacology ; Prefrontal Cortex/drug effects/metabolism ; Maze Learning/drug effects ; Antioxidants ; }, abstract = {This study examined the neuroprotective impacts of fucoidan on behavioral performance and oxidative damage in an animal model with scopolamine-induced cognitive deficits. Male Wistar rats, aged 8 weeks, were administered scopolamine (2 mg/kg) for 10 days. Fucoidan (15-60 mg/kg) or donepezil (1 mg/kg) was administered prior to behavioral tests over three consecutive weeks. To assess memory and learning, all rats underwent the Morris water maze (MWM) task and the Novel Object Recognition (NOR) test. Following the tests, the hippocampi and prefrontal cortex (PFC) of the rats were collected to evaluate oxidative stress parameters across all treatment groups. A significant decrease in the mean Q2 time was observed during the probe trial in the water maze task after scopolamine injection on the test day. Administration of fucoidan (15-60 mg/kg) or donepezil (1 mg/kg) notably improved cognitive dysfunction (p < 0.001). Biochemical analysis demonstrated a decline in protein carbonyl and malondialdehyde levels, along with an elevation in reduced glutathione and total antioxidant capacity in the fucoidan-treated rats (15-60 mg/kg). It is supposed that cholinergic dysfunction and oxidative stress are key contributors to cognitive deficits, and fucoidan may protect the hippocampus and prefrontal cortex by mitigating oxidative damage biomarkers.}, } @article {pmid41290806, year = {2025}, author = {Nasiri, H and Khosravi, F and Saberian, P and Kavian, M and Mozafar, M and Torabi, P and Malekzadeh, T and Hadavi, SM and Rezaee, A and Ghorbanalinejad, M and Heidari, Z and Zangene, D and Abdi, M and Houshyar, M and Habibzadeh, A and Bemanalizadeh, M}, title = {White matter hyperintensity burden predicts domain-specific cognitive decline across the Alzheimer's disease continuum.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {41780}, pmid = {41290806}, issn = {2045-2322}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging ; *White Matter/pathology/diagnostic imaging ; Male ; Female ; *Cognitive Dysfunction/pathology/diagnostic imaging ; Aged ; Magnetic Resonance Imaging ; Cross-Sectional Studies ; Aged, 80 and over ; Executive Function ; Neuropsychological Tests ; Neuroimaging ; Cognition ; }, abstract = {White matter hyperintensity (WMH), indicative of cerebral small vessel disease, has emerged as a potential biomarker for cognitive decline in Alzheimer's disease (AD). However, their predictive role across specific cognitive domains within the AD spectrum remains unclear. This study investigates the relationship between WMH volume and cognitive performance in memory, executive function, and language across the AD continuum. A cross-sectional analysis was conducted using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), comprising 557 participants categorized into cognitively normal (CN; n = 158), mild cognitive impairment (MCI; n = 334), and Alzheimer's dementia (AD; n = 65) groups. Cognitive function was assessed using composite scores for memory (ADNI-MEM), executive function (ADNI-EF), and language (ADNI-LAN). WMH volume was quantified through validated Bayesian segmentation of MRI data. Associations between cognitive scores and WMH volume, adjusted for age, gender, APOE ε4 status, and vascular risk factors, were evaluated via multiple linear regression analyses. WMH volume showed numerically progressive increases from CN to MCI and AD groups; however, between-group differences did not reach statistical significance. Within the MCI group, significant negative associations emerged between WMH volume and memory (β=-0.13, adjusted p = 0.045) and language scores (β=-0.12, adjusted p = 0.045). Conversely, these relationships were absent in both the CN and AD groups. WMH volume relates specifically to declines in memory and language abilities, particularly in individuals with MCI. These results support using WMH measurements as early markers to identify cognitive decline in AD, potentially helping to guide earlier diagnosis and treatment decisions.}, } @article {pmid41290768, year = {2025}, author = {Shafiee, L and Pishva, MS and Hosseinzadegsn, R and Bahadori, Z and Baziyar, P and Mehboodi, M and Khademee, S and Akbari, M and Motamed, M and Nadimi, E}, title = {Hesperetin reduces neuronal death in an SHSY5Y Alzheimer's model by inhibiting inflammation and apoptosis and pyroptosis cell death pathways.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {41901}, pmid = {41290768}, issn = {2045-2322}, mesh = {Humans ; *Hesperidin/pharmacology ; *Pyroptosis/drug effects ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Apoptosis/drug effects ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; *Inflammation/drug therapy/metabolism/pathology ; *Neurons/drug effects/metabolism/pathology ; Peptide Fragments/metabolism ; Lipopolysaccharides ; Cytokines/metabolism ; }, abstract = {Alzheimer's disease (AD) features amyloid-β (Aβ)1-42 plaques, neuroinflammation, and neuronal loss. Apoptosis and pyroptosis contribute to AD, with inflammatory cytokines involved. Flavonoids like Hesperetin may reduce Aβ1-42 deposition through anti-inflammatory effects. This study introduces a novel method combining LPS and Aβ1-42 to investigate Hesperetin's mechanism for potential AD treatments. Using computational and experimental methods, we evaluated the physicochemical properties and their correlation with protein aggregation at the molecular level. Human neuroblastoma SH-SY5Y cells were induced to differentiate and then exposed to Hesperetin (1 µM and 10 µM), LPS (1 µg/mL), and Aβ1-42 (20 µM) for 24 h. The expression levels of pro- (Bak, Bax, and Caspase-3) and anti-apoptotic genes (Bcl-2), pyroptosis-related genes (Caspase-1, Caspase-4, Caspase-5, NLRP3, and GSDMD), and pro-inflammatory cytokines genes (interleukins 6 and 1β, and TNF-α) were analyzed via qRT-PCR. The obtained simulation of our result clearly showed that Hesperetin led to the disintegration of the cross-linked structure of organized Aβ1-42 fibrils. Increased RMSD, Rg, and SASA values might lead to destabilization of Aβ1-42 fibrils in the presence of Hesperetin. Our experimental study also demonstrated that Hesperetin increased cell viability in SH-SY5Y cells induced by LPS and Aβ1-42. Hesperetin effectively reverses the enhanced apoptosis caused by LPS and Aβ1-42. Our findings indicated that Hesperetin significantly reduced the elevated expression levels of pro-inflammatory cytokines in the SH-SY5Y cells induced by LPS and Aβ1-42. Treatment with Hesperetin led to a notable downregulation of the enhanced expression of pyroptotic-related genes in LPS and Aβ1-42 induced cells. The details of the molecular level along with the investigation of the physicochemical properties of Hesperetin regarding the mechanism of destabilization of Aβ1-42 fibrils introduce it as a promising therapeutic agent for AD management. Our experimental findings also indicate that Hesperetin is a compound that prevents neuronal death by reducing inflammation and inhibiting apoptosis and pyroptosis.}, } @article {pmid41290365, year = {2025}, author = {Chiotis, K and Wang, Y and La Joie, R and Rabinovici, GD}, title = {The Role of Amyloid-β and Tau PET in the New Era of Alzheimer Disease Therapies.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.124.268339}, pmid = {41290365}, issn = {1535-5667}, abstract = {The advent of amyloid-β (Aβ) and tau PET imaging has revolutionized Alzheimer disease (AD) research, enabling in vivo detection of hallmark pathologies and transforming both diagnosis and therapeutic development. These imaging modalities have played a central role in the clinical trials that led to the recent approval of Aβ-targeting therapies, with Aβ PET used for participant selection and treatment monitoring and tau PET increasingly integrated to assess disease staging and prognosis. This continuing-education article reviews the current clinical validation of Aβ and tau PET imaging in AD, outlines the available evidence for the recently approved anti-Aβ therapies, and examines how PET imaging was operationalized in the trials for these novel therapeutic agents. We explore the potential for translating trial-based imaging protocols into clinical practice-particularly how PET quantification beyond binary visual reads can support nuanced decisions regarding patient eligibility, risk stratification, therapeutic monitoring, and duration of treatment. In addition, we discuss the emerging landscape of tau-targeting therapies and the anticipated central role of tau PET in their clinical evaluation. Finally, we identify key knowledge gaps and unmet needs that must be addressed to facilitate broader clinical adoption of PET imaging, including standardization efforts, accessibility and reimbursement, and evidence-based guidelines for interpretation and use.}, } @article {pmid41289912, year = {2025}, author = {Verma, A and Waiker, DK and Gupta, PS and Shrivastava, SK}, title = {Recent advances in bioisosteric modifications for targeting Alzheimer's disease pathways.}, journal = {Bioorganic chemistry}, volume = {167}, number = {}, pages = {109248}, doi = {10.1016/j.bioorg.2025.109248}, pmid = {41289912}, issn = {1090-2120}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Blood-Brain Barrier/metabolism/drug effects ; Animals ; Molecular Structure ; }, abstract = {The drug development process is highly challenging due to high cost, ethical consideration and takes a long time to reach in to the market for the ultimate benefit of the patients. Considering the global health issues, brain disorders such as Parkinsons disease (PD) and Alzheimer's disease (AD) are major concerns and are difficult to treat because of the complex nature of the disease. The complexity of these diseases, poor efficacy of the current drugs, and their low ability to cross blood brain barrier (BBB) limits the overall biological effectiveness of the treatment. These challenges must be addressed urgently to reduce the burden of these diseases and to improve the quality and expectancy of life. In a drug molecule its molecular properties are the key attributes in determining selectivity, stability, pharmacokinetics and BBB permeability. Any unfavorable changes in these molecular properties may compromise, whereas favorable modification can enhance the overall biological effectiveness of the drug molecule. Bioisosterism is a powerful chemical tool that offers replacement of undesired functional group on the drug molecule with more suitable group resulting in improved pharmacokinetics, minimizing side effects and toxicity, and could tailored it to complex environments such as brain. In this review we present recent bioisosteric replacement approaches which have been employed to optimize the existing molecular properties of the compound to improve their biological effectiveness particularly focusing on AD.}, } @article {pmid41289288, year = {2025}, author = {Angelvy, P and Badin, M and Pelletier-Visa, M and Givron, P and Pereira, B and Coudeyre, E}, title = {Musical intervention to reduce stress during botulinum toxin injection for spasticity: Protocol for a randomized controlled trial (MUSIBOT).}, journal = {PloS one}, volume = {20}, number = {11}, pages = {e0327259}, pmid = {41289288}, issn = {1932-6203}, mesh = {Humans ; *Music Therapy/methods ; *Muscle Spasticity/drug therapy/psychology ; *Stress, Psychological/therapy/prevention & control/etiology ; *Botulinum Toxins/administration & dosage/adverse effects/therapeutic use ; Adult ; Male ; Female ; Randomized Controlled Trials as Topic ; Prospective Studies ; Heart Rate ; Middle Aged ; Injections, Intramuscular ; }, abstract = {INTRODUCTION: Botulinum toxin injections are a common treatment for managing spasticity resulting from central nervous system damage, including stroke, multiple sclerosis, and traumatic brain injury. However, the injections are associated with perceived pain, and many patients experience significant anticipatory stress regarding future sessions. The intensity of this stress varies among individuals. Music therapy, particularly receptive musical interventions structured around a U-shaped sequence, promotes progressive relaxation through distinct musical phases. This method has demonstrated efficacy in reducing pain and anxiety across various clinical contexts, including chronic and acute pain, Alzheimer's disease, fibromyalgia, and neurologically mediated pain. Given the painful nature of botulinum toxin injections, this study proposes the use of receptive music therapy to improve patient tolerance of the procedure. We hypothesize that receptive musical intervention can reduce injection-induced stress in adults undergoing botulinum toxin treatment. To our knowledge, no studies have specifically investigated the effect of music therapy on stress related to botulinum toxin injections. We aim to conduct a prospective randomized (1:1) controlled trial to evaluate the impact of receptive music intervention on stress levels, measured via heart rate variability (HRV), during botulinum toxin injection sessions. The primary objective is to assess the effect of receptive musical intervention during botulinum toxin injections on injection-induced stress, measured by HRV. Secondary objectives include evaluating the intervention's effects on pain intensity and anxiety levels.

METHODS AND ANALYSIS: Patient satisfaction following the music-assisted injection session will also be assessed. Additionally, the physician's evaluation of the procedure and the patient's perception of time during the session will be recorded.

ETHICS AND DISSEMINATION: All participants will provide written informed consent prior to enrollment. The study has received approval from the relevant institutional ethics committee (Comité de Protection des Personnes - ID: 25.00156.000468, Sud-Méditerranée IV, approved on 3 April 2025). Findings will be disseminated through peer-reviewed publications and presentations at scientific conferences.

TRIAL REGISTRATION: ClinicalTrials.gov NCT06920524.}, } @article {pmid41287966, year = {2026}, author = {Cui, A and Patel, R and Bosco, P and Akcan, U and Richters, E and Barrilero Delgado, P and Agalliu, D and Sproul, AA}, title = {Generation of hiPSC-Derived Brain Microvascular Endothelial Cells Using Directed Differentiation and Transcriptional Reprogramming.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {46}, number = {1}, pages = {210-231}, pmid = {41287966}, issn = {1524-4636}, mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism ; *Endothelial Cells/metabolism ; *Blood-Brain Barrier/metabolism/cytology ; *Cell Differentiation ; *Microvessels/metabolism/cytology ; Coculture Techniques ; *Cellular Reprogramming ; Pericytes/metabolism ; Astrocytes/metabolism ; *Brain/blood supply ; Transcriptome ; Cells, Cultured ; Amyloid beta-Peptides ; Forkhead Transcription Factors/genetics/metabolism ; Transcription Factors/genetics/metabolism ; }, abstract = {BACKGROUND: Modeling the human blood-brain barrier (BBB) is limited by the lack of robust protocols to generate induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial cells (BMECs). Current methods generate cells that do not fully recapitulate key BMEC functions or the brain endothelial transcriptome identity.

METHODS: To address this gap, we combined directed differentiation of human iPSCs into BBB-primed endothelial cells with overexpression of FOXF2 (forkhead box F2) and ZIC3 (zic family zinc finger 3), transcription factors critical for BMEC identity, to generate reprogrammed BMECs (rBMECs) from 3 iPSC lines. We performed immunofluorescence, functional analyses, and bulk RNA sequencing to characterize these cells. We cocultured rBMECs with iPSC-derived astrocytes and pericytes in the MIMETAS microfluidics platform to assess how 3-dimensional culture influences their BBB properties. Finally, we generated rBMECs expressing familial Alzheimer disease mutation APP V717I to elucidate how this genetic variant affects barrier properties compared with exposure to oAβ42 (oligomeric amyloid-β [1-42] peptide).

RESULTS: Transcriptomic and functional analyses show that rBMECs express a subset of the BBB transcriptome and exhibit stronger paracellular barrier properties, lower caveolar-mediated transport, and comparable PGP (P-glycoprotein) activity compared with primary human BMECs. rBMECs interact with human iPSC-derived pericytes and astrocytes to form a 3D neurovascular system in the MIMETAS microfluidics platform with robust BBB properties. Finally, APP V717I rBMECs show decreased barrier integrity and upregulation of inflammatory markers. In contrast, treatment of control rBMECs with oAβ42 increases inflammatory markers, but does not alter barrier integrity.

CONCLUSIONS: This protocol generates rBMECs with strong BBB properties and a brain-specific transcriptome signature. In addition, the iPSC-derived 3D neurovascular unit system shows some similar properties to the in vivo human BBB. Finally, familial Alzheimer disease mutation APP V717I alters several BBB-related properties of rBMECs and their inflammatory state, independent of Aβ42 (amyloid-β [1-42] peptide).}, } @article {pmid41287525, year = {2025}, author = {Um, YH and Wynveen, P and Holland, M and Bhatt, K and Vucetic, Z and Engel, B and Carlson, C and Becker, A and Meier, IB and Narayan, VA and Wang, SM and Kang, DW and Kim, S and Kim, S and Kim, D and Choe, YS and Kim, REY and Ha, S and Lim, HK}, title = {Neuroimaging correlates and biomarker performance of a fully automated plasma p-tau217/Aβ42 ratio assay in a clinical cohort with Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70942}, pmid = {41287525}, issn = {1552-5279}, support = {//Korea Creative Content Agency/ ; R2022020030//Korea Ministry of Culture, Sports, and Tourism in 2023/ ; //Basic Medical Science Facilitation Program/ ; //Catholic University of Korea/ ; //Catholic Education Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging/pathology ; *tau Proteins/blood ; *Amyloid beta-Peptides/blood ; Male ; Female ; Biomarkers/blood ; Cross-Sectional Studies ; Aged ; Positron-Emission Tomography ; *Neuroimaging ; *Peptide Fragments/blood ; Phosphorylation ; Cohort Studies ; Aged, 80 and over ; Brain/diagnostic imaging/pathology ; Middle Aged ; }, abstract = {INTRODUCTION: Blood-based biomarkers offer scalable, non-invasive tools for Alzheimer's disease (AD) detection. We investigated the performance of plasma biomarkers associated with AD on the automated Beckman Coulter Access DxI 9000 analyzer.

METHODS: This cross-sectional study included 262 individuals from across the AD continuum. Plasma phosphorylated tau at threonine 217 (p-tau217), amyloid beta (Aβ)42, and their ratio were measured. Diagnostic accuracy for amyloid positron emission tomography (PET) positivity (Centiloid > 20), using a dual cutoff approach, was assessed via receiver operative characteristic curve. Associations with tau PET (n = 76) were also assessed.

RESULTS: The p-tau217/Aβ42 ratio showed the highest diagnostic accuracy for amyloid PET positivity (area under curve = 0.943) and the smallest indeterminate zone (8.0%). It correlated strongly and consistently with tau PET across Braak stages and with AD-related cortical atrophy.

DISCUSSION: The p-tau217/Aβ42 ratio was the most reliable plasma biomarker, closely tracking tau PET. It has potentials for clinical use in diagnosis and treatment monitoring.

HIGHLIGHTS: This is the first validation of the Beckman Coulter plasma immunoassay. The plasma phosphorylated tau at threonine 217 amyloid beta 42 ratio showed the highest accuracy across the full Alzheimer's disease (AD) spectrum. Plasma biomarkers correlated with tau positron emission tomography and AD-related brain atrophy. Glial fibrillary acidic protein offered complementary value reflecting astrocytic activation.}, } @article {pmid41287056, year = {2025}, author = {Gouilly, D and Da-Costa, A and Vrillon, A and Pistono, A and Goubeaud, M and Bertrand, E and Germain, J and Ainaoui, N and Bras, S and Catala, H and Planton, M and Lemesle, B and Hitzel, A and Salabert, AS and Nogueira, L and Mouton-Liger, F and Méligne, D and Jasse, L and Rafiq, M and Sarton, B and Silva, S and Alam, J and Paquet, C and Tauber, C and Thalamas, C and Payoux, P and Péran, P and Pariente, J}, title = {Inhibition of p38α MAPK increases short-term astrocyte reactivity: the exploratory VIP trial in early Alzheimer's disease.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {298}, pmid = {41287056}, issn = {1742-2094}, abstract = {BACKGROUND: Neuro-inflammation is an early mechanistic target in Alzheimer’s disease (AD). However, the effect of anti-inflammatory drugs on biomarkers of neuro-inflammation has yet to be described. Biomarkers of neuro-inflammation showed distinct evolution over the course of AD, suggesting that anti-inflammatory interventions could be beneficial or interfere with mechanisms of immune defense.

METHODS: We conducted a pilot and exploratory phase II trial to evaluate the short-term effects of neflamapimod, a drug known to inhibit the neuro-toxic pro-inflammatory properties of the p38α MAPK. Participants with early AD were randomized to receive neflamapimod 40 mg (n = 17) or placebo (n = 16) twice-daily for 12 weeks. The primary endpoint was the treatment-related change in PET imaging of the translocator protein (TSPO) using [18F]-DPA-714. The main secondary endpoints were cerebrospinal fluid (CSF) markers of microglial and astrocyte reactivity. We hypothesized that neuro-inflammation would be reduced at three months in PET and in CSF markers.

RESULTS: Neuro-inflammation was not reduced between the neflamapimod and placebo groups, and no change was observed in [18F]-DPA-714 PET. However, neflamapimod induced a significant increase in CSF GFAP levels compared to placebo. Multivariate analyses based on CSF biomarkers highlighted the contribution of sTREM2 in the pattern of variation that discriminated the two groups (accuracy = 71%). Patients who received neflamapimod and had baseline sTREM2 level above the median had the highest increase in GFAP compared to placebo, suggesting that neflamapimod may exacerbate reactive astrogliosis as a function of the TREM2-related microglial state. Safety analysis showed that three cases of CSF pleocytosis occurred during follow-up in participants receiving neflamapimod.

CONCLUSIONS: Neflamapimod at a dose of 40 mg twice-daily interfered with mechanisms of immune defense in early AD. Although this study is exploratory, our results may provide an explanation for the failure of previous anti-inflammatory interventions in early AD. Biomarkers of neuro-inflammation should be required in the next-generation trials targeting neuro-immune mechanisms in AD.

REGISTRY: ClinicalTrials.gov, Clinical Trial registration number: NCT03435861.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03625-x.}, } @article {pmid41286555, year = {2025}, author = {Zhang, J and Zheng, Z and Liu, Y and Feng, S and Feng, G}, title = {Blood-Brain Barrier-Permeable Dual-Responsive Fluorescent Probe Reveals an Increased Risk of Alzheimer's Disease in Diabetic Patients.}, journal = {Analytical chemistry}, volume = {97}, number = {48}, pages = {26939-26947}, doi = {10.1021/acs.analchem.5c06216}, pmid = {41286555}, issn = {1520-6882}, mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; *Blood-Brain Barrier/metabolism ; *Fluorescent Dyes/chemistry/metabolism/chemical synthesis ; Animals ; Humans ; Mice ; Optical Imaging ; *Diabetes Mellitus, Experimental/metabolism ; Viscosity ; Mitochondria/metabolism ; }, abstract = {Alzheimer's disease (AD) is a global concern, and revealing its early diagnostic signals is crucial for timely intervention and treatment. Fluorescent probes hold great promise in disease diagnosis due to their high sensitivity and specificity. However, most existing probes struggle to effectively penetrate the blood-brain barrier (BBB), which significantly limits their application in brain disease imaging, including AD. Herein, a novel BBB-permeable fluorescent probe CL was reported. CL contains a quinolinium group and a C12 alkyl chain, enabling it to effectively target mitochondria without being affected by mitochondrial membrane potential. CL exhibits a dual response to viscosity and ONOO[-], displaying sensitive fluorescence responses at 812 and 495 nm, respectively. These characteristics enable CL to simultaneously monitor fluctuations in mitochondrial viscosity and ONOO[-], thereby achieving dual-channel detection and providing more comprehensive pathological information. More importantly, compared with the control probe DL containing a short C1 chain, CL exhibits superior BBB penetration ability and efficient brain imaging performance. Utilizing CL, alterations in viscosity and ONOO[-] in the brains of AD and diabetes mice were successfully monitored. The results not only show that both viscosity and ONOO[-] are important biomarkers of brain diseases but also reveal that diabetes patients have a higher risk of AD, laying a foundation for AD diagnosis and prevention.}, } @article {pmid41286448, year = {2026}, author = {Albertini, G and Zielonka, M and Cuypers, ML and Snellinx, A and Xu, C and Poovathingal, S and Wojno, M and Davie, K and van Lieshout, V and Craessaerts, K and Wolfs, L and Pasciuto, E and Jaspers, T and Horré, K and Serneels, L and Fiers, M and Dewilde, M and De Strooper, B}, title = {The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia.}, journal = {Nature neuroscience}, volume = {29}, number = {1}, pages = {100-110}, pmid = {41286448}, issn = {1546-1726}, support = {ERC-834682 CELLPHASE_AD//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; METH/21/05//KU Leuven (Katholieke Universiteit Leuven)/ ; G087523N//Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)/ ; AARF-22-968623/ALZ/Alzheimer's Association/United States ; }, mesh = {*Microglia/drug effects/metabolism ; Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Humans ; *Amyloid beta-Peptides/metabolism ; Mice ; Plaque, Amyloid/pathology/metabolism/drug therapy ; Phagocytosis/drug effects ; Mice, Transgenic ; *Antibodies, Monoclonal, Humanized/pharmacology ; }, abstract = {Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer's disease.}, } @article {pmid41285347, year = {2026}, author = {Li, X and Liu, R and He, Y and Yang, X and Li, T and Feng, Y}, title = {TEMPOL alleviated tau pathology and cognitive deficits induced by P301S-tau.}, journal = {Neuroscience letters}, volume = {871}, number = {}, pages = {138465}, doi = {10.1016/j.neulet.2025.138465}, pmid = {41285347}, issn = {1872-7972}, mesh = {Animals ; Spin Labels ; *Cyclic N-Oxides/pharmacology/therapeutic use ; *tau Proteins/metabolism/genetics ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism/pathology ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; Phosphorylation/drug effects ; }, abstract = {Alzheimer's disease (AD) is the most frequent of neurodegenerative disease affecting elderly people. However, there is still no curative therapeutic strategies in clinical practice. Here, we studied whether TEMPOL as a free radical scavenger can prevent memory deficits in P301S-tau mice. We found that TEMPOL administration markedly restored learning and memory impairments inducing by P301S-tau. We showed that TEMPOL had a potent capacity of inhibiting the expression of tau protein and its phosphorylation levels. The inflammatory response and synaptic defects induced by P301S-tau was also obviously improved TEMPOL treatment. Furthermore, proteomics showed 121 reversed proteins by TEMPOL treatment were primarily involved in immune system processes, innate immune responses, inflammatory responses, autophagosome assembly, lysosome organization, and autophagy. Taken together, TEMPOL played a critical role in P301S-tau-related cognitive impairments. These findings demonstrate that TEMPOL shows promise as a multi-target therapeutic agent for AD by modulating critical pathways implicated in its pathogenesis.}, } @article {pmid41285280, year = {2026}, author = {Hu, Q and Xu, K and Ran, Q and Zhang, W and Gan, C and Fang, Q and Hui, A}, title = {Hybrid molecules with dual inhibition of acetylcholinesterase and tau hyperphosphorylation: design, inhibitory activity evaluation, apoptosis assessment, and mechanistic exploration.}, journal = {Chemico-biological interactions}, volume = {423}, number = {}, pages = {111848}, doi = {10.1016/j.cbi.2025.111848}, pmid = {41285280}, issn = {1872-7786}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/metabolism ; Humans ; *tau Proteins/metabolism/antagonists & inhibitors ; *Apoptosis/drug effects ; *Acetylcholinesterase/metabolism/chemistry ; Phosphorylation/drug effects ; Molecular Docking Simulation ; *Drug Design ; Cell Line, Tumor ; Structure-Activity Relationship ; Alzheimer Disease/drug therapy ; Phenothiazines/chemistry/pharmacology ; Tacrine/chemistry ; }, abstract = {A comprehensive therapeutic strategy for Alzheimer's disease (AD) requires simultaneous inhibition of acetylcholinesterase (AChE) and targeting of hyperphosphorylated Tau (P-Tau)-mediated pathogenesis. To address this need, the present study designed a series of hybrid molecules by integrating three pharmacophoric scaffolds with established P-Tau-modulating activity (phenothiazine, dibenzazepine and benzothiazepinones) into AChE-inhibiting frameworks: indanone (derived from the clinical AChE inhibitor Donepezil) or 9-chloro-1,2,3,4-tetrahydroacridine (derived from Tacrine, another clinically approved AChE inhibitor). Following preliminary in silico evaluations including druggability predictions and absorption, distribution, metabolism, excretion, toxicity (ADMET) profiling, twelve compounds (C1-C12) with potential AChE/P-Tau dual-target binding affinity were identified and subsequently synthesized. Among these, four compounds (C5, C6, C7, and C11) exhibited significant AChE inhibitory activity, with IC50 values ranging from 205.3 to 257.1 nM, comparable to that of tacrine (226.0 nM). Notably, the indanone-phenothiazine hybrid compound C11 stood out as the most promising candidate, it achieved the lowest P-Tau/total Tau (T-Tau) ratio (5.30 × 10[-6]) in okadaic acid (OA)-induced SH-SY5Y cells, outperforming hydromethylthionine mesylate (5.40 × 10[-6]), a leading clinical candidate for Tau aggregation inhibition. Beyond its dual inhibitory activities, C11 ameliorated OA-induced cell apoptosis, further supporting its potential as anti-AD agent. Subsequent mechanistic explorations confirmed that C11 alleviated oxidative stress and downregulated Tau phosphorylation at specific pathogenic sites (Ser396, Ser262, Thr181). Concurrently, C11 modulated the expression of glycogen synthase kinase-3β (GSK-3β), a critical kinase driving P-Tau formation. In conclusion, this study identifies novel dual-target inhibitors against AChE and P-Tau, and provides new therapeutic insights into AD treatment.}, } @article {pmid41284585, year = {2026}, author = {Ismail, Z and Guan, DX and Babulal, GM and Bateman, JR and Cantillon, M and Creese, B and D'Antonio, F and Fischer, CE and Gatchel, JR and Ghahremani, M and Guerrero-Cantera, J and Lanctôt, KL and Mielke, MM and Mortby, ME and Feldman, O and Pereira, AC and Pereiro, AX and Perry, G and Potter, WZ and Rabl, M and Ravona-Springer, R and Rosen, AC and Rouse, HJ and Sankhe, K and Schindler, SE and Udeh-Momoh, CT and Tarawneh, R and Oliveira, FF and , }, title = {Plasma biomarkers in neuropsychiatric syndromes: A narrative review.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {1}, pages = {44-69}, pmid = {41284585}, issn = {1875-8908}, support = {R01 AG068183/AG/NIA NIH HHS/United States ; R01 AG074562/AG/NIA NIH HHS/United States ; R01 AG074302/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 AG066749/AG/NIA NIH HHS/United States ; RF1 AG083744/AG/NIA NIH HHS/United States ; R01 CA241758/CA/NCI NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; R01 AG067428/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/blood ; *Mental Disorders/blood ; Cognitive Dysfunction/blood ; *Neurodegenerative Diseases/blood ; }, abstract = {Neuropsychiatric symptoms (NPS) are common features of neurodegenerative disease (NDD) but are relatively understudied compared to cognition, especially regarding biomarkers. Further, emerging evidence describes the utility of systematic assessment of NPS across the cognitive continuum, even in advance of dementia. In this narrative review, we discuss the role of plasma biomarkers in relation to NPS across the cognitive continuum of unimpaired, subjective cognitive decline, mild cognitive impairment, and dementia. While Alzheimer's disease is the primary focus, vascular, Lewy body, and frontotemporal dementia etiologies are also discussed. Literature searches included NPS and dementia-related search terms with additional literature identified based on the author group's subject area expertise. We found that plasma biomarkers are a burgeoning field, and scalability and accessibility make them well-suited for the study of NPS across the disease continuum. In early-stage NDD, diagnostic biomarkers are best suited for discriminating NDD-related NPS from non-NDD psychiatric syndromes and/or NPS due to other causes. In those with dementia, monitoring and prognostic biomarkers may enable the assessment of treatment response or help predict the risk of worsening symptoms. We conclude that plasma amyloid-β and tau show great promise in assessing NPS, especially during early-stage disease, but inflammatory and genetic biomarkers may also play a role across the disease course. Systematic research is required, keeping in mind the ethical considerations of knowing biomarker status in early-stage disease.}, } @article {pmid41284069, year = {2025}, author = {Rodrigues, KDC and Oliveira, MDC and de Souza, IC and Igansi, AW and Lopes, AVB and de Oliveira Pacheco, C and Hass, SE and Schumacher, RF and Luchese, C}, title = {Sex-dependent therapeutic effects of nano-curcumin on alzheimer's disease: enhanced cognitive and physiological restoration in female mice.}, journal = {Psychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {41284069}, issn = {1432-2072}, support = {PqG 24/2551-0001249-4//Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul/ ; 160674/2020-4//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; }, abstract = {Curcumin (Cur) is a bioactive compound with neuroprotective and anti-inflammatory effects, though its clinical application is limited by poor bioavailability. This study assessed the impact of nanocapsulated curcumin (NcCur), formulated Eudragit (EUD) polymer, in a sporadic Alzheimer's disease (AD) mouse model induced by intracerebroventricular streptozotocin (STZ), with attention to sex-specific differences. Mice received STZ (3 nmol/3 µL) or 0.9% saline on days 1 and 3, followed by intragastric treatment with Cur or NcCur (10 mg/kg, on alternate days) from day 22 until euthanasia - a dose previously shown to be effective in behavioral and biochemical modulation in rodent models of neurodegeneration. Behavioral assessments included open field, elevated plus maze (EPM), tail suspension (TST), object recognition, Y-maze, and step-down avoidance tasks (SDAT), performed before and after treatment. After euthanasia, thymus, spleen and adrenal glands were weighed; biochemical assays evaluated oxidative stress, monoaminergic and cholinergic enzymes, and Na[+]K[+]-ATPase activity. NcCur improved short- and long-term memory in both sexes, with greater effects in females (42% and 35%) than males (28% and 25%). In the EPM, NcCur increased open arm time more prominently in females (40%) than males (25%), while TST immobility time was reduced similarly in both. Spatial and aversive memory improved in both sexes, but females showed greater performance in the SDAT. Biochemical analyses showed reductions in reactive species in males (45%) and females (55%) with NcCur; Na[+]K[+]-ATPase activity increased in females (60%) and males (50%). AChE activity was restored in both sexes. NcCur reduced MAO-A/B activities more in females (65%/55%) than in males (45%/35%). Thymus and spleen weights were normalized in both sexes, with stronger effects in females. NcCur also mitigated alterations in thymus and spleen relative weights, suggesting immunomodulatory effects. Some biochemical and behavioral responses were more prominent in females, both sexes benefited from treatments. These findings suggest that NcCur enhances Cur therapeutic potential through multimodal actions linked involving modulation of oxidative stress, cholinergic and monoaminergic systems, and immune-related parameters. NcCur emerges as a promising candidate for AD-like intervention in both sexes.}, } @article {pmid41282905, year = {2025}, author = {Andrews, D and Golchi, S and Collins, DL}, title = {A digital twin methodology using real patient data for sample size reduction in Alzheimer's disease randomized controlled clinical trials.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41282905}, support = {U19 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Recruitment for Alzheimer's disease randomized controlled trials (RCTs) is difficult and expensive. To reduce RCT sample sizes, our Digital Twin Trial (DTT) methodology combines an interpretable cognitive decline prediction model with prediction-powered inference.

METHODS: For DTT participants, our model identifies similar individuals ("Digital Twins") from a retrospective database and uses their cognitive scores to predict decline. Predictions adjust observed scores, reducing variance within treatment groups. We simulated 18-month DTTs and standard RCTs using mixed effects models of decline in Alzheimer's Disease Neuroimaging Initiative subjects meeting lecanemab's Phase 3 inclusion criteria.

RESULTS: Predicted and observed change in Clinical Dementia Rating Sum-of-Boxes correlated at r = 0.4 . DTTs required 1,855 subjects versus 2,170 for standard RCTs to detect a simulated 25% decline-slowing drug effect at 0.9 power. DTT Type 1 error was consistent with 0.05.

DISCUSSION: DTTs could reduce recruitment and cost burdens. Model interpretability could help clinicians trust individualized prognoses.}, } @article {pmid41282780, year = {2025}, author = {Yang, B and Earnest, T and Bilgel, M and Albert, MS and Johnson, SC and Davatzikos, C and Erus, G and Masters, CL and Resnick, SM and Miller, MI and Bakker, A and Morris, JC and Benzinger, TLS and Gordon, BA and Sotiras, A}, title = {Predicting future cognitive impairment in preclinical Alzheimer's disease using multimodal imaging: a multisite machine learning study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41282780}, support = {R01 AG043434/AG/NIA NIH HHS/United States ; T32 EB014855/EB/NIBIB NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; S10 RR022984/RR/NCRR NIH HHS/United States ; RF1 AG059869/AG/NIA NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; P01 AG036694/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 AG067103/AG/NIA NIH HHS/United States ; S10 OD018091/OD/NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; U19 AG033655/AG/NIA NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; RF1 AG027161/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; S10 OD025200/OD/NIH HHS/United States ; }, abstract = {Predicting the likelihood of developing Alzheimer's disease (AD) dementia in at-risk individuals is important for the design of and optimal recruitment for clinical trials of disease-modifying therapies. Machine learning (ML) has been shown to excel in this task; however, there remains a lack of models developed specifically for the preclinical AD population, who display early signs of abnormal brain amyloidosis but remain cognitively unimpaired. Here, we trained and evaluated ML classifiers to predict whether individuals with preclinical AD will progress to mild cognitive impairment or dementia within multiple fixed time windows, ranging from one to five years. Models were trained on regional imaging features extracted from amyloid positron emission tomography and magnetic resonance imaging pooled across seven independent sites and from two amyloid radiotracers ([[18]F]-florbetapir and [[11]C]-Pittsburgh-compound-B). Out-of-sample generalizability was evaluated via a leave-one-site-out and leave-one-tracer-out cross-validation. Classifiers achieved an out-of-sample receiver operating characteristic area-under-the-curve of 0.66 or greater when applied to all except one hold-out sites and 0.72 or greater when applied to each hold-out radiotracer. Additionally, when applying our models in a retroactive cohort enrichment analysis on A4 clinical trial data, we observed increased statistical power of detecting differences in amyloid accumulation between placebo and treatment arms after enrichment by ML stratifications. As emerging investigations of new disease-modifying therapies for AD increasingly focus on asymptomatic, preclinical populations, our findings underscore the potential applicability of ML-based patient stratification for recruiting more homogeneous cohorts and improving statistical power for detecting treatment effects for future clinical trials.}, } @article {pmid41282773, year = {2025}, author = {Ackley, SF and La Joie, R and Caunca, M and Mukherjee, S and Choi, SE and Trittschuh, EH and Crane, PK and Hayes-Larson, E and , }, title = {Substituting Blood-Based Biomarkers for Imaging Measures in Alzheimer's Disease Studies: Implications for Sample Size and Bias.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41282773}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; R00 AG075317/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; R00 AG073454/AG/NIA NIH HHS/United States ; R01 AG082730/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Blood-based biomarkers for Alzheimer's disease (AD) pathology are appealing options in large population-based studies due to their low cost, minimal invasiveness, and feasibility of collection in non-clinical settings. Despite these benefits, blood-based biomarkers have lower test-retest reliability than neuroimaging measures like amyloid positron emission tomography (amyloid-PET) Centiloids; trade-offs in power and bias remain unexplored.

METHODS: We use data from Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) studies, which include both amyloid-PET and blood-based measures, to assess differences in statistical power, required sample size, and bias when replacing a neuroimaging measure with a blood-based measure. We use simulations parameterized based on these studies to show potential implications of using plasma p-tau181 or p-tau217, blood-based AD biomarkers, in place of Centiloids from amyloid-PET, when the biomarker is either the exposure or the outcome in an analysis of interest.

RESULTS: We demonstrated that substituting amyloid-PET Centiloids with a blood-based measure of p-tau can substantially reduce power, requiring 3 to 6 times the sample size to achieve 80% power compared to amyloid-PET. In addition, using a blood-based biomarker as the exposure can introduce significant regression dilution bias, attenuating estimated associations.

CONCLUSIONS: Due to their lower cost and ease of collection compared with neuroimaging, blood-based biomarkers facilitate AD pathology measures on larger, more diverse samples with longitudinal follow-up. Consideration of the sample sizes they necessitate and their potential for bias is critical for the design and interpretation of studies employing these biomarkers.}, } @article {pmid41282720, year = {2025}, author = {Khorsand, B and Teichrow, D and Ghanbarian, E and Zheng, L and Sajjadi, SA and Glover, CM and Grill, JD and Rabin, LA and Ezzati, A}, title = {Scalable Markers for Early Cognitive Decline: Plasma p-tau217, Subjective Cognitive Concerns, and Digital Testing: Results from the A4/LEARN studies.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41282720}, support = {R01 AG063689/AG/NIA NIH HHS/United States ; U24 AG057437/AG/NIA NIH HHS/United States ; U19 AG010483/AG/NIA NIH HHS/United States ; K23 AG063993/AG/NIA NIH HHS/United States ; R01 AG095017/AG/NIA NIH HHS/United States ; R01 AG080635/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Although amyloid positron emission tomography (PET) and Cerebrospinal fluid (CSF) biomarkers remain the standard for confirming Alzheimer's disease (AD) pathology, their use is impractical for screening or routine prognostic assessment. Plasma phosphorylated tau 217 (p-tau217), subjective cognitive concerns, and computerized cognitive testing are non-invasive, scalable, and feasible to implement in large populations. We tested whether these measures independently predict the onset of cognitive impairment and whether combining them improves prognostic accuracy.

METHODS: We analyzed 1,071 cognitively unimpaired adults aged 65-85 years from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial (amyloid-positive; solanezumab or placebo arms) and the parallel Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohort (amyloid-negative). At baseline, participants completed plasma p-tau217 measurement, the Cognitive Function Index (CFI), and the Cogstate Computerized Battery (CCB). Over 240 weeks of follow-up, incident impairment was defined as conversion from a Global Clinical Dementia Rating Score (CDR-GS) of 0 to 0.5 or higher. The predictive value of each measure for subsequent decline was examined after adjustment for demographic and genetic covariates.

RESULTS: During the follow-up, 365 of 1,071 participants (34.1%) developed cognitive impairment. Higher plasma p-tau217 (per-standard-deviation increase) was associated with higher odds of converting to CDR-GS>0 across all cohorts: A4-Placebo (HR=1.56; 95% CI, 1.37-1.78), A4-Solanezumab (HR=1.46; 95% CI, 1.29-1.65), LEARN (HR=1.25; 95% CI, 1.05-1.48). Similarly, higher CFI predicted incident impairment: A4-Placebo (HR=1.59; 95% CI, 1.42-1.79), A4-Solanezumab (HR=1.67; 95% CI, 1.47-1.91), LEARN (HR=1.37; 95% CI, 1.12-1.68). Lower CCB also conferred higher risk: A4-Placebo (HR=0.76; 95% CI, 0.65-0.91), A4-Solanezumab (HR=0.73; 95% CI, 0.62-0.87), LEARN (HR=0.68; 95% CI, 0.53-0.87). In models including all three predictors, each remained independently associated with progression.

CONCLUSION: Plasma p-tau217, subjective cognitive concerns, and computerized cognitive testing each independently predicted progression to cognitive impairment in cognitively unimpaired older adults. Together, these non-invasive and scalable measures provide practical tools for risk stratification years before clinical diagnosis. Combining biological, subjective, and digital markers may support earlier detection in clinical care and enhance efficiency in prevention trial enrollment.}, } @article {pmid41282187, year = {2025}, author = {O'Brien, EK and Cox, T and Fernandez, S and Bourgeat, P and Porter, T and Goudey, B and Doecke, JD and Masters, CL and Fripp, J and Nho, K and Villemagne, VL and Cruchaga, C and Rowe, CC and Saykin, AJ and Dore, V and Laws, SM}, title = {Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41282187}, issn = {2693-5015}, support = {R01 AG043434/AG/NIA NIH HHS/United States ; R01 AG058676/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; }, abstract = {Accumulation of brain amyloid beta (Aβ) is a key pathological hallmark of Alzheimer's disease (AD) and begins many years before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which this accumulation exceeds a critical threshold, may enable early intervention and treatment to slow or prevent the onset of AD. We utilised published genome-wide association studies (GWAS) to develop polygenic scores (PGS) based on AD risk (PGSrisk) and resilience (PGSresilience). We tested whether these could predict (i) whether an individual was an accumulator of Aβ ('Accumulator Status'), and (ii) in accumulators, the age at which brain Aβ is estimated to exceed a threshold of 20 centiloids (CL)('Estimated Age at onset of Aβ'; AAO-Aβ) among 2175 participants (1158 with AAO Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. Additionally, we conducted genome-wide association studies (GWAS) of these traits and developed phenotype-specific PGSs using cross-validation (CV). Higher PGSrisk was associated with a greater risk of being an accumulator and a younger AAO-Aβ. When stratified by number of APOE ε4 alleles, PGSrisk predicted Accumulator Status in APOE ε4 heterozygotes, and AAO-Aβ in ε4 non-carriers and heterozygotes, with the same directions of effect as were seen in the whole cohort. PGSresilience was not significantly associated with Accumulator Status, but higher PGSresilience was associated with later AAO-Aβ overall and in ε4 heterozygotes. Trait-specific PGSs, developed using CV, were not significantly associated with either trait overall and the direction of association varied across CV folds. Polygenic scores, alongside other risk factors, may be useful for identifying individuals at risk of accumulating Aβ, and predicting the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD.}, } @article {pmid41282120, year = {2025}, author = {Li, M and Niu, S and Xu, Y and Li, J and Hu, X and Liu, D and Atik, M and Xu, X and Wang, L and Ertekin-Taner, N and Tao, C}, title = {Bridging the Computational-Experimental Gap: Leveraging Large Language Model to Prioritize Alzheimer's Therapeutics Based on Comparison of Learning Models.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41282120}, issn = {2693-5015}, support = {P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; RF1 AG072799/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG084236/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; R01 AG072799/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; R01 AG083039/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's Disease (AD)[1] is a progressive neurodegenerative disorder with limited therapeutic options, driving interest in drug repurposing to accelerate treatment discovery. Drug repurposing has emerged as a promising strategy to accelerate therapeutic discovery by repositioning existing drugs for new clinical indications. Recent computational repurposing approaches, including knowledge graph reasoning, transcriptomic signature analysis, and integrative literature mining, have demonstrated strong predictive capabilities[2]. However, these methods often yield divergent drug rankings, which makes it difficult to decide which candidates to advance for experimental follow-up and results in substantial gaps between computational predictions and feasible in vivo validation[2]. To bridge this computational-experimental gap, we proposed an advanced prioritization framework leveraging large language models (LLMs). Our method systematically evaluated three state-of-the-art (SOTA) and representative computational methods (TxGNN[3], Composition-based Graph Convolutional Network (CompGCN)[4], and a regularized logistic regression (RLR)[5], to analyze both their predictive performance and pharmaceutical class distributions. By integrating the strengths and divergences of these models, we generated a unified, streamlined list of 90 candidate drugs for further prioritization. We then utilized an LLM-based agent to perform evidence synthesis from biomedical literature abstracts for each candidate. This process mimics expert manual curation but significantly reduces human effort and time by efficiently distilling vast textual data into actionable insights. Applying consistent and transparent selection criteria, we obtained a refined and prioritized list of drug candidates suitable for subsequent in vivo experimental validation. The robustness and clinical relevance of our framework were validated using real-world data from Alzheimer's patient cohorts, clinical trial registries, and expert pharmacological reviews. This comprehensive validation confirmed that our LLM-driven approach enhances efficiency, consistency, scalability, and generalizability. By integrating computational predictions with scalable evidence synthesis and multifaceted validation, our framework facilitated rapid and informed prioritization of repurposed drugs. Our framework can potentially accelerate the translational pathway toward viable AD therapeutics. Moreover, the versatility of our framework can also be applied to drug repurposing efforts for other diseases beyond AD.}, } @article {pmid41281734, year = {2025}, author = {Wang, D and Florian, H and Lynch, SY and Robieson, W and Zhuang, R and Kusiak, C and Ross, JL and Walsh, JR and Graff, O}, title = {Using AI-generated digital twins to boost clinical trial efficiency in Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {4}, pages = {e70181}, pmid = {41281734}, issn = {2352-8737}, abstract = {INTRODUCTION: Machine learning models leverage baseline data to create artificial intelligence (AI)-generated digital twins (DTs)-individualized predictions of each participant's clinical outcomes if they had received placebo. Incorporating DTs may increase statistical power or reduce required sample sizes in Phase 2 or 3 trials, and therefore improve efficiency in Alzheimer's disease (AD) trials. Here we demonstrate these properties using data from an AD Phase 2 clinical trial (AWARE, NCT02880956).

METHODS: A conditional restricted Boltzmann machine (CRBM) model was trained on historical clinical trials and observational data from 6736 unique subjects after data harmonization to generate DTs of participants from the AWARE trial. The AWARE trial enrolled 453 subjects with mild cognitive impairment (MCI) or mild AD. DTs were assessed as prognostic covariates to evaluate gains in variance and sample size reduction.

RESULTS: Positive partial correlation coefficients were found between DTs and change score from baseline in key cognitive assessments ranging from 0.30 to 0.39 at Week 96 in the AWARE trial. These correlations were consistent with validation results from three independent trials, which ranged from 0.30 to 0.46. Total residual variance was reduced by ~9% to 15% with DTs. While maintaining statistical power, DTs could reduce total sample size by ~9% to 15%, and control arm sample size by 17% to 26% in future AD trials.

DISCUSSION: Efficiency was improved in AD clinical trials using machine learning models to generate prognostic DTs by including them in statistical analysis modeling. This methodology aligns with regulatory guidance and represents an application of machine learning models suitable for the analysis of pivotal trial data. Validated DTs have the potential to improve clinical development efficiency in AD and in other neurological indications.

HIGHLIGHTS: Digital twins (DTs) were generated by artificial intelligence (AI) models trained on historical datasets.Use of digital twin (DT) as a covariate in the analysis model can reduce treatment effect variability.By coupling DT with the analysis model, trial sample size can be reduced.DT technology was accepted by the U.S. Food and Drug Administration and European Medicines Agency for applications in clinical trials.}, } @article {pmid41281561, year = {2025}, author = {Melamed, I and Buckley, C and Bayko, ME and Williams, JL and Or-Geva, N}, title = {Does C1 esterase inhibitor play a role in post COVID-19 neurological symptoms? A randomized, double-blind, placebo-controlled, crossover, proof-of-concept study.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1523814}, pmid = {41281561}, issn = {1664-2295}, abstract = {BACKGROUND: Many patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience neurologic changes post-infection, which has been hypothesized to be due to dysregulation in the infectious-immune axis that leads to a neuro-immune response. This immune dysfunction has been termed "Alzheimer's of the Immune System" or AIS and there are several immune factors that may play a key role. These include, among others, complement activation due to low levels of C1-esterase inhibitor (C1-INH) and function, and a decrease in signaling of Toll-like receptor (TLR)-3. We propose that C1-INH replacement may upregulate the immune dysfunction, thereby improving neurological symptoms.

METHODS: In this randomized, double-blind, placebo-controlled, crossover, proof-of-concept study, adults experiencing SARS-CoV-2 post-viral fatigue syndrome for >4 weeks post-recovery from coronavirus disease 2019 (COVID-19) infection were randomized 1:1 to two arms: Arm 1 (C1-INH for 8 weeks, then placebo for 8 weeks) or to Arm 2 (placebo for 8 weeks, then C1-INH for 8 weeks). Patients were assessed for adult executive function, abnormal cognitive decline, depression [Beck Depression Inventory-II (BDI-II)], migraine, fatigue [Fatigue Severity Scale (FSS)] and pain (Short-form McGill Pain Questionnaire). Percent change in TLR signaling in response to zymosan was compared with controls at baseline, Week 8 and Week 16. Safety was assessed throughout.

RESULTS: At this interim analysis, 36 patients with SARS-CoV-2 post-viral fatigue syndrome had completed the two 8-week treatment periods. In Arm 1, trends toward improvements from baseline at Week 8 of C1-INH therapy were observed in BDI-II score (-8.7 points), mean FSS score (0.6 points), and mean McGill Pain Questionnaire score (-0.4 points). These improvements were either sustained or worsened at Week 16, following crossover to placebo. The outcomes in Arm 2 were compatible with those in Arm 1. Patients with SARS-CoV-2 post-viral fatigue syndrome had low levels of TLR-related signaling biomarkers compared with healthy controls.

CONCLUSION: This proof-of-concept study demonstrates sustained dysregulation of the immune system after COVID-19 infection. Improvements in depression, fatigue, and pain were observed with C1-INH treatment in patients with SARS-CoV-2 post-viral fatigue syndrome, indicating C1-INH may be a potential therapeutic target.

CLINICAL TRIAL REGISTRATION: The study was registered on September 21, 2024, with the identifier number NCT04705831.}, } @article {pmid41281560, year = {2025}, author = {Sun, Q and Wang, F}, title = {Using artificial intelligence and radiomics to analyze imaging features of neurodegenerative diseases.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1624867}, pmid = {41281560}, issn = {1664-2295}, abstract = {INTRODUCTION: Neurodegenerative diseases such as Alzheimer's and Parkinson's are characterized by complex, multifactorial progression patterns that challenge early diagnosis and personalized treatment planning.

METHODS: To address this, we propose an integrated AI-radiomics framework that combines symbolic reasoning, deep learning, and multi-modal feature alignment to model disease progression from structural imaging and behavioral data. The core of our method is a biologically informed architecture called NeuroSage, which incorporates radiomic features, clinical priors, and graph-based neural dynamics. We further introduce a symbolic alignment strategy (CAIS) to ensure clinical interpretability and cognitive coherence of the learned representations.

RESULTS AND DISCUSSION: Experiments on multiple datasets-including ADNI, PPMI, and ABIDE for imaging, and YouTubePD and PDVD for behavioral signals-demonstrate that our approach consistently outperforms existing baselines, achieving an F1 score of 88.90 on ADNI and 85.43 on PPMI. These results highlight the framework's effectiveness in capturing disease patterns across imaging and non-imaging modalities, supporting its potential for real-world neurodegenerative disease monitoring and diagnosis.}, } @article {pmid41281523, year = {2025}, author = {Li, YP and Niu, Y and Ding, H and Chen, Z and Zhang, Q}, title = {Potential role of meningeal lymphatic drainage in repetitive transcranial magnetic stimulation-induced cognitive improvement: A call for further research.}, journal = {World journal of psychiatry}, volume = {15}, number = {11}, pages = {111985}, pmid = {41281523}, issn = {2220-3206}, abstract = {Mild cognitive impairment (MCI), which is a high-risk transitional phase leading to Alzheimer's disease, is characterized by mild memory deficits and specific cognitive dysfunctions. Without effective intervention, a significant proportion of patients with MCI progress to dementia. However, current pharmacological treatments are characterized by side effects and poor patient compliance. Therefore, it is necessary to develop effective, noninvasive alternative treatments. Repetitive transcranial magnetic stimulation (rTMS) is becoming a widely studied noninvasive treatment for central nervous system disease. The therapeutic effects of rTMS on patients with MCI and its underlying mechanism are noteworthy issues. Recently, a growing number of studies have shown that meningeal lymphatic vessel damage may be related to cognitive dysfunction. Whether the improvement of the meningeal lymphatic system is an important mechanism through which rTMS improves the clinical manifestations of MCI is worthy of further study.}, } @article {pmid41281504, year = {2025}, author = {Teixeira, AL and Kim, Y and Cordeiro, TM and de Erausquin, GA and Rocha, NP}, title = {Agitation in Alzheimer's disease: From assessment to therapeutics.}, journal = {World journal of psychiatry}, volume = {15}, number = {11}, pages = {109581}, pmid = {41281504}, issn = {2220-3206}, abstract = {Agitation is a neuropsychiatric syndrome characterized by excessive motor and/or verbal behaviors, with or without aggressive behaviors. The prevalence of agitation in Alzheimer's disease varies from 5% to over 50%. Multiple factors have been implicated in its pathophysiology, including disease stage, comorbidity with other symptoms (e.g., psychosis, anxiety/depression), and psychosocial factors. Ruling out delirium and identifying environmental triggers are fundamental steps in the management of agitation in Alzheimer's disease. For establishing an effective therapeutic plan, it is important to define duration, severity, and potential for harm. While non-pharmacological approaches are considered the first line of intervention, pharmacological agents are frequently used in the treatment of agitation. Antipsychotics are commonly used in acute agitation. For chronic agitation, serotonin-selective reuptake inhibitors, especially citalopram and escitalopram, are often preferred due to safety concerns associated with the long-term use of antipsychotics. Promising novel strategies, such as new compounds and neuromodulation, are likely to be incorporated into agitation therapeutics in the next few years.}, } @article {pmid41281281, year = {2025}, author = {Jing, S and Wang, Y and Liu, Y and Luo, Y and Wen, X and Ma, Y and Zhu, H and Chen, G and Ouyang, X}, title = {Folic acid as a potential therapeutic agent for Alzheimer's disease: Effects on inflammatory cytokines, amyloid deposition, and neurotransmitter metabolism.}, journal = {Journal of medical biochemistry}, volume = {44}, number = {7}, pages = {1551-1557}, pmid = {41281281}, issn = {1452-8258}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by neuroinflammation and amyloid deposition. Folic acid (FA), a B vitamin, may improve the course of AD by modulating inflammation and neuroprotection. This study aimed to investigate the effects of FA supplementation on serum inflammatory cytokines (IL-1b, IL-6, TNF-a), amyloid (Ab1-42), Tau proteins, and neurotransmitters (GABA, 5-HT, Ach) in AD patients.

METHODS: We conducted a follow-up-controlled trial; 114 AD patients were included and randomly divided into a control group (donepezil treatment) and an experimental group (donepezil + FA treatment) for 3 months. Inflammatory factors, Ab1-42, Tau, neurotransmitter levels and nutritional status were assessed before and after treatment.

RESULTS: The total effective rate of the experimental group (89.47%) was significantly higher than that of the control group (75.44%), and the levels of inflammatory factors (IL-1b, IL-6, and TNF-a), Ab1-42, and Tau were significantly lower (P<0.05), and neurotransmitters (GABA, 5-HT, and Ach) and nutritional indexes (albumin and hemoglobin) were substantially higher.

CONCLUSIONS: FA supplementation can effectively delay AD progression by inhibiting neuroinflammation, reducing amyloid deposition, regulating neurotransmitter metabolism and improving nutritional status.}, } @article {pmid41280486, year = {2025}, author = {Taube, PS and Fernandes, D and Vasconcelos, AA and Costa, JAS and de Araujo, MP and Lima, AKO and Wahab, N and Dos Santos, EKL and de Oliveira, MI and da Silva, JP and Andriani, KF and da Silva Oliveira, TP and Sampaio, MC and de Campos Braga, H and de Araújo, ACS and Gul, K}, title = {Perspectives and state-of-the-art use of metal-derived, porous nanomaterials and metallo-drugs for biomedical applications.}, journal = {3 Biotech}, volume = {15}, number = {12}, pages = {416}, pmid = {41280486}, issn = {2190-572X}, abstract = {Due to a combination of genetic, environmental, and behavioral factors, the number of infectious and non-infectious diseases affecting humans has been rising. Many illnesses are in the forefront of research and development such as neoplasms of different forms, chronic conditions related to inflammation and lifestyle (e.g., cancer, diabetes mellitus, Alzheimer's and Parkinson's diseases) and infectious diseases that are difficult to treat (e.g., due to drug resistance). Due to current challenges in diagnosis and treatment of diseases and health conditions, the field of nanotechnology has witnessed numerous advancements. In particular, metal-based, porous nanomaterials and metallo-drugs have gained attention due to their ability to be used for various diagnostic and therapeutic applications. These systems exhibit excellent physicochemical properties, with amenable functionalization and varying optical, scattering and electronic properties, enabling for both imaging and therapy of diseases (i.e., theranostics), involving techniques such as photoacoustic imaging, magnetic resonance imaging (MRI), computed tomography (CT), photothermal therapy (PTT), photodynamic therapy (PDT) and radiotherapy. This review discusses the important aspects of metal nanoparticles, porous-based materials and metallo-drugs for biomedical applications, exploring their physical and chemical characteristics, cellular/molecular processes and biopotencies that make them effective in treating a variety of illnesses or diseases.}, } @article {pmid41280332, year = {2025}, author = {Wu, Z and Yu, S and Tian, D and Cheng, L and Jing, J}, title = {Microglial TREM2 and cognitive impairment: insights from Alzheimer's disease with implications for spinal cord injury and AI-assisted therapeutics.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1705069}, pmid = {41280332}, issn = {1662-5102}, abstract = {Cognitive impairment is a frequent but underrecognized complication of neurodegenerative and traumatic central nervous system disorders. Although research on Alzheimer's disease (AD) revealed that microglial triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in inhibiting neuroinflammation and improving cognition, its contribution to cognitive impairment following spinal cord injury (SCI) is unclear. Evidence from AD shows that TREM2 drives microglial activation, promotes pathological protein clearance, and disease-associated microglia (DAM) formation. SCI patients also experience declines in attention, memory, and other functions, yet the specific mechanism of these processes remains unclear. In SCI, microglia and TREM2 are involved in inflammation and repair, but their relationship with higher cognitive functions has not been systematically examined. We infer that TREM2 might connect injury-induced neuroinflammation in the SCI with cognitive deficits, providing a new treatment target. Artificial intelligence (AI) offers an opportunity to accelerate this endeavor by incorporating single-cell transcriptomics, neuroimaging, and clinical data for the identification of TREM2-related disorders, prediction of cognitive trajectories, and applications to precision medicine. Novel approaches or modalities of AI-driven drug discovery and personalized rehabilitation (e.g., VR, brain-computer interface) can more precisely steer these interventions. The interface between lessons learned from AD and SCI for generating new hypotheses and opportunities for translation.}, } @article {pmid41280310, year = {2025}, author = {Inamdar, A and Bugadannavar, P and Palled, M and Umarani, S and Salve, P and Gurupadayya, B and Patil, P and Sharma, H}, title = {Biological determinants of blood-based biomarker levels in Alzheimer's disease: role of nutrition, inflammation, and metabolic factors.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1614962}, pmid = {41280310}, issn = {1663-4365}, abstract = {OBJECTIVES: The review discusses the effect of biological determinants such as nutritional deficiency, systemic inflammation, and metabolic disorders affect blood-based biomarker (BBBM) levels, influencing their use in diagnosing, prognosticating, and treatment in Alzheimer's disease (AD). While the individual contributions of neuroinflammation, brain insulin resistance, and micronutrient deficiencies to AD pathology are well-established, a significant knowledge gap exists in understanding their intricate, synergistic interactions. This review proposes a novel integrated framework of bidirectional crosstalk where these three factors create a self-perpetuating cycle of neurodegeneration.

METHODS: A comprehensive literature review was conducted, including all aspects of epidemiological and biological context associated with vitamins, micronutrients, and dietary patterns; inflammatory cytokines; insulin resistance; metabolic syndrome; and hormonal changes. Emerging integrative approaches such as multi-omics, AI modeling, and systems biology were also reviewed for their possible refinement in biomarker interpretation.

RESULTS: The results prove that the deprivation of vitamins E, D, B12, and antioxidants contributes to oxidative stress and subsequent neuroinflammation that changes levels of blood-based biomarkers. A chronic state of inflammation caused by cytokines like IL-6, IL-18, and TNF-α represents a major link to the formation of increased amyloid plaques and tau tangles. Metabolically deregulated states, such as insulin resistance, dyslipidemia, and thyroid imbalance, further alter variability in biomarkers. All these factors would act together to affect the expression of key biomarkers-Aβ, p-tau, and neurofilament light chain (NFL). Individualized interpretation, stratified clinical trials, and digital monitoring tools are potentially effective for achieving better diagnostic precision and boosting treatment efficacy.

CONCLUSION: To a large extent, factors must all be understood thoroughly from multiple biological angles to improve early diagnosis, risk prevention, and treatment personalization in AD. Future studies should develop integrative models that consider nutrition, metabolism, and inflammation to address and fully exploit biomarker utility as well as support precision medicine approaches.}, } @article {pmid41280213, year = {2025}, author = {Ali, SH and Osmaniye, D and Kaplancıklı, ZA}, title = {Synthesis and biological evaluation of novel hydrazone derivatives for the treatment of Alzheimer's disease.}, journal = {RSC advances}, volume = {15}, number = {53}, pages = {45729-45743}, pmid = {41280213}, issn = {2046-2069}, abstract = {In recent years, Alzheimer's disease has emerged as a silent epidemic neurodegenerative disorder. Due to its complex pathophysiology, there has been significant scientific interest in developing effective treatments that go beyond symptomatic relief. The main aim is to improve patients' quality of life and lower the death rate associated with Alzheimer's disease. Since this has not yet been achieved, continued research on Alzheimer's disease remains a global priority. In this study, a total of 27 hybrid molecules (D1a-D1i, D2a-D2i, and D3a-D3i) were designed based on the molecular scaffold of donepezil, a well-known acetylcholinesterase inhibitor (AChEI). These hybrids incorporate dihydrothiazolyl hydrazone and phenyl piperidine moieties. All compounds were synthesized and characterized using IR, NMR, and HRMS spectroscopy, and subsequently evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition using the in vitro Ellman method. Evaluation of biological activity revealed that compound D1f exhibited the highest inhibitory activity against the AChE enzyme, with an IC50 of (0.039 ± 0.001 Mm). In contrast, none of the compounds showed significant inhibitory activity against the BChE enzyme. Cytotoxicity testing of compound D1f on NIH3T3 fibroblast cells demonstrated non-cytotoxic effects (IC50 = 3.324 ± 0.155 µM) and the highest selectivity index (SI = 85.231), respectively. Molecular docking and molecular dynamics simulations verified the stable binding affinity and favorable interactions of compound D1f within the active site of acetylcholinesterase (AChE). The results further demonstrated that the AChE enzyme preserved its structural integrity and compactness throughout its interaction with D1f. Collectively, these observations highlight D1f as a promising lead molecule for subsequent optimization and development of novel anti-Alzheimer's therapeutic agents.}, } @article {pmid41280038, year = {2025}, author = {Terzioglu, G and Karp, ES and Heuer, SE and Haage, VC and De Jager, PL and Young-Pearse, TL}, title = {INPP5D/SHIP1 is a dual regulator of endo-lysosome function and selective phagocytosis in human microglia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41280038}, issn = {2692-8205}, support = {R01 AG055909/AG/NIA NIH HHS/United States ; U01 AG072572/AG/NIA NIH HHS/United States ; }, abstract = {INPP5D, the gene encoding SHIP1, is genetically associated with Alzheimer's disease (AD) risk and plays a central role in regulating immune function. Here, we aimed to elucidate the mechanism by which SHIP1 mediates its role in suppressing inflammatory pathways, with a focus on human microglia. Our findings illuminate an essential role for SHIP1 in endosome maturation and lysosomal function. We show that SHIP1 localizes to both the plasma membrane and to endo-lysosomal compartments and binds to the CapZ family of proteins, which are important for endosome maturation. Reduction of SHIP1 levels via genome editing impairs endosome maturation and lysosomal function, leading to lipid droplet accumulation and leakage of lysosomal cathepsin B into the cytosol, which in turn activates the NLRP3 inflammasome. CITE-seq profiling of SHIP1-deficient microglia revealed a shift from an immune-responsive state toward a DAM-like, phagocytic state, accompanied by impaired response to LPS and enhanced phagocytosis of synaptic material and apoptotic neurons via TREM2. While amyloid-β uptake was not affected, amyloid-β accumulated intracellularly due to defective lysosomal degradation, further driving lipid droplet formation. Together, these results identify SHIP1 as a regulator of endo-lysosomal function and selective phagocytosis of lipid-rich substrates in microglia. These findings have important implications for therapeutic hypotheses that target SHIP1 for treatment of AD, autoimmune diseases, and cancer.}, } @article {pmid41279689, year = {2025}, author = {Schurman, CA and Kaur, G and Kaya, S and Bons, J and Aguirre, CG and Liu, Q and King, CD and Wilson, KA and Baker, HL and Hady, M and Luna, NM and Bieri, G and Villeda, SA and Ellerby, LM and Schilling, B and Alliston, T}, title = {Alzheimer's disease risk factor APOE4 exerts dimorphic effects on female bone.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.10.16.682922}, pmid = {41279689}, issn = {2692-8205}, abstract = {Individuals diagnosed with Alzheimer's disease (AD) are at an increased risk of bone fractures. Conversely, a diagnosis of osteoporosis in women is the earliest known predictor for AD. However, mechanisms responsible for the coupled decline in cognitive and skeletal health remain unclear. Proteomic analysis of cortical bone from aged mice revealed neurological disease-associated proteins that are highly enriched in aged mouse bones, including apolipoprotein E (Apoe) and amyloid precursor protein. Further, Apoe localized specifically to bone-embedded osteocytes with expression twice as high in aged female bone as in young or male counterparts. In humans, APOE allele variants carry differing AD risk with age. To investigate APOE allelic roles in bone, we utilized a humanized APOE knock-in mouse model that expresses either the protective APOE2, the neutral APOE3, or the AD risk factor APOE4, and analyzed bone and hippocampus from the same mice. APOE4 exerted strong sex-specific effects on the bone transcriptome and proteome, relative to APOE2 or APOE3. Interestingly, the APOE4-associated perturbation in the female bone proteome was more pronounced than the corresponding alterations observed in the hippocampus. APOE4 protein causes bone fragility in females, but not males, even without changes in cortical bone structure. These bone quality deficits arose from suppression of osteocyte perilacunocanalicular remodeling. We find that APOE4 is a new molecular culprit capable of disrupting osteocyte maintenance of bone quality as early as midlife in a manner that disproportionately affects females. These findings highlight osteocytes as potential targets for early diagnosis of age-related cognitive impairment, and treatment for bone fragility, in females.}, } @article {pmid41279475, year = {2025}, author = {Veerareddy, V and Wang, Z and Kashyap, PC and Kandimalla, KK}, title = {Butyrate regulates the blood-brain barrier transport and intra-endothelial accumulation of Alzheimer's disease Amyloid-beta peptides.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.10.24.684335}, pmid = {41279475}, issn = {2692-8205}, abstract = {Alzheimer's disease (AD) is characterized by the pathological deposition of amyloid beta (Aꞵ) proteins as amyloid plaques, tau aggregates, and cerebrovascular dysfunction that drive disease progression. Butyrate, a gut microbial metabolite, has been found to be reduced in AD patients; butyrate supplementation improved cognition and decreased amyloid burden in animal models. However, the precise underlying mechanisms are unclear. Our previous studies have demonstrated that insulin signaling impacts Aꞵ transport kinetics at the blood-brain barrier (BBB). In this study, we investigated the effect of butyrate treatment on intra-endothelial Aꞵ accumulation and BBB integrity by modulating the insulin signaling pathway. The effect of butyrate on Aꞵ accumulation was assessed by flow cytometry in BBB cell culture models. Insulin signaling activation and the expression of various receptors and transporters at the BBB were evaluated by Western blots and confocal microscopy. The roles of various molecular mediators were confirmed using specific inhibitors (MK2206, Trametinib, Rapamycin, VX-745). The effect of butyrate on the expression of BBB receptors and transporters that play a critical role in Aꞵ trafficking was examined in mouse brains colonized with butyrate-producing bacteria via immunohistochemistry. Butyrate significantly decreased Aβ42 accumulation in endothelial cells. This effect was associated with insulin signaling pathway activation, particularly AKT and ERK phosphorylation. Inhibitor studies established the critical role of these specific arms, as co-incubation with MK2206 (AKT inhibitor) or Trametinib (ERK inhibitor) reversed the protective effect of butyrate and increased Aβ42 accumulation. However, mTOR and p38 inhibitors did not show a similar effect. In addition, butyrate restored P-glycoprotein efflux transporter expression and claudin-5 tight junction protein levels that were reduced with Aβ treatment. These effects were supported by in vivo work, which demonstrated the upregulation of Tissue Inhibitor of Metalloproteinases-2 (TIMP-2). This protein is associated with AKT activation and extracellular matrix stabilization in mice colonized with butyrate-producing bacteria. In conclusion, we have demonstrated that butyrate decreases Aβ42 uptake at the BBB endothelium by activating the AKT and ERK arms of the insulin signaling pathway. These changes may also improve the integrity of BBB tight junctions by increasing claudin-5 expression and extracellular matrix, and by upregulating TIMP-2 expression. This study highlights butyrate's potential as a therapeutic modulator of AD-related BBB dysfunction.}, } @article {pmid41278376, year = {2025}, author = {Li, J and Zhang, J and Xu, X and Xiao, L and Ling, Y and Liu, S and Gao, Y and Zhao, L and Jia, H}, title = {Quality and reliability of Alzheimer's disease videos on Douyin and Bilibili: A cross-sectional content analysis study.}, journal = {Digital health}, volume = {11}, number = {}, pages = {20552076251398464}, pmid = {41278376}, issn = {2055-2076}, abstract = {BACKGROUND: Alzheimer's disease (AD) poses a significant public health challenge to China's aging population. Patients and their families increasingly turn to short-video platforms such as Douyin and Bilibili for information. However, there is currently a lack of systematic analysis regarding the quality and reliability of advertising content on these platforms, creating a critical gap in understanding this emerging information ecosystem.

AIM: Systematically evaluate the quality and reliability of videos on Douyin and Bilibili, analyzing the relationship between content themes, upload sources, and user engagement metrics.

METHODS: Using "Alzheimer's disease" as the keyword, we retrieved the top 100 videos from multiple platforms. Videos were categorized by uploader type and content. Two qualified researchers assessed their reliability and quality using the JAMA, the modified DISCERN instrument (mDISCERN), and Global Quality Score (GQS) scale. Data analysis employed nonparametric statistical methods. Apply relevance and logistic regression analysis to discuss factors that may influence video quality.

RESULTS: This study analyzed a total of 171 videos. Results indicate that compared to Douyin, videos on the Bilibili platform scored higher across multiple quality evaluation metrics (GQS: 2.0(1.0-2.0) vs 1.0(1.0-2.0); mDISCERN: 2.0(2.0-2.0) vs. 2.0(2.0-2.0); JAMA: 2.0(1.0-2.0) vs. 1.0 (1.0-2.0); p < 0.001). This disparity may be attributed to Bilibili's longer video format, which allows for more in-depth content, and its user base that tends to favor detailed, knowledge-oriented media. Regarding uploader identity, videos posted by professionals (e.g. physicians) demonstrated superior quality compared to nonprofessional sources (e.g. patients). However, patient-uploaded videos exhibited stronger engagement metrics (e.g. likes, comments). Content-wise, videos focusing on disease prevention and treatment consistently achieved the highest overall quality (all comparisons p < 0.05). Correlation analysis indicated that while interaction metrics showed strong internal correlations, they did not significantly correlate with JAMA, mDISCERN, or GQS scores. Ordered logistic regression analysis indicates that uploader identity, content classification, and presentation format are the three key factors influencing video quality.

CONCLUSION: This study reveals a pronounced "quality-dissemination paradox" in AD content across mainstream short-video platforms: While scientifically rigorous content published by medical professionals receives high quality ratings, it significantly underperforms in user engagement metrics compared to nonprofessional content centered on patient narratives and lived experiences. This highlights a severe disconnect between scientific rigor and public participation within algorithmic dissemination ecosystems. To address this, platforms should optimize algorithms to enhance the visibility of authoritative content, encourage collaboration between professional and nonprofessional creators to boost content appeal, and strengthen health media literacy education for the public-particularly older adults-to improve their ability to discern information.}, } @article {pmid41278202, year = {2025}, author = {Larriba-González, T and García-Martín, M and Ojeda-Hernández, DD and Rincón-Cerrada, P and Martín-Blanco, L and Benito-Martín, MS and Selma-Calvo, B and de la Fuente-Martín, S and Matias-Guiu, JA and Matias-Guiu, J and Gómez-Pinedo, U}, title = {Modeling neurodegenerative diseases with brain organoids: from development to disease applications.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1663286}, pmid = {41278202}, issn = {2296-634X}, abstract = {Organoids derived from stem cells have significantly advanced disease modeling, particularly in neurodegenerative disorders, while advancing personalized and regenerative medicine. These three-dimensional structures reproduce key aspects of human brain organization and functionality, while remaining simplified models that do not yet recapitulate full neural circuitry or disease progression, providing an improved platform for studying disease mechanisms, drug responses, and potential therapeutic strategies. This review explores the methodologies used in organoid development, including the differentiation of stem cells and culture techniques that enable the formation of self-organizing tissues. Organoids have been successfully used to model key cellular and molecular aspects of neurodegenerative diseases such as Alzheimer's and Parkinson's, offering insights into early disease mechanisms and potential novel treatment strategies. Key findings highlight that organoids provide more physiologically relevant data than traditional two-dimensional cultures and animal models, making them valuable tools for preclinical research and personalized treatment approaches. However, challenges remain, including variability in organoid generation, lack of vascularization, and difficulties in large-scale production for clinical applications. For the effective integration of organoids into biomedical and clinical applications, future research should prioritize improving reproducibility, standardization, and vascularization methods. Addressing these limitations will enhance their translational potential, leading to more effective treatments for neurodegenerative disorders and broader applications in precision medicine.}, } @article {pmid41278077, year = {2025}, author = {Arai, H}, title = {Underestimated Centiloid Values in Amyloid PET: A Technical Report on Clinically Relevant Quantification Errors.}, journal = {Cureus}, volume = {17}, number = {11}, pages = {e97398}, pmid = {41278077}, issn = {2168-8184}, abstract = {Quantitative amyloid positron emission tomography (PET) interpretation using the Centiloid scale is increasingly adopted worldwide to guide eligibility and continuation of anti-amyloid monoclonal antibody therapy. However, discrepancies between visual and quantitative assessments occasionally occur, potentially leading to critical misjudgments in clinical decision-making. We present a representative 18F-florbetapir case in which cortical amyloid deposition was visually evident, yet the calculated Centiloid value was 0, falsely indicating a negative scan. This underestimation likely results from reference region selection: using the whole cerebellum (including white matter) lowers standardized uptake value ratios by approximately 7% compared with cerebellar gray matter, thereby decreasing Centiloid values. Consequently, patients with substantial amyloid burden may be incorrectly deemed ineligible for initiation or continuation of anti-amyloid therapy. Clinicians should therefore interpret Centiloid-based quantification with caution, always corroborating it with expert visual reads. Harmonization of reference region definitions and standardized reporting are urgently needed to prevent inappropriate treatment decisions and ensure the safe, effective use of disease-modifying therapies in Alzheimer's disease.}, } @article {pmid41278048, year = {2025}, author = {Lin, WC and Wu, A and Chen, NC and Ha, B}, title = {Observations of Triple Network Model Connectivity Changes by Functional Magnetic Resonance Imaging in a Single Early-Stage Dementia Participant Pre- and Post-craniosacral Therapy: A Case Report.}, journal = {Cureus}, volume = {17}, number = {11}, pages = {e97329}, pmid = {41278048}, issn = {2168-8184}, abstract = {Resting-state functional magnetic resonance imaging (rs-fMRI) is a noninvasive imaging technique that measures spontaneous brain activity to map functional connectivity within and between brain networks characterized as the triple network model (TNM). In Alzheimer's disease (AD), rs-fMRI has been used to detect early network disruptions, track disease progression, and evaluate therapeutic interventions. While craniosacral therapy (CST) has shown clinical benefits for conditions like chronic pain and migraine, its impact on TNM connectivity in AD, as evidenced by rs-fMRI, has not been explored. This case report involves a 79-year-old man with early-stage AD who presented with mild delusions, anxiety, irritability, and nighttime behaviors and a Mini-Mental State Examination (MMSE) score of 24 and a Clinical Dementia Rating (CRD) of 0.5, indicating a mild neurocognitive disorder. Preliminary rs-fMRI data revealed changes in the default mode network (DMN), salience network (SN), and central executive network (CEN) following CST. These changes suggest greater connectivity within the CEN and SN, alongside reduced variability in the DMN following CST. These observations suggest potential reorganization of TNM dynamics. The clinical relevance of these findings remains under evaluation. The observations from this single case report limit the ability to draw definitive conclusions about the impact of CST on TNM connectivity in early-stage AD. A further study is needed to determine if the TNM changes observed by rs-fMRI can be replicated in additional participants and if the changes are correlated with clinical outcomes. Further studies with larger cohorts, extended treatment durations, and longer follow-up periods are needed to explore the potential clinical benefits of CST in this population.}, } @article {pmid41277450, year = {2025}, author = {Wharton, T and Paulson, D and McClure, NV and Laird, RD and Campos, BM and Churchill, EG and Lysandrou, AE and Maynard, M}, title = {Pilot trial of the Florida-Resources for Enhancing Alzheimer's Caregiver Health (FL-REACH) intervention in an outpatient memory disorders clinic.}, journal = {Aging & mental health}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/13607863.2025.2585507}, pmid = {41277450}, issn = {1364-6915}, abstract = {OBJECTIVES: Translation of the foundational REACH II intervention for caregivers of persons with Alzheimer's disease and related dementias (ADRD) into practice has been limited. Most interventions generally focus on later-stage caregiving. The FL-REACH intervention was adapted from REACH II, addressing issues of implementation burden and shifting focus to prolonging in-home care through intervention delivered soon after diagnosis. Goals of this single-arm pilot study were to examine effectiveness of a six-session intervention delivered through an outpatient memory disorders clinic to caregivers of those diagnosed with mild to moderate stage memory disorders.

METHOD: Dementia caregivers were recruited from the AdventHealth Maturing Minds Program. The COVID-19 pandemic compelled transition of the intervention delivery from the clinic environment to online.

RESULTS: Dementia knowledge, caregiver burden, and caregiver preparedness all improved from baseline to post-treatment. Participants who completed the intervention online were disproportionately male, and more socioeconomically and ethnically diverse than those who completed the intervention in person.

CONCLUSION: Results support use of the FL-REACH intervention program and suggest that memory disorders clinics create a valuable opportunity for enrollment in dementia caregiver interventions that provide training and skills development early in the disease trajectory.}, } @article {pmid41277070, year = {2025}, author = {Casagrande, LR and Medeiros, EB and Venturini, LM and Zaccaron, RP and da Costa, C and Bittencourt, JVS and Modolon, HB and Lidio, AV and Arcaro, S and Budni, J and Gu, Y and Thirupathi, A and Lock Silveira, PC}, title = {Neuromodulation with low-intensity pulsed ultrasound (Lipus) combined with curcumin-gold nanoparticles (Cur-AuNPs) in an Alzheimer's disease model.}, journal = {Drug delivery}, volume = {32}, number = {1}, pages = {2577826}, pmid = {41277070}, issn = {1521-0464}, mesh = {Animals ; *Alzheimer Disease/drug therapy/therapy/metabolism ; *Curcumin/administration & dosage/pharmacology/chemistry ; *Gold/chemistry/administration & dosage ; Mice ; *Metal Nanoparticles/chemistry/administration & dosage ; Male ; Disease Models, Animal ; Amyloid beta-Peptides ; Maze Learning/drug effects ; Ultrasonic Waves ; Peptide Fragments ; Hippocampus/metabolism/drug effects ; Blood-Brain Barrier/metabolism ; }, abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that requires innovative therapeutic strategies. This is the first study to evaluate the synergistic effects of LIPUS and CUR-AuNPs in an AD model, which aimed to investigate the effects of these therapies on learning, memory and neuroinflammation in mice with β-amyloid peptide (βA1-42)-induced AD. Sixty mice were divided into five groups: control, βA1-42, βA1-42 + LIPUS, βA1-42 + CUR-AuNPs, and βA1-42 + LIPUS + CUR-AuNPs. Treatments began 24 hours after induction and continued for 17 days using intranasal CUR-AuNPs (25 μg/mL) and transcranial LIPUS (0.8 W/cm[2], 1 MHz). The results demonstrated that the isolated therapies reversed memory deficits in the Y-maze and radial maze tests. However, the combined therapy group was able to reverse these deficits only in the radial maze. Electron microscopy confirmed the ability of CUR-AuNPs to cross the blood‒brain barrier, especially in the combined group, and no liver toxicity was observed. All the treated groups presented increased BDNF in the hippocampus and cortex. IL-1β and IL-6 levels are reduced in the cortex, while IL-1β and TNF-α levels are decreased in the hippocampus. IL-10 increased only in the hippocampus, while GSH levels increased in both regions. Combination therapy also reduced nitrite concentrations in the hippocampus and cortex and NFκB expression in the hippocampus. APP expression decreased exclusively in the LIPUS group in the hippocampus. These results suggest that although single treatments are effective, their combination enhances neuroprotective responses through the modulation of inflammation, oxidative stress, and neurotrophic signaling, suggesting promising potential for AD treatment.}, } @article {pmid41276859, year = {2025}, author = {Noguchi-Shinohara, M and Yoshinobu, T and Ozaki, T and Muramatsu, D and Shima, A and Sakashita, Y and Tada, Y and Yamaguchi, H and Komatsu, J and Ikeda, T and Ono, K}, title = {Higher phosphorylated tau levels predict cognitive decline and amyloid-related imaging abnormalities during lecanemab treatment: clinical practice data.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {251}, pmid = {41276859}, issn = {1758-9193}, mesh = {Humans ; Female ; Male ; Aged ; *tau Proteins/metabolism/cerebrospinal fluid ; *Cognitive Dysfunction/drug therapy/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; Phosphorylation ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Biomarkers/cerebrospinal fluid/blood ; Middle Aged ; Aged, 80 and over ; Brain/diagnostic imaging ; Positron-Emission Tomography ; Neuropsychological Tests ; *Plaque, Amyloid/diagnostic imaging/drug therapy ; }, abstract = {BACKGROUND: Lecanemab was recently approved for the treatment of patients with early Alzheimer's disease (AD) and demonstrated reduced senile amyloid plaque and less decline on the measures of cognition and function in clinical trials. However, the real-world data on its efficacy and safety remain limited. We aimed to evaluate the effectiveness and tolerance of lecanemab treatment and determine biomarkers at baseline that could predict cognitive deterioration and the occurrence of amyloid-related imaging abnormaities (ARIA) in real-world clinical practice.

METHODS: To determine the indication for lecanemab, the patients were evaluated through neurological examinations, cognitive assessments, blood test, head magnetic resonance imaging (MRI), amyloid positron emission tomography, lumbar puncture, genetic testing, and clinical conferences. The Mini-Mental State Examination (MMSE) was used to assess cognition, and the MRI scans were used for safety monitoring of ARIA.

RESULTS: Between January 2024 and October 2025, 234 patients were screened, 100 initiated lecanemab treatment. The mean age was 72.7 years, and 68 (68.0%) patients were female. Among the 71 patients surveyed via MRI prior to the 14th infusion, 12 (16.9%) had ARIA detected. Compared with those of patients without ARIA, the baseline cerebrospinal fluid (CSF)-ptau181 levels of patients with ARIA significantly increased. When the patients were divided into high and low CSF-ptau181 groups according to the cutoff value (78.6 pg/ml) which derived from ROC analysis for ARIA prediction, the MMSE scores of the high ptau group were significantly declined compared to that of the low ptau group at 6 and 12 months after baseline. The infusion-reactions occurred only in 6.0% of patients. The longitudinal observation revealed that the plasma thrombomodulin levels significantly decreased after 6 months of lecanemab treatment.

CONCLUSION: Lecanemab was generally well tolerated by most patients with early AD and treatment appeared to be more effective and safer in patients with low CSF-ptau181 levels.　Our results suggest an association between lecanemab treatment and reduced markers of vascular endothelial injury.}, } @article {pmid41276781, year = {2025}, author = {Gürbüz, P and Doğan, ŞD and Gündüz, MG and Martínez-González, L and Pérez, C and Martinez, A}, title = {Screening Natural Phenolic Compounds for Blood-Brain Barrier Permeability, Alongside GSK-3β, CK-1δ, and AChE Inhibition, for the Treatment of Alzheimer's Disease.}, journal = {Drug development research}, volume = {86}, number = {8}, pages = {e70193}, doi = {10.1002/ddr.70193}, pmid = {41276781}, issn = {1098-2299}, support = {//The present study was supported by the Research Foundation of Erciyes University (Grant No: TSA-2022-11539)./ ; }, mesh = {*Alzheimer Disease/drug therapy ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Glycogen Synthase Kinase 3 beta/antagonists & inhibitors/metabolism ; *Cholinesterase Inhibitors/pharmacology/chemistry/pharmacokinetics ; *Neuroprotective Agents/pharmacology/pharmacokinetics/chemistry ; Molecular Docking Simulation ; *Phenols/pharmacology/chemistry ; Acetylcholinesterase/metabolism ; Permeability ; }, abstract = {Alzheimer's Disease (AD) is a neurological disorder characterized by progressive cognitive impairment and memory loss. In vitro artificial membrane permeability assays targeting the blood-brain barrier (BBB), such as the parallel artificial membrane permeability assay (PAMPA), are useful for pre-evaluating the BBB penetration of molecules during the early stages of drug development. Inhibitors of glycogen synthase kinase-3β (GSK-3β), casein kinase-1δ (CK-1δ), and acetylcholinesterase (AChE) exhibit neuroprotective effects, indicating a potential therapeutic approach for AD. This study aimed to assess the ability of 23 phenolic compounds derived from natural sources to penetrate the central nervous system (CNS) and examine their potential neuroprotective effects. Following the prediction of BBB penetration of the compounds by PAMPA, neuroprotective effects of CNS+ compounds were evaluated through in vitro inhibition of GSK-3β, CK-1δ, and AChE. Based on the data obtained, five flavonoids (hispidulin, nepetin, platanoside, apigenin, and kaempferol) and two furanocoumarins (isopimpinellin and bergapten) were predicted to penetrate the CNS. Apigenin (API) and kaempferol (KEM) exhibited the most potent dual inhibitory activity against CK-1δ and GSK-3β. Furthermore, API and KEM did not exhibit cytotoxic effects in SH-SY5Y cells. Molecular modeling studies, including molecular docking, molecular dynamics simulations, and dynophore analysis, were performed to understand the binding mechanism of these most potent compounds to their target enzymes. Overall, the current study offers a rational approach to designing new molecules inspired by natural compounds to treat Alzheimer's Disease.}, } @article {pmid41276735, year = {2025}, author = {Aghababaee, L and Farrokhi, K and Karimi-Jafari, MH and Shahpasand, K and Riazi, GH}, title = {Cross-Talk Between Tau O-GlcNAcylation and the Formation of the Early Driver of Neurodegeneration (Cis P-Thr231-Pro Tau) in Primary Cortical Neurons.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {158}, pmid = {41276735}, issn = {1559-1182}, mesh = {*tau Proteins/metabolism ; *Neurons/metabolism/pathology/drug effects ; Animals ; *Cerebral Cortex/pathology/metabolism ; Phosphorylation/drug effects ; *Acetylglucosamine/metabolism ; Cells, Cultured ; *Nerve Degeneration/metabolism/pathology ; Thiazoles/pharmacology ; Humans ; Pyrans ; }, abstract = {Tau is a microtubule-associated protein. Hyperphosphorylation of tau at neurotoxic sites, particularly at Thr231 within the Thr231-Pro motif, is a pathological hallmark of Alzheimer's disease (AD) and other tauopathies. Phosphorylated tau at Thr231 exists in two distinct conformations: cis and trans. The Cis pThr231-Pro Tau confomer is neurotoxic and promotes neurodegeneration. Furthermore, tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and it has been suggested that O-GlcNAcylation of tau can influence tau phosphorylation. In this study, we utilized Thiamet G, an O-GlcNAcase (OGA) inhibitor, to elevate tau O-GlcNAcylation levels. Our findings demonstrate that treatment of nutrient-deprived primary cortical neurons with this OGA inhibitor increased tau O-GlcNAcylation, inhibited the formation of the neurotoxic Cis p-Tau conformation, and reduced neuronal cell loss. Additionally, we observed that the Trans p-Tau conformation represents a normal conformer under physiological conditions. Collectively, our data support tau O-GlcNAcylation as a promising therapeutic strategy for Alzheimer's disease and other tauopathies.}, } @article {pmid41276485, year = {2026}, author = {Terao, I and Kodama, W}, title = {Comparative Efficacy and Tolerability of Multiple Antipsychotics Across Varying Doses for Neuropsychiatric Symptoms of Dementia Including Alzheimer's Disease: A Dose-Response Model-Based Network Meta-Analysis.}, journal = {Acta psychiatrica Scandinavica}, volume = {153}, number = {2}, pages = {82-94}, doi = {10.1111/acps.70051}, pmid = {41276485}, issn = {1600-0447}, mesh = {Humans ; *Antipsychotic Agents/administration & dosage/adverse effects/pharmacology ; *Alzheimer Disease/drug therapy ; Dose-Response Relationship, Drug ; *Dementia/drug therapy ; Risperidone/administration & dosage/adverse effects ; Randomized Controlled Trials as Topic ; Aripiprazole/administration & dosage/adverse effects ; Olanzapine/administration & dosage ; Thiophenes ; Quinolones ; }, abstract = {BACKGROUND: Antipsychotics are widely used for neuropsychiatric symptoms (NPSs) in dementia including Alzheimer's disease (AD), yet balancing efficacy and safety remains a major clinical challenge.

METHODS: Relevant randomized controlled trials were identified through a comprehensive literature search of CENTRAL, PubMed, CINAHL, and ClinicalTrials.gov. We conducted a dose-response model-based network meta-analysis to evaluate the efficacy as the change in overall NPS severity and the tolerability as treatment discontinuation due to adverse events of aripiprazole, brexpiprazole, risperidone, quetiapine and olanzapine at varying doses in patients with dementia including AD.

RESULTS: Twenty trials involving 5844 participants were included. Most of the included antipsychotics exhibited a generally positive dose-response relationship with respect to both efficacy and tolerability, except for olanzapine, which showed a bell-shaped curve in terms of efficacy. Only aripiprazole 10 mg, brexpiprazole 1-2.5 mg, risperidone 1-2 mg, and olanzapine 2.5-5 mg were significantly more effective than placebo. Tolerability did not significantly decrease compared to placebo for aripiprazole up to 10 mg, brexpiprazole up to 3 mg, risperidone up to 1 mg, olanzapine up to 2.5 mg and at 15 mg, and quetiapine up to 200 mg. Furthermore, significant differences in efficacy and tolerability were observed between certain doses of several antipsychotics.

CONCLUSIONS: Aripiprazole 10 mg, brexpiprazole 1-2.5 mg, risperidone 1 mg, and olanzapine 2.5 mg were both effective and well tolerated, indicating their potential as favorable treatment options. As the present model incorporates several sources of uncertainty, its findings should be interpreted with caution and regarded as a provisional framework to support clinical decision-making.}, } @article {pmid41276165, year = {2025}, author = {Bei, Y and Zhong, D and Lu, J and Qiu, Y and Bowen, TS and Chen, N and Dun, Y and Gao, F and Huang, Y and Li, G and Li, J and Li, J and Liu, F and Liu, W and Ma, X and Rosenzweig, A and Spanos, M and Tian, Z and Yin, P and Wang, R and Wang, Y and Xu, D and Xu, L and Zhang, L and Zhang, J and Zhang, X and Zhou, Q and Qiao, Y and Xu, M and Xiao, J}, title = {Expert consensus statement for basic research of animal exercise intervention studies in chronic disease prevention and treatment: A joint position paper of the Exercise Science branch of the Biophysical Society of China and the Metabolism and Genetics branch of the Genetics Society of China.}, journal = {Journal of sport and health science}, volume = {}, number = {}, pages = {101103}, doi = {10.1016/j.jshs.2025.101103}, pmid = {41276165}, issn = {2213-2961}, abstract = {Chronic diseases, broadly defined as long-duration conditions that require sustained medical care and/or limit activities of daily living, are a major problem that threatens human health and imposes large social and economic burdens. Physical activity has many beneficial effects for human health and is among the most cost-effective ways to prevent and treat chronic diseases. Animal exercise intervention studies are widely used and provide valuable scientific evidence about the cellular and molecular mechanisms underlying the effects of exercise training in a variety of chronic disease models. This consensus statement will provide expert opinions and recommendations for the appropriate design and application of animal exercise intervention studies and models in fundamental investigations of prevention and treatment of chronic diseases, especially focusing on cardiovascular and cerebrovascular diseases (coronary artery disease and stroke), metabolic diseases (obesity and type 2 diabetes mellitus), chronic respiratory diseases (chronic obstructive pulmonary disease), and neurological diseases (Alzheimer's disease). This statement highlights various exercise models (as determined by frequency, intensity, time, and type of exercise intervention) utilized for each disease. Additionally, it includes a list of functional, structural, biochemical, and disease-specific evaluation metrics of exercise effects, followed by outlined recommendations for the exercise study design and evaluations for the mentioned chronic diseases. This consensus aimed to offer practical recommendations for better design and conduct of fundamental research in animal exercise intervention studies to improve our understanding of the effects of exercise on chronic diseases, and to further develop physical exercise or exercise-mimetic interventions for disease prevention and treatment.}, } @article {pmid41275722, year = {2026}, author = {Xu, Y and Li, N and Li, X and Cui, X and Ju, R and Li, M and Zhao, J and Han, F}, title = {Integrated analysis strategies reveal the pharmacodynamic substances and action mechanisms of Huangqi San in the treatment of Alzheimer's disease.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {270}, number = {}, pages = {117251}, doi = {10.1016/j.jpba.2025.117251}, pmid = {41275722}, issn = {1873-264X}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Drugs, Chinese Herbal/pharmacology ; Rats ; PC12 Cells ; Molecular Docking Simulation/methods ; Amyloid beta-Peptides/toxicity ; Network Pharmacology/methods ; Oxidative Stress/drug effects ; Cell Survival/drug effects ; Signal Transduction/drug effects ; *Neuroprotective Agents/pharmacology ; Peptide Fragments/toxicity ; Phosphatidylinositol 3-Kinases/metabolism ; Rats, Sprague-Dawley ; Proto-Oncogene Proteins c-akt/metabolism ; Male ; Chromatography, High Pressure Liquid/methods ; Astragalus propinquus ; }, abstract = {Alzheimer's disease (AD), as a neurodegenerative disorder characterized primarily by memory impairment in its early stages, imposes a heavy burden on society and medical resources. This study aims to investigate the therapeutic effect of Huangqi San (HQS) on AD and elucidate its potential mechanism of action. This study analyzed the rat serum after treated by HQS using UHPLC-Q-Exactive Orbitrap MS, and identified the potential active components of HQS. Subsequently, key targets and pathways were identified through network pharmacology and molecular docking techniques, and were verified in PC12 cells damaged by Aβ25-35. The verification methods included cell viability assays, analysis of inflammatory/oxidative stress markers, and regulation of the PI3K/AKT/MAPK pathway. The results showed that a total of 40 serum adsorption components and 70 common targets were identified. Network analysis revealed that the PI3K-AKT, MAPK and Rap1 signaling pathways were at the core of the network. Molecular docking demonstrated strong binding affinity between 10 core components (e.g., isoliquiritigenin, moracin M) and pivotal targets (BCL2, MAPK3, PTGS2). In vitro validation showed HQS significantly attenuated Aβ25-35-induced neurotoxicity by enhancing cell viability, suppressing apoptosis, reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and oxidative markers (MDA, ROS, CYP2E1) while elevating GSH-Px activity. Moreover, HQS can bidirectionally regulate PI3K/AKT/MAPK pathways via upregulating PI3K/AKT/ERK1/2 and inhibiting JNK/p38 phosphorylation. In conclusion, this study innovatively established HQS as a multi-component/multi-target candidate drug for the treatment of AD. Its mechanism of action is related to its synergistic regulation of PI3K/AKT/MAPK-mediated neuroprotection. This comprehensive approach provides an example for interpreting complex traditional Chinese herbal preparations.}, } @article {pmid41275266, year = {2025}, author = {Roach, JC and Glusman, G and Rapozo, MK and Merrill, DA and Bramen, J and Hodes, JF and Siddarth, P and Meysami, S and Elhelou, SHK and Glatt, RM and Edens, L and Funk, C and Kelly, D and Shankle, WR and Bredesen, D and Raji, CA and Hood, L}, title = {Multidomain therapy for Alzheimer's disease: a scoping review of cognitive decline trials.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {125}, pmid = {41275266}, issn = {1750-1326}, abstract = {BACKGROUND: Alzheimer’s disease (AD) leading to cognitive decline and dementia results from the interplay of multiple interacting dysfunctional biological systems. These systems can be categorized by domain, such as inflammation, cardiovascular health, proteostasis, or metabolism. Specific causes of AD differ between individuals, but each individual is likely to have causes stemming from multiple domains. Personalized multidomain therapy has been proposed as a standard of care for AD.

OBJECTIVES: We sought to enumerate and describe prospective randomized controlled trials (RCTs) for multidomain interventions for AD, and to extract their inclusion criteria, trial design parameters (length, number of participants), and outcome measures. We sought to clarify gaps and opportunities in research and clinical translation.

METHODS: We conducted a scoping review using the standardized PRISMA-ScR methodological framework.

ELIGIBILITY CRITERIA: We include all cohort studies and RCTs for multidomain (also known as multimodal, multicomponent, multidimensional, or multisystem) therapy of any stage of AD, published for all dates through July 28, 2025.

RESULT: There have been 23 studies (completed or reported as ongoing) of multidomain interventions for AD, including 19 RCTs. Of the 15 completed RCTs, 12 demonstrate benefit from their intervention in at least one arm.

CONCLUSIONS: Although these RCTs differ widely in their parameters, the majority support the use of multidomain therapy, and show effect sizes greater than reported for unimodal therapies, including pharmaceuticals. Multidomain therapy should be the standard of care for AD. Multidomain interventions (also known as treatments) should be employed widely, early, and first-line. Treatment or prevention is likely to be most effective at early, presymptomatic stages, but is worthwhile at all stages of disease. In order to influence multiple domains, multiple modes of therapy are likely necessary in all patients. Some individual modes, such as particular lifestyle interventions, may target multiple domains. Nevertheless, most patients will benefit from multiple modes of intervention (multimodal intervention) that together target multiple domains. Standard-of-care guidelines should explicitly include multidomain interventions. Future clinical trials must be designed to iteratively improve multidomain therapies. Payors should embrace reimbursement for effective multidomain intervention, including personalized coaching.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00912-2.}, } @article {pmid41274321, year = {2026}, author = {Chu, CT and Uruno, A and Suzuki, T and Taguchi, K and Baird, L and Katsuoka, F and Yamamoto, M}, title = {NRF2 activation by CDDO-Im regulates inflammatory and autophagy pathways in human microglial cells.}, journal = {Free radical biology & medicine}, volume = {243}, number = {}, pages = {318-337}, doi = {10.1016/j.freeradbiomed.2025.11.046}, pmid = {41274321}, issn = {1873-4596}, mesh = {Humans ; *NF-E2-Related Factor 2/metabolism/genetics ; *Microglia/drug effects/metabolism/pathology ; *Autophagy/drug effects ; *Oleanolic Acid/analogs & derivatives/pharmacology ; Amyloid beta-Peptides/metabolism/pharmacology ; *Alzheimer Disease/pathology/genetics/metabolism/drug therapy ; *Inflammation/metabolism/pathology/genetics ; Interferon-gamma/pharmacology ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Cell Line ; }, abstract = {Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles, accompanied by elevated oxidative stress and inflammation. Microglia, the resident macrophages in the brain, play a key protective role by clearing plaques and damaged neurons. NRF2 (Nuclear factor erythroid 2-related factor 2) is a master regulator of cytoprotection against oxidative stress, whose activation alleviates oxidative damage, neuroinflammation, and cognitive deficits in AD models. However, direct targets of NRF2 in microglia remain unclear. In this study, we demonstrate that NRF2 activation by CDDO-Im significantly suppresses inflammation in human microglial cells (HMC3) stimulated by IFN-γ or Aβ. Through integrative RNA-sequencing and ChIP-sequencing analysis of NRF2, we identified five representative direct NRF2 target genes involved in inflammation (e.g., IL6, CDK6) and another five related to autophagy (e.g., TFE3, SQSTM1). Importantly, we also found that CDDO-Im treatment enhances autophagy as evidenced by an increased LC3-II/LC3-I ratio. Public single-cell transcriptomic data further underscored the critical role of microglia in NRF2-mediated autophagy regulation within AD brains. Together, our findings reveal new direct NRF2 target genes, highlight the dual role of NRF2 in suppressing inflammation and enhancing autophagy, and thus provide novel insights for therapeutic interventions in AD.}, } @article {pmid41274317, year = {2026}, author = {Anbaraki, A and Ghasemi, A and Seyedarabi, A and Yousefi, R and Saboury, AA}, title = {Dual glycation and oxidation of tau protein: impact of methylglyoxal and hydrogen peroxide on tau structure and fibril assembly.}, journal = {Free radical biology & medicine}, volume = {243}, number = {}, pages = {207-219}, doi = {10.1016/j.freeradbiomed.2025.11.044}, pmid = {41274317}, issn = {1873-4596}, mesh = {*Hydrogen Peroxide/pharmacology ; *Pyruvaldehyde/pharmacology ; *tau Proteins/chemistry/metabolism ; Humans ; Glycosylation ; Oxidation-Reduction ; Oxidative Stress ; *Alzheimer Disease/metabolism/pathology/genetics ; Protein Processing, Post-Translational ; *Diabetes Mellitus, Type 2/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) indicate overlapping pathogenic mechanisms including, protein glycation and oxidative stress. Tau protein, a key player in AD pathology, undergoes various post-translational modifications, disturbing its physiological function and facilitating its aggregation/fibrillation. Nevertheless, the cumulative influence of glycation and oxidation on the structural integrity and fibrillation of tau remains inadequately elucidated. In this study, we examined the effects of methylglyoxal (MGO)-induced glycation and hydrogen peroxide (H2O2)-mediated oxidation, individually or in combination, on tau structure, fibrillation and cytotoxicity. Structural and morphological alterations were evaluated using SDS-PAGE, fluorescence spectroscopy, circular dichroism, dynamic light scattering, Fourier transform infrared spectroscopy, and atomic force microscopy. Fibrillation kinetics were monitored under two conditions: (i) pre-fibrillation modification and (ii) simultaneous modification and fibrillation. Our results indicated that the co-treatment with MGO and H2O2 synergistically altered tau structure. Moreover, the fibrillation kinetics of pre-modified tau samples with MGO indicated a reduction in fibrillation through the generation of oligomeric species. Conversely, the fibrillation kinetics of pre-modified tau samples with H2O2 and both compounds increased tau fibrillation. On the other hand, simultaneous modification and fibrillation of tau samples with MGO and H2O2 resulted in an increase in tau fibrillation and structural changes. Collectively, our results indicated that co-treatment with MGO and H2O2 synergistically enhanced tau fibrillation and produced more ordered fibril structures with increased cytotoxicity toward SH-SY5Y cells. These findings provide mechanistic insights into how glycation and oxidative stress cooperatively modulate tau fibrillation and offer a molecular basis for the pathological link between diabetes and AD.}, } @article {pmid41274188, year = {2026}, author = {Khan, Y and Naeem, MU and Arooj, K and Naseem, M and Adnan, R and Azmatullah, }, title = {A comprehensive computational and experimental study of novel imidazole linked thiadiazole based amide derivatives as cholinesterase duel-target inhibitor for the treatment of Alzheimer's disease.}, journal = {Computational biology and chemistry}, volume = {120}, number = {Pt 1}, pages = {108789}, doi = {10.1016/j.compbiolchem.2025.108789}, pmid = {41274188}, issn = {1476-928X}, mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; *Thiadiazoles/chemistry/pharmacology/chemical synthesis ; *Imidazoles/chemistry/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; *Acetylcholinesterase/metabolism ; *Butyrylcholinesterase/metabolism ; Humans ; Molecular Docking Simulation ; Structure-Activity Relationship ; *Amides/chemistry/pharmacology/chemical synthesis ; Molecular Structure ; Dose-Response Relationship, Drug ; }, abstract = {The thiadiazole scaffold has gained prominence in modern drug discovery due to its remarkable structural adaptability. Its unique framework enables interactions with a wide spectrum of biological targets, making it a valuable pharmacophore for therapeutic development. Reflecting its growing clinical importance, efficient synthetic access to thiadiazole derivatives has become a focal point for medicinal chemists seeking to exploit its multifunctional activity. In our study, we synthesized a streamlined and high-throughput synthetic protocol to generate a novel library of imidazole linked thiadiazole analogues. All newly imidazole linked thiadiazole analogues were spectroscopically characterized by [1]HNMR and [13]CNMR spectroscopy and high-resolution electron impact mass spectrometry (HRMS). Biological screening across a panel of key metabolic enzymes revealed potent inhibitory action against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Remarkably, a majority of tested compounds outperformed standard inhibitors donepezil exhibited compounds 1, 2, 4 and 8 showing lower IC50 values of 5.32 ± 0.87 µM (AChE), 6.09 ± 0.97 µM (BuChE), 7.40 ± 0.76 µM (AChE), 6.97 ± 0.56 µM (BuChE), 7.56 ± 0.54 µM (AChE), 7.03 ± 0.39 µM (BuChE), and 5.13 ± 0.28 µM (AChE), 5.33 ± 0.61 µM (BuChE) respectively. Detailed structure-activity relationship (SAR) analyses revealed that strategic substitution patterns modulate inhibitory efficacy and selectivity. Complementing these findings, molecular docking study illuminated key interactions within the catalytic pockets of (AChE) and (BuChE), identifying critical amino acid residues mediating ligand engagement. Hence, our integrated synthetic, biochemical, and computational approach identifies compounds 1, 2, 4 and 8 as a promising lead compound that possess favorable pharmacological attributes for further preclinical development in metabolic disease interventions.}, } @article {pmid41273473, year = {2025}, author = {Yang, Z and Peng, X and Zhang, X and Guo, H and Li, Z and Wu, X and Zhao, M and Ruganzu, JB and Zhai, C and Ji, S and Yang, W}, title = {Tanshinone IIA Promotes Hippocampal Neurogenesis in ApoE[-/-] Mice Through cAMP/PKA/CREB/BDNF Signaling Pathway.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {144}, pmid = {41273473}, issn = {1559-1182}, support = {2023-JC-YB-735//the Natural Science Basic Research Plan in Shaanxi Province of China/ ; }, mesh = {Animals ; *Neurogenesis/drug effects ; *Brain-Derived Neurotrophic Factor/metabolism ; *Hippocampus/drug effects/metabolism ; *Signal Transduction/drug effects ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Cyclic AMP/metabolism ; *Cyclic AMP-Dependent Protein Kinases/metabolism ; *Abietanes/pharmacology ; *Apolipoproteins E/deficiency ; Cell Proliferation/drug effects ; Mice ; Neural Stem Cells/drug effects/metabolism ; Mice, Knockout ; Mice, Inbred C57BL ; Male ; Phosphorylation/drug effects ; }, abstract = {New cells are generated from neural stem cells (NSCs) in the subgranular zone (SGZ) of the dentate gyrus of the hippocampus throughout life to shape brain function. Apolipoprotein E (ApoE) deficiency impairs hippocampal dentate gyrus development by affecting the neural progenitor pool over time. Impaired adult hippocampal neurogenesis has been reported in human ApoE4 and ApoE-knockout (ApoE[-/-]) mice. The ApoE gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Our previous studies indicated that tanshinone IIA (tan IIA) has a broad range of pharmacological actions on AD. Here, we aimed to investigate the effects of 2 weeks of tan IIA (15 mg/kg, intraperitoneally, once daily) treatment on hippocampal neurogenesis in 1- and 3-month-old ApoE[-/-] mice. The results showed that tan IIA treatment significantly promoted cell proliferation and increased the density of immature neurons in the hippocampus. Mechanistically, tan IIA treatment elevated the levels of cyclic adenosine monophosphate (cAMP), cAMP/protein kinase A (PKA), and cAMP response element binding protein (CREB) phosphorylation, and subsequently increasing the production of brain-derived neurotrophic factor (BDNF). Furthermore, tan IIA is capable of promoting NSCs proliferation, differentiation, and survival in vitro. Collectively, the above findings indicated that tan IIA stimulates neurogenesis in the adult hippocampus of ApoE[-/-] mice possibly through the cAMP/PKA/CREB/BDNF signaling pathway. These results suggested that tan IIA may have neuroprotective effects against neurogenesis decline in ApoE[-/-] mice.}, } @article {pmid41273462, year = {2025}, author = {Su, Y and Zhang, D and Li, Y and Gu, H and Li, W and Zhou, W and Zhao, N and Huang, X}, title = {Caenorhabditis Elegans Ortholog of TNF Alpha-Induced Protein 1 is Upregulated by TOL-1 and Exacerbates Amyloid-Beta-Associated Pathology.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {146}, pmid = {41273462}, issn = {1559-1182}, support = {KC-23236341//Yunnan University Graduate Research Innovation Fund/ ; No. 202403AC100007//Yunnan Fundamental Research Projects/ ; No. 32170184//Natural Science Foundation Program of China/ ; }, mesh = {*Caenorhabditis elegans/metabolism/genetics ; Animals ; *Amyloid beta-Peptides/metabolism/toxicity ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Up-Regulation ; Animals, Genetically Modified ; *Toll-Like Receptors/metabolism ; Humans ; Alzheimer Disease/pathology/metabolism ; }, abstract = {Neuroinflammation has been recognized as a central pathological mechanism in Alzheimer's disease (AD), modulated by diverse molecular pathways. Among these, the tumor necrosis factor superfamily (TNFSF) pathway serves as a pivotal mediator of inflammatory responses in higher organisms, representing a potential therapeutic target for AD treatment. Notably, TNF alpha-induced protein 1 (TNFAIP1) is significantly upregulated following amyloid-beta1-42 (Aβ1-42) accumulation in the postmortem brains of patients with AD and in transgenic Caenorhabditis elegans models. However, the regulatory mechanism of its ortholog F22E5.6 in C. elegans and its role in Aβ neurotoxicity remain elusive due to the absence of the core TNFSF members in this model. Through systematic screening of TNFSF orthologs, the trf-1 gene that encodes the adapter protein, TNF receptor-associated factor (TRAF), has been identified as a critical regulator in Aβ1-42-induced F22E5.6 overexpression of C. elegans. In this genetic model, the only Toll-like receptor TOL-1 in C. elegans serves as a potential receptor to activate TRF-1 and to transmit this signal to the SRC-2/PMK-3 axis, thereby executing the effects on mitochondrial homeostasis disequilibrium. These findings reveal the regulatory mechanism on Aβ1-42-induced F22E5.6/TNFAIP1 overexpression and its involvement in AD model of C. elegans, providing a clue to resolve the paradox of TNFSF-mediated inflammation in organisms lacking the canonical TNFSF pathway.}, } @article {pmid41272752, year = {2025}, author = {Saraswathi, TS and Mothilal, M and Bukke, SPN and Thalluri, C and Chettupalli, AK}, title = {Recent advances in potential drug nanocarriers for CNS disorders: a review.}, journal = {Biomedical engineering online}, volume = {24}, number = {1}, pages = {137}, pmid = {41272752}, issn = {1475-925X}, mesh = {Humans ; *Central Nervous System Diseases/drug therapy ; *Drug Carriers/chemistry ; *Nanoparticles/chemistry ; Animals ; Blood-Brain Barrier/metabolism ; }, abstract = {BACKGROUND: Neurological disorders, including Parkinson's and Alzheimer's disease, impose a significant burden on individuals and healthcare systems. Effective treatment is often hindered by the restrictive nature of the blood-brain barrier (BBB), limiting drug access to the central nervous system (CNS).

AIM: The purpose of this review is to provide an overview of existing methods to deliver therapeutics to the CNS across the BBB with an emphasis on drug delivery systems that utilize nanotechnology.

METHOD/SOURCE: We performed a thorough review of the published literature on recently emerging trends in pharmacology and nanomedicine that have attempted to deliver drugs to the CNS by addressing the challenge of delivering therapeutics across the BBB.

RESULT/FINDING: Nanoparticles and nanocarriers have shown promise for crossing the blood-brain barrier (BBB), improving drug bioavailability in the brain, and facilitating targeted delivery. Several systems applying nanomaterials, including polymeric nanoparticles, liposomes, solid-lipid nanoparticles, and quantum dots, have successfully advanced through preclinical or early clinical studies. However, demonstrated evidence of the implementation and uptake of nanoparticles in specific antitumor and neurotherapeutic indications have several significant challenges, primarily due to safety, biocompatibility, and scalability.

CONCLUSION: The combination of traditional pharmacology and nanotechnology provides valuable opportunities for drug delivery to the CNS. Gains in the design of nanocarrier systems have great potential for addressing the limits of BBBs and for improving therapeutic outcomes in neurological disease, but more research is necessary for the development of translational clinical studies.}, } @article {pmid41272481, year = {2025}, author = {Li, Q and Degan, S and Galeffi, F and Colton, CA and Turner, DA}, title = {Dysregulated microvascular reactivity in hippocampus and cortex in CVN Alzheimer's disease mouse model.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {}, number = {}, pages = {271678X251383112}, pmid = {41272481}, issn = {1559-7016}, support = {I21 RX004081/RX/RRD VA/United States ; R01 AG074999/AG/NIA NIH HHS/United States ; R01 AG081774/AG/NIA NIH HHS/United States ; R21 AG051103/AG/NIA NIH HHS/United States ; }, abstract = {Microvascular reactivity in acute cortical and hippocampal brain slices and hippocampal synaptic- evoked cerebral blood flow (CBF) in vivo were analyzed in a mouse model of Alzheimer's disease (AD, CVN). Microvessels underwent initial vasoconstriction (2 µM noradrenaline) then treatment with either 0.5 mM glutamate or 100 µM NMDA. In acute brain slices from young mice (<20 weeks) the glutamate and NMDA treatment led to dilation of capillaries in cortex and hippocampus, but not in aged CVN mice (>30 weeks, with AD pathology). Furthermore, 1 mM adenosine restored pre-constricted capillaries to control levels in WT but not in aged CVN brain slices. Stimulation of endothelial ET-1 receptors (10 nM ET-1) showed enhanced vasoconstriction in hippocampal capillaries of aged CVN slices, but blockade of both ET-1A/1B receptors did not alter basal capillary tone in aged CVN slices. Stimulation-evoked hippocampal CBF in vivo was significantly reduced in aged CVN mice. These results provide evidence for a progressive, complex age- and AD pathology-related impairment of vascular reactivity and vasodilation in the CVN model. The dysregulation of NVC function and reduced functional hyperemia in aged CVN AD mice may underscore dynamic hypoperfusion and metabolic insufficiency, which could accelerate progression in AD.}, } @article {pmid41272422, year = {2025}, author = {Wilson, RF and Harrison, DD and Amoakohene, E and Lyons, BH}, title = {Homicides among people with disabilities, United States, 2003-2022.}, journal = {Injury epidemiology}, volume = {12}, number = {1}, pages = {88}, pmid = {41272422}, issn = {2197-1714}, abstract = {BACKGROUND: People with disabilities (PwD) are at an increased risk of experiencing nonfatal violence; however, the risk of fatal violence victimization (i.e., homicide) among this population is less well established.

METHODS: We used National Violent Death Reporting System (NVDRS) data for homicide victims with disabilities for 2003 to 2022 in 50 states, the District of Columbia, and Puerto Rico. NVDRS is a surveillance system that collects data on violent deaths, linking information from death certificates, coroner or medical examiner records, and law enforcement reports. NVDRS does not currently include standard variables on disability status or disability type; these decedent characteristics were identified using a literal text search of textual data. Descriptive statistics were used to characterize homicides among PwD.

RESULTS: From 2003 to 2022, NVDRS collected 1,498 homicides among people with disabilities. The largest proportion of victims had a neurological disability (36.7%), followed by cognitive disability (35.5%), physical disability (22.4%), or unspecified disability type (5.4%); 18.2% had multiple disability types. Those aged ≥ 65 years accounted for 45.1% of all victims; the largest proportion of victims were ≥ 75 years old (29.7%). A firearm was used in 38.5% of these homicides. The top three precipitating circumstances of these homicides were: caregiver abuse and neglect (27.0%), argument (26.0%), and intimate partner violence (IPV; 24.0%). Caregiver abuse or neglect precipitated 38.1% of homicides among female victims, versus 19.1% of male victims. IPV precipitated 43.7% of female homicides, versus 9.1% of male homicides. Half (49.5%) of all victims had a mental health problem at the time of death; 23.3% had a history of ever being treated for a mental health problem; 17.8% were receiving mental health treatment at the time of death.

CONCLUSION: This study characterized homicides among PwD. Older adults accounted for nearly half of all victims, and mental health conditions such as dementia and Alzheimer's disease were frequently present among decedents, especially female victims. Among older adults and child victims, caregiver abuse/neglect was common. Our results underscore the importance of supporting caregivers of PwD, creating protective environments for PwD, systematically collecting data on violence against PwD, and tailoring prevention strategies to address the needs of PwD.}, } @article {pmid41272400, year = {2026}, author = {Shao, S and Lu, H and Zu, R and Chen, Y and Peng, Z and Peng, Q and Ma, H and Sun, Y}, title = {Pharmacological Regulation of Mitophagy by Natural Plant Products as a Therapeutic Target for Alzheimer's Disease.}, journal = {Phytotherapy research : PTR}, volume = {40}, number = {1}, pages = {248-266}, doi = {10.1002/ptr.70131}, pmid = {41272400}, issn = {1099-1573}, support = {CMC 2021//Horizontal research project of Chengdu Medical College/ ; 242102311258//Scientific and Technological Project of Henan Province/ ; 2021LHPG-08//Joint Fund of Chengdu Medical College and Chengdu Pidu District People's Hospital/ ; 231111312900//Henan Province key research and development project/ ; No. 2022M711080//Postdoctoral Foundation of China/ ; No. 32301030//The National Natural Science Foundation of China/ ; No. 82274612//The National Natural Science Foundation of China/ ; No. 82305087//The National Natural Science Foundation of China/ ; 2024KYCX003//Henan University of Chinese Medicine/ ; }, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Mitophagy/drug effects ; *Biological Products/pharmacology/therapeutic use ; Animals ; Mitochondria/drug effects/metabolism ; }, abstract = {Alzheimer's disease (AD), a prevalent senile dementia, is characterized by the progressive decline in cognitive function, accumulation of tau tangles and Aβ plaques. Despite significant research efforts in the field of AD, effective therapeutic drugs for its prevention and treatment remain elusive. Consequently, a more comprehensive understanding of the molecular mechanisms underlying the pathological processes of AD is crucial for novel therapeutic strategies. Mitophagy, the selective degradation of mitochondria through autophagy, is an essential mechanism for maintaining mitochondrial homeostasis in terms of both quantity and quality. Mitophagy plays a crucial role in numerous cellular processes, including inflammation, differentiation, and apoptosis. Recent studies have increasingly demonstrated that mitophagy is extensively characterized in AD and may represent a novel therapeutic strategy for its treatment. Notably, a number of natural plant products (NPPs) have been demonstrated to modulate mitophagy and intervene in the pathological process of AD. For instance, NPPs such as urolithin A and β-asarone have been reported to enhance mitophagy by activating the PINK1/Parkin pathway, thereby alleviating Aβ-induced neurotoxicity. The distinctive multi-target properties and favorable safety profiles of NPPs endow them with significant research potential and developmental value, establishing them as a vital resource for novel drug discovery. This review explores the mechanistic hypotheses linking mitophagy to AD pathology and provides a systematic overview of recent advances in representative NPPs that regulate mitophagy to alleviate AD-related impairments, offering new perspectives for the development of therapeutic strategies against AD.}, } @article {pmid41272336, year = {2025}, author = {Tang, C and Ding, Y and Yang, S and Lei, X and Zhang, M and Xu, B and He, D}, title = {Dual Mechanisms of Cognitive Function and Pathological Improvements by the Selective S1PR1/5 Modulator Siponimod in 3xTg-AD Mice.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {133}, pmid = {41272336}, issn = {1559-1182}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism/physiopathology ; *Cognition/drug effects ; Microglia/drug effects/metabolism/pathology ; *Benzyl Compounds/pharmacology/therapeutic use ; Mice ; Mice, Transgenic ; *Azetidines/pharmacology/therapeutic use ; *Sphingosine-1-Phosphate Receptors/metabolism ; Disease Models, Animal ; Molecular Docking Simulation ; Signal Transduction/drug effects ; Male ; Cell Line ; Myelin Sheath/metabolism/drug effects ; *Sphingosine 1 Phosphate Receptor Modulators/pharmacology/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, with neuroinflammation and myelin dysfunction as crucial pathological mechanisms. Siponimod, a selective S1PR1/5 modulator, shows promising therapeutic potential through enhanced brain penetration and improved pharmacokinetic properties compared to first-generation modulators. Network pharmacology and molecular docking analyses were utilized to comprehensively elucidate the underlying mechanisms of Siponimod in the context of AD. Specifically, network pharmacology identified key targets and pathways associated with Siponimod, while molecular docking facilitated predictions of binding affinities to these targets. For in vitro assessments, BV2 microglia cells were used to investigate the effects of Siponimod after stimulation with LPS, focusing on inflammatory responses and cellular signaling pathways. Concurrently, in vivo studies employed the 3xTg-AD mouse model to investigate behavioral outcomes related to cognitive function, alongside evaluations of neuroinflammation and the integrity of myelin sheaths. Siponimod treatment resulted in a significant reduction in pro-inflammatory cytokines and ROS production in BV2 microglia cells, thereby indicating its robust anti-inflammatory and antioxidant properties. In the 3xTg-AD mouse model, administration of Siponimod led to marked improvements in cognitive performance as assessed through various behavioral tests. Additionally, there was a noteworthy decrease in Aβ plaque deposition, coupled with evidence of myelin repair, which was reflected in the increased expression of myelination-related proteins, namely OLIG2 and MBP. Furthermore, Siponimod was found to activate the PI3K-AKT signaling pathway, which plays a crucial role in promoting neuroprotection and enhancing cellular resilience against neurodegenerative processes. This study demonstrates that Siponimod effectively treats AD through dual mechanisms: reducing neuroinflammation and promoting myelin repair via the S1PR1/5 and PI3K-AKT signaling pathway. These findings suggest Siponimod's potential as a promising therapeutic agent for AD treatment.}, } @article {pmid41271757, year = {2025}, author = {Rabiei, K and Petrella, JR and Lenhart, S and Liu, C and Hao, W and , }, title = {Data-driven modeling of amyloid-β targeted antibodies for Alzheimer's disease.}, journal = {NPJ systems biology and applications}, volume = {11}, number = {1}, pages = {134}, pmid = {41271757}, issn = {2056-7189}, support = {R35 GM146894/GM/NIGMS NIH HHS/United States ; P30AG072958/NH/NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; 1R35GM146894/GM/NIGMS NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; DMS-2052676//National Science Foundation/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism/immunology/chemistry/antagonists & inhibitors ; Humans ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; Kinetics ; }, abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta, which is strongly associated with disease progression and cognitive decline. Despite the approval of monoclonal antibodies targeting Aβ, optimizing treatment strategies while minimizing side effects remains a challenge. This study develops a mathematical framework to model Aβ aggregation dynamics, capturing the transition from monomers to higher-order aggregates, including protofibrils, toxic oligomers, and fibrils, using mass-action kinetics and coarse-grained modeling. Parameter estimation, sensitivity analysis, and data-driven calibration ensure model robustness. An optimal control framework is introduced to identify the optimal dose of the drug as a control function that reduces toxic oligomers and fibrils while minimizing adverse effects, such as amyloid-related imaging abnormalities (ARIA). The results indicate that Donanemab achieves the most significant reduction in fibrils. These findings provide a quantitative basis for optimizing AD treatments, providing valuable insight into the balance between therapeutic efficacy and safety.}, } @article {pmid41271117, year = {2026}, author = {Yin, C and Tang, X and Zeng, J and Wang, Z and Mi, J and Liang, Y and Qin, D and Feng, Q and Wu, A}, title = {Next-generation biosensor technologies for Alzheimer's disease: Innovations in diagnosis, monitoring, and treatment.}, journal = {Ageing research reviews}, volume = {114}, number = {}, pages = {102954}, doi = {10.1016/j.arr.2025.102954}, pmid = {41271117}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Biosensing Techniques/methods/trends ; Biomarkers ; Artificial Intelligence ; Animals ; }, abstract = {Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, remains a global health crisis due to the lack of early diagnostic tools, dynamic monitoring strategies, and effective therapies. Current diagnostic methods such as cerebrospinal fluid (CSF) analysis and neuroimaging, while accurate, are invasive, expensive, and unsuitable for routine screening, highlighting the pressing need for alternative approaches. This review comprehensively examines the transformative role of next-generation biosensors in revolutionizing AD management. By leveraging breakthroughs in nanotechnology, materials science, and artificial intelligence (AI), modern biosensors enable ultrasensitive, non-invasive detection of AD biomarkers, including amyloid-β (Aβ), Tau proteins, and neurofilament light chain (NfL), across diverse biofluids such as blood, saliva, and tears. We critically evaluate electrochemical, optical, and acoustic biosensing platforms, highlighting their integration into wearable and portable devices for real-time disease monitoring and personalized therapeutic interventions. Emerging trends such as AI-driven analytics, CRISPR-based diagnostics, and closed-loop neuromodulation systems are explored for their potential to decode disease progression and optimize treatment responses. Challenges in clinical translation, including sensor stability, regulatory hurdles, and ethical considerations, are addressed to pave the way for scalable, patient-centric solutions. By synthesizing cutting-edge advancements and interdisciplinary insights, this review charts a roadmap for biosensor technologies to shift AD care from reactive to proactive, ultimately improving quality of life for patients and caregivers.}, } @article {pmid41270999, year = {2026}, author = {Parveen, N and Qais, FA and Faheem, M}, title = {Molecular insights into diosgenin's role in preventing protein aggregation in neurodegenerative diseases.}, journal = {Biochimica et biophysica acta. Proteins and proteomics}, volume = {1874}, number = {1}, pages = {141116}, doi = {10.1016/j.bbapap.2025.141116}, pmid = {41270999}, issn = {1878-1454}, mesh = {*Diosgenin/chemistry/pharmacology/metabolism ; Humans ; *Protein Aggregates/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; Molecular Dynamics Simulation ; *Serum Albumin, Human/chemistry/metabolism ; *Protein Aggregation, Pathological/metabolism/prevention & control ; Protein Binding ; Hydrogen Bonding ; }, abstract = {Neurodegenerative disorders (ND) such as Parkinson's and Alzheimer's progressively impair the nervous system, leading to cognitive deterioration and motor dysfunction. A primary factor in these diseases is the accumulation of misfolded protein aggregates, which interfere with cellular processes and ultimately result in neuronal death. Preventing the formation of these toxic aggregates has the potential to protect neurons and slow the advancement of disease. This study examined the impact of diosgenin on protein aggregation, utilizing human serum albumin (HSA) as model protein. Diosgenin reduced ThT fluorescence by 64.35 % and decreased turbidity by 62.61 %, indicating a notable suppression of protein aggregation. The % α-helix in HSA experienced a decline from 57.68 % to 8.82 %, but diosgenin treatment restored it to 43.89 %. Binding studies demonstrated that diosgenin interacts with HSA with -11.0 kcal/mol binding energy, facilitated by van der Waals, hydrophobic and hydrogen bonding interactions, and stability of HSA-diosgenin complex was also validated using molecular simulations. To further elucidate the aggregation inhibition mechanism by diosgenin, advanced molecular dynamics simulations were employed. Diosgenin increased the solvent accessibility of the HSA282-292 oligomers, reduced β-sheet formation, and prevented H-bond interactions, key factors in aggregate formation. Molecular simulation of Aβ oligomers (Aβ16-22) also showed the diosgenin prevents oligomerization and β-sheet formation. We show that diosgenin presents a promising alternative due to its ability to stabilize protein structures and inhibit protein aggregation, making it a potential therapeutic candidate for NDs. However, further experimental validation in animal models is necessary to confirm diosgenin's anti-aggregation effects, particularly of amyloid-forming proteins.}, } @article {pmid41270820, year = {2026}, author = {Mayr, D and Preishuber-Pflügl, J and Koller, A and Migschitz, SM and Michael, J and Altendorfer, B and Rabl, R and Amschl, D and Hitzl, W and Aigner, L and Reitsamer, HA and Trost, A}, title = {The effect of CysLTR1 inhibition on cells of the retinal neurovascular unit in 5xFAD Alzheimer mice.}, journal = {Experimental eye research}, volume = {262}, number = {}, pages = {110763}, doi = {10.1016/j.exer.2025.110763}, pmid = {41270820}, issn = {1096-0007}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; Disease Models, Animal ; Male ; *Retinal Vessels/pathology/drug effects/metabolism ; Female ; *Receptors, Leukotriene/metabolism ; Mice, Transgenic ; *Quinolines/pharmacology ; Cyclopropanes ; Sulfides ; *Acetates/pharmacology ; *Leukotriene Antagonists/pharmacology ; Pericytes/pathology/drug effects ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that affects both the brain and the retina. Many cerebral-associated AD pathologies, including neuroinflammation and vascular changes, have been reported to manifest in the retina. Furthermore, the neurovascular unit (NVU), composed of vascular cells, glia and neurons, regulates blood flow and neuronal metabolic activity and has been described to be dysfunctional in AD brains and retinas. As leukotrienes are modulators of both neuroinflammation and the vasculature, their receptors have been recognized as potential targets for ameliorating AD pathology. Therefore, the present study investigated the effects of the cysteinyl leukotriene receptor 1 (CysLTR1) antagonist montelukast (MTK) on retinal NVU cells in the 5xFAD mouse model of AD. Retinal analyses were performed in male and female 8-month-old 5xFAD mice and after 13-weeks of treatment with low and high doses of MTK or vehicle, and in age-matched controls. The retinal pericyte (PC) coverage was unchanged in AD, but CysLTR1 inhibition resulted in increased PC coverage in AD mice. Furthermore, an AD-associated decrease in capillary diameter was observed, which was not affected by CysLTR1 inhibition. The number of retinal microglial cells was increased in AD, independent of treatment. In addition, the astrocyte area and retinal ganglion cell density were not affected by either AD or CysLTR1 inhibition. In conclusion, the present study revealed minor AD-associated changes in retinal NVU cells in the 5xFAD mouse model. MTK treatment increased dose-independently PC coverage, but it remains to be clarified whether this affects the vessel tightness and blood flow.}, } @article {pmid41270732, year = {2025}, author = {Wang, JL and Sha, XY and Shao, Y and Zhang, ZH and Huang, SM and Lin, H and Gan, SY and Zhang, N and Xia, XY and Sun, YN and Ding, JH and Zhao, RQ and Cheng, J and Shang, P and Wang, JP and Liu, YJ and Yang, F and Xiao, P and Wang, LW and Zhao, DY and Tang, Y and Tie, L and Du, Y and Zhang, Y and He, JF and Sun, JP}, title = {Elucidating pathway-selective biased CCKBR agonism for Alzheimer's disease treatment.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2025.10.034}, pmid = {41270732}, issn = {1097-4172}, abstract = {Expressed in the entorhinal cortex (EC), the cholecystokinin (CCK) B receptor (CCKBR) plays an important role in memory and learning. Here, we identify that CCKBR-Gs and -Gq signaling, rather than CCKBR-Gi signaling, are beneficial for Alzheimer's disease (AD) treatment. Clinically, patients with more severe AD associated with lower CCKBR-Gq activity. The cryo-electron microscopy (cryo-EM) structures of CCKBR in complex with the endogenous agonist sulfated CCK8 (CCK8s) and 3 different G protein subtypes revealed that distinct receptor conformations contribute to selective G protein bias. Leveraging these structural insights, we rationally develop synthetic CCKBR agonists, including a Gi-biased agonist (z-44) and a Gq-biased agonist (3r1). Notably, 3r1 demonstrates therapeutic potential by ameliorating cognitive decline in 5×FAD mice, reducing the number of amyloid-β plaques, and promoting long-term potentiation (LTP) via upregulation of the α-secretase (ADAM10) and the calcium signaling molecule PLCB4. Our findings suggest that synthetic biased agonists targeting CCKBR-Gq signaling have therapeutic potential for AD.}, } @article {pmid41270541, year = {2026}, author = {Zhang, M and Liu, X and Ren, Y and Li, L and Wang, R and Sun, L and Ma, Q}, title = {Decoding alzheimer's: The role of EEG rhythms and aperiodic components in cognitive decline.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {181}, number = {}, pages = {2111437}, doi = {10.1016/j.clinph.2025.2111437}, pmid = {41270541}, issn = {1872-8952}, mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnosis/psychology ; Male ; Female ; *Cognitive Dysfunction/physiopathology/diagnosis ; Aged ; *Electroencephalography/methods ; Aged, 80 and over ; *Theta Rhythm/physiology ; *Alpha Rhythm/physiology ; Middle Aged ; *Brain/physiopathology ; }, abstract = {OBJECTIVE: To investigate detailed alterations in brain electrical activity and their relationship with cognitive decline in Alzheimer's disease (AD) using electroencephalogram (EEG) power spectrum analysis.

METHODS: EEG data from 80 AD patients and 80 healthy control (HC) were analyzed, focusing on theta and alpha band powers, aperiodic offset, and exponent. Topographic and gender-specific analyses were conducted to explore associations with disease progression and cognitive impairment.

RESULTS: AD patients showed increased theta and alpha band powers, with theta band power exhibiting statistically significant differences. Globally elevated theta band power correlated with cognitive impairment severity. Higher aperiodic offsets and exponents were observed in AD patients, exhibiting upward trends with disease progression. Male AD patients displayed more pronounced EEG abnormalities and unique Montreal Cognitive Assessment (MOCA) score patterns.

CONCLUSIONS: Our findings highlight the critical role of theta band power in AD pathology and suggest potential EEG biomarkers for neurodegenerative changes. Gender-specific differences emphasize the importance of personalized approaches in AD diagnosis and treatment.

SIGNIFICANCE: This study provides novel neurophysiological insights into AD, underscoring the clinical utility of EEG markers and the necessity for gender-specific considerations in precision medicine for AD.}, } @article {pmid41269690, year = {2025}, author = {Brickman, AM and Muller, C and Warren, JR and Grodsky, E and Kim, S and Culbertson, MJ and Thyagarajan, B and Manly, JJ}, title = {Alzheimer Disease Blood Biomarker Concentrations Across Race and Ethnicity Groups in Middle-Aged Adults.}, journal = {JAMA network open}, volume = {8}, number = {11}, pages = {e2545046}, pmid = {41269690}, issn = {2574-3805}, mesh = {Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/blood/ethnology ; Amyloid beta-Peptides/blood ; Biomarkers/blood ; Black or African American/statistics & numerical data ; Cohort Studies ; *Ethnicity/statistics & numerical data ; Glial Fibrillary Acidic Protein/blood ; Hispanic or Latino/statistics & numerical data ; Neurofilament Proteins/blood ; tau Proteins/blood ; United States/epidemiology ; White/statistics & numerical data ; }, abstract = {IMPORTANCE: The incidence and prevalence of clinical Alzheimer disease (AD) are higher among Black and Latinx older adults than among White older adults. Past studies that compared plasma AD biomarker concentrations among groups minoritized by their race and ethnicity yielded inconsistent findings; however, these efforts did not include population representative samples or statistical procedures to ensure population representation.

OBJECTIVE: To examine race and ethnicity differences in plasma AD biomarker concentrations and in the association between biomarkers and medical conditions in a US population-representative cohort of middle-aged adults (approximately 58 years of age).

Data for this cohort study came from the High School and Beyond sample, a nationally representative cohort of high school sophomores and seniors who were recruited in 1980. In 2021, a subset of participants provided blood samples that were assayed for amyloid-β (Aβ42/Aβ40 ratio), phosphorylated tau-181 (pTau-181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). The analyses for the present study were conducted between July 2, 2024, and August 26, 2025, using data collected during the 2021 follow-up study.

EXPOSURES: Race and ethnicity groups and common medical conditions.

MAIN OUTCOMES AND MEASURES: General linear models with Wald tests were used to compare biomarker concentrations between race and ethnicity groups and to test interactions with common medical conditions using unadjusted biomarker values and models adjusted to ensure population representation with inverse probability weighting and multiple imputation.

RESULTS: The sample included 4340 adults (mean [SD; range] age, 58.1 [1.1; 56-63] years; 2400 [55.3%] women); 630 (14.4%) were Black, 900 (20.7%) were Latinx, and 2610 (60.1%) were White. Black participants had a lower Aβ42/Aβ40 ratio (d = -0.002; 95% CI, -0.004 to -0.000; P = .04) and lower NfL concentrations (d = -1.16; 95% CI, -2.15 to -0.16; P = .02) than White participants, but these differences were attenuated when models were adjusted for population representation (d = 0.000; 95% CI, -0.002 to 0.002; P = .85 for Aβ ratio; d = -0.88; 95% CI, -1.78 to 0.02; P = .05 for NfL). Latinx participants had lower GFAP concentrations than White participants (d = -3.87; 95% CI, -7.30 to -0.45; P = .03), but these differences were also attenuated when models were adjusted for population representation (d = 3.36; 95% CI, -3.13 to 9.86; P = .31). In general, estimated biomarker means were similar between race and ethnicity groups. History of type 2 diabetes was associated with increased NfL concentration (d = 0.19; 95% CI, 0.07 to 0.30; P = .04), and high body mass index was associated with lower Aβ42/Aβ40 ratio (d = -0.13; 95% CI, -0.21 to -0.06; P = .02); whereas high cholesterol was associated with lower pTau-181 concentration (d = -0.18; 95% CI, -0.25 to -0.10; P = .01) and high BMI was associated with lower GFAP concentration (d = -0.30; 95% CI -0.44 to -0.16; P = .01). No differences in associations between morbidities and AD biomarker concentrations were detected across race and ethnicity groups.

CONCLUSIONS AND RELEVANCE: In this cohort of middle-aged adults, the use of appropriate statistical estimation to ensure population representation indicated that blood-based AD biomarker concentrations were not distinguishable among race and ethnicity groups. Common medical conditions were associated with plasma biomarker concentrations similarly across race and ethnicity groups. These results highlight the importance of considering population representation and comorbid conditions in AD research to ensure accurate characterization of disease pathophysiology and improve precision of diagnostic and treatment strategies for populations that experience AD disparities.}, } @article {pmid41269403, year = {2025}, author = {Jin, J and Hand, R and Meltzer, M and Abate, C and Geva, M and Hayden, MR and Ross, CA}, title = {Sigma-2 Receptor Antagonism Enhances the Neuroprotective Effects of Pridopidine, a Sigma-1 Receptor Agonist, in Huntington's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {121}, pmid = {41269403}, issn = {1559-1182}, mesh = {*Receptors, sigma/antagonists & inhibitors/agonists/metabolism ; *Huntington Disease/drug therapy/pathology/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Sigma-1 Receptor ; *Piperidines/pharmacology/therapeutic use ; Mice ; Humans ; Neurons/drug effects/metabolism/pathology ; Huntingtin Protein/metabolism ; }, abstract = {Pridopidine is a selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Activation of the S1R by pridopidine is neuroprotective in multiple preclinical models of neurodegenerative disease. The sigma-2 receptor (S2R) is evolutionarily and structurally unique from the S1R. Nevertheless, the S1R and S2R share an overlapping yet distinct ligand binding profile. Inhibition of the S2R is neuroprotective and S2R antagonists are in clinical development for Alzheimer's Disease (AD), ⍺-synucleinopathies, and dry age-related macular degeneration. In this study, we hypothesized that simultaneous activation of the S1R by pridopidine and inhibition of the S2R by the selective S2R antagonist FA10 might provide enhanced protection against mutant huntingtin (mHTT) expression in an in vitro model of neurodegeneration. Consistent with previous studies, pridopidine reduced neuronal cell death in a mouse primary neuron mHTT model. Similarly, we found that inhibition of the S2R by FA10 was also sufficient to protect against mHTT induced neurodegeneration in this model. The combination treatment of pridopidine and FA10 achieved greater efficacy than either compound alone, even at lower concentrations. The combination of these compounds may allow for lower efficacious doses leading to improved safety profiles and reduced off-target effects. This novel combinatorial approach, in which the S1R is activated while simultaneously inhibiting the S2R may prove to be a highly effective therapeutic strategy for HD and other neurodegenerative diseases.}, } @article {pmid41268794, year = {2025}, author = {Zhang, H and Ya, J and Liao, X and Du, X and Zhao, C and Ren, J and Qu, X}, title = {In Situ Activatable Hydrogen-Bonded Organic Framework-Based Nanozyme as NADH Peroxidase Mimic Restoring Homeostasis for Treatment of Alzheimer's Disease.}, journal = {Small (Weinheim an der Bergstrasse, Germany)}, volume = {}, number = {}, pages = {e09547}, doi = {10.1002/smll.202509547}, pmid = {41268794}, issn = {1613-6829}, support = {2022YFA1205804//National Key R&D Program of China/ ; T249526//National Natural Science Foundation of China/ ; 22437006//National Natural Science Foundation of China/ ; 22237006//National Natural Science Foundation of China/ ; }, abstract = {Nicotinamide adenine dinucleotide (NAD) serves as a vital regulator in metabolic networks, and the decrease in the level of its oxidized form, NAD+, is closely related to Alzheimer's disease (AD). However, unsatisfactory efficacy, non-targeted and imprecise treatment, along with interconnected pathogenic factors in AD, constrain the therapeutic efficacy of current AD therapeutic strategies. Herein, in lieu of complex multi-module treatments for pathogenesis, a bespoke in situ activatable hydrogen-bonded organic framework (HOF)-based nanozyme (denoted as NADH@Pre-Cu-HOF@KD8) has been constructed to modulate multiple interconnected homeostatic imbalances in AD. Benefiting from the specific organic monomers, 2,2'-bipyridine-5,5'-dicarboxylic acid, NADH@Pre-Cu-HOF@KD8 can sequester neurotoxic Cu[2+] from amyloid-β (Aβ)-Cu[2+] by competitive binding. The segregation of Cu[2+] from Aβ mitigated the generation of reactive oxygen species, Aβ toxicity, and alleviated the activation of microglia cells. Moreover, HOF-based nanozyme possessed NADH peroxidase (NPX)-like catalytic activity after binding Cu[2+], which can reduce oxidative stress and elevate compromised NAD+ levels, thereby restoring mitochondrial impairment and adenosine triphosphate (ATP) production. Spatiotemporally precise intervention is enabled through targeted delivery mediated by peptide modification and lesion-specific activation. Notably, cognitive deficits, neuropathology, and homeostatic markers in a 3xTg-AD mouse model are ameliorated upon treatment. By employing a facile HOF platform to modulate multiple interconnected pathological homeostatic imbalances in AD-copper toxicity, NAD[+] depletion, oxidative stress, and Aβ toxicity-this strategy offers a paradigm for ameliorating AD-associated homeostatic imbalances.}, } @article {pmid41268790, year = {2025}, author = {Coburn, MA and Eskandari-Sedighi, G and Hasselmann, J and England, W and Shabestari, SK and Mansour, K and McQuade, A and Mgerian, MA and Chadarevian, JP and Tu, C and Silva, J and Beck, J and Keulen, Z and Spitale, RC and Davtyan, H and Blurton-Jones, M}, title = {Human microglia differentially respond to β-amyloid, tau, and combined Alzheimer's disease pathologies in vivo.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70930}, pmid = {41268790}, issn = {1552-5279}, support = {//Cure Alzheimer's Fund/ ; Discovery23-10//Alzheimer Society of Canada/ ; //The Larry L. Hillblom Foundation : 2024-A-023-FEL and 2025-A-175-FEL/ ; A2025007F//BrightFocus Postdoctoral Fellowship Program in Alzheimer's/ ; P30CA-062203//NIH / ; 1S10RR025496-01//NIH / ; 1S10OD010794-01//NIH / ; 1S10OD021718-01//NIH / ; 2024-A-023-FEL//NIH / ; NS082174//NIH Training Grant/ ; AG000096//NIH Training Grant/ ; //Susan Scott Foundation/ ; ADSF-21-829655-C/ALZ/Alzheimer's Association/United States ; }, mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/pathology/metabolism ; Animals ; Humans ; Mice ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *tau Proteins/metabolism ; Plaque, Amyloid/pathology/metabolism ; Mice, Transgenic ; Neurofibrillary Tangles/pathology/metabolism ; }, abstract = {INTRODUCTION: Recent studies have identified important species-dependent differences in the response of microglia to β-amyloid (Aβ) pathology. Yet, whether human microglia also interact differently with the pathognomonic combination of amyloid and tau pathologies that occur in Alzheimer's disease (AD) remains unclear.

METHODS: We generated a xenotolerant mouse model of AD that develops both plaque and tangle pathologies, transplanted stem cell-derived microglial progenitors and examined the interactions between human microglia and AD pathologies with scRNA sequencing, immunohistochemistry, and in vitro modeling.

RESULTS: The combined amyloid and tau pathologies induced robust type-I interferon and proinflammatory cytokine responses, as well as an increased adoption of a distinct "rod" morphology in human microglia. The rod morphology could be induced with type-I interferon treatment in vitro.

DISCUSSION: We provide new insights into human microglial responses to combined AD pathologies and a novel platform to investigate and manipulate human microglia in vivo.

HIGHLIGHTS: Amyloid pathology promotes the rapid development of neurofibrillary tangles and neuronal loss in a novel chimeric model of AD. Combined Alzheimer's disease pathologies lead to an expansion of disease-associated microglia (DAM) and exacerbate Interferon-responsive and cytokine/chemokine-enriched states in xenotransplanted human microglia. The combination of amyloid and tau promotes the development of a distinctive rod microglial phenotype that closely correlates with tau pathology and neurodegeneration. Rod morphology and transcriptional changes can be modeled in vitro by treatment of induced pluripotent stem cells (iPSC) -microglia with type-I interferons.}, } @article {pmid41268620, year = {2026}, author = {Sun, L and Wang, J and Zhang, L}, title = {The Role of Sphingomyelin Synthase 2 in Lipid Metabolism and Its Implications in Diseases.}, journal = {Cell biology international}, volume = {50}, number = {1}, pages = {e70103}, doi = {10.1002/cbin.70103}, pmid = {41268620}, issn = {1095-8355}, support = {//This study was supported by National Natural Science Foundation of China (82272306), Taishan Scholars Program (tstp20221142), and Joint Innovation Team for Clinical & Basic Research [202409]./ ; }, mesh = {Humans ; *Transferases (Other Substituted Phosphate Groups)/metabolism ; *Lipid Metabolism/physiology ; Animals ; Signal Transduction ; Neoplasms/metabolism ; Sphingomyelins/metabolism ; *Nerve Tissue Proteins/metabolism ; Inflammation/metabolism ; }, abstract = {Sphingomyelin synthase 2 (SMS2) is a crucial enzyme predominantly localized to the plasma membrane, playing an essential role in sphingomyelin metabolism and signaling. SMS2 catalyzes the final step in the biosynthesis of sphingomyelin by transferring phosphocholine from phosphatidylcholine to ceramide, resulting in the production of sphingomyelin and diacylglycerol. This enzymatic activity dynamically regulates the intracellular levels of ceramide, diacylglycerol, and phosphatidylcholine, thereby influencing several critical cellular processes. SMS2 is integral to multiple signaling pathways, including TGF-β/Smad, NF-κB, and CXCL12/CXCR4, which are involved in cancer progression and platelet activation. SMS2 displays versatile enzymatic activities, including phospholipase C activity and ceramide phosphoethanolamine synthesis. Dysregulation of SMS2 is associated with various pathological conditions, such as skin barrier dysfunction, skeletal disorders, inflammatory diseases, and different types of cancer. Targeting SMS2 through inhibition or modulation demonstrates therapeutic potential in treating multiple conditions, including pancreatic cancer, Alzheimer's disease, and atherosclerosis, by impacting tumor growth dynamics and cellular migration. Given its multifaceted role in diverse pathological processes and its promise as a therapeutic target, further research on SMS2 is essential for the development of innovative treatment strategies aimed at cancer therapy, inflammation regulation, and overcoming drug resistance.}, } @article {pmid41268264, year = {2025}, author = {Chen, J and Zhao, J and Fan, Y and Jin, Y and Mi, R and Wang, H and Yu, S and Feng, X and Zhang, Y and Ren, G}, title = {Predictive value of beta amyloid, phosphorylated Tau, neurofilament light chain, and glial fibrillary acidic protein for depression in Alzheimer's disease.}, journal = {American journal of translational research}, volume = {17}, number = {10}, pages = {7789-7802}, pmid = {41268264}, issn = {1943-8141}, abstract = {OBJECTIVES: To investigate differences in biochemical markers and their association with depressive symptoms in patients with Alzheimer's disease (AD) with and without concurrent depression.

METHODS: In this retrospective case-control study, 329 AD patients admitted to Beijing Panjiayuan TCM-Western Integrated Hospital between May 2019 and May 2022 were included. Patients were categorized into a comorbid depression group (n=167) and a non-depression group (n=162) based on Cornell Scale for Depression in Dementia (CSDD) scores. Biochemical markers, including β-amyloid proteins (Aβ1-42, Aβ1-40), phosphorylated Tau proteins (p-Tau181, p-Tau217), neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP), and inflammatory cytokines, were measured and statistically analyzed.

RESULTS: High-density lipoprotein cholesterol (HDL-C) was significantly lower in the comorbid depression group (P<0.001). Levels of Aβ1-42 (P=0.012), Aβ1-40 (P=0.006), p-Tau181 (P=0.003), p-Tau217 (P=0.003), NfL (P<0.001), and GFAP (P=0.008) were significantly elevated in the depression group compared to the non-depression group. Additionally, interleukin-10 (P=0.004) and interleukin-6 (P=0.047) levels were higher, while interleukin-1β (P<0.001) was lower in the comorbid depression group. Receiver operating characteristic curve identified HDL-C (area under the curve [AUC]=0.602), p-Tau217 (AUC=0.595), NfL (AUC=0.692), GFAP (AUC=0.580), and IL-1β (AUC=0.600) as significant predictors of depression severity.

CONCLUSIONS: Specific biochemical markers, including HDL-C, Aβ42/40, p-Tau217, NfL, GFAP, and IL-1β, are independently associated with depression in AD patients. A combined biomarker model may improve prediction of comorbid depression in AD and provide guidance for personalized treatment.}, } @article {pmid41268048, year = {2025}, author = {Moczygemba, W and Bradley, D and Carmona, R and Celano, V and Farley, L and Valverde, S and Sampley, A and Stratton, L}, title = {Perspectives on meaningful dementia treatment and care from those with lived experience.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {4}, pages = {e70175}, doi = {10.1002/trc2.70175}, pmid = {41268048}, issn = {2352-8737}, abstract = {UNLABELLED: The ongoing conversations surrounding the importance of minimal clinically important differences and descriptions of meaningful impacts must include the voices of those living with Alzheimer's disease and related dementias. To provide this perspective, members of the Alzheimer's Association Early Stage Advisory Group were asked to describe what matters most to them, their experiences with treatment, how they define meaningful care, and what would provide them with feelings of progress and hope. Responses offer differing yet complementary definitions of a quality life, ways in which clinicians and providers can recognize and support the person behind the diagnosis, and how participating in clinical trials can bring hope - both now and for the future. By centering on the lived experiences and perspectives of those people living with dementia, this article provides insight for those seeking to develop novel treatments and provide care and support, both now and in the future.

HIGHLIGHTS: Maintaining independence, purposeful living, and social connection are among what matter most to those living with dementia.Meaningful treatment and care are person-centered and responsive to the needs and wants of the person living with dementia.Participating in clinical trials can have meaningful physical, cognitive, and psychosocial impacts for those living with dementia.}, } @article {pmid41267904, year = {2025}, author = {Zhao, F and Li, Y and Yi, C and Li, X and Huang, G and Chen, X and Li, Y and Zhang, J}, title = {Global, regional, and national burdens of early-onset Alzheimer's disease and other dementias in women, 1990 to 2021.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251395223}, pmid = {41267904}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease and other dementias disproportionally impacts women. Novel treatment makes understanding of early-onset cases unprecedentedly important.

OBJECTIVE: We aimed to examine Alzheimer's disease and other dementias incidence, DALYs, trends, and risk factors among women aged under 65 years from 1990 to 2021.

METHODS: Using Global Burden of Diseases Study, we estimated the trend of Alzheimer's diseases and other dementias age-standardized incidence and disability-adjusted life-years (DALYs) among women aged under 65 years by social development index (SDI) worldwide during 1990 to 2021.

RESULTS: Globally, in 2021 there were 4.3 million prevalent cases among middle-aged women, with the incident cases doubled from 0.4 million to 0.8 million during 1990-2021. The largest increases in incidence and DALYs were found in high-middle SDI countries (0.27%/year) and low-middle SDI countries (0.19%/year), respectively. The incidence rate doubled once with every five years of age increase. The two contributors, which were high body mass index and high fasting plasma glucose, rapidly grew from 1990 to 2021.

CONCLUSIONS: The substantial increase of early-onset Alzheimer's disease and other dementias among middle-aged women requires attention, especially targeted at the increasing reversible lifestyle risk factors.}, } @article {pmid41267515, year = {2025}, author = {Ünal, D and Sarıköse Özgüven, A}, title = {Exosomes: New biomarker and therapeutic candidates in autism spectrum disorder research.}, journal = {Acta neuropsychiatrica}, volume = {38}, number = {}, pages = {e6}, doi = {10.1017/neu.2025.10047}, pmid = {41267515}, issn = {1601-5215}, mesh = {*Exosomes/metabolism ; Humans ; *Autism Spectrum Disorder/metabolism/diagnosis/therapy ; Biomarkers/metabolism ; Animals ; Mice ; Disease Models, Animal ; Cytokines/metabolism ; DNA, Mitochondrial ; }, abstract = {BACKGROUND: There is no recognised cure or specific biomarker for autism spectrum disorder (ASD). Exosomes are small vesicles that carry proteins, lipids and nucleic acids. They have been investigated for diseases such as Parkinson’s and Alzheimer’s. As the conclusions were on the biological utility of exosomes as a non-invasive brain biopsy, some animal, human and in vitro exosome studies have also been presented in the ASD field. The purpose of this review is to compile the studies that have established a relationship between ASD and exosomes so far and discuss their potential for linking the gap between the laboratory and clinic.

METHODS: In this systematic review, 31 PubMed articles were identified using the keywords ‘exosomal’, ‘exosome and ‘autism spectrum disorder’. After excluding 16 reviews, 4 irrelevant studies and 1 preprint, and adding 5 relevant articles, 15 research articles were included based on PRISMA criteria. The articles were investigated and reviewed by both authors. Their methodology and results are also discussed according to two main streams in studies.

RESULTS: Numerous studies have identified potential biomarkers, including mitochondrial DNA (mtDNA7S), cytokines including IL-1β, TNF-α and IL-6, and different types of RNAs by comparing the exosomal contents of ASD patients or models with controls. In studies that focused on treatment, behavioural improvements were shown in ASD model mice.

CONCLUSION: Since there are presently no reliable biomarkers or effective treatments for ASD, exosome-based research offers a promising avenue for early diagnosis and the creation of tailored therapies.}, } @article {pmid41265552, year = {2026}, author = {Sardari, M and Hosseinzadeh Sahafi, O and Rezayof, A}, title = {Mitochondria serve as indispensable components of neuron-glia crosstalk in the trajectory of Alzheimer's disease.}, journal = {Brain research}, volume = {1870}, number = {}, pages = {150040}, doi = {10.1016/j.brainres.2025.150040}, pmid = {41265552}, issn = {1872-6240}, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Mitochondria/metabolism/pathology ; *Neurons/metabolism/pathology ; *Neuroglia/metabolism/pathology ; Animals ; }, abstract = {Alzheimer's disease (AD) is a multiplex and progressive neurodegenerative disorder commonly recognized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and dysfunction in the cholinergic and glutamatergic systems. At the early stages of AD, mitochondrion operates as a neuroprotective organelle in both neuronal and glial cells by compensating energy fluctuations. As the disease progresses, mitochondrial function in both neurons and glial cells deteriorates, culminating in impaired cellular metabolism and glial hyperactivation. This time-dependent hyperactivation of microglia and astrocytes sequentially promotes the release of pro-inflammatory cytokines, elevates reactive oxygen species, disrupts calcium homeostasis, and increases oxidative stress. Altogether, these processes drive neuroinflammation, which both influences and is influenced by mitochondrial activity. Additionally, mitochondrial dysfunction across the disease trajectory hampers communication between neurons and glial cells, promoting excitotoxicity in neurons. This review emphasizes the vital role of mitochondrial dynamics in AD pathophysiology across different stages and explores how cell-specific targeting of mitochondrial activity could mitigate neuroinflammation, restore neuronal function, and offer potential treatment benefits. Enhancing mitochondrial function in healthy neurons and glial cells, particularly in microglia as a compensatory mechanism, especially at the early stage of the disease or restoring mitochondrial function of surviving neurons at the later stages, may promote neuroprotection and improve neuron-glia interactions, thus offering a potential strategy for AD treatment.}, } @article {pmid41265341, year = {2026}, author = {Yuan, X and Gao, L and Peng, Y and She, T and Wang, J}, title = {A deep representation learning algorithm on drug-target interaction to screen novel drug candidates for Alzheimer's disease.}, journal = {Artificial intelligence in medicine}, volume = {171}, number = {}, pages = {103301}, doi = {10.1016/j.artmed.2025.103301}, pmid = {41265341}, issn = {1873-2860}, mesh = {*Alzheimer Disease/drug therapy/genetics ; Humans ; Molecular Docking Simulation ; *Algorithms ; *Deep Learning ; *Drug Discovery/methods ; }, abstract = {Alzheimer's disease (AD) is a serious neurodegenerative brain disorder with complex pathophysiology. While currently available drugs can provide symptomatic benefits, they often fail to cure the disease. Thus, there is an urgent need to explore new therapeutic agents. In this study, we developed DTIP (Drug-Target Interaction Prediction), a machine learning-based approach to search novel drugs for AD by utilizing the information of drug-target interaction (DTI). By training a Skip-gram model on drug-target sequences derived from known DTI information, the algorithm learned the drug-target relationship embeddings and to predict potential drug candidates for diseases like AD. For AD, we compiled 917 risk genes and identified 292 potential drugs via the new algorithm. We further performed molecular docking by AutoDock Vina and conducted Inverted Gene Set Enrichment Analysis (IGSEA) on these drug candidates. Our results identified that several drugs could be promising for AD treatment, including human C1-esterase inhibitor, quetiapine, dasatinib, miconazole, aniracetam, chlorpromazine, hypericin, entrectinib, torcetrapib, bosutinib, sunitinib, aniracetam, rosiglitazone, tarenflurbil, milrinone, and MITO-4509. Results from this study also provided insights for understanding the molecular mechanisms underlying AD. As a systematic and versatile method, our approach can also be applied to identify efficacious therapies for other complex diseases.}, } @article {pmid41265212, year = {2025}, author = {Patel, Y and Sharma, P and Kumar, A and Parmar, HS and Inwati, GK}, title = {Design, Ssynthesis, and biological evaluation of β-secretase inhibitors: An integrated study of molecular docking, dynamics, pharmacokinetics, quantum chemistry, and in-vitro analysis for Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {167}, number = {}, pages = {109267}, doi = {10.1016/j.bioorg.2025.109267}, pmid = {41265212}, issn = {1090-2120}, mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Molecular Docking Simulation ; Humans ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; *Drug Design ; Structure-Activity Relationship ; Molecular Structure ; *Enzyme Inhibitors/chemical synthesis/pharmacology/chemistry/pharmacokinetics ; Dose-Response Relationship, Drug ; Molecular Dynamics Simulation ; *Protease Inhibitors/chemical synthesis/chemistry/pharmacology/pharmacokinetics ; Quantum Theory ; }, abstract = {Present paper elicits the synthesis of a series of 2,2-dimethyl-2H-[1,3]dioxino[4,5-b]pyrrol-4(7H)-one derivatives as novel selective BACE1 inhibitors for the treatment of Alzheimer's disease (AD). A four-component, solvent-free condensation process, catalyzed by 10 mol% NiCl2·6H2O strategy was explored to achieve their synthesis. The structures of the synthesized compounds were ascertained using different spectroscopic techniques, including FT-IR, [1]H NMR, [13]C NMR, mass spectrometry, and elemental analysis. In silico molecular docking and molecular dynamics simulations suggest that these compounds exhibit strong potential as β-secretase (BACE1) inhibitors, demonstrating high interaction and binding energies compared to reference inhibitors AZD3293 and E2602. Notably, compounds 5p displayed significant inhibitory interactions, effectively suppressing the catalytic dyad (Asp A:228 and Asp A:32) of BACE1. To further validate the computational findings, in vitro BACE1 enzymatic inhibition assays were performed on the most interactive molecule 5p. Additionally, ADMET descriptors and density functional theory (DFT) calculations were employed to assess the pharmacokinetics, chemical stability, and binding affinity of the synthesized compounds. The findings from this study pave the way for future in vivo investigations to assess the reversal of Alzheimer's disease phenotypes, along with comprehensive safety and toxicity evaluations.}, } @article {pmid41264165, year = {2025}, author = {Gao, H and Cheng, F and Zhang, Z and Yan, B and Liao, P and Zhang, S and Li, D and Chen, F and Lei, P}, title = {Breaking the Alzheimer's Treatment Stalemate: Synergistic Application Strategies of Nanomaterials and Pharmaceutical Agents.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {107}, pmid = {41264165}, issn = {1559-1182}, support = {grant no. 82271401//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/drug therapy/diagnosis ; Humans ; *Nanostructures/therapeutic use ; Animals ; Drug Delivery Systems/methods ; Nanomedicine/methods ; }, abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid beta accumulation and tau pathology propagation. Nanomedicine, a discipline enabling targeted drug delivery with precision, holds significant promise in the treatment of neurodegenerative diseases. This review explores the diagnostic and therapeutic applications of nanomaterials in neurodegenerative diseases, particularly AD, emphasizing their properties and their role in modulating pathogenic proteins. Advances in the development of novel anti-AD nanomedicines and their clinical progress are also highlighted. Despite the growing potential of nanotechnology in AD therapy, a definitive cure remains elusive. The review further addresses the current challenges in the field of AD nanomedicines and outlines future research directions to propel their development.}, } @article {pmid41262573, year = {2025}, author = {Demsey, LL and Burch, D and Lin, E and Quach, D and Podvin, S and Boyarko, B and Levey, AI and Weinshenker, D and Edland, S and Galasko, D and Jacobs, H and Bang, A and Neil, A and Silverman, J and Feldman, HH and Hook, V}, title = {Atomoxetine Drug Properties for Repurposing as a Candidate Alzheimer's Disease Therapeutic Agent.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {11}, pages = {3757-3772}, pmid = {41262573}, issn = {2575-9108}, abstract = {Ongoing Alzheimer's disease (AD) drug development research addresses the need for therapeutic agents that can ameliorate cognitive symptoms and attenuate the course of AD synaptic deficits and neurodegeneration. There is growing interest in evaluating FDA-approved drugs for repurposing as candidate AD therapeutics. Such drugs have the advantage that data are available about their pharmaceutical properties, including doses, pharmacokinetics, pharmacodynamics, biomarkers, metabolism, and safety, to inform the design of clinical drug trials. Importantly, the suitability of such drugs with properties needed for AD requires evaluation. In the early stage of AD, degeneration of the locus coeruleus (LC) brain region results in the reduction of noradrenergic neurons and the loss of the neurotransmitter norepinephrine (NE) that regulates cognition and degeneration. Elevation of extracellular NE through inhibition of the NE transporter (NET) is hypothesized to ameliorate AD deficits. Notably, the NET reuptake inhibitor atomoxetine, an FDA-approved drug for the treatment of attention deficit hyperactivity disorder (ADHD), provides an attractive candidate as an AD therapeutic agent because it may attenuate cognitive decline in AD patients, positively impact AD biomarkers, and reduce neuropathology. The goal of this review is to assess atomoxetine for repurposing in AD based on its ability to improve cognition, regulate NE, impact AD biomarkers, and preserve LC neuronal function, with suitable pharmacokinetics, drug metabolism, and safety based on analysis of clinical and preclinical studies. Evidence for neuroprotective effects of atomoxetine in the early stage of AD at clinically safe doses with suitable pharmaceutical properties supports its candidacy as a repurposed drug for AD therapeutics.}, } @article {pmid41262391, year = {2025}, author = {Latella, D and Calderone, A and Casella, C and De Luca, R and Gangemi, A and Impellizzeri, F and Caliri, S and Quartarone, A and Calabrò, RS}, title = {Cognitive behavioral therapy for insomnia in neurodegenerative disorders-targeting sleep disturbances in Alzheimer's and Parkinson's disease: a scoping review.}, journal = {Frontiers in psychology}, volume = {16}, number = {}, pages = {1700496}, pmid = {41262391}, issn = {1664-1078}, abstract = {INTRODUCTION: Insomnia is highly prevalent in neurodegenerative disorders, yet pharmacological options carry safety and tolerability concerns. This scoping review mapped contemporary evidence for cognitive behavioral therapy for insomnia (CBT-I) across Alzheimer's disease (AD), mild cognitive impairment (MCI), and Parkinson's disease (PD).

METHODS: Following a preregistered protocol (OSF DOI: 10.17605/OSF.IO/8VP3F), we searched PubMed, Cochrane Library, Web of Science, and Scopus for studies published 2015-2025. We screened English-language studies in adults and applied dual independent review with consensus resolution. Of 105 records, 70 were screened after de-duplication, and 8 met eligibility criteria.

RESULTS: Across randomized trials, pilot and feasibility studies, and single-case experimental designs, CBT-I-delivered in person or via telehealth-consistently reduced insomnia severity and improved sleep quality, with frequent ancillary gains in mood, anxiety, and daytime functioning. Remote and digitally augmented delivery appeared feasible and acceptable for cognitively vulnerable adults and caregivers. Early signals suggested potential cognitive benefits in prodromal populations (AD/MCI), and exploratory observations linked improved sleep with plausible neurobiological mechanisms such as amyloid-beta dynamics. In PD, findings aligned with a mechanistic pathway in which presleep cognitive arousal, safety behaviors, and dysfunctional sleep beliefs are modifiable targets. Non-pharmacological comparators (e.g., mindfulness, therapeutic exercise, neuromodulation) also showed benefits, helping contextualize where CBT-I may offer disorder-relevant leverage on insomnia outcomes.

DISCUSSION: The overall strength of evidence is tempered by small samples, heterogeneity in comparators and dosing, short follow-up, and inconsistent reporting of clinically meaningful change. Priorities include multicenter randomized trials with standardized sleep and cognitive endpoints, longer observation, head-to-head comparative effectiveness with economic evaluation, adaptive protocols tailored to PD-specific disruptors, and mechanistic studies integrating digital phenotyping and biomarkers to test durability and downstream clinical impact.}, } @article {pmid41262225, year = {2025}, author = {Bayram, E}, title = {Sex and gender differences in Lewy body dementia: a narrative review.}, journal = {Equity neuroscience}, volume = {1}, number = {2}, pages = {}, pmid = {41262225}, issn = {3050-8401}, support = {R00 AG073453/AG/NIA NIH HHS/United States ; }, abstract = {Lewy body dementia (LBD), including Parkinson's disease dementia and dementia with Lewy bodies, is one of the most prevalent and burdensome type of dementias. Clinical diagnostic accuracy during life remains limited and there are currently only symptomatic therapy options without disease modification. However, recent advances in biomarkers and clinical trials are promising. Literature so far showed sex and gender differences in older adults without cognitive changes, people with all-cause dementia, Alzheimer's disease, and Parkinson's disease. While the number of studies in LBD are lower, understanding sex and gender differences and the underlying reasons can improve both diagnosis and treatment for LBD. Accordingly, the aim of this narrative review is to provide a summary of the literature for sex and gender differences in LBD. Majority of the studies for LBD investigating sex/gender differences so far focused on sex, with sex and gender terms being misused at times. Experiences of people in non-binary categories for sex or gender have yet to be investigated. While more research is needed, findings so far outline sex differences in prevalence, risk factors, biomarkers, symptoms, progression, treatment, daily life, and pathology for LBD. Sex-specific risk factors have also been reported, emphasizing the value of sex-stratified analyses and investigating female/male-specific factors such as sex hormones, menopause, and sex chromosomes. Lack of adequate research representation for females and women, as well as people from non-binary categories, is an important limitation that should be addressed to obtain more applicable findings in LBD.}, } @article {pmid41261421, year = {2025}, author = {Etani, H and Takatori, S and Wang, W and Omi, J and Amiya, Y and Akahori, A and Watanabe, H and Sonn, I and Okano, H and Hara, N and Hasegawa, M and Miyashita, A and Kikuchi, M and Ikeuchi, T and Morishima, M and Saito, Y and Murayama, S and Saito, T and Saido, TC and Takai, T and Ohwada, T and Aoki, J and Tomita, T}, title = {Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {248}, pmid = {41261421}, issn = {1758-9193}, mesh = {*Microglia/metabolism/drug effects ; Animals ; *Amyloid beta-Peptides/metabolism ; Humans ; Mice ; *Receptors, G-Protein-Coupled/agonists/metabolism ; Alzheimer Disease/metabolism/pathology ; Phagocytosis/drug effects ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; Cells, Cultured ; }, abstract = {BACKGROUND: Microglia play a crucial role in brain homeostasis through phagocytosis of amyloid-β (Aβ) fibrils, a hallmark of Alzheimer disease (AD) pathology. The balance between Aβ production and clearance is critical for AD pathogenesis, with impaired clearance mechanisms potentially contributing to disease progression. G-protein coupled receptor 34 (GPR34), a microglia-enriched Gi/o-coupled receptor, is highly expressed in homeostatic microglia and may regulate phagocytic functions, yet its role in Aβ clearance remains poorly understood.

METHODS: Using flow cytometry-based assays, we investigated the effect of a selective GPR34 agonist (M1) on Aβ uptake in mouse primary microglia and human induced pluripotent stem cell-derived microglia. We evaluated uptake specificity across different Aβ species and phagocytic substrates, and measured intracellular cyclic adenosine monophosphate (cAMP) levels to determine the signaling mechanism. We performed in vivo studies using human amyloid precursor protein knock-in mice with intrahippocampal M1 injections. Additionally, we analyzed GPR34 expression in Japanese AD patient brain samples using single-nucleus RNA sequencing and examined age-dependent expression changes across multiple datasets.

RESULTS: M1 specifically enhanced uptake of Aβ fibrils through reduction of intracellular cAMP levels, without affecting monomeric or oligomeric Aβ internalization. Gpr34 knockdown experiments confirmed GPR34 as the molecular target of M1. An intrahippocampal injection of M1 significantly increased microglial Aβ uptake in vivo, an effect that required functional TREM2 signaling. GPR34 expression was significantly reduced in microglia from AD patients and showed age-dependent decline in both humans and mice.

CONCLUSIONS: Our findings identify GPR34 as a promising therapeutic target for enhancing microglial Aβ clearance and highlight the potential of GPR34 agonists for AD treatment. The age-dependent decline in GPR34 expression may contribute to reduced Aβ clearance efficiency in aging brains, exacerbating amyloid accumulation. Pharmacological activation of GPR34 represents a novel strategy to counteract impaired Aβ clearance in both aging and AD brains, potentially modifying disease progression through enhancement of microglial phagocytic function.}, } @article {pmid41261317, year = {2025}, author = {Zhou, R and Tian, G and Yu, J and Wang, R and Peng, N and Guo, X and Li, R}, title = {Echinacoside Improves Memory Function and Bone Mineral Density in the Aged SAMP8 Mouse Model.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {102}, pmid = {41261317}, issn = {1559-1182}, mesh = {Animals ; Male ; Mice ; *Bone Density/drug effects ; *Aging/drug effects/pathology ; Disease Models, Animal ; *Memory/drug effects ; *Glycosides/pharmacology/therapeutic use ; Osteoporosis/drug therapy ; }, abstract = {Alzheimer's disease (AD) and osteoporosis (OP) are prevalent age-related degenerative diseases that often coexist. Echinacoside (ECH) has been extensively studied for its potential to mitigate AD and bone mineral density (BMD) loss. This study aimed to evaluate the simultaneous therapeutic effects of ECH on AD-OP comorbidity using the senescence-accelerated mouse-prone 8 (SAMP8) model, which exhibits both age-related memory deficits and bone metabolism abnormalities. Six-month-old male SAMP8 mice (n = 8-9) were used as the model group, while age-matched senescence-accelerated mouse resistant 1 (SAMR1) mice served as normal controls. SAMP8 mice were administered ECH intragastrically (100 mg/kg/day) for 10 weeks, while control groups received saline. Behavioral tests, including the open field test (OFT), novel object recognition test (NORT), and Morris Water Maze (MWM), assessed locomotor ability, emotionality, and cognitive functions. Bone microstructure was evaluated using micro-computed tomography (micro-CT), and pathological changes in the brain were analyzed via Western blotting and immunofluorescence. As compared to SAMR1 mice, SAMP8 mice exhibited significant locomotor activity issues, impaired memory (P < 0.05), glial activation (P < 0.01), reduced trabecular bone number (P = 0.007), and altered trabecular separation (P = 0.040). ECH treatment improved memory function and inhibited glial activation (P < 0.05). Bone-related parameters showed that ECH intervention had a trend of improvement in bone health, but this did not reach statistical significance. The SAMP8 model exhibits key features of both AD and OP, making it a valuable tool for investigating their comorbidity and underlying mechanisms. ECH improves cognitive functions and alleviates bone loss, indicating its potential as a therapeutic candidate for AD-OP comorbidity.}, } @article {pmid41261299, year = {2025}, author = {Zhang, R and Wu, K and Yang, Q and Kong, M and Guo, L and You, Q}, title = {Hyperprolactinemia and Brain Health: Exploring the Gut-Brain Axis and Therapeutic Strategies.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {101}, pmid = {41261299}, issn = {1559-1182}, mesh = {Humans ; *Hyperprolactinemia/therapy/metabolism ; *Brain/pathology/metabolism ; Animals ; *Gastrointestinal Tract ; Gastrointestinal Microbiome/physiology ; Prolactin/metabolism ; *Brain-Gut Axis/physiology ; }, abstract = {Prolactin is a pituitary anterior lobe hormone that plays a crucial role in milk secretion from the mammary glands. Hyperprolactinemia is a common endocrine disorder characterized by abnormally elevated levels of prolactin in the serum. Recent research findings indicate that prolactin also exerts important physiological effects beyond lactation, including effects on brain health and the central nervous system. The gut-brain axis has become an important area of neuroscience research, providing insights into the complex interactions between the gastrointestinal system and the central nervous system. Future research may involve developing new probiotic therapies or optimizing the gut microbiota through dietary and lifestyle interventions. In addition, understanding the mechanisms by which hyperprolactinemia contributes to various neurological disorders and targeting prolactin for treatment are crucial areas of research. Therefore, this study aimed to investigate the correlation between hyperprolactinemia and brain health from the perspective of the gut-brain axis, with the goal of discovering new approaches for preventing and treating neurodegenerative and mental health conditions. This synthesis highlights potential strategies for future therapeutic interventions.}, } @article {pmid41261295, year = {2025}, author = {Kritika, and Sood, R and Sanjay, and Lee, HJ}, title = {Nobiletin Reduces LPS-Induced Neuroinflammation through TLR4/MyD88/NF-κB and Oxidative Stress via Nrf2/HO-1 Signaling in Human Microglial HMC3 Cells.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {103}, pmid = {41261295}, issn = {1559-1182}, support = {GCU-202401020001//Gachon University research fund of 2023 (GCU-202401020001)/ ; (project No. RS-2022-RD010230)//Cooperative Research Program for Agriculture Science and Technology Development (project No. RS-2022-RD010230), Rural Development Administration, Republic of Korea./ ; }, mesh = {Humans ; *Oxidative Stress/drug effects ; *Myeloid Differentiation Factor 88/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Toll-Like Receptor 4/metabolism ; *Signal Transduction/drug effects ; Lipopolysaccharides ; *NF-kappa B/metabolism ; *Microglia/drug effects/metabolism/pathology ; *Heme Oxygenase-1/metabolism ; *Flavonols/pharmacology ; *Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced/pathology ; *Flavones/pharmacology ; Cell Line ; Inflammation/metabolism/drug therapy ; Reactive Oxygen Species/metabolism ; }, abstract = {Neuroinflammation and oxidative stress (OS) are the major contributors to the onset and progression of neurodegenerative diseases (NDs), where microglial activation and dysregulated inflammatory signaling exacerbate neuronal injury. Nobiletin (NOB), a polymethoxylated flavonoid abundant in citrus fruits, has been reported to possess excellent bioactivities; however, its effects in combating inflammation and OS in human microglial cells (HMC3) have not been comprehensively examined. In this study, we investigated the effects of NOB on lipopolysaccharide (LPS)-induced inflammatory and oxidative responses in HMC3 cells. The HMC3 cells exposed to LPS (1 µg/mL) in the presence/absence of NOB (5, 10, 20, and 40 µM) for 24 h showed that NOB could attenuate LPS-induced cytotoxicity. NOB treatment attenuated LPS-induced upregulation of pro-inflammatory cytokines including interleukin (IL)-1β, and IL-6, and suppressed activation of the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa-light-chain-enhancer of activated B (TLR4/MyD88/NF-κB) pathway. NOB enhanced the protein expression levels of TLR10, a negative regulator of TLR4-mediated inflammatory signaling. In addition, NOB increased the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression, along with other antioxidants including catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), leading to reduced intracellular reactive oxygen species (ROS). These findings suggest that NOB has promising anti-inflammatory and antioxidant effects in an in vitro model of LPS-induced neuroinflammation, potentially through modulation of TLR4/MyD88/NF-κB and Nrf2/HO-1 signaling pathways. However, further in vivo studies are needed to validate these effects and explore NOB's potential as a candidate for therapeutic development in NDs.}, } @article {pmid41261258, year = {2025}, author = {Rahmani, D and Chodari, L and Kakallahpour, M and Niknam, Z}, title = {Therapeutic Potential of Sodium Butyrate in Neurological and Psychiatric Disorders.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {90}, pmid = {41261258}, issn = {1559-1182}, mesh = {Humans ; *Mental Disorders/drug therapy ; Animals ; *Butyric Acid/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Histone Deacetylase Inhibitors/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are characterized by progressive neuronal loss associated with neuroinflammation, oxidative stress, and epigenetic dysregulation. Emerging evidence suggests that histone deacetylases (HDACs) are overexpressed in these conditions, making HDAC inhibitors (HDACIs) like sodium butyrate (NaB) promising candidates for therapeutic intervention. In addition, NaB has shown beneficial effects in various psychiatric disorders, including depression, anxiety, and schizophrenia, suggesting a broader neurotherapeutic potential. This review synthesizes findings from various in vitro and in vivo studies investigating the mechanisms and therapeutic applications of NaB, in both neurological and psychiatric disorders. We focus on its role as an HDACI, its impact on histone acetylation and gene expression, its ability to modulate gut microbiota, and its capacity to cross the blood-brain barrier (BBB) to exert neuroprotective effects. NaB demonstrates anti-inflammatory, antioxidant, anti-apoptotic, and neurotrophic properties, contributing to improved cognitive, motor, and behavioral outcomes in multiple models of central nervous system (CNS) dysfunction. Accumulating evidence supports its efficacy not only in NDDs but also in mental health disorders, highlighting its potential as a complementary treatment alongside conventional therapies. Given its multifaceted mechanisms and favorable safety profile, NaB holds promise as a novel therapeutic agent across a spectrum of neurological and psychiatric conditions. Further clinical investigation is warranted to fully establish its translational value.}, } @article {pmid41261002, year = {2026}, author = {Canney, M and Bouchoux, G and Carpentier, A and De Rossi, P}, title = {Repeated blood-brain barrier opening using low-intensity pulsed ultrasound mitigates amyloid pathology.}, journal = {Ultrasound in medicine & biology}, volume = {52}, number = {2}, pages = {418-430}, doi = {10.1016/j.ultrasmedbio.2025.10.008}, pmid = {41261002}, issn = {1879-291X}, mesh = {Animals ; *Blood-Brain Barrier/metabolism ; Mice ; *Ultrasonic Waves ; Disease Models, Animal ; *Alzheimer Disease/pathology/therapy/metabolism ; Microbubbles ; *Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; Brain ; Ultrasonic Therapy/methods ; }, abstract = {OBJECTIVE: The delivery of large molecules to the pathological brain is one of the main obstacles in the development of disease-modifying drugs. This is partly due to the presence of the blood-brain barrier (BBB), which blocks the free passage of lipophobic molecules and those larger than 400 Da. One strategy to bypass this natural barrier is to use low-intensity pulsed ultrasound to oscillate circulating micro-sized microbubbles, which then exert mechanical stress on the vessel walls. This procedure allows for temporary disruption of the BBB and enhanced local delivery of therapeutics from the blood to the brain parenchyma. In this study, the effect of repeated BBB opening on neuroinflammation in a healthy mouse model was first explored, followed by the effect of repeated opening on amyloid-beta (Aβ) pathology in an Alzheimer's disease model.

METHODS: A cohort of wild-type mice was used to determine the effect of a single BBB opening session mediated by ultrasound/microbubbles (US/MBs) on the inflammatory profile via real-time quantitative polymerase chain reaction on brain extracts at 2, 4, 8 and 15 d post-opening. A second cohort of ARTE10 mice, a mouse model for Aβ pathology, was treated with a different sequence of repeated US/MB-mediated BBB opening to explore the effect on Aβ pathology. Tissues were also analyzed for immune cell infiltration, microglia and astrocyte activation, as well as inflammatory response.

RESULTS: Our results demonstrate that opening the BBB leads to a mild inflammatory response in wild-type animals. However, repeated opening of the BBB in the ARTE10 model resulted in a mild decrease in Aβ pathology, along with a mild increase in growth factor.

CONCLUSION: Altogether, this study suggests that sonication is not only a safe method to deliver therapeutics to the brain but could also have synergistic effects in the treatment of neurodegenerative disease.}, } @article {pmid41260559, year = {2025}, author = {Peng, D and Wu, L and Zhang, L and Chen, H and Hu, B and Zhang, Q and Huang, Y}, title = {haFGF14-154 attenuates Aβ1-42-induced neurotoxicity by facilitating BDNF maturation in a neuron-astrocyte co-culture system.}, journal = {Molecular and cellular neurosciences}, volume = {135}, number = {}, pages = {104056}, doi = {10.1016/j.mcn.2025.104056}, pmid = {41260559}, issn = {1095-9327}, mesh = {*Alzheimer Disease/drug therapy ; *Neurons/cytology ; *Astrocytes/cytology ; Coculture Techniques ; Signal Transduction ; Brain-Derived Neurotrophic Factor/genetics/metabolism ; *Fibroblast Growth Factors/pharmacology ; Peptides/pharmacology ; *Neuroprotective Agents/pharmacology ; Male ; Animals ; Mice ; Cells, Cultured ; Amyloid beta-Peptides/metabolism ; Up-Regulation/drug effects ; Apoptosis/drug effects ; }, abstract = {haFGF14-154 improves cognitive impairment in animal models of Alzheimer's disease (AD), but the effects and mechanisms of astrocytes on the neuroprotection mediated by haFGF14-154 remain unclear. Here, a neuron-astrocyte co-culture system was established to investigate the functions of astrocytes. The results showed that astrocytes strengthened the protective effect of haFGF14-154 on Aβ1-42-treated neurons. This enhanced protective function of haFGF14-154 correlates with phenotypic transition in astrocytes, as demonstrated by the suppression of Aβ1-42-induced A1-like genes and the elevation of A2-like markers in vitro. These observations are consistent with the reduction of GFAP and C3 levels in the hippocampus and prefrontal cortex of APP/PS1 mice treated with haFGF14-154. haFGF14-154 modified the function of astrocytes by activating the AKT/CREB/BDNF pathway, thereby promoting neurite growth. Moreover, haFGF14-154 up-regulated the expression of Furin and MMP9 in astrocytes, leading to the processing of pro-BDNF. This effect was replicated in APP/PS1 mice administered with haFGF14-154. Compared to the Aβ group, the BDNF level in the co-culture system supernatant was increased, while the IL-1β level was decreased following haFGF14-154 treatment. Additionally, haFGF14-154 inhibited neuronal apoptosis in the co-culture system, as evidenced by a decrease in pro-BDNF/P75[NTR], an increase in Bcl-2, and a reduction of Bad and Cleaved-caspase-3. In conclusion, current results demonstrate that astrocytes are crucial for mediating the protective effect of haFGF14-154 against neuronal damage, and underline the importance of the AKT/CREB/BDNF pathway in promoting neurite growth and attenuating neuronal apoptosis.}, } @article {pmid41260522, year = {2025}, author = {Park, JK and Kim, HG and Lee, JS and Joo, JH and Yoo, HR}, title = {Traditional herbal medicine Ga-Mi Gongjindan improves muscarinic cholinergic dysfunction through regulation of BDNF/CREB signaling pathway using a scopolamine-induced cognitive impairment of mouse model.}, journal = {Brain research bulletin}, volume = {233}, number = {}, pages = {111644}, doi = {10.1016/j.brainresbull.2025.111644}, pmid = {41260522}, issn = {1873-2747}, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism/drug effects ; Scopolamine/pharmacology ; *Cognitive Dysfunction/drug therapy/chemically induced/metabolism ; Mice ; Signal Transduction/drug effects ; Mice, Inbred C57BL ; Male ; Cyclic AMP Response Element-Binding Protein/metabolism ; Hippocampus/metabolism/drug effects ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Maze Learning/drug effects ; Oxidative Stress/drug effects ; Medicine, Korean Traditional ; }, abstract = {BACKGROUND: Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by progressive memory loss and cognitive dysfunction, often linked to cholinergic system deterioration and hippocampal oxidative stress. Current pharmacological treatments offer only modest symptomatic relief and are often accompanied by adverse effects. In traditional Korean medicine, Ga-Mi Gongjindan (GJD), a modified formulation of Gongjindan, has long been used for enhancing cognitive function, but its neuropharmacological basis remains largely unexplored.

OBJECTIVE: This study aimed to investigate the neuroprotective potential and underlying mechanisms of GJD in a murine model of scopolamine-induced cognitive impairment, which mimics aspects of muscarinic cholinergic dysfunction observed in Alzheimer's disease (AD).

METHODS: C57BL/6 J mice were administered GJD or tacrine (positive control) for 14 days. Cognitive impairment was induced by a single intraperitoneal injection of scopolamine (2 mg/kg), and behavioral analysis was assessed using the Morris Water Maze. Hippocampal tissues were analyzed for markers of oxidative stress, inflammation, cholinergic function, and neurotrophic signaling by focusing on the BDNF/CREB signaling pathway.

RESULTS: GJD treatment significantly improved spatial learning and memory performance. It restored cholinergic function by reducing acetylcholinesterase (AChE) activity and increasing choline acetyltransferase (ChAT) levels. GJD also suppressed oxidative stress and neuroinflammation and markedly enhanced hippocampal expression of brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and their receptors (TrkA, TrkB, and M1 mAChR).

CONCLUSION: GJD exerted significant neuroprotective effects in a scopolamine-induced model of cognitive dysfunction, potentially via modulation of cholinergic and BDNF/CREB signaling pathways. These findings provide a scientific rationale for the traditional use of GJD in cognitive disorders and support its further development as a candidate for treating neurodegenerative diseases such as AD.}, } @article {pmid41260370, year = {2026}, author = {Xiao, K and Sayed, H and Xing, J and Zhang, XY and Ai, J and Kirichek, E and Le, GH and Wong, S and Valentino, K and Teopiz, KM and Vinberg, M and Rosenblat, JD and Lo, HKY and Zhang, MC and McIntyre, RS}, title = {The effects of Lithium on Beta-amyloid deposition and tau phosphorylation: A systematic review.}, journal = {Journal of affective disorders}, volume = {395}, number = {Pt A}, pages = {120721}, doi = {10.1016/j.jad.2025.120721}, pmid = {41260370}, issn = {1573-2517}, mesh = {Humans ; Phosphorylation/drug effects ; *tau Proteins/metabolism/drug effects ; Animals ; *Amyloid beta-Peptides/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Disease Models, Animal ; *Lithium/pharmacology ; *Lithium Compounds/pharmacology ; Neuroprotective Agents/pharmacology ; }, abstract = {BACKGROUND: Lithium demonstrates neuroprotective and neurotrophic effects, and preclinical studies indicate lithium reduces intracerebral amyloid deposition and tau phosphorylation. This systematic review evaluates lithium's effects on beta-amyloid, tau, and cognitive deficits in major neurocognitive disorders.

METHODS: A systematic review of primary research was conducted using Embase, PsycInfo, MEDLINE, and PubMed databases from inception to September 2024, following PRISMA criteria. Animal and adult human studies evaluating lithium monotherapy's effects on Alzheimer's Disease (AD) were included.

RESULTS: Long-term low-dose lithium treatment demonstrates inconsistent effects on lowering intracerebral amyloid deposition and reversing AD-related cognitive deficits in preclinical and clinical trials. Lithium was reported to slows amyloid plaque formation in pre-plaque stages through increasing heat shock proteins and suppressing protein synthesis in preclinical trials. Intracerebral lithium reduced phosphorylated tau through promoting tau ubiquitination and inhibiting CDK5 signalling in preclinical trials.

LIMITATIONS: A comprehensive animal model that accurately represents human AD symptoms and progression, as well as more clinical trials are needed. Several included studies utilize peripheral lithium administration, which complicates assessment of effective intracerebral concentrations.

CONCLUSIONS: Lithium potentially reduces intracerebral amyloid deposition and tau phosphorylation in AD animal models and may reverse associated cognitive deficits. Further research should seek to replicate similar findings in larger samples and explore lithium's optimal dosage range in promoting intracerebral amyloid clearance.}, } @article {pmid41260286, year = {2026}, author = {Altındağ, F and Bayır, MH and Alhalboosi, JKI and Yıldızhan, K}, title = {Syringic acid mitigates scopolamine-induced cognitive impairment by regulating PSD-95 and GSK-3β and by preventing neurodegeneration in an Alzheimer-like rat model.}, journal = {Experimental neurology}, volume = {396}, number = {}, pages = {115556}, doi = {10.1016/j.expneurol.2025.115556}, pmid = {41260286}, issn = {1090-2430}, mesh = {Animals ; *Disks Large Homolog 4 Protein/metabolism/biosynthesis ; *Glycogen Synthase Kinase 3 beta/metabolism/biosynthesis ; Rats ; Male ; *Cognitive Dysfunction/chemically induced/metabolism/drug therapy/prevention & control ; *Alzheimer Disease/metabolism/chemically induced/pathology/drug therapy/prevention & control ; *Gallic Acid/analogs & derivatives/pharmacology/therapeutic use ; Scopolamine/toxicity ; Disease Models, Animal ; Hippocampus/drug effects/pathology/metabolism ; *Nerve Degeneration/prevention & control/metabolism ; Rats, Sprague-Dawley ; Neuroprotective Agents/pharmacology ; Rats, Wistar ; }, abstract = {Alzheimer's disease (AD) is a disorder characterized by progressive cognitive impairment. Syringic acid (SA) is a phenolic compound with many beneficial effects, such as antioxidant, anti-inflammatory, anti-diabetic, anti-carcinogenic, and neuroprotective. Our study aimed to investigate the effects of SA (50 mg/kg/day) on scopolamine (SCO)-induced AD-like condition in rats. Immunohistochemical evaluation was performed using antibodies to postsynaptic density protein 95 (PSD-95), Glycogen synthase kinase-3β (GSK-3β), TNF-α, and caspase-3. The hippocampus was stained with Hematoxylin-Eosin, and the total number of hippocampal neurons and hippocampal volume were calculated using the stereological method. The Y-maze task behavioral test was performed. SCO decreased PSD-95 expression while increasing GSK-3β, TNF-α, and caspase-3 expression. SA treatment increased PSD-95 expression while decreasing GSK-3β, TNF-α, and caspase-3 expression. Compared to the control group, the number of hippocampal neurons was significantly decreased in the Alzheimer's group, but the number of neurons in the SA group was significantly higher than in the Alzheimer's group. Hippocampal volume was lower in the Alzheimer's group, although there was no statistical difference between the groups. SA also improved SCO-induced cognitive impairment. Our study findings suggest that SA may mitigate SCO-induced cognitive impairment in the AD rat model, modulating PSD-95 and GSK-3β and decreasing neuroinflammation and apoptosis.}, } @article {pmid41260167, year = {2026}, author = {Wang, X and Li, W and Liu, X and Liang, J and Wang, L and Liu, G and Liu, Y and Song, M and Li, Z and Guo, Y and Li, S and Fu, N and Zhang, B}, title = {Celastrol as a neuroprotective drug: current status and challenges.}, journal = {International immunopharmacology}, volume = {168}, number = {Pt 2}, pages = {115846}, doi = {10.1016/j.intimp.2025.115846}, pmid = {41260167}, issn = {1878-1705}, mesh = {*Pentacyclic Triterpenes/therapeutic use/pharmacology ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; Humans ; Disease Models, Animal ; Autophagy/drug effects ; Tripterygium ; *Neurodegenerative Diseases/drug therapy ; *Triterpenes/therapeutic use/pharmacology ; Mice ; }, abstract = {Neurological disorders are increasing worldwide, imposing a major social and economic burden. Therefore, there is an urgent need to explore effective treatment methods to alleviate neurological disorders. Celastrol, derived from the traditional Chinese medicine Tripterygium wilfordii Hook. f., has been shown in multiple studies to exhibit promising neuroprotective effects in neurodegenerative, including Parkinson's disease, Alzheimer's disease, and spinal cord injury. The targets or pathways through which celastrol exerts its neuroprotective effects are diverse. This paper primarily focuses on in vivo animal models (such as Parkinson's disease mouse models, Alzheimer's disease mouse models) and in vitro cell models (such as neuronal cell lines, primary cultured neurons) experiments to comprehensively summarize the molecular mechanisms underlying celastrol's neuroprotective effects. Celastrol exerts its neuroprotective effects through pathways such as reducing inflammation, activating the autophagy-lysosome pathway, and inhibiting ferroptosis. Additionally, we discuss the current challenges faced by celastrol and potential strategies to address them. Collectively, these findings highlight celastrol as a promising therapeutic candidate, although further pharmacokinetic optimization and clinical validation are essential.}, } @article {pmid41259985, year = {2026}, author = {Lin, C and Li, Q and Liu, G and Xi, Z and Yan, X and Li, S and He, L and Bai, P}, title = {Fe3O4@MoS2@Au-Ag microsphere-based ultrasensitive immunobiosensor for the early diagnosis of Alzheimer's disease.}, journal = {Talanta}, volume = {299}, number = {}, pages = {129127}, doi = {10.1016/j.talanta.2025.129127}, pmid = {41259985}, issn = {1873-3573}, mesh = {*Alzheimer Disease/diagnosis/blood ; *Gold/chemistry ; Humans ; *Amyloid beta-Peptides/blood/immunology ; *Biosensing Techniques/methods ; *Molybdenum/chemistry ; *Silver/chemistry ; *Microspheres ; *Disulfides/chemistry ; Early Diagnosis ; *Peptide Fragments/blood ; Limit of Detection ; Metal Nanoparticles/chemistry ; *Ferrosoferric Oxide/chemistry ; Immunoassay/methods ; }, abstract = {Alzheimer's Disease (AD), a most common neurodegenerative disease, has aroused people's great attention. Amyloid-β 1-42 (Aβ42) from serum/plasma has been listed as Core 1 biomarker in diagnostic guide and explore an ultrasensitive detection method of Aβ42 is of great significance for early AD diagnosis and treatment. Herein, an ultrasensitive fluorescent biosensor for Aβ42 detection is designed, which is composed of Fe3O4@MoS2 microsphere and Au-Ag alloy. Compared with typical single gold nanoparticles in traditional fluorescent biosensor, alloy nanoparticles can generate a stronger electromagnetic field to enhance the fluorescence of quantum dots via surface plasmon resonance, achieve the effect of signal amplification. Importantly, our design significantly improved the limit of detection to 11 ag/mL, with a linear response ranging from 0.1 to 10[4] fg/mL. Moreover, by replacing the detection antibody in the biosensor, it can also be applied to other common AD biomarkers, such as Aβ40 (linear range: 0.1 to 10[5] fg/mL, LOD: 61 ag/mL) and total Tau protein (linear range: 0.1 to 10[5] fg/mL, LOD: 40 ag/mL). The biosensor exhibited excellent performance in both spiked and real serum samples. This fluorescent biosensor based on Au-Ag alloy strategy with ultra-sensitivity and good selectivity, provides a reliable solution for AD's early diagnosis.}, } @article {pmid41258757, year = {2025}, author = {Saini, TC and Randhawa, S and Bathla, M and Nisha, A and Teji, N and Acharya, A}, title = {Nanoengineered Polyphenol-Quantum Dot Conjugates Inhibit Biofilm Protein-Aβ42 Heterotypic Fibrillogenesis, Restore Synaptic Transmission, and Suppress Apoptosis in Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {23}, pages = {4458-4478}, doi = {10.1021/acschemneuro.5c00467}, pmid = {41258757}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism ; *Biofilms/drug effects ; *Alzheimer Disease/metabolism/drug therapy ; *Apoptosis/drug effects/physiology ; Humans ; *Polyphenols/pharmacology/chemistry ; *Peptide Fragments/metabolism ; Animals ; *Quantum Dots/chemistry ; Escherichia coli ; Caenorhabditis elegans ; Cell Line, Tumor ; Bacterial Proteins/metabolism ; }, abstract = {The gut microbiota influences neurodegenerative disease progression, including Alzheimer's disease (AD), through microbial metabolites like amyloids in bacterial biofilms, such as the curli protein in Eshcherichia coli biofilm. In this context, the study focuses on two key aspects, namely, (i) how cross-kingdom bacterial biofilm proteins accelerate Aβ42 aggregation and induce neurotoxicity and (ii) whether a nanochaperone with hydrophobic sheets and hydrophilic polyphenolic moieties could inhibit cross-seeded aggregation. Considering this, we chemically synthesized and further characterized gallic acid-conjugated molybdenum disulfide quantum dots (GA@MoS2 QDs, ∼9.6 ± 4.2 nm) using spectroscopy and microscopy techniques, which showed ∼1.84-fold reduction in E. coli biofilm thickness, indicating interaction with biofilm components. The presence of the curli protein in E. coli was confirmed by dot blot and MALDI-TOF studies. Subsequent biophysical studies showed that isolated E. coli biofilm protein accelerated Aβ42 aggregation (heterotypic) by ∼6.76-fold, while GA@MoS2 QDs reduced this heterotypic aggregation by ∼9.49-fold reduction in Aβ42+ECBFP fluorescence relative to Aβ42 aggregates. In vitro studies with SH-SY5Y cells showed that heterotypic protein aggregation led to increased ROS production, intracellular calcium influx, and apoptosis induction, which were mitigated by GA@MoS2 QDs. The neuroprotective effect of GA@MoS2 QDs was also studied on Caenorhabditis elegans. Overall, the present studies suggested that the bacterial amyloid proteins may play a crucial role in Aβ42 aggregation, suggesting that targeting coaggregation could provide a novel therapeutic approach for the treatment of early onset AD.}, } @article {pmid41258645, year = {2025}, author = {Katsuse, K and Kakinuma, K and Niimi, Y and Iseki, C and Kawakami, N and Ota, S and Kawamura, A and Ogawa, N and Yano, S and Kakumoto, T and Takao, H and Hamada, M and Kanno, S and Toda, T and Suzuki, K}, title = {Lecanemab for posterior cortical atrophy: Two contrasting cases.}, journal = {The Clinical neuropsychologist}, volume = {}, number = {}, pages = {1-23}, doi = {10.1080/13854046.2025.2590527}, pmid = {41258645}, issn = {1744-4144}, abstract = {OBJECTIVE: This study aimed to evaluate the clinical implications, limitations, and potential risks of lecanemab treatment for posterior cortical atrophy (PCA) by conducting a comparative analysis of two cases.

METHOD: We retrospectively analyzed two patients with biomarker-confirmed PCA-pure who met the eligibility criteria for lecanemab. Clinical history, neuropsychological profiles, imaging findings, and treatment outcomes for more than 1 year were comprehensively reviewed.

RESULTS: At treatment initiation, Patients 1 and 2 were one year post-onset and five years post-onset, respectively, with comparable baseline Mini-Mental State Examination (25-26) and Clinical Dementia Rating (0.5) scores. Patient 1, who exhibited prominent agraphia with left-dominant parieto-occipital atrophy, began lecanemab early and maintained stable daily functioning despite a gradual decline in reading, figure copying, and visual cancelation tasks. Patient 2, with right-dominant posterior atrophy and more severe visuospatial deficits, including simultanagnosia and prosopagnosia, developed parkinsonism and hallucinations after treatment initiation, followed by rapid functional decline, possibly due to mixed pathology, ultimately leading to treatment discontinuation. Patient 1 reported high treatment satisfaction, whereas Patient 2 expressed regret.

CONCLUSION: These cases raise concerns regarding the direct application of treatment eligibility criteria developed for typical Alzheimer's disease to PCA. Clinical decision-making in PCA requires visual cognition-specific assessments that are less vulnerable to floor effects and tailored to phenotypic heterogeneity and hemispheric lateralization. Coexisting pathologies may influence the treatment response and complicate the interpretation of outcomes. A tailored, multimodal approach that integrates longitudinal neuropsychological assessments with advanced imaging is essential to ensure appropriate use of disease-modifying therapies for PCA.}, } @article {pmid41258002, year = {2025}, author = {Yang, C and Wang, P and Zhu, Z and Wu, H and Su, Q and Zhu, S and Shao, Y and Lin, H and Biswal, BB}, title = {Individualized functional connectome biomarkers predict clinical symptoms after rTMS treatment in Alzheimer's disease.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {511}, pmid = {41258002}, issn = {2158-3188}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology/diagnostic imaging ; *Connectome/methods ; *Transcranial Magnetic Stimulation ; Male ; Female ; Aged ; Magnetic Resonance Imaging ; Biomarkers ; *Brain/physiopathology ; *Nerve Net/physiopathology/diagnostic imaging ; Middle Aged ; *Cerebral Cortex/physiopathology/diagnostic imaging ; }, abstract = {Pharmacological treatments for Alzheimer's disease (AD) often show limited effectiveness, prompting growing interest in non-drug approaches such as repetitive transcranial magnetic stimulation (rTMS). However, the effects of rTMS can vary widely between individuals with AD, highlighting the need to better understand brain characteristics that may influence treatment response. In this study, we applied a personalized method to divide each participant's brain cortex into functionally meaningful regions based on their brain activity patterns, rather than relying on a standard brain template. Using this individualized brain mapping approach, we examined how rTMS changes functional connectivity (FC) across the brain. We further used support vector regression to estimate whether these individualized FC patterns could predict the severity of clinical symptoms. The results showed that rTMS significantly increased whole-brain individualized FC strength during resting state, with the most prominent effects observed in the default mode and visual networks (Cohen's d > 0.27, corrected p < 0.05). Importantly, the personalized FC features served as predictive biomarkers, demonstrating greater accuracy in forecasting clinical outcomes compared to the conventional group-based approach. These findings suggest that individualized brain connectivity holds significant potential for guiding personalized therapeutic strategies and improving treatment efficacy in AD.}, } @article {pmid41257439, year = {2025}, author = {Vázquez-Oliver, A and Pérez-García, S and Romero-Pérez, R and Pizarro, N and Galarraga-Shinin, D and Molina-Porcel, L and de la Torre, R and Maldonado, R and Ozaita, A}, title = {Targeting dysregulated CB1 receptors in a Down syndrome mouse model improves neurological outcomes.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70874}, pmid = {41257439}, issn = {1552-5279}, support = {RTI2018-099282-B-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PID2021-123482OB-I00-/MICIN/AEI/10.13039/501100011033/FEDER//Ministerio de Ciencia, Innovación y Universidades/ ; PID2020- 120029GB-I00/MICIN/AEI/10.13039/501100011033//Ministerio de Ciencia, Innovación y Universidades/ ; 1896_GRT-2019B//Fondation Jérôme Lejeune/ ; #2416_GRT-2024B//Fondation Jérôme Lejeune/ ; CA2018010//Bright Focus foundation/ ; RD16/0017/0020//Ministerio de Sanidad, Servicios Sociales e Igualdad/ ; 2017SGR-669//Departament de Recerca i Universitats, Generalitat de Catalunya/ ; 2017SGR-138//Departament d'Economia i Coneixement, Generalitat de Catalunya/ ; //Institució Catalana de Recerca i Estudis Avançats, ICREA-Acadèmia 2021/ ; }, mesh = {Animals ; *Down Syndrome/metabolism/drug therapy ; *Receptor, Cannabinoid, CB1/metabolism/antagonists & inhibitors ; Mice ; Disease Models, Animal ; *Hippocampus/metabolism/drug effects ; *Rimonabant/pharmacology ; Humans ; Male ; Female ; Alzheimer Disease/metabolism ; *Cannabinoid Receptor Antagonists/pharmacology ; Mice, Transgenic ; Middle Aged ; }, abstract = {INTRODUCTION: Down syndrome (DS) is the most common genetic cause of intellectual disability, affecting cognitive function and increasing the risk of early-onset Alzheimer's disease (AD). The endocannabinoid system may serve as a therapeutic target for cognitive deficits by inhibiting cannabinoid type-1 receptor (CB1R) function.

METHODS: CB1R expression was analyzed in the hippocampi of aged DS-associated AD (DSAD) individuals and middle-aged Ts65Dn mice. Long-term oral treatment with the CB1R antagonist rimonabant was used to assess its effects on memory and neuroinflammation in the Ts65Dn mouse model of DS.

RESULTS: CB1R expression was significantly increased in both aged DSAD subjects (specifically in the dentate gyrus and CA2 posterior hippocampal subregions) and Ts65Dn mice. Long-term rimonabant treatment improved memory performance, normalized microglial morphology, and reduced plasma inflammatory markers in trisomic mice without preventing neuron decline.

DISCUSSION: These findings suggest that sustained CB1R inhibition may enhance cognitive function by modulating neuroinflammation, highlighting its therapeutic potential for cognitive impairments in DS.

HIGHLIGHTS: Cannabinoid type-1 receptor (CB1R) expression is increased in the posterior hippocampus of aged Down syndrome (DS) subjects and Ts65Dn mice. Long-term rimonabant treatment enhances memory in middle-aged Ts65Dn mice. CB1R inhibition shifts neuroinflammatory features in Ts65Dn mice. CB1R inhibition does not halt noradrenergic/cholinergic neurodegeneration in Ts65Dn. CB1R inhibition presents potential for memory improvement in DS-related deficits.}, } @article {pmid41257084, year = {2025}, author = {Elshahary, A and Safwan, H and Abdelwaly, A and Arafa, RK and Helal, MA}, title = {Discovery of indole- and quinolone-based inhibitors of the mTOR/Akt/Pi3K pathway for the potential treatment of autism and certain types of cancer.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {41257084}, issn = {2632-8682}, abstract = {Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the PI3K-related protein kinase family. It is an integral part of two functionally distinct protein complexes: mTOR complex 1 and mTOR complex 2. Its signaling pathway is linked to cell survival, growth, proliferation, and motility. Deregulation of the mTOR pathway has been reported in many types of cancer. Hence, mTOR is an attractive target for the treatment of certain cancers such as renal cell carcinoma and pancreatic tumors. In addition, hyperactivity in mTOR-mediated signaling is associated with the pathogenesis of autism spectrum disorder (ASD) and Alzheimer's disease. Recently, mTOR inhibitors have been considered as emerging pharmacotherapy for these disorders. In this research, we have used molecular modeling techniques to design three series of compounds, indoles, β-carbolines, and 4-aminoquinolines, targeting the ATP site of the mTOR kinase. Based on insights from molecular docking, we developed twenty eight derivatives of these scaffolds to explore the SAR and optimize their affinities. The prepared compounds were evaluated for their inhibitory activity against mTOR as well as other closely related kinases such as PI3K and AKt. To our delight, twenty compounds have shown sub-micromolar activities towards the mTOR kinase. Compounds HA-2l and HA-2c showed a superior IC50 of 66 and 75 nM, respectively, for mTOR, while being selective against AKt and Pi3K. Upon optimization, these selective inhibitors could be useful for the management of ASD due to their relatively higher safety and, hence, suitability for long-term use. On the other hand, derivatives HA-1e, HA-2g, and HA-3d exhibited high affinities for the three enzymes, suggesting their potential utility as anticancer agents. Also, the cytotoxicity of the most active compounds was assessed using different cell-lines. Compounds HA-2g, HA-2l, and HA-3d showed sub-micromolar inhibition, in the range of 0.610-0.780 μM, against the tested cancer cell lines MDA-MB231 and HCT-116. The discovery of a clinically useful mTOR inhibitor would represent a new hope for patients of two important non-communicable diseases, cancer and ASD.}, } @article {pmid41257022, year = {2025}, author = {Abdel-Magid, AF}, title = {Inhibitors of Stearoyl-Coenzyme A Desaturase 1 and 5 May Provide a Novel Therapeutic Strategy for the Treatment of Neurological Disorders and Brain Cancer.}, journal = {ACS medicinal chemistry letters}, volume = {16}, number = {11}, pages = {2191-2193}, pmid = {41257022}, issn = {1948-5875}, abstract = {The invention in this patent application relates to heterocyclic compounds represented herein generally by formula 1. These compounds are inhibitors of stearoyl-coenzyme A desaturases (SCD1 and/or SCD5) and may provide a useful treatment for neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) as well as primary brain cancer such as glioblastoma (GBM).}, } @article {pmid41257016, year = {2025}, author = {Song, Z and Liang, SH}, title = {Novel 2H‑Pyrazolo[3,4‑d]thiazole Compounds Targeting NLRP3 for the Treatment of Neurodegenerative Diseases.}, journal = {ACS medicinal chemistry letters}, volume = {16}, number = {11}, pages = {2200-2201}, pmid = {41257016}, issn = {1948-5875}, abstract = {The invention discloses novel NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inhibitors featuring a 2H-pyrazolo-[3,4-d]-thiazole scaffold. These NLRP3 inhibitors exhibit significant potential as therapeutic candidates for neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.}, } @article {pmid41256885, year = {2025}, author = {Cottrell, S and Yoon, S and Wei, X and Dickson, A and Wei, GW}, title = {Computational Drug Repurposing for Alzheimer's Disease via Sheaf Theoretic Population-Scale Analysis of snRNA-seq Data.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {41256885}, issn = {2331-8422}, support = {R01 AI164266/AI/NIAID NIH HHS/United States ; }, abstract = {Single-cell and single-nucleus RNA sequencing (scRNA-seq /snRNA-seq) are widely used to reveal heterogeneity in cells, showing a growing potential for precision and personalized medicine. Nonetheless, sustainable drug discovery must be based on a population-level understanding of molecular mechanisms, which calls for the population-scale analysis of scRNA-seq/snRNA-seq data. This work introduces a sequential target-drug selection model for drug repurposing against Alzheimer's Disease (AD) targets inferred from population-level snRNA-seq studies of AD progression in microglia cells as well as different cell types taken from an AD affected brain vascular tissue atlas, involving hundreds of thousands of nuclei from multi-patient and multi-regional studies. We utilize Persistent Sheaf Laplacians (PSL) to facilitate a Protein-Protein Interaction (PPI) analysis of AD targets inferred from differential gene expression (DEG), and then use a machine learning models to predict repurpose-able DrugBank compounds for molecular targeting. We screen the efficacy of different DrugBank small compounds and further examine their central nervous system (CNS)-relevant ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity), resulting in a list of lead candidates for AD treatment. The list of significant genes establishes a target domain for effective machine learning based AD drug repurposing analysis of DrugBank small compounds to treat AD related molecular targets.}, } @article {pmid41256774, year = {2025}, author = {Yu, J and Bao, X and Shan, C and Yu, Z and Yu, Y and Wang, H and Zhang, Y}, title = {Traditional Chinese medicine's holistic approach: regulating microglia-driven neuroinflammation for the resolution of Alzheimer's disease.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1691253}, pmid = {41256774}, issn = {1662-5102}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive dysfunction, motor abnormalities, and memory disorders, with a persistently high and rising incidence. The pathological features of AD include the extracellular deposition of the amyloid beta peptide (Aβ), the accumulation of neurofibrillary tangles (NFTs), and neuroinflammation. Microglia (MG), the main immune cells in the central nervous system (CNS), can transform into different phenotypes. An imbalance in their phenotypic transformation may induce neuroinflammation and lead to neurological diseases, playing a central role in the onset and progression of AD.

PURPOSE: This article aims to briefly review the key role of microglia-mediated neuroinflammation in the pathogenesis of AD and to summarize and analyze the strategies of traditional Chinese medicine (TCM) for targeting microglia in AD treatment.

METHODS: Literature review and analysis were conducted to summarize the role of microglia-mediated neuroinflammation in AD pathogenesis and to collate TCM therapeutic strategies aimed at modulating microglia.

RESULTS AND CONCLUSION: Microglia-mediated neuroinflammation plays a central role in the pathological progression of AD. TCM demonstrates potential in intervening in AD neuroinflammation by regulating the microglial phenotype and function. These related therapeutic strategies warrant further summary and analysis.}, } @article {pmid41256155, year = {2025}, author = {Su, CW and Chen, K and Wu, T and Reiman, EM and Wang, Q and , }, title = {TAS2R38-Linked MGAM Expression in Alzheimer's Disease: A Novel Target for Precision Drug Repurposing.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41256155}, support = {U01 AG046152/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; U01 AG049505/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; U01 AG049507/AG/NIA NIH HHS/United States ; U01 AG052411/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; U01 AG046170/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; U24 AG061340/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; UF1 AG047133/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R01 AG033193/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; U01 AG049508/AG/NIA NIH HHS/United States ; U01 AG052410/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; U01 AG052409/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; U01 AG049506/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P50 AG025711/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG036836/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVE: TAS2R38 is a taste receptor implicated in innate immunity. Identifying its genetic connection with Alzheimer's disease (AD) could aid in developing new drugs or repurposing existing ones for treatment.

METHODS: We examined the relationship between TAS2R38 taster variants and AD risk using linear mixed-effects models, utilizing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 2,342). We investigated molecular mechanisms of the association by identifying expression quantitative trait loci (eQTLs) using RNA-seq data from postmortem tissues from the Religious Orders Study/Memory and Aging Project (ROSMAP) (n = 947). We evaluated whether FDA-approved drugs targeting the identified gene could reduce dementia risk using 1:1 propensity score-matched groups in the National Alzheimer's Coordinating Center (NACC) study, comparing cognitive performance between drug-taking and non-taking patients with linear mixed-effects models (n = 76).

RESULTS: TAS2R38 supertasters were linked to reduced AD risk with advancing age in various AD biomarkers (P < 0.001). eQTL analysis connected the nontaster allele to increased expression of the gene MGAM in AD-affected brain regions (P < 0.001). Elevated MGAM expression was also associated with more severe Tau burdens (P < 0.05). A significant group difference was observed in clinical dementia rating (CDR) progression (P < 0.001) in various domains for individuals taking MGAM-inhibiting diabetes drugs (Acarbose and Miglitol) compared to the non-taking group.

INTERPRETATION: The genetic association between TAS2R38 and AD biomarkers implicates MGAM as a novel drug target with existing FDA-approved inhibitors. This supports the potential of TAS2R38 haplotypes in guiding precision drug repurposing strategies for AD, warranting clinical trials.}, } @article {pmid41256144, year = {2025}, author = {Yakoub, Y and Qiu, T and Peyrot, C and Salvadó, G and Villeneuve, S and Binette, AP}, title = {Trajectories of plasma biomarkers, amyloid-beta burden and cognitive decline in Alzheimer's disease: A Longitudinal ADNI Study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41256144}, support = {U19 AG024904/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; }, abstract = {As novel amyloid-β targeted therapies emerge, plasma biomarkers have promising potential to serve as screening tools and as surrogate measures for treatment outcomes. Understanding longitudinal trajectories of these biomarkers and how their changes relate to changes in AD pathology and cognition is needed to help track treatment response and guide patient care. We analyzed data from 394 individuals in the ADNI-FNIH dataset who had plasma biomarkers available across 14 assays, Aβ-PET scans and cognitive assessments over a 10-year period. Plasma p-tau217, regardless of the assay used, had the greatest rate of change over time. This increase was related to concurrent increase in Aβ-PET burden only in individuals with low levels of Aβ. The rate of p-tau217 change, rather than its baseline level, was the strongest predictor of future Aβ-PET positivity. On the other hand, in individuals with elevated levels of Aβ, higher rate of change in p-tau217 was associated with faster cognitive decline. These findings highlight a "dual" role of plasma p-tau217 rate of change, being either predictive of accumulating Aβ pathology at early stages and of cognitive decline at later stages of the AD continuum.}, } @article {pmid41256136, year = {2025}, author = {Tang, AS and Zeng, BZD and Rankin, KP and Miller, B and Gorno-Tempini, ML and Seeley, WW and Rosen, HJ and Rabinovici, GD and Oskotsky, TT and Sirota, M and Pinheiro-Chagas, P}, title = {Characterizing Dementia Phenotypes from Unstructured EHR Notes with Generative AI and Interpretable Machine Learning.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41256136}, support = {P50 AG023501/AG/NIA NIH HHS/United States ; T32 GM007618/GM/NIGMS NIH HHS/United States ; R01 AG060393/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; F30 AG079504/AG/NIA NIH HHS/United States ; }, abstract = {Dementia encompasses diverse clinical syndromes where diseases of the brain can manifest as impaired cognitive abilities, such as in Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD). The diversity of symptom presentations often results in challenges in diagnosis. Crucial clinical information remains in unstructured narrative notes within electronic health records (EHRs). We leverage large language models (LLMs) for symptom phenotyping from notes in UCSF Information Commons, focusing on patients with expert dementia syndrome diagnosed from a multidisciplinary team of specialists from the UCSF Memory and Aging Center. We developed a pipeline to extract findings in a validated structured output, clustered into symptom groups, and then classified patients into syndromes with traditional machine learning paradigms. From over 9,000 cross-referenced patients and over 350,000 specialty-related notes, matched cohorts of bvFTD (122 patients) and AD (170) syndromes were identified. From notes, 12,637 distinct symptom phrases were extracted, with clustering analysis revealing 51 symptom groups. A logistic regression model separated AD and bvFTD with an AUC of 0.83. Disinhibition and obsessive-compulsive behaviors favored bvFTD, while anxiety and visuospatial abnormalities favored AD. This novel approach, combining LLM-based structured information extraction with traditional interpretable prediction paradigms, demonstrates a promising approach for enhanced symptom characterization in dementia. Our findings suggest potential future applications in improving diagnostic accuracy, developing prediction models, and optimizing treatment strategies in dementia care.}, } @article {pmid41255958, year = {2025}, author = {Biswas, P and Rahman, MH and Tabassum, A and Shoyshob, TZ and Jalouli, M and Islam Tareq, MM and Imtiaz, M and Dona, HA and Harrath, AH and Rahman, MA}, title = {Novel Drug Targets for Neurodegenerative Diseases of Elderly People to Develop Effective Therapeutics: A Comprehensive Analysis.}, journal = {Advances in pharmacological and pharmaceutical sciences}, volume = {2025}, number = {}, pages = {8847508}, pmid = {41255958}, issn = {2633-4690}, abstract = {Neurodegenerative diseases (NDs) represent an increasingly important burden of disease, particularly in the aging population. The etiology of NDs like Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) is associated with progressive neuronal degeneration and a paucity of effective therapies. Accumulating evidence suggests that common and intersecting genetic and pathological pathways play a critical role in disease onset and progression, revealing new opportunities for target discovery. Here, we review promising therapeutic targets based on the convergence of genetics, molecular pathology, and cellular signaling in neurodegeneration. This narrative will focus on key proteins (amyloid-beta [Aβ], tau, and α-synuclein) and enzymes (acetylcholinesterase and asparagine endopeptidase [AEP]), including their pathological significance and therapeutic implications. N-Methyl-D-aspartate receptors (NMDARs) and cholinergic receptor subtypes are highlighted as important regulators of neurotoxicity, synaptic transmission, and inflammation. Emerging advances in genomics, neuroimaging, and drug delivery are poised to advance precision medicine strategies for early diagnosis and intervention. Important challenges remain, including the complexity of the blood-brain barrier (BBB), pathology heterogeneity, and the need for new biomarkers. We propose that a shift from phenotype-driven diagnoses to mechanistic, genetically informed approaches may improve treatment efficacy. Target identification, validation, and targeted delivery are critical considerations for the success of future therapeutic development. This integrated view will help to inform and improve drug discovery and personalized medicine approaches in the field of neurodegeneration.}, } @article {pmid41255128, year = {2025}, author = {Nilsson, P and Sörgjerd, K and Kakiya, N and Sasaguri, H and Watamura, N and Johansson, L and Shimozawa, M and Tsubuki, S and Zhou, Z and Loera-Valencia, R and Takamura, R and Sekiguchi, M and Pegel, A and Schulz, S and Saito, T and Iwata, N and Winblad, B and Saido, TC}, title = {Somatostatin receptor subtypes 1 and 4 regulate neprilysin, the major amyloid-β degrading enzyme in brain.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251392782}, doi = {10.1177/13872877251392782}, pmid = {41255128}, issn = {1875-8908}, abstract = {BackgroundAlzheimer's disease (AD) brains are characterized by increased levels of the pathogenic amyloid-β (Aβ) peptide, which accumulates into extracellular plaques. Finding a way to lower Aβ levels is fundamental for the prevention and treatment of AD. Neprilysin is the major Aβ degrading enzyme which is regulated by the neuropeptide somatostatin.ObjectiveWe here aimed at identifying the subtype specificity of the five somatostatin receptors (SSTs) expressed in the brain, involved in the regulation of neprilysin.MethodsWe used a combination of in vitro and in vivo approaches using a battery of generated Sst double knockout (dKO) mice. We investigated SST specificity of neprilysin regulation using primary neuronal cultures in combination with SST agonist treatments and neprilysin activity measurements. Brains from Sst dKO mice were analyzed for neprilysin and Aβ by biochemical and immunohistological means. Amyloid-beta precursor protein (App) knock-in mice were treated with SST1,4 agonist and its effects on neprilysin and Aβ were assessed by immunostaining and ELISA.ResultsWe show that neprilysin is regulated by SST1 and SST4 in a redundant manner. Sst1 and Sst4 dKO mice exhibit a specific decrease of presynaptic neprilysin in the Lacunosum molecular layer. Moreover, a genetic deficiency of Sst1 and Sst4 in App knock-in mice aggravates the Aβ pathology in hippocampus. As a first proof of concept towards an Aβ-lowering strategy involving neprilysin, we demonstrate that treatment with an SST1,4 agonist ameliorates the Aβ pathology.ConclusionsSST1 and SST4 redundantly regulate neprilysin in the hippocampus where it controls Aβ metabolism.}, } @article {pmid41254914, year = {2025}, author = {Mackey-Alfonso, SE and Barrientos, RM}, title = {Neuroinflammatory mechanisms linking high-fat diets to Alzheimer's disease vulnerability: Beyond the amyloid hypothesis.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70911}, pmid = {41254914}, issn = {1552-5279}, support = {RFAG028271/AG/NIA NIH HHS/United States ; R21AG071133/AG/NIA NIH HHS/United States ; R03 AG067061/AG/NIA NIH HHS/United States ; //Ohio State University Presidential Fellowship/ ; R21 AG071133/AG/NIA NIH HHS/United States ; R03AG067061/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism/etiology/pathology ; Humans ; *Diet, High-Fat/adverse effects ; *Neuroinflammatory Diseases/metabolism ; Amyloid beta-Peptides/metabolism ; Toll-Like Receptor 4/metabolism ; Animals ; Brain/metabolism/pathology ; }, abstract = {As global life expectancy increases, Alzheimer's disease (AD) incidence is rising rapidly. While research has long focused on amyloid beta (Aβ) and tau pathology, recent controversies and limited clinical success of Aβ-targeting therapies have challenged their centrality in AD. Emerging evidence highlights neuroinflammation as an earlier and potentially more critical driver of disease, particularly in response to environmental and lifestyle factors. High saturated fat diets (HFD) are strongly associated with increased AD risk in both clinical and preclinical studies. This review examines how HFD promotes AD vulnerability via neuroinflammatory mechanisms, including toll-like receptor 4 activation and complement system overactivation, which contribute to synaptic loss and cognitive decline-often independent of Aβ burden and metabolic dysfunction. Short-term HFD exposure can rapidly induce neuroinflammation and impair memory, underscoring the direct impact of diet on brain health. These insights support a shift toward targeting immune pathways and synaptic preservation in AD prevention and treatment. HIGHLIGHTS: High saturated fat diets (HFDs) increases Alzheimer's disease risk independently of obesity or insulin resistance. Neuroinflammation is a key driver of HFD-induced cognitive decline. Toll-like receptor 4 (TLR4) activation links saturated fats to synaptic loss and memory deficits. HFDs promote complement-mediated microglial synaptic engulfment. Short-term HFD exposure rapidly impairs memory and increases brain inflammation.}, } @article {pmid41254870, year = {2025}, author = {Rathod, SS and Agrawal, YO}, title = {β-Caryophyllene Ameliorates STZ-Induced Alzheimer's Disease-Like Conditions in Rats via Modulation of Brain-Derived Neurotrophic Factor, Synaptic Plasticity, and Neuroinflammation.}, journal = {The European journal of neuroscience}, volume = {62}, number = {10}, pages = {e70317}, doi = {10.1111/ejn.70317}, pmid = {41254870}, issn = {1460-9568}, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; *Neuronal Plasticity/drug effects ; Male ; *Polycyclic Sesquiterpenes/pharmacology ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; Rats ; Rats, Sprague-Dawley ; Streptozocin/toxicity ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; *Neuroprotective Agents/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and neuroinflammation. Synaptic plasticity and neuroinflammation are hallmarks of AD, with their dysregulation forming a self-reinforcing cycle that aggravates neurodegeneration. Proinflammatory cytokines impair synaptic signaling by suppressing brain-derived neurotrophic factor (BDNF) expression and neuroplasticity markers, further compromising synaptic plasticity. β-Caryophyllene (BCP), a natural bicyclic sesquiterpene with anti-inflammatory and neuroprotective properties, may counteract these pathological processes. This study evaluated the effect of BCP in mitigating streptozotocin (STZ)-induced AD-like conditions in male Sprague-Dawley rats. Two doses of STZ (3 mg/kg) on Days 1 and 3 were administered intracerebroventricularly to induce AD-like pathology. Rats received BCP (10, 20 mg/kg, i.p.) or rivastigmine (2.5 mg/kg) for 28 days. Cognitive performance was assessed using the Barnes maze and novel object recognition tests. Hippocampal tissues were analyzed for BDNF expression, synaptic plasticity markers (e.g., synaptophysin, neural cell adhesion molecule [NCAM], and ciliary neurotrophic factor [CNTF]), neuroinflammatory markers (e.g., IL-1β, TNF-α, IL-6, COX2, and NF-κB), and oxidative stress markers. Histological (hematoxylin and eosin) and Golgi-Cox staining techniques were employed to evaluate neuronal integrity and synaptic organization. STZ-induced rats exhibited significant cognitive deficits, synaptic loss, and increased neuroinflammation. BCP treatment improved spatial learning and memory retention, increased BDNF expression, and restored synaptic plasticity markers. Furthermore, BCP attenuated neuroinflammation by reducing proinflammatory cytokine levels. Histopathology confirms normal hippocampal neuronal architecture in BCP-treated groups. These findings highlight the ability of BCP to modulate BDNF signaling, synaptic plasticity, and neuroinflammatory pathways, underscoring its potential as a multitarget therapeutic candidate for AD.}, } @article {pmid41254247, year = {2025}, author = {Kochman, U and Sitka, H and Kuźniar, J and Czaja, M and Kozubek, P and Beszłej, JA and Leszek, J}, title = {Targeted Nanoparticles for Drug Delivery Across the Blood-Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {75}, pmid = {41254247}, issn = {1559-1182}, mesh = {*Blood-Brain Barrier/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; *Nanoparticles/metabolism/chemistry ; Animals ; *Drug Delivery Systems/methods ; Drug Carriers ; }, abstract = {Alzheimer's disease (AD) presents important challenges for treatment. One significant factor that may reduce the effectiveness of therapy is the limited drug delivery to the brain due to the blood-brain barrier (BBB). Advancements in nanotechnology are offering innovative solutions to bypass this obstacle. This review highlights the role of targeted nanoparticles (NPs) as effective drug carriers across the BBB for both early and late stages of AD. The distinct pathophysiological traits of these stages-such as amyloid aggregation, abnormal accumulation of tau protein, neuroinflammation, and oxidative stress-are examined for their impact on therapy. The analysis includes lipid-based, polymeric, and inorganic NPs, exploring their unique properties for drug delivery. Strategies to target NPs to brain tissues affected by AD are discussed, emphasizing surface modifications to enhance BBB permeability. Uptake mechanisms like receptor-mediated and adsorptive-mediated transcytosis are detailed alongside safety, toxicity, and biocompatibility evaluations to assess clinical feasibility. Key findings indicate that targeted NPs significantly improve brain drug bioavailability and enable stage-specific therapeutic interventions, addressing challenges unique to early and late AD. Future research should focus on optimizing NP design for enhanced targeting specificity and minimizing long-term toxicity, ultimately paving the way for personalized nanomedicine approaches in AD treatment.}, } @article {pmid41252538, year = {2025}, author = {Depp, C and Holden, J and Granholm, E}, title = {Digital Measurement of Subjective Experiences in Alzheimer Disease and Related Dementias (AD/ADRD).}, journal = {JMIR aging}, volume = {8}, number = {}, pages = {e71920}, pmid = {41252538}, issn = {2561-7605}, mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis ; Caregivers/psychology ; Quality of Life ; Wearable Electronic Devices ; *Dementia/psychology ; }, abstract = {Symptoms such as loss of pleasure, agitation, and sadness are subjective experiences that contribute significantly to caregiver burden and health care costs in Alzheimer disease and related dementias (AD/ADRD). However, traditional self-report measures of subjective experiences are limited in AD/ADRD due to cognitive impairments and awareness. Passive sensing, which collects data without active participant input, has emerged as a promising approach to quantify aspects of subjective experiences. Smartphones, wearables, and in-home sensors can quantify mobility, physiology, speech, and social interaction markers of constructs relevant to AD/ADRD. Available research indicates potential but is largely at the proof-of-concept stage. In this Commentary, we discuss several roadblocks to future translation of passive sensing in measuring subjective experiences in AD/ADRD, including technical implementation, data harmonization, validation, ethical and privacy principles. Addressing these challenges could lead to transformative applications to care for AD/ADRD, enabling precise monitoring of behavioral symptoms and related treatment targets, ultimately improving quality of life for persons with AD/ADRD and their caregivers.}, } @article {pmid41252423, year = {2025}, author = {Aggarwal, G and Salas, J and Vellas, B and Nguyen, AD and Butler, AA and , }, title = {High circulating adropin levels predict long-term blood pressure variability in old adults: evidence from the Multidomain Alzheimer Prevention Trial.}, journal = {American journal of physiology. Heart and circulatory physiology}, volume = {329}, number = {6}, pages = {H1684-H1692}, doi = {10.1152/ajpheart.00763.2025}, pmid = {41252423}, issn = {1522-1539}, support = {ANR-23-IAHU-0011//Agence Nationale de la Recherche (ANR)/ ; }, mesh = {Humans ; Female ; Male ; Aged ; *Blood Pressure/drug effects ; Intercellular Signaling Peptides and Proteins/blood ; Biomarkers/blood ; *Hypertension/blood/physiopathology/diagnosis/drug therapy ; *Alzheimer Disease/prevention & control/blood/physiopathology ; Aged, 80 and over ; Blood Proteins ; Time Factors ; *Peptides/blood ; Age Factors ; }, abstract = {Hypertension and elevated visit-to-visit variability in blood pressure (BP) increase the lifetime risk of cardiovascular, kidney, and neurodegenerative diseases. Adropin, a hepatokine with autocrine/paracrine actions, contributes to cardiometabolic cross talk and mediates cellular stress responses across metabolic and cardiovascular tissues. Human cross-sectional and exercise studies suggest links between adropin, endothelial function, and vascular elasticity. Whether circulating adropin levels reflect risk of poor BP control remains unclear. We examined relationships between plasma adropin concentrations, BP, and visit-to-visit BP variability in older, community-dwelling participants from the Multidomain Alzheimer Prevention Trial (MAPT: n = 443; means ± SD age, 75.9 ± 4.5 yr; 60% female). BP and heart rate while in the supine position were assessed every 6 mo for 5 yr (8.1 ± 1.3 measurements/participant). Multivariate regression modeling revealed a positive association between adropin and variation independent of the mean (VIM) in systolic BP (R = 0.329, F7,429 = 7.454, P < 0.001). Predictors included adropin (β = 0.165, P < 0.001), age (β = 0.146, P < 0.005), sex (male = 1, female = 0; β = -0.130, P = 0.005), and antihypertensive medication use (yes = 1, no = 0; β = 0.188, P < 0.001). Stratification by medication use suggested that the association between adropin and systolic BP VIM is confined to participants on antihypertensive therapy (R = 0.347, F6,188 = 4.302, P < 0.001; adropin, β = 0.233, P = 0.001). However, analysis by grouping participants in tertiles ranked by adropin or systolic BP VIM suggests that, although the relationship is notably weaker, it is not absent for participants not on antihypertensive medications. In conclusion, elevated plasma adropin concentrations associate with systolic BP variability in older adults with hypertension. These findings identify adropin as a potential biomarker of poor BP control.NEW & NOTEWORTHY This study identifies circulating levels of the hepatokine adropin as a novel biomarker of blood pressure (BP) variability in older adults. Using longitudinal data from the Multidomain Alzheimer Prevention Trial, we show that higher adropin levels predict greater systolic BP variability, particularly in participants receiving antihypertensive therapy. These findings link a hepatokine with cardiovascular risk and suggest that adropin measurement may improve stratification of individuals at risk for poor BP control and treatment resistance.}, } @article {pmid41251074, year = {2025}, author = {Joshi, S and Chutia, P and Tripathi, SM}, title = {Paratonia in dementia: diagnosis and management strategies.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-4}, doi = {10.1080/17582024.2025.2591413}, pmid = {41251074}, issn = {1758-2032}, abstract = {Paratonia is a type of hypertonia with involuntary resistance to passive movement depending on the pace and force being applied. People with paratonia may find it challenging to modify their movements and posture. Limited awareness among healthcare professionals can lead to a delay in diagnosis and inadequate treatment. Here, we present two cases diagnosed with dementia due to Alzheimer's disease. The two patients developed stiffness in their bodies as the dementia progressed. Paratonia was diagnosed using the Paratonia Assessment Inventory. Severity of paratonia was assessed using the Modified Ashworth scale for paratonia (MAS-P). The caregiver's primary concern was the stiffness of the body, which created difficulties in routine care. Amantadine was initiated in both patients. Both patients demonstrated improvement in paratonia following amantadine treatment, with reduced stiffness and greater ease in caregiving tasks. The present case series highlights the role of amantadine in the management of paratonia and can contribute to the development of more treatment options.}, } @article {pmid41251026, year = {2025}, author = {Ahmad, N and Ambreen, N and Ayaz, M and Zainab, and Alam, A and Ahmad, I and Elhenawy, AA and Zghab, I and Shah, SAA and Ahmad, M}, title = {Synthesis, In Vitro Cholinesterase Inhibition, Molecular Docking, Density Functional Theory Analysis of Benzimidazole Based Hydrazone Schiff Bases.}, journal = {Journal of molecular recognition : JMR}, volume = {38}, number = {6}, pages = {e70012}, doi = {10.1002/jmr.70012}, pmid = {41251026}, issn = {1099-1352}, mesh = {*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology ; Schiff Bases/chemistry/chemical synthesis/pharmacology ; Molecular Docking Simulation ; *Hydrazones/chemistry/chemical synthesis/pharmacology ; *Benzimidazoles/chemistry/chemical synthesis/pharmacology ; Butyrylcholinesterase/chemistry/metabolism ; Acetylcholinesterase/chemistry/metabolism ; Molecular Dynamics Simulation ; Density Functional Theory ; Humans ; }, abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are the main therapeutic targets for the treatment of neurodegenerative diseases, predominantly Alzheimer's disease. This work reports the synthesis, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of synthesized hydrazone Schiff base derivatives of benzimidazole. The compounds have been structurally deduced by means of HR-ESI-MS, [1]H-NMR and [13]C-NMR techniques and finally assessed for their in vitro AChE and BuChE inhibitory activities. All the compounds attributed notable inhibitory potential with IC50 values ranging from 34.7 ± 0.02 to 185.2 ± 2.47 μM for AChE and 40.8 ± 0.32 to 188.8 ± 2.47 μM for BuChE enzymes. The molecular docking and TD-DFT studies attributed that the compound with methoxy groups, specifically compound (7) displays increased electronic properties and strong dual binding to AChE and BuChE enzymes. Molecular dynamics (MD) simulations for the most active compound (7) were performed, which showed that compound (7) exploits the integral flexibility of AChE and BuChE to encourage conformational variations that lock both enzymes into a two-site inhibitory state. These compounds presented orbitals and favorable electrostatic profiles that improve the inhibitory potential. The results authenticate the SAR trends and highlight the significance of methoxy groups in planning potent cholinesterase inhibitors.}, } @article {pmid41250246, year = {2025}, author = {Shang, J and Zhong, S and Shang, L and Zeng, Q and Zhao, S and Luo, X and Li, K and Zhang, X and Huang, P and Yan, Y and Liu, Z and Zhang, B and Chen, Y}, title = {Real-world application of lecanemab in early-stage alzheimer's disease: a single-center prospective cohort analysis.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {249}, pmid = {41250246}, issn = {1758-9193}, support = {82402209//National Natural Science Foundation of China/ ; 82271936//National Natural Science Foundation of China/ ; 82202090//National Natural Science Foundation of China/ ; 82271268//National Natural Science Foundation of China/ ; 82371190//National Natural Science Foundation of China/ ; LQ24H180002//Natural Science Foundation of Zhejiang Province/ ; LY24H090007//Natural Science Foundation of Zhejiang Province/ ; 2025C02113//Key Research and Development Program of Zhejiang Province/ ; }, abstract = {BACKGROUND AND OBJECTIVES: Lecanemab (Leqembi®) has been approved for the treatment of early Alzheimer’s disease (AD) patients. However, the safety and efficacy of lecanemab in clinical practice in Asia population remain unclear.

This prospective cohort study was conducted in a single center in Eastern China, including 76 early-stage AD participants treated with lecanemab. All participants underwent at least 1 lecanemab infusion.

RESULTS: The mean age was 66 years (65.53 ± 9.31), and 51 (67.1%) participants being female. A total of 49 (64.5%) participants were ApoE-ε4 carriers, including 34 (44.7%) heterozygotes and 15 (19.7%) homozygotes. Infusion-related side effects (IRSE), primarily occurred after the first infusion, were observed in 14 participants (18.4%). The most common IRSE were fever and fatigue. Until 9 Aug 2025, 58 participants had received treatment for more than 3 months, 44 for more than 6 months and 12 for more than 12 months. Amyloid-related imaging abnormalities (ARIA) were observed in 11 participants. Specifically, solitary ARIA-H (hemorrhage) was detected in 7 participants, while ARIA-E (edema) with or without cerebral micro-hemorrhage was identified in 4. Notably, all the 11 participants with ARIA were asymptomatic. Participants with isolated ARIA-H exhibited higher baseline Fazekas scores of PVWMHs (p = 0.008). Participants with a Clinical Dementia Rating Scale Global Score (CDR-GS) of 1 had a more rapid decline in Mini-Mental State Global Score (MMSE) scores as compared to those with a CDR-GS of 0.5. Following 12 months of lecanemab therapy, amyloid PET exhibited a significant reduction in brain amyloid burden.

CONCLUSION: These data support that lecanemab appears to be generally tolerated in Asian population. The IRSE and ARIA-E events were less common than the Clarity AD study.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01886-5.}, } @article {pmid41250235, year = {2025}, author = {Corbett, A and Sultana, J and Stych, K and Mills, R and Cummings, JL and Williams, G and Ismail, Z and Soto-Martin, M and Mintzer, J and Gauthier, S and Greig, NH and Noble, W and Killick, R and Lai, MKP and Routledge, C and Walsh, F and Fillit, H and Aarsland, D and Lane, R and Mills, K and Ballard, C}, title = {Drug repurposing for Alzheimer's disease: a Delphi consensus and stakeholder consultation.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {237}, pmid = {41250235}, issn = {1758-9193}, support = {P20 GM109025/GM/NIGMS NIH HHS/United States ; R01 NS139383/NS/NINDS NIH HHS/United States ; R25 AG083721/AG/NIA NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; }, mesh = {*Drug Repositioning/methods ; *Alzheimer Disease/drug therapy ; Humans ; Delphi Technique ; Consensus ; Stakeholder Participation ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is an escalating global challenge, with more than 40 million people affected, and this number is projected to increase to more than 100 million by 2050. While amyloid-targeting antibody treatments (lecanemab and donanemab) are a significant step forward, the benefits of these therapies remain limited. This highlights the necessity for safe and effective compounds that offer greater therapeutic benefits to the majority of individuals with or at risk of AD. Drug repurposing allows for a cost-effective, time-efficient strategy to accelerate the availability of treatments, owing to the availability of safety information.

METHOD: This study focuses on the third iteration of the Delphi consensus programme aimed at identifying new high-priority drug candidates for repurposing in AD. An international expert panel comprising academics, clinicians and industry representatives was convened. Through a combination of anonymized drug nominations, systemic evidence reviews, iterative consensus rankings, and lay advisory inputs, drug candidates were evaluated and ranked based on rational, non-clinical, and clinical evidence and overall safety profiles.

RESULTS: Among the 80 candidates that were nominated by the expert panel, seven underwent review, with only three candidates meeting the following consensus criteria of relevant mechanisms for targeting neurodegenerative pathways, non-clinical efficacy, and tolerability in older individuals. The three agents were: [1] the live attenuated herpes zoster (HZ) vaccine (Zostavax) [2], sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, and [3] riluzole, a glutamate antagonist. The HZ vaccine additionally offers potential for population-level dementia risk reduction.

CONCLUSION: This Delphi consensus identified three high-priority drug repurposing candidates for AD with favourable safety profiles and mechanistic plausibility, which are considered suitable for pragmatic clinical trials, including remote or hybrid designs. The PROTECT platform, which supports international cohorts in the UK, Norway, and Canada, offers a well-established means to conduct such trials effectively, thus helping to accelerate the evaluation and potential deployment of these drug candidates to benefit individuals with or at risk for AD.}, } @article {pmid41249122, year = {2025}, author = {Diamandis, N and van den Anker, JN and Denisova, K}, title = {Effect of Alzheimer's disease medications on neurocognitive outcomes in children and adolescents with autism spectrum disorder and low IQ: a scoping review.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {475}, pmid = {41249122}, issn = {2158-3188}, support = {R01 MH121605/MH/NIMH NIH HHS/United States ; R01MH121605//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; 614242//Simons Foundation/ ; }, mesh = {Humans ; Child ; Adolescent ; *Autism Spectrum Disorder/drug therapy/complications/psychology ; *Alzheimer Disease/drug therapy/complications ; *Intellectual Disability/complications ; Young Adult ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; Child, Preschool ; }, abstract = {BACKGROUND: Individuals with autism spectrum disorder (ASD) and comorbid intellectual disability (ID) are particularly vulnerable to poor developmental trajectories. These individuals are at increased risk of Alzheimer's disease (AD) relative to those without comorbid ID and the general population. Considering that there could be an important mechanistic link underlying ASD and AD, individuals with these conditions may stand to benefit from similar psychopharmacological treatments.

METHODS: This scoping review aimed to evaluate and synthesize the evidence on the effect of AD medications on neurocognitive outcomes in children and adolescents with ASD and low intelligence quotient (IQ). We performed the search according to PRISMA guidelines from inception to May 21[st], 2025 in four databases: PubMed, PsycInfo, Scopus, and Web of Science. We included studies of children and adolescents (2 - 21 years) with ASD and low IQ (<85) treated with at least one Food and Drug Administration (FDA)-approved AD medication (donepezil, galantamine, rivastigmine, benzgalantamine, memantine, aducanumab, lecanemab or donanemab) and investigating neurocognitive outcomes.

RESULTS: Twelve studies met the eligibility criteria. Six studies reported on neurocognitive outcomes from N-methyl-D-aspartate (NMDA) receptor antagonist treatment and six studies from cholinesterase inhibitor treatment. Among studies reporting on cholinesterase inhibitors, significant improvement was detected in language (60% of five reporting studies), executive function (100% of two reporting studies), complex attention (100% of one reporting study), and general cognitive ability (50% of two reporting studies). Among the NMDA receptor antagonist studies, evidence of improvement was detected in language (60% of five reporting studies), executive function (75% of four reporting studies), learning and memory (100% of two reporting studies), perceptual-motor functioning (66.6% of three reporting studies), complex attention (100% of one reporting study), and general cognitive ability (50% of two reporting studies). Across studies, treatment with either a cholinesterase inhibitor or an NMDA receptor antagonist was associated with improvements in language, executive function, complex attention, and general cognitive ability. A pattern of significance was detected with age, in that younger children may benefit more from these medications than adolescents.

CONCLUSION: This scoping review identified promising evidence of neurocognitive improvement in children and adolescents with ASD and low IQ following treatment with either a cholinesterase inhibitor or an NMDA receptor antagonist. Considering the lack of FDA-approved treatments for the cognitive deficits associated with ASD and an absence of medications approved to treat core features of ASD, our findings highlight an opportunity for innovative directions in autism research and treatment.}, } @article {pmid41249052, year = {2025}, author = {Szatmari, EM and Moran, C and Cohen, SJ and Bashtovyy, D and Jacob, A and Bunner, W and Phipps, M and Lora, JC and Stackman, RW and Yasuda, R}, title = {Lack of ADAP1/Centaurin-α1 Ameliorates Cognitive Impairment and Neuropathological Hallmarks in a Mouse Model of Alzheimer's Disease.}, journal = {eNeuro}, volume = {12}, number = {11}, pages = {}, pmid = {41249052}, issn = {2373-2822}, support = {R15 NS125564/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/genetics ; Disease Models, Animal ; Mice ; *Cognitive Dysfunction/metabolism/pathology/genetics ; Mice, Knockout ; Male ; Plaque, Amyloid/pathology/metabolism ; *GTPase-Activating Proteins/genetics/metabolism ; Spatial Memory/physiology ; *Brain/pathology/metabolism ; *Adaptor Proteins, Signal Transducing/genetics ; }, abstract = {ArfGAP, with dual PH domain-containing protein 1/Centaurin-α1 (ADAP1/CentA1), is a brain-enriched and highly conserved Arf6 GTPase-activating and Ras-anchoring protein. CentA1 is involved in dendritic outgrowth and arborization, synaptogenesis, and axonal polarization by regulating the actin cytoskeleton dynamics. CentA1 upregulation and association with amyloid plaques in the human Alzheimer's disease (AD) brain suggest the role of this protein in AD progression. To understand the role of CentA1 in neurodegeneration, we crossbred CentA1 knock-out (KO) mice with the J20 mouse model of AD. We evaluated AD-associated behavioral and neuropathological hallmarks and gene expression profiles in J20 and J20 crossed with CentA1 KO (J20xKO) male mice to determine the impact of eliminating CentA1 expression on AD-related phenotypes. Spatial memory assessed by the Morris water maze test showed significant impairment in J20 mice, which was rescued in J20xKO mice. Moreover, neuropathological hallmarks of AD, such as amyloid plaque deposits and neuroinflammation, were significantly reduced in J20xKO mice. To identify potential mediators of AD phenotype rescue, we analyzed differentially expressed genes between genotypes. We found that changes in the gene profile by deletion of CentA1 from J20 (J20xKO vs J20) were anticorrelated with changes caused by APP overexpression (J20 vs wild type), consistent with rescue of J20 phenotypes by CentA1 KO. In summary, our data indicate that CentA1 is required for the progression of AD phenotypes in this model and that targeting CentA1 signaling might have therapeutic potential for AD prevention or treatment.}, } @article {pmid41249005, year = {2026}, author = {Shepard, CD and Chang, X and Seidler, PM and Curran, SP}, title = {Polyphyletic screen defines distinct classes of plant-derived natural products that oppose tauopathy.}, journal = {Life science alliance}, volume = {9}, number = {2}, pages = {}, pmid = {41249005}, issn = {2575-1077}, support = {P30 AG068345/AG/NIA NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; R01 AG058610/AG/NIA NIH HHS/United States ; }, mesh = {Caenorhabditis elegans/metabolism ; Animals ; tau Proteins/metabolism ; *Biological Products/pharmacology ; *Tauopathies/drug therapy/metabolism ; Humans ; Alzheimer Disease/drug therapy/metabolism ; Disease Models, Animal ; Protein Aggregation, Pathological/drug therapy ; Naphthoquinones/pharmacology ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Protein Aggregates/drug effects ; Animals, Genetically Modified ; }, abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disease hallmarked by the presence of amyloid-β (Aβ) plaques and tau fibrils but with limited treatment options. Here, we describe two plant-derived natural products with distinct mechanisms of action on tau fibril disaggregation and prionogenic seeding. We first characterized the effects of oolonghomobisflavan A (OFA) and oolonghomobisflavan B (OFB) treatments, which alter the transcriptional landscape toward enhanced proteostasis and reverse the shortened lifespan in a Caenorhabditis elegans model expressing pathogenic human tau ("hTau-expressing"), but increase healthspan. Mechanistically, OFA treatment reduced the burden of tau protein aggregation and promoted tau disaggregation in hTau-expressing C. elegans and also inhibited seeding in assays using ex vivo brain-derived paired helical filament tau protein fibrils from Alzheimer's disease brain donors. We leveraged this finding to develop a facile screening approach for compounds, like OFA, that could mitigate tau aggregation, which revealed plumbagin (PB) as a potent inhibitor of tau monomer aggregation which is mechanistically distinct from the tau fibril disaggregase activity associated with OFA. Collectively, this study reveals a new strategy for identifying therapeutic compounds that target tauopathy and provides mechanistic insight supporting the neuroprotective effects of plant-derived natural products.}, } @article {pmid41248588, year = {2025}, author = {Mondal, P and Banerjee, P and Basuli, K}, title = {CPMFD: An algorithm for Classification of Point Mutations together with Frameshift Determination in related mRNA sequences.}, journal = {Mutation research}, volume = {831}, number = {}, pages = {111918}, doi = {10.1016/j.mrfmmm.2025.111918}, pmid = {41248588}, issn = {1873-135X}, mesh = {*Algorithms ; *RNA, Messenger/genetics ; *Point Mutation ; *Frameshift Mutation ; Animals ; Plasmodium falciparum/genetics ; Humans ; Pan troglodytes/genetics ; beta-Globins/genetics ; Mutation, Missense ; Haplotypes ; }, abstract = {Mutations are responsible for the genetic origin of various diseases. Existing techniques for mutation identification often fails to detect the full spectrum of mutations in complex genomes hindering progress in diagnosis, treatment and prevention of diseases. Here we propose an algorithm to identify the location and type of mutation occurring in a mutated string with respect to a reference mRNA sequence. In addition to identifying insertion and deletion, by constructing suitable rational combinations of the prime numbers, our algorithm is able to classify point mutations in a novel way by distinguishing missense mutation from silent mutation. Amino acid transformation at each missense mutation site is identified. Moreover, the method allows to locate regions in the sequence undergoing frameshift. It turns out to be efficient when applied on sample dataset. Application of this framework to two haplotypes of the Plasmodium falciparum datasets exhibits different mutation profile to develop similar chloroquine resistance. Despite the overwhelming similarity between the β-globin genes of pygmy and common chimpanzees, our algorithm is able to pinpoint the minute details of the mutations occurring in them differentiating the two species. Additionally, in Alzheimer datasets, the method meticulously identifies true variations in related genes.}, } @article {pmid41248418, year = {2025}, author = {Sahin-Lodge, Z and Pisani, S and Nderitu, P and Guu, TW and Aarsland, D and Jackson, TL and Ffytche, D and Venkataraman, AV}, title = {Using retinal diagnostics as a biomarker for neurodegenerative diseases: protocol for a systematic review.}, journal = {BMJ open}, volume = {15}, number = {11}, pages = {e106531}, pmid = {41248418}, issn = {2044-6055}, mesh = {Humans ; Systematic Reviews as Topic ; *Neurodegenerative Diseases/diagnosis/diagnostic imaging ; Biomarkers ; Tomography, Optical Coherence ; *Retina/diagnostic imaging/pathology ; Research Design ; Electroretinography ; *Retinal Diseases/diagnosis ; }, abstract = {INTRODUCTION: Retinal neurodegeneration has recently been shown to occur in tandem with neurodegenerative disease. In the expectation that disease-modifying treatments for Alzheimer's disease (AD) and Parkinson's disease (PD) will soon become available, it will be important to have clinically useful biomarkers for neurodegenerative disease subtyping to guide early diagnosis, inform on prognosis and stratify subgroups for treatment. Understanding differences in detectable retina changes in individuals with different neurodegenerative disease subtypes is therefore fundamental. The emerging field of oculomics posits that systemic and neurodegenerative disease can be characterised using detectable ocular biomarkers within retinal diagnostics. The aim of this review is to compare the performance of common retinal imaging modalities in neurodegenerative disease detection and subtyping.

METHODS AND ANALYSIS: This protocol has been reported in accordance with the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols) guidelines. A comprehensive literature search will be conducted in PubMed, Web of Science and Scopus. Eligible studies will have reported using retinal diagnostic tools defined as optical coherence tomography (OCT), OCT angiography (OCTA), colour fundus photography (CFP) and electroretinography (ERG) in individuals with neurodegenerative diseases, including AD, PD, dementia with Lewy bodies, frontotemporal dementia, vascular dementia and mild cognitive impairment. There will be no time restrictions placed in these searches. Studies not written in English, not peer-reviewed and grey literature will be excluded. Screening for eligible studies and data extraction will be conducted by two independent reviewers, using predefined inclusion criteria. Any disagreements between the reviewers will be settled by discussion, and if required, third senior reviewer arbitration. The systematic review primary outcome is the performance of retinal diagnostics, namely OCT, OCTA, CFP and ERG in the detection and subtyping of aforementioned neurodegenerative diseases. The secondary outcome is to evaluate the association between changes in retinal diagnostic features (eg, retinal layer thicknesses) and neurodegenerative disease subtypes. The quality of the included studies will be assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluations) tool. A narrative synthesis approach will be used to analyse the results, with meta-analysis performed if there is sufficient data.

ETHICS AND DISSEMINATION: Ethical approval for this manuscript is not required, as this is a protocol for a systematic review and therefore no data are to be collected. Findings for this systematic review will be disseminated as a peer-reviewed publication and presentations at national and international symposiums including International Lewy Body Dementia Conference, International Congress of Parkinson's Disease and Movement Disorders, The Association for Research in Vision and Ophthalmology.

PROSPERO REGISTRATION NUMBER: CRD42023434024.}, } @article {pmid41248283, year = {2025}, author = {Akhter, F and Akhter, A and Zhu, X and Schiff, H and Maffei, A and Douglas, JT and Zhou, Q and Zhao, Z and Zhu, D}, title = {Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer's pathogenesis via VDAC1-dependent mtDNA efflux.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {47}, pages = {e2505046122}, pmid = {41248283}, issn = {1091-6490}, mesh = {Animals ; *Voltage-Dependent Anion Channel 1/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology/genetics ; Mice ; Humans ; *Mitochondria/metabolism/pathology ; *Neurons/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *DNA, Mitochondrial/metabolism/genetics ; Nucleotidyltransferases/metabolism/genetics ; Membrane Proteins/metabolism/genetics ; Receptor for Advanced Glycation End Products/metabolism/genetics ; Glycation End Products, Advanced/metabolism ; Mice, Transgenic ; Glycosylation ; Male ; }, abstract = {Glycation, the nonenzymatic attachment of reactive dicarbonyls to proteins, lipids, or nucleic acids, contributes to the formation of advanced glycation end-products (AGEs). In Alzheimer's disease (AD), amyloid-beta (Aβ) undergoes posttranslational glycation to produce glycated Aβ (gAβ), yet its pathological role remains poorly understood. Here, we demonstrate that gAβ promotes neuronal mitochondrial DNA (mtDNA) efflux via a VDAC1-dependent mechanism, activating the innate immune cGAS-STING pathway. Using aged AD mice and human AD brain samples, we observed cGAS-mtDNA binding and cGAS-STING activation in the neuronal cytoplasm. Knockdown of RAGE, cGAS, or STING, as well as pharmacological inhibition of VDAC1, protected APP mice from mitochondrial dysfunction and Alzheimer's-like pathology. Neuron-specific cGAS knockdown confirmed its pivotal role in driving neuroinflammation and cognitive deficits. Treatment with ALT-711, an AGE cross-link breaker, alleviated gAβ-associated pathology. Furthermore, RAGE inhibition in APP knock-in mice suppressed innate immune activation and disease-associated gene expression, as revealed by spatially resolved transcriptomics. Collectively, our findings establish a mechanistic link between gAβ and innate immune activation, identifying VDAC1, the AGE-RAGE axis, and the cGAS-STING pathway as promising therapeutic targets in AD.}, } @article {pmid41247815, year = {2025}, author = {Rathnam, M and Hunter, H and Paul, PS and Schirrmacher, R and Serpe, MJ and Kar, S}, title = {Native PEG-PLGA Attenuates β-Amyloid Aggregation and Toxicity under In Vitro Conditions.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {23}, pages = {4446-4457}, pmid = {41247815}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; *Polyethylene Glycols/pharmacology/chemistry ; Animals ; Nanoparticles/chemistry ; *Peptide Fragments/metabolism/toxicity ; *Neurons/drug effects/metabolism ; Mice ; Cells, Cultured ; Cell Survival/drug effects ; Polylactic Acid-Polyglycolic Acid Copolymer ; Humans ; Alzheimer Disease/metabolism ; Polyesters ; }, abstract = {Self-aggregation of amyloid-β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD), the most prevalent cause of dementia affecting the elderly population. The development of an effective treatment for AD pathology remains elusive due to the presence of the blood-brain barrier (BBB) and the heterogeneous nature of disease progression. Recently, we reported that FDA-approved native poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles without any conjugated/encapsulated agent can attenuate Aβ aggregation/toxicity in cellular and animal models of AD. Given the limitation associated with the fast clearance of the native PLGA by the reticuloendothelial system (RES), in the present study, we synthesized PEGylated native PLGA nanoparticles (PEG-PLGA-1) to reduce their clearance via the RES and evaluated their effects on Aβ aggregation/toxicity after biochemical and structural characterization. Determined with Thioflavin T kinetic assay, dynamic light scattering and fluorescence imaging, it was revealed that the native PEG-PLGA-1, which exhibits increased stability, not only inhibits the aggregation of Aβ peptides, but also triggers the disassembly of Aβ aggregates. Additionally, we showed that PEG-PLGA-1 are nontoxic and can significantly enhance the viability of mouse primary cortical cultured neurons against Aβ-mediated toxicity. Collectively, these results suggest that native PEG-PLGA-1 nanoparticles can inhibit Aβ aggregation and trigger disassembly of Aβ aggregates and can protect neurons against Aβ-mediated toxicity, thus suggesting their unique therapeutic potential in the treatment of AD pathology.}, } @article {pmid41247623, year = {2025}, author = {Dosseto, A and Tonge, K and Karl, T}, title = {Cannabidiol Modulates Brain Copper Homeostasis in Wild-Type-Like But Not Alzheimer's Disease Transgenic Female Mice: Implications for Neuroprotective Therapy.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {57}, pmid = {41247623}, issn = {1559-1182}, mesh = {Animals ; *Copper/metabolism ; Mice, Transgenic ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Female ; *Cannabidiol/pharmacology/therapeutic use ; *Homeostasis/drug effects ; *Brain/metabolism/drug effects/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Iron/metabolism ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and neuroinflammation. Disrupted metal homeostasis-especially copper (Cu), zinc (Zn), and iron (Fe)-is implicated in AD pathogenesis, contributing to amyloid-beta (Aβ) aggregation and oxidative stress. Cannabidiol (CBD), a non-toxic phytocannabinoid with antioxidant and neuroprotective properties, has unclear effects on brain metal regulation. Using high-resolution laser ablation-inductively coupled plasma mass spectrometry (LA‑ICP‑MS), we quantified regional metal distributions in sagittal brain sections from 12‑month‑old female wild‑type (WT) and APP/PS1 transgenic mice treated chronically with CBD or vehicle. CBD significantly elevated whole‑brain Cu in WT mice but not in APP/PS1 mice. Although Zn and Fe concentrations did not differ significantly, effect-size trends revealed regional differences in Cu and Zn patterns across treatment groups, particularly in the hippocampus. Correlation analysis revealed coordinated inter‑regional metal regulation in WT and vehicle‑treated APP/PS1 groups, which was disrupted in CBD‑treated APP/PS1 mice. Additionally, CBD‑treated WT mice exhibited increased variance in cerebellar Cu, suggesting individual differences in response. These findings suggest that CBD influences Cu homeostasis in WT animals, though not significantly altered in transgenic animals under the conditions tested. Our results support integrating spatially resolved metallomics into preclinical AD frameworks and highlight the utility of metrics beyond mean concentration-such as regional ratios, correlation structures, and variability-for detecting subtle treatment effects.}, } @article {pmid41247384, year = {2025}, author = {Schönberger, A and Schild, AK and Steinmetz, A and Simandi, F and Benson, GS and Hausner, L and Schöttler, M and Hennig, B and Knudsen, A and Maier, F and Frölich, L and Jessen, F}, title = {[Optimization of the work of outpatient memory clinics under aspects of value-based healthcare-An approach from the Center for Memory Disorders of the University Hospital Cologne].}, journal = {Der Nervenarzt}, volume = {}, number = {}, pages = {}, pmid = {41247384}, issn = {1433-0407}, abstract = {BACKGROUND: Memory clinics in Germany are facing major challenges due to increasing numbers of patients and the first available disease-modifying treatments for Alzheimer's disease. Capacities for counselling, biomarker-based diagnostics, drug administration and follow-up examinations must be achieved, which creates the need for modified workflows. Value-based healthcare (VBHC) aims at optimizing the value for patients (outcome in relation to costs) and can serve as a framework for a patient-oriented increase in efficacy.

OBJECTIVE: This project applied approaches of VBHC to analyze and improve the diagnostic processes in our memory clinic in order to achieve a better value for patients and care partners with a more efficient use of existing resources.

METHODS: In a first survey among memory clinic patients and relatives the essential aspects in relation to VBHC were collated and based on the results the existing workflow processes were modified. These modifications were evaluated by a second survey and analysis particularly of process-oriented aspects.

RESULTS: The first survey revealed a general satisfaction with the presentation in the memory clinic. The main point of criticism was the duration of the diagnostic process. After the modification the duration and extent of the diagnostics could be reduced. The second evaluation showed improved patient and care partner satisfaction. The respondents considered the modified trajectories to be better and resources were conserved.

CONCLUSION: In our memory clinic an improvement in the sense of VBHC could be achieved through an increased satisfaction with the treatment (outcome) and reduced personnel binding times (costs). This approach can serve as a model for other memory clinics for the development of a more efficient and patient-centered care.}, } @article {pmid41246746, year = {2025}, author = {Bethea, JP and Sharma, H and Doberstein, N and Shenker, T and Gregory, B and Hoffman, R and Aizenman, D and Guirguis, G and Hoffmann, J and Tazani, S and Harris, Z and Costin, J}, title = {Application of Osteopathic Manipulative Treatment (OMT) in Neurodegenerative Disorders: A Scoping Review.}, journal = {Cureus}, volume = {17}, number = {10}, pages = {e94748}, pmid = {41246746}, issn = {2168-8184}, abstract = {Neurodegenerative diseases are comprised of a host of chronic conditions that impair the central nervous system. Osteopathic manipulative treatment (OMT) consists of many non-invasive modalities that can be used to treat a wide variety of ailments and conditions. OMT is reported to increase the range of motion and lymphatic flow, as well as decrease pain in a wide array of disorders. However, the efficacy of using OMT in neurodegenerative disorders has not been well established. The objective of this scoping review is to map the evidence that pertains to the application of OMT in treating neurodegenerative disorders and identify the gaps in the literature on this subject. This study was designed according to the Joanna Briggs Institute (JBI) guidelines for scoping reviews to gather information on OMT's potential efficacy in managing Parkinson's disease (PD), Alzheimer's disease (AD) dementia, amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Peer-reviewed literature was collected through the Excerpta Medica database (EMBASE), Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), and Web of Science. The criteria were limited to papers in English published between 1999 and 2023. The following search string was utilized: "osteopathic manipulative treatment" OR "osteopathic manipulation" AND "neurodegenerative disorders" OR "Alzheimer's disease" OR "dementia" OR "amyotrophic lateral sclerosis" OR "Parkinson's disease" OR "Huntington's chorea". One hundred and forty-three articles were identified following final screening and critical appraisal, with eleven articles selected for analysis in this study. Data from the selected articles demonstrated that OMT can possibly attenuate symptoms in patients diagnosed with neurodegenerative diseases. Studies in rats showed that OMT techniques were found to alter cholinergic neuronal genes, improve spatial learning and memory, reduce amyloid β protein levels, modulate synaptic transmission, and increase levels of the cytokines IL-1, IL-10, IL-13, RANTES, IL-17A, and EOTAXIN effects in AD dementia. ALS patients demonstrated a high level of satisfaction with OMT and did not report any adverse effects, though there was no decrease in pain or increased quality of life reported. PD patients reported improved postural stability, balance, and gait after OMT. No results were returned regarding OMT's effects on HD. Preliminary results in human PD and ALS patients who received OMT as an adjunct to traditional treatment regimens showed promising results, though few studies were found that address the topic, and the sample sizes of the studies that were found were small. There were no studies of the effects of OMT on human patients with AD or HD found, though preclinical studies in rats supported their trial in subsequent human studies. While current research on the impact of OMT on these neurodegenerative diseases is promising, there remain large gaps in the literature. Further research is necessary to support the use of and long-term efficacy of OMT in neurodegenerative diseases.}, } @article {pmid41246229, year = {2025}, author = {Şahin, TÖ and Cemali, Ö and Özdemir, M and Ayten, Ş and Ağagündüz, D}, title = {Flavonoids and phenolic compounds: a promising avenue for neurodegenerative disease therapy.}, journal = {Turkish journal of biology = Turk biyoloji dergisi}, volume = {49}, number = {5}, pages = {635-659}, pmid = {41246229}, issn = {1303-6092}, abstract = {BACKGROUND/AIM: Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are characterized by a progressive loss of nerve cells, for which no definitive cure currently exists. These conditions share common pathological mechanisms, including chronic neuroinflammation, oxidative stress, protein aggregation, and mitochondrial dysfunction. Flavonoids and other plant-derived phenolic compounds have recently attracted attention for the treatment of such conditions due to their antiinflammatory and antioxidant properties. This review explores the neuroprotective mechanisms of flavonoids and evaluates their potential for the prevention and treatment of neurodegenerative diseases.

MATERIALS AND METHODS: A literature search of the Web of Science, PubMed, and ScienceDirect databases was conducted to evaluate the therapeutic potential of flavonoids and phenolic compounds against neurodegenerative diseases. The search terms included "polyphenols", "flavonoids", and related compounds, along with "Alzheimer's", "Parkinson's", "Huntington's", and "Amyotrophic lateral sclerosis". Eligible studies included clinical trials, randomized controlled trials, and in vitro and in vivo research published in English. Priority was given to studies from the last decade, although older but significant publications were also included.

RESULTS: The findings of multiple studies report the ability of flavonoid compounds such as quercetin, myricetin, apigenin, and epigallocatechin gallate (EGCG) to modulate critical signaling pathways, reduce oxidative stress, prevent the accumulation of neurotoxic proteins, and support mitochondrial function. These bioactive molecules have exhibited significant potential in slowing disease progression and preserving neuronal integrity. Their therapeutic application, however, has been limited by their poor bioavailability, low stability, and rapid metabolism.

CONCLUSION: Flavonoids have shown promise as naturally derived agents with multi-targeted activity against neurodegenerative processes. Enhancing their absorption and stability through novel delivery systems and structural modifications could significantly improve their clinical efficacy. When administered early or as a complementary therapy, flavonoids can be considered a safe and effective approach to the management of neurodegenerative diseases.}, } @article {pmid41245880, year = {2025}, author = {Mahdavi, SA and Maghooli, K and Farokhi, F}, title = {A Fuzzy Cognitive Map-based Framework for Alzheimer's Disease Diagnosis Using Multimodal Magnetic Resonance Imaging-Positron Emission Tomography Registration.}, journal = {Journal of medical signals and sensors}, volume = {15}, number = {}, pages = {31}, pmid = {41245880}, issn = {2228-7477}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive and irreversible brain disorder, characterized by a gradual decline in cognitive and memory function, with memory loss being one of the most prominent symptoms. Accurate and early diagnosis of AD is essential for effective management and treatment. Structural magnetic resonance imaging (sMRI) and positron emission tomography (PET) are widely utilized neuroimaging modalities for diagnosing AD due to their ability to provide complementary structural and functional insights into brain abnormalities.

METHODS: This study introduces a novel computer-aided diagnosis system that integrates sMRI and PET data using Fuzzy Cognitive Maps (FCM) to improve diagnostic accuracy. The research is conducted using the ADNI dataset, where preprocessing of sMRI and PET images is performed using FSL and statistical parametric mapping tools, respectively. In a key innovation, features extracted from both modalities are fused and dimensionality reduction is achieved through an Autoencoder model. The reduced feature set is then classified using FCM, Support Vector Machine, k-Nearest Neighbors, and Multilayer Perceptron.

RESULTS: The FCM-based approach demonstrates superior performance, achieving the highest accuracy of 93.71%, surpassing other classifiers tested.

CONCLUSIONS: This study underscores the effectiveness of integrating FCM with multimodal neuroimaging data and highlights its potential for enhancing the early and reliable diagnosis of AD.}, } @article {pmid41245492, year = {2025}, author = {Hines, D and Tobey, H and Dugan, P and Boehringer, S and Helm, R and Anandakrishnan, R and Werre, S and VandeVord, P and Costa, BM}, title = {A preliminary study on the effect of quantified cranial osteopathic manipulation on wild-type and transgenic rat models of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251393742}, pmid = {41245492}, issn = {2542-4823}, abstract = {Alzheimer's disease is a chronic progressive neurodegenerative disorder that impairs the meningeal lymphatics, glymphatic system, and compartmental fluid exchange, leading to a decline in cognitive function. Due to the lack of non-pharmacological and physiological treatments, cranial osteopathic manipulation (COM) poses a potential minimally invasive therapeutic choice. To understand the treatment and related effects objectively, we have established a technique to quantify the force applied during COM on an animal model of AD for the first time. Our results indicate that quantified COM can be applied to rodents to study behavioral and biochemical phenotype changes.}, } @article {pmid41245147, year = {2025}, author = {Pluta, R}, title = {Direct and indirect role of non-coding RNAs in company with amyloid and tau protein in promoting neuroinflammation in post-ischemic brain neurodegeneration.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1670462}, pmid = {41245147}, issn = {1662-5102}, abstract = {Post-ischemic brain neurodegeneration with subsequent neuroinflammation is a major cause of mortality, permanent disability, and the development of Alzheimer's disease type dementia in the absence of appropriate treatment. The inflammatory response begins immediately after ischemia and can persist for many years. Post-ischemic neuroinflammation plays a dual role: initially, it is essential for brain repair and maintenance of homeostasis, but when it becomes uncontrolled, it causes secondary damage and worsens neurological outcome. Neuroinflammation is a complex phenomenon involving interactions between infiltrating immune cells from the peripheral circulation and resident immune cells in ischemic brain areas. This review focuses on the complex relationship between non-coding RNAs, amyloid accumulation, tau protein modifications, and the development of neuroinflammation in the post-ischemic brain. In particular, it clarifies whether the cooperation of non-coding RNAs with amyloid and tau protein enhances neuroinflammation and whether the vicious cycle of neuroinflammatory responses affects the production, behavior, and aggregation of these molecules. Ultimately, elucidating these interactions is critical, as they may contribute to resolving the phenomenon of post-ischemic brain neurodegenerative mechanisms. Furthermore, this review highlights the role of neuroinflammation as a functionally complex immune response regulated/mediated by transcription factors and cytokines. Additionally, it examines how the presence of non-coding RNAs, amyloid aggregation, and modified tau protein may shape the inflammatory landscape. This review aims to advance our understanding of post-ischemic neuroinflammation and its implications for long-term brain health.}, } @article {pmid41244831, year = {2025}, author = {Ye, S and Zhang, S and Zhang, L and Peng, G and Xie, M and Huang, X and Hu, Y}, title = {Screening and experimental validation of modified Gandou Decoction-targeted inhibitors for alleviating AD components via network pharmacology, machine learning, and molecular dynamics simulation.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1685866}, pmid = {41244831}, issn = {1663-9812}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by abnormal accumulation of β-amyloid (Aβ) and hyperphosphorylation of the Tau protein. Currently, there is a lack of effective and safe therapeutic approaches. In Traditional Chinese medicine (TCM), Gandou Decoction has shown significant efficacy in improving cognitive decline and dementia-related symptoms, but its specific mechanism remains unclear.

METHODS: This study systematically analyzed the active components and anti-AD mechanism of Modified Gandou Decoction (MGD) by integrating network pharmacology, machine learning, molecular docking, molecular dynamics (MD) simulation, and in vitro experimental validation. Obtain the components of Chinese medicines in MGD from TCMSP and screen them via ADMET; obtain AD targets by combining databases and select core targets through machine learning; verify their effects through various analyses and experiments.

RESULTS: A total of 21 potential active molecules of MGD and 68 intersection targets were screened out. Among them, 8 core targets (EIF2AK2, PPARG, BACE1, ESR1, GSK3B, ACE, CASP3, MAPK14) were confirmed to be significantly associated with AD pathology by gene expression difference analysis (P ≤ 0.05). KEGG enrichment analysis showed that MGD mainly intervenes in the amyloid production pathway, the MAPK pathway, and the IL-17 pathway. Molecular docking demonstrated that the majority of the 21 potential active compounds exhibited strong binding affinities to the 8 core targets. Moreover, some potential active molecules exhibited better binding energy and similar binding modes compared with known inhibitors when binding to the corresponding target proteins. Molecular dynamics simulation showed that Alisol B, a potential active component of MGD, could stably bind to BACE1, EIF2AK2, and CASP3. In vitro cell experiments confirmed that Alisol B could significantly reverse okadaic acid-induced damage in SH-SY5Y cells (p < 0.001).

CONCLUSION: MGD exerts its anti-AD effect through its potential active component Alisol B, which binds to target proteins BACE1, EIF2AK2, and CASP3, and synergistically inhibits Aβ production, Tau phosphorylation, and neuroinflammatory processes through multiple pathways. This study provides a foundation for developing MGD-derived natural products for AD treatment, although the precise mechanisms require further experimental validation.}, } @article {pmid41243261, year = {2025}, author = {Bramen, JE and Siddarth, P and Popa, ES and Kress, GT and Rapozo, MK and Hodes, JF and Ganapathi, AS and Sparks, WM and Tongson, YM and Torres, AM and Meysami, S and Slyapich, CB and Glatt, RM and Pierce, K and Miller, KJ and Elhelou, SH and Porter, VR and Wong, C and Kim, M and Panos, S and Hirsch, DA and Raji, CA and Bookheimer, SY and Hood, L and Roach, JC and Merrill, DA}, title = {A multi-modal medical management and lifestyle intervention increase cerebral blood flow and lowers diabetic risk in persons with early Alzheimer's disease: Mid-trial results from the PREVENTION trial.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1819-1833}, pmid = {41243261}, issn = {1875-8908}, support = {P41 EB015909/EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; Male ; *Alzheimer Disease/therapy/physiopathology/diagnostic imaging/complications ; Female ; *Cerebrovascular Circulation/physiology ; Aged ; *Diabetes Mellitus/prevention & control ; Magnetic Resonance Imaging ; *Life Style ; Middle Aged ; Exercise Therapy/methods ; Combined Modality Therapy ; Aged, 80 and over ; Exercise ; }, abstract = {BackgroundMedical and lifestyle management are crucial for Alzheimer's disease (AD). Cerebral blood flow (CBF), vital for brain health, and influenced by modifiable risk factors, is reduced in AD and may become uncoupled from metabolism due to neurovascular dysfunction in later stages.ObjectiveThis mid-trial analysis tested the hypothesis that a coached, multi-modal intervention (PREVENTION) improved ASL-MRI-measured CBF and diabetic risk (QUICKI) in patients with early AD.MethodsThe control arm received recommendations and medical management for one year; the active arm additionally received coaching, exercise training, and supplementation. We hypothesized that those in (1) the active arm and (2) with higher intervention adherence would have improved post-trial QUICKI and CBF, particularly in regions relevant to exercise, cardiovascular, diabetic, and AD risk. Post-trial CBF was analyzed using a linear model including arm, baseline CBF, adherence, age, education, and depressive symptoms. Change in QUICKI was analyzed using mixed effects general linear models, including arm, adherence, time, and interactions between time and treatment group and time and adherence, controlling for age.ResultsThe active arm (n = 18) showed greater post-trial CBF in regions related to exercise, cardiovascular, diabetic, and AD risk, compared to control (n = 20), but did not differ in global CBF, QUICKI, or adherence. Higher adherence scores were associated with greater regional post-trial CBF and improvement in QUICKI, but not global CBF.ConclusionsIn this small sample, we found evidence that a multi-modal intervention focused on medical management, exercise, and a carbohydrate-restricted diet improved diabetic risk and CBF in patients with AD.}, } @article {pmid41242500, year = {2025}, author = {Gungor, D and Muratoglu, S and Aytekin, E and Reçber, T and Telli, G and Akdag, Y and Sahin, S and Gulsun, T}, title = {Assessment of intranasal permeability and pharmacological activity of glyburide-loaded nanosuspension formulation for Alzheimer's disease.}, journal = {Journal of pharmaceutical sciences}, volume = {115}, number = {2}, pages = {104064}, doi = {10.1016/j.xphs.2025.104064}, pmid = {41242500}, issn = {1520-6017}, abstract = {Glyburide is an anti-diabetic drug with promising potential implications for Alzheimer's disease. This study evaluated the permeability and activity of glyburide via intranasal administration in Alzheimer's disease using both in vivo and ex vivo studies. A glyburide nanosuspension, was used as the drug delivery system. Stability studies demonstrated that the nanosuspension formulation presented suitable stability during in vitro and in vivo studies. The chosen in vivo glyburide dose demonstrated a non-toxic profile via MTT. Additionally, the in vitro permeability of the nanosuspension was assessed. Pharmacological activity was further evaluated through in vivo behavioural tests, including the Morris water maze and novel object recognition tests, and amyloid-beta levels were measured in mice brain tissues with ELISA. Ex vivo quantification of glyburide concentration in various tissues was also conducted. In vitro permeability studies showed that the nanosuspension formulation significantly enhanced permeability of glyburide. In vivo behavioural tests demonstrated that the nanosuspension formulation yielded favourable and promising outcomes even it was administered intranasally. This study suggests that, through the solubility enhancement provided by nanocrystal technology increased the bioavailability of glyburide comparing the intranasal administration of glyburide, leading to improve in vivo activity compared to the raw glyburide suspension in the treatment of Alzheimer's disease.}, } @article {pmid41242034, year = {2026}, author = {Bruyère, O and Leroy, L and Olivier, C and Demonceau, C and Buckinx, F and Blavier, M and Lekeu, F}, title = {Exploring the knowledge, attitudes, and practices of physical therapists in care facilities assisting individuals with Alzheimer's disease.}, journal = {Geriatric nursing (New York, N.Y.)}, volume = {67}, number = {}, pages = {103710}, doi = {10.1016/j.gerinurse.2025.103710}, pmid = {41242034}, issn = {1528-3984}, mesh = {Humans ; *Alzheimer Disease/nursing/therapy ; *Physical Therapists/psychology ; *Health Knowledge, Attitudes, Practice ; *Nursing Homes ; Surveys and Questionnaires ; Female ; Male ; Belgium ; Aged ; Middle Aged ; }, abstract = {INTRODUCTION: Physical therapists (PTs) in nursing homes often treat patients with Alzheimer's disease. This study evaluated their knowledge, attitudes, and practices (KAP) concerning Alzheimer's care.

METHODS: A KAP survey-based questionnaire was administered to PTs in Belgian nursing homes and long-term care facilities, focusing on their understanding of Alzheimer's, care approaches, and practical care aspects.

RESULTS: The survey, completed by 133 PTs, revealed strong knowledge and positive attitudes. PTs adapted communication methods, managed treatment refusals, and prioritized fall prevention and safety. Care practices focused on maintaining patient autonomy through exercises for strength, balance, and coordination. Techniques like massage or aromatherapy were less commonly used, despite potential benefits. Notably, knowledge, experience, or exposure to Alzheimer's patients did not significantly influence attitudes or practices.

CONCLUSION: Targeted practical training in dementia care techniques is needed to enhance caregiving skills, despite a solid foundation in knowledge and attitudes. Future research should examine diverse samples and evaluate training impact on practices.}, } @article {pmid41241266, year = {2026}, author = {Sharma, A and Singh, TG}, title = {Next-generation neurotherapeutics: mechanistic insights on monoclonal antibodies in Alzheimer's disease.}, journal = {Brain research}, volume = {1870}, number = {}, pages = {150047}, doi = {10.1016/j.brainres.2025.150047}, pmid = {41241266}, issn = {1872-6240}, mesh = {*Alzheimer Disease/drug therapy/immunology/metabolism/therapy ; Humans ; *Antibodies, Monoclonal/therapeutic use ; Animals ; Amyloid beta-Peptides/metabolism/immunology ; tau Proteins/immunology ; }, abstract = {Monoclonal antibodies (mAbs) for Alzheimer's disease (AD) present a fundamental translational challenge, as demonstrated by amyloid-beta (Aβ)-targeting mAbs that successfully employed Fragment crystallizable gamma receptor (FcγR)/Immunoreceptor tyrosine-based activation motif (ITAM)-mediated microglial phagocytosis yet achieved only modest cognitive improvements while introducing significant Amyloid-related imaging abnormalities (ARIA) risk, thereby highlighting inherent single-therapy limitations. Building on these findings, tau-directed antibodies show preclinical promise by targeting pathological seeding and propagation, but face translational challenges including limited extracellular accessibility and variable efficacy across disease stages, necessitating expansion beyond single-target approaches. Consequently, the translational field is advancing toward innovative multi-mechanistic strategies, including synaptic restoration through anti-PrP and neurotrophic receptor agonists that provide functional benefits independent of plaque reduction, neuroinflammation modulation via anti-CD33 and complement inhibitors requiring careful patient selection due to variable outcomes, and emerging anti-TREM2 and anti-APOE4 mAbs enabling precision medicine tailored to individual genetic profiles. Importantly, comparative studies also reveal that combination therapies-especially dual Aβ/tau targeting-demonstrate superior synergistic effectiveness, driving next-generation engineering advances including Fc modifications that reduce ARIA risk, nanobodies/single-chain variable fragments (scFvs) with enhanced blood-brain barrier (BBB) penetration, cell-penetrating formats for intracellular tau access, and pH-sensitive glycoengineering for optimized tissue-specific binding. Ultimately, successful clinical translation depends on integrating biomarker-guided patient selection, optimized dosing strategies, and disease-stage-appropriate timing, with future progress anticipated through bispecific/multispecific antibodies targeting complementary pathways alongside personalized biomarker approaches, collectively providing realistic potential for achieving genuine neuroprotection and meaningful disease modification beyond symptomatic treatment in AD patients.}, } @article {pmid41240919, year = {2025}, author = {Kaila, LV and Ikeda, M and Sultana, J and Chouliaras, L and O'Brien, JT and Taylor, JP}, title = {The evolving therapeutic landscape of dementia with Lewy bodies.}, journal = {The Lancet. Neurology}, volume = {24}, number = {12}, pages = {1038-1052}, doi = {10.1016/S1474-4422(25)00323-0}, pmid = {41240919}, issn = {1474-4465}, mesh = {Humans ; *Lewy Body Disease/therapy/diagnosis ; }, abstract = {Dementia with Lewy bodies has a complex clinical presentation, with symptoms spanning cognitive, neuropsychiatric, motor, autonomic, and sleep domains. The disorder causes high morbidity, is associated with high caregiver burden, and can result in considerable health-care costs. Although symptomatic treatments remain scarce, emerging evidence supports a multipronged approach that integrates pharmacological and non-pharmacological interventions that target different signs and symptoms. Novel frameworks, such as the DIAMOND Lewy toolkit, provide structured management guidance. Beyond symptom control, research is at a turning point, with increasing focus on disease-modifying therapies. Ongoing clinical trials are exploring many therapeutic targets, including α-synuclein aggregation and neuroinflammation. Other potential targets in the treatment of dementia with Lewy bodies include amyloid β, given that the presence of Alzheimer's disease copathology is common in patients with this disease.}, } @article {pmid41240389, year = {2025}, author = {Jahanmehr, D and Ahmadi, A and Fadaei, M and Sangi Nasab Lahijan, A and Shafiee Sabet, M and Kalantari Dehaghi, H and Asadi-Golshan, R}, title = {The Ketogenic Diet: A Possible Intervention for Improving Hippocampal Function in Neurological Disorders.}, journal = {Nutrition reviews}, volume = {}, number = {}, pages = {}, doi = {10.1093/nutrit/nuaf210}, pmid = {41240389}, issn = {1753-4887}, abstract = {With a focus on the hippocampus, in this review we examined the emerging role of the ketogenic diet (KD) in treating neurological disorders. There are multiple pathways through which various versions of the KD influence the hippocampus: energy metabolism shifts, neurotransmitter modulation, neuroinflammation control, and synaptic plasticity and epigenetic regulation modifications. Both animal studies and clinical research, with emphasis on epilepsy and Alzheimer disease, have revealed the therapeutic potential of KDs. By modifying energy metabolism and lowering neuroinflammation, KDs may have therapeutic uses such as treatment of epilepsy and Alzheimer disease. In addition, ketones may stabilize hippocampal neuronal networks and reduce amyloid-beta toxicity. Individualized factors and the duration and timing of KD intervention play critical roles in achieving optimal outcomes, such as enhanced hippocampal function and neuroprotection. While preclinical studies have demonstrated enhanced hippocampal synaptic plasticity and neuroprotection, the long-term neurological and metabolic effects of KDs require further clinical validation. There are still a number of important research gaps, especially with regard to the application of animal findings to humans. Future studies should concentrate on long-term human trials using standardized designs to investigate how KDs can affect the nervous system.}, } @article {pmid41240365, year = {2025}, author = {Zammit, MD and Bruzzone, H and Cody, KA and Morse, J and Wilson, R and Bettcher, BT and McLachlan, MJ and McVea, AK and DiFilippo, AH and Carey, FJ and Janelidze, S and Hansson, O and Price, JC and Laymon, CM and Minhas, DS and Luo, W and Rosas, HD and Lai, F and Lee, JH and Lao, PJ and Ances, BM and Krinsky-McHale, SJ and Hom, CL and Hartley, SL and Zaman, SH and Johnson, SC and Cohen, AD and Head, E and Mapstone, ME and Handen, BL and Christian, BT and Tudorascu, DL and Langhough, RE and Betthauser, TJ and , }, title = {The tau biomarker cascade is condensed in Down syndrome compared to sporadic Alzheimer's disease.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf428}, pmid = {41240365}, issn = {1460-2156}, abstract = {Characterizing the timing and progression of Alzheimer's disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer's disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium - Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer's Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analyzed on Lilly MSD were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modeling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4-6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help identify optimal treatment windows for these individuals.}, } @article {pmid41240244, year = {2025}, author = {Jayathilaka, NS and Weththasinghe, AV and Amarasekara, CI and Amasha, EADH and Wijekoon, KJ and Firdous, SM}, title = {Targeting the Gut-Brain Axis Through Insulin-like Growth Factors: Therapeutic Implications and Future Directions.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {4}, pages = {150}, pmid = {41240244}, issn = {1559-1166}, mesh = {Humans ; Animals ; *Brain/metabolism ; Gastrointestinal Microbiome ; *Somatomedins/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy/therapy ; *Insulin-Like Growth Factor I/metabolism ; *Brain-Gut Axis ; *Gastrointestinal Tract/metabolism ; Insulin-Like Peptides ; }, abstract = {The gut-brain axis represents a sophisticated bidirectional communication network connecting the gastrointestinal tract and central nervous system through neural, endocrine, and immune pathways. Insulin-like growth factors (IGFs), particularly IGF-1 and IGF-2, function as pivotal mediators within this communication framework. These polypeptide growth factors regulate intestinal barrier integrity, microbiota homeostasis, neurogenesis, and synaptic plasticity mechanisms. Clinical evidence from 1989 to 2024 demonstrates that gut microbiota-derived short-chain fatty acids enhance IGF-1 production through novel molecular mechanisms. This narrative review examines IGF roles in gut-brain communication and evaluates therapeutic potential for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and depression, as well as inflammatory bowel disorders. Current clinical trials investigating IGF-based interventions show preliminary promising results, though studies remain limited in scope and patient numbers. Key therapeutic challenges include delivery mechanisms across biological barriers, oncogenic safety concerns related to cell proliferation, and substantial individual variability in treatment responses. Future directions emphasize development of tissue-specific IGF modulators, microbiome-targeted interventions, and precision medicine approaches utilizing advanced biomarkers. Understanding IGF-mediated gut-brain communication presents therapeutic opportunities for complex pathological conditions simultaneously affecting gastrointestinal and neurological systems.}, } @article {pmid41240183, year = {2025}, author = {García-Castro, P and Conejo, NM and González-Pardo, H}, title = {Transcranial photobiomodulation therapy in older women regarding cognitive functions: a systematic review.}, journal = {Lasers in medical science}, volume = {40}, number = {1}, pages = {480}, pmid = {41240183}, issn = {1435-604X}, mesh = {Humans ; *Low-Level Light Therapy/methods ; Female ; *Cognition/radiation effects ; Aged ; *Cognitive Dysfunction/therapy ; Animals ; Alzheimer Disease/therapy ; }, abstract = {Transcranial photobiomodulation therapy (tPBM) is a promising non-invasive treatment that uses red or near-infrared light to modulate biological functions and elicit therapeutic effects. This systematic review aimed to summarise the evidence on the effectiveness of tPBM in improving cognitive function in older women, in experimental animal models and in humans, by analyzing the optimal tPBM parameters and behavioral and neurobiological outcomes. tPBM offers advantages specific to older women as a non-invasive brain stimulation technique, applied to a sensitive population with increased risk of ageing-related brain dysfunction due to increased life expectancy. A comprehensive literature search was conducted in PubMed, Scopus, and PsycINFO databases, and only seven articles on older women were included in the review. Studies have shown that tPBM significantly improves cognitive impairment in Alzheimer's disease and related dementias, stroke, cognition and Parkinson's disease in older women. Despite the heterogeneity in the application parameters and limited number of studies, tPBM therapy was preliminarily found to be a safe, feasible, and effective non-pharmacological therapy for several neurological and mental health conditions in older women. Further research is required to establish standardized protocols for optimal therapeutic applications.}, } @article {pmid41239797, year = {2025}, author = {Garg, N and Dhankhar, S and Dhariya, A and Parkash, C and Chauhan, S and Singh, TG}, title = {Role of Liposomes in the Treatment of Neurodegenerative Disorders: A Comprehensive Review.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {25}, number = {4}, pages = {496-512}, pmid = {41239797}, issn = {1875-6166}, mesh = {Humans ; *Liposomes/metabolism/chemistry ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Drug Delivery Systems/methods ; *Neuroprotective Agents/administration & dosage/therapeutic use ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {The complex etiology and limited therapy options of neurodegenerative illnesses pose daunting challenges to modern medicine. Nonetheless, novel treatment approaches have exciting new possibilities because of developments in nanotechnology. Liposomes have garnered a lot of interest as a potential treatment for neurological illnesses due to the fact that they are able to adapt to their role as nanocarriers. This review article discusses various uses of liposomes, including their ability to help treat neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, as well as their diagnostic and neuroprotective uses. Liposomes allow for the targeted delivery of medicines to specific brain areas with minimal systemic side effects since they encapsulate and carry therapeutic molecules across the blood-brain barrier. Due to the fact that they are biocompatible, have surface features that can be adjusted, and have the ability to co-deliver many drugs, liposomes are excellent candidates for combination therapy and personalized medicine procedures. In spite of this, there is a growing body of research that suggests liposomes could serve as a versatile platform for the improvement of neurodegenerative disease treatment. This is a positive sign for the future results of patients and their quality of life.}, } @article {pmid41239092, year = {2025}, author = {Kong, W and Miao, X and Dang, R and Jiang, P and Feng, L}, title = {Mechanisms and Clinical Significance of Endosomal Toll-Like Receptors in Neurological Diseases.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {54}, pmid = {41239092}, issn = {1559-1182}, support = {82373585//National Natural Science Foundation of China/ ; 2023M741364//the China Postdoctoral Science Foundation/ ; ZR2022MH007//the Natural Science Foundation of Shandong Province/ ; 2022YXNS124//the Jining Key R&D Projects/ ; 2022YXNS137//the Jining Key R&D Projects/ ; 202304040457//the Medical and Health Science and Technology Development Project of Shandong Province/ ; }, mesh = {Humans ; *Toll-Like Receptors/metabolism ; *Endosomes/metabolism ; Animals ; *Nervous System Diseases/metabolism ; Signal Transduction ; Clinical Relevance ; }, abstract = {Neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and epilepsy constitute a major global public health burden, affecting millions of patients. Recent studies have shown that the complex interactions between the immune system and the nervous system play a significant role in these diseases, especially Toll-like receptors (TLRs), among which endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) are crucial in neuroinflammation and disease progression. This review systematically elaborates on the biological characteristics of endosomal TLRs, their distribution, and signaling pathways within the central nervous system, with a particular focus on their "double-edged sword" effect in specific disease contexts: on the one hand, they may provide neuroprotection, while on the other hand, they can exacerbate neural injury and neurodegeneration during immune dysregulation. Furthermore, this article evaluates the potential and challenges of utilizing endosomal TLRs as early diagnostic biomarkers. It summarizes research progress in targeted regulatory strategies as emerging therapeutic approaches, along with the encountered bottlenecks in clinical translation. The review aims to systematically integrate fundamental mechanistic research with clinical application prospects, emphasizing the critical importance of in-depth elucidation of the mechanistic roles of endosomal TLRs in neurological disorders and their translational value in diagnosis and treatment. Clinical trial number: not applicable.}, } @article {pmid41239049, year = {2025}, author = {Ma, H and Cong, C}, title = {Insights and advances of theranostic nanoscale metal-organic frameworks.}, journal = {Mikrochimica acta}, volume = {192}, number = {12}, pages = {809}, pmid = {41239049}, issn = {1436-5073}, mesh = {*Metal-Organic Frameworks/chemistry ; Humans ; *Theranostic Nanomedicine/methods ; Contrast Media/chemistry ; Animals ; }, abstract = {As one class of multifunctional materials, metal-organic frameworks (MOFs) with virtues like large surface area, high porosity, and tailorability have been found in many applications. Particularly, the investigation on health is rapidly growing. Accurate diagnosis and efficient treatment of diseases are increasingly important but challenging. Nanoplatforms based on MOFs are receiving much attention, which has made significant progress in imaging and drug delivery during the past few years. This review article will summarize and discuss the latest development of nanoscale MOFs in the following topics: contrast agents for magnetic resonance imaging (MRI); X-ray computed tomography imaging (CT); optical imaging (OI); photoacoustic imaging (PAI); photothermal imaging (PTI); positron emission tomography (PET); single-photon emission computed tomography (SPECT); and multimodal imaging (MI). In addition, targeting drug delivery by MOFs to treat diseases will be categorized into the followings: cancers; lung diseases; bone diseases; diabetes; infections; wound healing; bowel diseases; Alzheimer's disease; ocular diseases; and atherosclerosis.}, } @article {pmid41238774, year = {2025}, author = {Cerman, J and Škorvagová, A and Vyhnálek, M and Veverová, K and Dvořák, K and Kozák, Š and Kavka, A and Hort, J}, title = {Concordance between amyloid PET and CSF biomarkers in clinical setting: a cross-platform comparison and in-depth analysis of discordant cases.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {39963}, pmid = {41238774}, issn = {2045-2322}, mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/diagnosis/metabolism ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Female ; *Positron-Emission Tomography/methods ; Aged ; tau Proteins/cerebrospinal fluid ; Middle Aged ; Peptide Fragments/cerebrospinal fluid ; *Amyloid/metabolism ; Aged, 80 and over ; Enzyme-Linked Immunosorbent Assay ; Apolipoprotein E4/genetics ; }, abstract = {Reliable detection of amyloid pathology is essential for Alzheimer's disease (AD) diagnosis and treatment. We directly compared routine ELISA assays and the automated Lumipulse platform against quantitative amyloid PET in a real-world memory clinic cohort. In 153 participants, flutemetamol amyloid PET and CSF biomarkers were assessed across platforms. Concordance with PET and predictors of discordance were evaluated. PET visual reads and Centiloids showed near-perfect agreement (AUC = 0.99). The p-tau181/Aβ42 ratio achieved the highest concordance with PET (OPA 87% ELISA, 92% Lumipulse), while the Lumipulse Aβ42/40 ratio reached 93%. About 6% of participants showed consistent discordance between CSF and PET, associated with APOE ε4 and mixed or non-AD pathologies. Automated CSF assays align strongly with amyloid PET and support biomarker standardization. Persistent discrepancies between CSF and PET likely reflect underlying biological heterogeneity such as mixed or non-AD pathologies and APOE ε4 carriage.}, } @article {pmid41238601, year = {2025}, author = {Alzarea, SI}, title = {Identification of novel neuraminidase 1 modulators as potential therapeutics for Alzheimer's disease using virtual screening and molecular dynamics simulations.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {39901}, pmid = {41238601}, issn = {2045-2322}, support = {KSRG-2024-340//King Salman Center for Disability Research/ ; }, mesh = {*Neuraminidase/antagonists & inhibitors/metabolism/chemistry ; *Alzheimer Disease/drug therapy/enzymology/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Humans ; *Enzyme Inhibitors/pharmacology/chemistry ; Drug Evaluation, Preclinical ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder caused by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, resulting in neuronal dysfunction and cognitive decline. The neuraminidase isoenzyme NEU1 is a most ubiquitous mammalian enzyme, involved in various cellular mechanisms. The deficiency of NEU1 has been implicated in the pathophysiology of AD, significantly in amyloid precursor protein (APP) metabolism and Aβ clearance. Despite extensive research, no potent NEU1 modulator has been developed to regulate its activity for therapeutic intervention in AD. The present work aims to identify potential NEU1 modulators from a library of seaweed Metabolites Database through molecular docking, ADMET analysis, and molecular dynamics (MD) simulations. A library of 1,077 seaweed metabolites was screened, identifying 20 active compounds, of which 4 met Lipinski's Rule of Five criteria. ADMET profiling revealed favorable pharmacokinetic properties for BE003, BS032, and RG007, with good blood-brain barrier permeability and bioavailability. Molecular docking demonstrates that BE003, BS032, RG007, and BD039 metabolites exhibited the highest binding affinities for the NEU1 active site. Additionally, MD simulation and MM-GBSA validated the stability of the metabolite-protein complex, with BE003 demonstrating the most stable interactions. Comparative docking against a natural substrate (Neu5Ac) and a NEU1 inhibitor (17f) revealed that BE003 shares significant interaction, RMSD stability profiles with the substrate and loop conformational dynamics while differing from the inhibitor. Our findings emphasize the potential of this modulator as a novel therapeutic target against NEU1 in AD treatment. Further experimental validation and preclinical studies are needed to confirm its efficacy in modulating NEU1 activity.}, } @article {pmid41238155, year = {2026}, author = {Heath, AM and Mojabi, FS and Kraybill, EP and Beard, C and Venkataramanan, V and Cuéllar, V and Piekarski, D and McNerney, MW}, title = {Comparison of treatment schedules on cognitive effects of rTMS in the 3xTg-AD model of Alzheimer's disease.}, journal = {Experimental neurology}, volume = {396}, number = {}, pages = {115551}, doi = {10.1016/j.expneurol.2025.115551}, pmid = {41238155}, issn = {1090-2430}, mesh = {Animals ; *Alzheimer Disease/therapy/genetics/complications/pathology/psychology ; *Transcranial Magnetic Stimulation/methods ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Male ; Mice, Inbred C57BL ; Maze Learning/physiology ; Brain-Derived Neurotrophic Factor/metabolism ; tau Proteins/genetics/metabolism ; Amyloid beta-Protein Precursor/genetics ; *Cognition Disorders/etiology/therapy ; Memory, Short-Term/physiology ; Presenilin-1/genetics ; Choline O-Acetyltransferase/metabolism ; Cognition/physiology ; }, abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a promising non-invasive therapy for improving cognition in Alzheimer's disease (AD), but the optimal treatment parameters have yet to be elucidated. One important parameter is the treatment schedule. In this study, we used an established rodent low intensity rTMS stimulation protocol to compare cognitive and biochemical effects of an intensive treatment protocol (daily for 12 days) to a distributed protocol (twice a week for six weeks) in 12-month-old 3xTg-AD mice and B6 controls. We found that both protocols improved object place memory function, but only the distributed protocol improved working memory as measured with the Y-Maze. We did not find any effect of either rTMS protocol on BDNF or amyloid pathology, although these measures correlated well with activity and cognitive performance, suggesting rTMS improvement was independent of these mechanisms. Intensive rTMS increased choline acetyltransferase-positive neurons in the anterior bed nucleus of the stria terminalis (BNST), which may be due to the function of this region in mediating cognitive and limbic circuitry. These results indicate that while both treatment protocols can improve specific aspects of recognition memory, only distributed rTMS improves working memory function, possibly due to causing less cognitive fatigue and physiological stress. Future studies should examine region specific changes relating working memory function and stress related signaling to further understand the mechanisms behind this important rTMS treatment parameter.}, } @article {pmid41238102, year = {2026}, author = {Long, J and Liu, S and Shi, Y and Zhang, C and Qin, L and Ai, Q}, title = {Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical.}, journal = {Metabolism: clinical and experimental}, volume = {175}, number = {}, pages = {156436}, doi = {10.1016/j.metabol.2025.156436}, pmid = {41238102}, issn = {1532-8600}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Lipid Metabolism/drug effects/physiology ; Animals ; Brain/metabolism ; }, abstract = {The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases-including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)-are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.}, } @article {pmid41238077, year = {2025}, author = {Ancy, A and Mohan, S}, title = {Development and optimization of flavonoid-enriched solid lipid nanoparticles of Peperomia pellucida for enhanced brain delivery in Alzheimer's disease: A Quality by Design approach.}, journal = {Annales pharmaceutiques francaises}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.pharma.2025.11.003}, pmid = {41238077}, issn = {2772-803X}, abstract = {OBJECTIVES: The Peperomia pellucida plant exhibits notable neuroprotective potential but has low oral bioavailability in the brain. Herein, we aimed to enhance the oral bioavailability and brain distribution of P. pellucida, by formulating its flavonoid-enriched fraction into solid lipid nanoparticles as a potential therapeutic approach for Alzheimer' disease.

MATERIALS AND METHODS: Flavonoid-enriched solid lipid nanoparticles of P. pellucida were formulated using an ultrasonication method. A Box-Behnken design was utilized to optimize particle size, entrapment efficiency, and burst release. The optimized formulation was identified via numerical and graphical optimization, and validated through reproducibility studies. Further characterization included scanning electron microscopy and in vivo drug release studies in rats.

RESULTS: Glycerol tripalmitate-based solid lipid nanoparticles exhibited superior entrapment efficiency and reduced burst release. The mean particle size of the solid lipid nanoparticles ranged 110-884nm, with entrapment efficiency ranging 55-94%. Oral administration of the optimized formulation significantly improved bioavailability in rats and enhanced drug distribution in the cortex and hippocampus of the brain.

CONCLUSION: The results highlight the potential of solid lipid nanoparticles as an effective delivery system for the flavonoid-enriched fraction of P. pellucida, enhancing its therapeutic impact in the treatment of Alzheimer's disease.}, } @article {pmid41237463, year = {2025}, author = {Cho, E and Yi, JH and Jeon, SJ and Kim, DH and Kwon, H and Jeon, J and Kwon, KJ and Jang, DP and Moon, M and Shin, CY and Kim, DH}, title = {Increases in brain catecholamine levels counteract memory deficits and reduces Aβ deposition in 5XFAD male mice.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {193}, number = {}, pages = {118764}, doi = {10.1016/j.biopha.2025.118764}, pmid = {41237463}, issn = {1950-6007}, mesh = {Animals ; Male ; *Memory Disorders/metabolism/drug therapy ; *Amyloid beta-Peptides/metabolism ; Mice ; Norepinephrine/metabolism ; Bupropion/pharmacology ; *Alzheimer Disease/metabolism/drug therapy ; Hippocampus/metabolism/drug effects/physiopathology ; Mice, Transgenic ; Dopamine/metabolism ; Disease Models, Animal ; *Catecholamines/metabolism ; *Brain/metabolism/drug effects ; Memory/drug effects ; Long-Term Potentiation/drug effects ; }, abstract = {Alzheimer's disease (AD) is a degenerative brain disease that presents with neurological symptoms and memory loss, with no clear treatment. Catecholamines, including dopamine, epinephrine, and norepinephrine, can inhibit or degrade the abnormal aggregation of proteins that cause diseases; however, developing these catecholamines as medication is difficult. This study aimed to demonstrate that increasing the levels of catecholamines in the brain may help improve symptoms of AD. We tested whether an increase in catecholamines by bupropion, a dopamine and norepinephrine re-uptake inhibitor, improves the symptoms of AD. Dopamine and norepinephrine showed similar effects in inhibiting amyloid β (Aβ) aggregation and the decomposition of Aβ aggregates as curcumin, a positive control. Dopamine and norepinephrine blocked Aβ aggregates-induced abnormal hippocampal long-term potentiation. The intraperitoneal administration of bupropion increased the concentrations of dopamine and norepinephrine in the hippocampus from 1 to 6 h after administration. In the Aβ-induced memory decline model, bupropion showed a dose-dependent improvement in learning and memory. In 5XFAD mice administered bupropion for 2 months, significant improvements in memory and Aβ deposition were also found compared to vehicle-treated 5XFAD mice. These results suggest that the symptoms of AD can be improved or delayed by increasing the amount of dopamine and norepinephrine using bupropion.}, } @article {pmid41237058, year = {2026}, author = {Xu, F and Wang, J and Gao, P and Li, D and Liu, X}, title = {Neuroprotective Effects of Triterpenoids From Rosa laevigata Root: Identification, Molecular Docking, and In Vitro Evaluation for Alzheimer's Disease Treatment.}, journal = {Chemistry & biodiversity}, volume = {23}, number = {1}, pages = {e02742}, doi = {10.1002/cbdv.202502742}, pmid = {41237058}, issn = {1612-1880}, mesh = {*Neuroprotective Agents/pharmacology/chemistry/isolation & purification ; Humans ; *Molecular Docking Simulation ; *Alzheimer Disease/drug therapy/metabolism ; Plant Roots/chemistry/metabolism ; *Triterpenes/pharmacology/chemistry/isolation & purification ; Acetylcholinesterase/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification ; *Rosa/chemistry ; Cell Survival/drug effects ; Hydrogen Peroxide/antagonists & inhibitors/pharmacology ; Cell Line, Tumor ; Structure-Activity Relationship ; Antioxidants/pharmacology/chemistry/isolation & purification ; Molecular Structure ; Dose-Response Relationship, Drug ; }, abstract = {This study investigates the neuroprotective effects of triterpenoid compounds from Rosa laevigata Michx. roots against Alzheimer's disease (AD). A total of 62 compounds were identified using ultra-performance liquid chromatography-Orbitrap-tandem mass spectrometry analysis, which included 55 triterpenoids and seven flavonoids. Among 15 isolated compounds, compound 13 demonstrated the strongest acetylcholinesterase (AChE) inhibitory activity, with an IC50 of 3.38 µmol/L, and a maximum inhibition rate of 87.20%. Compound 13 exhibited favorable and stable binding with AChE in molecular docking studies, whilst demonstrating mixed-type inhibition in enzyme kinetics. In the H2O2-induced SH-SY5Y cell model, compound 13 exhibited 84.45% viability at 25 µmol/L, surpassing Trolox's 74.16%. Research indicates that R. laevigata Michx. root triterpenes exert neuroprotective effects through AChE inhibition and antioxidant activity, with compound 13 potentially serving as a multi-target lead compound for treating AD.}, } @article {pmid41236865, year = {2025}, author = {Hanyu, H and Koyama, Y and Momose, T and Watanabe, S}, title = {Patient With Mild Alzheimer's Disease Homozygous for ApoE ε4 Showing Improved Cognition, No Brain Volume Loss, and Complete Amyloid Clearance After Lecanemab Treatment.}, journal = {Geriatrics & gerontology international}, volume = {25}, number = {12}, pages = {1968-1970}, pmid = {41236865}, issn = {1447-0594}, } @article {pmid41236362, year = {2025}, author = {Zide, BS and Barker, MS and Silverman, HE and Manoochehri, M and Fremont, R and Stein, C and Kunicki, ZJ and Lee, S and Devanand, DP and Huey, ED}, title = {Feasibility and tolerability of low-dose lithium for the treatment of agitation and abnormal motor behaviors in Frontotemporal Dementia.}, journal = {International review of psychiatry (Abingdon, England)}, volume = {37}, number = {8}, pages = {827-837}, doi = {10.1080/09540261.2025.2572365}, pmid = {41236362}, issn = {1369-1627}, mesh = {Humans ; Female ; *Psychomotor Agitation/drug therapy/etiology ; *Frontotemporal Dementia/complications/drug therapy ; Middle Aged ; Feasibility Studies ; Male ; Double-Blind Method ; Aged ; }, abstract = {Agitation and abnormal motor behaviors are common, distressing symptoms of Frontotemporal Dementia (FTD). While these symptoms currently lack efficacious and safe pharmacological treatments, case reports in FTD and a clinical trial in Alzheimer's disease suggest that patients may benefit from lithium treatment. We designed a randomized, double-blind, placebo-controlled, 12-week clinical trial to evaluate low-dose lithium for the treatment of agitation and abnormal motor behaviors in FTD. However, the trial did not meet its recruitment target (n = 60). This report assesses the trial's feasibility and tolerability using recruitment, study completion, and safety metrics. Sixteen adults with FTD (median age 59.5 years; 69% female) were enrolled from 2017 to 2021. Fourteen participants (88%) completed the trial. The majority of participants on lithium were taking the maximum daily dose by Week 12 (600 mg), had median (interquartile range) final serum lithium levels of 0.42 (0.37-0.57), and reported minimal side effects, including drowsiness, diarrhea, constipation and insomnia. Preliminary data from intended efficacy outcomes showed no median pre-post changes between treatment groups. Low-dose lithium is feasible and well-tolerated in an FTD population. Further systematic study of lithium and its efficacy to treat agitation and abnormal motor behaviors in FTD is warranted.}, } @article {pmid41235150, year = {2025}, author = {Nigdelioglu Dolanbay, S}, title = {Monoterpene-rich essential oil from Artemisia santonicum L. exerts neuroprotective effects in Aβ-induced SH-SY5Y cells: Modulation of tau pathology, neuroinflammation, oxidative stress, and synaptic-metabolic pathways.}, journal = {Toxicology research}, volume = {14}, number = {6}, pages = {tfaf155}, pmid = {41235150}, issn = {2045-452X}, abstract = {Understanding the complex biological mechanisms of ad requires innovative treatment approaches for this disease. In this context, natural compounds, especially monoterpenes, attract attention with their potential for biological activity. In this study, the therapeutic potential of monoterpene rich essential oil obtained from Artemisia santonicum L. for the treatment of ad was comprehensively evaluated. GC-MS analysis showed that the major monoterpenes were limonene, camphor, pinene, terpineol, and carvone in essential oil obtained from A. santonicum L. Possible common targets of monoterpenes with ad were predicted and their PPI networks were analyzed. Furthermore, gene set enrichment analysis was applied to understand the functional roles of these possible common targets and their relationships with biological pathways. Molecular docking studies revealed the binding affinities and interaction abilities of monoterpenes with the predicted possible common targets. The monoterpene rich essential oil obtained from A. santonicum L. used in our study provides a neuroprotective effect by targeting the pathological mechanisms of ad. We designed in vitro experiments to elucidate the mechanism of the mentioned neuroprotective effect. Within the scope of the study, neuroprotective effect analyses were performed to evaluate cell viability rates and in vitro AChE enzyme activity, while the ELISA method was used to determine phosphorylated tau levels and to assess neuroinflammatory responses. In addition, apoptosis levels, MMP changes and intracellular ROS accumulation were examined by flow cytometry analyses. These comprehensive analyses aimed to reveal the molecular mechanisms of the neuroprotective effect of monoterpene rich essential oil obtained from A. santonicum L. and to shed light on its potential therapeutic applications in ad.}, } @article {pmid41235113, year = {2025}, author = {Zampieri, TT and Higa, GSV and Borges, FS and Viana, FJC and Cruvinel, E and Bentivoglio, LE and Lugao, AB and Ulrich, H and Britto, LR and Katti, KV and Chesne, AM and de Pasquale, R}, title = {Exposure to β-hydroxybutyrate reduces the operating set point and increases excitability in hippocampal circuitry of healthy mice.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1557612}, pmid = {41235113}, issn = {1663-9812}, abstract = {The ketogenic diet is a therapeutic strategy applied to reduce brain hyperexcitability in conditions such as epilepsy, Parkinson's and Alzheimer's disease, migraines, and autism. This diet reduces circulating glucose levels and increases ketone bodies, with β-hydroxybutyrate (BHB) being one of the leading promoters of the beneficial effects. BHB was previously reported as a mediator of cognitive restoration and memory formation. Herein, we investigate the effect of exogenous BHB on hippocampal neuronal excitability and synaptic plasticity mechanisms, regardless of the pathological or neurodegenerative conditions. Electrophysiological experiments were conducted to explore both passive and active neuronal properties, including action potential firing and spontaneous and evoked postsynaptic responses. Electrical stimulation along the CA3-CA1 pathway enabled the assessment of both short- and long-term synaptic plasticity, as well as the mechanisms mediated by AMPA and NMDA receptors. Experiments were conducted in hippocampal slices treated with 3-β-hydroxybutyrate glycerides (DHB) and niacin (HCAR2 agonist). Although DHB incubation did not alter passive membrane properties, it significantly increased neuronal excitability, reflected in an elevated firing rate upon depolarizing stimulation and enhanced spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons, which were dependent on synaptic inputs. DHB treatment led to a reduction in long-term potentiation (LTP) in CA1 neurons, suggesting a metaplastic effect independent of NMDA receptor activation. Importantly, these DHB-induced neuronal alterations were found to be independent of HCAR2 receptor activation, supporting the involvement of distinct intracellular pathways and long-term modulatory mechanisms. Our findings indicate that DHB exerts a modulatory effect on hippocampal neural activity by enhancing excitability and concurrently promoting a compensatory reduction in LTP, suggesting a homeostatic balancing mechanism.}, } @article {pmid41234939, year = {2025}, author = {Wang, R and Peng, S and Zhu, J and Xu, Y and Wang, M and Zhang, L and Qiu, Y and Hou, D and Wang, Q and Liu, R}, title = {Innovations in Alzheimer's disease diagnostic technologies: clinical prospects of novel biomarkers, multimodal integration, and non-invasive detection.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1651708}, pmid = {41234939}, issn = {1664-2295}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) plaques and the formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, ultimately leading to cognitive decline and neuronal loss. Current diagnostic methods, including clinical evaluations, neuroimaging examinations, and cerebrospinal fluid biomarker testing, face challenges such as insufficient sensitivity and specificity, as well as operational complexity. In recent years, significant advancements have been made in diagnostic technologies, with the emergence of new biomarkers and detection methods, including blood-based Aβ and tau protein detection, ocular biomarker testing, and non-invasive screening through urine or breath analysis. These innovative developments, combined with multimodal diagnostic technologies that integrate imaging, genomics, and proteomics, have opened new possibilities for the early diagnosis and precise staging of Alzheimer's disease. Furthermore, advancements in microfluidic chips and biosensor technologies have enhanced the capability for rapid, efficient, and cost-effective diagnosis. As research continues to evolve, the gradual application of these advanced technologies in clinical practice is expected to revolutionize the management of Alzheimer's disease, facilitating early intervention and the formulation of individualized treatment strategies.}, } @article {pmid41234220, year = {2025}, author = {Fujishiro, H and Kawakami, I and Oshima, K and Torii, Y and Arafuka, S and Iritani, S and Ikeda, K}, title = {Systematized delusions in a patient with covert hepatic encephalopathy: A clinicopathological insight into prodromal dementia with Lewy bodies.}, journal = {PCN reports : psychiatry and clinical neurosciences}, volume = {4}, number = {4}, pages = {e70247}, pmid = {41234220}, issn = {2769-2558}, abstract = {BACKGROUND: Late-onset psychosis is an early clinical manifestation of psychiatric-onset prodromal dementia with Lewy bodies (DLB); however, its underlying neuropathology remains poorly understood. Clinicopathological correlations are often limited by the gap between symptom onset and the autopsy.

CASE PRESENTATION: A 66-year-old man with autopsy-confirmed DLB presented with persistent systematized delusions. After treatment for liver cirrhosis during hospitalization, the patient's physical symptoms improved; however, persecutory delusions developed. The patient was clinically diagnosed with covert hepatic encephalopathy (HE). The delusions were atypical for covert HE, suspecting delusional disorder. His systematized delusions persisted for 3 months until his death, without the development of cognitive decline or Parkinsonism during his lifetime. An autopsy revealed an early transitional type of Lewy body disease with minimal Alzheimer's type II astrocytes indicative of HE. Severe neuronal loss was observed in the locus coeruleus (LC), while the substantia nigra (SN) and nucleus basalis of Meynert (nbM) were preserved. Abundant alpha-synuclein-positive structures were identified in the LC, periaqueductal gray matter, nbM, amygdala, and thalamus, with sparse involvement of the SN, neocortex, peripheral autonomic nervous system, including the heart and gastrointestinal tract.

CONCLUSION: Selective Lewy body involvement, sparing the SN and neocortex, may explain the isolated psychiatric symptoms in the absence of Parkinsonism or dementia. Systemic conditions such as covert HE may have contributed to the emergence of persistent delusions. This case highlights the need for multidisciplinary approaches that integrate psychosomatic assessments with neuropathological investigations to evaluate late-onset psychosis.}, } @article {pmid41233409, year = {2025}, author = {Lai, Y and Zhao, H}, title = {Therapeutic efficacy of rehmannioside A on 5×FAD mice in Alzheimer's disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {39825}, pmid = {41233409}, issn = {2045-2322}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; Oxidative Stress/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism/pathology ; Male ; *Saponins/pharmacology/therapeutic use ; Amyloid beta-Peptides/metabolism ; Memory/drug effects ; Mice, Transgenic ; Plaque, Amyloid/drug therapy/pathology ; Drugs, Chinese Herbal ; }, abstract = {Alzheimer's disease (AD), characterized by Aβ plaques and cognitive decline, remains a significant therapeutic challenge due to limited efficacy of current pharmacotherapies, while Rehmannioside A (ReA) has shown promising neuroprotective effects against neurodegenerative diseases. This research focuses on investigating the therapeutic effects of ReA on 5×FAD mice, emphasizing its potential application in AD treatment. The 5×FAD mice were divided into experimental groups and treated with ReA at varied dosages or donepezil for a twelve-week continuous treatment period. A series of evaluation methods, including behavioral tests, histopathological analysis, Western blotting, and measurement of oxidative and inflammatory markers, were implemented. The findings demonstrated that optimal ReA doses significantly improved learning, memory, and cognitive functions in 5×FAD mice, reduced Aβ plaque accumulation in the hippocampus, decreased microglial cell counts, increased PSD 95 and synapsin-1 protein expression, mitigated oxidative stress and inflammation, and showed no harmful effects on liver or kidney function. ReA's diverse biological activities suggest its potential in reducing neural damage. More extensive studies are needed to fully understand its molecular mechanisms in AD, which could lead to the development of innovative and effective treatments for this severe neurodegenerative condition.}, } @article {pmid41233403, year = {2025}, author = {Kovač, V and Huntosova, V and Fedorova, V and Georgiou, N and Lai, JZ and Chien, FC and Chen, SJ and Dolenec, F and Siposova, K}, title = {Unraveling the structure-activity relationships of organometallic ferrocene-pyrazole and ferrocene-pyrimidine curcumin analogues in amyloid-β aggregation and glioblastoma treatment.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {39867}, pmid = {41233403}, issn = {2045-2322}, support = {HRZZ-IP-2020-02-9162//Hrvatska Zaklada za Znanost/ ; No. 09-I02-03-V01-00021//NextGenerationEU/ ; SAS-NSTC-JRP-2024-03_SUPRA-SIGHT//Slovenská Akadémia Vied/ ; 2/0034/22//Vedecká Grantová Agentúra MŠVVaŠ SR a SAV/ ; No.101007642; PhytoApp//European Union's Horizon 2020 Research and Innovation programme/ ; }, mesh = {Humans ; *Ferrous Compounds/chemistry/pharmacology ; *Glioblastoma/drug therapy/metabolism/pathology ; *Metallocenes/chemistry/pharmacology ; *Curcumin/pharmacology/chemistry/analogs & derivatives ; *Amyloid beta-Peptides/metabolism/chemistry ; *Pyrazoles/chemistry/pharmacology ; *Pyrimidines/chemistry/pharmacology ; Structure-Activity Relationship ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Apoptosis/drug effects ; Protein Aggregates/drug effects ; Cell Survival/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; }, abstract = {Neurodegenerative and oncological disorders, such as Alzheimer's disease (AD) and glioblastoma (GBM), are major global health challenges. Recent evidence indicates shared molecular mechanisms between these diseases, including dysregulated oxidative stress, mitochondrial dysfunction, and protein aggregation. We hypothesized that ferrocene-containing curcumin derivatives could exert dual-functional effects by simultaneously modulating amyloid-β (Aβ) aggregation and inhibiting glioblastoma cell proliferation. This study explores organometallic ferrocene compounds linked to four pyrazole and two pyrimidine analogues of curcumin with different substituents for their effects on amyloid-β-peptide (Aβ) aggregation and glioblastoma. To test this, pyrazole (FcPy-Cur-H, FcPy-Cur-COPh, FcPy-Cur-COFc, FcPy-Cur-Me) and pyrimidine (FcPyn-Cur-O, FcPyn-Cur-S) analogues were synthesized and evaluated. Thioflavin T fluorescence, atomic force microscopy, and single-molecule localization microscopy revealed structure-dependent inhibition of Aβ fibrillogenesis, with FcPyn-Cur-O, FcPyn-Cur-S, and FcPy-Cur-H showing the strongest anti-amyloidogenic activity. Concurrently, these derivatives reduced U87MG glioblastoma cell viability in a dose-dependent manner, inducing apoptotic features, mitochondrial disruption, and α-tubulin destabilization. Our results demonstrate that specific structural modifications of ferrocene-curcumin analogues enhance their dual anti-amyloidogenic and anticancer activities, highlighting the therapeutic potential of multifunctional compounds. This study provides a conceptual advance by combining neurodegenerative and oncological targets within a single chemical framework, offering a promising strategy for the development of multitargeted therapeutics for complex brain disorders.}, } @article {pmid41233387, year = {2025}, author = {Park, JS and Kim, S and Jeong, D and Choi, JP and Jeong, H and Park, AJ and Kim, YS and Lee, J and Kim, SH}, title = {Dementia in older adults with schizophrenia: a 12-year analysis of prevalence, incidence, and treatment patterns in South Korea.}, journal = {Schizophrenia (Heidelberg, Germany)}, volume = {11}, number = {1}, pages = {134}, pmid = {41233387}, issn = {2754-6993}, abstract = {Older adults with schizophrenia face a significantly elevated risk of dementia. However, recent trends remain unclear within South Korea's rapidly aging schizophrenia population. This study aimed to quantify the burden of dementia in older schizophrenia patients by examining prevalence, incidence, dementia subtypes, pharmacologic treatment, and healthcare utilization. Using nationwide Health Insurance Review and Assessment (HIRA) data from 2010 to 2021, we identified 220,378 individuals aged ≥50 with schizophrenia. Dementia was diagnosed in 14.6% of patients, with 20.7% of cases occurring before age 60. Patients with dementia were more likely to be female and to have a higher comorbidity burden. Age-standardized all-cause dementia prevalence rose from 11.8% (2010) to 15.8% (2021) in those aged ≥50, and from 24.2% to 32.8% in those aged ≥65-exceeding estimates in the general population. In contrast, incidence declined from 3.4% to 1.7% over the same period. Alzheimer's disease (AD) was the most prevalent subtype (12.2%), followed by vascular dementia (VD, 2.4%), and frontotemporal dementia (0.5%). A lower AD/VD prevalence ratio in schizophrenia (5.3 vs. 8.6 in the general population) suggests a relatively higher burden of vascular pathology. Cognitive enhancer prescriptions increased from 62% to 77% in patients with dementia, compared to 4% to 10% in those without dementia. In 2021, those with dementia were more likely to live in nursing homes (68% vs. 56%) and had greater annual increases in psychiatric hospitalization duration (+2.30 vs. +1.11 days/year). These findings underscore growing care demands and need for integrated treatment strategies for aging schizophrenia patients with dementia.}, } @article {pmid41233182, year = {2025}, author = {Nakayama, H}, title = {[Brain Pathology of Cognitive Dysfunction in Aged Non-human Animals].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {11}, pages = {1241-1247}, doi = {10.11477/mf.188160960770111241}, pmid = {41233182}, issn = {1881-6096}, mesh = {Animals ; *Cognitive Dysfunction/pathology ; *Brain/pathology/metabolism ; *Aging/pathology ; Humans ; Alzheimer Disease/pathology ; Cats ; Amyloid beta-Peptides/metabolism ; }, abstract = {Cognitive dysfunction, characterized by the deposition of amyloid β (Aβ), such as senile plaque (SP) and cerebral amyloid angiopathy (CAA), and phosphorylated tau are observed in several animal species, including primates, dogs, and cats, suggesting that these disorders are universal age-related phenomena in vertebrates. Additionally, argyrophilic neurofibrillary tangles positive for phosphorylated tau have been observed in primates, marine mammals, and felines. Recent findings regarding the pathology of cognitive dysfunction in aged non-human animals provide valuable information from a comparative perspective for advancing research on the pathogenesis, diagnosis, and treatment of Alzheimer's disease.}, } @article {pmid41233181, year = {2025}, author = {Yoshiyama, K}, title = {[Agitation].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {11}, pages = {1231-1240}, doi = {10.11477/mf.188160960770111231}, pmid = {41233181}, issn = {1881-6096}, mesh = {Humans ; *Dementia/therapy/complications ; *Psychomotor Agitation/therapy/etiology ; }, abstract = {Agitation is a behavioral and psychological symptom of dementia (BPSD); however, until recently, there has been no consensus-based definition. When initiating therapeutic interventions, the type of dementia that is the cause of the BPSD must be considered and treatment must be tailored accordingly. As with other types of BPSD, non-pharmacological interventions are considered the first-line treatment for agitation, unless the symptoms present an exceptional level of urgency. Person-centered care is effective as a non-pharmacological intervention for agitation. Other examples include music therapy, animal-assisted therapy, and aromatherapy; however, these are not very effective for agitation. Useful information on non-pharmacological interventions for agitation can be obtained from the website "Ninchisho Chienowa-net," which is a web-based system that collects information on the coping strategies of caregivers for BPSD. If non-pharmacological interventions are ineffective or the symptoms are urgent, pharmacological treatment should be considered. Brexpiprazole has been approved as effective for agitation in Alzheimer's disease. For the treatment of agitation, medications other than brexpiprazole are frequently used in clinical settings and may offer some degree of efficacy.}, } @article {pmid41232717, year = {2025}, author = {Castellano Candalija, A and Díez Porres, L and Notario Leo, H and Roca Martiartu, A and Mayoral Canalejas, N and Alonso Babarro, A}, title = {Prevalence and decision-making in advanced dementia.}, journal = {Revista clinica espanola}, volume = {225}, number = {10}, pages = {502388}, doi = {10.1016/j.rceng.2025.502388}, pmid = {41232717}, issn = {2254-8874}, mesh = {Humans ; Female ; Aged, 80 and over ; Male ; Retrospective Studies ; Prevalence ; *Dementia/epidemiology/therapy/diagnosis ; *Decision Making ; *Clinical Decision-Making ; Aged ; Hospitalization/statistics & numerical data ; }, abstract = {INTRODUCTION: Dementia is a chronic neurodegenerative disease with a high prevalence and economic cost. Our objective was to evaluate the prevalence of advanced dementia (AD) in patients hospitalized in the Internal Medicine service; to analyze the therapeutic and diagnostic measures implemented, the degree of adequacy of the therapeutic effort and the information of the family.

METHODOLOGY: Descriptive study that included a retrospective analysis of medical records and a telephone interview with family. Patients with GDS 6-7 dementia admitted to Internal Medicine were included, for 3 weeks in 3 different months.

RESULTS: 194 (22%) patients with dementia were included. The prevalence of admissions with AD was 11%. The median age was 87.5 years (QR 81.75-93), 65% women. 45% came from residence for the elderly. The most frequent etiology was Alzheimer's (48%). The most frequent cause of admission was infection (72%). 37% died. Regarding the measures implemented: 100% were treatment intravenous; 89% received anticoagulation; 26% received artificial nutrition; 81% received pharmacological restraint and 63% physical restraint; and 48% underwent invasive diagnostic tests. Regarding adequacy: lipid-lowering treatment was withdrawn in 19%, antidementia drugs in 23%, anticoagulation in 21%; cardiopulmonary resuscitation was not performed in 30%, adequacy of care in 34%, and 13% were assessed by Palliative Care. A telephone interview was conducted with 55 patients. 42% were not aware of any complications. Care planning was carried out in 2 patients.

CONCLUSIONS: The prevalence of admission to AD is high, and almost half of the patients come from residence for the elderly. Associated mortality is high and therapeutic adequacy and planning are very scarce.}, } @article {pmid41232709, year = {2025}, author = {Zhou, W and Qu, R and Luo, W and Zhang, H and Gong, L and , }, title = {Identification of cognitive brain diseases using a dual-branch siamese network on structural magnetic resonance imaging data.}, journal = {Neuroscience}, volume = {591}, number = {}, pages = {83-92}, doi = {10.1016/j.neuroscience.2025.11.011}, pmid = {41232709}, issn = {1873-7544}, mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Alzheimer Disease/diagnostic imaging ; Aged ; *Cognitive Dysfunction/diagnostic imaging ; Male ; Female ; *Brain/diagnostic imaging/pathology ; *Neural Networks, Computer ; *Neuroimaging/methods ; Aged, 80 and over ; }, abstract = {Early diagnosis of Alzheimer's Disease is crucial for optimizing treatment efficacy, as delayed detection often limits therapeutic outcomes. Traditional diagnostic approaches, such as cognitive assessments, PET scans, and lumbar punctures, are often invasive, costly, and less accessible. To address these limitations, we propose a Dual-Branch Siamese Network aimed at enhancing the classification accuracy of Alzheimer's Disease, Mild Cognitive Impairment, and Cognitively Normal individuals using structural MRI data. Our model integrates neuroimaging features from both Subcortical Segmentation and Cortical Parcellation, leveraging their complementary strengths to improve diagnostic precision. Experimental evaluations demonstrate that our model achieves a classification accuracy of 93% on the original dataset. To further validate the model's generalizability, we tested the trained model on a separate independent test set from the new ADNI4 database (N=191). On this independent cohort, the model achieved a robust classification accuracy of 88.48%, demonstrating its potential for real-world application. Additionally, by implementing network pruning, we reduced the model's complexity by 60% without sacrificing accuracy, thereby enhancing its feasibility for clinical use. Compared to other methods, such as convolutional neural networks and ensemble learning systems, our model demonstrates superior accuracy in multi-class classification and remains competitive in binary classification tasks. Notably, our pruned model balances accuracy with efficiency, outperforming other models in terms of computational feasibility without compromising diagnostic precision. These findings highlight the potential of our approach to facilitate early diagnosis and intervention for neurodegenerative diseases like Alzheimer's Disease.}, } @article {pmid41232397, year = {2025}, author = {Zuo, Y and Ding, X and Sun, Y and Wang, L and Song, Y and Zhao, Z and Liu, C}, title = {Critical nodes in precision diagnosis and treatment of Alzheimer's disease: exploration of multidimensional biomarkers and prospects for targeted intervention.}, journal = {Journal of the neurological sciences}, volume = {479}, number = {}, pages = {123734}, doi = {10.1016/j.jns.2025.123734}, pmid = {41232397}, issn = {1878-5883}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/metabolism ; Biomarkers/metabolism ; *Precision Medicine/methods ; tau Proteins/metabolism ; }, abstract = {Alzheimer' s disease (AD), characterized by cognitive decline and progressive neurodegeneration, remains a major clinical and scientific challenge due to its complex pathophysiology and marked heterogeneity. Important signs of the disease, like the buildup of β-amyloid, changes in Tau proteins, inflammation in the brain, and problems with mitochondria, form the basis for developing targeted treatments. This review summarizes recent advances in the identification of therapeutic targets and multi-dimensional biomarkers, such as liquid, imaging, and multi-omics-based markers. These biomarkers hold potential for early diagnosis, disease subtyping, and therapeutic response monitoring. We suggest that combining biomarkers and treatment targets could be a key approach to improving personalized care for AD.}, } @article {pmid41232357, year = {2025}, author = {Castillo-Moral, Á and Tchoumtchoua, J and Leonard, K and Del Bas, JM and Ortega, N and Escoté, X and Teichenné, J}, title = {Neuroprotective effects of polyphenol-rich extracts obtained from agricultural by-products in an induced cognitive decline model of zebrafish larvae and in human neurons.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {193}, number = {}, pages = {118776}, doi = {10.1016/j.biopha.2025.118776}, pmid = {41232357}, issn = {1950-6007}, mesh = {Animals ; Zebrafish ; Humans ; *Neuroprotective Agents/pharmacology/isolation & purification ; *Polyphenols/pharmacology/isolation & purification ; *Plant Extracts/pharmacology/isolation & purification ; Larva/drug effects ; *Neurons/drug effects/metabolism/pathology ; *Cognitive Dysfunction/drug therapy/chemically induced/prevention & control ; Disease Models, Animal ; Cell Line, Tumor ; Aluminum Chloride ; }, abstract = {Neurodegenerative diseases are closely associated with chronic neuroinflammation and oxidative stress, which contribute to progressive neuronal dysfunction and cell death. Due to their antioxidant and anti-inflammatory properties, polyphenols have gained attention as potential neuroprotective agents. Agricultural by-products represent a promising and sustainable source of polyphenols, yet their neuroprotective value remains underexplored. In this study, we evaluated four polyphenol-rich extracts derived from red onion peels (ROPE), olive pruning (OPE), vineyard pruning (VPE) and chicory leaves (CLE), obtained by subcritical water extraction. Their effects were tested in two complementary models of neurodegeneration: in vitro human neurons (SH-SY5Y cells) exposed to D-galactose and a basic cognitive decline model of zebrafish larvae exposed to aluminium chloride (AlCl3). All extracts exhibited anti-inflammatory effects in vitro, significantly reducing IL-1β and IL-8 mRNA expression, at doses ranging 12.5-50 μg/mL in cell medium. In the zebrafish model, treatment with 100 μg/mL ROPE or VPE in medium restored the normal sensorimotor pattern in the Dark-Light-Dark test, while ROPE treatment additionally rescued basal startle responses and enhanced habituation indexes, even surpassing healthy control larvae. Overall, these results highlight the potential of polyphenol-rich agri-food extracts, particularly ROPE, as neuroprotective and cognitive-enhancing compounds and support their further investigation as natural and sustainable interventions to slow or prevent neurodegenerative processes.}, } @article {pmid41230868, year = {2025}, author = {Cavagnero, PS and Sánchez, Y and Fell, B and Ramírez Molina, O and Gavilán, J and Polo, EA and Fuentealba, J and Gutierrez, M and Jiménez, CA and López, JJ}, title = {Neuroprotective Activity of 3-((6-(Phenylethynyl)pyridin-3-yl)oxy)quinuclidine: A Potential Ligand for the Treatment of Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {23}, pages = {4502-4510}, pmid = {41230868}, issn = {1948-7193}, mesh = {*Neuroprotective Agents/pharmacology ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Quinuclidines/pharmacology/chemistry ; Rats ; PC12 Cells ; Amyloid beta-Peptides/metabolism ; Cell Survival/drug effects ; Ligands ; alpha7 Nicotinic Acetylcholine Receptor/metabolism ; Peptide Fragments ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by the accumulation of β-amyloid (Aβ) peptides, which disrupt neuronal homeostasis through their neurotoxic effects. Aβ aggregates interfere with synaptic function by interacting with nicotinic acetylcholine receptors (nAChRs), particularly the α7 subtype, thereby impairing cholinergic signaling, which is crucial for cognition and memory. Pharmacological advancements have identified Positive Allosteric Modulators (PAMs) as promising therapeutic agents to counteract Aβ neurotoxicity. PAMs enhance nAChR activity by binding to allosteric sites, thereby reducing Aβ-induced neurotoxicity without competing with acetylcholine. This study evaluates 3-((6-(phenylethynyl)pyridine-3-yl)oxy)quinuclidine (EQ-04), a novel PAM with high selectivity for the α7 nAChR subtype, demonstrating neuroprotective potential. In vitro analyses using PC-12 cells evaluated the cytotoxic and neuroprotective properties of EQ-04. Cytotoxicity assays confirmed EQ-04's safety, showing no adverse effects on cell viability across concentrations. EQ-04 significantly enhanced cell viability by 37% at 1 nM against Aβ toxicity and inhibited Aβ aggregation. These findings highlight the potential of EQ-04 as a neuroprotective agent for Alzheimer's disease (AD) therapy, warranting further investigation into its pharmacokinetics and in vivo efficacy.}, } @article {pmid41230514, year = {2025}, author = {Wang, X and Liu, Y and Fan, S and Zhao, H and Sun, C and Liu, L and Wang, X and Zou, L}, title = {Combined 64-channel EEG and PET evaluation of lecanemab efficacy: Two case reports.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251395615}, pmid = {41230514}, issn = {2542-4823}, abstract = {Lecanemab, an anti-amyloid-β (Aβ) monoclonal antibody, has shown potential in slowing Alzheimer's disease (AD) progression. We report divergent responses in two AD patients with similar backgrounds following lecanemab treatment. Subject 1 showed worsened daily functioning, increased Aβ/tau deposition, and elevated electroencephalogram (EEG) slow/fast wave ratios (>30%) in right fronto-occipital regions (Fp2/F8/O1). Subject 2 improved cognitively, with modest Aβ reduction, marked tau suppression, and mixed EEG frontal declines (F3/F7/O1/Pz) and parietal/occipital gains (P3/P4/T3/T6). EEG alterations corresponded with positron emission tomography findings, suggesting its potential for therapeutic monitoring. Multimodal analysis revealed region-specific lecanemab effects, supporting EEG's role in evaluating treatment efficacy.}, } @article {pmid41230033, year = {2025}, author = {Oviedo, DC and Haughbrook, R and Culjat, C and Ramirez Surmeier, L and Tratner, AE and Carreira, MB and Villarreal, AE and Harmon, SL and Batista, OI and Meng, Z and Millender, E and Xavier Hall, CD and Britton, GB}, title = {Ethical disclosure of biomarkers for Alzheimer risk in Latin American participants.}, journal = {Frontiers in dementia}, volume = {4}, number = {}, pages = {1672075}, pmid = {41230033}, issn = {2813-3919}, abstract = {INTRODUCTION: In recent years, the disclosure of Alzheimer's disease (AD) biomarkers has become increasingly common, offering critical insights into disease risk and progression. However, in low-resource settings, where healthcare access, provider training, and patient support are often limited, disclosing AD biomarkers presents unique ethical, logistical, and psychological challenges.

OBJECTIVE: This perspective explores the implications of AD biomarker disclosure in these settings, highlighting the potential risks of patient distress, misinformation, and inadequate follow-up care. For this purpose, we conducted a review of available literature, peer-reviewed studies, regional reports, and policy documents addressing AD in Latin America. Our literature search prioritized diagnostic advances, biomarker disclosure, treatment access, and health system challenges, providing a focused evidence base to frame the discussion of regional gaps and opportunities.

DISCUSSION: We discuss strategies to support responsible disclosure practices, including culturally sensitive participant education, enhanced provider training, and policy adaptations to improve accessibility and support systems. Ultimately, we advocate for a careful, context-specific approach to AD biomarker disclosure that prioritizes patient well-being and equity in low-resource environments.}, } @article {pmid41229208, year = {2025}, author = {Bosire, EN and Kamau, LW and Kiio, C and Blackmon, K and Taylor, ON and Shah, J and Sokhi, D and Mbugua, S and Meier, I and Hooker, J and Narayan, V and Merali, Z and Udeh-Momoh, C}, title = {Community perceptions and willingness to donate biospecimen for Alzheimer's disease research in Nairobi, Kenya.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1537-1548}, doi = {10.1177/13872877251389227}, pmid = {41229208}, issn = {1875-8908}, mesh = {Humans ; Kenya ; Female ; Male ; *Alzheimer Disease/psychology/diagnosis ; Middle Aged ; Focus Groups ; Aged ; Adult ; *Biomedical Research ; *Perception ; Biological Specimen Banks ; Aged, 80 and over ; *Tissue Donors/psychology ; *Health Knowledge, Attitudes, Practice ; }, abstract = {BackgroundBiomarkers play a critical role in understanding disease mechanisms and advancing diagnostic and treatment options for Alzheimer's disease and related dementias (AD/ADRD). However, in many African countries, biomarker research is limited by insufficient knowledge, infrastructure, funding, and trained personnel.ObjectiveThis study explored community perceptions and willingness to donate biospecimens for AD/ADRD research in Kenya.MethodsEight focus group discussions were conducted in the informal settlements of Mathare and Kibera in Nairobi, Kenya, stratified by age and gender (n = 81). Data were transcribed verbatim and thematically analyzed using QSR Nvivo 14.ResultsParticipants generally expressed a positive attitude toward brain health research and donating biospecimens. Willingness to participate was influenced by altruism, perceived benefits, and improved understanding of AD/ADRD. Non-invasive samples such as saliva, blood, and stool were widely accepted due to perceptions of safety and familiarity. However, several barriers were identified, including cultural beliefs (e.g., fear of witchcraft linked to donating hair), religious beliefs, fear of invasive procedures (spinal taps), and low awareness about biospecimen research. To address these barriers, participants recommended community sensitization, inclusive and transparent research processes, clear communication of benefits, involvement of family members in consenting, and assurance of safety measures for managing potential risks.ConclusionsCommunity willingness to donate biospecimens for AD/ADRD research in Kenya is shaped by a complex interplay of cultural, ethical, and practical considerations. Culturally sensitive, community-driven approaches are essential to enhance participation in AD/ADRD biomarker research in Kenya and similar low-resource settings.}, } @article {pmid41229078, year = {2025}, author = {Zhang, N and Liu, Y and Guan, Y}, title = {Piceatannol ameliorates the memory ability and cognitive behavior in Alzheimer's disease mice.}, journal = {Neurological research}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/01616412.2025.2581245}, pmid = {41229078}, issn = {1743-1328}, abstract = {OBJECTIVE: To investigate the effects of different doses of Piceatannol (PIC) on oxidative stress and cognitive function in a mouse model of Alzheimer's disease (AD).

METHODS: Firstly, a mouse model was established by inducing 70 days with D-gal and AlCl3. Sixty male mice are randomly divided into a normal control group (Control), an AD group (AD Model), positive control group (treated with donepezil), an AD model+low-dose group (PIC-L) receiving low-dose piceatannol treatment, an AD model+medium-dose group (PIC-M) receiving medium-dose piceatannol treatment, and an AD model+high-dose group (PIC-H) receiving high-dose piceatannol treatment, with 10 mice in each group. After 35 days of establishing an AD mouse model, different doses of piceatannol are continuously applied for treatment.

RESULTS: After 2 days of treatment, the AD Model had a longer escape latency than the Control. The escape latency time of PIC-L, PIC-M, and PIC-H was below AD Model, (p < 0.05). After treatment for 4d and 5d, the escape latency time of PIC-L, PIC-M, and PIC-H was below the AD Model, and the PIC-H group was even lower, with statistical significance (p < 0.05). PIC-L, PIC-M, and PIC-H crossed the platform more frequently than the AD Model, (p < 0.05). The SOD and GSH-Px levels in AD Model were below the Control, (p < 0.05). The MDA of AD Model exceeded the Control, (p < 0.05). The SOD, and GSH-Px in PIC-L, PIC-M, PIC-H exceeded the AD Model, (p < 0.05).

CONCLUSION: PIC significantly improved memory and cognition in AD mice, elevated serum SOD and GSH-Px, lowered MDA, and attenuated oxidative tissue injury with minimal organ toxicity.}, } @article {pmid41228597, year = {2025}, author = {Gomes, ACC and Almeida, A and Freire, CSR and Ferreira, BL}, title = {Chitosan (Nano)formulations as Therapeutic Tools for Neurodegenerative Diseases: A Comprehensive Review.}, journal = {Polymers}, volume = {17}, number = {21}, pages = {}, pmid = {41228597}, issn = {2073-4360}, support = {UIDB/50011/2020 (DOI 10.54499/UIDB/50011/2020)//FCT/MCTES (PIDDAC)/ ; UIDP/50011/2020 (DOI 10.54499/UIDP/50011/2020)//FCT/MCTES (PIDDAC)/ ; LA/P/0006/2020 (DOI 10.54499/LA/P/0006/2020)//FCT/MCTES (PIDDAC)/ ; (UIDP/50017/2020+UIDB/50017/2020+LA/P/0094/2020)//FCT/MCTES (PIDDAC)/ ; 2022.10449.BD (https://doi.org/10.54499/2022.10449.BD)//Fundação para a Ciência e Tecnologia/ ; DOI 10.54499/ND/00464/2017/CP1459/CT0033//Fundação para a Ciência e Tecnologia/ ; DOI: 10.54499/DL57/2016/CP1482/CT0019//National funds (OE), through FCT/ ; }, abstract = {According to the World Health Organization, Alzheimer's disease and other forms of dementia were the seventh leading cause of death in 2021. The prevalence of these disorders is predictable to increase with life expectancy, and their control is hampered by several factors, including late diagnosis due to the lack of specific biomarkers and the absence of disease-modifying treatments, as currently available therapies can only lighten some of the symptoms. Nanotechnology could be the key to overcoming some of the limitations associated with neurodegenerative diseases, as nanomaterials have excellent properties compared to their bulk counterparts and can be used as drug delivery systems, diagnostic tools and platforms for tissue regeneration. Chitosan is a biopolymer with numerous properties that impart it with great potential for biomedical applications, in particular its ability to cross the blood-brain barrier and its versatility in nanoscale design. In this context, the aim of this review is to provide an in-depth analysis of the latest developments and future opportunities for chitosan (nano)formulations for the treatment and management of neurodegenerative diseases.}, } @article {pmid41228523, year = {2025}, author = {Liu, Y and Dong, Y and Cao, Z and Ji, Y and Cheng, X and Zheng, X}, title = {The Multi-Dimensional Action Map of Resveratrol Against Alzheimer's Disease: Mechanism Integration and Treatment Strategy Optimization.}, journal = {Nutrients}, volume = {17}, number = {21}, pages = {}, pmid = {41228523}, issn = {2072-6643}, support = {//the Youth Talent Cultivation Fund Project of Dalian Medical University./ ; }, mesh = {*Resveratrol/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Oxidative Stress/drug effects ; *Antioxidants/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; Plaque, Amyloid/drug therapy ; Energy Metabolism/drug effects ; Mitochondria/drug effects/metabolism ; Neurofibrillary Tangles/drug effects/metabolism ; }, abstract = {Alzheimer's disease (AD) represents a prevalent neurodegenerative disorder marked by a gradual decline in cognitive and behavioral functions. Despite advancements in elucidating several potential mechanisms underlying the pathogenesis of AD, there remains a limitation in effective supplements or medications for its intervention. Resveratrol, a natural antioxidant, has emerged as a significant player in the treatment of AD. This article reviews the role of resveratrol in four key aspects: amyloid plaque deposition and neurofibrillary tangles, inflammatory response and oxidative stress, energy metabolism and mitochondrial homeostasis, and neuroprotection and regeneration. Furthermore, we also explore treatment strategies to enhance the therapeutic effect of resveratrol.}, } @article {pmid41228437, year = {2025}, author = {Kim, G and Lee, HG and Kwon, S}, title = {Current Utilization and Research Status of the Herbal Medicine Guibi-Tang and Its Variants for Cognitive Impairment: A Scoping Review.}, journal = {Nutrients}, volume = {17}, number = {21}, pages = {}, pmid = {41228437}, issn = {2072-6643}, support = {RS-2022-KH127675//Korea Health Industry Development Institute/Republic of Korea ; }, mesh = {Aged ; Humans ; Middle Aged ; Cognition/drug effects ; *Cognitive Dysfunction/drug therapy ; *Drugs, Chinese Herbal/therapeutic use/adverse effects ; }, abstract = {Background/Objectives: Guibi-tang (GBT) and its variant Kami-guibi-tang (KGBT) are traditional East Asian multi-herb formulas prescribed for memory loss, insomnia, and fatigue. Preclinical data suggest multimodal neuroprotective actions, including cholinergic signaling modulation and activation of the cAMP response element-binding protein (CREB)/extracellular signal-regulated kinase (ERK) pathway; however, clinical evidence for cognitive disorders remains scattered. This scoping review aimed to map the breadth, design characteristics, efficacy signals, and safety profile of GBT and KGBT across the full spectrum of cognitive impairment. Methods: Following the Arksey-O'Malley framework and PRISMA-ScR guidelines, seven databases were searched (MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure, ScienceON, Scopus, Citation Information by the National Institute of Informatics) from inception to 31 January 2025, for human studies evaluating GBT or KGBT in subjective cognitive decline, mild cognitive impairment (MCI), dementia, or post-stroke cognitive impairment (PSCI). Two reviewers independently screened, extracted, and charted data on study design, participants, interventions, outcomes, and adverse events. Results: Fifteen studies met the inclusion criteria-nine randomized controlled trials, one crossover trial, and five observational reports-enrolling 555 participants (age range, 59-87 years). All were conducted in the Republic of Korea, Japan, or China. GBT or KGBT, given as monotherapy or adjunctive therapy for 4 weeks to 9 months, produced modest but consistent improvements in global cognition (Mini-Mental State Examination/Montreal Cognitive Assessment), memory domains, activities of daily living, and neuropsychiatric symptoms across MCI, Alzheimer's disease, and PSCI cohorts. Reported adverse event rates were comparable to or lower than those of placebo, usual care, or conventional drugs, and no serious treatment-related toxicity was identified. Conclusions: Current evidence-although limited by small sample sizes, heterogeneous formulations, short follow-up durations, and regional concentration-indicates that GBT and KGBT are well tolerated and confer clinically meaningful cognitive and functional benefits. Standardized, multicenter, placebo-controlled trials with biomarker end points are warranted to confirm long-term efficacy, clarify mechanisms, and guide integrative clinical use.}, } @article {pmid41227390, year = {2025}, author = {Habib, SA and Kamal, MM and Aly, MH and Ghaiad, HR and Rizk, SM and Banks, WA and Erickson, MA}, title = {Streptozotocin Causes Blood-Brain Barrier and Astrocytic Dysfunction In Vitro.}, journal = {Cells}, volume = {14}, number = {21}, pages = {}, pmid = {41227390}, issn = {2073-4409}, support = {ACOS Research Fund//VA Puget Sound Health Care System/ ; Graduate Scholarship//United States Agency for International Development/ ; }, mesh = {*Blood-Brain Barrier/drug effects/pathology/metabolism ; *Astrocytes/drug effects/pathology/metabolism ; Humans ; *Streptozocin/pharmacology/toxicity ; Endothelial Cells/drug effects/metabolism/pathology ; Induced Pluripotent Stem Cells/drug effects/metabolism ; Glucose Transporter Type 1/metabolism ; Cells, Cultured ; }, abstract = {Streptozotocin (STZ) is an alkylating agent that has neurotoxic effects when injected into the cerebral ventricles (ICV) and also models many other features of Alzheimer's disease. However, the mechanisms of STZ neurotoxicity are not well understood. In this study, we hypothesized that some of the neurotoxic effects of STZ could be due to direct activities on brain endothelial cells and astrocytes, which are key in forming and supporting the functions of the blood-brain barrier (BBB), respectively. To test this hypothesis, we characterized the changes induced by STZ either in cultures of human-induced pluripotent stem cell (iPSC)-derived brain endothelial-like cells (iBECs), which form an in vitro BBB model, or in primary human astrocytes. We found that STZ at a dosage of 5 mM caused a delayed reduction in the transendothelial electrical resistance (TEER) of iBECs at 7-11 days post-treatment, indicating induction of BBB leakage. Additionally, we observed significant increases in albumin leakage across the monolayer, altered iBEC morphology, and reductions in tight junction proteins, suggesting that STZ causes BBB disruption. We further found that the BBB glucose transporter GLUT-1 was reduced in iBECs, as was the total number of iBECs. In astrocytes, the 5 mM dose of STZ reduced the GFAP signal and total number of cells, suggesting that STZ has anti-proliferative and/or toxic effects on astrocytes. Together, these data support that STZ's neurotoxic effects could be due, in part, to its direct toxic activities on brain endothelial cells and astrocytes.}, } @article {pmid41226838, year = {2025}, author = {Zhao, Y and Wang, Z and Xi, E and Yang, F and Gao, N}, title = {Hydrophobic Drug Delivery Platforms Based on Covalent Organic Frameworks for Combined Treatment of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {21}, pages = {}, pmid = {41226838}, issn = {1422-0067}, support = {2022YFB3805902//the National Key R&D Program of China/ ; 22077118//National Natural Science Foundation of China/ ; B18012//the "111" project/ ; 20210101353JC//the National Natural Science Foundation of Jilin Province/ ; }, mesh = {*Alzheimer Disease/drug therapy ; Animals ; *Curcumin/chemistry/administration & dosage/pharmacology/therapeutic use ; Hydrophobic and Hydrophilic Interactions ; Mice ; *Drug Delivery Systems/methods ; *Metal-Organic Frameworks/chemistry ; *Drug Carriers/chemistry ; Humans ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease. The pathogenesis of AD remains incompletely understood. It is characterized by a variety of neuropathological changes, including neuroinflammation, neuronal loss and synaptic damage. Multiple pathological changes make achieving good therapeutic effects with a single drug treatment difficult, and using multiple drugs for combination therapy is currently the most effective method. Currently, the mainstay drugs used for AD treatment are hydrophobic drugs, such as curcumin, donepezil, and resveratrol. Because hydrophobic drugs cannot dissolve in bodily fluids and often aggregate or precipitate, their efficacy is greatly reduced. Therefore, there is an urgent need for a drug carrier that can effectively load and continuously release drugs. However, currently, there are few drug carriers that can achieve efficient co-loading of multiple hydrophobic drugs. Therefore, three of two-dimensional imine covalent organic frameworks (COFs) with different monomers were synthesized through rational design and screening. These three synthesized COFs are simultaneously loaded with curcumin (CUR) and benzofurazan (BZ) to achieve combined therapy. The results indicate that among this series of synthesized COFs, the COF synthesized from 4,4',4″-(1,3,5-Triazine-2,4,6-triyl) trianiline and benzene-1,3,5-tricarboxaldehyde (COF-TB) exhibits optimal hydrophobic drug-loading capacity, enabling effective co-loading of CUR and BZ (BC@COF-TB). After treatment with BC@COF-TB, the cognitive function of 5×FAD mice was significantly improved. The COF platform provides a new way to deliver hydrophobic drugs for AD treatment.}, } @article {pmid41226821, year = {2025}, author = {Paszternák, A and Varga, K and Gyöngyössy, R and Tarnóczi, K and Sikur, N and Szökő, É and Tábi, T}, title = {Resveratrol Analogs Ameliorate Mitochondrial Impairment and Insulin Resistance in a Streptozotocin-Induced In Vitro Model of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {21}, pages = {}, pmid = {41226821}, issn = {1422-0067}, support = {2024-2.1.1-EKÖP-2024-0004 (203)//National Research, Development and Innovation Office/ ; EFOP-3.6.3.-VEKOP-16-2017-00009//National Research, Development and Innovation Office/ ; }, mesh = {*Resveratrol/pharmacology/analogs & derivatives ; *Insulin Resistance ; Humans ; *Alzheimer Disease/metabolism/drug therapy/chemically induced/pathology ; *Mitochondria/drug effects/metabolism/pathology ; Streptozocin/toxicity ; Cell Line, Tumor ; *Neuroprotective Agents/pharmacology/chemistry ; Autophagy/drug effects ; Oxidative Stress/drug effects ; Stilbenes/pharmacology/chemistry ; Antioxidants/pharmacology ; }, abstract = {Alzheimer's disease (AD) is characterized by mitochondrial dysfunction, oxidative stress, insulin resistance, and aberrant protein aggregation. Neurodegeneration model with neuronal insulin resistance was induced in SH-SY5Y human neuroblastoma cells by streptozotocin (STZ). We evaluated the neuroprotective effects of resveratrol (RZV) and three structural analogs: oxyresveratrol (OXI), monomethyl resveratrol (MONO), and trimethyl resveratrol (TRI). Mitochondrial function, plasma membrane integrity, oxidative stress) and autophagy were studied by fluorescent assays. Phosphorylated GSK3 levels were measured by ELISA as an indicator of insulin sensitivity. TRI exhibited significant mitochondrial protective effects and strongly induced autophagy. OXI demonstrated excellent antioxidant activity but showed no detectable mitochondrial protective or autophagy-inducing effects. RZV and MONO exhibited moderate antioxidant effects along with strong insulin-sensitizing and autophagy-inducing properties. Insulin sensitivity was most potently restored by RZV (IC50 = 54 pM) and MONO (IC50 = 50 pM), whereas TRI (IC50 = 160 pM) was less potent, and OXI (IC50 = 97 pM) showed moderate potency. Our findings suggest that the neuroprotective effects of resveratrol analogs significantly depend on their molecular structure and that they exert their beneficial effects through distinct mechanisms. This research may contribute to the development of novel, multi-target compounds for the treatment of neurodegenerative diseases.}, } @article {pmid41226793, year = {2025}, author = {Machowska, M and Leszek, J and Rączy-Krzemianowska, M and Tomasiewicz, B and Hurkacz, M and Rąpała, M and Piechota, J and Głowacka, K and Wiela-Hojeńska, A}, title = {ABC Transporters, APOE, CYP46A1, and LRP1 Gene Polymorphisms as Markers of Dementia Development in Patients with Hyperlipidemia.}, journal = {International journal of molecular sciences}, volume = {26}, number = {21}, pages = {}, pmid = {41226793}, issn = {1422-0067}, support = {RPDS.01.02.01-02-0002/20//Regional Operational Programme of the Lower Silesian Voivodeship 2014-2020, co-financed by the European Union, European Regional Development Fund/ ; }, mesh = {Humans ; *Hyperlipidemias/genetics/complications ; Male ; Female ; *Apolipoproteins E/genetics ; *Dementia/genetics/etiology ; Aged ; *Polymorphism, Single Nucleotide ; *ATP Binding Cassette Transporter 1/genetics ; Genetic Predisposition to Disease ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics ; Genotype ; Middle Aged ; Alleles ; Gene Frequency ; Biomarkers ; Alzheimer Disease/genetics ; Aged, 80 and over ; *ATP-Binding Cassette Transporters/genetics ; Case-Control Studies ; }, abstract = {In an aging society, solving problems associated with the diagnosis and treatment of dementia-related diseases represents a serious challenge. The aim of the study was to evaluate the possibility of applying molecular biology methods to test polymorphisms recognized in the global literature as potentially useful in assessing the risk of developing dementia in a group of patients with hyperlipidemia. A sample of 203 patients: 109 diagnosed with both dementia and hyperlipidemia, 94 with hyperlipidemia, and 101 individuals as an allele frequency control group-were genotyped. Additional data about cognitive decline and neuropsychological assessment were collected. Among all the studied polymorphisms, the frequency of the ABCA1 rs2230806 polymorphism differed between the analyzed groups. The GG genotype (p = 0.0002, RR = 3.22, CI = 1.63 ÷ 6.37) and the G allele (p = 0.0007, RR = 1.53, CI = 1.19 ÷ 1.97) were more frequent in patients diagnosed with dementia, specifically in those with Alzheimer's disease. Furthermore, the GG genotype was more common in individuals with a shorter disease duration and lower scores on the Montreal Cognitive Assessment (MoCA) scale, and consequently, with greater cognitive function deficits during early stages of the diagnostic process. ABCA1 rs2230806 genotyping is a potential marker for the early identification of dementia risk in patients with hyperlipidemia, which supports the validity of exploring options for incorporating diagnostics based on molecular biology methods.}, } @article {pmid41226707, year = {2025}, author = {Hale, HK and Elias, KM and Ho, S and Kwakye, GF}, title = {Methylene Blue Attenuates 3-Nitropropionic Acid-Induced Oxidative Stress and Mitochondrial Dysfunction in Striatal Cells: Therapeutic Implications in Huntington's Disease Neuropathology.}, journal = {International journal of molecular sciences}, volume = {26}, number = {21}, pages = {}, pmid = {41226707}, issn = {1422-0067}, support = {Research and Professional Development Portfolio//Oberlin College Arts and Sciences Dean's Office (GFK)/ ; Endowed Professor Research Portfolio//Robert W. & Eleanor H. Biggs Endowed Professor of Neuroscience (GFK)/ ; }, mesh = {*Oxidative Stress/drug effects ; *Huntington Disease/drug therapy/metabolism/pathology ; *Nitro Compounds/toxicity ; *Propionates/toxicity ; *Methylene Blue/pharmacology ; *Mitochondria/drug effects/metabolism/pathology ; Animals ; *Corpus Striatum/drug effects/metabolism/pathology ; Humans ; Reactive Oxygen Species/metabolism ; *Neuroprotective Agents/pharmacology ; Huntingtin Protein/genetics/metabolism ; Cell Survival/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Mice ; }, abstract = {There are no disease-modifying treatments available for Huntington's disease (HD), a neurodegenerative disease caused by a genetic mutation in the Huntingtin gene. Previous research suggests that disruptions in the bioenergetics of the mitochondria and increased oxidative stress are potential inducers of HD. Therapies that enhance antioxidant pathways intend to target and attenuate the overproduction of reactive oxygen species associated with mitochondrial dysfunction. We have investigated the effect of Methylene Blue (MB) as a potential therapy for HD. MB is a small molecule demonstrated to exhibit neuroprotective effects in other neurodegenerative disease models, including Parkinson's and Alzheimer's, by attenuating the oxidative stress pathways implicated in their pathophysiology. We used an established striatal cell model of HD expressing wild-type (STHdh[Q7/Q7]) or mutant (STHdh[Q111/Q111]) HTT and a chemical inducer of HD, 3-Nitropropionic acid (3-NPA), to determine the HD-specific mechanisms regulated by 3 h of MB pre-treatment. Upon 24 h of exposure to 3-NPA, mutant HD cells exhibited a significant concentration-dependent decrease in cell survival and a concomitant increase in cell death compared to wild-type, confirming that 3-NPA exacerbates mutant HTT neurotoxicity. Examination of mitochondrial membrane potential and mitochondrial function in the striatal cells by JC-1 and ATP assays, respectively, revealed MB mediated neuroprotection against 3-NPA-induced reduction in mitochondrial activity. Immunoblotting analysis revealed that MB restores baseline expression of oxidative-stress-related proteins, including HO1 and p62, in both wild-type and mutant cells exposed to 3-NPA. Our findings establish a novel neuroprotective role of MB in both genetic and pharmacological models of HD, suggesting that MB might be a promising therapeutic candidate for altering the underlying pathophysiology of HD by improving mitochondrial function.}, } @article {pmid41226670, year = {2025}, author = {Bayo Jimenez, MT and Rivas-García, L and Sánchez-González, C and Grosso, G and Lipari, V and Vera-Ramírez, L and Battino, M and Giampieri, F and Quiles, JL and Forbes-Hernández, TY}, title = {Natural Products in Alzheimer's Disease: A Systematic Review of Clinical Trials and Underlying Molecular Mechanisms.}, journal = {International journal of molecular sciences}, volume = {26}, number = {21}, pages = {}, pmid = {41226670}, issn = {1422-0067}, support = {PID2019-106778RB-I00//MCIN/AEI/10.13039/501100011033 FEDER "Una manera de hacer Europa/ ; Visiting Scholars 2022//Universidad de Granada/ ; }, mesh = {Aged ; Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Biological Products/therapeutic use/pharmacology ; Clinical Trials as Topic ; Cognitive Dysfunction/drug therapy ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Plant Extracts/therapeutic use/pharmacology ; }, abstract = {This systematic review included 31 clinical trial articles examining the effects of natural compounds on Alzheimer's disease (AD) and mild cognitive impairment (MCI), involving 3582 participants aged 50-90. Treatment durations ranged from 8 weeks to 2 years, with an average of 12.5 months. Notably, 11 studies focused on herbal extracts highlighting their prominence in current research. These extracts showed potential cognitive and neuroprotective benefits, although results varied across compounds and study designs. Other natural compounds-including flavonoids, polyphenols, omega-3 fatty acids, Aloe vera, Spirulina, and citrus phytochemicals-may provide cognitive and neuroprotective benefits, with ginseng and Ginkgo biloba combinations also showing promise. Curcumin and Melissa officinalis had limited effects, resveratrol showed mixed outcomes with some side effects, and matcha green tea may improve cognition and sleep quality. Despite generally favorable results, the studies varied considerably in design and quality; nonetheless, herbal extracts represent a prominent category of natural interventions in AD and MCI, underscoring the need for further large-scale, high-quality clinical trials to confirm their therapeutic potential.}, } @article {pmid41226604, year = {2025}, author = {Hu, C and Lin, M and Wang, C and Zhang, S}, title = {Current Understanding of Protein Aggregation in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {21}, pages = {}, pmid = {41226604}, issn = {1422-0067}, support = {32170784, 32170707//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; *Protein Aggregates ; *Protein Aggregation, Pathological/metabolism ; Autophagy ; Protein Folding ; }, abstract = {Protein aggregates are central to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. This comprehensive review explores the mechanisms of protein misfolding and aggregation, their prion-like propagation, and the critical role of oligomeric species in neurotoxicity. It further examines cellular clearance pathways, including the ubiquitin-proteasome system and autophagy, alongside the regulatory functions of molecular chaperones. The review also covers advanced diagnostic imaging and biomarker techniques, as well as emerging therapeutic strategies such as pharmacological agents, gene therapy, and immunotherapy. Controversies regarding the toxicity of aggregates and future directions, including novel degradation technologies and targeted therapeutic approaches, are discussed. By integrating current knowledge, this review aims to provide a broad yet detailed overview of the field, highlighting both established concepts and promising avenues for research and treatment.}, } @article {pmid41226584, year = {2025}, author = {Costea, D and Dobrin, N and Tataru, CI and Toader, C and Șerban, M and Covache-Busuioc, RA and Munteanu, O and Diaconescu, IB}, title = {The Glymphatic-Venous Axis in Brain Clearance Failure: Aquaporin-4 Dysfunction, Biomarker Imaging, and Precision Therapeutic Frontiers.}, journal = {International journal of molecular sciences}, volume = {26}, number = {21}, pages = {}, pmid = {41226584}, issn = {1422-0067}, mesh = {Humans ; *Glymphatic System/metabolism/diagnostic imaging ; *Aquaporin 4/metabolism ; Biomarkers/metabolism ; Animals ; *Brain/metabolism/diagnostic imaging/blood supply ; *Neurodegenerative Diseases/metabolism/therapy/diagnostic imaging ; Precision Medicine ; }, abstract = {The identification of brain clearance failure as a precursor to a large variety of neurodegenerative diseases has shifted fluid dynamics from a secondary to a tertiary target of brain health. The identification of the glymphatic system, detailing cerebrospinal fluid entry along perivascular spaces and exit via perivenous and meningeal lymphatic pathways, provided a challenge to previous diffusion models and established aquaporin-4-dependent astroglial polarity as a governing principle of solute transport. Multiple lines of evidence now support a coupled glymphatic-venous axis, wherein vasomotion, venous outflow, and lymphatic drainage are functionally interrelated. Failure of any axis will cascade and affect the entire axis, linking venous congestion, aquaporin-4 disassembly, and meningeal lymphatic failure to protein aggregation, neuroinflammation, edema, and intracranial hypertension. Specific lines of evidence from diffusion tensor imaging along vascular spaces, clearance MRI, and multi-omic biomarkers can provide a measure of transport. Therapeutic strategies are rapidly advancing from experimental strategies to translational approval, including behavioral optimization, closed-loop sleep stimulation, vascular and lymphatic therapies, focused ultrasound, pharmacological polarity recoupling, and regenerative bioengineering. Novel computational approaches, such as digital twin dynamic modeling and adaptive trial designs, suggest that clearance measures may serve as endpoints to be approved by the FDA. This review is intended to bridge relevant mechanistic and translational reviews, focusing on impaired clearance as an exploitable systems defect rather than an incapacitating secondary effect. Improving our understanding of the glymphatic-venous axis Injury may lead to future target strategies that advance cognitive resilience, alleviate disease burden, and improve quality of life. By clarifying the glymphatic-venous axis, we provide a mechanistic link between impaired interstitial clearance and the pathological accumulation of amyloid-β, tau, and α-synuclein in neurodegenerative diseases. The repair of aquaporin-4 polarity, venous compliance, and lymphatic drainage might therefore open new avenues for the diagnosis and treatment of Alzheimer's and Parkinson's disease, supplying both biomarkers of disease progression and new targets for early intervention. These translational implications not only locate clearance failure as an epiphenomenon of neurodegeneration but, more importantly, as a modifiable driver of the course of neurodegeneration.}, } @article {pmid41226231, year = {2025}, author = {Ananda, SH and Kuragano, M and Tokuraku, K}, title = {Elucidation of the Neuroprotective Effects of Astaxanthin Against Amyloid β Toxicity in the SH-SY5Y Human Neuroblastoma Cell Line.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {21}, pages = {}, pmid = {41226231}, issn = {1420-3049}, support = {SUNBOR GRANT//Suntory Foundation for Life Sciences/ ; JPMJPF2213//Japan Science and Technology Agency/ ; JP24K08627//JSPS KAKENHI/ ; }, mesh = {Humans ; Xanthophylls/pharmacology/chemistry ; *Amyloid beta-Peptides/metabolism/toxicity ; *Neuroprotective Agents/pharmacology ; Cell Line, Tumor ; *Neuroblastoma/metabolism/pathology/drug therapy ; Apoptosis/drug effects ; Cell Movement/drug effects ; Cell Survival/drug effects ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and cognitive decline, primarily due to amyloid β (Aβ) aggregation in the brain. Astaxanthin (AxN), a xanthophyll carotenoid derived from Haematococcus pluvialis, possesses antioxidant and neuroprotective properties. This study investigated the neuroprotective effects of AxN against Aβ aggregation in human neuroblastoma SH-SY5Y cells. Initially, AxN inhibited Aβ aggregation in DMEM/F12 culture medium but not in PBS, suggesting a medium-dependent effect. Using quantum dot nanoprobes, Aβ aggregation was visualized in the presence of SH-SY5Y cells. AxN treatment (0.032-20 µM) significantly reduced Aβ aggregation and accumulation on SH-SY5Y cells. AxN also prevented Aβ-induced early apoptotic cell death but was less effective against late necrosis. Furthermore, a wound-healing assay showed that AxN restored the impaired cell motility caused by Aβ aggregation. Thioflavin T staining confirmed the reduction in Aβ fibril formation around the cells following AxN treatment. In conclusion, our study suggests that AxN prevents Aβ aggregation and accumulation on the cell surface, thereby restoring cell motility and preventing early apoptosis in neuronal cells.}, } @article {pmid41226137, year = {2025}, author = {Guaya, D and Espinoza, LC and Jaramillo-Fierro, X and Gualotuña Campoverde, D and Sosa, L and Calpena, AC}, title = {Zinc-Modified Mordenite Zeolite as a Molecular Carrier for Donepezil: A Framework for Drug Delivery Applications.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {21}, pages = {}, pmid = {41226137}, issn = {1420-3049}, support = {PROY_INV_QU_2022_3585//Universidad Técnica Particular de Loja (UTPL)/ ; }, mesh = {*Zeolites/chemistry ; *Donepezil/chemistry/pharmacology/administration & dosage ; *Zinc/chemistry ; *Drug Carriers/chemistry ; *Drug Delivery Systems ; Adsorption ; Drug Liberation ; Kinetics ; Cholinesterase Inhibitors/chemistry ; Hydrogen Bonding ; }, abstract = {The development of advanced drug delivery systems is essential for improving therapeutic efficacy, particularly in the treatment of neurodegenerative disorders such as Alzheimer's disease. This study investigates zinc-modified mordenite zeolite (MR-ZN) as a novel platform for the controlled delivery of donepezil (DPZ), a cholinesterase inhibitor. Natural mordenite was modified with zinc, enhancing its surface area from 62.1 to 85.4 m[2]/g and improving its adsorption properties. Donepezil was successfully loaded at two doses (10 mg and 23 mg), achieving high loading efficiencies of 95% and 94%, respectively. Adsorption kinetics followed a pseudo-second-order model (R[2] > 0.99), indicating that chemisorption predominates through coordination between DPZ functional groups and Zn[2+] sites, while complementary physisorption via hydrogen bonding and van der Waals interactions also contributes to molecular stabilization within the zeolite framework. In vitro release studies under simulated gastrointestinal conditions demonstrated sustained and pH-responsive release profile with 80% and 82% of donepezil released after 24 h for 10 mg and 23 mg formulations, respectively. Density Functional Theory (DFT) calculations revealed favorable adsorption energy (-26.4 kJ/mol), while Bader and Electron Localization Function (ELF) analyses confirmed hydrogen bonding and electrostatic interactions without compromising the zeolite framework. These findings validate MR-ZN as structurally stable, efficient, cost-effective and biocompatible matrix for oral drug delivery. The combination of experimental data and theoretical modeling supports its potential to improve bioavailability and therapeutic performance in neurodegenerative treatment.}, } @article {pmid41225966, year = {2025}, author = {Hayat, MT and Allawi, YM and Alamro, W and Sultan, SM and Abadleh, A and Kang, H and Zreikat, AI}, title = {A Hybrid Convolutional Neural Network-Long Short-Term Memory (CNN-LSTM)-Attention Model Architecture for Precise Medical Image Analysis and Disease Diagnosis.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {21}, pages = {}, pmid = {41225966}, issn = {2075-4418}, support = {PNURSP2025R829//Princess Nourah bint Abdulrahman University/ ; }, abstract = {Background: Deep learning (DL)-based medical image classification is becoming increasingly reliable, enabling physicians to make faster and more accurate decisions in diagnosis and treatment. A plethora of algorithms have been developed to classify and analyze various types of medical images. Among them, Convolutional Neural Networks (CNNs) have proven highly effective, particularly in medical image analysis and disease detection. Methods: To further enhance these capabilities, this research introduces MediVision, a hybrid DL-based model that integrates a vision backbone based on CNNs for feature extraction, capturing detailed patterns and structures essential for precise classification. These features are then processed through Long Short-Term Memory (LSTM), which identifies sequential dependencies to better recognize disease progression. An attention mechanism is then incorporated that selectively focuses on salient features detected by the LSTM, improving the model's ability to highlight critical abnormalities. Additionally, MediVision utilizes a skip connection, merging attention outputs with LSTM outputs along with Grad-CAM heatmap to visualize the most important regions of the analyzed medical image and further enhance feature representation and classification accuracy. Results: Tested on ten diverse medical image datasets (including, Alzheimer's disease, breast ultrasound, blood cell, chest X-ray, chest CT scans, diabetic retinopathy, kidney diseases, bone fracture multi-region, retinal OCT, and brain tumor), MediVision consistently achieved classification accuracies above 95%, with a peak of 98%. Conclusions: The proposed MediVision model offers a robust and effective framework for medical image classification, improving interpretability, reliability, and automated disease diagnosis. To support research reproducibility, the codes and datasets used in this study have been publicly made available through an open-access repository.}, } @article {pmid41225766, year = {2025}, author = {Jeon, SY and Byun, MS and Choi, HJ and Kim, YH and Gwag, CH and Oh, Y and Park, JE and Yi, D and Jung, G and Ahn, H and Sohn, BK and Jung, JH and Chang, YY and Kong, N and Choi, H and Kang, KM and Sohn, CH and Lee, DY}, title = {Eligibility for lecanemab and donanemab in Korea under Appropriate Use Recommendations.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70875}, pmid = {41225766}, issn = {1552-5279}, support = {//New Faculty Startup Fund from Seoul National University/ ; //National Research Foundation of Korea/ ; RS-2022-00165636//Ministry of Science and ICT, South Korea/ ; 2014M3C7A1046042//Ministry of Science and ICT, South Korea/ ; //Korea Health Technology R&D Project/ ; //Korea Health Industry Development Institute/ ; HI18C0630//Ministry of Health and Welfare, Republic of Korea/ ; HI19C0149//Ministry of Health and Welfare, Republic of Korea/ ; //Korea Dementia Research Project/ ; //Korea Dementia Research Center (KDRC)/ ; //Ministry of Health & Welfare and Ministry of Science and ICT/ ; RS-2023-KH136195//Republic of Korea/ ; //Basic Science Research Program through the NRF/ ; RS-2023-00210380//Ministry of Education/ ; U01AG072177//National Institute of Aging/ ; //National Institute of AGING/ ; RS-2023-KH136195//Korea Dementia Research Center/ ; HI18C0630//Ministry of Health and Welfare/ ; HI19C0149//Ministry of Health and Welfare/ ; //Seoul National University/ ; }, mesh = {Humans ; Republic of Korea ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Mental Status and Dementia Tests ; Aged, 80 and over ; Brain/diagnostic imaging ; Middle Aged ; Antibodies, Monoclonal, Humanized ; }, abstract = {INTRODUCTION: Appropriate Use Recommendations (AURs) guide real-world use of lecanemab and donanemab in early symptomatic Alzheimer's disease (AD), but their applicability to Asian populations with diverse education backgrounds remains unclear.

METHODS: Among 2726 participants who visited a Korean memory clinic, 1005 amyloid-positive participants with magnetic resonance imaging (MRI) and Clinical Dementia Rating data were included. Eligibility for lecanemab and donanemab was assessed using AUR criteria, including age, Mini-Mental State Examination (MMSE), brain MRI, apolipoprotein E genotype (for donanemab), and anticoagulant use, applying both raw and z-score-based MMSE thresholds.

RESULTS: Among 1005 amyloid-positive participants, 24.6% were eligible for lecanemab and 28.0% for donanemab (9.1% and 10.3% of the initial sample). Applying MMSE z-scores increased eligibility to 38.4% and 33.7%, respectively. Over a third of participants were excluded due to MRI findings, mainly vascular lesions associated with increased amyloid-related imaging-abnormality risks.

DISCUSSION: Incorporating demographically adjusted MMSE z-score threshold improves real-world eligibility and promotes equitable access to anti-amyloid therapies.

HIGHLIGHTS: About a fourth of A+ patients in Korea met AUR criteria for anti-amyloid therapy. Donanemab eligibility slightly exceeded lecanemab despite narrower age criteria. MMSE z-score adjustment increased eligibility in older, less-educated individuals. Over 30% of eligible patients were excluded due to ARIA-related MRI findings. Culturally adapted cognitive thresholds are essential for equitable treatment access.}, } @article {pmid41224179, year = {2025}, author = {Tigro, H and Moëlo, C and Pelcman, J and Paslawski, W and Chen, G and Poska, H and Shimmo, R and Svenningsson, P and Kronqvist, N and Johansson, J}, title = {Bri2 BRICHOS, a molecular chaperone-like domain that can cross brain vascular endothelial cells and deliver proteins into neurons.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {388}, number = {Pt 2}, pages = {114403}, doi = {10.1016/j.jconrel.2025.114403}, pmid = {41224179}, issn = {1873-4995}, mesh = {Animals ; Humans ; *Endothelial Cells/metabolism ; *Neurons/metabolism ; Blood-Brain Barrier/metabolism ; Brain/metabolism/blood supply ; Mice ; *Molecular Chaperones/administration & dosage/metabolism ; Adaptor Proteins, Signal Transducing ; Protein Domains ; Recombinant Fusion Proteins/administration & dosage/pharmacokinetics ; Astrocytes/metabolism ; Drug Delivery Systems ; }, abstract = {The transport of biological drugs from the bloodstream into the central nervous system is hindered by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier, creating a need for efficient and safe delivery systems to the brain parenchyma. Recombinant human (rh) BRICHOS, a chaperone-like domain from the protein Bri2, can access the brain after systemic injection and has shown therapeutic efficiency in Alzheimer model mice. Here, we show that rh Bri2 BRICHOS and cargo proteins fused to it are efficiently transcytosed over human BBB models made of cerebral microvascular endothelial cells and astrocytes. Moreover, intravenously injected protein fused with Bri2 BRICHOS can access the brain parenchyma of mice and enter neurons and astrocytes. Our results suggest that rh Bri2 BRICHOS can be harnessed to deliver cargo from the bloodstream into neurons.}, } @article {pmid41224085, year = {2026}, author = {Gharedaghi, P and Faridi, N and Wang, P and Bathaie, SZ}, title = {Natural C20 carotenoids protect dPC12 cells from Aβ-induced cell cycle re-entry, Tau phosphorylation, and Nrf2 activation via the Akt/GSK-3β pathway.}, journal = {Journal of ethnopharmacology}, volume = {358}, number = {}, pages = {120816}, doi = {10.1016/j.jep.2025.120816}, pmid = {41224085}, issn = {1872-7573}, mesh = {*Carotenoids/pharmacology ; Animals ; *Glycogen Synthase Kinase 3 beta/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Phosphorylation/drug effects ; *NF-E2-Related Factor 2/metabolism ; *tau Proteins/metabolism ; PC12 Cells ; *Amyloid beta-Peptides/toxicity ; *Neuroprotective Agents/pharmacology ; Signal Transduction/drug effects ; Vitamin A/analogs & derivatives ; Apoptosis/drug effects ; Cell Cycle/drug effects ; Crocus/chemistry ; }, abstract = {Saffron has been known to improve mood and memory since ancient times. Crocin and Crocetin, bioactive C20 carotenoids, were isolated from saffron stigma and demonstrated multiple biological and pharmacological effects.

AIM OF THE STUDY: We recently demonstrated the effect of Crocin/Crocetin on apoptosis inhibition in an amyloid beta oligomer (AβO)-induced Alzheimer's disease (AD) model using neuronally differentiated PC12 (dPC12) cells. This study investigates their neuroprotective effects on the Akt/GSK-3β pathway in these cells, focusing on NRF2 activity, NQO1 expression, and Tau phosphorylation.

METHODS: dPC12 cells were exposed to AβO to mimic the AD condition. The cells were treated with Crocin/Crocetin before and after to produce preventive and therapeutic modalities. The expression of key pathway markers was evaluated using Western blot and immunocytochemistry. Flow cytometry was employed to assess cell cycle arrest and apoptosis.

RESULTS: Crocin/Crocetin significantly attenuated AβO-induced toxicity in dPC12 cells in both modalities mentioned. The named carotenoids significantly suppressed GSK3β kinase activity and reduced Tau phosphorylation (p-Thr231). Furthermore, they increased AKT phosphorylation, promoted NRF2 translocation into the nucleus, and induced NQO1 expression. These effects were observed in a time-dependent manner. Flow cytometry analyses revealed the involvement of both cell cycle arrest and apoptosis in response to AβO treatment. Crocin and Crocetin inhibited this response.

CONCLUSIONS: Collectively, Crocin/Crocetin effectively mitigated AβO-induced injury in dPC12 cells. Although Crocetin was more effective than Crocin and improved at lower concentrations, both carotenoids exhibited neuroprotective effects against AβO toxicity in preventive and therapeutic modalities via activating the Akt/GSK-3β signaling pathway.}, } @article {pmid41224062, year = {2025}, author = {Tiwari, P and Tiwari, S}, title = {Comparative anti-amyloidogenic potential of pristine and nitrogen doped graphene quantum dots against amyloid beta protein.}, journal = {International journal of biological macromolecules}, volume = {333}, number = {Pt 2}, pages = {148951}, doi = {10.1016/j.ijbiomac.2025.148951}, pmid = {41224062}, issn = {1879-0003}, mesh = {*Fullerenes/chemistry/pharmacology ; *Nitrogen/chemistry ; *Graphite/chemistry/pharmacology ; *Amyloid beta-Peptides/antagonists & inhibitors ; *Quantum Dots/chemistry ; *Peptide Fragments/antagonists & inhibitors/chemistry ; Protein Folding/drug effects ; Microscopy, Atomic Force ; *Amyloid/antagonists & inhibitors/chemistry ; Alzheimer Disease/metabolism ; Circular Dichroism ; Benzothiazoles/chemistry ; Cell Line, Tumor ; Humans ; Apoptosis/drug effects ; }, abstract = {This study investigates the effect of nitrogen doping of graphene quantum dots (GQDs) upon their ability to inhibit the fibrillation of amyloid beta fragments containing 1-42 amino acids (Aβ). Misfolded aggregates of Aβ have been implicated in the pathogenesis of Alzheimer's disease, the most prevalent form of dementia. We employed spectroscopic and microscopic techniques to characterize both quantum dots. Anti-amyloidogenic potential was assessed using circular dichroism spectroscopy and the thioflavin T binding. Atomic force microscopy was utilized to characterize the morphological and nanomechanical properties of Aβ fibrils following treatment with the quantum dots. We observed that nitrogen doping significantly alters the absorbance and fluorescence emission profiles, likely due to an increased surface charge density induced by the incorporation of nitrogen atoms. N-GQDs exhibited superior anti-amyloidogenic activity in comparison to pristine quantum dots. This effect varied in accordance to the dose. Using the data of MTT, trypan blue exclusion, differential staining and apoptosis assays on SH-SY5Y neuroblastoma cells, we infer that adsorption of Aβ on doped quantum dots was accompanied with reduction in the stiffness of fibrils and their toxicity to the cells.}, } @article {pmid41223445, year = {2025}, author = {Vlachos, I}, title = {Spectral brain connectivity in dementia: coherence, imaginary coherence and partial coherence analysis of EEG signals.}, journal = {Journal of neural engineering}, volume = {22}, number = {6}, pages = {}, doi = {10.1088/1741-2552/ae1ea1}, pmid = {41223445}, issn = {1741-2552}, mesh = {Humans ; Male ; *Electroencephalography/methods ; Female ; Aged ; *Alzheimer Disease/physiopathology/diagnosis ; Middle Aged ; *Brain/physiopathology ; *Nerve Net/physiopathology ; *Frontotemporal Dementia/physiopathology/diagnosis ; *Dementia/physiopathology/diagnosis ; Aged, 80 and over ; }, abstract = {Objective.As the prevalence of dementia continues to rise, the need for accurate and early diagnostic tools becomes increasingly critical. Despite diverse underlying causes, dementia types share common cognitive symptoms, making accurate diagnosis essential for effective treatment.Approach: This study investigates electroencephalographic (EEG)-based spectral brain connectivity in individuals with Alzheimer's disease (AD,N=36), frontotemporal dementia (FTD,N=23), and healthy controls (HCs,N=29), with the dual aim of identifying condition-specific connectivity patterns and evaluating three coherence-based connectivity measures: coherence, imaginary coherence, and partial coherence. Resting-state, eyes-closed EEG data (19 channels) were analyzed, and connectivity was estimated across frequencies to assess both global and local network alterations.Main results.The results indicate that dementias (both AD and FTD) are characterized by decreased connectivity in higher frequency bands and increased connectivity in lower frequencies, reflecting respectively impaired neural communication and neurodegeneration. Moreover, the severity of cognitive impairment correlates with the spatial extent and magnitude of connectivity disruptions. Notably, partial coherence-unlike coherence and imaginary coherence-effectively distinguishes between the AD and FTD groups, suggesting that direct connectivity measures may provide more discriminative information for differential diagnosis.Significance.These findings highlight the potential of EEG-based spectral connectivity analysis, particularly partial coherence, as a non-invasive tool to aid in the diagnosis and differential diagnosis of dementia subtypes, supporting early clinical decision-making.}, } @article {pmid41223194, year = {2025}, author = {Yoo, SS and Reddy, A and Carroll, W and Ploypradith, K}, title = {Repeated application of transcranial ultrasound maintains spatial and recognition memory in 5xFAD mice with reduction of amyloid-β burden.}, journal = {PloS one}, volume = {20}, number = {11}, pages = {e0336114}, pmid = {41223194}, issn = {1932-6203}, mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/therapy/metabolism/pathology ; Mice ; Male ; Mice, Transgenic ; *Spatial Memory ; *Recognition, Psychology ; Disease Models, Animal ; Hippocampus/metabolism/pathology ; Maze Learning ; *Ultrasonic Therapy/methods ; }, abstract = {Pharmacological removal of amyloid beta protofibrils has emerged as a promising therapeutic strategy to delay the onset of Alzheimer's disease (AD) symptoms. As a non-pharmacological and noninvasive alternative, transcranial application of low-intensity ultrasound through intact skull can induce convective acoustic streaming, which has been shown to enhance cerebrospinal fluid solute transport and facilitate the clearance of interstitial solutes. This has led to the development of device-based approaches aimed at removing the precursors of amyloid beta (Aβ) plaques and mitigating cognitive decline in AD. We applied non-thermal, non-cavitational ultrasound (400 kHz frequency) in a pulsed mode (75 ms pulse duration, 2 Hz repetition rate) to the hippocampal region of male 5xFAD mice for 30 minutes weekly, starting at 10 weeks of age and continuing for 15 weeks (until 6 months of age). Spatial and recognition memory performance was assessed monthly using the Y-maze spontaneous alternation (SA) and novel object recognition (NOR) tests. A control group of age-matched mice underwent the same procedures with receiving zero acoustic output. Mice subjected to transcranial ultrasound (tUS) treatment maintained both SA and NOR performance throughout the entire experimental period, whereas mice that received sham tUS exhibited a progressive decline in memory beginning at 3-4 months of age. Congo Red staining of the brain sections revealed a significant (> 40%) reduction in Aβ plaques in the sonicated group. Histological analysis confirmed that repeated ultrasound exposure did not cause any detectable tissue damage. These findings suggest that low intensity tUS may serve as a novel, noninvasive therapeutic strategy to delay the onset of AD symptoms through the reduction of Aβ burden.}, } @article {pmid41223122, year = {2025}, author = {Wiest, R and Radojewski, P and Lieb, JM and Psychogios, M and Benzinger, TLS and Franceschi, AM and Wanke, I and Draganski, B and Kurz, FT and Lövblad, KO}, title = {Clinical practice recommendations of the Swiss Society for Neuroradiology*: Neuroimaging standards for enrollment and disease monitoring in Anti-Amyloid Immunotherapies.}, journal = {Neuro-degenerative diseases}, volume = {}, number = {}, pages = {1-24}, doi = {10.1159/000549521}, pmid = {41223122}, issn = {1660-2862}, abstract = {INTRODUCTION: The Swiss Society for Neuroradiology (SSNR) has established clinical practice recommendations to guide the use of neuroimaging techniques in the enrollment and disease monitoring of patients undergoing anti-amyloid immunotherapies for Alzheimer's disease (AD). In Switzerland, anti-amyloid immunotherapy (AAT) has not been approved by Swissmedic ahead of this publication. This paper therefore reflects the existing international standards of care and will be updated after market clearance of AATs in Switzerland.

BACKGROUND AND RATIONALE: Neuroimaging is a key requirement to assess therapeutic responses and manage potential adverse effects, particularly amyloid-related imaging abnormalities (ARIA). The SSNR recommendations specify the appropriate use of MRI biomarkers to support therapy inclusion, routine monitoring and decision-making in case of manifestations of ARIA-E and ARIA-H during treatment.

CONCLUSIONS: This paper reviews the required image protocols and neuroimaging criteria for patient eligibility and discusses the key findings of ARIA-E and ARIA-H. These findings are required to be recognized by the practicing radiologist to ensure patient safety. The practice recommendations of the SSNR align with previous published recommendations of the American Society of Neuroradiology and the European Society of Neuroradiology. We also provide practical recommendations for workflows and candidate selection to continue or discontinue therapy.}, } @article {pmid41221473, year = {2025}, author = {Perez, FP and Bandeira, J and Morisaki, J and Kanakri, H and Rizkalla, M}, title = {Electromagnetic Field Stimulation Effects on Intrinsically Disordered Proteins and Their Role in Aging and Neurodegeneration.}, journal = {Journal of biomedical science and engineering}, volume = {18}, number = {10}, pages = {408-438}, pmid = {41221473}, issn = {1937-6871}, support = {UL1 TR000006/TR/NCATS NIH HHS/United States ; }, abstract = {There is increasing evidence from preclinical studies. There is growing evidence from preclinical studies in cell cultures and small organisms that exposure to Electromagnetic Fields (EMFs) produces beneficial biological effects. However, controversy persists due to the absence of a clearly defined mechanism. Classical physics, constrained by the non-ionizing nature of these exposures, cannot account for these effects, which do not involve the breaking of chemical bonds to induce conformational changes in proteins. Emerging studies suggest that these effects are mediated through quantum mechanical phenomena-specifically, quantum tunneling and particle-wave duality-acting on the water surrounding proteins at their interfaces. Furthermore, we present evidence of EMF-induced conformational changes in Intrinsically Disordered Proteins (IDPs), including beta-amyloid, tau, alpha-synuclein, and Heat Shock Factor 1 (HSF1). These findings offer a new framework for understanding EMF bioeffects and open promising avenues for research in biophysics and quantum biology. In this context, we address the challenge of reproducibility by examining how variables such as frequency, intensity, Specific Absorption Rate (SAR), and exposure time windows interact, along with how parameters like polarization, phase, pulse modulation, and scheduling influence outcomes. Experimental data identify specific RF frequencies and SAR levels that activate proteostasis and autophagy in cell cultures and small animal models, with potential applications in human treatments that remain consistent with safety thresholds established by regulatory agencies.}, } @article {pmid41220866, year = {2025}, author = {Kim, J and Kim, GH and Kang, K and Kim, HJ and Suh, J and Yoon, B and Cho, H and Pyun, JM and Park, YH and Choe, HK and Kim, YK and Lee, KH and Kim, JG and Yang, SJ and Baek, MJ and Chin, J and Jang, H and Moon, SY and , }, title = {Executive Summary of 2025 International Conference of the Korean Dementia Association and International Congress of the Asian Society Against Dementia (IC-KDA/ASAD 2025): A Report From the Academic Committee of the Korean Dementia Association.}, journal = {Dementia and neurocognitive disorders}, volume = {24}, number = {4}, pages = {209-232}, pmid = {41220866}, issn = {2384-0757}, abstract = {The International Conference of the Korean Dementia Association (IC-KDA) 2025 was held jointly with the 19th International Congress of the Asian Society Against Dementia (ASAD) in Seoul, South Korea (May 8-10, 2025), under the theme "Breaking Barriers of Dementia: From Research to Real-world Practice." The program opened with a Pre-Conference Symposium on "Dementia Treatment Update: Lecanemab and NPH" featuring 14 speakers, followed by the main meeting comprising 3 plenary sessions (5 speakers), 7 luncheon-symposium presentations, 16 parallel symposia (48 speakers), a special symposium (2 speakers), and 4 oral-presentation sessions (20 presenters). The congress was attended by 1,052 participants from 27 countries and included 213 poster presentations. Scientific highlights spanned the continuum from discovery to implementation: plasma and imaging biomarkers, retinal and electroencephalogram/voice-based digital biomarkers, and multimodal neuroimaging for risk stratification and outcome prediction; updates on anti-amyloid monoclonal antibodies (MABs) (lecanemab, donanemab), safety/amyloid-related imaging abnormalities management, and real-world data frameworks; mechanistic and multi-omics insights (genetics, metabolomics, epigenomics, transcriptomics); neuroinflammation and glia-mediated pathways; young-onset dementia cohorts across Asia-Pacific; vascular cognitive impairment trials and pathophysiology; neuropsychiatric symptoms and evidence-based behavioral and psychological symptoms of dementia care; lifestyle and multidomain prevention (Mediterranean-Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay-based interventions); dementia-friendly communities and caregiver support; and emerging neuromodulation modalities (low-intensity ultrasound, photobiomodulation, vagus nerve stimulation). Together, the joint IC-KDA & ASAD 2025 meeting emphasized precision medicine and implementation science, bridging laboratory advances with clinical practice and health-system delivery to improve outcomes for people living with dementia and their caregivers.}, } @article {pmid41220257, year = {2025}, author = {Wang, HJ and Ruthirakuhan, M and Andreazza, AC and Beroncal, EL and Black, SE and Gallagher, D and Herrmann, N and Kiss, A and Verhoeff, NPLG and Lanctôt, KL}, title = {Identifying a combination of biomarkers to predict treatment response to nabilone for agitation in Alzheimer's disease - an exploratory post hoc analysis.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/17582024.2025.2587549}, pmid = {41220257}, issn = {1758-2032}, abstract = {BACKGROUND: To identify if a combination of blood-based biomarkers related to inflammation and oxidative stress predict treatment response to nabilone for Alzheimer's disease (AD)-associated agitation.

RESEARCH DESIGN AND METHODS: Agitation was assessed using the Cohen-Mansfield Agitation Inventory (CMAI). Serum concentrations of 13 markers were quantified. Univariable and multivariable regression were used to determine differences in CMAI change given nabilone and placebo. A model combining biomarkers with clinical predictors was also evaluated.

RESULTS: Overall, 38 participants enrolled in the original trial (76% male, mean ± SD age 87 ± 10). Nabilone was more efficacious in participants with higher IL-6, higher 8-ISO, higher 24S-OHC, and lower clusterin. Participants in the first tertile (T1) of index scores demonstrated better response to nabilone compared to placebo with a mean difference in CMAI change of -20.6 (95%CI: -30.3, -10.4). During the nabilone phase, 83% of participants in T1 were responders versus 38% in T2 + 3 (Fisher's p = .01). In the combined model, T1 showed better response to nabilone with a mean difference in CMAI change of -26.4 (95%CI: -34.0, -19.6). The proportion of responders was significantly higher in T1 (91%, n = 11) compared to T2 + 3 (32%, n = 19) (Fisher's p = .002).

CONCLUSION: A combination of biomarkers could help characterize responders and non-responders to nabilone.}, } @article {pmid41219714, year = {2025}, author = {Blasi, V and Isernia, S and Rossetto, F and Pagliari, C and Borgnis, F and Pirastru, A and Marzulli, M and Foglia, E and Garagiola, E and Baglio, F}, title = {Study protocol for a randomized controlled trial assessing clinical efficacy of digital cognitive rehabilitation for preclinical and mild clinical stages of alzheimer's disease continuum: the MI-RICORDO project.}, journal = {BMC psychiatry}, volume = {25}, number = {1}, pages = {1075}, pmid = {41219714}, issn = {1471-244X}, support = {FP-1321//THCS Horizon Europe Programme/ ; }, mesh = {Humans ; *Alzheimer Disease/rehabilitation ; *Cognitive Dysfunction/rehabilitation ; Single-Blind Method ; Magnetic Resonance Imaging ; Female ; Male ; Randomized Controlled Trials as Topic ; Aged ; Neuronal Plasticity ; *Cognitive Behavioral Therapy/methods ; Treatment Outcome ; Cognitive Training ; }, abstract = {BACKGROUND: Early or preclinical stages of AD continuum may benefit from lifestyle interventions and cognitive rehabilitation strategies that can delay or prevent progression to dementia. In this context, digital health technologies offer a disruptive potential to expand access to cognitive rehabilitation and meet the increasing demand for early interventions. This study protocol outlines a randomized controlled trial (RCT) designed to evaluate the efficacy and efficiency of a personalized, multidomain digital cognitive rehabilitation approach compared to conventional paper-and-pencil therapy. A secondary objective is to investigate the structural and functional neuroplasticity mechanisms associated with both interventions, using advanced magnetic resonance imaging techniques.

METHODS: The study presents a single-blinded (assessors) 1:1 parallel-arm RCT design involving 102 patients with Subjective Cognitive Decline, o Mild Cognitive Impairment or early-stage dementia. For the experimental intervention group (EG) the digital therapeutic RICORDO-DTx will be employed, while the control group (CG) will perform an unstructured pencil-paper stimulation program. Both interventions will last 5 weeks with 3 session/week. Outcome measures will evaluate efficacy as changes in: behavioural and cognitive abilities, patients' engagement, and structural and functional neuroplasticity mechanisms by means of Magnetic Resonance Imaging. Additional evaluation will include efficiency measures related to usability, acceptability, safety, sustainability and user experience. Patients will be evaluated at baseline (T0), after treatment (T1) and at follow up six months post baseline (T2). Data analyses will involve repeated measures ANOVA models on primary and secondary outcome measures to compare efficacy of intervention between EG and CG. Finally, efficiency measures will be reported with descriptive statistics.

CONCLUSIONS: The expected results lay on the ability of RICORDO DTx, to adapt task difficulty automatically based on patients' performance and perceived difficulty. This adaptive approach is anticipated to yield superior treatment outcomes relative to traditional pencil-and-paper exercises.

TRIAL REGISTRATION: ClinicalTrials.gov NCT07064226. Date of registration 30th July 2025.}, } @article {pmid41219645, year = {2025}, author = {Hoang, VD and Nguyen, HMT and Nguyen, TA and Garg, S}, title = {Pharmaceutical Formulations and Analytical Methods of Donepezil.}, journal = {AAPS PharmSciTech}, volume = {27}, number = {1}, pages = {28}, pmid = {41219645}, issn = {1530-9932}, support = {R01AG064688 (Hinton/Nguyen MPI)//the National Institute of Aging (NIA) of the National Institutes of Health (NIH)/ ; }, mesh = {*Donepezil/chemistry ; Chemistry, Pharmaceutical/methods ; Humans ; Alzheimer Disease/drug therapy ; *Cholinesterase Inhibitors/chemistry/administration & dosage ; Drug Compounding/methods ; Drug Delivery Systems/methods ; *Indans/chemistry ; *Piperidines/chemistry ; Tandem Mass Spectrometry/methods ; Nanoparticles/chemistry ; }, abstract = {Donepezil is a selective acetylcholinesterase inhibitor widely prescribed for the symptomatic treatment of Alzheimer's disease. As therapeutic needs grow and delivery systems evolve, ensuring product quality, efficacy, safety and patient compliance becomes increasingly important. Meanwhile, pharmaceutical formulation innovations can improve clinical outcomes and usability, and analytical methods help ensure accurate assessment of drug behavior and quality control. This narrative review first provides a concise overview of donepezil's physicochemical properties and synthesis, then focuses on two interrelated domains: (i) pharmaceutical formulations and (ii) analytical methodologies. The former highlights advancements in novel delivery systems-such as liposomes, nanoparticles, microneedles, nasal gels, and long-acting injectable depots-developed to enhance brain targeting, prolong drug release, and reduce systemic side effects. The latter reviews validated analytical methods for quantifying and characterizing donepezil in pharmaceutical and biological matrices, with emphasis on RP-HPLC, LC-MS/MS, chiral separations, and emerging electrochemical and spectroscopic techniques. These analytical strategies are essential for evaluating formulation performance, monitoring drug stability, and ensuring regulatory compliance. Collectively, this review underscores that progress in both formulation design and analytical science is vital to optimizing donepezil-based therapies for Alzheimer's disease management.}, } @article {pmid41219231, year = {2025}, author = {Mahadik, N and Paruchuri, SN and Arif, R and Coutts, AS and Barron, GA and Kong Thoo Lin, P and Chatterjee, S and Thompson, CJ}, title = {Evaluation of the toxicity and efficacy of a multi-target polymer-drug nano-polyplex in SH-SY5Y cells and Drosophila model of tauopathy.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {39454}, pmid = {41219231}, issn = {2045-2322}, support = {C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; C23-1720928079//Royal Society of Chemistry/ ; }, mesh = {Animals ; *Tauopathies/drug therapy/metabolism/pathology ; Humans ; Disease Models, Animal ; tau Proteins/metabolism ; Cell Survival/drug effects ; *Acrylic Resins/chemistry ; Drosophila melanogaster ; Drosophila ; Cell Line, Tumor ; Phosphorylation/drug effects ; *Polymers/chemistry ; *Nanoparticles/chemistry ; }, abstract = {Hyperphosphorylated tau contributes to synaptic damage and neuronal dysfunction in neurodegenerative diseases such as Alzheimer's disease (AD), making it a key therapeutic target. This study evaluated the toxicity and therapeutic potential of a novel polymer-drug nano-polyplex, N5NM15, and polyacrylic acid (PAA) in Drosophila tauopathy models and undifferentiated human SH-SY5Y cells. Cellular uptake was demonstrated by N5NM15, and SH-SY5Y cell viability was significantly enhanced (45%, p ≤ 0.0001) under okadaic acid-induced stress, and total tau levels were reduced (1.43-fold, p ≤ 0.01). In comparison, PAA had a modest effect on decreasing tau phosphorylation (1.3-fold) at the pSer202/pThr205 site. Toxicity studies in Drosophila revealed that N5NM15 (3.5:1 and 44:12.5 µg/mL) and PAA (44 µg/mL) were toxic to adult flies expressing the eye-specific driver (GMR-GAL4) but were well-tolerated in flies overexpressing the pan-neuronal driver ELAV-GAL4. Furthermore, treatment with N5NM15 and PAA did not improve the ommatidial arrangement, eye bristle count, or eye length in tauopathy models. Climbing and survival assays indicated a potential mild protective effect at a lower concentration (3.5:1 µg/mL) at the early stage of the disease, but at a higher dose (44:12.5 µg/mL) was significantly toxic, in both wild-type (p ≤ 0.0001) and tauopathy models (p < 0.05). These findings highlight the need for N5NM15 and PAA dose optimisation and reformulation with non-toxic buffers to enhance therapeutic potential while minimising adverse effects in normal and Drosophila tauopathy models for AD treatment.}, } @article {pmid41219110, year = {2025}, author = {Rose, DK and Lyketsos, CG and Rosenberg, PB and Nowrangi, MA}, title = {Neuropsychiatric symptoms in Alzheimer's disease: Bridging mechanisms, management, and emerging innovations.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {}, number = {}, pages = {e00788}, doi = {10.1016/j.neurot.2025.e00788}, pmid = {41219110}, issn = {1878-7479}, abstract = {Neuropsychiatric symptoms (NPS) are among the most distressing and functionally disruptive features of Alzheimer's disease (AD), affecting the vast majority of individuals across the disease continuum. These symptoms, ranging from apathy and depression to agitation and psychosis, not only worsen quality of life but also predict faster decline, earlier institutionalization, and heightened caregiver burden. Yet, despite their clinical significance, NPS remain under-recognized and undertreated. This review synthesizes current understanding of the biological underpinnings of NPS in AD, highlighting network-level dysfunction, neurotransmitter imbalances, neuroinflammation, and emerging roles for tau pathology and circadian disruption. We critically examine current treatment paradigms, noting that pharmacologic interventions offer benefit but often carry significant risks. In contrast, non-pharmacological approaches, particularly those that integrate caregiver training, environmental design, and sensory engagement, hold promise but are inconsistently applied in routine care. Emerging innovations, including neuromodulation, repurposed agents (e.g., beta-blockers, cannabinoids), and digital therapeutics such as virtual reality and AI-enabled monitoring tools, offer new therapeutic avenues. We call for a paradigm shift toward person-centered, mechanistically-informed care that aligns intervention strategies with biological drivers of NPS. Future progress hinges on inclusive clinical trials, implementation of first-line behavioral strategies, and development of biomarker-guided, precision approaches to symptom management. Effective care for NPS in AD demands integration, not substitution, of pharmacologic and non-pharmacologic strategies, grounded in a deeper understanding of both disease biology and lived patient experience.}, } @article {pmid41219002, year = {2026}, author = {Radhakrishna, BK and Kaladiyil, AP and Chakraborty, A and Gautam, V and Muddashetty, RS}, title = {Group 1 mGluR stimulation rescues APOE4-mediated translation defects in neurons.}, journal = {Life science alliance}, volume = {9}, number = {2}, pages = {}, pmid = {41219002}, issn = {2575-1077}, mesh = {Animals ; *Apolipoprotein E4/metabolism/genetics ; *Receptors, Metabotropic Glutamate/metabolism ; *Neurons/metabolism/drug effects ; Rats ; Rats, Sprague-Dawley ; *Protein Biosynthesis/drug effects ; Neuronal Plasticity ; TOR Serine-Threonine Kinases/metabolism ; Phosphorylation ; Cells, Cultured ; Alzheimer Disease/metabolism/genetics ; Humans ; Ribosomal Protein S6/metabolism ; }, abstract = {The E4 isoform of apolipoprotein (APOE4) is the most recognized risk factor for Alzheimer's disease, implicated in early neurodegeneration and impaired synaptic plasticity. In neurons, exposure to APOE4 disrupts basal and NMDAR-mediated calcium signaling, further disrupting protein synthesis response. Group 1 mGluRs, a major class of glutamate receptors, also play a critical role in synaptic plasticity through activity-dependent protein synthesis. In this study, we examine neuronal protein synthesis response to mGluR stimulation in the background of APOE4 treatment. In DIV15 primary cortical neurons from Sprague-Dawley rat embryos, exposure to APOE4 induces inhibition of protein synthesis, which is rescued by stimulation of mGluRs for 5 min. mGluR stimulation also rescued the APOE4-induced reduction in synaptic activity as measured by the multi-electrode array. This mGluR-mediated rescue is driven by phosphorylation of RPS6, downstream of the mammalian target of rapamycin (mTOR) pathway as it is abolished by rapamycin treatment. This p-RPS6-driven rescue is independent of calcium-mediated translation inhibition induced by APOE4, demonstrating a specific and independent role of mTORC1 activity in maintaining mGluRs' translation capacity under APOE4 exposure. The potential of mGluR-mediated response to compensate for the effect of APOE4 suggests a dynamic mechanism for the induction of plasticity in human APOE4 carriers. This study provokes a critical need to explore the altered synaptic dynamics in the presence of APOE4 and its impact on cognition.}, } @article {pmid41218737, year = {2026}, author = {Ahangaran, S and Pourgholaminejad, A and Nosrati, R and Babaei, P}, title = {TLR4 inhibition attenuates facilitatory effects of JQ1 on learning & memory via polarization of microglia, and BDNF expression in Alzheimer's disease model.}, journal = {Behavioural brain research}, volume = {499}, number = {}, pages = {115919}, doi = {10.1016/j.bbr.2025.115919}, pmid = {41218737}, issn = {1872-7549}, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism/drug effects ; *Alzheimer Disease/metabolism/drug therapy ; *Microglia/drug effects/metabolism ; Male ; *Toll-Like Receptor 4/antagonists & inhibitors/metabolism ; Rats, Wistar ; Rats ; *Azepines/pharmacology/administration & dosage ; *Triazoles/pharmacology/administration & dosage ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Sulfonamides/pharmacology/administration & dosage ; Amyloid beta-Peptides ; Avoidance Learning/drug effects ; Maze Learning/drug effects ; Cell Cycle Proteins ; Bromodomain Containing Proteins ; Nuclear Proteins ; Transcription Factors ; }, abstract = {OBJECTIVE: Neuroinflammation is a core event in the pathogenesis of Alzheimer's disease (AD), which is mediated by microglia. The present study aimed to investigate the effect of co-inhibition of Toll-like receptor (TLR4) and chromatin reader of BRD4 on cognition deficit, polarization of microglia, and Brain-derived neurotrophic factor in the hippocampus.

METHODS: Forty male Wistar rats were randomly divided into five groups: saline +saline, Aβ+saline, Aβ+JQ1(BRD4 inhibitor), Aβ+TAK242 (TLR4 inhibitor), Aβ+JQ1 +TAK-242, and received the related treatments. Then cognitive functions were assessed by passive avoidance learning (PAL) and Morris water maze (MWM) tests and the polarization of microglia and BDNF level in the hippocampus, were measured using flow cytometry and western blotting, respectively.

RESULTS: Chronic intracerebroventricular administration of JQ1, either alone or in combination with TAK-242, significantly reduced escape latency and increased the time spent in the target quadrant (TTS) during the probe test of the Morris Water Maze (MWM), compared with the Aβ + saline group (p < 0.05). In contrast, TAK-242 alone prolonged escape latency and reduced TTS (p < 0.05). Moreover, JQ1 treatment markedly elevated the M2/M1 microglial polarization and the mBDNF/proBDNF ratio in the hippocampus (p < 0.05), suggesting that JQ1 promotes neuroprotective and facilitatory effects on cognitive function in AD model.

CONCLUSION: Our results indicate that JQ1 successfully improves learning and memory in the rat model of AD, primarily by inducing the transcription of mature BDNF expression and suppressing inflammatory factors related to the M1 microglia. In contrast, co-treatment with a TLR4 inhibitor attenuates both spatial and aversive memories, probably through a decrease in BDNF expression.}, } @article {pmid41218709, year = {2026}, author = {Ruoff, LK and Bänfer, IWH and Liedtke, DE and China, SE and Wiltfang, J and Bayer, TA and Bock, SF and Spandau, F and Bouter, C and Beindorff, N and Bouter, Y}, title = {Long-term thiethylperazine treatment in the Tg4-42 mouse model of Alzheimer's disease mouse: Therapeutic potential vs. adverse effects.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {258}, number = {}, pages = {174127}, doi = {10.1016/j.pbb.2025.174127}, pmid = {41218709}, issn = {1873-5177}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Mice, Inbred C57BL ; Disease Models, Animal ; Male ; Mice, Transgenic ; *Piperazines/adverse effects/therapeutic use/pharmacology/administration & dosage ; Anxiety/drug therapy ; Maze Learning/drug effects ; Memory/drug effects ; Amyloid beta-Peptides/metabolism ; Behavior, Animal/drug effects ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments. Thiethylperazine, a dopamine receptor antagonist with antiemetic and antidopaminergic properties, has been proposed as a potential therapeutic agent for AD. However, its impact on cognitive function in AD remains unclear.

AIMS: This study investigated the long-term effects of thiethylperazine on memory, anxiety-like behavior, motor function, and AD pathology in Tg4-42 mice, a model characterized by Aβ4-42 overexpression and progressive neurodegeneration. Additionally, the impact of prolonged thiethylperazine treatment on behavioral outcomes and cerebral glucose metabolism in healthy adult C57BL/6J wild-type (WT) mice were examined.

METHODS: Tg4-42 and WT mice were treated daily with 10 mg/kg thiethylperazine for 6 months, starting at 10 weeks of age. Memory, anxiety-related, and motor tests were performed at 7.5 months. Immunohistochemical analyses were conducted to quantify effects on Aβ pathology, neurogenesis, neuron number, and neuroinflammation. Additionally, [18]F-FDG-PET imaging was used to evaluate metabolic activity in WT mice following treatment.

RESULTS: Thiethylperazine improved recognition memory in Tg4-42 mice in the Novel Object Recognition test and exhibited anxiolytic properties. However, it impaired spatial learning in the Morris Water Maze (MWM), reduced locomotion, and failed to mitigate motor impairments. No effects on neuron loss or neuroinflammation were observed. In WT mice, thiethylperazine altered learning processes in the MWM, as indicated by shifts in search strategies, induced hypometabolism and increased neurogenesis.

CONCLUSION: Although thiethylperazine offers mild cognitive benefits in Tg4-42, its adverse effects on learning strategies and locomotion raise questions about its potential as a therapeutic option for AD.}, } @article {pmid41216966, year = {2025}, author = {Hovde, MJ and Maaser-Hecker, A and Bae, JS and Tanzi, RE}, title = {Inhibition of Acyl-CoenzymeA: Cholesterol Acyltransferase 1 promotes shedding of soluble triggering receptor on myeloid cells 2 (TREM2) and low-density lipoprotein receptor 1 (LRP1)-dependent phagocytosis of amyloid beta protein in microglia.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70879}, pmid = {41216966}, issn = {1552-5279}, support = {//NIH/ ; T32 AG000222-31//Cure Alzheimer's Fund/ ; //Freedom Together Fund/ ; T32AG000222/AG/NIA NIH HHS/United States ; T32 AG000222/AG/NIA NIH HHS/United States ; }, mesh = {*Microglia/metabolism/drug effects ; Animals ; *Amyloid beta-Peptides/metabolism ; *Low Density Lipoprotein Receptor-Related Protein-1/metabolism/genetics ; *Receptors, Immunologic/metabolism/genetics ; Humans ; Mice, Knockout ; *Phagocytosis/physiology/drug effects ; *Membrane Glycoproteins/metabolism/genetics ; Mice ; *Sterol O-Acyltransferase/antagonists & inhibitors/metabolism ; *Acetyl-CoA C-Acetyltransferase/antagonists & inhibitors/metabolism ; }, abstract = {INTRODUCTION: Lipid regulation is crucial role in Alzheimer's disease (AD) pathogenesis. In AD, microglia show elevated sterol O-acyltransferase 1/Acyl-coenzymeA: Choleseterol Acyltransferase 1 (SOAT1) expression, encoding Acyl-coenzymeA: Cholesterol Acyltransferase 1 (ACAT1), which produces cholesteryl esters (CEs) in lipid droplets. Inhibiting ACAT1 has been shown to reduce amyloid beta (Aβ) pathology, though the mechanism is unclear.

METHODS: We inhibited ACAT1 using avasimibe (AV) in wild-type, triggering receptor expressed on myeloid cells 2 (TREM2) knockout (KO), and low-density lipoprotein receptor related protein 1 (LRP1) KO mouse BV2 and human induced pluripotent stem cell-derived microglia and measured the impact on Aβ uptake to determine the mechanism through which the inhibition of ACAT1 enhances Aβ uptake.

RESULTS: ACAT1 inhibition increased LRP1 levels and soluble TREM2 (sTREM2) release via enhanced TREM2 cleavage by ADAM metallopeptidase domain 10/17 (ADAM10/17). KO of TREM2 or blockade of sTREM2 release prevented AV-enhanced Aβ uptake. This effect was rescued by recombinant sTREM2, but only when LRP1 was present.

DISCUSSION: ACAT1 inhibition promotes microglial Aβ uptake in a sTREM2- and LRP1-dependent manner, offering insights into novel therapeutic strategies for AD.

HIGHLIGHTS: Inhibition of ACAT1, the major enzyme that catalyzes cholesterol storage via esterification enhances microglia-mediated Aβ uptake. Increased Aβ uptake is dependent on the presence of both TREM2 and LRP1. Inhibition of ACAT1 increases cleavage of TREM2 via ADAM10/17 to release sTREM2. Treatment of microglial cells with sTREM2 rescues Aβ uptake in TREM2 KO BV2 cells. Inhibition of ACAT1 promotes Aβ uptake through increased shedding of TREM2, which enhances Aβ uptake through a LRP1-dependent mechanism.}, } @article {pmid41216919, year = {2025}, author = {Heikal, SA and Fawi, G and Khedr, EM and Othman, M and Moustafa, SA and Elsheikh, NG and Tawfik, HM and Elfarrash, S and Salama, S and Ali, EM and Hassanin, HI and Salama, M}, title = {The Egyptian Dementia Network (EDN): Baseline characteristics from the first dementia registry in an African Arab country.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70770}, pmid = {41216919}, issn = {1552-5279}, support = {//100 PhDs for Africa programme/ ; //UM6P- EPFL Excellence in Africa Initiative/ ; //American University in Cairo, Research Support/ ; }, mesh = {Humans ; *Registries ; Egypt/epidemiology ; Female ; Male ; *Dementia/epidemiology ; Aged ; Middle Aged ; Aged, 80 and over ; Comorbidity ; }, abstract = {INTRODUCTION: Dementia is a growing public health challenge in low- and middle-income countries (LMICs) like Egypt, where data are scarce. The Egyptian Dementia Network (EDN) registry addresses this gap by capturing epidemiological, clinical, and environmental data across Egypt.

METHODS: In this multicenter study, 662 participants from six governorates were enrolled using standardized tools.

RESULTS: The cohort had advanced age (mean 68.3 years), low education (65.9% illiterate), and high comorbidities including hypertension (55%) and diabetes (23%). Alzheimer's disease (62%) and vascular dementia (23%) predominated. Only 24.4% received pharmacological treatment and 2.1% psychosocial support, highlighting care gaps. Household insecticide exposure (20.4%) was notable.

DISCUSSION: EDN demonstrates the feasibility of implementing a national dementia registry in LMICs, generating baseline insights into demographic, clinical, and environmental risks. In addition, registry-linked biosamples have enabled pilot multi‑omics and exposome analyses, underscoring its potential as a scalable scientific platform for future dementia research.

HIGHLIGHTS: Established Egypt's first national, multicenter dementia registry. Aimed to characterize dementia profiles and care gaps across diverse regions. Identified late-stage diagnosis and limited access to dementia interventions. Uncovered unique environmental risk factors relevant to the Egyptian context. Provides a foundation for policy, research, and improved dementia care in Egypt.}, } @article {pmid41216806, year = {2025}, author = {Oveisgharan, S and Yu, L and Wang, Y and Yang, J and Vialle, R and Lopes, KP and Tasaki, S and Young-Pearse, TL and De Jager, PL and Petyuk, VA and Schneider, JA and Seyfried, NT and Bennett, DA}, title = {Amyloid beta binding partners in the brain tissue of older adults.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70882}, pmid = {41216806}, issn = {1552-5279}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; R01 AG088643/AG/NIA NIH HHS/United States ; R01AG088643/NH/NIH HHS/United States ; U01 AG072572/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; P30AG72975/NH/NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; U01AG072572/NH/NIH HHS/United States ; R01AG17917. R01AG015819/NH/NIH HHS/United States ; R01AG088643/AG/NIA NIH HHS/United States ; P30AG10161/NH/NIH HHS/United States ; U01AG046152/NH/NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; tau Proteins/metabolism ; Aged ; Aged, 80 and over ; *Alzheimer Disease/pathology/metabolism ; *Brain/metabolism/pathology ; Neurofibrillary Tangles/pathology/metabolism ; rac1 GTP-Binding Protein/metabolism ; Sodium-Potassium-Exchanging ATPase/metabolism ; }, abstract = {INTRODUCTION: The mechanism linking extracellular amyloid beta (Aβ) with intraneuronal tau tangles, pathological hallmarks of Alzheimer's disease (AD), is not understood; it was tested in the current study through Aβ binding partners.

METHODS: Data were from decedents of community-based clinical-pathological studies. Of 52 Aβ binding partners, suggested by non-human studies, levels of 34 together with total Aβ protein were quantified in the dorsolateral prefrontal cortex. Post mortem pathological assessment immunohistochemically quantified Aβ load and tau tangle density.

RESULTS: The strongest mediations between Aβ and tau tangles were observed for Ras-related C3 botulinum toxin substrate 1 (RAC1) and sodium/potassium-transporting ATPase subunit alpha-3 (ATP1A3), which collectively mediated 10.1% of the association between Aβ and tau tangles. In contrast, Aβ mediated >70% of the associations of matrix proteins with tau tangles.

DISCUSSION: Identification of Aβ binding partners that mediate the association between Aβ and tau tangles may provide new targets for AD treatment.

HIGHLIGHTS: RAC1 linked Aβ with tau tangles. ATP1A3 linked Aβ with tau. RAC1 and ATP1A3 collectively mediated 10.1% of the association between Aβ and tau. Aβ mediated >70% of the associations of matrix proteins, such as APOE, with tau.}, } @article {pmid41216805, year = {2025}, author = {Lopergolo, D and Gasparini, D and Bianchi, S and Pucci, B and Tripodi, D and Leoni, V and Chincarini, A and Sestini, S and Zetterberg, H and De Stefano, N and Mignarri, A}, title = {Miglustat in Alzheimer's Disease Associated With Heterozygous NPC1 Mutation: Exploratory Case Series and Preliminary Findings.}, journal = {European journal of neurology}, volume = {32}, number = {11}, pages = {e70419}, pmid = {41216805}, issn = {1468-1331}, support = {2023-00356//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//Alzheimer Drug Discovery Foundation (ADDF), USA/ ; ADSF-21-831376-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831381-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-21-831377-C//AD Strategic Fund and the Alzheimer's Association/ ; ADSF-24-1284328-C//AD Strategic Fund and the Alzheimer's Association/ ; 22HLT07//European Partnership on Metrology/ ; //Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Olav Thon Foundation/ ; //Erling-Persson Family Foundation/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *1-Deoxynojirimycin/analogs & derivatives/therapeutic use/pharmacology/analogs & derivatives ; *Alzheimer Disease/genetics/drug therapy/diagnostic imaging ; Brain/diagnostic imaging/metabolism/drug effects ; *Enzyme Inhibitors/therapeutic use ; Heterozygote ; Intracellular Signaling Peptides and Proteins ; *Membrane Glycoproteins/genetics ; Mutation/genetics ; Niemann-Pick C1 Protein ; }, abstract = {INTRODUCTION: Several studies have previously demonstrated an increased risk of dementia and brain amyloid deposition in individuals with heterozygous NPC1 mutations. Moreover, in a recent study, we identified the first family with autosomal dominant late-onset Alzheimer's disease (AD) caused by a heterozygous NPC1 mutation. Unfortunately, there are currently no effective treatments available for this condition. Miglustat, which impacts the metabolism of oxysterols, has been shown to exert an anti-amyloidogenic effect in a human cellular model of AD.

METHODS: In our exploratory uncontrolled study, three patients from the previously published family were orally treated with miglustat for 12 months. They underwent monthly clinical evaluations and routine blood tests. Additionally, neuropsychological evaluations, brain amyloid-PET imaging, and biochemical analyses on plasma and CSF were performed.

RESULTS: All three patients achieved clinical stability, showed a sustained reduction in serum oxysterol levels, and experienced a marked decrease in brain amyloid burden.

DISCUSSION: Based on our preliminary observations and hypothesis-generating findings, along with the growing evidence suggesting AD as a lipid disorder, miglustat should be further tested in a larger cohort of heterozygous NPC1 mutated patients and probably evaluated as a potential disease-modifying treatment for AD.}, } @article {pmid41216328, year = {2025}, author = {Mohammadi, S and Zarei, S}, title = {Predicting Alzheimer's disease from environmental risk factors: An fMRI-based functional connectivity and advanced machine learning approach.}, journal = {Journal of environmental health science & engineering}, volume = {23}, number = {2}, pages = {39}, pmid = {41216328}, issn = {2052-336X}, abstract = {Alzheimer's disease (AD) is a prevalent and severe neurodegenerative disorder influenced by both genetic and environmental factors-such as air pollution, toxic elements, pesticides, and infectious agents. In recent years, machine learning techniques have become essential in biomedical research, advancing fields like drug delivery and medical imaging through predictive modeling and pattern recognition. Functional connectivity derived from functional magnetic resonance imaging (fMRI) serves as a promising noninvasive biomarker for AD by mapping the brain's connectome and revealing neural network disruptions. In this study, we employed the Robust Multitask Feature Extraction Method to evaluate six supervised machine learning algorithms logistic regression, naïve Bayes, support vector machine, random forest, XGBoost, and CatBoostmfor AD diagnosis. A dataset of 140 fMRI images from an equal number of AD patients and healthy individuals (mean age 67.3 ± 6.7 years) was analyzed. The XGBoost algorithm demonstrated exceptional performance, achieving an accuracy of 98.2%, a recall of 96.6%, perfect precision (100%), an F1-Score of 98.2%, and a Matthews correlation coefficient of 0.96 effectively minimizing false positives and negatives. Although CatBoost and Random Forest also yielded robust results, logistic regression and naïve Bayes showed lower reliability. Overall, XGBoost emerges as a robust solution for the early and precise prediction of Alzheimer's disease, carrying significant implications for proactive patient care and treatment strategies. Beyond these findings, emerging research is exploring multimodal imaging techniques-such as PET and EEG and deeper neural network architectures to further enhance early diagnostic accuracy and treatment personalization in AD.}, } @article {pmid41215663, year = {2025}, author = {Guo, Z and Ni, H and Lu, Y and Cui, Z and Wang, Y and Zhu, Z and Wei, X and Xia, C and Xu, M and Du, L and Yang, Y and Shu, S and Wang, K and Wang, Z and Shan, C and Wang, D}, title = {TNEA Regulates Hippocampal Oscillation by Improving Inhibitory Synaptic Plasticity to Ameliorates Cognitive Impairment in Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e10885}, doi = {10.1002/advs.202510885}, pmid = {41215663}, issn = {2198-3844}, support = {62127810//National Natural Science Foundation of China/ ; 82272612//National Natural Science Foundation of China/ ; 82374581//National Natural Science Foundation of China/ ; 21DZ2271000//Shanghai Key Laboratory of Health Identification and Assessment/ ; YC-2023-0604//Pudong New Area of Highland Discipline development program/ ; PWRq2023-36//Pudong New Area Outstanding Young Medical Professionals Training Program/ ; YC-2024-0104//Pudong Traditional Chinese Medicine Standardization & Capacity Building Project/ ; }, abstract = {Three-needle electroacupuncture (TNEA) has demonstrated efficacy in improving cognitive function in both Alzheimer's disease (AD) model animals and patients, although its underlying mechanism remains unclear. Here this work investigates the potential connection between cognitive-enhancing effect and TNEA in 5×familial Alzheimer disease（5xFAD) mice model, a model characterized by Amyloid-beta (Aβ) pathology. This work finds alterations in gamma/theta oscillations and deficits in inhibitory monosynaptic transmission in the hippocampal CA1 region of AD. Parvalbumin-positive (PV[+]) interneurons are crucial for generating gamma oscillations and modulating theta oscillation, thereby maintaining the excitation-inhibition (E/I) balance in local neural circuits. In 5xFAD mice, TNEA modulated PV[+] interneuron function, enhancing gamma oscillations during quiescent states. Furthermore, during the novel object recognition test (NORT), TNEA increased theta oscillation power by strengthening presynaptic inhibitory interneurons involved in monosynaptic connections. Collectively, these findings suggest TNEA is a viable minimally invasive treatment approach for AD.}, } @article {pmid41215623, year = {2025}, author = {Li, LL and Wang, RZ and Wang, Z and Hu, H and Xu, W and Zhu, L and Sun, Y and Chen, KL and Chen, SF and He, XY and Yuan, MY and Huang, YY and Liu, X and Liu, P and Ye, QY and Wang, J and Ju, ZZ and Zhang, W and Hu, B and Guo, Y and Cao, XY and Li, YX and Zuo, CT and Cheng, W and Jiang, T and Tan, L and Chen, XC and Zhao, QH and Cui, M and Peng, GP and Xin, JW and Yu, JT}, title = {Safety and short-term outcomes of lecanemab for Alzheimer's disease in China: a multicentre study.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awaf427}, pmid = {41215623}, issn = {1460-2156}, abstract = {Lecanemab is a newly approved monoclonal antibody targeting amyloid plaques for the treatment of early Alzheimer's disease. This study aimed to evaluate the safety and short-term biomarkers and cognition changes of lecanemab in Chinese clinical practice. This multicenter real-world study involved patients receiving lecanemab treatment across seven hospitals in China. Patients underwent comprehensive assessments before treatment. Lecanemab was administered via intravenous infusion every 2 weeks. Treatment-related symptoms were monitored through self-report, and amyloid-related imaging abnormalities were assessed via magnetic resonance imaging. Amyloid and tau biomarker changes were measured using positron emission tomography imaging or plasma testing. Follow-up cognitive assessments were evaluated after 6 months of treatment. Short-term outcomes were analyzed using linear mixed-effect models, without an untreated control group. A total of 407 patients who received at least one lecanemab infusion were involved in this study, with a mean follow-up time of 5.6±3.39 months. The mean age was 68.08 years, with 67.57% of patients being female. Of the participants, 56.51% were APOE ε4 carriers, and 83.19% were at biological stage C. During the study period, 22.22% of the patients experienced treatment-related symptoms, and 12.15% developed at least one amyloid-related imaging abnormality. Only four symptomatic and seven severe amyloid-related imaging abnormality cases were reported. APOE ε4 status was not related to adverse events in the Chinese population. Patients with a higher number of microhemorrhages at baseline were more likely to develop adverse events. No significant differences in adverse events were observed between the moderate Alzheimer's disease dementia group and the mild cognitive impairment group. By the end of the research period, 9.38% of the patients withdrew from lecanemab. After 6 months of treatment, favourable short-term outcomes in biomarkers and stable cognitive function were observed. This study demonstrates that lecanemab treatment is feasible and well-tolerated among the Chinese population, with lower rates of adverse events and favourable short-term outcomes observed. Administration of lecanemab in moderate AD dementia population was relatively safe and further studies are warranted.}, } @article {pmid41213497, year = {2025}, author = {Hu, K and Li, C and Liu, Y and Pan, C and Xie, P and Wen, L and Xu, H and Tang, Y and Zheng, P and Huang, Y}, title = {Arabinoxylan ameliorates memory deficits and amyloid pathology in male 5 × FAD mice via modulation of gut microbiota structure.}, journal = {Neuroscience}, volume = {591}, number = {}, pages = {52-62}, doi = {10.1016/j.neuroscience.2025.11.010}, pmid = {41213497}, issn = {1873-7544}, mesh = {Animals ; *Gastrointestinal Microbiome/drug effects/physiology ; Male ; Mice ; *Alzheimer Disease/metabolism/pathology ; *Memory Disorders/metabolism/drug therapy/pathology ; *Xylans/pharmacology ; Hippocampus/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Dysbiosis ; Mice, Inbred C57BL ; Fatty Acids, Volatile/metabolism ; Brain/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD), a prevalent neurodegenerative disorder, is primarily characterized by β-amyloid (Aβ) deposition. Current therapies alleviate symptoms but lack agents capable of modifying disease progression. Meanwhile, cross-regional studies indicate that AD patients exhibit disrupted gut microbiota composition, which is closely associated with cerebral molecular dysregulation. Building on this gut-brain connection, this study aimed to attenuate AD progression by targeting gut microbiota through microbially metabolized carbohydrates. Specifically, using 5 × FAD mice modeling AD pathology, we conducted 16S rRNA sequencing, targeted metabolomics of microbiota-derived metabolites, and bulk RNA sequencing experiments to investigate gut-brain axis alterations. Our results show that AD mice exhibited gut dysbiosis, depletion of short chain fatty acids (SCFAs), and transcriptomic dysregulation in the hippocampus, particularly affecting aging and synaptic plasticity-related genes. Dietary intervention with arabinoxylan significantly increased SCFAs-producing bacteria (Oscillospiraceae and Eubacterium_coprostanoligenes_group), elevated butyric acid, and thereby reversed expression levels of these aging and synaptic plasticity-related genes. Mechanistically, arabinoxylan alleviated AD-like symptoms by modulating the microbiota-gut-brain (MGB) axis; this beneficial effect occurred through enrichment of probiotic bacteria that produce SCFAs to regulate hippocampal synaptic plasticity genes. Collectively, this work proposes arabinoxylan as a novel prebiotic strategy and identifies candidate therapeutic targets for AD treatment.}, } @article {pmid41213496, year = {2026}, author = {Abdulkhaliq, AA and Alasiri, G and Almoghrabi, Y and Kim, B and Khan, J and Ajoolabady, A and Ren, J and Tuomilehto, J and Borai, A and Pratico, D}, title = {Role of TREM2 in neuroinflammation.}, journal = {Experimental neurology}, volume = {396}, number = {}, pages = {115547}, doi = {10.1016/j.expneurol.2025.115547}, pmid = {41213496}, issn = {1090-2430}, mesh = {Humans ; *Receptors, Immunologic/metabolism ; Animals ; *Membrane Glycoproteins/metabolism ; *Neuroinflammatory Diseases/metabolism/pathology ; Microglia/metabolism ; Signal Transduction/physiology ; }, abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is cell surface transmembrane receptor of the TREM family, predominantly expressed on microglia within the central nervous system (CNS). Accumulating evidence has highlighted a critical role for microglial TREM2 in modulating inflammatory signaling pathways, thereby influencing the course of neuroinflammation - a central pathological hallmark of various neurodegenerative and CNS disorders. In this review, we aim to elucidate the molecular mechanisms by which TREM2 regulates neuroinflammatory processes, with a particular focus on the most recent advances in the field. A deeper understanding of TREM2-mediated signaling may uncover novel therapeutic targets and pathways with significant translational potential for treatment of CNS diseases.}, } @article {pmid41213450, year = {2025}, author = {Huang, Y and Han, M and Fu, Y and Wang, G and Kong, L and Mo, J and Cao, D and Chu, Z and Li, W}, title = {HY-021068 improves neuronal ferroptosis by activating Nrf2 signaling in APP/PS1 Mice and Aβ1-42-induced HT22 cells.}, journal = {European journal of pharmacology}, volume = {1008}, number = {}, pages = {178349}, doi = {10.1016/j.ejphar.2025.178349}, pmid = {41213450}, issn = {1879-0712}, mesh = {Animals ; *Ferroptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Amyloid beta-Peptides ; Mice ; Signal Transduction/drug effects ; *Neurons/drug effects/metabolism/pathology ; *Peptide Fragments/pharmacology/toxicity ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Transgenic ; Cell Line ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Reactive Oxygen Species/metabolism ; Male ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unclear pathogenesis and no effective treatment methods. HY-021068 (HY), a novel class I drug, exhibits significant neuroprotective properties in ischemic brain injury. Recent studies suggest that neuronal ferroptosis may be a critical contributor to the onset and progression of AD. However, it is still unclear whether HY treatment has protective effects on AD by inhibiting ferroptosis. In this study, APP/PS1 double transgenic mice were used to investigate the effect and mechanism of HY in AD. In vitro, HT22 cells were stimulated with Amyloid β1-42 (Aβ1-42) (5 μM) to elucidate the therapeutic effect of HY and its potential mechanism. The present study indicated that HY treatment significantly improved cognitive dysfunction, enhanced synaptic integrity by upregulating PSD95 and Synapsin I, and reduced Aβ plaque load, APP, beta-secretase 1 (BACE1) expression, and Tau hyperphosphorylation. Furthermore, HY increased glutathione peroxidase 4 (Gpx4) and Cystine/glutamate transporter (xCT) levels, while reduced DMT1 and transferrin receptor expression, eventually inhibiting neuronal ferroptosis. Mechanistically, HY decreased reactive oxygen species (ROS) accumulation and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway by elevating Nrf2, heme oxygenase 1 (HO1), and NAD(P)H quinone oxidoreductase 1 (NQO1) expression. The in vitro study also suggested that the Nrf2 inhibitor ML385 markedly diminished the protective effects of HY, while the Nrf2 activator dimethyl fumarate (DMF) resulted in a significant enhancement of HY's therapeutic effects in Aβ1-42-induced HT22 cells. Molecular docking and cellular thermal shift assay showed that HY had an interaction with Nrf2. These results suggested that HY could ameliorate AD-related cognitive decline and neuronal ferroptosis through activating Nrf2 pathway, positioning it as a promising therapeutic strategy for AD.}, } @article {pmid41213069, year = {2025}, author = {Lin, Y and Zhao, H and Meng, D and Wang, M}, title = {The Role of T Cells in Alzheimer's Disease.}, journal = {Critical reviews in immunology}, volume = {45}, number = {6}, pages = {53-67}, doi = {10.1615/CritRevImmunol.2025061107}, pmid = {41213069}, issn = {2162-6472}, mesh = {Humans ; *Alzheimer Disease/immunology/metabolism/pathology/etiology ; *T-Lymphocytes/immunology/metabolism ; Animals ; *Brain/immunology/pathology/metabolism ; tau Proteins/metabolism ; Blood-Brain Barrier/immunology ; Amyloid beta-Peptides/metabolism ; Plaque, Amyloid/immunology ; }, abstract = {Alzheimer's disease (AD) is a global neurodegenerative disorder characterized by progressive cognitive decline. Its core pathology involves neurofibrillary tangles mediated by hyperphosphorylated tau protein and senile plaques formed by extracellular deposits of β-amyloid. As the global incidence of AD continues to rise, human health faces a serious threat. However, the complexity of its pathogenesis poses significant challenges to current prevention and treatment strategies. Recent studies reveal that T cells, as key components of the adaptive immune system, exhibit abnormalities in both quantity and function within the brains of AD patients. They infiltrate brain parenchyma through multiple pathways-including the blood-brain barrier, choroid plexus, and meningeal lymphatics-and are deeply involved in AD pathology. In this review, we first introduce recent discoveries in the pathogenesis of AD, including tau protein, β-amyloid plaques, and neuroinflammation. We then describe the immune mechanisms and infiltration pathways of T cells in AD. Finally, we focus on the mechanisms by which different T cell subtypes contribute to brain damage in AD, aiming to provide a theoretical foundation for developing AD therapies guided by neuroimmune homeostasis.}, } @article {pmid41212646, year = {2026}, author = {Song, W and Fang, M and Geng, Z and Pang, X and Yang, C and Chen, M and Song, B and Hu, C and Hu, Y and Hu, W and Zhou, S and Yan, Y and Wu, X and Wang, K}, title = {Mechanistic study of Alzheimer's disease with behavioral and psychological symptoms based on electroencephalography microstates.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {1}, pages = {447-457}, doi = {10.1177/13872877251393715}, pmid = {41212646}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/psychology/physiopathology/complications ; Male ; Female ; *Electroencephalography/methods ; Aged ; Neuropsychological Tests ; *Behavioral Symptoms/physiopathology/etiology ; Aged, 80 and over ; *Brain/physiopathology ; Middle Aged ; }, abstract = {BackgroundBehavioral and psychological symptoms of dementia (BPSD) are common in Alzheimer's disease (AD), yet their mechanisms remain unclear.ObjectiveWe aim to explore the possible neurophysiological mechanisms of BPSD using high temporal resolution electroencephalography (EEG) microstate technology, laying the foundation for clinical evaluation and subsequent treatment.MethodsWe enrolled 52 AD patients (25 with BPSD, 27 without) and 29 age- and gender-matched healthy controls (HC). All participants underwent various neuropsychological assessments and resting-state EEG recordings. Resting-state EEG data were analyzed employing microstate analysis techniques, with a focus on four key microstate parameters: duration, occurrence, coverage, and transition probability. Inter-group comparisons were performed using post-hoc tests, with statistical significance determined through False Discovery Rate (FDR) correction. Furthermore, the correlations between the indicators and neuropsychological assessment scores were analyzed.ResultsCompared to the HC and non-BPSD groups, the BPSD group showed an increase in the transition rate from microstate A to microstate C. Compared to the HC group, the BPSD group showed an extension in the duration of microstate A and a decrease in the frequency of microstate D. Compared to the HC group, the non-BPSD group showed prolonged durations (A, B, mean) and reduced occurrences (C, D, mean).The partial correlation analysis with years of education as a covariate showed that in the BPSD group, the duration of microstate A was correlated with the severity of the Neuropsychiatric Inventory (NPI) and the Hamilton Anxiety Scale (HAMA).ConclusionsAD with and without BPSD exhibits different altered brain dynamics.}, } @article {pmid41212436, year = {2025}, author = {Vizuete, AFK and Moreira, AP and Zin, LEF and de Oliveira Marques, C and Pacheco, RF and Leal, MB and Menezes, L and Gonçalves, CA}, title = {Neuroprotective Roles of Metformin in a Streptozotocin-Induced Dementia Model in Rats.}, journal = {Neurotoxicity research}, volume = {43}, number = {6}, pages = {48}, pmid = {41212436}, issn = {1476-3524}, mesh = {Animals ; *Metformin/pharmacology/therapeutic use/administration & dosage ; Streptozocin/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use/administration & dosage ; Rats ; Male ; *Dementia/chemically induced/drug therapy/metabolism/prevention & control ; Rats, Wistar ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is the leading cause of dementia in humans, with high social and economic costs. AD is predominantly a sporadic disorder, and its risk increases with age and in individuals with type 2 diabetes mellitus (T2DM). Metformin is considered the first line drug for treatment of T2DM and has a plethora of effects in the peripheral and nervous system. However, the neuroprotective mechanism of action of this drug is still under debate. In order to assess the effects of metformin in dementia, we investigated the optimal time to start metformin treatment in animals that were submitted to intracerebroventricular (ICV) administration of streptozotocin (STZ) (3 mg/kg) to induce a sporadic AD-like rodent model of dementia. We used two protocols of metformin administration: early metformin (50 mg/Kg/daily) treatment (2 days after STZ model induction, lasting 28 days) and late metformin (50 mg/Kg/daily) treatment (20 weeks after STZ model induction, lasting 28 days). Both time points improved cognitive behavior in STZ rats, as evaluated by the novel object recognition and Morris's water maze tasks. Moreover, both treatments reduced neuroinflammatory parameters, such as TLR4, RAGE, TNF-α and NF-κB protein expression, induced in STZ animals. Metformin downregulated the methylglyoxal/RAGE/NOX‑2 signaling pathway by restoring glyoxalase 1 activity and GSH levels, which are impaired in the STZ-induced dementia model. Our data contribute to understanding the neuroprotective role of metformin, particularly in conditions involving insulin resistance, such as diabetic encephalopathy and AD.}, } @article {pmid41212353, year = {2025}, author = {Shademan, B and Yousefi, H and Sharafkhani, R and Nourazarian, A}, title = {LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models.}, journal = {Cellular and molecular neurobiology}, volume = {45}, number = {1}, pages = {102}, pmid = {41212353}, issn = {1573-6830}, support = {(IR.KHOY.REC.1402.030//Khoy University of Medical Sciences/ ; }, mesh = {*Brain-Derived Neurotrophic Factor/metabolism ; Humans ; *Lipopolysaccharides/toxicity/pharmacology ; *Alzheimer Disease/metabolism/pathology ; Cell Line, Tumor ; *Signal Transduction/drug effects ; *Neuroinflammatory Diseases/metabolism/pathology/chemically induced ; Neurons/metabolism/drug effects/pathology ; *Inflammation/pathology/metabolism ; *Models, Biological ; *Protein Kinases/metabolism ; Cell Survival/drug effects ; }, abstract = {Alzheimer's disease (AD) leads to a progressive loss of cognitive abilities and memory. A critical factor now recognized as driving AD pathology is neuroinflammation-inflammation occurring in the nervous system, which contributes to neuronal harm and communication breakdowns. our research investigated the specific effects of neuroinflammation on neuronal signaling pathways. In this study, we primarily employed the SH-SY5Y neuroblastoma cell line as an in vitro neuronal model to investigate inflammatory responses relevant to AD etiology, alongside supplementary observations in primary neurons and 3D spheroids for comparative analysis. Our analysis focused on modifications of key molecules, including the neuroprotective protein Brain-Derived Neurotrophic Factor (BDNF), pro-inflammatory cytokines such as IL-6 and TNF-α, and crucial regulatory kinases. Our results demonstrated that LPS treatment dramatically lowered the vitality and decreased BDNF levels in the SH-SY5Y cells. Furthermore, we observed a considerable elevation in the pro-inflammatory cytokines IL-6 and TNF-α, coupled with elevated levels of COX-2 and iNOS. Gene expression data validated that LPS treatment altered the expression of essential signaling kinases (Protein Kinase A (PKA), Protein Kinase B (AKT), and Mitogen-Activated Protein Kinase (MAPK)). Our first comparative analysis revealed that 3D spheroid cultures may elicit more pronounced inflammatory responses than standard 2D cultures; nevertheless, our detailed investigation primarily focused on the SH-SY5Y model. This study revealed that LPS-induced neuroinflammation affects neuronal signaling in vitro, thereby revealing a relationship between inflammation and neuronal dysfunction in cellular models of neuroinflammation. These findings highlight pathways that may be relevant to AD pathophysiology; however, further in vivo studies are necessary to demonstrate their translational relevance to humans.}, } @article {pmid41211282, year = {2025}, author = {Olaolorun, F and Howes, MR and Elufioye, T and Odeku, OA and Olopade, J and Chazot, P}, title = {Iron chelation as a therapeutic target in vanadium neurotoxicity and Parkinson's disease: role of medicinal plants.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1667943}, pmid = {41211282}, issn = {1664-2295}, abstract = {Bioprospecting plant natural products has yielded significant success in the development of symptomatic treatment of neurodegenerative diseases, including the two most common, Alzheimer's and Parkinson's diseases (PD). Dysregulation of iron has been strongly implicated in the pathophysiology of these serious intractable diseases. A series of Nigerian endemic plants' methanolic extracts were explored using a Ferrozine binding iron chelation assay. This identified Spondias purpurea L. (SP) leaves as a potential therapeutic candidate and this was determined by evaluation of oxidative stress in 6-hydroxydopamine (6-OHDA)-exposed monoamine cell culture and Drosophila models of PD and vanadium neurotoxicity. SP treatment protected CAD cells against 6-OHDA toxicity and improved survival in PINK-1 mutant flies, though it had little effect on motor deficits. Furthermore, SP treatment reduced the vanadium-induced reactive oxygen species, and notably, staggered SP treatment significantly extended lifespan in vanadium-treated flies. Overall, Spondias purpurea L. leaf methanolic extract exhibited iron-chelating, antioxidant, neuroprotective, and life-extending properties, relevant to Parkinson's disease and vanadium-induced toxicity.}, } @article {pmid41211099, year = {2025}, author = {Viani, A and Custo, A and d'Angremont, E and Garibotto, V and Frisoni, GB and Gutman, BA and Lorenzi, M}, title = {Disease Progression Modeling and Stratification for detecting sub-trajectories in the natural history of pathologies: Application to Alzheimer's disease trajectory modeling.}, journal = {Imaging neuroscience (Cambridge, Mass.)}, volume = {3}, number = {}, pages = {}, pmid = {41211099}, issn = {2837-6056}, abstract = {Quantifying the progression of degenerative diseases remains crucial for early diagnosis, prevention, and treatment. However, accurately modeling disease biomarker evolution is hindered by substantial variability in disease trajectories among individuals, driven by demographic, genetic, and lifestyle factors. This variability gives rise to heterogeneous phenotypic manifestations, underscoring the need for stratification based on underlying disease subtypes. Recent advances have shown promise in unsupervised stratification of disease trajectories. Yet, current approaches face significant challenges related to robustness, biomarker specificity, interpretability, and temporal resolution of clustering results. To address these challenges, we introduce Disease Progression Modeling and Stratification (DPMoSt), a new probabilistic model designed to optimize clusters of continuous trajectories along a long-term disease time axis. This approach allows for the determination of subtype-specific biomarkers, improving the accuracy of patient stratification and generalization on external cohorts. We demonstrate DPMoSt on both synthetic and real-world data for the modeling of Alzheimer's disease (AD) evolution. In the synthetic experiments, DPMoSt shows high accuracy in reconstructing trajectory subtypes and identifying the biomarkers' specificity for the clustering problem. Our experiments in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate the ability of DPMoSt to identify AD subtypes associated with accelerated cognitive decline and higher prevalence of the APOE4 variants. This result was validated on the external memory clinic cohort of the Geneva University Hospitals, confirming the association between cognitive decline and APOE4 in the pathological subtype. These results highlight the robustness of DPMoSt as well as its potential for broader applicability, offering a powerful tool for studying disease progression and subtype differentiation across diverse populations.}, } @article {pmid41209367, year = {2025}, author = {Xie, Z and Hu, J and Stallings-Smith, S and Kulshreshtha, A and Hong, YR}, title = {Rural-urban differences in modifiable dementia risk factors among U.S. populations aged 45 years or older.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251395318}, pmid = {41209367}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) have become a significant public health concern, and the burden is disproportionately concentrated in rural areas.

OBJECTIVE: To examine rural-urban differences in the prevalence of modifiable dementia risk factors and their treatment among U.S. adults aged 45 years and older, and to investigate how these disparities vary by age group and geographic region.

METHODS: This cross-sectional study analyzed nationally representative data from the 2023 National Health Interview Survey in 2025. Prevalence of 11 modifiable dementia risk factors (hypertension, high cholesterol, diabetes, obesity, hearing loss, visual impairment, traumatic brain injury, low education, depression, social isolation, smoking) and 7 corresponding treatments were assessed via self-report. Adjusted rate ratios (aRR) were estimated using robust Poisson regression models.

RESULTS: The study population consisted of 16,981 individuals (mean age: 62.4, 51.6% female, 68.7% non-Hispanic White, 15.5% in rural areas). Rural residents had significantly higher prevalence of hypertension (aRR, 1.11; 95% CI, 1.06-1.17), obesity (aRR, 1.22; 95% CI, 1.15-1.30), diabetes (aRR, 1.29; 95% CI, 1.15-1.45), and hearing loss (aRR, 1.22; 95% CI, 1.12-1.34) compared to urban residents. Disparities were most significant among adults aged 45-64 years and in South/Midwest regions. Treatment rates for cardiometabolic conditions were high (>85%) and similar across regions, but treatment for sensory/behavioral risk factors remained low.

CONCLUSIONS: Rural U.S. adults face higher burden of modifiable dementia risk factors, particularly cardiometabolic and sensory impairments. Targeted public health strategies are needed to address structural inequities and improve dementia prevention in rural communities.}, } @article {pmid41208730, year = {2026}, author = {Ke, J and Ding, J and Xu, Y and Yu, C and Hong, Y and Li, S and Meng, T and Ping, Y and Yuan, H and Hu, F}, title = {Engineering microglial exosome-mediated microRNA-124-3p delivery for Alzheimer's disease combinational therapy.}, journal = {Biomaterials science}, volume = {14}, number = {1}, pages = {186-197}, doi = {10.1039/d5bm01080b}, pmid = {41208730}, issn = {2047-4849}, mesh = {*MicroRNAs/genetics/administration & dosage/metabolism ; *Alzheimer Disease/drug therapy/therapy/metabolism/pathology ; *Exosomes/metabolism/chemistry ; Animals ; *Microglia/metabolism ; Mice ; Humans ; Blood-Brain Barrier/metabolism ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; }, abstract = {Currently, single-target therapy and difficulty in brain drug delivery gravely impede the treatment of Alzheimer's disease (AD). The promising development of microRNA-124-3p (miR-124-3p) serves as a possibility for multiple therapeutic approaches for AD. However, the effective delivery of miR-124-3p to AD-affected brain regions remains a major challenge, primarily due to the blood-brain barrier (BBB) and the inherent instability of therapeutic miR-124-3p. Herein, we engineered miR-124-3p-enriched microglial exosomes (Exo-124-3p) as a biomimetic nanomedicine for the multifunctional treatment of AD. Exo-124-3p can traverse the BBB and facilitate activated-microglia targeting. Subsequently, the on-demand release of miR-124-3p from Exo-124-3p decreased the aggregation of β-amyloid (Aβ) plaques, attenuated the activation of microglia/astrocytes, and exhibited a valuable neuroprotective effect, thereby remolding the AD focal microenvironment. Notably, the in vivo results demonstrated that Exo-124-3p significantly improved the cognitive function in an AD mouse model. Mechanistically, it was elucidated that Exo-124-3p can bind to the 3'UTR region of MEKK3, ultimately inhibiting the MEKK3/NF-κB signaling pathway, thereby ameliorating AD neuroinflammation. Consequently, this study not only provides a promising therapeutic approach for AD combinational therapy, but also advances the development of miRNA delivery in other brain diseases.}, } @article {pmid41208522, year = {2025}, author = {Wrigley, S and Huynh, ALH and Amadoru, S and Zeimer, H and Tan, I and Woodward, M and Braitberg, G and Yates, PA}, title = {Monoclonal Antibody Therapies in Alzheimer's Disease: A Guide for Emergency Physicians.}, journal = {Emergency medicine Australasia : EMA}, volume = {37}, number = {6}, pages = {e70167}, pmid = {41208522}, issn = {1742-6723}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Emergency Service, Hospital/organization & administration ; Australia ; *Emergency Medicine/methods ; }, abstract = {Whilst the advent of novel disease-modifying medications for Alzheimer's disease represents potential benefit for patients and caregivers, they may be associated with adverse events that present important considerations for emergency and primary care. This article seeks to highlight some of the challenges Emergency Departments may encounter in relation to clinical presentations of people being treated with novel anti-amyloid monoclonal antibodies in the Australian context. Given the potential for harm if not recognised and managed appropriately, it is imperative that emergency clinicians are aware of possible treatment-related adverse events and have access to appropriate decision-making support and resources.}, } @article {pmid41208074, year = {2025}, author = {Gupta, RA and Rajni, and Shah, K and Dewangan, HK}, title = {Review on Molecular Targeting, Pharmacological Action, and Advanced Biopharmaceutical Aspects for the Management of Alzheimer's Disease.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128387875250805042824}, pmid = {41208074}, issn = {1873-4286}, abstract = {Alzheimer's disease (AD) is an ongoing progressive neurodegenerative disorder that predominantly affects elderly individuals. A systematic literature search was conducted using electronic databases such as PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trial reports, and experimental studies published in English within the last 15 years were considered. The keywords used for the search included "Alzheimer's disease," "amyloid-beta," "tau protein," "neuroinflammation," "immunotherapy," "drug repurposing," and "experimental treatment strategies." It is the most common form of dementia, ultimately leading to death in advanced stages. Recent advances in AD have featured the expected role of antiamyloid, anti-tau, and anti-inflammatory therapies. Nonetheless, these treatments are still in various stages of preclinical and clinical trials. Moreover, drug repurposing is another promising avenue to identify effective therapeutic alternatives for Alzheimer's disease. This review highlights the underlying pathophysiological mechanisms of AD along with the limits of existing treatments. It also includes two methodologies, specifically; active immunotherapy and passive immunotherapy. Active immunotherapy tactics include the administration of antigens to stimulate antibody production. Additionally, this study discusses several experimental drugs and novel pharmaceutical approaches for AD.}, } @article {pmid41206815, year = {2025}, author = {Tian, S and Liu, Y and Hu, H and Li, S}, title = {Tau Liquid-Liquid Phase Separation in Alzheimer's Disease: Mechanisms, Pathogenesis, and Therapeutic Implications.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {18}, pmid = {41206815}, issn = {1559-1182}, support = {U24A20806//National Natural Science Foundation of China/ ; 82404605//National Natural Science Foundation of China/ ; U23A20510//National Natural Science Foundation of China/ ; BX20220048//National Postdoctoral Program For Innovative Talents/ ; 2022MD723713//China Postdoctoral Science Foundation/ ; }, mesh = {*Alzheimer Disease/metabolism/therapy/pathology ; Humans ; *tau Proteins/metabolism/chemistry/isolation & purification ; Animals ; Neurofibrillary Tangles/metabolism/pathology ; *Liquid-Liquid Extraction/methods ; Phase Separation ; }, abstract = {Tau protein undergoes liquid-liquid phase separation (LLPS), forming dynamic condensates that act as intermediates in the transition to neurofibrillary tangles in Alzheimer's disease (AD). This review highlights tau's dynamic and reversible LLPS behavior, an underexplored aspect of tau's role, particularly as an early pathogenic driver in AD. We summarize the molecular mechanisms and regulatory factors governing tau LLPS, with a focus on its physiological functions in microtubule stability, synaptic activity, and cellular stress responses. Additionally, we discuss how metal ions, RNA, and neurodegenerative cofactors influence tau's phase behavior in a cell-type-specific manner. Emerging strategies targeting tau LLPS-such as nanobodies, AAV-based delivery, engineered degradation platforms, and CRISPR tools-show promise for early, reversible intervention. We also explore the potential of LLPS-informed biomarkers for diagnosing and monitoring disease progression. Overall, LLPS provides a dynamic, targetable framework linking early AD pathogenesis with therapeutic innovation, opening opportunities for earlier intervention and more effective treatment strategies.}, } @article {pmid41206776, year = {2025}, author = {Mulet I Piera, X and Del Campo-Montoya, R and Cuadrado-Tejedor, M and Garcia-Osta, A and Garbayo, E and Blanco-Prieto, MJ}, title = {Intranasal delivery of lipid-based nanoparticles for the treatment of neurodegenerative diseases: advances, challenges and future perspectives.}, journal = {Expert opinion on drug delivery}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/17425247.2025.2587903}, pmid = {41206776}, issn = {1744-7593}, abstract = {INTRODUCTION: Neurodegenerative diseases such as Parkinson's or Alzheimer's disease urgently require new therapeutic approaches. Despite significant efforts, no disease-modifying therapies targeting specific molecular pathways have demonstrated consistent clinical efficacy. This challenge has shifted attention toward drug delivery strategies that improve bioavailability, targeting, and patient accessibility. Intranasal delivery has emerged as a promising, non-invasive approach that bypasses the blood-brain barrier, and improves patient compliance. Lipid-based systems, especially following the success of COVID-19 vaccines, have gained attention as versatile platforms for delivering RNAs. Their ability to encapsulate diverse payloads and tunable composition makes them ideal candidates for targeting neurodegenerative disorders via the intranasal route.

AREAS COVERED: This review discusses recent advances in intranasal delivery for the treatment of neurodegenerative disorders, emphasizing on lipid-based nanoparticles. It addresses formulation challenges such as stability, targeting efficiency, and compatibility with nasal physiology, and outlines key design parameters affecting brain delivery. Future directions are explored to advance formulation development and clinical translation.

EXPERT OPINION: Intranasal lipid-based drug delivery represents a promising strategy to bypass the blood-brain barrier in neurogenerative disorder treatment. Although regulatory gaps and the absence of long-term safety evaluation, intranasal administration offers clear advantages for CNS targeting underscoring strong potential for future clinical translation.}, } @article {pmid41205639, year = {2026}, author = {Bhosale, S and Chakor, R and Lohidasan, S and Sivakkumar, S and Sathiyanarayanan, A}, title = {Neuroprotective and nootropic effects of a standardised Siddha polyherbal formulation, Bhiramiyadhi bhavanai choornam, against β-amyloid-Induced neurodegeneration.}, journal = {Journal of ethnopharmacology}, volume = {357}, number = {}, pages = {120850}, doi = {10.1016/j.jep.2025.120850}, pmid = {41205639}, issn = {1872-7573}, mesh = {Animals ; Rats, Wistar ; Male ; *Amyloid beta-Peptides/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; *Nootropic Agents/pharmacology/therapeutic use ; Brain-Derived Neurotrophic Factor/metabolism ; Oxidative Stress/drug effects ; Peptide Fragments/toxicity ; Brain/drug effects/metabolism/pathology ; Acetylcholinesterase/metabolism ; *Plant Extracts/pharmacology ; Plants, Medicinal ; Disease Models, Animal ; Behavior, Animal/drug effects ; Cytokines/metabolism ; }, abstract = {Bhiramiyadhi bhavanai choornam (BBC) is a traditional Siddha polyherbal formulation composed of 15 medicinal plants. The classical text claims that regular intake of BBC strengthens cognitive function, improves memory, boosts morale, enhances longevity, and promotes overall physical vitality.

AIM OF THE STUDY: The present investigation focused on standardising Bhiramiyadhi bhavanai choornam and assessing its neuroprotective effect against β-amyloid-induced neurodegeneration in Wistar rats.

MATERIALS AND METHODS: Standardisation of BBC was carried out following the AYUSH guidelines. A validated HPTLC method was developed for the marker compounds ascorbic acid, gallic acid, quercetin, piperine, and asiaticoside. Experimental neurodegeneration was induced by intracerebroventricular injection of Aβ1-42 in male Wistar rats. The effects of BBC were evaluated using behavioural paradigms, such as the Morris water maze, locomotor activity, social recognition, and novel object recognition tests. Biochemical assessments included acetylcholinesterase activity, brain-derived neurotrophic factor (BDNF), oxidative stress and antioxidant indices, and inflammatory cytokines. Brain histopathology was performed to assess neuronal architecture and the deposition of amyloid plaques.

RESULTS AND DISCUSSION: The HPTLC method developed provided accurate and reliable chemical profiling of BBC. Treatment with BBC significantly improved cognitive and memory performance in Aβ1-42-treated rats. It enhanced brain BDNF levels, improved antioxidant defence mechanism, reduced acetylcholinesterase activity, and suppressed oxidative stress and inflammatory cytokines. Histological studies further confirmed its protective effect by attenuating neuronal damage and plaque formation.

CONCLUSION: A validated HPTLC method was developed for the standardisation of BBC. Pharmacological findings indicate its strong neuroprotective and nootropic activities, highlighting its potential for Alzheimer's disease and related neurodisorders.}, } @article {pmid41205178, year = {2025}, author = {Royo Marco, A and Bruch, KR and Cowan, MN and Dill, JG and Moore, KA and Bolte, AC and Lukens, JR}, title = {Therapeutic VEGFC treatment provides protection against traumatic-brain-injury-driven tauopathy pathogenesis.}, journal = {Cell reports}, volume = {44}, number = {11}, pages = {116521}, pmid = {41205178}, issn = {2211-1247}, support = {R01 NS106383/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Tauopathies/pathology/metabolism/drug therapy/etiology ; *Brain Injuries, Traumatic/complications/pathology/drug therapy/metabolism ; *Vascular Endothelial Growth Factor C/therapeutic use/metabolism/pharmacology/genetics ; Mice ; Disease Models, Animal ; tau Proteins/metabolism ; Mice, Transgenic ; Brain/pathology/metabolism ; Male ; Mice, Inbred C57BL ; Humans ; }, abstract = {Traumatic brain injury (TBI) increases one's risk of developing Alzheimer's disease and tauopathy. Yet, the mechanisms linking TBI to neurodegenerative disease remain poorly defined. Mounting recent evidence indicates that defects in brain lymphatic drainage contribute to multiple neurodegenerative diseases. Here, we investigated whether promoting brain lymphatic drainage recuperation following TBI via treatment with the lymphangiogenic factor vessel endothelial growth factor C (VEGFC) mitigates the ability of TBI to exacerbate tauopathy. In this study, we show that a single mild TBI leads to worsened neuropathology, brain macrophage activation, and neurodegeneration in the PS19 mouse model of tauopathy. Moreover, we find that viral-vector-based delivery of VEGFC into the meningeal compartment 24 h post-TBI ameliorates tau-mediated neurodegenerative disease pathogenesis. Findings from these studies offer new insights into how TBI leads to the development of tauopathy later in life and suggest that VEGFC-based treatments might offer a therapeutic strategy to limit tauopathy after sustaining a head injury.}, } @article {pmid41205008, year = {2025}, author = {Jana, K and Ghosh, S and Parua, P and Debnath, B and Halder, J and Sahoo, RK and Rai, VK and Pradhan, D and Dash, P and Das, C and Kar, B and Ghosh, G and Rath, G}, title = {Insights into the Versatile Role of Extracellular Vesicles in the Treatment of CNS Disorders.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {14}, pmid = {41205008}, issn = {1559-1182}, mesh = {Humans ; *Extracellular Vesicles/metabolism ; Animals ; *Central Nervous System Diseases/therapy/metabolism ; Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism ; }, abstract = {E xtracellular vesicles (EVs) are lipid bilayer-enclosed nanocarriers composed primarily of phospholipids and membrane proteins. They are released by cells into the surrounding extracellular environment and vary in size, composition, and biogenesis pathways. Beyond their natural role in intercellular communication, mediating the transfer of proteins, lipids, and nucleic acids (like mRNA and miRNA) between cells, EVs have emerged as a highly versatile and promising therapeutic platform for a range of challenging disorders, particularly those affecting the central nervous system (CNS) and various cancers. The CNS presents unique therapeutic challenges, notably the formidable blood-brain barrier (BBB), which restricts the entry of most conventional drugs. EVs, however, possess an inherent capacity to traverse this barrier, either naturally or through engineered modifications. This characteristic positions them as ideal nanocarriers for delivering therapeutic payloads such as neurotrophic factors, gene therapy constructs, or anti-inflammatory agents directly to target neural cells for conditions like Alzheimer's disease, Parkinson's disease, stroke recovery, multiple sclerosis, and even glioblastoma. Their biocompatibility and low immunogenicity further reduce systemic side effects, making them a safer alternative to synthetic delivery systems. This review outlines recent progress in extraction techniques using EVs for treating neurological disorders. It covers clinical applications in neurodegenerative, infectious diseases, inflammatory, genetic, and oncological diseases and highlights current limitations and considerations for advancing future research in this evolving field.}, } @article {pmid41204969, year = {2025}, author = {Phuong, HT and Tomas, RF and Akmese, C and Mijares, A and Gerstin, IM and Guo, S and Bell, LR and Ellwood, R and Yegorova, S and Ng, SK and Massey, G and Phillips, J and Melloni, A and Pletnikova, O and Lou, X and Clark, HB and Troncoso, JC and Hyman, BT and Prokop, S and Ranum, LPW and Nguyen, L}, title = {PolyGR-containing aggregates link with pathology and clinical features of Alzheimer's disease.}, journal = {Acta neuropathologica}, volume = {150}, number = {1}, pages = {49}, pmid = {41204969}, issn = {1432-0533}, support = {P30 AG066507/AG/NIA NIH HHS/United States ; R00 AG065511/AG/NIA NIH HHS/United States ; P50 AG047266/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; K99 AG065511/AG/NIA NIH HHS/United States ; RF1 NS126536/NS/NINDS NIH HHS/United States ; RF1 NS098819/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; Male ; Female ; Aged ; Aged, 80 and over ; *Brain/pathology/metabolism ; tau Proteins/metabolism ; Plaque, Amyloid/pathology/metabolism ; Middle Aged ; Amyloid beta-Peptides/metabolism ; Protein Aggregates ; *Protein Aggregation, Pathological/pathology/metabolism ; Neurofibrillary Tangles/pathology/metabolism ; }, abstract = {Alzheimer's disease is the most common form of dementia; however, its molecular mechanisms are not fully understood. We recently identified polymeric glycine-arginine-containing (polyGR+) aggregates as a novel type of proteinopathy in AD autopsy brains. Here, we performed a comprehensive analysis to study if polyGR+ aggregates are associated with AD neuropathological changes (ADNC) and clinical features of AD cases. We show polyGR+ aggregates are detected in ~ 60% of AD postmortem brains from three AD cohorts but not age-similar controls or disease controls with primary age-related tauopathy (PART). A subtype of polyGR+ aggregates with a clustered-punctate morphology that is positive for the markers of dystrophic neurites is associated with earlier onset and shortened survival in AD cases. Increased levels of Aβ plaques and phosphorylated tau (pTau) tangles are detected in the hippocampus of AD autopsy brains with high levels of polyGR+ aggregates compared to AD autopsy brains with minimal polyGR+ staining. In addition to ADNC, a subset of polyGR+ aggregates coexists with limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) or Lewy body pathology (LBP). Hippocampal polyGR+ aggregate levels are ~ 3.8- and ~ 3.71-fold higher in late-onset AD cases who experienced stroke or high blood pressure, respectively. In SH-SY5Y cells, hydrogen peroxide treatment which mimics oxidative stress leads to increased levels of polyGR+ proteins produced by the CASP8 GGGAGA repeat expansion, which was recently shown to associate with increased AD risk. In addition, we show the accumulation of pTau induced by CASP8 polyGR+ protein aggregates is elevated upon hydrogen peroxide treatment. In summary, our results demonstrate polyGR+ aggregates are a frequent and understudied type of proteinopathy in AD autopsy brains and that polyGR proteinopathy is associated with ADNC.}, } @article {pmid41204210, year = {2025}, author = {Afxenti, S and Zachariou, M and Athieniti, E and Lambrianides, A and Pantzaris, M and Spyrou, GM}, title = {Integrating imaging and omics for enhanced subtyping of mild cognitive impairment associated with Alzheimer's disease.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {1240}, pmid = {41204210}, issn = {1479-5876}, support = {This research was supported by the Muscular Dystrophy Association Cyprus/Telethon Cyprus.//This research was supported by the Muscular Dystrophy Association Cyprus/Telethon Cyprus./ ; }, mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/complications/classification ; *Alzheimer Disease/diagnostic imaging/complications/cerebrospinal fluid ; Male ; *Neuroimaging ; Female ; Aged ; Magnetic Resonance Imaging ; *Proteomics ; Biomarkers/metabolism ; Cluster Analysis ; }, abstract = {BACKGROUND: Mild Cognitive Impairment (MCI), considered the prodromal stage of Alzheimer's disease (AD), is a heterogeneous condition characterised by mild but measurable cognitive decline. However, not all individuals with MCI follow the same trajectory-some remain stable, while others progress rapidly to AD. Understanding variation in clinical, molecular, and imaging features is crucial for reducing disease heterogeneity, improving prognosis, and developing targeted interventions. This study aims to increase MCI subtyping resolution by generating enriched individual-level profiles through the integration of imaging and omics data, facilitating precision medicine approaches for AD prevention and treatment.

METHODS: We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including structural MRI, CSF peptidomics/proteomics, and clinical indices. Using a multi-modal integration and clustering framework, we identified distinct MCI subgroups, characterised by clinical and neuropsychological scores, AD biomarkers, biological pathway enrichments, and imaging patterns. We further employed supervised multi-modal integration and correlation analyses to explore the links between imaging, peptidomic/proteomic and clinical features within each subgroup. Additionally, we labelled individuals by future conversion to AD and analysed longitudinal cognitive function (CDRSB and MMSE scores). Finally, we performed in silico drug repurposing to identify candidate drugs targeting each subgroup's molecular profile.

RESULTS: (1) Multi-modal integration revealed two distinct MCI subgroups. (2) The Resilient Neuronal Hyperplasticity subgroup was characterised by elevated markers of neuronal plasticity, minimal brain atrophy and cortical thinning, better clinical scores, and upregulated peptide/protein markers associated with less severe structural changes. In contrast, the Vulnerable Neurodegenerative subgroup exhibited AD-like disturbances, pronounced atrophy and cortical thinning, primarily affecting executive functions, and downregulation of peptide/protein markers linked to significant structural changes. (3) Future conversion analysis revealed the second subgroup predominantly comprised fast converters, while the first predominantly consisted of stable individuals. (4) Longitudinal cognitive analysis showed a more pronounced decline in the second subgroup compared to the first. (5) Drug repurposing identified both shared and subgroup-specific candidate compounds aligned with the underlying pathologies.

CONCLUSIONS: This study delineates two MCI subgroups, using multi-modal integration, offering insights into disease heterogeneity and laying the foundation for precision medicine and AI-driven strategies in MCI and AD research and clinical care.}, } @article {pmid41203507, year = {2025}, author = {Zhang, YP and Kedia, S and Klenerman, D}, title = {Rethinking neurodegeneration through a co-proteinopathy lens.}, journal = {Trends in neurosciences}, volume = {48}, number = {12}, pages = {952-963}, doi = {10.1016/j.tins.2025.10.006}, pmid = {41203507}, issn = {1878-108X}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/pathology ; Animals ; tau Proteins/metabolism ; alpha-Synuclein/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Neurodegenerative diseases have long been considered distinct proteinopathies: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TDP-43 in amyotrophic lateral sclerosis. This single-protein paradigm has guided therapeutic development for decades; yet clinical outcomes remain modest. Mounting evidence, however, reveals that protein aggregates rarely occur in isolation; instead, they coexist, colocalise, and modulate each other's pathogenicity. Here, we propose a co-proteinopathy framework that views neurodegeneration as an interactive network of misfolded proteins rather than as isolated disorders. Adopting this framework demands multiplexed quantification of protein aggregates and disease models that better reflect the biological complexity of human neurodegeneration. The co-proteinopathy perspective offers a more realistic foundation for next-generation approaches to neurodegeneration research and treatment.}, } @article {pmid41202963, year = {2025}, author = {Padhy, DS and Dhanve, P and Chaturvedi, K and Banerjee, S}, title = {Ambroxol rescues cognitive impairment by ameliorating oxidative stress and autophagic dysfunction in the streptozotocin-induced Alzheimer's disease model.}, journal = {European journal of pharmacology}, volume = {1008}, number = {}, pages = {178334}, doi = {10.1016/j.ejphar.2025.178334}, pmid = {41202963}, issn = {1879-0712}, mesh = {Animals ; *Ambroxol/pharmacology/therapeutic use ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Streptozocin ; Male ; Rats ; Disease Models, Animal ; *Autophagy/drug effects ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced/pathology ; Hippocampus/drug effects/metabolism/pathology ; Behavior, Animal/drug effects ; Maze Learning/drug effects ; Rats, Wistar ; *Neuroprotective Agents/pharmacology/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, contributing to the majority of dementia cases worldwide. Due to its multifaceted and complex pathogenesis, drugs that completely halt the disease progression are still elusive. Several reports suggest that repurposing a clinically approved drug could be an excellent strategy to tackle this devastating disease. Ambroxol, a US-FDA and EMA-approved generic mucolytic drug, possess ameliorative action on various neurological ailments. However, its role as a disease-modifying drug targeting AD is yet to be studied. In this study, we elucidate the therapeutic potential of ambroxol in the streptozotocin (STZ)-induced AD model by assessing the behavioural, biochemical, and histological parameters. Intracerebroventricular (ICV) administration of STZ (3 mg/kg) was performed to mimic the AD pathology in rats. Ambroxol was administered (p.o.) at doses of 500 and 1000 mg/kg for three weeks. On day 21, behavioural tests, including the Y-maze test, novel object recognition test, and passive avoidance test, were performed to assess memory function. Subsequently, the animals were euthanised and the hippocampus was collected for biochemical, molecular and histological analysis. Three weeks of ambroxol treatment improved the cognitive performance in ICV-STZ-treated rats. Ambroxol treatment reduces oxidative stress by upregulating heme oxygenase-1 (HO-1) and lowering inducible nitric oxide synthase (iNOS) levels in the hippocampus of diseased rats. It also attenuates inflammatory and autophagic dysfunction, facilitating the clearance of amyloid beta (Aβ) aggregates in the hippocampus of ICV-STZ rats. The findings of this study suggest that ambroxol could be a viable repurposed drug candidate for AD treatment.}, } @article {pmid41202483, year = {2026}, author = {Yuan, C and Li, L and Lin, HY and Aubry, AV and Parise, LF and Morel, C and Chen, F and Wong, J and Russo, SJ and Wang, J}, title = {Targeting neuronal activity and neuroinflammation for the treatment of Alzheimer's disease in a mouse model.}, journal = {Neurobiology of aging}, volume = {157}, number = {}, pages = {111-118}, doi = {10.1016/j.neurobiolaging.2025.10.006}, pmid = {41202483}, issn = {1558-1497}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/psychology/metabolism ; Disease Models, Animal ; *Neurons/physiology/drug effects ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Caffeic Acids/pharmacology/therapeutic use/administration & dosage ; tau Proteins/metabolism ; *Neuroinflammatory Diseases/drug therapy ; Microglia/physiology ; *Glucosides/pharmacology/therapeutic use/administration & dosage ; Brain/pathology/metabolism ; Cognition/drug effects ; Mice ; Male ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline driven by complex pathological processes, including tau hyperphosphorylation (p-Tau), amyloid-beta (Aβ) accumulation, and neuroinflammation. In this study, we investigated the effects of two bioactive compounds, dihydrocaffeic acid (DHCA) and malvidin-glucoside (Mal-gluc), targeting inflammation and neuronal activity, respectively, on cognitive function and AD pathology in a mouse model of AD. Our results demonstrate that chronic DHCA/Mal-gluc treatment significantly improves recognition memory in 3xTg-AD mice without reducing p-Tau or Aβ burden. Employing a newly developed whole-brain cFOS and IBA-1 mapping technique, we found that this combination treatment enhances neuronal activity and promotes microglial homeostasis across multiple brain regions in 3xTg-AD mice. These findings underscore the potential of restoring neuronal function and immune homeostasis as a therapeutic approach for AD. Future study will explore the underlying mechanisms and evaluate whether DHCA/Mal-gluc, combined with currently approved Aβ monoclonal therapy, can synergistically prevent or delay AD onset and progression.}, } @article {pmid41202479, year = {2025}, author = {Samsami, S and Parvar, MD and Mehralitabar, H and Dehghanbanadaki, N and Naderi-Manesh, H}, title = {In silico investigation of CNS-11 as a potential inhibitor of Aβ42 aggregation and its protofibril disassembly.}, journal = {Biochemical and biophysical research communications}, volume = {790}, number = {}, pages = {152899}, doi = {10.1016/j.bbrc.2025.152899}, pmid = {41202479}, issn = {1090-2104}, mesh = {*Amyloid beta-Peptides/chemistry/metabolism/antagonists & inhibitors ; *Peptide Fragments/chemistry/metabolism/antagonists & inhibitors ; Molecular Dynamics Simulation ; Humans ; Protein Aggregates/drug effects ; Protein Aggregation, Pathological ; Alzheimer Disease/metabolism/drug therapy ; Computer Simulation ; Protein Multimerization/drug effects ; }, abstract = {Amyloidogenic peptide aggregation and fibril formation are key components in neurodegenerative diseases such as Alzheimer's disease (AD). One effective strategy for treating these conditions involves preventing amyloid peptide aggregation by using interfering agents, such as small molecules, at the onset of amyloid peptide assembly. Another approach could involve destabilizing the formed fibrils using small molecules as well. In this study, we utilized both all-atom and coarse-grained molecular dynamics (MD) simulation methods to investigate the aggregation mechanistic details of amyloid-β42 (Aβ42) peptides, the impact of CNS-11 (a small molecule inhibitor with proven Tau fibrils decomposing agent) on this Aβ42 aggregation, and the destabilization effect of CNS-11 on an Aβ42 fiber section, alongside the Aβ42 fiber section itself. Our results demonstrated that Aβ42 monomers in the free state strongly tend to dimerize and form beta-sheets by integrating the hydrophobic sections of the Aβ42 peptides. Still, as CNS-11 was added to the system, the ligand formed a hydrophobic core composed of CNS-11 and Aβ42 peptides surrounding this core, resulting in an amorphous and significantly disordered structure. Additionally, CNS-11 could interact with the Aβ42 pre-formed fiber section, partially destabilizing it through interactions with the buried hydrophobic core. Moreover, simulating the Aβ42 fiber section revealed that the N-terminal region of these peptide aggregates is naturally flexible and capable of becoming disorganized even without the addition of external disrupting agents. This study provides comprehensive insights into the molecular-level mechanisms underlying the dual effects of CNS-11 on amyloid beta aggregation and fibril degradation. This study can provide a computational framework with the potential to be applied to various small molecules, exploring their potential in the prevention and treatment of Alzheimer's disease.}, } @article {pmid41201547, year = {2025}, author = {Akkaya, EC and Ilgin, R and Adil, H and Çelik, A}, title = {Magnesium L-Threonate Reduces Hippocampal Amyloid-β Load without Cognitive Improvement in a PTU-induced Hypothyroidism Model in Young Rats.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {8}, pmid = {41201547}, issn = {1559-1182}, support = {TSA-2024-565//Usak University Research Foundation/ ; }, mesh = {Animals ; *Hippocampus/metabolism/drug effects/pathology ; *Amyloid beta-Peptides/metabolism ; *Hypothyroidism/chemically induced/drug therapy/metabolism ; *Cognition/drug effects ; Disease Models, Animal ; Male ; Rats ; Rats, Wistar ; Brain-Derived Neurotrophic Factor/metabolism ; Maze Learning/drug effects ; }, abstract = {The brain is among the most critical target organs for thyroid hormones. Therefore, both congenital and acquired hypothyroidism can have significant neuropsychiatric consequences. Learning and memory problems, concentration disorders, and some psychiatric disorders such as depression can be observed in diseases causing acquired hypothyroidism. Although thyroid hormone therapy is the standard treatment, it does not always fully reverse these neuropsychiatric complications. Several studies have demonstrated the positive effects of magnesium L-threonate (MgT) supplementation on cognitive functions. Research suggests that MgT may help alleviate cognitive deficits, particularly in neurodegenerative conditions like Alzheimer's disease, where it has been associated with improvements in memory and reductions in hippocampal amyloid-β accumulation. However, there is limited data on the effect of MgT supplementation on hypothyroid conditions in the brain. The purpose of this study was to evaluate the effects of MgT supplementation on cognitive functions in hypothyroid rats. We report that while MgT supplementation did not significantly improve cognitive performance in behavioral tasks or inflammatory markers in hypothyroid rats, it did increase hippocampal BDNF levels in euthyroid animals and reduced hippocampal amyloid-β load under both euthyroid and hypothyroid conditions. The reduction in amyloid beta load under hypothyroid conditions suggests that MgT may exert partial therapeutic effects even in the absence of thyroid hormone replacement. These findings highlight the need for further studies to evaluate the therapeutic potential of MgT, particularly in combination with thyroid hormone replacement.}, } @article {pmid41200978, year = {2025}, author = {Zhang, Y and Fan, J and Nan, S and Pan, J and Guo, W and Zhang, Y}, title = {Rubiadin Alleviates Alzheimer's Disease Pathology via NF-κB Pathway Regulation.}, journal = {Journal of integrative neuroscience}, volume = {24}, number = {10}, pages = {33497}, doi = {10.31083/JIN33497}, pmid = {41200978}, issn = {0219-6352}, support = {20210101293JC//Natural Science Foundation of Jilin Province/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *NF-kappa B/metabolism/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Signal Transduction/drug effects ; Mice, Transgenic ; Male ; Amyloid beta-Peptides/metabolism ; Plaque, Amyloid/metabolism/drug therapy ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a severe neurodegenerative disorder that impacts the global impact on the population. Nevertheless, the intricate nature of its pathogenesis has posed significant challenges to drug discovery in this field. This study aimed to verify the therapeutic potential of rubiadin (RB) on AD through both in vivo and in vitro experiments, thereby facilitating translational research for the advancement of AD treatment.

METHODS: We investigated the neuroprotective effects of RB on AD using both in vivo and in vitro models. Immunohistochemistry and western blot analysis were employed to evaluate inflammatory factors and the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in Mo/HuAPP695swe (APP)/PS1-dE9 (PS1) mice and N2a cells.

RESULTS: RB enhanced the memory performance of APP/PS1 mice in various tests, including the Morris water maze, step-down and step-through passive avoidance tasks, and novel object recognition. RB reduced the accumulation of Amyloid-beta (Aβ) plaques, as shown by immunohistochemical analysis. It also decreased the expression levels of pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), while increasing the release of IL-4. Additionally, RB inhibited the NF-κB pathway, as demonstrated by western blot. Moreover, a cell viability test showed that RB protected N2a cells against toxicity caused by Aβ1-42 through a cell viability test. Western blot analysis revealed that neuroinflammation and the NF-κB pathway were inhibited by RB treatment in Aβ1-42-induced N2a cells. Accordingly, RB suppressed the nuclear translocation of NF-κB in Aβ1-42-induced N2a cells.

CONCLUSIONS: Our results provide experimental evidence supporting the preclinical research and future clinical applications of RB, thereby facilitating the development of new drugs for AD clinical therapy.}, } @article {pmid41200903, year = {2025}, author = {Chockchowwat, W and Hannongbua, S and Saparpakorn, P}, title = {Role of triterpenoid derivatives from Centella asiatica as quantum chemical calculations.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/07391102.2025.2578225}, pmid = {41200903}, issn = {1538-0254}, abstract = {To date, the treatment for Alzheimer's disease (AD) has focused on the cholinergic hypothesis, particularly through the inhibition of acetylcholinesterase (AChE). Asiatic acid, madecassic acid, asiaticoside, and madecassoside, which are triterpenoid derivatives from Centella asiatica, have previously been reported to exhibit the AChE inhibitory activity. This study aimed to investigate their binding modes and to determine efficient computational methods for analyzing their interactions with AChE. Molecular dynamics simulations demonstrated that most of their equilibrated structures remained within the AChE binding site. Principal component analysis and free energy landscape (FEL) confirmed their stability of the binding. Among the evaluated methods, the MM-(ALPB)SA binding energies, when combined with ligand surface binding efficiency index, showed the best correlation with experimental binding free energy. Density functional theory (DFT) calculations revealed the common key interaction between triterpenoids and AChE, including hydrogen bonds (Tyr124, Arg296, Tyr337, and Tyr341), H-π (Tyr341) and van der Waals (Trp86) interactions. Additionally, pharmacokinetics and drug-likeness predictions indicated that madecassic acid and asiatic acid are promising candidates for drug development. This study highlights the potential of triterpenoid derivatives in AChE inhibition and provides valuable insights into their binding efficiency, which could contribute to future drug discovery targeting Alzheimer's disease.}, } @article {pmid41200863, year = {2025}, author = {Wang, C and Shao, X and Cao, X and Fan, T and Li, Z and Wang, K and Li, M and Wang, X and Guan, P and Hu, X}, title = {Silver-functionalized carbon dots regulate amyloid aggregation and microbial infection.}, journal = {Nanoscale}, volume = {17}, number = {45}, pages = {26429-26441}, doi = {10.1039/d5nr03379a}, pmid = {41200863}, issn = {2040-3372}, mesh = {*Silver/chemistry/pharmacology ; *Amyloid beta-Peptides/chemistry/metabolism ; *Carbon/chemistry/pharmacology ; Humans ; Alzheimer Disease/drug therapy/metabolism/pathology ; Peptide Fragments/chemistry/metabolism ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Quantum Dots/chemistry ; *Amyloid/chemistry/metabolism ; Animals ; Protein Aggregates/drug effects ; Cell Survival/drug effects ; }, abstract = {Amyloid accumulation and microbial infections are major risk factors for Alzheimer's disease (AD). However, most of the current drugs are limited to single-target therapeutic strategies against amyloid or microbial infections, resulting in poor clinical treatment effects. Herein, we propose a novel multi-targeted strategy that can achieve multiple effects of inhibition of amyloid aggregation, depolymerization of mature amyloid fibrils, and anti-microbial infection. Experiments conducted in vitro have shown that silver-functionalized carbon dots (Ag@TACDs), at concentrations as low as 10 μg mL[-1], significantly impact the misfolding of Aβ42 and the depolymerization of Aβ42 fibrils. Moreover, Ag@TACDs exhibit outstanding ability to resist bacterial infections. At the same time, Ag@TACDs have good biocompatibility, enhance cell activity, and alleviate the cytotoxicity caused by Aβ42 oligomers. Our approach provides an effective strategy for the design of multi-target inhibitors for Alzheimer's disease.}, } @article {pmid41199875, year = {2025}, author = {Chande, K and Nirmal, R and Varpe, N and Doke, R and Vinchurkar, K and Singh, S}, title = {Alkaloid's undiscovered neuroprotective potential: a multi-target strategy to fight against neurodegenerative illnesses.}, journal = {3 Biotech}, volume = {15}, number = {12}, pages = {409}, pmid = {41199875}, issn = {2190-572X}, abstract = {Neurodegeneration (ND) refers to the progressive decline of neurons, leading to Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. These conditions are marked by gradual neuronal loss and cognitive impairment, with limited treatment options currently available. The available strategies only provide symptomatic relief and having more side effects, however none of them able to halt the disease progression, so there is strong need to develop alternative therapeutic strategies with no or less toxicity. Alkaloids, a class of naturally occurring compounds, exhibit diverse biological activities, including antioxidant and neuroprotection. Emerging research suggests that these molecules can influence key signaling pathways associated with neurodegeneration, potentially offering therapeutic benefits. By targeting multiple aspects of disease progression and modulating neuroinflammatory responses, alkaloids interact with critical molecular components such as transcription factors, receptors, and enzymes essential for neuronal survival and homeostasis. This review underscores the therapeutic potential of alkaloids in ND treatment and emphasizes the need for further research to explore their clinical applications. Future studies should aim to identify neuroprotective alkaloids, elucidate their mechanisms of action, and assess their effectiveness in treating neurodegenerative diseases. A deeper understanding of their interactions with key disease pathways is crucial for the development of effective therapeutic strategies.}, } @article {pmid41199470, year = {2025}, author = {Shao, Y and Liu, L and Zhu, S and Zhu, Z and Wang, P and Biswal, BB and Lin, H}, title = {Fornix Mediates Information Propagation in Brain Networks Following DLPFC-Targeted rTMS in Alzheimer's Disease: A Randomized Controlled Trial.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {11}, pages = {e70630}, pmid = {41199470}, issn = {1755-5949}, support = {CFH2022-2-2014//Capital's Funds for Health Improvement and Research/ ; 2022YFC2402205//National Key R&D Program of China/ ; 51977205//National Natural Science Foundation of China/ ; NSFC62401106//National Natural Science Foundation of China/ ; NSFC62171101//National Natural Science Foundation of China/ ; NSFC-AF 82211530041//NSFC Projects of International Cooperation and Exchanges/ ; 2024NSFSC1661//Sichuan Science and Technology Program/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/diagnostic imaging/physiopathology ; Male ; Female ; *Transcranial Magnetic Stimulation/methods ; Aged ; *Fornix, Brain/diagnostic imaging/physiopathology/physiology ; *Dorsolateral Prefrontal Cortex/diagnostic imaging/physiopathology/physiology ; Diffusion Tensor Imaging ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology ; White Matter ; Aged, 80 and over ; Neural Pathways ; }, abstract = {AIMS: Repetitive transcranial magnetic stimulation (rTMS) could improve the clinical manifestations in Alzheimer's disease (AD), but its impact on deep brain tissue related to memory remains unclear. This study explored whether rTMS targeting cortical gray matter could regulate the white matter (WM) and exert modulatory effects on the network through WM bundles.

METHODS: Seventy-three AD patients underwent 14-day rTMS over the left dorsolateral prefrontal cortex (44 real, 25 sham). Granger causality analysis assessed changes in effective connectivity (EC) between the fornix and whole-brain voxels. Furthermore, the effects of rTMS treatment on fiber tracking parameters were analyzed.

RESULTS: After rTMS therapy, patients with AD showed increased EC based on fornix in the real-stimulation group. Functional network projections indicated that these clusters belonged to the frontoparietal network, the somatomotor network, as well as three white matter networks. Additionally, increased EC associated with fornix exhibited lateralization on the right side. Diffusion tensor imaging results showed no significant differences after the 14-day rTMS treatment.

CONCLUSION: In conclusion, a 14-day rTMS treatment in AD could regulate fornical function by increasing cortical-fornix EC, indicating neuroplasticity changes in response to therapy.

TRIAL REGISTRATION: Chinese Clinical Trial Registry (https://www.chictr.org.cn/index.html; ChiCTR2200062564).}, } @article {pmid41198610, year = {2025}, author = {Pirraglia, E and Osorio, RS and Glodzik, L and Ashebir, Y and Shao, Y}, title = {Subtypes of multiple-etiology dementias and the heterogeneous impact of APOE variants.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70872}, pmid = {41198610}, issn = {1552-5279}, support = {R01 HL111724/HL/NHLBI NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30AG066530/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P30AG072979/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30AG062429/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30AG072972/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30AG062422/AG/NIA NIH HHS/United States ; P20AG068024/AG/NIA NIH HHS/United States ; P20 AG068053/AG/NIA NIH HHS/United States ; R01 NS104364/NS/NINDS NIH HHS/United States ; R01 AG067523/AG/NIA NIH HHS/United States ; P30AG072976/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30AG072973/AG/NIA NIH HHS/United States ; P30AG066518/AG/NIA NIH HHS/United States ; U01 OH012486/OH/NIOSH CDC HHS/United States ; R01 AG066870/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30AG072947/AG/NIA NIH HHS/United States ; R01AG066870/AG/NIA NIH HHS/United States ; P30AG066515/AG/NIA NIH HHS/United States ; P30AG066509/AG/NIA NIH HHS/United States ; P30AG079280/AG/NIA NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30AG072946/AG/NIA NIH HHS/United States ; P30AG072959/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; R01NS104364/NH/NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; P30AG066511/AG/NIA NIH HHS/United States ; U24 AG072122/NH/NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; P20AG068077/AG/NIA NIH HHS/United States ; P30AG066468/AG/NIA NIH HHS/United States ; P30AG072977/AG/NIA NIH HHS/United States ; R21 AG067549/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P20AG068053/AG/NIA NIH HHS/United States ; R01 AG056531/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30AG072975/AG/NIA NIH HHS/United States ; P30AG066508/AG/NIA NIH HHS/United States ; P01 AG060882/AG/NIA NIH HHS/United States ; P30AG066462/AG/NIA NIH HHS/United States ; R01AG067523/AG/NIA NIH HHS/United States ; P30AG066506/AG/NIA NIH HHS/United States ; P30AG066546/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30AG066519/AG/NIA NIH HHS/United States ; P30AG066514/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; R01AG056531/AG/NIA NIH HHS/United States ; R01 AG056031/AG/NIA NIH HHS/United States ; P30AG062421/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; R01HL111724/NH/NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; P30AG072978/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P20 AG068024/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P20AG068082/AG/NIA NIH HHS/United States ; R21AG067549/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; U01OH012486//Centers for Disease Control and Prevention (CDC)/ ; P30 AG072972/AG/NIA NIH HHS/United States ; P30AG066507/AG/NIA NIH HHS/United States ; R01AG056031/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; P30AG072931/AG/NIA NIH HHS/United States ; P30AG062715/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Dementia/genetics/mortality/pathology/classification ; *Apolipoproteins E/genetics ; *Alzheimer Disease/pathology/genetics/mortality ; Aged ; Aged, 80 and over ; Autopsy ; *Apolipoprotein E4/genetics ; Brain/pathology ; Mixed Dementias ; }, abstract = {INTRODUCTION: Multiple-etiology dementias (MEDs) are frequently identified at autopsy but often missed in clinical diagnosis, limiting the efficiency of dementia research and treatment. This study aimed to characterize subtypes of MEDs, evaluate clinical underdiagnosis, and assess the heterogeneous impact of apolipoprotein E (APOE) variants on mortality across MED subtypes.

METHODS: Data from the National Alzheimer's Coordinating Center (NACC) repository, which includes standardized clinical and autopsy assessments, were analyzed using competing risks survival models.

RESULTS: Pure Alzheimer's disease (AD) neuropathology was rare, whereas mixed neuropathologies were common and frequently misdiagnosed as AD alone. APOE ε4 decreased mortality risk in decedents without AD neuropathology and increased mortality in decedents with mixed AD neuropathology, but not in those with AD alone. APOE ε2 increased mortality in decedents having vascular neuropathology with cerebral amyloid angiopathy.

DISCUSSION: Heterogeneity in MEDs remains substantially underrecognized clinically. The effects of APOE variants vary by dementia subtype, emphasizing the need for refined diagnostic tools and personalized dementia treatment and care approaches.

HIGHLIGHTS: Autopsy data revealed that pure Alzheimer's disease (AD) neuropathology is rare, whereas mixed pathologies are highly prevalent and frequently misdiagnosed as AD alone in clinical settings, underscoring the limitations of current diagnostic practices. Comprehensive neuropathological characterization of multiple-etiology dementia (MED) subtypes is crucial for uncovering the true complexity of dementia, which is often masked in clinical assessments. This approach enables a more accurate understanding of disease mechanisms and progression. We found that apolipoprotein E (APOE) ε4 was associated with increased mortality risk in AD with co-pathologies, but not in pure AD without other neuropathologies. Conversely, APOE ε4 was associated with decreased mortality risk in decedents who did not have AD neuropathology. APOE ε2 was protective in some AD-related subtypes but was associated with higher mortality risk in cerebral amyloid angiopathy with other vascular neuropathologies, highlighting the heterogeneous impact of genetic risk factors across subtypes. The differential effects of APOE variants across MED subtypes emphasize the need to evaluate biomarkers and risk factors within the context of underlying neuropathological profiles rather than broad clinical categories. These findings reinforce the need to develop and implement more refined, subtype-specific biomarkers and diagnostic protocols to enable precision prevention and personalized treatment strategies for the diverse forms of MED.}, } @article {pmid41198603, year = {2025}, author = {Crowley, P and Henry, AL and Flanagan, E and Antonsdottir, I and Bentley, A and Blackman, J and Bliwise, DL and Bubu, OM and Buysse, DJ and Camargos, EF and Cassidy-Eagle, E and Cote, K and Coulthard, E and D'Rozario, AL and Espie, CA and Falck, RS and Gabb, VG and Harvey, AG and Hmwe, NTT and Hoyos, CM and Jobbins, L and Kennelly, S and Kent, BA and Köpke, S and Krystal, A and Leroi, I and Liguori, C and Lim, YY and Lorenz, R and Lucey, BP and Mander, B and Moline, M and Naismith, SL and Ogunniyi, A and Rapaport, P and Reynolds, CF and Richards, K and Siengsukon, CF and Sindi, S and Singer, CM and Wirz-Justice, A and Yaffe, K and O'Caoimh, R}, title = {Development of a core outcome set for clinical trials of interventions to improve sleep in people with cognitive impairment-the Sleep in Cognitive Impairment Core Outcome Set (SCICOS).}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {11}, pages = {e70890}, pmid = {41198603}, issn = {1552-5279}, support = {HRB DTICTN-2021-003//Dementia Trials Ireland, Health Research Board Clinical Trial Network/ ; HRB DTICTN-2021-003/HRBI_/Health Research Board/Ireland ; }, mesh = {Humans ; *Cognitive Dysfunction/complications/therapy ; *Sleep Wake Disorders/therapy/etiology/complications ; *Clinical Trials as Topic ; *Outcome Assessment, Health Care ; Delphi Technique ; *Sleep ; }, abstract = {INTRODUCTION: Sleep disturbances are common in older people with cognitive impairment, potentially contributing to negative outcomes. A core outcome set (COS) is required to reduce heterogeneity in clinical trials and promote the development of high-quality evidence to support clinical management.

METHODS: A multi-stage mixed methods study was conducted in accordance with The Core Outcome Set Standards for Development.

RESULTS: A systematic review identified 287 sleep outcomes from previous clinical trials. Qualitative interviews ensured the COS was informed by what matters most to people with cognitive impairment and their caregivers. A modified Delphi process identified nine outcomes for the COS: total sleep time, sleep onset latency, wakefulness after sleep onset, number of night-time awakenings, sleep efficiency, and measures of sleep quality, daytime sleepiness, cognition, and mood.

DISCUSSION: This COS will support researchers to produce more reliable and coherent trial data to guide the management of sleep disturbances in people with neurodegenerative cognitive impairment.

HIGHLIGHTS: Evidence is lacking regarding the treatment of sleep disturbances in people with cognitive impairment. Heterogeneity of reported outcomes in clinical trials limits data synthesis. A qualitative analysis established what matters most to people with cognitive impairment and their caregivers when determining treatment effectiveness. A Delphi panel of experts agreed upon a core outcome set. This core outcome set will improve the reliability and comparability of data from future trials.}, } @article {pmid41198506, year = {2025}, author = {Lafon, PA and Prézeau, L and Pin, JP and Rondard, P}, title = {Nanobodies: a new paradigm for brain disorder therapies.}, journal = {Trends in pharmacological sciences}, volume = {46}, number = {11}, pages = {1049-1051}, doi = {10.1016/j.tips.2025.10.004}, pmid = {41198506}, issn = {1873-3735}, mesh = {Humans ; *Single-Domain Antibodies/therapeutic use/immunology ; Animals ; *Brain Diseases/drug therapy/immunology/therapy ; Alzheimer Disease/drug therapy/immunology ; }, abstract = {Camelid-derived nanobodies offer a promising alternative to conventional antibodies for the treatment of brain disorders. Their current development in models of schizophrenia or Alzheimer's disease highlights their strong therapeutic potential. Optimizing their delivery and ensuring their safety are major challenges, but their modularity and low immunogenicity make them promising candidates for neurotherapy.}, } @article {pmid41198224, year = {2025}, author = {Yadav, D and Knight-Greenfield, A and Moirano, J and Nordvig, A and Salgado, MW and Hamed, M and Lin, M and RoyChoudhury, A and Blum, S and Keil, SA and Intorcia, B and Ebani, EJ and Osborne, J and Chiang, G and Ivanidze, J}, title = {Amyloid PET Z-score Quantification and correlation with visual semiquantitative grading.}, journal = {AJNR. American journal of neuroradiology}, volume = {}, number = {}, pages = {}, doi = {10.3174/ajnr.A9079}, pmid = {41198224}, issn = {1936-959X}, abstract = {BACKGROUND AND PURPOSE: Amyloid PET imaging plays a crucial role in the diagnosis of Alzheimer's disease (AD) and determines eligibility for anti-amyloid therapies. While visual interpretation using Regional Cortical Tracer Uptake (RCTU) and Brain Amyloid Plaque Load (BAPL) scores remains standard in clinical practice, it is subject to inter-reader variability and may not fully depict the amyloid distribution pattern. RCTU scoring evaluates cortical tracer uptake quantified as 1: no uptake, 2: focal and 3: diffuse uptake, while BAPL provides an overall summary score of amyloid plaque load depending on highest RCTU score. Quantitative techniques such as Centiloid scale or Z-scores may assist in diagnosis, grading and treatment monitoring. This study evaluates the feasibility of a Z-score quantification generated from normative database comparison and its correlation with visual RCTU grading.

MATERIALS AND METHODS: We retrospectively analyzed 100 patients who underwent [F18]-Florbetaben PET imaging between August and October 2024 for cognitive impairment. Visual interpretation was performed using RCTU scoring and overall BAPL score. Quantitative Z-scores were calculated for four cortical regions (frontal, parietal, posterior cingulate/precuneus, and lateral temporal) using a normative database. Correlation between visual and quantitative scores was assessed using Spearman's correlation. Z-score differences among RCTU categories were evaluated with Kruskal Wallis and Mann Whitney tests.

RESULTS: Among 100 patients (median age 78), 31 were amyloid negative (BAPL1), and 69 were amyloid positive (11 BAPL2, and 58 BAPL3). A total of 400 cortical regions were evaluated (143 RCTU1, 46 RCTU2, 211 RCTU3). Strong positive correlations were observed between RCTU and Z-scores in all regions (ρ = 0.78-0.88, p < 0.0001). The regional Z-scores showed significant differences between RCTU1 and RCTU2, RCTU1 and RCTU3, as well as between RCTU2 and RCTU3 across all four regions (p<0.05 for all comparisons. Pooled regional analysis also showed statistically significant differences in Z-scores between all RCTU groups (p < 0.0001).

CONCLUSIONS: Quantitative regional Z-scores derived from amyloid PET imaging demonstrate a strong correlation with visual assessment (RCTU score), validating their feasibility in clinical interpretation. These findings support the integration of quantitative tools into routine practice to enhance diagnostic confidence, reduce reader variability, and monitoring for amyloid-targeted therapies.

ABBREVIATIONS: AD = Alzheimer's Disease; RCTU = Regional Cortical Tracer Uptake; BAPL = Brain Amyloid Plaque Load; PiB = Pittsburgh Compound B; SUVR = Standardized Uptake Value Ratio; SPM = Statistical Parametric Mapping; SSP = Stereotactic Surface Projections.}, } @article {pmid41197936, year = {2025}, author = {Choi, H and Hwang, S and Cho, H and Ahn, S and Yun, HY and Song, JS}, title = {Memantine modulates neuroinflammation and motor coordination in a Parkinson's disease model.}, journal = {Brain research}, volume = {1869}, number = {}, pages = {150034}, doi = {10.1016/j.brainres.2025.150034}, pmid = {41197936}, issn = {1872-6240}, mesh = {Animals ; *Memantine/pharmacology ; Mice ; Mice, Transgenic ; Microglia/drug effects/metabolism ; *Neuroinflammatory Diseases/drug therapy ; Disease Models, Animal ; *Parkinson Disease/drug therapy ; Male ; Mice, Inbred C57BL ; Excitatory Amino Acid Antagonists/pharmacology ; }, abstract = {Memantine, an NMDA receptor antagonist clinically approved for Alzheimer's disease, has been implicated in modulating neuroinflammatory responses beyond its anti-excitotoxic actions. To explore its potential relevance in Parkinson's disease, this study evaluated memantine's effects in both LPS-activated microglial cells and a synucleinopathy mouse model. In BV-2 cells, memantine elicited a modest but measurable attenuation of TNF-α and IL-6 secretion, which was accompanied by downregulation of TLR4 and IκB signaling. In vivo, 5-month oral administration of memantine to mThy1-αSyn transgenic mice led to moderate improvements in motor function as assessed by beam-walk performance. Immunohistochemical analyses revealed decreased microglial activation in the cerebral cortex; however, phosphorylated α-synuclein accumulation and tyrosine hydroxylase expression remained unaffected. Furthermore, spatial working memory was not improved by treatment. Taken together, these findings suggest that memantine may exert beneficial effects on neuroinflammatory processes and behavioral deficits in PD-relevant models. However, its impact on the hallmark neuropathology of PD appears limited.}, } @article {pmid41197760, year = {2026}, author = {Yao, M and Li, Z and Lin, Y and Cai, H and Sun, C and Liu, L and Long, Y and Ge, Z}, title = {Hyperbaric oxygen therapy ameliorates Alzheimer's disease pathology by restoration of mitophagy and suppressing neuroinflammation in 5xFAD mice.}, journal = {Experimental neurology}, volume = {396}, number = {}, pages = {115534}, doi = {10.1016/j.expneurol.2025.115534}, pmid = {41197760}, issn = {1090-2430}, mesh = {Animals ; *Alzheimer Disease/therapy/pathology/genetics/metabolism ; *Hyperbaric Oxygenation/methods ; Mice, Transgenic ; Mice ; *Mitophagy/physiology ; *Neuroinflammatory Diseases/therapy/pathology ; Male ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, synaptic dysfunction, and chronic neuroinflammation. Here, we demonstrate that hyperbaric oxygen therapy (HBOT) has multiple therapeutic effects in 5xFAD transgenic mice. HBOT significantly improved cognitive function. Treated mice increasingly moved to the center of the open field in Y-maze tests and preferred a new arm. Longitudinal [18]F-AV-45 PET-MR scans showed progressive reduction in amyloid tracer uptake, which was corroborated by histologically verified reduced plaque burden and upregulation of LRP1, a key Aβ clearance transporter. HBOT preserved neuronal density and enhanced synaptic proteins. Mechanistically, HBOT promoted mitochondrial quality control by upregulating PINK1 and parkin expression, enhancing autophagosome formation, and modulating mitophagy-associated pathways. The transition of microglia to a surveillance phenotype was reflected in decreased soma area and increased branching. The coordinated improvement in amyloid clearance, mitochondrial quality control and synaptic maintenance, and modulation of neuroinflammation suggest that the ability of HBOT to simultaneously act on multiple pathological cascades-in combination with its noninvasive nature and favorable safety profile-makes it a uniquely promising therapeutic strategy. Furthermore, these results suggest that HBOT may be particularly effective at an early stage of the disease. These studies will be critical in establishing the clinical applicability of HBOT in the treatment of Alzheimer's disease.}, } @article {pmid41197747, year = {2026}, author = {Ozturk, B and Demir, H and Silindir-Gunay, M and Akdag, Y and Sahin, S and Gulsun, T}, title = {Application of artificial neural network to determine optimum formulation development and in vitro characterization of methylene blue and galantamine loaded polymeric nanoparticles for the treatment of Alzheimer's disease.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {216}, number = {}, pages = {107364}, doi = {10.1016/j.ejps.2025.107364}, pmid = {41197747}, issn = {1879-0720}, mesh = {*Methylene Blue/chemistry/administration & dosage ; *Galantamine/chemistry/administration & dosage ; *Neural Networks, Computer ; *Alzheimer Disease/drug therapy ; *Nanoparticles/chemistry ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Poloxamer/chemistry ; Particle Size ; Cholinesterase Inhibitors/chemistry/administration & dosage ; Drug Carriers/chemistry ; Chemistry, Pharmaceutical ; Glutathione/chemistry ; }, abstract = {Alzheimer's disease is a major neurodegenerative disorder characterized by complex pathophysiology and currently lacks a curative treatment. This study aims to develop and characterize methylene blue and galantamine co-loaded PLGA nanoparticles, surface-modified with poloxamer 188 and GSH, to increase blood residence time and improve brain-targeted delivery. The nanoparticles were prepared using the double emulsion solvent evaporation method, and their physicochemical properties were characterized by TEM, FT-IR, DSC, XRD, and [13]C NMR. Artificial neural network modeling was used to optimize the formulation parameters, including PLGA %, PVA %, and sonication time, for predicting particle size and encapsulation efficiencies of methylene blue and galantamine. Results showed that the optimized nanoparticles had particle sizes <200 nm, appropriate zeta potential, and high encapsulation efficiencies. DSC, FT-IR, XRD, and NMR analyses confirmed the absence of crystalline peaks for methylene blue and galantamine, indicating successful encapsulation. Artificial neural network models demonstrated high predictive accuracy, serving as a valuable tool for formulation optimization. This dual-drug, surface-modified nanoparticle approach offers promising potential for multi-target therapy in Alzheimer's disease.}, } @article {pmid41196512, year = {2025}, author = {Li, Y and Fan, H and Han, X and Ni, M and Hou, X and Xia, H and Shi, Y and Zhang, L and Sun, J}, title = {RRBP1 Inhibition Reduces Microglial M1 Polarization and Inflammation-Mediated Neuronal Loss and Oxidative Stress by Regulating ERK Pathway in Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {63}, number = {1}, pages = {5}, pmid = {41196512}, issn = {1559-1182}, support = {No. ZC23456043 and No. ZC2020259//The 23456 Talent Project of Henan Provincial People's Hospital/ ; }, mesh = {*Oxidative Stress/drug effects/physiology ; *Microglia/metabolism/pathology/drug effects ; *Alzheimer Disease/pathology/metabolism ; Animals ; Humans ; *Neurons/metabolism/pathology/drug effects ; *Inflammation/pathology/metabolism ; *MAP Kinase Signaling System/drug effects/physiology ; Mice ; *Cell Polarity/drug effects ; Cell Line ; Reactive Oxygen Species/metabolism ; Amyloid beta-Peptides ; Cell Line, Tumor ; Apoptosis/drug effects ; }, abstract = {Ribosome-binding protein 1 (RRBP1) regulates ribosome assembly and stability to modify several important biological processes such as mitochondrial function, stress, cell differentiation, immunity, and axonal structure. This study aimed to investigate RRBP1 inhibition on microglial polarization and inflammation, and its mediated neuronal loss and oxidative stress in Alzheimer's disease (AD). Mouse microglia (BV-2), mouse hippocampal neuron (HT-22), human microglia (HMC3), and human neuroblastoma (SH-SY5Y) cell lines were cultured. A classical culture system containing BV-2 and HT-22, as well as HMC3 and SH-SY5Y, under β-amyloid treatment was applied to mimic AD cellular models. RRBP1 siRNA and control siRNA were transfected into BV-2 and HMC3 cells with no transfection as normal control; moreover, the ERK pathway was inactivated by PD98059 reagent. Microglial M1 phonotype marker (iNOS) and inflammatory cytokines (TNF-α and IL-1β levels) were decreased, while microglial M2 phonotype marker (ARG1) and pERK/ERK were increased by RRBP1 inhibition in BV-2 and HMC3 cells. Then microglial RRBP1 inhibition further elevated cell viability and superoxide dismutase (SOD), while reducing the cell apoptosis rate and reactive oxygen species (ROS) in HT-22 and SH-SY5Y cells. pERK/ERK was lowered after PD98059 treatment, which attenuated the effect of RRBP1 inhibition on microglial M1/M2 phenotypes and inflammatory cytokines in BV-2 and HMC3 cells, and further weakened the effect of microglial RRBP1 inhibition on cell viability, apoptosis rate, ROS, and SOD in HT-22 and SH-SY5Y cells. RRBP1 inhibition represses microglial M1 polarization and inflammation-mediated neuronal loss and oxidative stress by modifying the ERK pathway in AD.}, } @article {pmid41196470, year = {2025}, author = {Vaja, R and Vohra, M and Ramachandran, AV and Baxi, D}, title = {Development of a Novel Aluminium Chloride-Induced Zebrafish Model of Alzheimer's Disease: Involvement of Oxidative Stress, Cholinergic Dysfunction, and Gut Pathophysiology.}, journal = {Neurotoxicity research}, volume = {43}, number = {6}, pages = {46}, pmid = {41196470}, issn = {1476-3524}, mesh = {Animals ; Zebrafish ; *Oxidative Stress/drug effects/physiology ; *Alzheimer Disease/chemically induced/physiopathology/pathology/metabolism ; *Disease Models, Animal ; Female ; Male ; *Aluminum Chloride/toxicity ; Brain/pathology/drug effects/metabolism ; }, abstract = {Alzheimer's Disease (AD) is a progressive and fatal neurodegenerative disorder (NDD), and the leading cause of dementia globally, with females being more susceptible than males. Existing animal models for AD are primarily pharmacologically induced or transgenic, yet many fail to recapitulate the full spectrum of human AD pathology and thereby elucidating its sex-based differences. This underscores the need for a cost-effective and robust experimental model that reliably mimics the multifactorial nature of AD taking into account the differences that arise due to sex. In recent years, the zebrafish (Danio rerio) has emerged as a promising model organism for studying central nervous system (CNS) disorders, including AD, owing to its high genetic and physiological homology to humans, transparent embryonic development, and amenability to high-throughput screening. This study aims to establish a novel chronic neurotoxicity induced ZF model, using AlCl3 as an inducing neurotoxic agent. The hypothesis centers on AlCl3-induced oxidative stress, cholinergic pathway dysfunction, and gut pathophysiological changes as drivers of AD-like pathology. Adult zebrafish, of both sexes were exposed to chronic AlCl3 treatment over a 28-day period. Post-treatment assessments included histopathological, biochemical, and behavioural analyses to evaluate changes in brain and gut tissues, oxidative stress biomarkers, and cognitive performance. Zebrafish exposed to AlCl3 exhibited distinct pathological changes in both brain and gut tissues compared to controls. In the brain, hallmarks such as pyknotic neurons, neuronal vacuolisation, and neural tissue necrosis was observed. Gut tissue displayed significant abnormalities, including reduced villi number, epithelial cell loss, and fused or shortened villi. Biochemical analyses revealed elevated oxidative stress, evidenced by altered levels of catalase (CAT), glutathione (GSH), and lipid peroxidation (LPO). Additionally, disruption of the cholinergic system was evident. Behavioural analyses using locomotor tracking revealed marked cognitive deficits, including reduced average speed, decreased distance travelled, and increased immobility. Lastly, our sex specific differences revealed that females were more affected by the biochemical, histological and neurobehavioural parameters as compared to males, thereby indicating that females pose a greater susceptibility towards developing AD. The AlCl3 -induced zebrafish model successfully replicates key features of human neurotoxicity, which may lead to AD like features including oxidative stress, cholinergic dysfunction, neurodegeneration, and gut-brain axis alterations. This novel and cost-effective model provides a comprehensive platform for exploring sex-mediated neurotoxicity experimental animal model and offers potential utility for screening therapeutic interventions and understanding disease-modifying mechanisms. Keywords: Alzheimer's Disease, Chronic Neurotoxicity, Gut-brain axis, Zebrafish, Sex differences, Alumnium chloride.}, } @article {pmid41196440, year = {2025}, author = {Li, S and Gao, Y and Zhang, X and Lang, J and Liu, X and Zhang, Y and Zhang, J and Zhao, Y and Chang, C and Gao, X and Zhou, J and Yu, D and Yang, G}, title = {Bicyclol improves cognition deficits and inhibits oxidative stress-induced neuronal cell apoptosis in alzheimer's disease via Nrf2/HO-1 pathway.}, journal = {Metabolic brain disease}, volume = {40}, number = {8}, pages = {310}, pmid = {41196440}, issn = {1573-7365}, support = {Grant No. 20220997//the Medical Science Research Project of Hebei Provincial Health Commission/ ; Grant No. 82471453//the National Natural Science Foundation of China/ ; Grant No. H2022206231//the Hebei Natural Science Foundation/ ; }, mesh = {Animals ; *Apoptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; *Biphenyl Compounds/pharmacology/therapeutic use ; Mice ; *Neurons/drug effects/metabolism ; *Heme Oxygenase-1/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism ; Neuroprotective Agents/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Male ; Mice, Transgenic ; Disease Models, Animal ; Antioxidants/pharmacology ; Amyloid beta-Peptides ; Membrane Proteins ; }, abstract = {Alzheimer's disease (AD) is identified as the prevalent neurodegenerative condition globally, ultimately resulting in dementia. Currently, the mechanisms that contribute to AD are not well comprehended, and there are few therapeutic alternatives available. Bicyclol, a substance extracted from the Chinese herb Schisandra Chinensis, has shown remarkable antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective characteristics. However, there is a shortage of research focusing on the therapeutic effects of bicyclol on AD as well as the molecular pathways that may be involved. This study sought to evaluate the effects of bicyclol on cognitive impairments in a mouse model of AD, explore its neuroprotective benefits associated with antioxidant functions and apoptosis suppression, and reveal the mechanisms involved. In this study, APP/PS1 mice underwent a 2-month treatment with bicyclol administered via gavage, after which their cognitive abilities were evaluated through behavioral assessments. The apoptosis of cortical neurons was evaluated using TUNEL staining and immunofluorescence techniques. N2A cells, which were exposed to Aβ1-42 oligomers, received a pretreatment with bicyclol, and their viability was subsequently measured. The expression levels of proteins such as nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P) H-quinine oxidoreductase-1 (NQO1), BCL2 associated X Protein (Bax), B-cell lymphoma-2 (Bcl-2), and Cleaved caspase-3 were quantified in vitro and in vivo using western blotting and qPCR methods. Moreover, N2A cells lacking Nrf2 were utilized to investigate the underlying mechanisms through which bicyclol exerts its effects in Alzheimer's disease. Bicyclol has been shown to enhance cognitive function while simultaneously reducing the levels of cortical Aβ1-40 and Aβ1-42, and it also protects against neuronal degeneration in the APP/PS1 mouse model. Moreover, it increases the activity of cortical SOD and GSH-Px, concurrently decreasing levels of ROS and MDA in vivo. Additionally, bicyclol significantly lessened oxidative stress and apoptosis induced by Aβ1-42 in N2A cells. It further elevated the expression of proteins such as Nrf2, HO-1, and NQO1, along with mRNA levels in both in vitro and in vivo experiments. Furthermore, the silencing of Nrf2 via siRNA transfection counteracted the regulatory effects of bicyclol on apoptotic markers including Bax, Bcl-2, and Cleaved caspase-3 in vitro. Our study provides compelling evidence that bicyclol effectively alleviates cognitive impairments observed in APP/PS1 mice. Furthermore, our findings indicate that bicyclol plays a significant role in reducing oxidative stress-induced injury and neuronal apoptosis. This protective effect is associated with the activation of the Nrf2/HO-1 signaling pathway. These results suggest that bicyclol has the potential to be developed as a therapeutic agent for the treatment of Alzheimer's disease, highlighting its promise in addressing the cognitive decline associated with this debilitating condition.}, } @article {pmid41196439, year = {2025}, author = {Yadav, P and Dabas, A and Singh, R}, title = {Six-membered N-heterocyclic alkaloids as ChE inhibitors in alzheimer's disease treatment.}, journal = {Metabolic brain disease}, volume = {40}, number = {8}, pages = {309}, pmid = {41196439}, issn = {1573-7365}, mesh = {*Alzheimer Disease/drug therapy/enzymology ; *Cholinesterase Inhibitors/therapeutic use/pharmacology ; Humans ; *Alkaloids/therapeutic use/pharmacology/chemistry ; Animals ; Butyrylcholinesterase/metabolism ; Acetylcholinesterase/metabolism ; *Heterocyclic Compounds/therapeutic use/pharmacology ; }, abstract = {Cholinesterase (ChE) refers to a group of enzymes that play a critical role in the hydrolysis of choline-based esters, particularly acetylcholine, a key neurotransmitter presents in the nervous system. The two types of cholinesterase are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), each with distinct functions and locations found within the body. Cholinesterase inhibitors (ChEIs) have been utilized to treat Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder characterized by memory loss, impacting on the quality of life. Many studies have highlighted the potential of alkaloids as inhibitors of cholinesterase enzymes. There are various alkaloids which have potential to treat AD with their different modes of actions. This review summarizes more than 14 well-known alkaloids possessing six-membered N-heterocycles as AChE and BuChE inhibitors, such as berberine, boldine, crytolepine, harmine, huperzine A, 6-hydroxycrinamine, nicotine, piperine, salsoline, skimmianine, trigonelline, valerianofal A, 7'-multijuguinone, and 12'-hydroxy-7'-multijuguinone, hamayne, and lycorine.}, } @article {pmid41195067, year = {2025}, author = {Ye, K and Li, L and Guan, L and Qin, MM and Xu, XY and Wu, J and Huang, LZ and Gao, JJ}, title = {Exploring the molecular mechanisms of Pueraria in Alzheimer's disease treatment using machine learning and network pharmacology.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1683852}, pmid = {41195067}, issn = {2296-861X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder, characterized by amyloid-β deposition, tau pathology, neuroinflammation, and metabolic dysfunction. While conventional treatments have been widely studied, food-based interventions are emerging as potential neuroprotective strategies. Pueraria, a nutrient-rich food, has shown promise in promoting brain health, but its mechanisms in AD prevention and management remain insufficiently understood.

METHODS: In this study, we utilized network pharmacology, transcriptomics, and machine learning to investigate the neuroprotective effects of Pueraria. Through analysis of five transcriptomic datasets (GSE5281, GSE29378, GSE36980, GSE37263, and GSE138260), we identified genes associated with AD and screened 15 active compounds from Pueraria lobata using HERB and TCMSP databases. Machine learning models prioritized key targets, and molecular docking simulations assessed the binding affinities of Pueraria compounds to these targets. In vivo validation was performed in AD model mice to evaluate the cognitive-enhancing effects of Pueraria.

RESULTS: We identified 45 overlapping targets between Pueraria and AD, primarily related to synaptic plasticity and neurotransmission. Among these, PFKFB3 emerged as a key mediator of Pueraria's neuroprotective effects. Molecular docking confirmed strong binding affinities between Pueraria compounds and PFKFB3, supporting their functional role. Experimental data showed that Pueraria improved cognitive function in AD mice, underscoring its potential as a neuroprotective agent.

CONCLUSION: This study highlights Pueraria as a promising functional food for AD prevention and management, emphasizing the potential of plant-based dietary interventions for brain health. Our findings provide a basis for further exploration of food-derived neuroprotective strategies.}, } @article {pmid41193962, year = {2025}, author = {Jahani, S and Roshanaei, G and Tapak, L and , }, title = {Assessing the accuracy of survival machine learning and traditional statistical models for Alzheimer's disease prediction over time: a study on the ADNI cohort.}, journal = {BMC medical research methodology}, volume = {25}, number = {1}, pages = {250}, pmid = {41193962}, issn = {1471-2288}, mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging ; *Machine Learning ; Male ; Female ; Aged ; *Cognitive Dysfunction/diagnosis/diagnostic imaging ; Disease Progression ; *Models, Statistical ; Aged, 80 and over ; Neuroimaging/methods ; Prognosis ; Cohort Studies ; Proportional Hazards Models ; Survival Analysis ; }, abstract = {BACKGROUND: Mild cognitive impairment (MCI) represents a transitional stage to Alzheimer's disease (AD), making progression prediction crucial for timely intervention. Predictive models integrating clinical, laboratory, and survival data can enhance early diagnosis and treatment decisions. While machine learning approaches effectively handle censored data, their application in MCI-to-AD progression prediction remains limited, with unclear superiority over classical survival models.

METHODS: We analyzed 902 MCI individuals from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with 61 baseline features. Traditional survival models (Cox proportional hazards, Weibull, elastic net Cox) were compared with machine learning techniques (gradient boosting survival, random survival forests [RSF]) for progression prediction. Models were evaluated using C-index and IBS.

RESULTS: Following feature selection, 14 key features were retained for model training. RSF achieved superior predictive performance with the highest C-index (0.878, 95% CI: 0.877-0.879) and lowest IBS (0.115, 95% CI: 0.114-0.116), demonstrating statistically significant superiority over all evaluated models (P-value < 0.001). RSF demonstrated effective risk stratification across individual biomarker categories (genetic, imaging, cognitive) and achieved optimal patient separation into three distinct prognostic groups when combining all features (p < 0.0001). SHAP-based feature importance analysis of RSF revealed cognitive assessments as the most influential predictors, with Functional Activities Questionnaire (FAQ) achieving the highest importance score (1.098), followed by Logical Memory Delayed Recall Total (LDELTOTAL) (0.906) and Alzheimer's Disease Assessment Scale (ADAS13) (0.770). Among neuroimaging biomarkers, Fluorodeoxyglucose (FDG) emerged as the leading predictor (0.634), ranking fifth overall. Feature importance ranking differed between classical and machine learning approaches, with FDG maintaining consistent importance across all models. RSF demonstrated excellent predictive calibration with positive net benefit across risk thresholds from 0.2 to 0.8.

CONCLUSIONS: The RSF model outperformed other methods, demonstrating superior potential for improving prognostic accuracy in medical diagnostics for MCI to AD progression.}, } @article {pmid41193931, year = {2025}, author = {Nagarajan, R and Zhang, H and Lyu, J and Kambali, M and Wang, M and Rudolph, U}, title = {Intranasal Insulin Mitigates Memory Impairment and Neuroinflammation in a Mouse Model of Hippocampal Aging.}, journal = {Pharmacology research & perspectives}, volume = {13}, number = {6}, pages = {e70186}, pmid = {41193931}, issn = {2052-1707}, support = {R01 GM128183/GM/NIGMS NIH HHS/United States ; R35 GM153232/GM/NIGMS NIH HHS/United States ; R35GM153232/GM/NIGMS NIH HHS/United States ; R01GM128183/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Administration, Intranasal ; *Insulin/administration & dosage/pharmacology ; Mice ; *Memory Disorders/drug therapy ; Disease Models, Animal ; *Hippocampus/drug effects/metabolism ; *Aging/drug effects ; *Neuroinflammatory Diseases/drug therapy ; Male ; Somatostatin/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; }, abstract = {Aging is a complex process that frequently includes cognitive decline with memory loss. In the hippocampus, the number of somatostatin-positive (Sst[+]) GABAergic interneurons in the hilar region of the dentate gyrus decreases with age. We previously showed that selective ablation of Sst[+] dentate hilar interneurons is sufficient to induce cognitive dysfunction, resulting in a model of hippocampal aging (pseudo-aged mice). Brain insulin levels and insulin receptor expression also decline with age, and intranasal insulin (INS) has shown promise in improving learning and memory in Alzheimer's disease. Here, we investigated the effects of INS in pseudo-aged mice with genetically ablated dentate hilar Sst[+] interneurons, which were generated by bilateral injection of AAV5-EF1α-mCherry-flex-dtA into the dentate hilus of Sst-IRES-Cre mice (3-5 months old). Following a 3-week recovery period post-injection, INS was administered daily for 9 days. INS treatment in pseudo-aged mice improved working memory in the Y-maze, recognition memory in the novel object recognition test, and non-declarative associative memory in trace fear conditioning. At the molecular level, INS reversed the increase in Iba-1 and pTBK1 expression, indicating attenuation of microglial activation and cGAS-STING pathway signaling, and restored hippocampal BDNF levels. No significant effects of INS were observed in control mice. These findings indicate that INS alleviates memory impairment and reduces neuroinflammation in this hippocampal aging model. Together, the results suggest that intranasal insulin may provide a non-invasive therapeutic approach for mitigating age-related cognitive decline by modulating neuroinflammatory and neurotrophic mechanisms.}, } @article {pmid41192715, year = {2025}, author = {Wang, J and Du, Z and Wang, W and Liang, Z and Hou, Y and Liu, Q and Wang, J and Wang, S and He, M and Li, Z and Yang, R and Wang, K and Zhao, L and Wei, Y and Huang, D}, title = {Lactoferrin-driven delivery of Kaixinsan nanomedicine for Alzheimer's disease neuroprotection: Mechanistic insights from bioinformatics and multi-target validation.}, journal = {International journal of biological macromolecules}, volume = {333}, number = {Pt 1}, pages = {148746}, doi = {10.1016/j.ijbiomac.2025.148746}, pmid = {41192715}, issn = {1879-0003}, mesh = {*Lactoferrin/chemistry ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; *Neuroprotective Agents/pharmacology/chemistry ; Mice ; Computational Biology/methods ; Blood-Brain Barrier/metabolism/drug effects ; Humans ; *Neuroprotection/drug effects ; *Nanomedicine ; Caenorhabditis elegans ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Drug Delivery Systems ; }, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder characterised by neurapoptosis and neuroinflammation-induced neuronal damage. However, the exact pathogenic mechanism of AD is still controversial, and the existing treatment methods are only effective for the early stage of the disease. Kaixinsan (KXS), a classic anti-amnestic traditional Chinese medicine, can effectively reduce oxidative stress and provide neuroprotection to the brain, but the exact molecular mechanism remains unclear. Herein, we synthesised a biomimetic KXS-delivery system (LTF@GO-PEG/KXS, LGPK), which significantly enhanced the blood-brain barrier (BBB) penetration efficiency was significantly improved, attributed to lactoferrin (LTF)-mediated receptor binding. LGPK exhibits excellent neuroprotection and repolarizes BV2 microglia from pro-inflammatory to anti-inflammatory phenotypes. Further bioinformatics analysis and western blot results indicated that LGPK could inhibit the progression of AD by inhibiting the production of amyloid precursor protein (APP) and hyperphosphorylated Tau (p-Tau), and downregulating TNF/NF-κB signalling pathways. In vivo studies using a transgenic Caenorhabditis elegans strain confirmed that LGPK both suppresses Aβ fibrillogenesis and attenuates oxidative stress, thereby highlighting its potential as a combination therapy for AD. Mechanistic investigations indicated that these neuroprotective effects were mediated through the suppression of the TNF/NF-κB signalling pathway, along with profound alterations in alternative splicing (AS) events. Collectively, these findings highlight LGPK as a promising multi-target nanomedicine for AD treatment by enhancing brain-targeted delivery and exerting combined anti-neuroapoptosis and anti-inflammatory.}, } @article {pmid41192695, year = {2026}, author = {Kong, M and Xu, Z and Lu, H and Chen, Y and Zhang, Y and Jiang, X and Wang, P}, title = {ShengHui Decoction mitigates oxidative stress and neuroinflammation in AlCl3-induced AD zebrafish via activating Nrf2/HO-1 and inhibiting NF-κB signaling pathway.}, journal = {Journal of ethnopharmacology}, volume = {356}, number = {}, pages = {120785}, doi = {10.1016/j.jep.2025.120785}, pmid = {41192695}, issn = {1872-7573}, mesh = {Animals ; Zebrafish ; *Oxidative Stress/drug effects ; Aluminum Chloride/toxicity ; NF-E2-Related Factor 2/metabolism ; NF-kappa B/metabolism ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Signal Transduction/drug effects ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; Disease Models, Animal ; Zebrafish Proteins/metabolism ; Heme Oxygenase-1/metabolism ; *Neuroinflammatory Diseases/drug therapy ; }, abstract = {ShengHui decoction (SHD), a traditional Chinese herbal formula, has long been used clinically to mitigate Alzheimer's disease (AD), demonstrating significant efficacy in alleviating cognitive impairment. However, its molecular mechanisms remain insufficiently understood.

AIM OF THE STUDY: To clarify the effects of SHD on oxidative stress-related markers and inflammatory cytokines in an aluminum chloride (AlCl3)-induced zebrafish model of AD and as well as uncover its underlying mechanisms in alleviating oxidative stress and neuroinflammation.

MATERIALS AND METHODS: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to identify the bioactive constituents of SHD. Behavioral tests and histopathological analyses were then conducted to evaluate the effects of SHD (0.74, 1.48, and 2.96 mg/mL) on apoptosis and amyloid-beta (Aβ) deposition in an AlCl3-induced AD zebrafish model. Biochemical assays and enzyme-linked immunosorbent assay were used to quantify superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1 beta (IL-1β), and IL-18. Western blot analysis was performed to determine the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor-kappa B p65 (NF-κB p65), phosphorylated NF-κB p65 (p-NF-κB p65), and NOD-like receptor family pyrin domain containing 3 (NLRP3).

RESULTS: UPLC-MS/MS profiling identified phenolic acids, saponins, lignans/coumarins, flavonoids, and aliphatic alcohols as the main constituents of SHD. SHD significantly ameliorated cognitive deficits and histopathological abnormalities in AlCl3-induced zebrafish. Moreover, SHD attenuated oxidative stress by upregulating Nrf2, HO-1, and NQO1 expression, while downregulating AlCl3-induced levels of NF-κB p65, p-NF-κB p65, NLRP3 and pro-inflammatory factors.

CONCLUSIONS: SHD effectively improved cognitive performance and reduced AD-like pathological lesions in AlCl3-induced zebrafish. Importantly, SHD exhibits both antioxidant and anti-inflammatory activities by activating the Nrf2/HO-1 axis and inhibiting NF-κB signaling, thereby alleviating oxidative stress and neuroinflammatory responses in AD. These findings provide experimental evidence supporting SHD as a potential therapeutic agent for AD, and substantiate the traditional Chinese medicine principle of tonifying the kidney and replenishing essence in the treatment of AD.}, } @article {pmid41192434, year = {2025}, author = {Wagemann, O and Tesky, VA and Schall, A and Nübling, G and Wlasich, E and Hüer, T and Walendzik, A and Weitzel, M and Giebel, GD and Raszke, P and Wasem, J and Pantel, J and Levin, J}, title = {[A review and guideline for the adequate and interdisciplinary (socio-)medical care of people with Down syndrome and dementia development].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {}, number = {}, pages = {}, doi = {10.1055/a-2708-3648}, pmid = {41192434}, issn = {1439-3522}, support = {Projekt-Nr. 01VSF21030//Innovationsfonds des Gemeinsamen Bundesausschusses/ ; 022_EKEA.133//Else-Kröner-Fresenius-Stiftung/ ; }, abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in older age. Individuals with Down syndrome (DS) are at significantly increased risk due to trisomy 21 and the resulting overexpression of the amyloid precursor protein. Prevalence rates of AD-related dementia in DS (DSAD) reach up to 88% beyond the age of 65. Despite this, structured diagnostic and therapeutic guidelines for DSAD are lacking.A narrative review of current literature on etiology, diagnosis, treatment, and care pathways for DSAD was conducted. Currently employed dementia diagnostic standards were evaluated in regard to the specific needs of individuals with DS.Established diagnostic methods are applicable to individuals with DS but require adaptations regarding symptom recognition, test administration, and interpretation. Early awareness among caregivers and healthcare providers, as well as timely referral to specialized centers, is essential for accurate diagnosis and treatment planning.Improving care for individuals with DSAD requires close coordination between general healthcare services and specialized centers. This review highlights the medical, diagnostic, and structural challenges in suspected DSAD and provides practical recommendations for patient care. The proposed guideline aims to reduce uncertainties in clinical practice and support sustainable, needs-based care.}, } @article {pmid41192010, year = {2025}, author = {Yang, M and Wang, Z and Zhou, Q and Zhang, Q and Li, Y and Wang, Z}, title = {The adjunctive efficacy of repetitive transcranial magnetic stimulation with non-pharmacological interventions in cognitive disorders: A meta-analysis of randomized sham-controlled trials.}, journal = {Asian journal of psychiatry}, volume = {114}, number = {}, pages = {104758}, doi = {10.1016/j.ajp.2025.104758}, pmid = {41192010}, issn = {1876-2026}, mesh = {Humans ; *Randomized Controlled Trials as Topic ; *Cognitive Dysfunction/therapy ; *Transcranial Direct Current Stimulation/methods ; Combined Modality Therapy ; *Transcranial Magnetic Stimulation/methods ; *Alzheimer Disease/therapy ; *Tai Ji ; *Outcome Assessment, Health Care ; *Cognitive Behavioral Therapy/methods ; }, abstract = {OBJECTIVE: This meta-analysis aimed to systematically evaluate the specific, adjunctive efficacy of repetitive transcranial magnetic stimulation (rTMS) when combined with non-pharmacological interventions-namely, transcranial direct current stimulation (tDCS), Tai Chi, or cognitive training (CT)-in patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI). The goal is to isolate the net therapeutic contribution of rTMS beyond the effects of the base interventions alone.

METHODS: A comprehensive search of Chinese and English databases was conducted from their inception until April 26, 2025. Randomized controlled trials (RCTs) that compared "a non-pharmacological intervention plus active rTMS" versus "the same non-pharmacological intervention plus sham rTMS".This "add-on" study design was selected to precisely isolate the effect of rTMS. The risk of bias was assessed using the PEDro scale and Cochrane tools. Statistical analyses were performed using Review Manager 5.4 software.

RESULTS: 9 studies involving 391 participants were included. The pooled analysis revealed that the adjunctive use of rTMS was significantly superior to the sham control in improving global cognitive function at the immediate post-treatment assessment (SMD=0.38, 95 %CI[0.20,0.56], P < .001, n = 9). This benefit was consistent across the MMSE (SMD=0.38, n = 6), MoCA (SMD=0.37, n = 2), and ADAS-cog (SMD=0.39, n = 3) scores. Subgroup analysis suggested that the rTMS-tDCS combination might offer a short-term advantage in improving MMSE scores (MD=4.67, P = .008). Furthermore, the adjunctive effect of rTMS was sustained, as particularly evidenced by the ADAS-cog at follow-up (SMD=0.74, P = .02). The pooled analysis indicated that rTMS combined with non-pharmacological therapy demonstrated a short-term, sustained (4-8weeks) improvement in global cognitive function (SMD=0.34, 95 % CI[0.07, 0.60], P = .01). Subgroup analysis revealed that this sustained benefit reached statistical significance on the ADAS-cog scale (SMD = 0.41, 95 %CI[0.01, 0.81], P = .04) but showed a non-significant positive trend on the MMSE (SMD=0.26, 95 %CI[-0.19, 0.72], P = .26). However, a key limitation was that most studies did not systematically report outcomes related to activities of daily living or behavioral function.

CONCLUSION: The evidence indicates that rTMS as an adjunct to non-pharmacological interventions provides a significant specific effect on global cognitive function in patients with AD and MCI shortly after treatment, which may be sustained in the short-term. However, long-term follow-up data are extremely limited, and the effect on activities of daily living remains to be validated. The combination of rTMS and tDCS shows promise,but conclusions are constrained by the small number of studies,limited sample sizes,and heterogeneity in intervention protocols. Future large-scale studies incorporating long-term, standardized follow-up and assessments of daily living abilities are warranted to confirm the specific clinical value of rTMS as an augmentative therapy.}, } @article {pmid41191186, year = {2025}, author = {Zhang, Y and Liu, S and Xu, K and Shen, Y and Liu, Z and Wang, Y and Bai, Y and Wang, S}, title = {Repetitive transcranial magnetic stimulation for cognitive and emotional symptoms in neurodegenerative diseases: a systematic review and dose-response meta-analysis.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {12}, pages = {6243-6259}, pmid = {41191186}, issn = {1590-3478}, support = {2023ZX06C16//Heilongjiang Province Key Research and Development Project: Evidence-based Evaluation Study on the Interventions of Traditional Chinese Medicine at Key Stages of the Whole Cycle of Parkinson's Disease/ ; }, mesh = {Humans ; *Transcranial Magnetic Stimulation/methods ; *Parkinson Disease/therapy/complications/psychology ; *Affective Symptoms/therapy/etiology ; *Alzheimer Disease/therapy/psychology ; *Neurodegenerative Diseases/therapy/complications/psychology ; *Cognitive Dysfunction/therapy/etiology ; }, abstract = {OBJECTIVE: We summarized the existing clinical evidence of repetitive transcranial magnetic stimulation (rTMS) for cognitive and emotional symptoms in Parkinson's disease (PD) and alzheimer's disease (AD), and conducted a series of dose-response meta-analyses to determine the magnitude and curve relationship between pulse quantity changes and treatment effect sizes.

METHODS: We retrieved existing evidence from 5 databases and collected relevant results data on rTMS treatment for cognitive and emotional symptoms in PD and AD. We analyzed the data using R software to evaluate the effect size using MD or SMD and 95% confidence intervals (CI), used heterogeneity tests to evaluate the differences in efficacy among the evidence, and used restricted cubic splines (RCS) to fit the dose-response curve.

RESULTS: A total of 17 studies were included in this study. We found that the total pulse quantity showed a significant bell-shaped curve in MoCA (χ[2] = 6.82, df = 2, p = 0.03), HAMA (χ[2] = 9.16, df = 2, p = 0.01), and ADL (χ[2] = 8.22, df = 2, p = 0.01), with optimal effects achieved at 16153, 12138, and 17,237 pulses respectively-indicating that clinical application should control pulses within these ranges to avoid insufficient or excessive doses weakening efficacy. A significant upward curve was observed in MMSE (χ[2] = 12.94, df = 2, p = 0.001), meaning higher pulse counts (up to the 80,000-pulse upper limit in this study) may further improve basic cognitive function, providing a reference for dose adjustment in patients with cognitive impairment.

CONCLUSION: Our meta-analysis results show that rTMS exhibits significant efficacy in cognitive and emotional symptoms of PD and AD. The dose-response results show that the total pulse quantity in MoCA, HAMA, and ADL of PD and AD patients presents a typical bell-shaped curve, and a typical upward curve in MMSE. This indicates that there is a curve relationship between pulse stimulation quantity and efficacy, and the pulse stimulation quantity should be emphasized in the clinical application of rTMS.}, } @article {pmid41191158, year = {2025}, author = {Pal, B and Panda, S and Bashir, B and Vishwas, S and Chaitanya, M and Hussain, MS and Gupta, G and Kumbhar, P and Gupta, S and Singh, SK}, title = {Nanomedicine-enabled neuroprotection: therapeutic role of berberine in neurodegenerative diseases.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {49}, pmid = {41191158}, issn = {1573-4978}, mesh = {Humans ; *Berberine/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Nanomedicine/methods ; Animals ; *Neuroprotection/drug effects ; Nanoparticles/chemistry ; Oxidative Stress/drug effects ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {Neurodegenerative diseases (NDs), including Alzheimer's, Amyotrophic lateral sclerosis, Huntington's, and Parkinson's, present an increasingly widespread health burden globally with limited curative or treatment modalities, mostly having symptomatic attenuation. Berberine (BBR) is an isoquinoline alkaloid that occurs naturally and has been proposed as a potential neuroprotectant, since it has been found to exert multiple effects to modulate most of the pathological hallmarks of NDs, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and protein aggregation. Although it shows promise, the practical utilization of BBR is marred by low oral bioavailability, high rate of oxidation, and low blood-brain barrier permeability. To combat these issues, recent developments in nanotechnology, especially in the use and creation of lipidic, inorganic, and polymeric nano-particles, have dramatically altered the pharmacokinetics and pharmacodynamics of BBR. This article summarizes recent advances in BBR-based nanoformulations and emphasizes the translational potential of BBR-based nanopreparations to improve treatment response in NDs. It also describes the molecular foundation of the neuroprotective effects of BBR and its possible place in clinical practice. Future nanocarrier development and investigation of BBR mechanisms will be essential to the development of the next generations of therapeutics in NDs.}, } @article {pmid41189798, year = {2025}, author = {Sudevan, ST and Oh, JM and Prabhakaran, P and Abdelgawad, MA and Ghoneim, MM and Al-Serwi, RH and Kim, H and Mathew, B}, title = {Inhibition of monoamine oxidase by fluorobenzyloxy chalcone derivatives.}, journal = {RSC advances}, volume = {15}, number = {50}, pages = {42376-42394}, pmid = {41189798}, issn = {2046-2069}, abstract = {Inhibition of monoamine oxidase-B (MAO-B) decelerates the breakdown of dopamine in the brain, consequently augmenting dopaminergic neurotransmission, which is a critical pathway for ameliorating motor symptomatology of Parkinson's disease (PD). Chalcones are widely recognized as the lead inhibitors of MAO-B and hold significant therapeutic value for PD. Inspired by safinamide's pharmacophoric features, the study focuses on designing, synthesizing, and evaluating a novel series of fluorinated benzyloxy chalcone derivatives as selective MAO-B inhibitors. Thirteen fluorobenzyloxy chalcone derivatives were synthesized and evaluated for their inhibition of monoamine oxidase (MAO). All compounds showed better inhibition of MAO-B than of MAO-A. Compound (E)1-(4-bromophenyl)-3-(2-((3-fluorobenzyl)oxy)phenyl)prop-2-en-1-one (FBZ13) most potently inhibited MAO-B with an IC50 value of 0.0053 μM, followed by (E)3-(2-((3-fluorobenzyl)oxy)phenyl)-1-(thiophen-2-yl)prop-2-en-1-one (FBZ6) (IC50 = 0.023 μM). The IC50 value of FBZ13 was 4.0 times lower than that of reference drug safinamide. All compounds showed weak MAO-A inhibition, FBZ13 and FBZ6 displayed exceptionally high selectivity for MAO-B. Kinetic studies confirmed that these two compounds function as competitive and reversible MAO-B inhibitors. Additionally, PAMPA results indicated excellent membrane permeability and CNS bioavailability for FBZ13 and FBZ6, highlighting their promise as central nervous system-active agents. In vitro antioxidant assays evaluated the activities of enzymes (SOD, CAT, GSH, and GPx) in human neuroblastoma cells exposed to lipopolysaccharide (LPS). Treatment with compounds FBZ6 and FBZ13 (10 μM each) significantly enhanced enzyme activities, mitigating LPS-induced oxidative stress. Lead compounds were stabilized in protein-ligand complexes by the π-π stacking, which enabled them to bind to the active site of hMAO-B effectively. These results suggest that FBZ6 and FBZ13 are potent reversible selective MAO-B inhibitors, and they can be used as potential agents for the treatment of neurological disorders such as Alzheimer's diseases and PD.}, } @article {pmid41189652, year = {2025}, author = {Guo, H and Yang, Z and Zhang, G and Lv, L and Zhao, X}, title = {Meta analysis of the diagnostic efficacy of transformer-based multimodal fusion deep learning models in early Alzheimer's disease.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1641548}, pmid = {41189652}, issn = {1664-2295}, abstract = {INTRODUCTION: This study aims to systematically evaluate the diagnostic efficacy of Transformer-based multimodal fusion deep learning models in early Alzheimer's disease (AD) through a Meta-analysis, providing a scientific basis for clinical applications.

METHODS: Following PRISMA guidelines, databases such as PubMed and Web of Science were searched, and 20 eligible clinical studies (2022-2025) involving 12,897 participants were included. Study quality was assessed using the modified QUADAS-2 tool, statistical analyses were performed with Stata 16.0, effect sizes were pooled via random-effects models, and subgroup analyses, sensitivity analyses, and publication bias tests were conducted.

RESULTS: Results showed that Transformer-based multimodal fusion models exhibited excellent overall diagnostic performance, with a pooled AUC of 0.924 (95% CI: 0.912-0.936), sensitivity of 0.887 (0.865-0.904), specificity of 0.892 (0.871-0.910), and accuracy of 0.879 (0.858-0.897), significantly outperforming traditional single-modality methods. Subgroup analyses revealed that: Three or more modalities achieved a higher AUC (0.935 vs. 0.908 for two modalities, p =0.012). Intermediate fusion strategies (feature-level, AUC=0.931) significantly outperformed early (0.905) and late (0.912) fusion (p <0.05 for both). Multicenter data improved AUC (0.930 vs. 0.918 for single-center, p =0.046), while sample size stratification (<200 vs. ≥200 cases) showed no significant difference (p =0.113). Hybrid Transformer models (Transformer +CNN) trended toward higher AUC (0.928 vs. pure Transformer 0.917, p =0.068) but did not reach statistical significance.

DISCUSSION: Notable studies included Khan et al.'s (2024) Dual-3DM[3]AD model (AUC=0.945 for AD vs. MCI) and Gao et al.'s (2023) generative network (AUC=0.912 under data loss), validating model robustness and feature complementarity. Sensitivity analysis confirmed stable results (AUC range: 0.920-0.928), and Egger's test (p =0.217) and funnel plot symmetry indicated no significant publication bias. Limitations included a high proportion of single-center data and insufficient model interpretability. Future research should focus on multicenter data integration, interpretable module development, and lightweight design to facilitate clinical translation. Transformer-based multimodal fusion models demonstrate exceptional efficacy in early AD diagnosis, with multimodal integration, feature-level fusion, and multicenter data application as key advantages. They hold promise as core tools for AD "early diagnosis and treatment" but require further optimization for cross-cohort generalization and clinical interpretability.}, } @article {pmid41189641, year = {2025}, author = {Nasrallah, IM and Polacek, C and Frech, FH and Tariot, PN and Vawter, J and Zabar, Y and Divers, C and Shang, WY and Geldmacher, DS and Towman, M and Reiter, H and Marshall, CD and Baldivieso, V and Jones, DR and Musiek, ES and Toyosaki, H and Tousi, B}, title = {Early Alzheimer's disease patient care pathway and health system readiness: A framework for integrated care.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {4}, pages = {e70162}, pmid = {41189641}, issn = {2352-8737}, abstract = {UNLABELLED: Alzheimer's disease (AD) is often underdiagnosed, especially at early stages when symptoms are mild, and patients may benefit from new and recently approved anti-amyloid therapies. An updated patient care pathway may facilitate timely diagnosis and intervention. We conducted a scan of published information and convened an expert panel of health care professionals to gain insights on early AD care pathways. We developed an Early AD Patient Care Pathway as an implementation guide that includes new diagnostic and treatment modalities and addresses needs and opportunities. The Early AD Patient Care Pathway focuses on patient identification, assessment, diagnosis, treatment, and management and monitoring. Operational readiness considerations aid pathway implementation and include evaluating and addressing gaps in program and business planning, technology, education and resources, access and reimbursement, and care coordination. The pathway is adaptable to health system needs and may be further tested and refined for sustainability.

HIGHLIGHTS: We analyzed published information and insights from subject matter experts on care pathways for early Alzheimer's disease.We identified opportunities to improve screening of at-risk patients, make appropriate specialist referrals, and ensure timely access and care coordination for diagnosis, treatment, and monitoring as a means of incorporating the latest diagnostics and therapy options.We developed a care pathway that promotes an integrated approach to patient care and is adaptable to various healthcare settings with input from subject matter experts.}, } @article {pmid41189609, year = {2025}, author = {Perneczky, R and Quevenco, FC and Hendrix, J and Epelbaum, S and Teunissen, C and van der Flier, WM and Suárez-Calvet, M and Shi, J and Mielke, MM and Iwatsubo, T and Palmqvist, S and Hansson, O}, title = {How can Alzheimer's disease blood-based biomarkers reach clinical practice?.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {4}, pages = {e70207}, pmid = {41189609}, issn = {2352-8729}, abstract = {INTRODUCTION: Alzheimer's disease (AD) diagnosis has been based largely on clinical symptoms, despite their limited sensitivity and specificity. Biomarker use was proposed to support a more accurate and timely diagnosis. However, neuroimaging or cerebrospinal fluid (CSF) is rarely used in primary care due to their perceived invasiveness, cost, and need for appropriate infrastructure. Blood-based biomarkers (BBMs) could represent an economical, minimally invasive alternative, but barriers exist to a seamless translation to the clinic.

METHODS: Ten international experienced AD clinicians and biomarker experts participated in a diagnostic roundtable to discuss the implementation of BBMs for diagnosing early symptomatic AD.

RESULTS: The participants proposed an optimal AD diagnostic pathway and highlighted three main gaps to implementing BBMs for early symptomatic AD diagnosis: limited real-world data, resource gaps, and system barriers.

DISCUSSION: Although BBMs could streamline the AD diagnostic pathway, further real-world evidence and collaboration among multiple stakeholders are needed.

HIGHLIGHTS: Early symptomatic Alzheimer's disease (AD) diagnosis improves treatment strategy and lowers costs.Currently available biomarkers are not widely used across all clinical settings.Blood-based biomarkers (BBMs) could be a cost-effective, minimally invasive alternative.BBMs could accelerate an accurate AD diagnosis.There are barriers to the inclusion of BBMs in clinical practice.}, } @article {pmid41189255, year = {2025}, author = {Sleiay, M and Almohammad, TY and Sleiay, B and Sadeq, D and Salibie, N and Alkarkoukly, M and Alsleba, AA and Albalkhi, S and Alchalabi, E and Kilooh, T and Alsmadi, N and Alobeid, A and Esber, H and Mousa, A and Hasan, Z and Alabdullah, Y and Tannous, E and Hamsho, RM and Abu Ras, N and Khanje, L and Khanje, K and Othman, AA}, title = {Assessing Alzheimer's disease knowledge in the Syrian population using the ADKS: A cross-sectional study.}, journal = {Medicine}, volume = {104}, number = {42}, pages = {e45045}, pmid = {41189255}, issn = {1536-5964}, mesh = {Humans ; Cross-Sectional Studies ; *Alzheimer Disease/psychology ; Female ; Syria ; *Health Knowledge, Attitudes, Practice ; Male ; Adult ; Surveys and Questionnaires ; Middle Aged ; Young Adult ; Adolescent ; }, abstract = {Alzheimer disease (AD), a leading neurodegenerative disorder, disproportionately affects women and presents increasing global socioeconomic challenges. Despite growing identification of modifiable risk factors, public knowledge about AD's causes and progression remains limited in many regions. This study assesses AD knowledge among Syrian adults using the Alzheimer Disease Knowledge Scale (ADKS) and examines demographic correlations. This study evaluates the level of AD knowledge in the Syrian population and identify demographic factors associated with knowledge levels. A cross-sectional study was conducted from June to August 2024 using the validated Arabic version of the ADKS. The questionnaire (30 true/false items across 7 domains) was distributed electronically to Syrian adults (≥18 years). Descriptive statistics, t tests, 1-way analysis of variance, Pearson correlation, and Welch t test were performed using Statistical Package for the Social Sciences version 27. Ethical approval was granted by Aleppo University (No. 2408), and informed consent was obtained. A total of 685 participants responded (69.5% aged 18-25; 72.3% university-educated). While knowledge was high in domains related to life impact and treatment, substantial gaps were observed in understanding preventive drugs (20.4% correct) and caregiving strategies (11.1%). Higher knowledge scores were significantly associated with higher education levels, accessing healthcare-related information, and having relatives with AD (P < .001). This first Syrian study utilizing the ADKS revealed moderate public knowledge of AD (mean score: 18.79/30). Key knowledge gaps in caregiving and treatment underscore the need for targeted educational campaigns. Outreach led by healthcare professionals is essential to enhance awareness, promote early diagnosis, and support caregivers of individuals with AD.}, } @article {pmid41188985, year = {2025}, author = {Abouelmagd, ME and Almosilhy, NA and Makhlouf, HA and Hassan, AK and Osman, ASA and Hindawi, MD and Elshahat, A and Alnajjar, AZ and Mustafa, MMM and Abdelsalam, OK and Mady, A and Shaheen, A and Barrett, MJ and Negida, A}, title = {Comparative safety of cholinesterase inhibitors and memantine for dementia: a protocol for a network meta-analysis of randomized controlled trials.}, journal = {Systematic reviews}, volume = {14}, number = {1}, pages = {213}, pmid = {41188985}, issn = {2046-4053}, mesh = {Humans ; *Memantine/therapeutic use/adverse effects ; *Cholinesterase Inhibitors/adverse effects/therapeutic use ; Systematic Reviews as Topic ; Network Meta-Analysis as Topic ; Randomized Controlled Trials as Topic ; *Dementia/drug therapy ; Meta-Analysis as Topic ; Alzheimer Disease/drug therapy ; }, abstract = {BACKGROUND: Dementia is a growing public health concern, affecting over 55 million people worldwide, with Alzheimer's disease (AD) being the most prevalent cause. Cholinesterase inhibitors (ChEIs) and memantine remain the mainstay pharmacological treatment for AD and other dementias, despite their modest benefits and potential adverse effects. The safety profiles of these medications, particularly at different doses and formulations, remain inadequately explored, necessitating a comprehensive evaluation.

METHODS: This systematic review and network meta-analysis (NMA) will assess the safety of ChEIs (donepezil, galantamine, rivastigmine) and memantine in dementia treatment. We will include randomized controlled trials (RCTs) with ≥ 3 months of follow-up, evaluating adverse events (AEs), serious adverse events (SAEs), and treatment discontinuation rates. A comprehensive literature search will be conducted in PubMed, Scopus, Web of Science, and Cochrane Library, with additional searches in Google Scholar and reference lists of included studies. Data extraction will follow a standardized approach, and study quality will be assessed using the Cochrane risk-of-bias tool-2. A Frequentist or Bayesian NMA framework will be used to compare safety profiles, with heterogeneity assessed using the I[2] test.

DISCUSSION: By addressing gaps in prior NMAs, this study aims to provide an in-depth evaluation of safety outcomes associated with different ChEI and memantine doses and formulations across various dementia types. The findings will support clinicians in making informed treatment decisions and guide future research and policy development for dementia management.

PROSPERO (CRD42025642902).}, } @article {pmid41186822, year = {2025}, author = {Voronova, AD and Karsuntseva, EK and Shishkina, VS and Fursa, GA and Chadin, AV and Shport, SV and Stepanova, OV and Chekhonin, VP}, title = {Cell Therapy Is a New Treatment Option to Prevent Neurodegenerative Changes and Restore Cognitive Functions in Alzheimer's Disease (Review).}, journal = {Bulletin of experimental biology and medicine}, volume = {179}, number = {4}, pages = {507-517}, pmid = {41186822}, issn = {1573-8221}, mesh = {*Alzheimer Disease/therapy/pathology/physiopathology ; Humans ; *Cognition/physiology ; Animals ; *Cell- and Tissue-Based Therapy/methods ; Brain/pathology ; Disease Models, Animal ; }, abstract = {This review considers cell therapy and possible mechanisms underlying beneficial effects of cells in prevention of neurodegenerative changes as a promising approach to the treatment of Alzheimer's disease. The results of using various types of cells in experimental models of Alzheimer's disease and their effect on the regeneration of the brain and recovery of cognitive functions are presented.}, } @article {pmid41186808, year = {2025}, author = {Jafni, S and Nagakanni, M and Indhirakumar, B and Rani, RKS and Preethi, S and Hemamalini, V and Vanathi, G and Saraswathy, SD and Devi, KP}, title = {Synergistic neuroprotective effects of Vitexin and Thymol against Okadaic acid-induced neurotoxicity: Computational and In vitro evaluation.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {43}, pmid = {41186808}, issn = {1573-4978}, support = {CRG/2022/000847-G//Anusandhan National Research Foundation (ANRF)/ ; }, mesh = {*Neuroprotective Agents/pharmacology ; *Apigenin/pharmacology/metabolism ; *Thymol/pharmacology/metabolism ; Molecular Docking Simulation ; Drug Synergism ; Animals ; Mice ; Molecular Dynamics Simulation ; Neurons/drug effects/metabolism ; Blood-Brain Barrier/metabolism/drug effects ; Cell Survival/drug effects ; Alzheimer Disease/drug therapy/metabolism ; Cell Line, Tumor ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and inexorable loss of neurons. Despite extensive research, the currently approved drugs offer only limited efficacy which highlights the need for exploring novel synergistic natural compounds capable of mitigating multiple targets of AD.

METHODS AND RESULTS: This study evaluated the neuroprotective potential of the synergistic combination of Vitexin and Thymol using computational and in vitro model systems in N2a cells. Computational pharmacokinetic screening revealed the blood-brain barrier (BBB) permeability of thymol and 0.55 bioavailability score for Vitexin. Molecular docking studies showed higher binding affinity of Vitexin with JNK and Thymol with COX-1 and CAMK-II and 100 ns molecular dynamics simulation exhibited stable binding with sustained hydrogen bond and hydrophobic interactions. Based on the IC50 values [Vitexin (135.24 µg/ml, 312.9 µM) and Thymol (36.91 µg/ml, 245.7 µM)] and combination index (CI < 1) determined by the acetylcholinesterase (AChE) inhibition assay and checkerboard assay (performed with 15 different combinations) respectively, the effective combination (Vitexin 45.08 µg/ml; Thymol 7.382 µg/ml; CI = 0.53) was fixed for further studies. In okadaic acid (OA) induced neurotoxicity model, pre-treatment with the combination significantly increased the cell viability (88.36 ± 3.73%) (n = 3). Real-time PCR results revealed the upregulation of PP1 gene expression and modulation of MAPK family (MEK1/2, ERK1/2 and JNK), and other tau related kinases (GSK3β, CAMKII and P70 s6).

CONCLUSION: The above findings demonstrate that the combination of Vitexin and Thymol effectively protect the neuronal cells from OA induced cytotoxicity and modulate the hyperactivation of kinases, suggesting its potential in preventing tau hyperphosphorylation in AD conditions.}, } @article {pmid41185525, year = {2026}, author = {Liu, Q and Feng, E and Li, S and Zhu, Y and He, X and Xu, X and Zheng, T and Tian, Y}, title = {High-Efficient Raman Enhancement on Organic Semiconductor-Stabilized Perovskite Heterostructures for Guiding Early Theranostics of Alzheimer's Disease.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {65}, number = {1}, pages = {e18319}, doi = {10.1002/anie.202518319}, pmid = {41185525}, issn = {1521-3773}, support = {2024YFC3406405//National Key Research and Development Program of China/ ; 22222405//National Natural Science Foundation of China/ ; 22393930//National Natural Science Foundation of China/ ; }, mesh = {*Semiconductors ; *Titanium/chemistry ; *Spectrum Analysis, Raman ; *Oxides/chemistry ; *Alzheimer Disease/diagnosis ; *Calcium Compounds/chemistry ; Humans ; *Theranostic Nanomedicine ; }, abstract = {Perovskites have recently emerged as attractive optoelectronic semiconductors due to tunable bandgap, large absorption coefficient, and long carrier lifetime, making it ideal as a kind of chemical-mechanism based surface-enhanced Raman scattering (SERS) substrates. However, perovskites generally demonstrate poor stability at ambient conditions, limiting their applications for SERS bioanalysis. Herein, we created a perovskite-based heterostructure through effectively passivating defects at the interface with hydrophobic organic semiconductors, which simultaneously enhanced the stability and efficiency of perovskite SERS substrate. The significant enhancement factor of 10[7] was mainly stemmed from the resonance Raman effect and the highly-efficient charge transfer process driven by a novel light-induced hot electron transfer mechanism in plasmon-free substrates previously never reported. This system was subsequently developed as an integrated theranostic SERS platform for miR-146a monitoring with a detection limit down to 0.2 fM, successfully guiding the early theranostics to enhance the therapeutic efficiency for Alzheimer's disease (AD). This work brings new light into the design of efficient and stable semiconductor SERS substrate and opens novel diagnosis and treatment options for AD.}, } @article {pmid41185054, year = {2025}, author = {Leung, LY and Tam, HL and Asiamah, N and Ho, JK}, title = {Effect of melatonin on cognitive function in adults with cognitive impairment: a multi-dimensional meta-analysis of randomized trials.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {238}, pmid = {41185054}, issn = {1758-9193}, mesh = {Humans ; *Melatonin/therapeutic use/pharmacology ; *Cognitive Dysfunction/drug therapy/psychology ; Randomized Controlled Trials as Topic ; *Cognition/drug effects ; }, abstract = {BACKGROUND: Cognitive impairment leads to poor daily social and occupational functions and sleep disturbances. Approximately two-thirds of all individuals with mild cognitive impairment (MCI) experience sleep problems that further reduce cognitive function. Melatonin, a hormone secreted by the pineal gland, has proven effective in mitigating sleep problems and cognitive function in individuals with MCI. The current review investigated the efficacy of melatonin in improving cognitive function in adults with cognitive impairment.

METHODS: Seven databases were systematically searched for relevant randomized controlled trials published (in English or Chinese) until April 2025. Two reviewers independently selected studies, assessed quality (using the Physiotherapy Evidence Database scale), and extracted data.

RESULTS: In total, 394 potentially eligible articles were identified. Finally, 8 studies (518 participants) were included. Five, one, and two studies had good, excellent, and low quality, respectively. Pooled results indicated that melatonin significantly improved cognitive function in adults with cognitive impairment (mean difference [MD]: 1.08; p < 0.0001). Subgroup analyses by treatment duration, administration time, and cognitive impairment level revealed that the effects of melatonin were significant when it was administered for 13-24 weeks (MD: 2.04; p < 0.00001), between the times of 20:30 and 21:00 (MD: 2.2; p < 0.00001), and to individuals with MCI (MD: 2.63; p < 0.000001).

CONCLUSIONS: Our findings suggest that melatonin is relatively safe for individuals with cognitive impairment. Thus, we recommend it for adults with MCI. It should be administered between 20:30 and 21:00 for 13-24 weeks.}, } @article {pmid41184619, year = {2025}, author = {Choe, K and Ali, J and Park, HY and Jang, SH and Choi, EY and Kang, MH and Park, TJ and Kim, MO}, title = {The mGluR2/3 agonist xanthurenic acid improves memory, attention, and synaptic deficits by modulating glutamate release in Alzheimer's disease model.}, journal = {Acta pharmacologica Sinica}, volume = {}, number = {}, pages = {}, pmid = {41184619}, issn = {1745-7254}, abstract = {Amyloid-beta (Aβ) aggregation is the key component of neuritic plaques that drives Alzheimer's disease (AD) progression and cognitive decline. Although synaptic dysfunction strongly correlates with cognitive impairment, its underlying mechanisms remain unclear. Recently, the kynurenine pathway (KP) of tryptophan metabolism has emerged as a key contributor to AD pathology, and xanthurenic acid (XA), a naturally occurring end-product of the KP, has been implicated in neuroprotection. In this study, we investigated the neuroprotective effects of intranasally administered XA in an Aβ-induced AD mouse model. AD-like pathology was induced in mice by intracerebroventricular injection of Aβ1-42. The mice received daily intranasal instillation of XA (0.5 μg/5 μL per nostril) for 6 weeks. After XA treatment was completed, the cognitive performance was assessed in behavioral tests, then the mice were euthanized, and the brain were collected for molecular and biochemical analyses. We showed that XA treatment significantly improved the cognitive function of AD mice, and reduced AD-related pathological markers such as APP, Aβ and BACE-1 in the cortex, hippocampus and olfactory bulb. XA treatment also attenuated Aβ-induced oxidative stress through upregulation of the Nrf2/HO-1/SOD1 and key enzymatic antioxidants (GSH, GST, CAT, SOD), while concurrently reducing lipid peroxidation. Furthermore, XA treatment preserved synaptic integrity, evidenced by restoring both pre- and postsynaptic markers (SNAP-25, SYP, SNAP-23, PSD-95) and enhancing signaling via the cAMP-PKA-CREB pathway. Notably, XA differentially modulated metabotropic glutamate receptors, decreasing mGluR2 and increasing mGluR3 expression. In vitro experiments were conducted in APPswe/ind-transfected SH-SY5Y neuroblastoma cells. XA (3-100 µM) dose-dependently improved the cell viability while reducing cytotoxicity and apoptosis. Overall, these results demonstrate that XA confers multifaceted neuroprotection by modulating Aβ pathology, oxidative stress, synaptic function, and glutamatergic signaling, suggesting its potential as a novel therapeutic strategy to mitigate cognitive decline and pathological progression in AD.}, } @article {pmid41184442, year = {2025}, author = {Garnier-Crussard, A and Landeau, B and Mezenge, F and Gonneaud, J and Roquet, D and Cotton, F and Chetelat, G}, title = {Heterogeneity of white matter hyperintensities in Alzheimer's disease captured by multimodal neuroimaging.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {38433}, pmid = {41184442}, issn = {2045-2322}, support = {667696//European Union's Horizon 2020 Research and Innovation Program/ ; 667696//European Union's Horizon 2020 Research and Innovation Program/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/metabolism ; *White Matter/diagnostic imaging/pathology/metabolism ; Aged ; Male ; Female ; *Neuroimaging/methods ; *Multimodal Imaging/methods ; Positron-Emission Tomography ; Aged, 80 and over ; Magnetic Resonance Imaging ; Fluorodeoxyglucose F18 ; }, abstract = {White matter hyperintensities (WMH) are common in older adults and are associated with cognitive disorders. They typically arise from small vessel disease, leading to demyelination and axonal loss. WMH are thus considered markers of cerebrovascular changes. However, other pathophysiological processes can lead to WMH, particularly in Alzheimer's disease (AD). Understanding the diverse origins of WMH could enhance the diagnosis and treatment of AD patients. We hypothesize that multimodal neuroimaging could help understand the heterogeneity of WMH and pinpoint their specific origin. We included 142 older adults from the community and memory clinic (with an emphasis on patients within the Alzheimer's continuum), and tested if multimodal neuroimaging signal within regional WMH (including T1w, T2w, [18]F-florbetapir [AV45] and [18]F-fluorodeoxyglucose [FDG] PET), is associated with amyloid load and cognition. We showed that intra-WMH T1w and T2w signal in the parietal and frontal lobes were linked to amyloid status; intra-WMH T2w signal in all regions negatively correlated with amyloid load, while intra-WMH T1w signals in the parietal lobe positively correlated with amyloid load; finally, intra-WMH T1w signal negatively correlated with cognition while T2w and marginally AV45 signals positively correlated with cognition. This study demonstrates the potential of multimodal neuroimaging to unravel the heterogeneity of WMH, which could enhance their interpretation and improve clinical decision-making.}, } @article {pmid41183995, year = {2025}, author = {Okamura, N and Nakayama-Naono, R and Harada, R}, title = {[In vivo imaging of Alzheimer's disease lesion].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {160}, number = {6}, pages = {398-403}, doi = {10.1254/fpj.25055}, pmid = {41183995}, issn = {0015-5691}, mesh = {Animals ; Humans ; *Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; }, abstract = {In the development of Alzheimer's disease (AD) therapeutics, positron emission tomography (PET) imaging techniques play an important role in the selection of patients for administration and objective evaluation of treatment effects. The clinical implementation of amyloid-β (Aβ) and tau PET agents is progressing, with the aim of noninvasively visualizing brain lesions in AD. Furthermore, the development of PET agents for imaging neuroinflammation is advancing. Near-infrared fluorescence (NIRF) imaging has attracted attention as an alternative technology to nuclear imaging. Near-infrared light in the wavelength range of 650-900 nm, known as the optical window, is absorbed less by living tissue compared to visible light. Therefore, by using probes that emit NIRF, it is possible to noninvasively measure the distribution of probes within the body. Indocyanine green (ICG), a non-specific NIRF probe, is already being used in surgical procedures, but NIRF probes specifically for AD lesions are still in the developmental stage. The characteristics required for NIRF Aβ probe include high binding affinity and selectivity for Aβ, excitation and fluorescence wavelengths in the optical window, and blood-brain barrier permeability. Numerous NIRF probes for Aβ have been developed, reaching levels suitable for use in animal experiments. In recent years, research has also progressed on the development of multi-target fluorescence imaging probes that can identify multiple targets with a single probe by utilizing differences in fluorescence wavelengths according to the binding targets.}, } @article {pmid41183202, year = {2025}, author = {Yang, X and Lee, JY and Moghadam, F and Steiner, J and Kim, SK and Ganjur, N and de Almenara, AJ and Stoltz, BM and Loh, YP and Goddard, WA}, title = {Predicted molecules followed by experimental validation for protecting human neurons from oxidative stress-induced cytotoxicity.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {45}, pages = {e2505359122}, pmid = {41183202}, issn = {1091-6490}, support = {no numbef//HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; R01HL155532 R35HL150807 and R35GM145239//HHS | NIH (NIH)/ ; CAP23011-200//National Research Council of Science and Technology (NST)/ ; }, mesh = {Humans ; *Oxidative Stress/drug effects ; *Neurons/drug effects/metabolism/pathology ; *Neuroprotective Agents/pharmacology/chemistry ; Animals ; }, abstract = {Alzheimer neurodegenerative disease (AD) has had a major impact worldwide, with no effective drugs for treatment. We discovered and reported earlier that neurotrophic factor-α1 (NF-α1)/carboxypeptidase E (CPE) reversed neurodegeneration and cognitive dysfunction in AD mouse models. We then predicted computationally and validated experimentally that CPE interacts with a pharmacophore of six residues on the 5-HT1E receptor (HTR1E) to activate the ERK-BCL2 signaling pathway leading to protection of human neurons against oxidative stress-induced cell death. We now report using this pharmacophore for in silico virtual screening of ~6 million small molecules to discover candidates with similar binding and neuroprotective properties as CPE. This in silico search identified a molecule (Z124) that was verified experimentally to bind to HTR1E with protective efficacy comparable to NF-α1/CPE but requiring a higher concentration. Next, we carried out R-group design optimization based on Z124 to identify 4 compounds predicted to have much better efficacy than Z124. These compounds were synthesized and tested for neuroprotective activity. All four compounds showed binding to HTLA-HTR1E cells comparable to CPE. We determined the Kd for two of these compounds: R9, 1.38 ± 0.2 nM, and R10, 2.1 ± 0.2 nM, to be over 15 times better than CPE. Furthermore, all four new compounds showed protective activity against oxidative stress-induced cytotoxicity in human HEK293 cells stably transfected with HTR1E, as well as human primary neurons. Mechanistically, R9 and R10 activated ERK phosphorylation and increased the mitochondria prosurvival protein, BCL2, making them excellent candidates for further development as a drug to treat neurodegenerative diseases.}, } @article {pmid41183099, year = {2025}, author = {Liu, J and Zhang, ZZ and Yu, GR and Han, X}, title = {Quercetin Targets HSP90α and Regulates Keap1/Nrf2 Pathway to Inhibit Crosstalk between Apoptosis and Ferroptosis in Oxidatively Stressed Neurons.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {11}, pages = {e70583}, doi = {10.1002/jbt.70583}, pmid = {41183099}, issn = {1099-0461}, support = {//This study was supported by the National Key Research and Development Program of China (2022YFC3501400) and Jiangsu Province Graduate Practice and Innovation Program (SJCX25_0998)./ ; }, mesh = {*Quercetin/pharmacology ; *HSP90 Heat-Shock Proteins/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Ferroptosis/drug effects ; *Oxidative Stress/drug effects ; *Neurons/metabolism/pathology/drug effects ; *Apoptosis/drug effects ; *Signal Transduction/drug effects ; Humans ; Animals ; }, abstract = {The rising incidence and mortality rates associated with Alzheimer's disease (AD) have garnered significant attention. The interplay between ferroptosis and apoptosis, both of which are driven by oxidative stress, contributes to neuronal death and accelerates the progression of AD. In this study, we observed that neuronal cells exhibited characteristics of both ferroptosis and apoptosis following exposure to a specific concentration of hydrogen peroxide; both processes could be effectively inhibited by quercetin. To further investigate the precise mechanisms, we conducted target enrichment analysis utilizing databases pertinent to quercetin, AD, oxidative stress, ferroptosis, and apoptosis. Our findings identified HSP90AA1 as a potential key target through which quercetin disrupts the interplay between ferroptosis and apoptosis. We subsequently focused on HSP90α, encoded by HSP90AA1, and validated its role in ferroptosis and apoptosis using HSP90α and Nrf2 inhibitors. Our results demonstrate that under oxidative stress conditions, quercetin induces the activation of HSP90α. This activated chaperone binds to kelch-like ECH-associated protein 1 (Keap1), which disrupts the Keap1-Nrf2 complex and facilitates the release of nuclear factor erythroid 2-related factor 2 (Nrf2). The liberated Nrf2 translocates to the nucleus, initiating the expression of cytoprotective genes. Once in the nucleus, Nrf2 activates the Glutathione peroxidase 4 (GPX4) pathway and the expression of B-cell lymphoma-2 (Bcl-2) family proteins to inhibit ferroptosis and apoptosis. This study elucidates the crosstalk mechanism by which quercetin modulates neuronal ferroptosis and apoptosis under oxidative stress, providing new insights and potential therapeutic targets for the prevention and treatment of AD.}, } @article {pmid41182777, year = {2026}, author = {Thomas, ML and Edland, SD and Duehring, J}, title = {The MMSE can yield biased and imprecise estimates of change: A novel IRT analysis of latent change scores from the A4 clinical trial.}, journal = {Psychological assessment}, volume = {38}, number = {1}, pages = {64-70}, pmid = {41182777}, issn = {1939-134X}, support = {R01 MH121546/MH/NIMH NIH HHS/United States ; //National Institutes of Health; National Institute of Mental Health/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis ; Male ; Female ; *Mental Status and Dementia Tests/standards/statistics & numerical data ; Aged ; *Psychometrics ; Aged, 80 and over ; }, abstract = {The measurement precision of change scores has previously been investigated from the perspective of classical test theory. However, the measurement precision of change scores has not been thoroughly explored from an item response theory (IRT) perspective. In this study, we provide, to our knowledge, one of the first direct investigations of change score precision within an IRT framework. Specifically, using archival data from the antiamyloid treatment in asymptomatic Alzheimer's trial, we examined standard error of estimate for change scores on the mini-mental state examination, one component of the preclinical Alzheimer cognitive composite used to measure change between intervention arms. Multidimensional two-parameter IRT models were fitted to the mini-mental state examination item data with one latent dimension reflecting baseline ability and a second reflecting change in ability over time (i.e., latent change scores). Results showed that standard error depended on change magnitude and that change scores were expected to be biased toward zero when baseline performance scores were near ceiling. The results demonstrate why measures with pronounced ceiling effects should not be used to assess change in clinical trials or other longitudinal studies, and should be used cautiously in clinical settings. This study also demonstrates how IRT can be used to evaluate change score precision. (PsycInfo Database Record (c) 2026 APA, all rights reserved).}, } @article {pmid41182353, year = {2025}, author = {Cai, Y and Huang, S and Dong, Y and Li, S and Jin, X}, title = {PIWI-Interacting RNAs in brain health and disease: biogenesis, mechanisms, and therapeutic horizons.}, journal = {Psychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {41182353}, issn = {1432-2072}, support = {81971083//National Natural Science Foundation of China/ ; 25JCLZJC00190//Tianjin Natural Science Foundation Project/ ; }, abstract = {PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs originally identified for their role in transposon silencing in germ cells, have recently been recognized as pivotal regulators of gene expression in the central nervous system. Beyond their canonical functions in genome defense, emerging evidence highlights piRNAs as key modulators of neuronal development, synaptic plasticity, axonal regeneration, and neuroimmune interactions-processes central to brain function and dysfunction. This review provides a comprehensive overview of piRNA biogenesis, molecular mechanisms, and regulatory pathways relevant to neurobiology. We focus on the growing body of evidence implicating piRNA dysregulation in major neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, glioma, autism spectrum disorder, and schizophrenia. Importantly, we discuss the neuropharmacological implications of piRNA pathways as novel targets for therapeutic intervention and their potential utility as biomarkers for early diagnosis and treatment stratification. By integrating mechanistic insights with emerging translational evidence, this review highlights piRNAs as promising molecular targets in the development of next-generation neurotherapeutics aimed at modifying disease progression and improving brain health.}, } @article {pmid41181807, year = {2025}, author = {Richardson, DL and Whitney, E}, title = {Deep Brain Stimulation: Overview and Applications in the Context of Neuropsychiatric Conditions.}, journal = {Cureus}, volume = {17}, number = {10}, pages = {e93661}, pmid = {41181807}, issn = {2168-8184}, abstract = {Deep brain stimulation (DBS) is a neuromodulatory therapy involving the implantation of electrodes into brain structures in order to help normalize brain activity in a variety of neurological disorders. The mechanisms of DBS operate at micro-, meso-, and macroscale levels to influence neuronal signaling, synaptic reorganization, and network-wide connectivity between brain regions. Recent advances in connectomics and sensing technologies have allowed for more precise and adaptive stimulation strategies, increasing the potential to target complex, heterogeneous neuropsychiatric conditions. DBS has already been well-explored as a treatment for obsessive-compulsive disorder. Emerging research has explored the use of DBS for other neuropsychiatric conditions as well, including autism spectrum disorder (ASD), treatment-refractory depression (TRD), and dementia associated with Alzheimer's disease (AD). DBS for ASD shows promise in reducing self-injurious behaviors and aggression by targeting the nucleus accumbens (NAc), amygdala, and posteromedial hypothalamus. In TRD, DBS to the subcallosal cingulate gyrus (SCG), medial forebrain bundle (MFB), and ventral capsule/ventral striatum (VC/VS) has demonstrated significant antidepressant effects. For dementia and AD, DBS targeting the fornix and nucleus basalis of Meynert (NBM) has shown promise in slowing cognitive decline. Despite the variety of targets, connectomic analyses reveal overlapping cortical-subcortical network dysfunctions across these disorders. These findings offer insight into shared neurobiological mechanisms of these disorders, as well as guide refinement of therapeutic targets for future study. Overall, DBS for neuropsychiatric conditions remains in its early stages, hindered by disorder heterogeneity and challenges in identifying optimal brain targets. Advances in functional neuroimaging, closed-loop stimulation, and machine learning-driven connectomic approaches can aid in target selection as well as better understanding the neuroanatomy and physiology underlying these complex conditions, which, in turn, lead to improved patient outcomes. Further research is necessary to establish standardized protocols and expand the therapeutic applications of DBS in neuropsychiatry.}, } @article {pmid41180952, year = {2025}, author = {Zammit, M and Price, J and Christian, B and Rafii, M and , }, title = {A comparison of multiple amyloid PET radiotracers for Down syndrome clinical trials.}, journal = {Brain communications}, volume = {7}, number = {6}, pages = {fcaf406}, pmid = {41180952}, issn = {2632-1297}, support = {UL1 TR001857/TR/NCATS NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; UL1 TR002373/TR/NCATS NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; R01 AG080766/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; UL1 TR002366/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; R61 AG066543/AG/NIA NIH HHS/United States ; RF1 AG094739/AG/NIA NIH HHS/United States ; }, abstract = {Adults with Down syndrome carry high risk of developing Alzheimer's disease and efforts to include this population in clinical trials remain limited. A barrier to recruitment for anti-amyloid trials includes the availability of the same amyloid PET radiotracer to multiple treatment centres. The objective of the study is to compare longitudinal rates of change between different amyloid PET radiotracers, particularly Pittsburgh compound B and florbetapir, in Down syndrome and to compare the estimated age at amyloid-positivity derived from these radiotracers. Two hundred thirty-seven adults with Down syndrome from the Trial Ready Cohort-Down syndrome and Alzheimer's Biomarker Consortium-Down syndrome studies were imaged using T1-weighted MRI and using PET images of Pittsburgh compound B, florbetapir, NAV4694 or flutemetamol to screen for amyloid plaque burden. Currently, Pittsburgh compound B and florbetapir have longitudinal data from these cohorts, while NAV4694 has one individual with longitudinal scans and flutemetamol has no available longitudinal data. Pittsburgh compound B displayed a greater effect size to measure amyloid change compared to florbetapir. NAV4694 and Pittsburgh compound B, which are structurally similar compounds, displayed similar sensitivity to measure longitudinal amyloid increase. The estimated age at amyloid onset showed no significant difference between Pittsburgh compound B, florbetapir, NAV4694 or flutemetamol. The findings suggest that different amyloid PET radiotracers provide consistent estimates of amyloid onset age for adults with Down syndrome. Multicentre studies of Alzheimer's disease therapeutics can utilize multiple amyloid PET radiotracers to facilitate recruitment; however, these radiotracers have different sensitivity to detect longitudinal change.}, } @article {pmid41180843, year = {2025}, author = {Ceccarelli, MC and Lai, L and Carmignani, A and Battaglini, M and Ciofani, G}, title = {Polydopamine nanoparticles as immunomodulators: inhibition of M1 microglial polarization.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {13}, number = {}, pages = {1672520}, pmid = {41180843}, issn = {2296-4185}, abstract = {Neuroinflammation is a central feature of numerous neurodegenerative diseases, including Alzheimer's and Parkinson's disease, where excessive activation of microglia can contribute to neuronal damage. The pro-inflammatory M1 phenotype of microglia is characterized by increased production of reactive oxygen species (ROS), overexpression of surface markers such as CD40 and CD86, and secretion of cytokines like IL-6, IL-8, and TNF-α, all of which exacerbate oxidative stress and neurodegeneration. The development of strategies to control and tune microglial pro-inflammatory activation is therefore critical for reducing the progression of these conditions. In this study, the potential of polydopamine nanoparticles (PDNPs) as novel immunomodulatory agents for attenuating M1 microglial polarization was investigated. PDNPs were synthesized via a simple and reproducible protocol and thoroughly characterized in terms of size, morphology, hydrodynamic diameter, and surface charge, confirming their uniformity and stability. Biocompatibility assays showed that PDNPs are well tolerated by human microglial clone 3 (HMC3) cells, with minimal cytotoxicity even at relatively high concentrations. Confocal microscopy and flow cytometry analyses demonstrated efficient internalization of PDNPs by microglia, with preferential accumulation in lysosomal compartments and negligible mitochondrial localization. To mimic neuroinflammatory conditions, HMC3 cells were stimulated with interferon-gamma (IFN-γ), which significantly increased intracellular ROS levels, surface expression of CD40 and CD86, and secretion of pro-inflammatory cytokines. The co-treatment with PDNPs effectively mitigated these effects by reducing oxidative stress, suppressing the upregulation of M1 markers, and decreasing cytokine release, thereby preventing the shift toward a pro-inflammatory state. The results of this work demonstrate that PDNPs not only exhibit excellent biocompatibility and cellular uptake but also provide a robust means of counteracting IFN-induced microglial activation. These results establish PDNPs as promising nanoplatforms for modulating neuroinflammation and microglial activation. This study highlights the potential of PDNPs for future applications in the treatment of neurodegenerative diseases.}, } @article {pmid41179212, year = {2025}, author = {Yuan, C and Lv, S and Han, Y and Li, Y and Xian, Z and Liu, G and Xiao, S}, title = {Quercetagitrin Ameliorates Alzheimer-Like Pathologies Associated with TNFα/NFκB Pathway in APP/PS1 Mice.}, journal = {ACS omega}, volume = {10}, number = {42}, pages = {49816-49827}, pmid = {41179212}, issn = {2470-1343}, abstract = {Background: Alzheimer's disease (AD) is a neurodegenerative disease with two pathological features in the brain: amyloid β (Aβ) plaques and tau tangles. Neuroinflammation plays an important role in the development of AD, closely related to both Aβ and tau pathologies. Tumor necrosis factor α (TNFα) and nuclear factor-κB (NFκB) behave as key regulators of neuroinflammation in AD. It is pressing to develop effective AD drugs. Objective: This study aimed to explore the effects and mechanisms of quercetagitrin in AD using a combination of network pharmacology analyses and in vivo experiments. Methods: The potential target of quercetagitrin in AD was predicted by network pharmacology. The interaction between the compound and the target protein was measured by molecular docking. The in vivo effects were performed in APP/PS1 mice via mouse behavior tests, Western blotting, ThS staining, immunohistochemical staining, and immunofluorescence staining. Results: First, network pharmacology analyses were conducted to predict the primary target of the compound, which is TNFα. Then, molecular docking showed that quercetagitrin interacts with TNFα with a high affinity. Finally, the level of TNFα was reduced, and the activation of NFκB signaling was inhibited by quercetagitrin in APP/PS1 mice. Meanwhile, quercetagitrin treatment ameliorated Aβ pathology, cognitive impairments, and neuroinflammation in the AD mice. Conclusions: These findings demonstrate quercetagitrin as a potential therapeutic drug for AD.}, } @article {pmid41179172, year = {2025}, author = {da Silva, LRG and de Sá, CB and do Amaral, BS and Romeiro, NC and Cass, QB and Valverde, AL}, title = {Affinity Selection-Mass Spectrometry for the Identification of Ligands of Acetylcholinesterase from Topsentia ophiraphidites and Docking Studies for the Dereplicated Ligands.}, journal = {ACS omega}, volume = {10}, number = {42}, pages = {50275-50284}, pmid = {41179172}, issn = {2470-1343}, abstract = {Acetylcholinesterase (AChE) inhibition has been successful for the treatment of Alzheimer's disease and still stands as an important target in the search for novel ligands. In this context, affinity selection-mass spectrometry (AS-MS) has been acknowledged as a high-throughput screening (HTS) technique for large molecular libraries in drug discovery programs and natural product investigations. In this work, an AS-MS assay with AChE immobilized onto magnetic beads (AChE-MB) has been used to search for ligands in samples of the sponge Topsentia ophiraphidites collected in the archipelago of Fernando de Noronha, Brazil. Ligand dereplication disclosed 6-desmethyl-6-ethyl-9,10-dihydrospongosoritin A, 3,5-dibromo-O-methyltyrosine, 3-bromo-5-iodo-O-methyltyrosine, and 3,5-di-iodo-O-methyltyrosine as AChE ligands, which showed affinity ratios of 1.84, 1.34, 1.26, and 1.20, respectively, in the AS-MS assay. As a complementary approach, molecular docking analysis with human AChE has been carried out for the disclosed dereplicated ligands, in which the (R, R) stereoisomer of 6-desmethyl-6-ethyl-9,10-dihydrospongosoritin A stood out, performing important intermolecular interactions with the active sites of AChE, especially with the peripheral anionic site, at the entrance of the gorge. The results stimulate further investigations of these ligands in other pharmacological assays in order to better understand their mechanisms of action.}, } @article {pmid41178976, year = {2025}, author = {Bae, HJ and Kim, SI and Kim, SY and Cho, YE and Sung, S and Lim, S and Cho, K and Park, SJ and Lim, S}, title = {Lacticaseibacillus rhamnosus CBT LR5 with skim milk alleviates scopolamine-induced cognitive impairment in mice.}, journal = {Frontiers in microbiology}, volume = {16}, number = {}, pages = {1672153}, pmid = {41178976}, issn = {1664-302X}, abstract = {INTRODUCTION: Emerging evidence highlights the gut-brain axis as a pivotal pathway linking gastrointestinal health with cognitive function, particularly in neurodegenerative conditions such as Alzheimer's disease (AD).

METHODS: This study investigated the cognitive-enhancing effects of the probiotic strain Lacticaseibacillus rhamnosus CBT LR5 (LR5), alone or in combination with skim milk, in a mouse model of scopolamine-induced cognitive impairment. The cognitive functions were evaluated using the novel object recognition test (NOR) and the passive avoidance test (PAT).

RESULTS: The results demonstrated that the oral administration of LR5, especially when combined with skim milk, significantly ameliorated scopolamine-induced cognitive deficits. Mechanistically, treatment with LR5 combined with skim milk restored the diversity and composition of the gut microbiota increased the abundance of beneficial genera, such as Muribaculaceae and enhanced intestinal barrier integrity by increasing the expression of tight junction proteins, including claudin-1, occludin, and zonula occludens-1. Additionally, this combination reduced systemic inflammation by lowering serum TNF-α and PGE2 levels and promoted increased expression of BDNF by activating the CREB-BDNF-TrkB signaling pathway in hippocampal and cortical tissues. Furthermore, correlation analyses revealed significant associations between specific gut bacterial genera, such as Lacticaseibacillus, Turicibacter, Cryptobacteroides, Ruminococcus, and Muribaculaceae, and cognitive or inflammatory biomarkers.

DISCUSSION: Collectively, these findings suggest that the synergistic effects of L. rhamnosus CBT LR5 combined with skim milk may represent an effective dietary intervention for cognitive enhancement, potentially through gut microbiota modulation, improved barrier integrity, reduced inflammation, and enhanced neurotrophic signaling.}, } @article {pmid41178777, year = {2025}, author = {Yigitturk, G and Cavusoglu, T}, title = {A Review of The Place of Adipose-Derived Stem Cells among Stem Cell Applications in Neurodegenerative Diseases.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266363649250620113954}, pmid = {41178777}, issn = {1873-4294}, abstract = {Treatment of neurodegenerative diseases aims to slow disease progression, alleviate symptoms, and improve life quality. Adipose-Derived Stem Cells (ADSCs) have emerged as a promising treatment for neurodegenerative diseases that can be easily obtained from adipose tissues. Their abundance, accessibility, and potential for multilinear differentiation make them an attractive candidate for regenerative medicine. ADSCs can release neurotrophic factors, modulate neuroinflammation, and potentially differentiate into neurons, giving hope for neuronal repair and replacement. Preclinical studies have shown the efficacy of several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and spinal cord injuries. ADSC has demonstrated the potential to improve functional results, promote neurogenesis, induce tissue integrity, and reduce neuron loss. Clinical trials are still underway, but evidence of the effectiveness of ADSC in neurodegeneration is still being developed. The first clinical studies focused on safety and feasibility and achieved promising results. Optimizing cell transmission, controlling tumor growth, standardizing treatment protocols and such challenges remain. Current research is aimed at addressing these obstacles and transforming ADSC therapy into a widespread clinical practice. This review focuses on the characteristics, problems, and future approaches of ADSC in the context of neurodegenerative diseases and therapeutic processes.}, } @article {pmid41178581, year = {2026}, author = {Şen, İ and Yeşildal, TK and Abdulqadir, AH and Yaman, İ and Tosun, SN and Zengin, G and Cakmak, YS}, title = {Comprehensive evaluation of Onosma rostellatum: antioxidant, enzyme inhibitory and anticancer properties of root and leaf extracts.}, journal = {Journal of the science of food and agriculture}, volume = {106}, number = {3}, pages = {1662-1673}, doi = {10.1002/jsfa.70284}, pmid = {41178581}, issn = {1097-0010}, support = {//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; }, mesh = {*Plant Extracts/chemistry/pharmacology/isolation & purification ; *Antioxidants/chemistry/pharmacology/isolation & purification ; Plant Leaves/chemistry ; Humans ; Plant Roots/chemistry ; *Enzyme Inhibitors/chemistry/pharmacology ; alpha-Amylases/antagonists & inhibitors/chemistry ; *Antineoplastic Agents, Phytogenic/chemistry/pharmacology ; Phenols/chemistry ; Cell Line, Tumor ; alpha-Glucosidases/chemistry ; *Bignoniaceae/chemistry ; }, abstract = {BACKGROUND: The incidence and mortality of diseases such as cancer, Alzheimer's, and diabetes have increased in recent years. Along with limited treatment success, severe side effects of synthetic drugs are a major concern. Therefore, natural bioactive compounds are gaining attention as alternative therapeutic agents due to their efficacy and lower toxicity. This study investigated the protective and therapeutic potential of extracts of different parts of Onosma rostellatum, a plant used in traditional medicine, in terms of their antioxidant, enzyme inhibitory and anticancer activities.

RESULTS: Antioxidant, enzyme inhibition, anticancer activities and phenolic composition of the extracts were evaluated. Methanol leaf extract showed the strongest activity in antioxidant assays, with the highest 2,2-diphenyl-1-picrylhydrazyl (46.59 ± 0.03 g Trolox equivalents (TE) kg[-1]) and ferric reducing antioxidant power (90.74 ± 0.59 g TE kg[-1]) activities, while the root methanol extract exhibited the strongest 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical scavenging activity (453.86 ± 2.20 g TE kg[-1]) and the highest cupric reducing antioxidant capacity value (243.64 ± 0.49 g TE kg[-1]). The aqueous leaf extract demonstrated superior metal-chelating ability (32.59 ± 0.13 g ethylenediaminetetraacetic acid kg[-1]). Leaf extracts displayed the highest copper ion reducing capacity (94.64 ± 0.23 g TE kg[-1]). Ethyl acetate leaf extracts showed the most significant inhibition against α-amylase and α-glucosidase. High-performance liquid chromatographic analysis revealed rosmarinic acid and quercetin as major phenolic constituents. In cell culture experiments, the ethyl acetate leaf extract demonstrated the most potent anticancer effect, with an IC50 value of 167.2 ± 0.32 μg mL[-1] after 72 h.

CONCLUSION: Onosma rostellatum extracts possess strong antioxidant, enzyme inhibitory and anticancer activities, largely associated with their phenolic components. These findings highlight the potential of this plant as a natural source of therapeutic agents. © 2025 Society of Chemical Industry.}, } @article {pmid41178110, year = {2025}, author = {Polk, S and Rassaeikashuk, M and Thilagavathi, R and Selvam, C}, title = {Targeting Poly (ADP-Ribose) Polymerase-1 for the Treatment of Neurodegenerative Diseases.}, journal = {Chemical biology & drug design}, volume = {106}, number = {5}, pages = {e70189}, doi = {10.1111/cbdd.70189}, pmid = {41178110}, issn = {1747-0285}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology/enzymology ; *Poly (ADP-Ribose) Polymerase-1/metabolism/antagonists & inhibitors ; alpha-Synuclein/metabolism ; Animals ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/chemistry/pharmacology ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Poly (ADP-ribose) Polymerase 1 (PARP1) has many functions that intertwine with the pathology of many diseases. Because of PARP1's function in DNA repair and cell death, neurodegeneration research is another pathology that PARP1 included. By PARylation, PARP1 acts as a direct and indirect modulator of amyloid β, α-Synuclein (α-syn), tau protein, and other proteins indicated in neurodegenerative diseases. PARylation influences the function, activation, and localization of these proteins. This review paper overviews neurodegeneration and the significant diseases resulting from neurodegeneration and compiles mechanisms and functions Poly (ADP-ribose) Polymerase-1 has in neurodegenerative diseases.}, } @article {pmid41177743, year = {2025}, author = {Pereira da Silva, AM and de Deus, O and Ribeiro, FV and Tudella, GCN and Cabeça, LS and Silva, LL and Han, ML and Franco, JO and Costa, JGP and Santos do Nascimento, MDV and Andrade Fernandes, JV and Franco, ES and de Sousa Maia, MB}, title = {Efficacy and Safety of Lithium for Behavioral and Cognitive Symptoms in Alzheimer's Disease Dementia: A Systematic Review With Frequentist and Bayesian Meta-Analysis.}, journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jagp.2025.10.001}, pmid = {41177743}, issn = {1545-7214}, abstract = {BACKGROUND: Alzheimer's disease (AD) dementia is the leading cause of cognitive decline in late life, yet treatment options remain limited. Lithium, widely used in bipolar disorder, has been suggested to exert neuroprotective effects through inhibition of GSK-3β and modulation of amyloid and tau pathology. We aimed to evaluate the efficacy and safety of lithium in AD dementia.

METHODS: This systematic review and meta-analysis was prospectively registered in PROSPERO and conducted following PRISMA guidelines. We searched PubMed, Embase, and Cochrane Library through April 2025 for randomized controlled trials (RCTs) comparing lithium with placebo or standard therapy in patients with AD dementia or amnestic mild cognitive impairment. Outcomes included cognition (MMSE, ADAS-Cog, memory tasks), function (CDR-SB, conversion to AD), neuropsychiatric symptoms (NPI), CSF biomarkers, and safety (adverse events [AEs], serious AEs [SAEs]). Random-effects meta-analyses were complemented by Bayesian methods and trial sequential analyses.

RESULTS: Six RCTs involving 394 participants (196 lithium, 198 placebo) met inclusion criteria. Lithium did not significantly improve global cognition (MMSE: MD -1.61, 95% CI -4.11 to 0.88; ADAS-Cog: MD -1.82, -3.05 to -0.60; both with high heterogeneity). Memory outcomes were mixed, with possible benefit for figure recall but not delayed verbal recall. No consistent benefits were observed for episodic memory, functional outcomes (CDR-SB), neuropsychiatric symptoms, or CSF biomarkers. Safety analyses showed no increased risk of SAEs; drug-related AEs were more frequent but heterogeneous across trials.

CONCLUSIONS: Lithium demonstrated an acceptable safety profile within the dosing regimens studied. However, current evidence does not support consistent cognitive or functional benefits in AD dementia. Larger, well-designed RCTs are warranted to clarify its potential therapeutic role.}, } @article {pmid41177416, year = {2025}, author = {Bashir, B and Gulati, M and Vishwas, S and Hussain, MS and Gupta, G and Kumar, P and Negi, P and Mittal, N and Dua, K and Singh, SK}, title = {Bridging the gap in the management of Alzheimer's disease using fecal microbiota transplantation.}, journal = {Molecular and cellular neurosciences}, volume = {135}, number = {}, pages = {104052}, doi = {10.1016/j.mcn.2025.104052}, pmid = {41177416}, issn = {1095-9327}, mesh = {Humans ; *Alzheimer Disease/therapy/microbiology ; *Fecal Microbiota Transplantation/methods ; *Gastrointestinal Microbiome ; Animals ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that greatly impairs the health status of human beings and creates significant burdens on individuals, families, and society. AD is characterized by the buildup of pathological proteins and glial cell dysregulated activity. Additional hallmark features include oxidative stress, neuroinflammation, impaired autophagy, cellular senescence, mitochondrial dysfunction, epigenetic alterations, reduced neurogenesis, increased blood-brain barrier permeability, and age-inappropriate intestinal dysbiosis. There is significant evidence that shows that microbiota in the gut affects the development and progression of AD. As a result, gut microbiota modulation has been identified as a new method of clinical management of AD, and more and more efforts have been devoted to identifying new methodologies for its prevention and treatment. This paper will discuss the role of gut microbiome in the etiopathogenesis of AD and consider the possibilities of fecal microbiota extract (FME) supplementation, commonly referred to as fecal microbiota transplantation (FMT). It is both a prophylactic and curative approach. The FMT therapy is grounded on the premise that anti-inflammatory effects, modifications of amyloid β, improved synaptic plasticity, short-chain fatty acids, and histone acetylation are the principles behind the enhancement of AD. The current review will present an overview of the linkage between FMT and AD as well. It further examines and evaluates the effects of FMT on aging-based mechanisms that support the development of AD. It also provides a broad description of the recent clinical and preclinical evidence on the application of FMT to AD.}, } @article {pmid41177383, year = {2025}, author = {Gu, T and Ma, S and Liu, W and Wang, L}, title = {Pregnane X receptor activation regulate amyloid transport to improve cognition functions in Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1007}, number = {}, pages = {178310}, doi = {10.1016/j.ejphar.2025.178310}, pmid = {41177383}, issn = {1879-0712}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/physiopathology/pathology/psychology ; *Pregnane X Receptor/agonists/metabolism ; Humans ; *Amyloid beta-Peptides/metabolism ; Mice ; *Cognition/drug effects ; Male ; Endothelial Cells/metabolism/drug effects ; Mice, Inbred C57BL ; Brain/metabolism/drug effects/blood supply ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; *Peptide Fragments/metabolism ; Cerebrovascular Circulation/drug effects ; ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Disease Models, Animal ; }, abstract = {OBJECTIVES: To explore the concept about nuclear receptor pregnane X receptor (PXR) activation could be beneficial for the Alzheimer's disease (AD) treatment, as well as the underlying mechanism.

METHODS: For in vitro experiments, human brain microvascular endothelial cells (hCMEC/D3) were exposed to Aβ42 and hyperforin (HPF), a human PXR agonist followed by measurement of P-glycoprotein(P-gp)and low-density lipoprotein receptor-related protein 1 (LRP1) expression. Further, 7 months old 5 × FAD mice were used for in vivo experiments. Due to the species-difference characteristics of PXR, these mice were treated with pregnenolone carbonitrile (PCN, a rodent PXR agonist) rather than hPXR agonist, or corn oil for 28 days. Meanwhile, untreated C57BL/6 mice were used as the control group. The improvements of animal behavior were evaluated by Morris water maze and novel arm exploration test. The pathological profiles were assessed by immunohistochemistry and transmission electron microscopy. The cerebral blood flow (CBF) and Aβ transporters were analyzed by speckle contrast imaging and Western blot respectively.

RESULTS: In vitro experiments showed that the P-gp and LRP1 levels in hCMEC/D3 were reduced due to exposure of Aβ42, while HPF can restore their expression levels. 5 × FAD mice treated with the PCN improved cognitive functions and cerebral blood flow. These functional improvements were associated with a reduction in amyloid plaques, cerebral amyloid angiopathy, neuroinflammation and a recovery of blood-brain barrier transport function. The underlying mechanisms could be that PXR activation up-regulates the expression of P-gp and LRP1 and inhibits inflammation via STAT3, and increases the clearance of Aβ42 in the brain.

CONCLUSIONS: These results demonstrate the beneficial impact of PXR activation on cognitive functions, parenchymal amyloid plagues and cerebral angiopathy, and highlights the therapeutic potential of PXR agonists for treatment of AD patients.}, } @article {pmid41176545, year = {2025}, author = {El Hajj, W and Pujo-Menjouet, L and Tine, LM and Volpert, V}, title = {Modelling of anti-inflammatory treatment in the Alzheimer disease: optimal regimen and outcome.}, journal = {Bulletin of mathematical biology}, volume = {87}, number = {12}, pages = {171}, pmid = {41176545}, issn = {1522-9602}, support = {Project-ANR-21-CE15-0011//PrionDiff/ ; }, mesh = {*Alzheimer Disease/drug therapy/immunology ; Humans ; *Anti-Inflammatory Agents, Non-Steroidal/administration & dosage/therapeutic use ; Mathematical Concepts ; Cytokines/metabolism ; *Models, Biological ; Treatment Outcome ; Computer Simulation ; Microglia/drug effects ; Disease Progression ; Inflammation Mediators/metabolism/antagonists & inhibitors ; }, abstract = {The application of non-steroidal anti-inflammatory drugs (NSAIDs) for Alzheimer's disease is considered to be a promising therapeutic approach. Epidemiological studies suggest potential benefits of NSAIDs; however, these findings are not consistently supported by clinical trials. This long-standing discrepancy has persisted for decades and remains a significant barrier to developing effective treatment strategies. To assess the efficacy of NSAIDs in Alzheimer's disease, we have developed a mathematical model based on a system of ordinary differential equations. The model captures the dynamics of key players in disease progression, including A β -monomers, oligomers, pro-inflammatory mediators (M1 microglial cells and pro-inflammatory cytokines), and anti-inflammatory mediators (M2 microglial cells and anti-inflammatory cytokines). The effects of NSAIDs are modeled through a reduction in the production rate of inflammatory cytokines (IC). While a single NSAID administration temporarily reduces IC levels, their concentration eventually returns to baseline due to drug elimination. The return time depends on the drug dose, resulting in a patient-specific return time function. By analyzing this function, we propose an optimal treatment regimen and identify conditions under which NSAID treatment is most effective in reducing IC levels. Our results suggest that NSAID efficacy in Alzheimer's disease is influenced by the stage of the disease (with earlier intervention being more effective), patient-specific parameters, and the treatment regimen. The approach developed here can also be generalized to evaluate the efficacy of anti-inflammatory treatments for other diseases.}, } @article {pmid41175945, year = {2025}, author = {Fujii, K and Takeuchi, T and Fujino, Y and Tanaka, N and Fujino, N and Takeda, A and Minakawa, EN and Nagai, Y}, title = {Oral administration of arginine suppresses Aβ pathology in animal models of Alzheimer's disease.}, journal = {Neurochemistry international}, volume = {191}, number = {}, pages = {106082}, doi = {10.1016/j.neuint.2025.106082}, pmid = {41175945}, issn = {1872-9754}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism/genetics ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors/genetics ; Administration, Oral ; *Arginine/administration & dosage ; Mice ; Disease Models, Animal ; Mice, Transgenic ; Humans ; *Peptide Fragments/metabolism/antagonists & inhibitors ; Mice, Inbred C57BL ; Dose-Response Relationship, Drug ; Male ; }, abstract = {Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain. In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an App[NL-G-F] knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated App[NL-G-F] knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes. These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.}, } @article {pmid41175916, year = {2025}, author = {Vanya, and Kumari, S and Bagri, K and Deshmukh, R}, title = {Tangles and Plaques: A deep dive into the pathological hallmarks of Alzheimer's disease.}, journal = {Neuroscience}, volume = {590}, number = {}, pages = {170-185}, doi = {10.1016/j.neuroscience.2025.10.050}, pmid = {41175916}, issn = {1873-7544}, mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/genetics ; *Plaque, Amyloid/pathology/metabolism ; Animals ; *Neurofibrillary Tangles/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Brain/pathology/metabolism ; Blood-Brain Barrier/pathology/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. In AD, there is a gradual impairment of memory and cognitive function that interferes with daily living. The pathophysiology of AD revolves around complex interactions between amyloid-β (Aβ) overproduction and accumulation, followed by tau hyperphosphorylation, which together promote a cascade of neuronal dysfunction and degeneration. AD has two forms, sporadic and familial, with genetic variants such as triggering receptor expressed on myeloid cells-2 (TREM2). Various other variants also lead to impaired amyloid clearance and altered immune responses. Along with these genetic factors, aging remains the primary risk factor, and environmental as well as lifestyle factors can act synergistically to accelerate disease onset and progression. Although significant advances have been made in the last five decades, there has been only limited progress in the treatment because of a poor understanding of the molecular basis of AD. This makes current treatments largely focus on symptomatic management. This narrative review provides an updated synthesis of Alzheimer's disease pathophysiology, focusing on Aβ and tau pathology, glial activation, neuroinflammatory cascades, disrupted neurogenesis, and blood-brain barrier dysfunction. A focus and deeper understanding can help to develop new strategies that might work beyond the present conventional treatment. Due to the increasing global prevalence of AD, it is important to continue research into these mechanisms for the development of more effective interventions and improved patient outcomes.}, } @article {pmid41175892, year = {2025}, author = {Prajapati, P and Desai, A and Shah, P and Pulusu, V and Haque, A and Kalam, MA and Shah, S}, title = {Comparative in-vivo and in-vitro characterization of Donepezil loaded Lactoferrin linked PEG coated and uncoated nanocarriers as intranasal drug delivery system.}, journal = {Journal of liposome research}, volume = {35}, number = {4}, pages = {619-635}, doi = {10.1080/08982104.2025.2573681}, pmid = {41175892}, issn = {1532-2394}, mesh = {*Lactoferrin/chemistry ; *Donepezil/administration & dosage/chemistry/pharmacokinetics ; Animals ; Administration, Intranasal ; *Polyethylene Glycols/chemistry ; Rats ; *Drug Carriers/chemistry ; *Nanoparticles/chemistry ; Male ; *Drug Delivery Systems ; Alzheimer Disease/drug therapy ; Micelles ; Molecular Docking Simulation ; Particle Size ; }, abstract = {Alzheimer's disease treatment faces challenges with conventional oral formulations of donepezil (DNP). This study aims to develop and characterize DNP-loaded Lactoferrin (LCF)-linked PEG-coated nano-carriers for intranasal delivery. The formulation was developed using a Quality by Design (QbD) approach integrated with molecular docking. A novel micelle-enhanced spectrofluorimetric method was developed and validated for in-vitro and in-vivo characterization of the nano-carriers. The method was optimized using Analytical Quality by Design (AQbD) principles. In-vivo pharmacokinetic and bio-distribution studies were conducted in rats to compare the developed formulation with uncoated NLCs and conventional dosage forms. The LCF-PEG-coated NLCs showed improved brain targeting efficiency compared to uncoated NLCs and conventional formulations. The spectrofluorimetric method demonstrated high sensitivity and reliability for both in-vitro and in-vivo analyses. The developed DNP-loaded LCF-PEG-coated NLCs show promise as an effective intranasal delivery system for Alzheimer's disease treatment. The novel spectrofluorimetric method offers a sustainable and efficient alternative to conventional LC-MS/MS techniques for characterizing DNP formulations.}, } @article {pmid41175671, year = {2025}, author = {Träuble, J and Hiscox, LV and Johnson, CL and Aviles-Rivero, A and Schönlieb, CB and Kaminski Schierle, GS}, title = {Brain age prediction and early neurodegeneration detection using contrastive learning on brain biomechanics: a retrospective, multicentre study.}, journal = {EBioMedicine}, volume = {121}, number = {}, pages = {105996}, pmid = {41175671}, issn = {2352-3964}, mesh = {Humans ; *Brain/diagnostic imaging/pathology/physiopathology ; Middle Aged ; Male ; Female ; Aged ; Adult ; Magnetic Resonance Imaging ; Aged, 80 and over ; Adolescent ; *Neurodegenerative Diseases/diagnosis/diagnostic imaging ; Young Adult ; Retrospective Studies ; Biomechanical Phenomena ; Cognitive Dysfunction/diagnostic imaging ; Elasticity Imaging Techniques/methods ; *Aging ; Alzheimer Disease/diagnostic imaging/diagnosis ; }, abstract = {BACKGROUND: One of the main reasons why drugs for neurodegenerative diseases often fail is that treatment typically begins only after symptoms have appeared-by which point significant, and possibly irreversible, damage may have already occurred. Non-invasive imaging techniques, such as Magnetic Resonance Imaging (MRI), have previously been explored for presymptomatic diagnosis, but with limited success. More recently, Magnetic Resonance Elastography (MRE)-a technique capable of mapping the brain's biomechanical properties, including stiffness and damping ratio-has shown promise in detecting early changes. However, current studies have been limited by small sample sizes, and a lack of robust algorithms capable of accurately interpreting data under such constraints.

METHODS: We developed a self-supervised contrastive regression framework trained on 3D MRE-derived stiffness and damping ratio maps from 311 healthy individuals (aged 14-90) and evaluated its performance against structural 3D T1-weighted MRI. Brain age predictions were used to compute brain age gaps (BAGs), quantifying deviations from normative ageing trajectories. We applied the models to Alzheimer's disease (AD, n = 11) and mild cognitive impairment (MCI, n = 20) cohorts, and analysed whole-brain and region-specific predictions using occlusion-based saliency maps and subcortical segmentation.

FINDINGS: Self-supervised models using MRE achieved a mean absolute error (MAE) of 3.51 years in brain age prediction-significantly outperforming MRI (MAE: 4.79 years, p < 0.05) under matched conditions. The greater age sensitivity of MRE translated into improved differentiation of Alzheimer's disease (AD) and mild cognitive impairment (MCI) from healthy individuals. Stiffness was the dominant ageing biomarker in AD (BAG increase: +9.2 years, p < 0.05), whereas damping ratio revealed early MCI-related changes (BAG increase: +6.3 years, p < 0.05). Region-wise analysis identified the caudate (stiffness) and thalamus (damping ratio) as key markers for AD and MCI, respectively. Notably, some cognitively normal individuals exhibited biomechanical profiles resembling patients with MCI or AD, suggesting that these individuals may share some biomechanical characteristics with clinical populations.

INTERPRETATION: In our controlled experimental setting, MRE combined with contrastive learning provides a sensitive, non-invasive biomarker of brain ageing and neurodegeneration, outperforming MRI and differentiating disease stage-specific biomechanical signatures. Regional BAG profiling may have the potential to identify at-risk, cognitively normal individuals, which could facilitate timely intervention trials in the future, pending longitudinal validation.

FUNDING: Gates Cambridge Trust; Cambridge Centre for Data-Driven Discovery (Schmidt Sciences); Wellcome Trust; NIH (R01-AG058853, U01-NS112120); UK EPSRC; UK MRC; Alzheimer's Research UK; Michael J. Fox Foundation; Infinitus China Ltd.}, } @article {pmid41175292, year = {2025}, author = {Pennington, B and Davis, S and Cranmer, H}, title = {Caring for and Caring about in Economic Evaluation: Modelling the Family and Caregiving Effects.}, journal = {PharmacoEconomics}, volume = {}, number = {}, pages = {}, pmid = {41175292}, issn = {1179-2027}, support = {NIHR300160//NIHR/ ; }, abstract = {Current methods for modelling spillover effects on carers in economic evaluation include four main methods: (absolute) utilities, disutilities, increments and multipliers. Each of these approaches assumes that the spillover effect is one-dimensional. We aimed to develop a new approach that better reflects the complexity of caring and the nuances of how a new treatment may impact the caregiver. We propose a new method based on the established concepts of the 'family effect' (or caring about someone) and the 'caregiving effect' (providing care for someone). These effects can be disentangled through analysis of carer-patient dyads or using patient and carer (dis)utilities and estimates from the literature. We consider case studies in Duchenne Muscular Dystrophy, Spinal Muscular Atrophy and Alzheimer's Disease. Our approach models a small carer health-related quality of life (HRQoL) gain for each intervention, whereas the utility approach consistently models a substantial carer HRQoL gain, and the disutility approach models a carer HRQoL loss in two case studies. Our method allows explicit consideration of the benefits to carers of extending patient survival or improving patient health, with the negative HRQoL impact of increased caregiving burden. We propose that our method can be used with published data at present, and further research should analyse the family and caregiving effects in different conditions.}, } @article {pmid41174898, year = {2025}, author = {Wang, C and Guo, R and Wang, X and Li, H and Zhong, T}, title = {Post-Translational Modifications of Tubulin in Oocyte Maturation and Female Infertility.}, journal = {Cytoskeleton (Hoboken, N.J.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/cm.70062}, pmid = {41174898}, issn = {1949-3592}, support = {82101864//National Natural Science Foundation of China/ ; ZR2025MS508//Natural Science Foundation of Shandong Province/ ; 2023KJ262//Shandong Provincial Youth Innovation Technology Support Program/ ; 2023YXNS228//Key R&D Plan of Jining City/ ; 2023-1-43//Ji'nan Municipal Health Commission Science and Technology Plan Project/ ; 202412//High-Level Talents in the Medical and Health Industry in Ji'nan/ ; }, abstract = {Microtubules are critical components of the cytoskeleton that are extensively involved in various cellular and biological processes. The execution of these functions is intricately linked to post-translational modifications of tubulin. Post-translational modifications of tubulin include acetylation, tyrosination, de-tyrosination, glutamylation, SUMOylation, and so on. These modifications are closely associated with a wide range of biological processes. Accumulating evidence indicates that aberrant microtubule modifications are implicated in various diseases, including cancer, Alzheimer's disease, neurodevelopmental disorders, cardiac atrial hypertrophy, and even infertility. Aneuploid oocytes are a common cause of infertility, spontaneous abortion, trisomy syndrome, and other congenital abnormalities. The occurrence of aneuploidy is often closely associated with defects in spindle assembly, which are influenced by a series of tubulin modifications. In this review, we aimed to summarize the factors that affect tubulin modification and explore the key mechanisms underlying aneuploidy in human oocytes, thereby providing new insights and strategies for the treatment of infertility and prevention of congenital defects in newborns.}, } @article {pmid41174000, year = {2025}, author = {Zhao, Q and Gou, C and Luo, G and Dai, S and Wang, D and Zhang, S and Wang, F and Xu, H and Han, Y and Wang, S}, title = {Combined multi-omics and brain pathology reveal novel biomarkers for alzheimer's disease.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {38239}, pmid = {41174000}, issn = {2045-2322}, support = {81260199, 81660228, and 82160261//National Natural Science Foundation of China/ ; L-2019019//Yunnan Province Talent Training Program/ ; RLMY20200005//Yunnan High-Level Talent Training Support Program Famous Doctor Special Project/ ; 202303AC100026//Yunnan Province Key Research and Development Program/ ; 202401AY070001-008//Kunming Medical University Joint Special Key Project/ ; }, mesh = {*Alzheimer Disease/pathology/metabolism/genetics ; Animals ; *Biomarkers/metabolism ; Mice ; Proteomics/methods ; Protein Interaction Maps ; *Hippocampus/metabolism/pathology ; Transcriptome ; Gene Expression Profiling ; *Brain/pathology/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics/metabolism ; Multiomics ; }, abstract = {Alzheimer's disease (AD) is a complex disorder with significant genetic contributions, yet only a limited number of risk loci have been conclusively identified. This research aimed to discover novel potential biomarkers for AD through multi-omics and brain pathology analysis. In this study, we investigated hippocampal molecular alterations in APP/PS1 mouse using transcriptomics and data-independent acquisition (DIA) proteomics. To further validate the involvement of differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in AD pathology and potential drug treatment, we performed an integrative analysis incorporating pathological data and protein-protein interaction networks. We identified 263 DEGs and 448 DEPs. Integrative transcriptomic and proteomic analyses revealed five co-upregulated DEGs/DEPs and one co-downregulated DEG/DEP. Comparison of KEGG pathway enrichment between the two datasets showed significant involvement in the complement and coagulation cascade, as well as neurodegeneration-multiple diseases. Furthermore, mRNA levels of LY86, CD180, and C1QB were strongly associated with amyloid-β plaque load in the AD mouse hippocampus. Protein-protein interaction analysis suggested that APP, LY86, CD180, and C1QB could serve as potential therapeutic targets for AD. The study identified three novel AD loci (EGFL8, ERMN, and CD180), with CD180 showing association with AD at both the expression and pathological levels, highlighting their potential roles in disease progression and therapeutic intervention.}, } @article {pmid41173323, year = {2025}, author = {Morrow, CB and Sah, E and Onyike, CU}, title = {Examining neuropsychiatric symptoms and functional decline in behavioral variant frontotemporal dementia.}, journal = {International review of psychiatry (Abingdon, England)}, volume = {37}, number = {8}, pages = {772-780}, pmid = {41173323}, issn = {1369-1627}, support = {P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; K23 AG088248/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; L30 AG083912/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Frontotemporal Dementia/physiopathology/complications ; Aged ; Middle Aged ; Apathy ; *Behavioral Symptoms/physiopathology/etiology ; }, abstract = {AIM: Neuropsychiatric symptoms (NPS) are core features of behavioral variant frontotemporal dementia (bvFTD), but their association with functional decline is incompletely understood.

METHODS: Participants (N = 219) were individuals enrolled in Alzheimer's Disease Research Centers between 2005 and 2024 with early-stage bvFTD (CDR ≤ 0.5). Functional status was coded as a binary variable based on the Functional Activities Questionnaire. Behavioral data were derived from the Neuropsychiatric Inventory Questionnaire and Clinician Judgement of Symptoms. Descriptive statistics and Cox proportional hazard analyses were used to characterize functional impairments and their association with NPS.

RESULTS: Impairments in transactions (47%) and verbal communication (44%) were common at baseline, while impairments in self-care and incontinence (<10%) were rare. Apathy (65%), disinhibition (55%), depression, anxiety, irritability, and agitation were common at baseline (>40%). Psychosis was rare at baseline (<10%). By visit 4, impairments in transactions (81%), meal-preparation (65%), self-care (55%) and verbal communication (61%) were common. Emergence of apathy, disinhibition, depression, anxiety, and irritability were associated with an increased hazard of impairments in ambulation, meal preparation, self-care, and transactions.

CONCLUSION: NPS in bvFTD are frequent, occur early, and are associated with functional decline. Timely recognition and treatment of NPS may mitigate their impact on function.}, } @article {pmid41173224, year = {2026}, author = {Zheng, M and Zhang, Q and Siebert, HC and Loers, G and Wen, M and Wang, Q and Zhang, R and Han, J and Zhang, N}, title = {Semaglutide attenuates Alzheimer's disease model progression by targeting microglial NLRP3 inflammasome-mediated neuroinflammation and ferroptosis.}, journal = {Experimental neurology}, volume = {396}, number = {}, pages = {115537}, doi = {10.1016/j.expneurol.2025.115537}, pmid = {41173224}, issn = {1090-2430}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Mice ; *Microglia/drug effects/metabolism ; *Ferroptosis/drug effects/physiology ; *Neuroinflammatory Diseases/metabolism/drug therapy/pathology ; Mice, Transgenic ; *Inflammasomes/metabolism/drug effects ; *Glucagon-Like Peptides/pharmacology/therapeutic use ; Disease Progression ; Disease Models, Animal ; Mice, Inbred C57BL ; Male ; Glucagon-Like Peptide 1 ; }, abstract = {Microglial activation driven by NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling exacerbates Alzheimer's disease (AD) pathology through enhanced neuroinflammation and amyloid beta (Aβ) accumulation. Semaglutide (SEM) has attracted growing attention for its potential therapeutic effects in AD, while its underlying mechanisms remain unclear. In this study, we investigated the neuroprotective effects of SEM in both APP/PS1 transgenic mice and LPS + ATP-stimulated BV2 microglia. Our results demonstrate that SEM treatment rescued APP/PS1 mice from cognitive impairment and suppressed Aβ aggregation and tau hyper-phosphorylation in the hippocampus of APP/PS1 mice. Furthermore, we found that SEM inhibited microglial NLRP3 activation, promoted microglial M2 polarization and alleviated ferroptosis via NLRP3/nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/ cystine/glutamate antiporter SLC7A11 (xCT)/glutathione peroxidase 4 (GPX4) pathways in APP/PS1 mice and LPS + ATP-stimulated BV2 microglia. These findings were further corroborated by microglia-specific NLRP3 knockdown, which reduced Aβ deposition, promotied M2 polarization, attenuated neuroinflammation, and suppressed ferroptosis. Our findings provide further theoretical support for the clinical application of SEM in AD treatment, while also establishing a scientific foundation for AD therapeutic strategies targeting the microglial NLRP3 pathway.}, } @article {pmid41172319, year = {2025}, author = {Avdeenko, TA and Guseinova, NM and Dzhafarzade, FY and Zagorul'ko, AA}, title = {[Modern therapeutic strategies for the treatment of Alzheimer's disease (literature review).].}, journal = {Advances in gerontology = Uspekhi gerontologii}, volume = {38}, number = {3}, pages = {441-449}, pmid = {41172319}, issn = {1561-9125}, mesh = {*Alzheimer Disease/therapy/drug therapy/metabolism ; Humans ; *Cholinesterase Inhibitors/therapeutic use ; Amyloid beta-Peptides/metabolism ; *Diabetes Mellitus, Type 2/complications/drug therapy/metabolism ; Immunotherapy/methods ; tau Proteins/metabolism ; Calcium Channel Blockers/therapeutic use ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; }, abstract = {The article analyzes contemporary literature data on standard and alternative therapeutic methods for Alzheimer's disease (AD). The main approaches currently include the use of cholinesterase inhibitors and NMDA receptor antagonists, which help slow disease progression and improve patients' quality of life. Due to their insufficient effectiveness, there is a search for new treatment methods based on the connection between AD and other conditions. This article will examine the cross-mechanisms of pathogenesis linking type 2 diabetes and AD, as well as analyze new therapeutic approaches, including intranasal insulin administration and the use of insulin sensitizers. Neurodegenerative processes, including AD, are based on a violation of intracellular calcium metabolism, which suggested the potential efficiency of calcium channel blocker drugs currently used in the treatment of arterial hypertension. Key hypotheses regarding the pathogenesis of AD include the amyloid hypothesis, based on the accumulation of beta-amyloid, and the tau hypothesis, related to hyperphosphorylated tau protein aggregation. Alternative mechanisms such as neuroinflammation are also discussed. In this context, an innovative method for treating AD is immunotherapy, aimed at eliminating beta-amyloid that causes neurodegeneration. Thus, the necessity for integrating various hypotheses for a more comprehensive understanding of pathology and developing effective therapeutic strategies is emphasized. The article highlights the importance of further research in this field.}, } @article {pmid41170731, year = {2026}, author = {Duan, T and Mao, H and Jiang, X and Tian, Y and Zhang, J and Tan, J}, title = {Harnessing copper: Innovative approaches to combat neurodegenerative diseases and cancer (Review).}, journal = {International journal of molecular medicine}, volume = {57}, number = {1}, pages = {}, pmid = {41170731}, issn = {1791-244X}, mesh = {Humans ; *Copper/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Neoplasms/metabolism/drug therapy ; Animals ; Chelating Agents/therapeutic use ; }, abstract = {Copper is an important trace element in the human body and plays an essential role in cells, where it is involved in synthesizing copper‑dependent enzymes, including superoxide dismutase, cytochrome c oxidase, tyrosinase, lysyl oxidase, dopamine‑β‑hydroxylase and other related copper‑containing enzymes. Copper overload or deficiency affects cell activity, leading to the development of neurodegenerative diseases or cancer. Neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's disease, as well as cancer, represent significant chronic health burdens. The complexity of their pathophysiological mechanisms, coupled with the limitations of current targeted therapies, complicates the development of effective treatments. This review provides a comprehensive overview of the current understanding of copper's regulatory mechanisms in health and disease, with particular emphasis on its roles in neurodegenerative disorders and cancer. Recent advances in copper‑targeted therapeutic strategies, including copper chelators, ionophores and copper‑based nanoparticles, were highlighted. Furthermore, the clinical potential, key challenges and future prospects of these interventions were assessed. By synthesizing recent preclinical and clinical evidence, this review aims to contribute novel perspectives for improving the treatment of copper‑associated diseases.}, } @article {pmid41170545, year = {2025}, author = {Li, XJ and Zheng, B and Lan, P and Zhang, WX and Li, YP and He, Z}, title = {[Research progress in the role of HCN channels in Alzheimer's disease].}, journal = {Sheng li xue bao : [Acta physiologica Sinica]}, volume = {77}, number = {5}, pages = {867-875}, doi = {10.13294/j.aps.2025.0078}, pmid = {41170545}, issn = {0371-0874}, mesh = {Humans ; *Alzheimer Disease/physiopathology ; *Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/physiology ; Animals ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is the commonest neurodegenerative disease that causes memory decline, cognitive dysfunction and behavior disorders in the aged people. Primary pathological hallmarks of AD include amyloid-β (Aβ), neurofibrillary tangles (NFTs), gliosis, and neuronal loss. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have important physiological functions, especially in aspects of controlling the resting membrane potential, pacemaker activity, memory formation, sleep and arousal. This article reviews the structure, distribution, regulation of HCN channels and the role of HCN channels in the pathological mechanisms of AD, aiming to provide drug therapeutic targets for the prevention and treatment of AD.}, } @article {pmid41170438, year = {2025}, author = {Zhang, X and Huang, X and Chang, M}, title = {Association between periodontal disease and Alzheimer's disease: a scoping review.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1588008}, pmid = {41170438}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, with mild cognitive impairment (MCI) as its early reversible stage. Periodontal disease (PD) is a chronic inflammatory condition associated with systemic diseases. Recent studies suggest a potential link between PD and AD/MCI. This scoping review evaluates the existing evidence on the association between PD and AD and explores possible mechanisms.

METHODS: A literature search was conducted in PubMed, Embase, and Cochrane databases (September 2025), covering studies from 2004 to 2025. Human clinical studies, animal models, and in vitro experiments were included, while reviews were excluded. Two independent researchers performed study selection, data extraction, and quality assessment.

RESULTS: A total of 52 studies were included after screening 1,369 records. Among them, 25 clinical studies examined the PD-AD association, including case-control, cohort, and cross-sectional studies. Additionally, 24 studies investigated underlying mechanisms, and 3 animal studies assessed PD-related interventions for AD. Evidence suggests PD increases the risk of AD and accelerates cognitive decline. Potential mechanisms include amyloid-β (Aβ) and tau protein aggregation, neuroinflammation triggered by Porphyromonas gingivalis (Pg) infection, and gut-brain axis dysregulation. Periodontal treatment and probiotics may have protective effects against AD-related pathology.

CONCLUSIONS: PD may be a modifiable risk factor for AD, and periodontal interventions could contribute to AD prevention and management. Further clinical studies are needed to confirm the therapeutic potential of targeting oral microbiota in AD.}, } @article {pmid41170189, year = {2025}, author = {Pakdel, M and Asle-Rousta, M and Sadegh, M and Eidi, A}, title = {Linalool vs linalool-loaded chitosan nanoparticles in an Aβ-induced rat model of Alzheimer's disease: A molecular, biochemical, histological, and behavioral study.}, journal = {Iranian journal of basic medical sciences}, volume = {28}, number = {11}, pages = {1495-1504}, pmid = {41170189}, issn = {2008-3866}, abstract = {OBJECTIVES: Recent studies have increasingly focused on applying nanotechnology to treat neurodegenerative diseases. In this study, we compared the effects of the monoterpene linalool and linalool-loaded chitosan nanoparticles on key pathological features of Alzheimer's disease (AD), including oxidative stress, neuroinflammation, neuronal death, amyloid plaque deposition, alterations in tryptophan metabolism, and memory deficit in a rat model of AD.

MATERIALS AND METHODS: An intracerebroventricular injection of Aβ42 (10 µg) was used to induce the AD model. Linalool (25 mg/kg) and nano-linalool (25 mg/kg) were administered orally once daily for 30 consecutive days.

RESULTS: Both linalool and nano-linalool significantly reduced malondialdehyde levels and enhanced superoxide dismutase activity in the hippocampus. They also decreased the mRNA levels of monocyte chemoattractant protein-1, inhibited the up-regulation of beta-secretase, reduced amyloid plaque deposition, and attenuated pyramidal neuron death in the CA1 region. Additionally, treatment with both compounds down-regulated indoleamine 2,3-dioxygenase, lowered kynurenine levels, and increased serotonin concentrations in the hippocampus. Although both treatments improved learning and spatial memory in Aβ-injected rats, nano-linalool's effectiveness was more significant than that of linalool in modulating the molecular, biochemical, and histological parameters.

CONCLUSION: Encapsulating linalool in chitosan nanoparticles enhances its effectiveness in improving molecular, biochemical, and histological changes in the hippocampus of rat models of AD.}, } @article {pmid41169672, year = {2025}, author = {Teipel, S and Baena, A and He, B and Martinez, L and Aguillon, D and Quiroz, YT and Grazia, A}, title = {Thalamus not basal forebrain is atrophied in non-demented PSEN1 E280A carriers.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {4}, pages = {e70206}, pmid = {41169672}, issn = {2352-8729}, abstract = {INTRODUCTION: A previous study of non-demented presenilin-1 (PSEN1) E280A carriers found basal forebrain and hippocampus, but not the thalamus, to be preserved. This study tested the hypothesis of preservation in an independent PSEN1 E280A sample and explored associations with amyloid and tau pathology.

METHODS: We analyzed multimodal neuroimaging data from 57 individuals in the Colombia-Boston (COLBOS) cohort (non-carriers: 30 and carriers: 27). We used Bayesian multiple regression with priors to test our hypothesis.

RESULTS: Carrier status had no effect on basal forebrain (Bayes factor [BF10] = 0.54) and hippocampal volume (BF10 = 1.05). However, smaller volumes were found in the thalamus of mutation carriers (BF10 = 8.74). We found evidence against an effect of amyloid and tau pathology on basal forebrain, but evidence for an effect on the thalamus.

DISCUSSION: Our results support the preservation of the cholinergic basal forebrain and hippocampus, while highlighting early thalamic involvement in PSEN1 E280A carriers. This has implications for future selection of treatment targets.

HIGHLIGHTS: Basal forebrain volume preserved in non-demented presenilin-1 (PSEN1) E280A carriers.Hippocampal volume preserved in non-demented PSEN1 E280A carriers.Thalamic atrophy observed in non-demented PSEN1 E280A carriers.No link between amyloid/tau pathology and basal forebrain volume.Tau burden linked to hippocampal and thalamic volume loss.}, } @article {pmid41169223, year = {2025}, author = {Chen, Z and Wang, X and Wang, S and Wu, Z and Wang, H and Chiu, K and Zheng, X and So, KF}, title = {Lycium barbarum glycopeptide protects neurons from amyloid-beta toxicity.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00501}, pmid = {41169223}, issn = {1673-5374}, abstract = {Oligomeric amyloid-beta deposition within neurons and its associated neurotoxicity are among the most direct indicators of the onset of Alzheimer's disease. Investigations into strategies aimed at reducing amyloid-beta accumulation or promoting its clearance in neurons are currently being carried out. Lycium barbarum glycopeptide is rich in biologically active compounds and possesses antioxidant, anti-inflammatory, and neuroprotective properties. This study verified that the oligomer amyloid-beta1-42 induced toxic effects in mouse N2a neuroblastoma cells, resulting in elevated levels of reactive oxygen species and increased expression of the inflammatory enzyme inducible nitric oxide synthase. Lycium barbarum glycopeptide counteracted these effects by alleviating cell damage, enhancing cell viability, reducing the levels of reactive oxygen species and inducible nitric oxide synthase expression, and up-regulating the mRNA levels of antioxidant enzymes, including superoxide dismutase 1, superoxide dismutase 2, and glutathione peroxidase 4. Lycium barbarum glycopeptide also activated the phosphoinositide 3-kinase/Akt/p70S6K signaling pathway and promoted the expression of brain-derived neurotrophic factor, thus exerting neuroprotective effects. These findings indicate that Lycium barbarum glycopeptide may be a promising candidate for the treatment of Alzheimer's disease.}, } @article {pmid41169221, year = {2025}, author = {Zhang, Z and Deng, W and Hu, L and Hu, Y and Zhang, S and Xiong, Y and Liu, X and Yu, P and Yu, S and Yuan, L and Zhang, J}, title = {Zinc homeostasis imbalance: Potential therapeutic value in neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00632}, pmid = {41169221}, issn = {1673-5374}, abstract = {Zinc homeostasis genes are a general term for a family of genes responsible for regulating the concentration of intracellular and extracellular zinc ions, including the SLC39 (ZIP) family, the SLC30 (ZnT) family, and the metallothionein family. As an essential trace element, zinc is involved in biomolecular synthesis, energy metabolism, redox regulation, and gene expression. Recent studies have shown that abnormal expression of zinc homeostasis genes mediates neuronal apoptosis through multiple pathways, including oxidative stress and neuroinflammation. Imbalance in zinc homeostasis can result in the pathological development of various neurodegenerative disorders, including the deposition of amyloid-β in Alzheimer's disease and the aberrant aggregation of α-synuclein in Parkinson's disease. Therefore, regulating the expression of zinc homeostasis genes to restore normal zinc levels in vivo may be an effective strategy for treating neurodegenerative diseases. This review comprehensively summarizes the current status of research exploring zinc homeostasis genes across various family subtypes, as well as the altered expression of these genes in different neurodegenerative diseases and the underlying mechanisms. Finally, we propose zinc chelator supplementation as a novel interventional therapy for neurodegenerative diseases. This proposal includes an evaluation of the feasibility, safety, and limitations of this treatment, providing an innovative perspective for the clinical management of neurodegenerative diseases in the future.}, } @article {pmid41169131, year = {2025}, author = {Mikellides, G and Emam Jomeh, AA and Roy, EA and Kyriazis, M}, title = {Repetitive Transcranial Magnetic Stimulation in Dementia.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098392580251003064940}, pmid = {41169131}, issn = {1874-6128}, abstract = {Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive neuromodulatory technique that is increasingly being investigated for its therapeutic potential in cognitive impairment associated with dementia and Alzheimer's disease. This narrative review synthesizes and critically appraises the current evidence surrounding rTMS, with particular focus on clinical efficacy, neurobiological mechanisms, and emerging innovations. High-frequency stimulation over the Dorsolateral Prefrontal Cortex (DLPFC) has consistently demonstrated improvements in memory, executive function, and attention, likely mediated by enhanced synaptic plasticity, increased neurotrophic factor expression, and modulation of large-scale brain networks, such as the default mode and fronto-parietal networks. Recent high-quality studies have built upon earlier research to highlight the comparative efficacy of target-specific stimulation, including precuneus- and parietal-based protocols, as well as multi- site strategies that engage language and associative regions. It also examines the use of TMSEEG and DMN connectivity as predictors of treatment response, supporting a shift toward personalized, biomarker-guided rTMS paradigms. Moreover, the synergistic potential of combining rTMS with cognitive training and pharmacotherapy is explored as a promising avenue for multimodal treatment. While preliminary results are encouraging, heterogeneity in study design and stimulation parameters continues to limit the generalizability of the findings. Standardization of protocols, longterm efficacy validation, and large-scale clinical trials remain critical to translating rTMS into routine dementia care.}, } @article {pmid41168999, year = {2025}, author = {Zhang, J and He, Y and Yang, P and Zhang, H and Tong, Y and Jiang, L and Li, Z and Yan, M and Li, X and Yang, Q and Yang, J and Yuan, Z and Zhang, J and Cheng, J}, title = {Microglial Rack1 Deficiency Alleviates Alzheimer's Disease Pathology through Enhancing IGF1-Mediated Astrocytic Phagocytosis.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {}, number = {}, pages = {e15877}, doi = {10.1002/advs.202515877}, pmid = {41168999}, issn = {2198-3844}, support = {82071218//National Nature Science Foundation of China/ ; 82271237//National Nature Science Foundation of China/ ; 81930029//National Nature Science Foundation of China/ ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder. Microglia make significant contributions to neuroinflammation and the progression of AD. However, the regulatory role of microglial activation and the communication between microglia and astrocytes in AD are largely unknown. Here, it is found that Rack1 levels are elevated in microglia of patients with AD and AD model mice. The conditional knockout of Rack1 in microglia reduced Aβ aggregation, alleviated neuroinflammation, and rescued cognitive impairments in AD model mice. Mechanistically, the knockout of Rack1 in microglia decreased the number of microglia while increasing both the numbers and phagocytic activities of astrocytes by upregulating the levels of IGF1. The inhibition of IGF1R blocked microglial Rack1 deficiency-induced astrocyte proliferation and astrocyte-mediated phagocytosis both in vitro and in vivo. Collectively, the results demonstrated that microglial Rack1 contributes to AD pathology, at least partially through influencing IGF1-IGF1R signaling between microglia and astrocytes, thus providing a potential target for AD treatment.}, } @article {pmid41167569, year = {2026}, author = {Xiong, R and Liu, H and Zhang, S and Wang, L and Zhang, P and Wang, Y and Ou, X and Wu, A and Lai, X}, title = {Acorus tatarinowii Schott attenuates Alzheimer's disease via neuronal ferroptosis inhibition: A synergistic network pharmacology and multi-omics profiling study.}, journal = {Journal of ethnopharmacology}, volume = {356}, number = {}, pages = {120829}, doi = {10.1016/j.jep.2025.120829}, pmid = {41167569}, issn = {1872-7573}, mesh = {Animals ; *Ferroptosis/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; *Acorus/chemistry ; *Neurons/drug effects/metabolism/pathology ; Network Pharmacology ; Mice, Transgenic ; Male ; Amyloid beta-Peptides ; Disease Models, Animal ; Cell Line ; NF-E2-Related Factor 2/metabolism ; *Drugs, Chinese Herbal/pharmacology ; Rhizome ; *Neuroprotective Agents/pharmacology ; *Plant Extracts/pharmacology ; Mice, Inbred C57BL ; Multiomics ; }, abstract = {The dried rhizome of Acorus tatarinowii Schott (ATR) is the most widely used traditional Chinese medicine for the treatment of dementia due to its effect of opening orifices and eliminating phlegm (Kai-Qiao-Huo-Tan in Chinese), reviving the mind and enhancing intelligence (Xing-Shen-Yi-Zhi in Chinese), but its mechanism remains not fully understood.

AIM OF THE STUDY: To reveal the mechanism of ATR in the treatment of Alzheimer's disease (AD), which is a major type of dementia.

MATERIALS AND METHODS: The effects of ATR on cognitive function and neuronal loss in APP/PS1 mice were evaluated by the novel object recognition test, nesting test, hematoxylin-eosin staining, and Nissl staining. The underlying mechanisms were studied by serum metabolomics, transcriptomics, network pharmacology, RT-PCR, Western blot, immunofluorescence, and immunohistochemistry.

RESULTS: ATR significantly improved cognitive function, neuronal loss, and altered lipid metabolism in APP/PS1 mice. In β-amyloid (Aβ)1-42 and ferric citrate (FC)-induced HT22 cells, ATR significantly improved the cell viability, reduced the intracellular free iron, reactive oxygen species, and lipid peroxidation, and transcriptome analysis showed that the mechanism was related to ferroptosis and iron metabolism. Network pharmacology analysis indicated that ATR may regulate Nrf2 signaling. Both in vitro and in vivo results showed that ATR increased the mRNA and protein expression of Nrf2 and GPX4. ATR also reduced brain iron deposition, downregulated TFR1, and upregulated FPN1 expression in APP/PS1 mice.

CONCLUSIONS: ATR ameliorated AD by improving iron metabolism and inhibiting neuronal ferroptosis through activation of the Nrf2/GPX4 axis, which provided modern medical evidence for the use of ATR to improve AD.}, } @article {pmid41166911, year = {2025}, author = {Barth, SW and Efferth, T}, title = {Network pharmacology to elucidate the role of phytotherapy in neurocognitive disorders.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {148}, number = {}, pages = {157031}, doi = {10.1016/j.phymed.2025.157031}, pmid = {41166911}, issn = {1618-095X}, mesh = {Animals ; Humans ; Alzheimer Disease/drug therapy ; *Network Pharmacology ; *Neurocognitive Disorders/drug therapy ; *Phytotherapy ; Systems Biology ; }, abstract = {BACKGROUND: To date, there are no entirely satisfactory drugs available to treat neurocognitive disorders. In light of the increasing incidences of these disorders in societies with aging populations, there is an urgent need to further improve treatment options.

HYPOTHESIS: Phytotherapy modulates diseases and symptoms by addressing multiple rather than single targets. Therefore, phytotherapy might be suited to treat complex diseases such as neurocognitive disorders.

METHODS AND BACKGROUND: We performed a systematic review of the literature with defined search terms using the PubMed database. The search terms were: [(network pharmacology) OR (systems pharmacology) OR (microarray) OR (proteomic) OR (metabolomic) OR (transcriptomic) OR (RNA-seq)] AND [Alzheimer) OR (dementia)]. These search strings were connected with [(herbal) OR (botanical)] for polyherbal formulations and [(phytochemical) OR (natural product)] for single-herb preparations. Systems biology focuses on the human organism as dynamic networks that cooperate in an orchestrated manner in the healthy as well as in the diseased body. The diseasome concept integrates disease phenotypes with hierarchical networks across various biological levels-organ networks, cellular networks, and signaling networks. Network pharmacology aims to interfere with such networks to treat complex, multifactorial diseases. Diseases may be caused by exposure to external factors harmful to health (exposomes). Phytotherapy might beneficially influence diseasomes thus restoring disturbed networks. Here, the "phytome" which integrates herbal drug ingredients into the exposome may be a rich source with which to counteract diseased networks.

RESULTS: Our literature search identified 642 hits. The final number of papers included was 41. Using sophisticated animal models (transgenic mice, injection of amyloid β fragments or specific chemicals, surgical interventions) conditions have been generated that resemble Alzheimer's disease, vascular dementia, and other types of dementia. Brain tissues (mainly hippocampus and cortex), blood serum, urine, and feces were investigated using metabolomic, proteomic, and transcriptomic methods. In these experimental dementia models, specific signaling networks were reported to be affected: they regulate pathophysiological mechanisms of inflammation, signal processing and transmission, neuroplasticity, vascular function and blood, cellular integrity and metabolism as well as cellular redox balance. About two dozen polyherbal formulations (mainly derived from traditional Chinese medicine) were used for treatment in these models and partially or fully restored not only the diseased networks (diseasomes) but also the disease symptoms. Another dozen mono-herbal preparations were used to treat dementia in experimental models, and similar beneficial effects were observed.

CONCLUSION: The selected 41 papers from the literature provided a good basis for a detailed analysis of the role of network pharmacology in understanding the multimodal modes of action of herbal preparations in neurocognitive disorders. Complex signaling networks add valuable new information to classical pharmacology. The understanding of phytopharmaceuticals' modes of action underpin the necessity to expand the search from classic pharmacological models to complex network interactions.}, } @article {pmid41166828, year = {2026}, author = {Gomes, LS and Schüler, MCGM and Giannini, GB and Zapp, E and de Oliveira, AS and Nascimento, V}, title = {Multifunctional Carvacrol-based Organoselenium hybrids as anticholinesterase and antioxidant candidates for Alzheimer's therapy.}, journal = {Bioorganic & medicinal chemistry}, volume = {132}, number = {}, pages = {118447}, doi = {10.1016/j.bmc.2025.118447}, pmid = {41166828}, issn = {1464-3391}, mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; *Antioxidants/chemistry/pharmacology/chemical synthesis ; *Alzheimer Disease/drug therapy/metabolism ; Acetylcholinesterase/metabolism ; *Cymenes/chemistry/pharmacology ; *Organoselenium Compounds/chemistry/pharmacology/chemical synthesis ; Humans ; Molecular Docking Simulation ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Animals ; Electrophorus ; }, abstract = {BACKGROUND: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Acetylcholinesterase (AChE) inhibition remains a validated approach for symptomatic management. Natural compounds such as carvacrol and selenium-based organochalcogenides are promising due to their antioxidant and neuroprotective properties.

OBJECTIVES: This study aimed to design, synthesize, and evaluate twelve selenium-containing carvacrol derivatives as multifunctional anti-Alzheimer agents.

METHODS: The compounds were synthesized via copper-catalyzed azide-alkyne cycloaddition (CuAAC), forming triazole-linked hybrids. Structural characterization was performed using NMR and HRMS. Biological evaluation included in vitro AChE inhibition assays (IC50 determination), antioxidant profiling by cyclic voltammetry, and cytotoxicity screening. Computational studies involved molecular docking (GOLD software), DFT calculations, and ADMET predictions using pkCSM and SwissADME platforms.

RESULTS: Compounds 18e and 18h showed the most potent AChE inhibition (IC50 = 75 and 93 nM, respectively), exhibiting strong interactions with key residues such as Trp286 and Tyr341. Electrochemical assays identified 18l, 18f, and 18c as the most antioxidant derivatives, based on their low oxidation energy. ADMET predictions indicated high intestinal absorption (>95 %), BBB permeability, and no violations of Lipinski's rules. A strong correlation (R[2] = 0.9377) between docking scores and experimental IC50 values supported the reliability of the in silico screening.

CONCLUSION: The synthesized selenium-carvacrol hybrids exhibit a favorable combination of enzyme inhibition, antioxidant capacity, and pharmacokinetic properties. Compounds 18e and 18h demonstrated the most potential and represent valuable leads for future in-depth pharmacological studies and rational optimization in the context of Alzheimer's therapy.}, } @article {pmid41166555, year = {2025}, author = {}, title = {Erratum.}, journal = {Neuro-degenerative diseases}, volume = {25}, number = {4}, pages = {228}, doi = {10.1159/000548755}, pmid = {41166555}, issn = {1660-2862}, abstract = {In the article "Active Immunization Targeting Amyloid β for the Treatment of Alzheimer's Disease" [Neurodegener Dis. 2025; <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="https://doi.org/10.1159/000546287">https://doi.org/10.1159/000546287</ext-link>] by Triplett et al., the wrong copyright license was displayed. It has been corrected to a CC-BY 4.0 license. The section title was also corrected to Review Article.The original online article has been updated to reflect this.</sec></body>.}, } @article {pmid41165744, year = {2025}, author = {Xiong, S and Cui, M and Liu, H and Wu, L and Xiong, X and Zhang, S and Yang, J and Wang, P}, title = {Rational Design of a Dual-Channel Fluorescent Probe for the Simultaneous Imaging of Brain Amyloid-β Plaques and HClO/ClO[-] in Alzheimer's Disease.}, journal = {Analytical chemistry}, volume = {97}, number = {44}, pages = {24656-24667}, doi = {10.1021/acs.analchem.5c04718}, pmid = {41165744}, issn = {1520-6882}, mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; *Fluorescent Dyes/chemistry/chemical synthesis ; Animals ; *Hypochlorous Acid/analysis/metabolism ; PC12 Cells ; *Amyloid beta-Peptides/metabolism/analysis ; Rats ; *Brain/metabolism/diagnostic imaging ; Mice ; *Plaque, Amyloid/metabolism/diagnostic imaging ; Optical Imaging ; Humans ; Coumarins/chemistry ; }, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia. The pathological hallmarks of AD are characterized by the presence of amyloid-β (Aβ) plaques and elevated production of hypochlorous acid (HClO/ClO[-]) in the brain. However, there is a lack of effective tools to image the biological functions of Aβ aggregates and HClO/ClO[-] in the AD brain. In this study, we presented the first single-molecule fluorescent probe, CTAD-MB, capable of detecting both Aβ aggregates and HClO/ClO[-]. The design strategy for this probe combines an N,N-dimethyl-phenylcoumarin moiety, which has high affinity for Aβ aggregates, with a methylene blue derivative that specifically responds to hypochlorite. This bifunctional fluorescent probe provided distinct fluorescent signals for Aβ aggregates and HClO/ClO[-]. CTAD-MB demonstrated completely independent spectral responses to Aβ and HClO/ClO[-], offering high selectivity, sensitivity, and rapid response. The probe was successfully employed in imaging the HClO/ClO[-] stimulated by Aβ aggregates in PC12 cells. Also, it was effectively applied for dual-channel detection of Aβ and HClO/ClO[-] in the live AD mouse, which could be used to distinguish from the brain inflammation mouse. This insight not only advances our understanding of AD but also provides new avenues for its diagnosis and treatment.}, } @article {pmid41165739, year = {2025}, author = {Dalal, N and Jaiswal, J and Kushwaha, M and Verma, H and Rana, P and Gupta, S and Panwar, R and Janmeda, P and Jain, P and Singh, AK and Mohan, A and Kumar, A}, title = {Implications of Gut Microbiota-Derived Metabolites in Neurological Disorders.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {22}, pages = {4315-4326}, doi = {10.1021/acschemneuro.5c00414}, pmid = {41165739}, issn = {1948-7193}, mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Nervous System Diseases/metabolism/microbiology ; Animals ; Methylamines/metabolism ; Blood-Brain Barrier/metabolism ; Cresols/metabolism ; Oxidative Stress/physiology ; Brain/metabolism ; Neuroinflammatory Diseases/metabolism ; }, abstract = {Neurological disorders (NDs) represent a significant global health challenges, with neurodegeneration being a common pathological feature. Recent investigations indicate the involvement of gut microbiota-derived metabolites in these disorders, such as neuroinflammation, oxidative stress, and cognitive decline. The gut-brain axis, a communication network between the gut and the central nervous system (CNS), is influenced by microbial metabolites, which can cross the blood-brain barrier and impact brain function. Key metabolites such as trimethylamine N-oxide (TMAO), para-cresol sulfate (pCS), 4-ethylphenyl sulfate (4-EPS), and indoxyl sulfate (IS) have been linked with the progression of neurological disorders. TMAO disrupts blood-brain barrier integrity, promotes oxidative stress, and activates microglial cells, which lead to the apoptosis of neurons, resulting in neuroinflammation. This could also result in psychiatric changes and behavioral disorders. pCS produced from gut bacteria metabolizing dietary proteins is correlated with amplified oxidative stress, neuroinflammation, and cognitive impairments in disorders like Parkinson's disease and Alzheimer's disease. Similarly, elevated 4-EPS levels are linked to autism spectrum disorder, contributing to anxiety-like behavior and blood-brain barrier disruption. Understanding the mechanisms by which gut-derived metabolites affect neurological health could lead to novel therapeutic strategies that can target gut microbiota for the medication and treatment of neurological disorders. Dietary precursors and gut microbiota metabolites, modulated by probiotics, prebiotics, postbiotics, and synbiotics, play a critical role in maintaining microbiota homeostasis and influencing neurological health, needing sophisticated biosensors to enable real-time monitoring and early intervention in disorders linked to gut metabolite imbalances.}, } @article {pmid41165158, year = {2025}, author = {Hao, J and Wan, Q and Chen, C}, title = {Atractylenolide III Promotes Astrocyte Aβ Clearance by Up-regulating AQP4 to Improve Alzheimer's Disease.}, journal = {Folia biologica}, volume = {71}, number = {3}, pages = {140-148}, doi = {10.14712/fb2025071030140}, pmid = {41165158}, issn = {0015-5500}, support = {D202303076913//Health Commission of Hunan Province/ ; D202304017019//Health Commission of Hunan Province/ ; }, mesh = {*Astrocytes/metabolism/drug effects ; Animals ; *Aquaporin 4/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; *Sesquiterpenes/pharmacology/therapeutic use/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Lactones/pharmacology/therapeutic use/chemistry ; Mice ; *Up-Regulation/drug effects ; Molecular Docking Simulation ; Male ; Disease Models, Animal ; Cell Survival/drug effects ; Mice, Inbred C57BL ; Peptide Fragments/metabolism ; }, abstract = {Astrocytes actively phagocytose amyloid beta (Aβ), enhancing cerebral clearance and positioning themselves as viable therapeutic targets for Alz-heimer's disease (AD). Atractylenolide III (ATL-III), the primary bioactive compound in the traditional Chinese herb Baizhu, demonstrates established neuroprotective properties. However, the research on its effects on astrocytes has not yet been elaborated. To induce an astrocyte-based AD model, Aβ1-42 was utilized. Cell viability assays were conducted to screen for the optimal concentration of ATL-III treatment. Molecular docking was performed to investigate the binding between ATL-III and aquaporin 4 (AQP4). Additionally, an Aβ1-42-induced AD mouse model was adopted. In this study, ATL-III effectively reduced the accumulation level of Aβ1-42 in the cell supernatant, and at the same time, significantly enhanced the internalization of Aβ by astrocytes. Of interest, the study reveals that ATL-III not only has the property of binding to AQP4 but also up-regulates the expression level of this protein. Mechanistic probes suggest that the role of ATL-III in promoting Aβ clearance by astrocytes may be partially dependent on its regulation of AQP4 expression. Animal behavioural experiments confirmed that the compound ameliorated Aβ1-42-induced cognitive dysfunction, and pathological analyses revealed significantly elevated AQP4 expression in the hippocampus. The combined findings suggest that ATL-III may play a role in ameliorating the pathological process of AD by enhancing the efficiency of astrocyte-mediated Aβ clearance through the up-regulation of AQP4 expression.}, } @article {pmid41165142, year = {2025}, author = {Chen, YN and Xiong, ZE and Wen, X and He, SJ and Zhang, XL and Zhang, R and Wang, T and Zou, J}, title = {Anthocyanins in the treatment of Alzheimer's disease: a systematic review and meta-analysis of animal studies.}, journal = {Nutritional neuroscience}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/1028415X.2025.2578641}, pmid = {41165142}, issn = {1476-8305}, abstract = {BACKGROUND: To comprehensively evaluate the therapeutic potential of anthocyanins in animal models of Alzheimer's disease (AD). METHODS: The PubMed, Web of Science, and Embase databases were searched for preclinical animal studies investigating anthocyanin intervention in AD models up to June 2025. Studies reporting outcomes related to cognitive behavior, neuropathological changes such as amyloid-β (Aβ) deposition, or molecular mechanisms including oxidative stress and inflammatory markers, were included in the analysis. Data analysis was performed using RevMan 5.4 software. The SYRCLE tool was used to assess the risk of bia. RESULTS: Anthocyanin intervention significantly improved cognitive function in animal models of AD. Meta-analysis revealed that in the Morris water maze test, the anthocyanin treatment group exhibited a significantly higher number of crossings in the target quadrant compared to the control group (SMD = 1.83, 95% CI: 1.48 -2.18, p < 0.00001). Regarding pathological indicators, anthocyanin administration was associated with a significant reduction in Aβ protein deposition (SMD = -5.39, 95% CI: - 6.89 to - 3.88, p < 0.00001). Furthermore, anthocyanin effectively alleviated oxidative stress, as evidenced by a significant decrease in malondialdehyde (MDA) levels (SMD = -4.19, 95% CI: - 6.76 to - 1.63, p = 0.001). In terms of neuroinflammatory markers, anthocyanin treatment significantly reduced the expression levels of tumor necrosis factor-alpha (TNF-α) (SMD = -3.30, 95% CI: - 4.91 to - 1.68, p < 0.0001) and interleukin-1 beta (IL-1β) (SMD = -2.23, 95% CI: - 3.12 to - 1.34, p < 0.00001). CONCLUSION: This systematic review and meta-analysis suggest that anthocyanins could improve cognitive function and mitigate neuropathology in animal models of AD.}, } @article {pmid41164883, year = {2025}, author = {André, C and Stankeviciute, L and Michaelian, JC and Antonsdottir, IM and Benca, RM and Coulthard, EJ and D'Rozario, AL and Dijk, DJ and Gimenez, S and Gorgoni, M and Leng, Y and Lucey, BP and Pase, MP and Rainey-Smith, SR and Rosenzweig, I and Spira, AP and Winer, JR and Rauchs, G and Naismith, SL and , }, title = {International recommendations for sleep and circadian research in aging and Alzheimer's disease: A Delphi consensus study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70742}, pmid = {41164883}, issn = {1552-5279}, support = {//Alzheimer's Association International Society/ ; //Advance Alzheimer's Research and Treatment/ ; //Sleep and Circadian Rhythms/ ; //PIA membership, ISTAART,/ ; /ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Alzheimer Disease/physiopathology ; Delphi Technique ; *Aging/physiology ; *Circadian Rhythm/physiology ; Consensus ; *Sleep/physiology ; *Sleep Wake Disorders ; *Biomedical Research ; }, abstract = {INTRODUCTION: Research in the field of sleep, aging, and dementia is rapidly growing. Consensus guidance is needed to facilitate high-quality research, comparability, and consistency. METHODS: A modified Delphi consensus study was conducted by the Sleep and Circadian Rhythms Professional Interest Area of the International Society to Advance Alzheimer's Research and Treatment (ISTAART) and an international panel of experts to establish recommendations for future research. RESULTS: After two voting rounds, the group (1) determined by consensus the most relevant sleep and circadian features to assess in the context of aging and dementia research, (2) established recommendations on data acquisition and report for future studies, and (3) identified high-priority future directions. DISCUSSION: This expert consensus study provides guidance to develop high-quality sleep and circadian research in the context of aging and dementia. Similar recommendations will need to be established for clinical practice. HIGHLIGHTS: We report the results of an international expert consensus study. Sleep and circadian rhythms features relevant to aging and dementia were identified. Recommendations on data acquisition and reporting were established. High-priority future research directions were identified.}, } @article {pmid41164820, year = {2025}, author = {Summanwar, D and Owora, AH and Ben Miled, Z and Dexter, PR and Kulshreshtha, A and Strunk, S and Jiang, B and Coppedge, K and Disla, S and Galvin, JE and Boustani, M and Fowler, NR}, title = {Prevalence of Multiple Chronic Conditions in Older Adults with Undiagnosed Mild Cognitive Impairment and Alzheimer's Disease and Related Dementias in Primary Care.}, journal = {Clinical interventions in aging}, volume = {20}, number = {}, pages = {1799-1809}, pmid = {41164820}, issn = {1178-1998}, support = {R01 AG069765/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Aged ; *Cognitive Dysfunction/epidemiology/diagnosis ; Male ; Female ; Cross-Sectional Studies ; *Primary Health Care/statistics & numerical data ; *Alzheimer Disease/epidemiology/diagnosis ; Aged, 80 and over ; Prevalence ; *Multiple Chronic Conditions/epidemiology ; Indiana/epidemiology ; Florida/epidemiology ; *Dementia/epidemiology/diagnosis ; }, abstract = {BACKGROUND: Most adults aged ≥65 years live with multiple chronic conditions (MCC), and nearly one in four have recognized or unrecognized Alzheimer's disease and related dementias (ADRD), including an estimated 7.2 million Americans. Together, MCC and ADRD increase treatment complexity, medication burden, and the risk of adverse outcomes. Among patients who meet clinical criteria for mild cognitive impairment (MCI) or ADRD but lack a formal diagnosis, MCC burden remains unclear. This study examined the association between MCC burden and undiagnosed MCI and ADRD in a diverse cohort of older adults in primary care. METHODS: We conducted a cross-sectional analysis of 324 adults aged ≥65 from primary care clinics in Indiana and South Florida (2021-2023), as part of a larger ADRD detection study. Patients without documented MCI or ADRD completed standardized cognitive assessments. Cognitive status (normal, MCI, ADRD) was determined by interdisciplinary consensus. Chronic conditions and medications were extracted from electronic health records. Multinomial logistic regression was used to examine the association between MCC profiles and cognitive status. RESULTS: Among 324 older adults, 51.9% were determined to have MCI and 8% ADRD. Patients with MCI and ADRD had more chronic conditions (mean = 5-6) and medications (mean = 4-5) than those with normal cognition (p < 0.001). Anticholinergic use was more common in the MCI (23.8%) and ADRD (23.1%) groups than in those with normal cognition (10.8%). In adjusted models, MCI and ADRD were associated with higher odds of having more chronic conditions. Cerebrovascular disease was associated with both MCI and ADRD; diabetes, sleep apnea, and insomnia with MCI; and ischemic heart disease and insomnia with ADRD. CONCLUSION: Older adults with unrecognized MCI and ADRD experience substantial MCC and medication burden. These findings highlight the need for targeted primary care interventions that integrate cognitive screening, support MCC management, optimize self-management capacity, and promote safer prescribing.}, } @article {pmid41164318, year = {2025}, author = {Yaghmaei, E and Dillard, A and Rezaei, M and Rezaie, A and Pierce, A and Lu, H and Adams, E and Todorov, N and Ehwerhemuepha, L and Zheng, J and Sajjadi, SA and Bazargan, M and Rakovski, C}, title = {Comprehensive descriptive analysis of large Alzheimer's disease patient cohorts.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251385560}, pmid = {41164318}, issn = {2542-4823}, support = {R25 MD007610/MD/NIMHD NIH HHS/United States ; U54 MD007598/MD/NIMHD NIH HHS/United States ; }, abstract = {BACKGROUND: Precise estimates of the prevalence of Alzheimer's disease (AD), the distribution of demographic characteristics, comorbidities, treatment plans, insurance types, cost of treatment and survival probabilities at various time points are crucially important to advancing our understanding and for improving future AD research studies. OBJECTIVE: We analyzed two of the largest and high-quality medical databases, Oracle EHR Real-World Data and IQVIA. The results provide the most complete description of the AD patients in the US. METHODS: We present high-accuracy summary statistics of many important variables related to AD patients. Proportions, means and 95% confidence intervals were provided for all levels of the categorical and quantitative variables. RESULTS: We report high accuracy estimates of the overall survival probabilities for the first five years after initial diagnosis, drug treatments and patterns of use, demographics, insurance types, hospitalization duration, number of hospital visits, and a detailed list of comorbidities. We also report estimates of the annual total average cost of treatment per patient as well as itemized allocations for drugs, hospitalizations, surgery, and management costs. CONCLUSIONS: We present the most complete, detailed and high-accuracy descriptive analysis of AD patients to date.}, } @article {pmid41164084, year = {2025}, author = {Zhu, L and Cai, M and Lu, Z and Wang, Q and Zhai, T and Hu, J}, title = {The impact of high-intensity interval training on cerebrovascular function in the APP/PS1 mice.}, journal = {Frontiers in aging}, volume = {6}, number = {}, pages = {1647628}, pmid = {41164084}, issn = {2673-6217}, abstract = {ABSTRACT: Alzheimer's disease (AD), the most commonly diagnosed form of senile dementia worldwide, is closely associated with aging and distinct neuropathological features. Recent studies highlight that up to 90% of individuals, either preclinical or clinical, diagnosed with vascular pathology in the context of AD exhibit thickening and hyalinization of the media in small and medium-sized cerebral vessels. Exercise has emerged as a potential, non-pharmaceutical, and cost-effective intervention for the prevention and treatment of AD. However, there is limited research exploring the effects of high-intensity interval training (HIIT) on cerebrovascular function in AD. METHODS: Four-month-old female C57BL/6 J mice and APP/PS1 transgenic mice were initially acclimated to a standard diet for 1 week. The two groups were then divided into sedentary and exercise cohorts, with the exercise group engaging in a 6-week HIIT regimen. Post-intervention, hippocampal specimens were collected for analysis. Aβ and Tau protein levels were measured to assess AD pathology, while cognitive function was evaluated using the eight-arm radial maze and BDNF mRNA expression. Additionally, markers of cerebrovascular function-including VEGF, EPO, eNOS, GPR68, and ET-1-were examined, and HIF-1α was utilized to assess the hippocampal response to AD pathology. RESULTS: HIIT significantly reduced reference memory errors (p = 0.025) and markedly upregulated Bdnf mRNA expression (p < 0.001) specifically in APP/PS1 mice. Furthermore, HIIT significantly decreased protein levels of AD pathological markers p-TAU (p = 0.001) and APP (p = 0.002) in APP/PS1 mice. HIIT significantly increased the mRNA (p < 0.001) and protein (p = 0.003) levels of EPO and Vegfa mRNA (p < 0.001) levels to stimulate pro-angiogenic signal in APP/PS1 mice. HIIT also significantly increased both the mRNA and proteins levels of eNOS expression (p < 0.001) while decreasing the mRNA and proteins levels of ET-1 (p < 0.001) and GPR68 (p < 0.001) to enhance vasodilation in APP/PS1 mice. Finally, HIIT significantly increased HIF-1α expression at both protein and mRNA levels (p < 0.001), independent of genotype. CONCLUSION: HIIT ameliorates cognitive function and reduces hallmark AD pathology. This positive effect is potentially mediated through cerebral microangiogenesis, cerebrovascular function regulation, and hypoxic metabolism. HIIT represents a promising non-pharmacological strategy for targeting multiple aspects of AD pathophysiology.}, } @article {pmid41163934, year = {2025}, author = {Jafari, M and Alipour, M and Zamani, S and Mohtasham Amiri, A and Pourabbas, P and Hasannejad-Bibalan, M}, title = {Probiotics as a Complementary Medicine in Neurologic Disorders.}, journal = {Health science reports}, volume = {8}, number = {11}, pages = {e71422}, pmid = {41163934}, issn = {2398-8835}, abstract = {BACKGROUND AND AIMS: Today, neurological and neuropsychiatric disorders, including depression, anxiety, Parkinson's disease (PD), Alzheimer's disease (AS), autism spectrum disorder (ASD), and multiple sclerosis (MS), contribute significantly to global disability and healthcare burden. Most current treatment options only provide symptomatic relief and are limited by challenges such as drug resistance, systemic side effects, and poor blood-brain barrier permeability. The growing interest in the gut-brain axis has encouraged exploration of the gut microbiota as a potential therapeutic target. Probiotics-live microorganisms that may confer health benefits to the host-have been proposed to modulate the gut-brain axis through immune, metabolic, and neurochemical pathways. METHODS: In this narrative review, a targeted search was performed across multiple databases to identify relevant articles, from which the key relationships and strategies were extracted. Then, we represented the findings to provide a comprehensive overview of the topic and highlight emerging trends and gaps in the literature. RESULTS: Emerging preclinical and clinical studies suggest that specific probiotic strains can improve neurological symptoms by reducing neuroinflammation, supporting gut barrier integrity, and influencing neurotransmitter production. However, findings remain heterogeneous due to strain specificity, individual microbiome diversity, and methodological differences across studies. Preclinical and clinical studies suggest that specific probiotic strains can improve neurological symptoms by reducing neuroinflammation, enhancing gut barrier integrity, and influencing neurotransmitter production. Evidence supports their potential as adjunctive treatments for major neurological and neuropsychiatric disorders, including depression, anxiety, ASD, PD, AD, and MS, particularly in patients with gut dysbiosis or gastrointestinal comorbidities. However, findings remain heterogeneous due to strain specificity, individual microbiome variability, and methodological differences across studies. CONCLUSION: This brief review summarizes the current evidence on the use of probiotics in neurological disorders, discusses potential mechanisms of action, and highlights safety considerations and limitations. Future directions include personalized probiotic therapies, large-scale randomized controlled trials, and integration with conventional neurological therapies. Overall, probiotics could be a low-risk, complementary option in the evolving field of neurotherapy, but more rigorous evidence is needed before definitive clinical recommendations can be made.}, } @article {pmid41163844, year = {2025}, author = {Kurban, B and Sağlık Özkan, BN and Osmaniye, D and Levent, S and Özkay, Y and Kaplancıklı, ZA}, title = {Structure-based design, synthesis, and biological activity evaluation of chalcone-piperazine derivatives as dual AChE and MAO B inhibitors.}, journal = {RSC advances}, volume = {15}, number = {48}, pages = {40897-40911}, pmid = {41163844}, issn = {2046-2069}, abstract = {The development of pharmaceutical compounds for the treatment of Alzheimer's Disease (AD) and other neurodegenerative diseases is crucial, as the pathophysiology of AD remains incompletely understood and effective treatments are still lacking. In this study, a series of novel compounds based on Donepezil, incorporating piperazine and chalcone structures, were designed, synthesized, and characterized. The structures of the compounds were confirmed using IR, [1]H-NMR, [13]C-NMR, and HRMS techniques. Biological activities of the compounds were evaluated against cholinesterase enzymes and monoamine oxidase enzymes. The most potent derivative against acetylcholinesterase (AChE) was compound 4g, with an IC50 value of 0.027 ± 0.001 μM, and the most potent against monoamine oxidase B (MAO B) was also 4g, with an IC50 value of 0.114 ± 0.003 μM. In silico studies further elucidated the interaction of compound 4g with AChE. Molecular docking revealed key interactions between 4g and amino acids in the AChE active site. A 100 ns molecular dynamics simulation confirmed the stability of the 4g-AChE complex.}, } @article {pmid41163274, year = {2025}, author = {Sanghvi, G and Deepak, A and R, R and Ariffin, IA and Kashyap, A and Chahar, M and Nanda, A and Ray, S and Joshi, KK}, title = {Chondroitinase ABC in Neural Regeneration: Advances in CNS and Peripheral Nerve Repair.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128392818251012115510}, pmid = {41163274}, issn = {1873-4286}, abstract = {Chondroitinase ABC (ChABC) is a bacterial enzyme that can potentially address the inhibitory effects of Chondroitin Sulfate Proteoglycans (CSPGs) in various neurological disorders and injuries. CSPGs are key components of the extracellular matrix that, when accumulated after Central Nervous System (CNS) injury or neurodegenerative diseases, inhibit axonal growth and tissue repair. This review explores the therapeutic potential of ChABC in Spinal Cord Injury (SCI), Traumatic Brain Injury (TBI), stroke, Parkinson's Disease (PD), Alzheimer's Disease (AD), and peripheral nerve regeneration. ChABC's mechanism of action involves the degradation of CSPGs, promoting neural plasticity, axonal regeneration, and functional recovery in SCI and other CNS injuries. In stroke and TBI, ChABC treatment has been shown to enhance neurogenesis, reduce glial scar formation, and support neuronal survival. In neurodegenerative conditions like PD and AD, ChABC's ability to modify the inhibitory extracellular environment offers novel strategies for promoting neuronal repair and cognitive function. Additionally, ChABC has been explored in cancer therapy, where its ability to degrade the tumor extracellular matrix facilitates improved drug delivery and tumor infiltration. While ChABC holds promise, challenges remain in its clinical application, particularly regarding stability, targeted delivery, and long-term effects. This review discusses the mechanism of action of ChABC and various delivery strategies, including viral vectors and localized infusion, and emphasizes the need for further research to optimize ChABC's potential. The future of ChABC in regenerative medicine depends on overcoming these barriers, improving delivery methods, and exploring synergistic treatments for enhanced recovery outcomes.}, } @article {pmid41163120, year = {2025}, author = {Juan, Y and Wei, T and Weiwei, Z and Dongdong, S and Mengjie, Z and Xuefeng, W and Xianglong, L and Yuelong, S and Jinhua, Z and Xiumei, L}, title = {Regulation on microbial composition,serotonergic synapse, and apoptotic signaling pathway by extracts fromSonchus brachyotus DC. (SBE) to improve ethanol-induced acute oxidative stress in mice.}, journal = {Microbiome}, volume = {13}, number = {1}, pages = {221}, pmid = {41163120}, issn = {2049-2618}, support = {CAAS-IFR-ZDRW202406//The Agricultural Science and Technology Innovation Program/ ; }, mesh = {Animals ; *Oxidative Stress/drug effects ; Mice ; *Gastrointestinal Microbiome/drug effects ; *Apoptosis/drug effects ; Signal Transduction/drug effects ; *Plant Extracts/pharmacology ; Ethanol/toxicity/adverse effects ; Male ; *Synapses/drug effects/metabolism ; Bacteria/classification/genetics/drug effects/isolation & purification ; Antioxidants/pharmacology ; *Sonchus/chemistry ; RNA, Ribosomal, 16S/genetics ; }, abstract = {BACKGROUND: Oxidative stress has been firmly established as a pivotal contributor to the pathogenesis of inflammatory bowel disease, diabetes mellitus, Alzheimer's disease, and other multifactorial disorders. Our previous findings have demonstrated the extracts from Sonchus brachyotus DC. (SBE) mitigates intestinal oxidative stress through interactions between the oxidative stress biomarkers and gut microbiota. However, we did not focus on the mechanism by which SBE exerts antioxidant stress effects through regulating metabolites and genes, nor the correlation between the two and gut microbiota. Therefore, this study aimed to elucidate the underlying mechanism by which SBE mitigates oxidative stress through the gut microbiota, metabolites, and genes. RESULTS: Supplementation with SBE exerts a promising regulatory effect on oxidative stress by modulating key oxidative stress biomarkers (e.g., GSH, SOD, etc.) in serum, intestine, liver, and brain tissues in ethanol-model mice. And the SBE treatment exhibited a notable reparative effect on intestine, liver, and brain tissue damage. Concomitantly, 16S rRNA and ITS sequencing revealed significant alterations in the composition of intestinal bacteria and fungi in SBE-treated mice, suggesting the restoration of gut microbiota homeostasis. Spearman correlation analysis further indicated significant associations (p < 0.05) between gut microbes, particularly fungal genera, and oxidative stress biomarkers. Notably, the abundance of specific fungal genera (Alternaria and Pichia), the levels of 14,15-DiHETrE, 5-Hydroxyindole-3-acetic acid, and prostaglandin C2 key metabolites of the serotonergic synapse pathway, and the expression of Fas and Tnfsf10 key genes of apoptosis signaling pathway were significantly correlated (p < 0.05) based on the constructed correlation network. This mechanism likely triggers coordinated changes in metabolites and gene expression associated with the serotonergic synapse and apoptosis signaling pathways, ultimately leading to multi-targeted amelioration of oxidative stress. Molecular docking further revealed that trigonelline, mesaconic acid, and salicylic acid, bioactive components of SBE, may exhibit considerable binding affinity with Fas and Tnfsf10, providing a potential structural basis for SBE's regulatory effects on oxidative stress via modulation of the apoptotic signaling. CONCLUSIONS: The antioxidant effects of SBE likely involve multi-pathway and multi-target mechanisms, consistent with the combinatorial properties of its herbs constituents. These findings lays a foundation for subsequent research. Video Abstract.}, } @article {pmid41162940, year = {2025}, author = {Arif, M and Musleh, S and Alam, T}, title = {DeepB[3]Pred: blood-brain barrier peptide predictor using stacked BiGRU model with novel features.}, journal = {BMC biology}, volume = {23}, number = {1}, pages = {325}, pmid = {41162940}, issn = {1741-7007}, mesh = {*Blood-Brain Barrier/metabolism ; *Deep Learning ; *Computational Biology/methods ; *Cell-Penetrating Peptides/chemistry ; *Peptides/chemistry ; }, abstract = {BACKGROUND: The blood-brain barrier (B[3]) acts as a membrane that is a major concern in treating central nervous system (CNS) disorders. The B[3] penetrating peptides (B[3]PPs) play a significant role in delivering therapeutic drugs to a wide range of disorder diseases such as multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Therefore, the correct identification of drug agents is important for the disease treatment. Generally, the computational methods are more cost effective and faster than conventional wet-lab methods in predicting B[3]PPs. Consequently, we have developed a novel deep learning-based predictor called DeepB[3]Pred that accurately predicts the B[3]PPs and non-B[3]PPs from sequence data. RESULTS: In the proposed method, we used three types of novel features namely Pseduo residue energy content matric (PseRECM), graphical and statistical-based feature engineering (GSFE), and composition-transition and distribution (CTD)-based features. These features capture the energy-, graphical-, and compositional-based properties of from the primary peptide sequences. The data skewness is recognized as an inevitable issue that was tackled by employing a random under sampling technique. The extracted data were fed into various deep learning, i.e., stacked bidirectional gated recurrent unit (BiGRU), Deep Forest, and machine learning models, i.e., CatBoost, Support Vector Machine. BiGRU-based DeepB[3]Pred model attained better results than the other state-of-the-art B[3]PPs predictors. The prediction efficacy of the proposed model on fivefold cross-validation in terms of accuracy is 0.945, MCC of 0.877, and area under the curve (AUC) of 0.965. The generalization performance on the unseen data is reported as 0.869 for accuracy, 0.635 for MCC, and 0.933 for AUC. CONCLUSION: We believe our research will accelerate the peptide-based drug discovery for neurological diseases in particular.}, } @article {pmid41161455, year = {2025}, author = {Ishaq, K and Arputharaj, E and Khan, MB and Dahms, HU and Delattre, C and Chao, YY and Huang, YL}, title = {Turning an adversary into an ally: Self-assembled amyloid-like fibril aerogel packed 3D-printed microfluidic sample pre-treatment device for elemental analysis.}, journal = {International journal of biological macromolecules}, volume = {332}, number = {Pt 1}, pages = {148590}, doi = {10.1016/j.ijbiomac.2025.148590}, pmid = {41161455}, issn = {1879-0003}, mesh = {*Printing, Three-Dimensional ; *Amyloid/chemistry ; Gels/chemistry ; Muramidase/chemistry ; *Lab-On-A-Chip Devices ; Polyethyleneimine/chemistry ; Graphite/chemistry ; Limit of Detection ; Humans ; Nitrogen Compounds ; }, abstract = {In this study, we transformed well-known disease-causing amyloid fibrils into a functional ally. Instead of using Alzheimer's disease associated amyloid-beta fibrils we employed synthetic lysozyme derived amyloid-like fibrillar aggregates. We developed a simple and effective method for enriching and detecting various toxic elements in complex serum samples. This method employs a reusable 3D-printed microfluidic sample pre-treatment device, packed with a bio-based aerogel elemental ion extractant composed of self-assembled amyloid-like lysozyme fibrillar aggregates (AF), graphitic carbon nitride nanosheets (g-C3N4 NSs), and polyethyleneimine (PEI). The developed setup is integrated with inductively coupled plasma mass spectrometry (ICP-MS), enabling accurate elemental analysis without interference from the sample matrix. The synthesized elemental ion extractant aerogel is rich in diverse functional groups, significantly enhances the element extraction efficiency compared to conventional toxic element sorbents lacking structured amyloid-like networks. The established method yielded significant detection limits ranging from 1 to 100 μg L[-1] for Ag[+], Cr[3+] and Se IV over other elements with relative standard deviations (RSDs) between 2.1 and 4.6 %. Specifically, the approach achieved a limit of detection (LOD) of 0.2 μg L[-][1] for Cr, 0.4 μg L[-][1] for Se, and 1.1 μg L[-][1] for Ag. High recovery rates ranging from 85 to 102 % were achieved in spiked complex serum matrices. Moreover, the proposed multifunctional 3D-printed microfluidic approach significantly enhanced the selective extraction and detection of toxic elements in complex serum samples, demonstrating robust performance over seven adsorption-desorption cycles and representing a sustainable and significant analytical advancement.}, } @article {pmid41161293, year = {2025}, author = {Sahoo, SS and Paidesetty, SK and Sahu, PK and Pattanaik, S and Dandela, R}, title = {Therapeutic innovation through drug repurposing: A multidimensional approach toward treating Parkinson's disease.}, journal = {Bioorganic chemistry}, volume = {166}, number = {}, pages = {109129}, doi = {10.1016/j.bioorg.2025.109129}, pmid = {41161293}, issn = {1090-2120}, mesh = {Animals ; Humans ; *Antiparkinson Agents/chemistry/therapeutic use/pharmacology ; *Drug Repositioning ; Molecular Structure ; *Neuroprotective Agents/chemistry/therapeutic use/pharmacology ; *Parkinson Disease/drug therapy ; Rifaximin/chemistry/pharmacology ; }, abstract = {Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease, primarily affecting the aging population. Despite the introduction of levodopa in the 1960s and significant progress in managing PD symptoms, no treatment has yet demonstrated neuroprotective efficacy. The complexity and multifactorial nature of PD continue to present substantial therapeutic challenges, prompting researchers to explore alternative approaches such as drug repurposing. This strategy offers a time- and cost-efficient route to drug development. Recent efforts have focused on repurposing agents originally developed for metabolic and other non-neurological disorders. Ongoing research is actively investigating several repurposed drugs originally intended for different conditions, including anti-hypertensives (isradipine, dexmedetomidine), anti-asthmatics (montelukast), phosphodiesterase5 inhibitors (sildenafil), antimicrobials (rifaximin), and various CNS-active agents (aripiprazole, escitalopram, paroxetine, venlafaxine, duloxetine, caffeine). While drug repurposing holds considerable promise, comprehensive preclinical and clinical studies are essential to validate these candidates for PD-specific therapeutic applications. This review aims to provide an in-depth overview of PD, encompassing its pathological and molecular characteristics, and to critically evaluate the current landscape of drug repurposing strategies to develop effective therapies for PD.}, } @article {pmid41160917, year = {2025}, author = {Rößler, H and Hamzehpour, L and Grimm, O}, title = {Transdiagnostic neuroanatomical risk in schizophrenia: integrating regional vulnerability indices with anthropometric and fitness-based markers of cardiometabolic health.}, journal = {NeuroImage. Clinical}, volume = {48}, number = {}, pages = {103897}, pmid = {41160917}, issn = {2213-1582}, mesh = {Humans ; *Schizophrenia/diagnostic imaging/physiopathology/pathology/epidemiology ; Male ; Female ; Middle Aged ; Adult ; Magnetic Resonance Imaging ; *Physical Fitness/physiology ; Anthropometry ; Hand Strength/physiology ; *Cardiorespiratory Fitness/physiology ; Neuroimaging/methods ; }, abstract = {Schizophrenia is a multisystem disorder affecting both brain and body, with patients exhibiting substantial somatic comorbidities including obesity, reduced physical fitness, and elevated cardiometabolic risk. While neuroimaging-derived Regional Vulnerability Indices (RVIs) have quantified brain structural deviations from disorder-specific patterns, their relationship to physical health in schizophrenia remains largely unexplored. In this study, we combined RVIs with detailed anthropometric and fitness assessments in 42 schizophrenia patients and 43 matched healthy controls. Participants underwent MRI-based cortical thickness analyses to derive RVIs for nine psychiatric, neurological, and metabolic disorders, alongside measurements of body composition, cardiorespiratory fitness, handgrip strength, and jump performance. Patients exhibited significantly higher RVIs for schizophrenia (Cohen's D = -1.1), bipolar disorder (Cohen's D = -0.9), Alzheimer's (Cohen's D = -0.6) and Parkinson's disease (Cohen's D = -0.7), and type 2 diabetes (Cohen's D = -0.9). These overlapping neuroanatomical vulnerabilities across psychiatric, neurodegenerative, and metabolic conditions might reflect shared underlying genetic and physiological mechanisms. Principal component analysis revealed three latent dimensions: (1) general risk factors, (2) physical fitness deficits, and (3) psychosis-spectrum vulnerability, with the latter two showing significant differences between groups. These findings highlight that metabolic impairment and reduced physical fitness in schizophrenia are not merely secondary phenomena but constitute distinct dimensions of systemic vulnerability. Overall, our results support a brain-body conceptualization of schizophrenia, suggesting that RVIs may serve as biomarkers to guide precision medicine interventions integrating neuroprotective strategies with lifestyle management. Future research should incorporate longitudinal and multimodal assessments to clarify causal relationships and optimize individualized treatment approaches.}, } @article {pmid41160464, year = {2026}, author = {Kim, M and Kwon, H and Sohn, S and Lee, WJ and Cho, K and Kim, GW}, title = {Alzheimer's disease diagnosis and treatment: From pathophysiological insights to therapeutic advances in the era of precision neurology (2025 review).}, journal = {Journal of Alzheimer's disease : JAD}, volume = {109}, number = {1}, pages = {17-33}, doi = {10.1177/13872877251391820}, pmid = {41160464}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/physiopathology ; *Precision Medicine/methods/trends ; Biomarkers/cerebrospinal fluid ; Neuroimaging ; *Neurology/trends/methods ; Artificial Intelligence ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder marked by progressive cognitive decline, functional impairment, and ultimately, loss of independence. Traditional models centered on amyloid-β and tau pathology have expanded to encompass interconnected processes such as neuroinflammation, synaptic dysfunction, and gut-brain axis disruption, underscoring the multifactorial nature of the disease. In this review, we delivered that advances in diagnosis now integrate fluid biomarkers within the A/T/N/X framework, high-resolution neuroimaging, and artificial intelligence, enabling earlier and more precise disease characterization. On the therapeutic front, the approval of anti-amyloid monoclonal antibodies marks a paradigm shift toward disease-modifying approaches, yet challenges remain regarding efficacy, safety, and accessibility. Complementary strategies, including cognitive interventions and innovative drug delivery systems, highlight the need for multidimensional care that extends beyond pharmacology to improve patient quality of life. Furthermore, emerging avenues such as stem cell therapy, multitarget drug development, and precision medicine approaches illustrate a field in transition-shifting from symptomatic management toward personalized strategies aimed at altering the course of AD.}, } @article {pmid41160460, year = {2025}, author = {Cury, RM and da Silva, T and Cezar-Dos-Santos, F and Fakih, YRC and Narvaez, KAR and Gouvea, MC and Espínola, C and Ferreira, CF and de Castro, WAC and Pamplona, FA and Silva, EGD and Bicca, MA and Nascimento, FP}, title = {A randomized clinical trial of low-dose cannabis extract in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1602-1613}, doi = {10.1177/13872877251389608}, pmid = {41160460}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Double-Blind Method ; Male ; Female ; Aged, 80 and over ; Aged ; *Dronabinol/therapeutic use/administration & dosage ; *Plant Extracts/therapeutic use/administration & dosage ; Middle Aged ; Treatment Outcome ; *Cannabidiol/therapeutic use/administration & dosage ; Mental Status and Dementia Tests ; *Cannabis ; }, abstract = {BackgroundPreclinical and clinical evidence suggest that low-dose cannabinoids could ameliorate Alzheimer's disease (AD) signs and symptoms. We designed this trial to evaluate the safety and efficacy of low-dose THC-CBD balanced cannabinoid extract in the treatment of patients with AD-associated dementia.ObjectiveThe objective of this phase 2 trial was to evaluate the safety and efficacy of a balanced THC-CBD cannabinoid extract for symptomatic patients with AD.MethodsA Phase 2, randomized, double-blind, placebo-controlled, clinical trial including patients between 60 and 80 years-old diagnosed with AD-associated dementia. For 26 weeks, participants orally received either placebo or THC-CBD extract (0.350 mg/THC and 0.245 mg/CBD), daily.ResultsAt week 26, Mini-Mental State Exam total score was significantly higher in cannabis- when compared to placebo-treated patients, which was assessed using the mixed model analysis. No significant difference was detected between placebo and cannabis groups in terms of secondary outcomes and adverse events incidence.ConclusionsTo this date, this is the longest clinical trial evaluating cannabinoids effects on AD patients. We initially demonstrate that low-dose THC-CBD potentially can be an effective and safe therapeutic option for AD-related dementia. Nonetheless, larger and longer trials are necessary to confirm this finding and establish cannabinoid administration as therapy for AD dementia.Trial RegistrationThe Brazilian Registry of Clinical Trials (ReBEC) registration #U1111-1258-2058 - REBEC (ensaiosclinicos.gov.br).}, } @article {pmid41160443, year = {2025}, author = {Lim, MJ and Cheung, CY and Chong, JR and Chua, J and Hilal, S and Lai, MK and Maier, AB and Schmetterer, L and Tan, BY and Venketasubramanian, N and Wong, TY and Xu, X and Yeo, BT and Zhou, JH and Chen, CL}, title = {HARMONISATION - A multimodal prospective study of vascular cognitive impairment in multi-ethnic Asians: Cohort profile, progress, current contributions, and future impact.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1452-1474}, doi = {10.1177/13872877251389006}, pmid = {41160443}, issn = {1875-8908}, mesh = {Aged ; Female ; Humans ; Male ; Asian People/ethnology ; Biomarkers ; *Cerebrovascular Disorders/complications ; *Cognitive Dysfunction/ethnology/diagnostic imaging ; Cohort Studies ; *Dementia, Vascular/ethnology ; Prospective Studies ; Observational Studies as Topic ; Middle Aged ; Aged, 80 and over ; }, abstract = {Vascular cognitive impairment (VCI) describes cerebrovascular disease (CeVD)-associated cognitive disorders regardless of pathogenesis, ranging from a prodrome to dementia. Heterogeneity in the etiology and severity of CeVD, and significant co-occurrence with Alzheimer's disease (AD) pathology has hampered investigations. Research into VCI is especially relevant in Asia, where cognitive impairment and dementia, often due to VCI, grows due to rapidly aging populations and high prevalence of vascular risk factors. This manuscript reviewed the rationale, unique positioning, design, methodology, and findings from the HARMONISATION study, a prospective observational study of VCI and AD in multi-ethnic Asians. HARMONISATION aimed to discover and validate novel biomarkers as effective diagnostic and prognostic tools, and translate findings into improved patient care, disease management and treatment-utilizing comprehensive multimodal clinical, neuroimaging, retinal, and blood biomarker data to address critical research gaps such as the etiology and clinical importance of mixed dementia, relationships between AD and CeVD pathology, and challenges of heterogenous CeVD pathology. HARMONIZATION recruited and deeply phenotyped 700 older multi-ethnic Asians with no cognitive impairment, mild cognitive impairment, and dementia for up to 5 years of follow-up. It has yielded developments in biomarker identification, validation, interactions and analysis methods; disease mechanisms and progression; clinical prognostics for VCI and AD; improved patient care and management; and enabled future development of novel interventions in Asians, and globally. An ongoing extension study will allow up to 10 years follow-up to further explore specific modifiable processes of VCI and the contributions of vascular events to cognitive impairment.}, } @article {pmid41160347, year = {2025}, author = {Brixner, DI and Zhao, C and Toyosaki, H and Frech, FH and Rosenbloom, MH}, title = {Initial Real-World Evidence for Lecanemab in the United States.}, journal = {Drugs & aging}, volume = {}, number = {}, pages = {}, pmid = {41160347}, issn = {1179-1969}, abstract = {BACKGROUND: Lecanemab is the first anti-amyloid monoclonal antibody with full approval in the US for the treatment of early Alzheimer's disease (AD). This observational study aimed to provide information about patient demographics, clinical characteristics, provider specialty, and lecanemab utilization patterns. METHODS: This observational study used open administrative claims from the PurpleLab, a database encompassing medical and pharmacy claims derived from diverse sources, such as clearinghouses and Pharmacies. We included patients receiving one or more lecanemab doses between January 6, 2023 and October 31, 2024, and having continuous clinical activity ≥ 6 months prior to the first lecanemab infusion. The observation period ran from the first lecanemab infusion to the latest clinical activity or data availability. Treatment gaps were calculated as the number of gap days in lecanemab supply between consecutive infusions. RESULTS: Among the study population (n = 4261), mean age was 75.2 years, 77.8% were White, 98.4% lived in urban settings, 81.7% were treated by neurologists, 77.3% had AD, and 31.7% had mild cognitive impairment. Mean follow-up period was 171.1 days. Lecanemab infusions averaged 1.9 per patient per month (SD 1.0), 16.3 days apart (SD 11.0), and 2.8% of patients experienced a treatment interruption ≥90 days. CONCLUSIONS: Lecanemab utilization followed US FDA-approved prescribing information. Disparities for minority and rural-based populations were observed suggesting opportunities to improve access for underserved populations.}, } @article {pmid41160319, year = {2025}, author = {Sarikamis Johnson, B and Ercin, N and Kalkan Cakmak, R and Besli, N and Beker, M and Beker, MC and Celik, U}, title = {Exploring the effects of squalene in the PERK/ATF4/eIF2α/CHOP signalling pathway in an in vitro Alzheimer Disease model and in silico approach.}, journal = {Metabolic brain disease}, volume = {40}, number = {8}, pages = {300}, pmid = {41160319}, issn = {1573-7365}, support = {123Z925//Scientific and Technological Research Council of Türkiye/ ; 2021-067//University of Health Sciences, Türkiye/ ; }, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; Activating Transcription Factor 4/metabolism ; eIF-2 Kinase/metabolism ; *Signal Transduction/drug effects ; Eukaryotic Initiation Factor-2/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Transcription Factor CHOP/metabolism ; *Squalene/pharmacology/therapeutic use ; Unfolded Protein Response/drug effects ; Reactive Oxygen Species/metabolism ; Molecular Docking Simulation ; Amyloid beta-Peptides ; Oxidative Stress/drug effects ; Mesenchymal Stem Cells/drug effects/metabolism ; Cells, Cultured ; Peptide Fragments ; }, abstract = {Recent studies emphasize the pivotal role of endoplasmic reticulum (ER) stress in Alzheimer's disease (AD), highlighting the need for further investigation into this critical link. In response to ER stress, cells increase reactive oxygen species (ROS) production, leading to heightened oxidative stress. This interplay has sparked interest in antioxidant molecules such as squalene (SQ) as potential therapeutic agents. The primary objective of this study was to examine the impact of SQ on the unfolded protein response (UPR) pathway triggered by ER stress in an in vitro AD model. Herein, molecular docking analysis was performed to evaluate SQ interactions with target proteins, followed by in vitro assays. Human bone marrow-derived mesenchymal stem cells were differentiated into neuronal-like cells and characterized via immunostaining. The cells were then exposed to Aβ1-42 toxicity to establish an in vitro AD model. To assess the effects of SQ treatment following Aβ1-42 exposure, UPR-related proteins (BIP, p-PERK, PERK, eIF2α, p-eIF2α, ATF4, CHOP) were analysed by Western blotting; ROS levels were quantified to evaluate oxidative stress, and a TUNEL assay was performed to assess apoptosis. Our findings indicate that SQ alters protein expression within the UPR pathway in the AD experimental model. Notably, amyloid-β levels were significantly reduced in the SQ-treated group (p˂0.001). Furthermore, SQ reduced ROS levels. These results suggest that SQ holds potential as a therapeutic agent for mitigating amyloid-β toxicity.}, } @article {pmid41160288, year = {2025}, author = {Motamedzadeh, A and Karimzad, Y and Ferdosi, F and Nabavizadeh, F and Rahmati-Dehkordi, F and Dadgostar, E and Aschner, M and Validad, A and Kazemi, B and Tamtaji, OR}, title = {Potential of Benfotiamine in the treatment of neuropsychological disorders.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {26}, pmid = {41160288}, issn = {1573-4978}, mesh = {Humans ; *Thiamine/analogs & derivatives/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Mental Disorders/drug therapy/metabolism ; Signal Transduction/drug effects ; Thiamine Deficiency/drug therapy/metabolism ; }, abstract = {Neuropsychiatric disorders pose significant health challenges. Current drug therapies are often inadequate, highlighting the urgent need for new and effective treatments. Thiamine deficiency has been implicated in the pathophysiology of various neuropsychiatric disorders. In this context, benfotiamine, a synthetic thiamine derivative, has gained increasing attention for its potential therapeutic effects across a range of neuropsychiatric conditions. Emerging evidence supports the neuroprotective effects of benfotiamine, which are mediated through its modulation of diverse cellular and molecular pathways, i.e., Tau phosphorylation, amyloid β, oxidative stress, neuroinflammation, as well as synaptic plasticity via the glycogen synthase kinase-3β (GSK3β) signaling pathway. In this narrative review, we provide a comprehensive overview of the cellular and molecular pathways modulated by benfotiamine in the context of neuropsychiatric disorders. Specifically, we highlight its effects on oxidative stress, inflammatory signaling, mitochondrial function, glucose metabolism, and advanced glycation end-product (AGE) formation, all of which contribute to its neuroprotective and potentially therapeutic properties.}, } @article {pmid41158654, year = {2025}, author = {Chiba, T and Hattori, Y and Asakura, K and Sano, Y and Saito, S and Minami, M and Yamamoto, H and Ihara, M}, title = {Taxifolin for prevention of COGnitive impairment (T-COG trial): a study protocol for a randomized, double-blind, placebo-controlled trial.}, journal = {Frontiers in nutrition}, volume = {12}, number = {}, pages = {1686381}, pmid = {41158654}, issn = {2296-861X}, abstract = {BACKGROUND: In 2023 and 2024, the novel anti-β-amyloid antibodies lecanemab and donanemab have been approved for treatment of mild cognitive impairment and mild dementia in several countries, including Japan and the United States. Although they successfully eliminate accumulated β-amyloid, they merely delay cognitive deterioration and do not improve cognitive function. This suggests that β-amyloid elimination is insufficient for cognitive improvement. Therefore, novel treatments with pleiotropic neuroprotective effects are warranted. Taxifolin, a bioactive flavonoid, shows pleiotropic effects, such as inhibition of amyloid-β aggregation and oligomerization and hippocampal neuroinflammation, as well as stimulation of brain lymphatic vessel formation in our previous experimental studies. Furthermore, our preliminary observational study showed that oral administration of taxifolin was associated with cognitive improvement in patients with mild cognitive impairment or mild dementia. METHODS: This is a randomized, double-blind, placebo-controlled, crossover trial involving 60 patients with mild cognitive impairment or mild dementia. All participants will take 100-mg taxifolin or placebo capsules orally once daily for 12 weeks. The washout period will be 6 weeks. The primary objective is to determine the effect of taxifolin on cognitive impairment using the Montreal Cognitive Assessment. The main secondary objectives are to evaluate the impact of taxifolin on (i) prevention further cognitive decline, as evaluated by changes in the scores for total Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 and trail making test and (ii) changes in white matter hyperintensity volume and number of cerebral microbleeds on brain magnetic resonance imaging. DISCUSSION: This T-COG trial may provide valuable insights into new therapeutic approaches, considering that taxifolin has multitarget neuroprotection, which could prevent further cognitive decline, along with its highly safe profile and inexpensive cost. CLINICAL TRIAL REGISTRATION: https://jrct.mhlw.go.jp, jRCTs051250004.}, } @article {pmid41157961, year = {2025}, author = {Cruz-Aguilar, MA and Hernández-Arteaga, E and Ramírez-Salado, I and Hernández-González, M and Guevara, MA}, title = {Melatonin reorganizes the sleep EEG spectral power in Alzheimer's disease: a preliminary principal component analysis-based comparison of placebo and treatment effects.}, journal = {Neurological research}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/01616412.2025.2578344}, pmid = {41157961}, issn = {1743-1328}, abstract = {OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaque accumulation, tau pathology, and cortical atrophy, leading to widespread synaptic dysfunction and cognitive decline. Sleep disturbances are highly prevalent in AD and are thought to both reflect and exacerbate underlying neurodegenerative processes. Melatonin, an indoleamine synthesized by the pineal gland, is central to the regulation of circadian rhythms and sleep - wake cycles. In healthy individuals, melatonin enhances non-rapid eye movement (NREM) sleep and attenuates beta activity during wakefulness. In AD populations, it has been associated with improved sleep quality and potential neuroprotective effects against amyloid-related pathology. Electroencephalography (EEG) offers a non-invasive method to monitor neurophysiological changes associated with AD. Principal component analysis (PCA), a dimensionality reduction technique, enables the identification of latent neural patterns within complex EEG data. METHODS: In this preliminary study, PCA was applied to EEG recordings from eight individuals with mild-to-moderate AD during both wakefulness and sleep under placebo and melatonin conditions. EEG derivations included bipolar (F7-T3, F8-T4, F3-F4, O1-O2) and referential (C3-A1, C4-A2) configurations. RESULTS: Preliminary PCA suggests that melatonin administration may induce a stage-dependent reorganization of EEG spectral activity, characterized by a relative enhancement of slow-frequency activity and an apparent increase in spectral segregation during NREM sleep. DISCUSSION: These preliminary findings suggest that melatonin could optimize stage-specific neural dynamics, supporting its therapeutic potential in AD-related sleep disruption.}, } @article {pmid41156471, year = {2025}, author = {Zhang, J and Zhang, J}, title = {Natural Small-Molecule Bergapten Ameliorates Amyloid-β Pathology and Neuroinflammation in Alzheimer's Disease.}, journal = {Nutrients}, volume = {17}, number = {20}, pages = {}, pmid = {41156471}, issn = {2072-6643}, support = {2022QH2300//Fujian Medical University/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Amyloid beta-Peptides/metabolism ; Microglia/drug effects/metabolism ; Molecular Docking Simulation ; *Neuroinflammatory Diseases/drug therapy ; Disease Models, Animal ; Male ; Maze Learning/drug effects ; MAP Kinase Signaling System/drug effects ; Memory/drug effects ; *Anti-Inflammatory Agents/pharmacology ; }, abstract = {BACKGROUND: The pathogenesis of Alzheimer's disease (AD) is complex, and effective treatments remain elusive. Growing evidence suggests that dietary factors may play a significant role in preventing or alleviating AD. Bergapten (BG), a natural compound with anti-inflammatory properties, has been studied; however, its specific role in neuroinflammation and AD pathogenesis remains unclear. METHODS: Through public databases and bioinformatics tools, the possible molecular mechanisms of BG's effects on AD were analyzed. Six-month-old 5×FAD mice underwent intragastric administration of BG for 30 consecutive days. Learning and memory abilities were assessed using the novel object recognition (NOR) test and the Morris water maze (MWM) test. Immunofluorescence staining, Western blot and q-PCR was conducted to assess the underlying mechanisms. In vitro experiments used Aβ-stimulated BV2 microglial cells for BG intervention. RESULTS: Bioinformatics analysis revealed the MAPK signaling pathway as the top-ranked pathway. Molecular docking studies further demonstrated strong binding interactions between BG and key proteins within the MAPK pathway. In behavioral studies, NOR test and MWM test demonstrated that BG treatment improved learning and memory abilities in 5×FAD mice. Additionally, BG treatment significantly reduced Aβ deposition, pro-inflammatory cytokine levels, and inhibited excessive microglial activation in these mice. Consistent with in vivo findings, BG effectively decreased pro-inflammatory cytokines in Aβ-stimulated BV2 microglial cells. Mechanistic studies revealed that BG attenuates neuroinflammatory responses by inhibiting the MAPK signaling pathway both in vivo and in vitro. CONCLUSIONS: Our findings suggest that BG mitigates AD pathological features by suppressing MAPK-mediated neuroinflammation and represents a promising natural small molecule for the prevention and treatment of AD.}, } @article {pmid41155570, year = {2025}, author = {Atanasova, M}, title = {Small-Molecule Inhibitors of Amyloid Beta: Insights from Molecular Dynamics-Part B: Natural Compounds.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {10}, pages = {}, pmid = {41155570}, issn = {1424-8247}, support = {Grant No BG16RFPR002-1.014-0018//the Centre of Excellence in Informatics and ICT funded by the Research, Innovation and Digitalization for Smart Transformation Programme 2021-2027 and co-financed by the European Union/ ; agreement D01-98/26.06.2025//the National Road Map/ ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive decline. Its key pathological hallmarks include extracellular amyloid plaques composed of amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. Although numerous studies have investigated the complex pathology of AD, its underlying mechanisms remain incompletely understood. The amyloid cascade hypothesis continues to be the leading model of AD pathogenesis. It suggests that Aβ aggregation is the initial trigger of neurotoxicity, setting off a cascade of pathological events including inflammation, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, and, ultimately, dementia. Molecular dynamics (MD) is a powerful tool in structure-based drug design (SBDD). By simulating biomolecular motions at the atomic level, MD provides unique insights into molecular properties, functions, and inhibition mechanisms-insights often inaccessible through other experimental or computational techniques. When integrated with experimental data, MD further deepens our understanding of molecular interactions and biological processes. Natural compounds, known for their pleiotropic pharmacological activities, favorable safety profiles, and general tolerability (despite occasional side effects), are increasingly explored for their potential in both the treatment and prevention of various diseases, including AD. In this review, we summarize current findings from MD simulations of natural compounds with anti-amyloidogenic potential. This work builds upon our previous publication, which focused on endogenous compounds and repurposed drugs. The review is structured as follows: an overview of the amyloid cascade hypothesis; a discussion of Aβ oligomeric structures and their stabilizing interactions; a section on molecular dynamics, including its challenges and future directions; and a comprehensive analysis of the inhibitory mechanisms of natural compounds, categorized by their shared structural features.}, } @article {pmid41155541, year = {2025}, author = {Perez, DM}, title = {α1A-Adrenergic Receptor as a Target for Neurocognition: Cautionary Tale from Nicergoline and Quinazoline Non-Selective Blockers.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {10}, pages = {}, pmid = {41155541}, issn = {1424-8247}, support = {R01 AG066627/AG/NIA NIH HHS/United States ; RO1AG066627/GF/NIH HHS/United States ; }, abstract = {Decades ago, previous studies that used non-selective ergot derivatives suggested that blockage of the α1A-adrenergic receptor mildly increased cognition through increased blood flow to the brain due to vasodilation and, thus, could be used as a treatment for dementia. However, further studies indicated that nicergoline was non-specific and hit many different targets. Today, a similar scenario is developing with the use of non-selective α1-AR antagonists of the quinazoline class, referred to as "osins", as potential treatments for COVID-19/SARS, post-traumatic stress disorder, cancer, and neurodegenerative disorders, such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. While there is extensive evidence of neuroprotection from many clinical trials, the mechanism of action of quinazolines is often not α1-AR-mediated but keyed to its glycolysis-enhancing effects through activation of the enzyme phosphoglycerate kinase 1 (PGK1). These studies have incorrectly labeled the α1A-adrenergic receptor as an "old target" to treat Alzheimer's and other neurocognitive diseases, hampering drug development. This review will summarize these and other studies to indicate that activation, not blockage, of norepinephrine's actions, through α1A-AR, mediates cognitive, memory, and neuroprotective functions that may reverse the progression of neurocognitive diseases.}, } @article {pmid41155525, year = {2025}, author = {Lin, GB and Liu, HH and Kuo, YY and Chen, YM and Hsu, FT and Wang, YW and Kung, Y and Ching, C and Chao, CY}, title = {Thermal Cycling Stimulation via Nasal Inhalation Attenuates Aβ25-35-Induced Cognitive Deficits in C57BL/6 Mice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155525}, issn = {1422-0067}, support = {NSTC 113-2112-M-002-024//National Science and Technology Council/ ; NSTC 112-2112-M-002-033//National Science and Technology Council/ ; MOST 110-2112-M-002-004//Ministry of Science and Technology/ ; }, mesh = {Animals ; *Amyloid beta-Peptides/metabolism/toxicity ; Mice ; Mice, Inbred C57BL ; *Cognitive Dysfunction/therapy/metabolism/chemically induced ; Male ; *Peptide Fragments/toxicity ; Hippocampus/metabolism ; Disease Models, Animal ; Alzheimer Disease/therapy/metabolism ; *Hyperthermia, Induced/methods ; Administration, Inhalation ; Maze Learning ; }, abstract = {Alzheimer's disease (AD) remains a significant public health challenge, with current treatments limited partly due to the difficulty of delivering therapeutics across the blood-brain barrier (BBB). The nose-to-brain (N-2-B) pathway offers a promising alternative to circumvent the BBB, but no drugs have yet been clinically applied via this route for AD. Mild stress is thought to activate intrinsic protective mechanisms against neurodegeneration, but traditional methods lack specificity and practicality. To address this, we propose the inhalation of mildly heated air as thermal stimulation, which utilizes the N-2-B pathway to induce mild stress and stimulate cerebral activity. This study employs thermal cycling-hyperthermia (TC-HT) in developing thermal cycling-stimulation via nasal inhalation (TCSNI), providing cyclic stimulation to maintain pathway activity while minimizing thermal injury. In C57BL/6 mice, TCSNI showed no adverse olfactory effects. In β-amyloid (Aβ)-treated mice, TCSNI significantly enhanced cognitive performance in Y-maze and novel object recognition (NOR) assessments, suggesting cognitive improvement. Mice hippocampal protein analyses indicated a reduction in Aβ accumulation, alongside increased expression of heat shock protein 70 (HSP70), insulin-degrading enzyme (IDE), and phosphorylated Akt (p-Akt). These results suggest that N-2-B-delivered TCSNI effectively modulates protein expression and enhances cognitive function, highlighting its potential for further exploration in AD treatment.}, } @article {pmid41155356, year = {2025}, author = {Trifonova, EA and Pashchenko, AA and Ivanov, RA and Kochetov, AV and Lashin, SA}, title = {Genetic and Pathogenic Overlaps Between Autism Spectrum Disorder and Alzheimer's Disease: Evolutionary Features and Opportunities for Drug Repurposing.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155356}, issn = {1422-0067}, mesh = {*Autism Spectrum Disorder/genetics/drug therapy ; Humans ; *Alzheimer Disease/genetics/drug therapy/metabolism ; *Drug Repositioning ; Gene Regulatory Networks ; TOR Serine-Threonine Kinases/metabolism/genetics ; Genetic Predisposition to Disease ; Evolution, Molecular ; Signal Transduction ; }, abstract = {Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are neurodevelopmental and neurodegenerative disorders, respectively. While exome sequencing is routinely employed during the early stages of ASD diagnosis, it rarely influences therapeutic strategies. To address this gap, we have reconstructed and analyzed the gene networks linking autism spectrum disorders, Alzheimer's disease, and mTOR signaling. In addition, we have performed a phylostratigraphic analysis that reveals similarities and differences in the evolution of both ASD and Alzheimer's disease predisposition genes. We have shown that almost half of the genes predisposing to autism and two-fifths of the genes predisposing to Alzheimer's disease are directly related to the mTOR signaling pathway. Analysis of Phylostratigraphic Age Index (PAI) value distributions revealed a significant enrichment of evolutionarily ancient genes in both ASD- and AD-related gene sets. When studying the distribution of ASD predisposition genes by Divergence Index (DI) values, a significant enrichment with genes having extremely low DI = 0 has been found. Such low DI values indicate that most likely these genes are under stabilizing selection. Using the ANDVisio tool, both pharmacological and natural mTOR regulators with potential for ASD treatment were selected, such as propofol, dexamethasone, celecoxib, statins, berberine, resveratrol, quercetin, myricetin, mio-inositol, and several amino acids.}, } @article {pmid41155218, year = {2025}, author = {Lee, J and Lee, E and Kwon, H and Moon, S and Bae, HJ and Hwang, JH and Cho, GH and Kong, H and Park, MH and Kim, SK and Kim, DH and Jung, JW}, title = {Synaptic Plasticity-Enhancing and Cognitive-Improving Effects of Standardized Ethanol Extract of Perilla frutescens var. acuta in a Scopolamine-Induced Mouse Model.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155218}, issn = {1422-0067}, support = {S3400191//Ministry of SMEs and Startups/ ; }, mesh = {Animals ; Scopolamine/toxicity ; Mice ; Male ; *Plant Extracts/pharmacology/chemistry ; *Perilla frutescens/chemistry ; *Neuronal Plasticity/drug effects ; Disease Models, Animal ; Mice, Inbred ICR ; Hippocampus/drug effects/metabolism ; Long-Term Potentiation/drug effects ; Ethanol/chemistry ; *Cognition/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism ; *Cognitive Dysfunction/drug therapy/chemically induced ; Maze Learning/drug effects ; }, abstract = {In our previous study, we demonstrated that a standardized ethanol extract of Perilla frutescens var. acuta (PE) alleviates memory deficits in an Alzheimer's disease mouse model by inhibiting amyloid β (Aβ) aggregation and promoting its disaggregation. However, the extent to which PE exerts additional cognitive benefits independent of Aβ pathology remained unclear. Here, we aimed to evaluate the effects of PE on synaptic plasticity and learning and memory functions. Male ICR mice were used, and cognitive impairment was induced by scopolamine administration. PE was orally administered at doses determined from previous studies, and cognitive performance was assessed using the passive avoidance, Y-maze, and Morris water maze tests. In parallel, hippocampal slices were employed to examine the effects of PE on synaptic plasticity. PE (100 and 300 μg/mL) significantly enhanced long-term potentiation (LTP) in a concentration-dependent manner without altering basal synaptic transmission. This facilitation of LTP was blocked by scopolamine (1 μM), a muscarinic acetylcholine receptor (mAChR) antagonist, and IEM-1460 (50 μM), a calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) inhibitor, indicating the involvement of mAChR and CP-AMPAR pathways. In vivo, PE (100, 250, and 500 mg/kg) treatment improved memory performance across all behavioral tasks and upregulated hippocampal synaptic proteins including GluN2B, PSD-95, and CaMKII. Collectively, these results demonstrate that PE ameliorates scopolamine (1 mg/kg)-induced cognitive impairment by enhancing synaptic plasticity, likely through modulation of mAChR, CP-AMPAR, and NMDA receptor signaling. These findings highlight the therapeutic potential of PE for memory deficits associated with cholinergic dysfunction.}, } @article {pmid41155192, year = {2025}, author = {Kowalczyk, T and Muskała, M and Piekarski, J and Kowalski, M and Staszewski, M and Konuklugil, B and Rijo, P and Sitarek, P}, title = {Therapeutic Promise and Biotechnological Prospects of Dendroaspis polylepis Venom Proteins: Mambalgins, Fasciculins, and Dendrotoxins.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155192}, issn = {1422-0067}, mesh = {Humans ; Animals ; *Snake Venoms/chemistry/therapeutic use/pharmacology ; *Neurotoxins/therapeutic use/pharmacology/chemistry ; Neoplasms/drug therapy ; Biotechnology/methods ; }, abstract = {Animal toxins contain various bioactive peptides and proteins which have evolved to interact in specific ways. As such, they are a good starting point for developing new drugs and vaccines. This paper examines three natural neurotoxins derived from the black mamba (Dendroaspis polylepis), which show significant pharmacological potential: mambalgins, fasciculins and dendrotoxins. All three may be of value in the treatment of pain, cancer and neurodegenerative disease. Mambalgins provide similar pain relief to opioids but without the risk of addiction; they act by selectively blocking acid-sensitive ion channels (ASICs), especially ASIC1a. Thanks to this inhibitory activity they also demonstrate selective activity against glioblastoma, melanoma and leukemia cells as innovative anticancer drugs. Fasciculins are very strong inhibitors of acetylcholinesterase (AChE) and hence offer promise in multi-target drugs and as treatments for treating Alzheimer's disease. Dendrotoxins such as DTX-K and DTX-I are able to modulate neuronal excitability and synaptic transmission by blocking voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.6); both have been shown to be effective against cancer cells, and to influence the cardiovascular, immune, and digestive systems. Recent advances in recombinant biotechnology and protein engineering have allowed their safe production with increased therapeutic value. The review examines the translational potential of D. polylepis venom proteins and highlights the need for additional preclinical research on bioactive molecules of toxin origin.}, } @article {pmid41155149, year = {2025}, author = {Frei, M and Wirawan, R and Wein, T and Bracher, F}, title = {Lead Structure-Based Hybridization Strategy Reveals Major Potency Enhancement of SirReal-Type Sirt2 Inhibitors.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155149}, issn = {1422-0067}, support = {project ID: 325871075-SFB1309//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) with funds from SFB1309 (Chemical Biology of Epigenetic Modifications)/ ; }, mesh = {*Sirtuin 2/antagonists & inhibitors/chemistry/metabolism ; Molecular Docking Simulation ; Humans ; Structure-Activity Relationship ; *Histone Deacetylase Inhibitors/chemistry/pharmacology ; }, abstract = {Selective and potent inhibitors of the NAD[+]-dependent deacetylase Sirt2 represent a valuable epigenetic strategy for the treatment of currently incurable diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, and multiple sclerosis. Guided by molecular docking and MM/GBSA validation studies, a lead structure-based hybridization strategy was developed, resulting in a series of very effective Sirt2 inhibitors. With RW-93, we present a highly potent and subtype selective Sirt2 inhibitor (IC50 = 16 nM), which as a next generation SirReal-type inhibitor significantly surpasses established Sirt2 inhibitors and contributes to the extension of the current SAR profile. The structural modification strategy employed in this study proved to be highly promising, resulting in the identification of the most potent low-molecular-weight Sirt2 inhibitor reported to date, providing a promising target for further medicinal chemistry-driven SAR studies.}, } @article {pmid41155106, year = {2025}, author = {Rahman, S and Rahman, MM and Bhatt, S and Sundararajan, R and Faezipour, M}, title = {NeuroNet-AD: A Multimodal Deep Learning Framework for Multiclass Alzheimer's Disease Diagnosis.}, journal = {Bioengineering (Basel, Switzerland)}, volume = {12}, number = {10}, pages = {}, pmid = {41155106}, issn = {2306-5354}, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia. This disease significantly impacts cognitive functions and daily activities. Early and accurate diagnosis of AD, including the preliminary stage of mild cognitive impairment (MCI), is critical for effective patient care and treatment development. Although advancements in deep learning (DL) and machine learning (ML) models improve diagnostic precision, the lack of large datasets limits further enhancements, necessitating the use of complementary data. Existing convolutional neural networks (CNNs) effectively process visual features but struggle to fuse multimodal data effectively for AD diagnosis. To address these challenges, we propose NeuroNet-AD, a novel multimodal CNN framework designed to enhance AD classifcation accuracy. NeuroNet-AD integrates Magnetic Resonance Imaging (MRI) images with clinical text-based metadata, including psychological test scores, demographic information, and genetic biomarkers. In NeuroNet-AD, we incorporate Convolutional Block Attention Modules (CBAMs) within the ResNet-18 backbone, enabling the model to focus on the most informative spatial and channel-wise features. We introduce an attention computation and multimodal fusion module, named Meta Guided Cross Attention (MGCA), which facilitates effective cross-modal alignment between images and meta-features through a multi-head attention mechanism. Additionally, we employ an ensemble-based feature selection strategy to identify the most discriminative features from the textual data, improving model generalization and performance. We evaluate NeuroNet-AD on the Alzheimer's Disease Neuroimaging Initiative (ADNI1) dataset using subject-level 5-fold cross-validation and a held-out test set to ensure robustness. NeuroNet-AD achieved 98.68% accuracy in multiclass classification of normal control (NC), MCI, and AD and 99.13% accuracy in the binary setting (NC vs. AD) on the ADNI dataset, outperforming state-of-the-art models. External validation on the OASIS-3 dataset further confirmed the model's generalization ability, achieving 94.10% accuracy in the multiclass setting and 98.67% accuracy in the binary setting, despite variations in demographics and acquisition protocols. Further extensive evaluation studies demonstrate the effectiveness of each component of NeuroNet-AD in improving the performance.}, } @article {pmid41154564, year = {2025}, author = {Wei, C and Chen, X and Sun, M and Cao, J and Liao, D and Cheng, Z and Wang, H}, title = {α-Asarone Maintains Protein Homeostasis Through SKN-1-Mediated Proteasome and Autophagy Pathways to Mitigate Aβ-Associated Toxicity in Caenorhabditis elegans.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {14}, number = {10}, pages = {}, pmid = {41154564}, issn = {2076-3921}, support = {32370420//National Natural Science Foundation of China/ ; 31670347//National Natural Science Foundation of China/ ; 23ZR1467200//Natural Science Foundation of Shanghai/ ; }, abstract = {Acorus tatarinowii Schott (A. tatarinowii), a traditional Chinese medicine, has been widely used in the treatment of dementia, particularly AD. α-Asarone is the main active component of A. tatarinowii oil, and its neuroprotective effects and underlying molecular mechanism in AD remain unclear. In this study, we utilized different transgenic Caenorhabditis elegans (C. elegans) AD models to investigate the neuroprotective mechanism of α-asarone in vivo. Our findings revealed that α-asarone significantly ameliorated Aβ- and tau-induced phenotypic abnormalities, including deficits in chemotaxis-related learning, hyposensitivity to exogenous serotonin, and impaired neuronal integrity. Furthermore, the α-asarone treatment effectively reduced Aβ-induced oxidative stress. Mechanistically, α-asarone reduced Aβ accumulation and maintained protein homeostasis by stimulating proteasome degradation and autophagy in an SKN-1/Nrf2-dependent manner. Our study highlights the potential of α-asarone as an SKN-1/Nrf2 activator and its capability to facilitate proteostasis, supporting its therapeutic potential for AD treatment.}, } @article {pmid41154171, year = {2025}, author = {Zou, J and Liao, R and Zhang, W and Kuang, Z}, title = {Acupuncture Modulation of the Lung-Brain Axis in Alzheimer's Disease: Mechanisms and Therapeutic Perspectives.}, journal = {Brain sciences}, volume = {15}, number = {10}, pages = {}, pmid = {41154171}, issn = {2076-3425}, support = {2025A1515012049//Natural Science Foundation of Guangdong Province/ ; 20251096//the Research Project of the Traditional Chinese Medicine Bureau of Guangdong Province/ ; 2023A1515110788//Basic and Applied Basic Research Foundation of Guangdong Province/ ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and an impaired quality of life, for which no curative treatment is currently available. Recent research indicates that chronic pulmonary conditions-including chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA)-exhibit significant epidemiological associations with AD pathogenesis, suggesting that the lung-brain axis may contribute to AD development. Acupuncture, a core TCM intervention, shows promise for modulating multisystem functions and enhancing cognitive performance. This review synthesizes the current evidence regarding pulmonary diseases influencing AD through the lung-brain axis, elucidates potential mechanisms by which acupuncture may modulate pulmonary function and mitigate AD pathology, and explores future directions for lung-brain axis-targeted acupuncture interventions. Our overarching aim is to propose integrative, evidence-based strategies that combine Chinese and Western medicine for the prevention and management of AD.}, } @article {pmid41153730, year = {2025}, author = {Danesin, L and D'Este, G and Barresi, R and Piazzalunga, E and Di Garbo, A and Giustiniani, A and Semenza, C and Bottini, G and Oliveri, M and Burgio, F}, title = {Preliminary Evidence of Biological and Cognitive Efficacy of Prismatic Adaptation Combined with Cognitive Training on Patients with Mild Cognitive Impairment.}, journal = {Biomedicines}, volume = {13}, number = {10}, pages = {}, pmid = {41153730}, issn = {2227-9059}, support = {Ricerca Corrente//Ministero della Salute/ ; }, abstract = {Background/Objectives: This study evaluated a novel rehabilitation tool that combines prismatic adaptation (PA) and cognitive training through serious games (SGs) in patients with mild cognitive impairment (MCI) due to prodromal Alzheimer's dementia or consequent to Parkinson's disease. While non-pharmacological interventions have been shown to improve cognition or delay dementia onset, their underlying neurobiological mechanisms, such as brain plasticity, remain unclear. Leveraging studies suggesting neuromodulatory effects of PA, we investigated whether the combined PA+SGs treatment could influence plasticity-related mechanisms, assessed through brain-derived neurotrophic factor (BDNF) serum levels, compared to cognitive training with only SGs and standard cognitive rehabilitation (SCR). Methods: Twenty three MCI patients were randomized into three intervention groups: PA+SGs (experimental group), SG-only (control group), and SCR (control group), completing ten treatment sessions. Patients underwent neuropsychological assessments and blood sampling pre- and post-treatment. Results: At baseline, demographic, clinical, and biological characteristics were comparable across groups. Post-treatment, though differences from control groups were not statistically significant, the PA+SGs group showed significant within-group improvements in memory, with trend-level changes also in executive function and visuospatial abilities, which, however, did not reach the significance threshold. Notably, only the PA+SGs group exhibited increased BDNF levels, which positively correlated with memory and language performance. Conclusions: Our findings suggest that combining PA with cognitive training may enhance cognitive functioning in MCI patients, yielding results comparable to SCR. Furthermore, PA appears to enhance neuroplasticity mechanisms that may support the behavioral improvements observed in cognitive training. Future research should validate these findings and further explore the relationship between cognitive impairment and its rehabilitation, while also considering the underlying neurobiological mechanisms.}, } @article {pmid41152946, year = {2025}, author = {Bali, ZK and Bruszt, N and Göntér, K and Hernádi, I}, title = {Differential cognitive enhancer effects of acetylcholinesterase inhibitors and memantine on age-related deficits in vigilance and sustained attention: a preclinical validation study.}, journal = {Behavioral and brain functions : BBF}, volume = {21}, number = {1}, pages = {35}, pmid = {41152946}, issn = {1744-9081}, support = {KK/492/2019//Gedeon Richter Plc., Budapest, Hungary/ ; RRF-2.3.1-21-2022-00015//National Research, Development and Innovation Office/ ; K 143816//National Research, Development, and Innovation Office of the Hungarian Government/ ; }, mesh = {Animals ; *Memantine/pharmacology ; Donepezil/pharmacology ; *Cholinesterase Inhibitors/pharmacology ; Galantamine/pharmacology ; *Attention/drug effects ; Rats ; Male ; *Nootropic Agents/pharmacology ; Psychomotor Performance/drug effects ; Reaction Time/drug effects ; *Aging/drug effects/psychology ; Cognition/drug effects ; *Arousal/drug effects ; Indans/pharmacology ; Cognitive Dysfunction/drug therapy ; }, abstract = {BACKGROUND: The psychomotor vigilance task (PVT) is a cognitive test commonly used to measure sustained attention and vigilance in humans in healthy and diseased states. Here, we aimed to utilize a recently designed rat version of the PVT to assess potential cognitive enhancer effects of various pharmacological compounds in a natural model of age-related cognitive decline. Therefore, we treated aged rats (> 28 months old) with different doses of three approved Alzheimer's disease drugs: donepezil, galantamine, and memantine. RESULTS: Aged rats made significantly slower responses to the cue stimuli compared to young animals and fewer correct responses, mainly because of an increased number of missed trials (i.e., when the trial was not initiated by the rat). Donepezil improved the performance of aged rats by accelerating their responses at a dose of 0.03 mg/kg. However, galantamine treatment showed no beneficial effects on either reaction time or the number of correct trials. Furthermore, both donepezil (0.3 and 1.0 mg/kg) and galantamine (3.0 mg/kg) increased the reaction time and number of missed trials at high doses. Memantine did not affect the reaction time of aged rats, but it increased the number of correct responses at 0.1 and 0.3 mg/kg doses. CONCLUSIONS: Here, we showed that PVT is suitable for addressing pharmacological effects on various cognitive domains in a single behavioral paradigm. Our findings also indicate that different cognitive enhancer compounds (even when their targets are thought to be the same) may differentially influence distinct cognitive domains and modulate task performance.}, } @article {pmid41152341, year = {2025}, author = {Fujii, K and Koshidaka, Y and Yanagibashi, Y and Adachi, M and Matsuo, M and Kimura, K and Saito, T and Saido, TC and Takao, K}, title = {Ovariectomy attenuates phenotypes related to Alzheimer's disease in a preclinical mouse model and in C57BL/6 J mice.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {36995}, pmid = {41152341}, issn = {2045-2322}, support = {22H04922//Japan Society for the Promotion of Science/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology/physiopathology ; *Ovariectomy ; Disease Models, Animal ; Female ; Mice ; Mice, Inbred C57BL ; Phenotype ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice, Transgenic ; Behavior, Animal ; Mutation ; Amyloid beta-Peptides/metabolism ; Fear ; Anxiety ; Gene Knock-In Techniques ; Memory ; }, abstract = {Women are at higher risk for Alzheimer's disease (AD) than men and hormonal changes during perimenopause are considered a risk factor. The relationship between ovarian hormones and AD has been explored using AD animal models, especially through ovariectomy (OVX) in established AD models. The link between early-stage AD and ovarian hormones, however, remains unclear, largely due to the lack of suitable animal models. Appropriate models for studying early-stage AD pathology, treatment, and prevention are critically needed. The App knock-in mouse model, which carries a single amyloid precursor protein (App) gene mutation, effectively reproduces early amyloid AD pathology. To elucidate the relationship between ovarian hormone deficiency and the behavioral phenotypes of a preclinical AD model, we applied a comprehensive behavioral test battery to this mouse model with bilateral OVX. The App mutation reduced anxiety-like behavior and impaired performance in the fear memory task. OVX restored the anxiety-like behavior of the App mutation mice to a level comparable to that in wild-type (WT) mice. Furthermore, OVX enhanced performance in a fear memory task in both genotypes and reduced amyloid-β staining in WT mice. Together, these findings suggest that OVX attenuates AD-related phenotypes in a preclinical AD model and in C57BL/6 J WT mice.}, } @article {pmid41152189, year = {2025}, author = {Snyder, A and Samra, K and Wu, T and Russell, LL and Farren, J and Crook, J and Haselhuhn, T and Porter, K and Szabo, M and Duckett, A and Lin, F and Danielian, L and Traynor, BJ and Scholz, SW and Boeve, BF and Rosen, HJ and Rohrer, JD and Kwan, JY}, title = {Integrating a motor domain enhances disease severity scales in an FTD-ALS spectrum cohort.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70786}, pmid = {41152189}, issn = {1552-5279}, support = {U19 AG063911/AG/NIA NIH HHS/United States ; U19AG063911//The National Institute on Aging/ ; U01AG045390//The National Institute on Aging/ ; U54NS092089//The National Institute on Aging/ ; U01 AG045390/AG/NIA NIH HHS/United States ; //The Intramural Research Program of the National Institutes of Health/ ; U54 NS092089/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Male ; *Severity of Illness Index ; Female ; *Frontotemporal Dementia/diagnosis/physiopathology ; Middle Aged ; *Amyotrophic Lateral Sclerosis/diagnosis/physiopathology ; Aged ; Longitudinal Studies ; Cohort Studies ; Neuropsychological Tests ; }, abstract = {INTRODUCTION: The Genetic Frontotemporal Initiative (GENFI) and Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)-Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Longitudinal Frontotemporal Lobar Degeneration Study (ALLFTD) consortia developed Clinical Dementia Rating (CDR)-derived scales with a motor domain to overcome systematic underestimation of disease severity by the CDR. We calculated disease severity scores using these scales in a mixed neurodegenerative cohort and correlated them with objective motor measures. METHODS: The CDR plus National Alzheimer's Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD), CDR + NACC FTLD-M (Motor), and Multidomain Impairment Rating (MIR) scores and motor measures were determined and correlated in 242 participants. RESULTS: Both CDR + NACC FTLD-M and MIR showed increased disease severity scores and correlated with motor measures. These findings were held in 81 amyotrophic lateral sclerosis (ALS) participants and correlated with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Including a motor domain required fewer study participants in a simulated clinical trial sample size calculation. DISCUSSION: With a motor domain, CDR + NACC FTLD-M and MIR improve disease severity classification and correlate with quantitative motor assessments. This addition more fully captures the extent of symptoms across the FTD-ALS spectrum and improves clinical trial efficiency. HIGHLIGHTS: CDR + NACC FTLD-M and MIR strongly correlate with objective motor measures. The enhanced scales improve disease severity classification in FTD and ALS. Greater clinical trial efficiency is achieved using these enhanced scales.}, } @article {pmid41151846, year = {2025}, author = {Kuzuya, A and Ohara, T and Akamatsu, N}, title = {Pathogenesis of comorbid epilepsy in Alzheimer's disease and use of perampanel, an AMPA receptor inhibitor.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {12}, pages = {1399-1409}, doi = {10.1080/14737175.2025.2581758}, pmid = {41151846}, issn = {1744-8360}, mesh = {Humans ; Nitriles ; *Pyridones/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/complications/epidemiology ; *Epilepsy/drug therapy/epidemiology/complications ; *Receptors, AMPA/antagonists & inhibitors ; *Anticonvulsants/therapeutic use/pharmacology ; Comorbidity ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) and epilepsy frequently co-occur and are risk factors for each other's onset. In patients with AD-comorbid epilepsy, seizure control with appropriate anti-seizure medications (ASMs) is crucial, yet no established treatment guidelines exist. Recent studies indicate that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) are involved in the pathogenesis of both diseases. Perampanel, an AMPAR antagonist, has been approved as an ASM. AREAS COVERED: This review explains the relationship between AD and epilepsy and discusses the involvement of AMPARs. Furthermore, it focuses on and presents opinions regarding the role of AMPAR inhibitors in the treatment of AD-comorbid epilepsy. The authors searched for clinical studies that were published and identifiable in PubMed and Scopus (Jan 2015-Dec 2024) including the terms 'Alzheimer's disease' or 'dementia' with 'epilepsy' or 'seizure'. EXPERT OPINION: Considering the hypothesis that AD and epilepsy are linked, creating a cycle that progresses both diseases via AMPARs, AMPAR inhibition may have beneficial effects in treatment of epilepsy in AD. Although evidence is limited, studies of perampanel have demonstrated symptomatic improvement in patients with AD-comorbid epilepsy. Perampanel may be particularly useful for specific subgroups of patients with AD-comorbid epilepsy, such as those with myoclonus, sleep disturbances, or poor medication adherence.}, } @article {pmid41151285, year = {2025}, author = {Song, J and Ding, X and Li, M and Xin, Y and Lu, Y and Yang, X and Lu, X}, title = {N[6]-methyladenosine reader YTHDF1 mediates neuronal apoptosis induced by aluminum via m[6]A/Bcl-2 manner.}, journal = {Ecotoxicology and environmental safety}, volume = {306}, number = {}, pages = {119270}, doi = {10.1016/j.ecoenv.2025.119270}, pmid = {41151285}, issn = {1090-2414}, mesh = {*Apoptosis/drug effects ; Animals ; *Adenosine/analogs & derivatives/metabolism ; *RNA-Binding Proteins/metabolism/genetics ; *Neurons/drug effects ; *Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; *Aluminum/toxicity ; Mice ; Male ; Humans ; }, abstract = {Aluminum (Al) has emerged as a pervasive environmental and industrial risk factor for cognitive impairment and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Nowadays, N6-methyladenosine (m[6]A) modification mechanism contributing to aluminum toxicity is gradually gaining attention. m[6]A modification determines the fate of RNA through m[6]A "readers". Novel findings indicate that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1, a kind of "readers") participates in various pathological processes induced by some toxic chemicals. Here, we investigated the function of YTHDF1 in neuronal apoptosis induced by aluminum and explored the molecular mechanisms. We first observed the YTHDF1 expression both in vivo and in vitro neuronal apoptosis model induced by aluminum, as well as the reversal effect of YTHDF1 overexpression by lentivirus transfection in vitro. Further, we explored Bcl-2 as a target gene of YTHDF1 and probed their m[6]A modification manner and molecular mechanism using RIP assay, Me-RIP assay, and Actinomycin D (ActD) assay. Finally, we examined the regulatory role of YTHDF1/m[6]A/Bcl-2 axis in aluminum neurotoxicity in vitro and in vivo. Functionally, Al(mal)3 treatment decreased YTHDF1 expression, which negatively regulates apoptosis via m[6]A modification manner. Mechanistically, Bcl-2 acted as the target of YTHDF1, and YTHDF1 regulated Bcl-2 by enhancing its mRNA stability. Collectively, Al(mal)3 treatment inhibited the YTHDF1/m[6]A/Bcl-2 axis, thereby promoting neuronal apoptosis and subsequent cognitive impairment. This study provides a novel protective strategy against aluminum toxicity.}, } @article {pmid41151129, year = {2026}, author = {Yang, F and Guo, Q and Chen, M and Wang, W and Chen, X and Zhang, S and Bian, H and Li, J and Jiao, Z and Wang, Q and Xiong, W and Huang, YY and Liu, Y and Xu, C and Huang, L}, title = {Discovery of novel 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one derivatives as PDE2 inhibitors with Alzheimer's disease therapeutic potential.}, journal = {European journal of medicinal chemistry}, volume = {302}, number = {Pt 1}, pages = {118302}, doi = {10.1016/j.ejmech.2025.118302}, pmid = {41151129}, issn = {1768-3254}, mesh = {*Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors/metabolism ; Animals ; Humans ; Structure-Activity Relationship ; Mice ; Molecular Structure ; *Drug Discovery ; Male ; Dose-Response Relationship, Drug ; *Phosphodiesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Microsomes, Liver/metabolism ; *Pyridines/chemistry/pharmacology/chemical synthesis ; *Pyrazoles/chemistry/pharmacology/chemical synthesis ; }, abstract = {Phosphodiesterase 2 (PDE2), a dual-substrate cyclic nucleotide hydrolase, represents a potential therapeutic target for cognitive impairment. This study aims to develop 2,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridine-7-one-based PDE2 inhibitors with favorable drug-like properties for the treatment of Alzheimer's disease. Through scaffold hopping and cocrystal structure analysis, compound 14c was identified as an effective PDE2 inhibitor (IC50 = 0.6 μM, aqueous solubility = 60.36 μg/mL). Moreover, 14c demonstrated favorable hepatic microsomal stability, pharmacokinetic properties (t1/2 = 4.4 h, F% = 95.66 %) and promising safety both in vitro and in vivo. In the OKA-induced AD mice models, administration of 14c significantly improved memory deficits and cognitive impairment. Molecular mechanism studies revealed that the neuroprotective effects of 14c were mediated through the PKA/CREB/BDNF signaling pathway. Collectively, these findings represent significant advances in developing PDE2 inhibitors with favorable drug-like properties and establish a solid foundation for their therapeutic application in AD.}, } @article {pmid41149051, year = {2025}, author = {Valdez Gayosso, N and Omaña Covarrubias, A and Nez Castro, AT and López Pontigo, L and Acuña Gurrola, MDR and Pimentel Pérez, BM}, title = {The Effect of Bacteria Modulation with Probiotic Consumption in Neurodegeneration During Aging: A Narrative Review of the Literature.}, journal = {Diseases (Basel, Switzerland)}, volume = {13}, number = {10}, pages = {}, pmid = {41149051}, issn = {2079-9721}, support = {NA//Universidad Autónoma del Estado de Hidalgo/ ; }, abstract = {Aging is the result of the accumulation of a great variety of molecular and cellular damage over time. During aging, the brain undergoes changes and diseases such as depression, dementia, anxiety, Alzheimer's, delirium, behavioral disorders and aggression, and prolonged mourning, among others, appear. The gut-brain axis suggests that the gut and the brain have a bidirectional communication, so it is important to maintain proper intestinal health to strengthen the neurological changes of this age group. The intestinal microbiota is a dynamic and highly complex ecosystem of microorganisms residing in the gastrointestinal tract. The bidirectional and dynamic communication between the homeostatic systems, such as the endocrine and immune systems, as well as the nervous system, allow us to face problems associated with several diseases. Probiotics are defined as non-pathogenic live microorganisms that provide beneficial effects to the organism and participate in the prevention and treatment of diseases, which is the reason why it is important to promote interventions that keep intestinal microbiota in eubiosis (microbiota balance). The concentration and balance of the intestinal microbiota depend on several conditions, such as diet, antibiotic consumption, and lifestyle, to mentioned a few. However, interventions with probiotics have shown improvements in both cognitive function and processes that promote neurodegeneration. It is such that the research has been directed on designing strategies that improve not only oral bioavailability but also intestinal adhesion and retention, to clarify the frequency and dosage that should be consumed.}, } @article {pmid41148458, year = {2025}, author = {Goel, F and Kumar, D and Singh, P and Rai, SN and Yadav, DK}, title = {Molecular crosstalk between miRNAs and lncRNAs in neurodegenerative disease pathways.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {16}, pmid = {41148458}, issn = {1573-4978}, mesh = {Humans ; *RNA, Long Noncoding/genetics/metabolism ; *MicroRNAs/genetics/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/therapy ; Gene Expression Regulation ; Animals ; Signal Transduction ; Gene Regulatory Networks ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal degeneration and dysfunction. Of recent interest, a series of studies have been targeting the role of non-coding RNAs, particularly miRNAs and lncRNAs, in regulating gene expression and influencing cellular pathways that may play a critical role in the pathogenesis of these diseases. miRNAs regulate many biological processes by degrading or repressing the translation of target mRNAs, whereas lncRNAs act as scaffolds, sponges, and guides to control gene expression and cellular activities. Both miRNAs and lncRNAs participate in neurodegenerative mechanisms such as protein aggregation, inflammation, oxidative stress, and neuroinflammation. While targeting miRNAs and lncRNAs holds promise for potential therapeutic benefits, problems persist with their efficient delivery, specificity, and off-target effects. New techniques like viral vectors, lipid nanoparticles, and CRISPR-based gene editing will further enhance the development of therapies based on miRNA and lncRNA. Moreover, their interaction with regulatory networks may present new avenues toward understanding disease mechanisms and guiding therapeutic design. This review covers the role of miRNAs and lncRNAs in neurodegenerative disorders, their therapeutic potential, challenges, and future directions in ncRNA-based treatment approaches.}, } @article {pmid41147168, year = {2025}, author = {Hu, D and Li, X and Li, Y and Zhang, Q and Dai, Y and Teng, X and Hou, H and Li, J}, title = {A Drug Screening Targeting Upregulation of Syk Gene Identifies Neochlorogenic Acid and L-Arabinitol Capable of Inducing the M2 Phenotype of Microglia in Alzheimer's Disease.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {26}, number = {23}, pages = {e202500515}, doi = {10.1002/cbic.202500515}, pmid = {41147168}, issn = {1439-7633}, support = {2023000CA0050//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024100CA0080//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024101RPIA02//Beijing Life Science Academy Initiative Scientific Research Program/ ; 2024501QPIC05//Beijing Life Science Academy Initiative Scientific Research Program/ ; }, mesh = {*Syk Kinase/genetics/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Up-Regulation/drug effects ; *Microglia/drug effects/metabolism/pathology ; Animals ; Phagocytosis/drug effects ; Amyloid beta-Peptides/metabolism ; Humans ; Drug Evaluation, Preclinical ; Mice ; Phenotype ; }, abstract = {Despite numerous therapeutic attempts of Alzheimer's disease (AD), treatment options remain limited. Targeting microglia (MG) polarization from M1 to M2 is considered a promising approach, yet no drug specifically modulating this transition has been identified. The spleen tyrosine kinase (Syk) has emerged as a potential therapeutic target due to its role in regulating AD risk genes and promoting Amyloid-β (Aβ) clearance. Herein, a microglial reporter gene screening model targeting Syk is developed and two small molecules, neochlorogenic acid (NCGA) and L-arabinitol (L-Ara), that can upregulate Syk gene expression, leading to the activation of MG M2 phenotype, are identified. Furthermore, these compounds markedly enhance the capacity of MG to migrate toward Aβ and phagocytose Aβ. However, when Syk expression is silenced using shRNA, the ability of these small molecules to induce the MG M2 phenotype and promote Aβ phagocytosis by MG is substantially attenuated. These findings offer new insights into AD therapy development.}, } @article {pmid41145342, year = {2025}, author = {Dickson, SP and Mallinckrodt, C and Burstein, AH and Nisenbaum, L and Fillit, HM and Zhang, C and Hendrix, SB}, title = {The impact of recent approvals on future alzheimer's disease clinical development: Statistical considerations for combination trials.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {10}, pages = {100391}, pmid = {41145342}, issn = {2426-0266}, mesh = {*Alzheimer Disease/drug therapy/prevention & control ; Humans ; Drug Therapy, Combination ; *Research Design ; *Antibodies, Monoclonal/therapeutic use ; *Clinical Trials as Topic ; *Drug Approval ; *Drug Development ; Sample Size ; Disease Progression ; }, abstract = {BACKGROUND: A new era of Alzheimer's disease (AD) research is beginning with multiple approved anti-amyloid monoclonal antibodies (mABs). These drugs are currently not widely used, but may be soon, especially at clinical trial sites. Putative disease-modifying therapies (DMTs) may alter the progression rate, potentially reducing our ability to detect effects on top of mABs. Co-administration of amyloid-targeted agents may diminish benefit (antagonism, due to the overlapping mechanism of action); alternatively, complementary treatment mechanisms may increase benefit (synergy). METHOD: We consider several clinical trial design scenarios: a 2-arm trial added-on to a mAB, a 2-arm combination compared to double placebo, and a 4-arm full factorial trial. We calculate the required sample sizes for the shortest practical study for secondary prevention (prevention of AD clinical diagnosis in biomarker positive individuals, 2-year study), early AD (18-months), and mild-to-moderate AD (1-year). We consider additivity, antagonism, and synergy. RESULT: The expected interaction between investigational and mAB treatment can have a large effect on power and study design. Antagonistic treatment effects often require double the sample size of synergistic effects. The 4-arm scenario required ∼10-fold increase compared to a 2-arm combination study. CONCLUSION: Studies evaluating investigational therapies as add-on to mABs are complex, and their cost will depend on the interaction between treatments. An inescapable fact in add-on trials is the slower progression of the control arm; and it is difficult to further slow already slow progression. Treatments that are likely to work better with amyloid removal will be easier to study due to their complementary MOA. Symptomatic treatments may require fewer additional subjects than disease-modifying treatments since they are less affected by the presence or absence of mABs.}, } @article {pmid41145339, year = {2025}, author = {Ballard, C and Sultana, J and Doherty, P and Williams, G and Corbett, A}, title = {Identifying synergistic combinations of repurposed treatments for Alzheimer's Disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {10}, pages = {100329}, pmid = {41145339}, issn = {2426-0266}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Drug Repositioning ; Drug Therapy, Combination ; Drug Synergism ; Delphi Technique ; }, abstract = {There is considerable opportunity to fast-track novel treatments for Alzheimer's Disease (AD) through repurposing of existing licensed medications as a way of complementing ongoing drug discovery efforts. Given the complex interplay between AD neuropathological mechanisms, there is also a strong rationale that treatment benefits may be enhanced by examining combinations of treatments to identify potential synergies that would address multiple disease-modifying mechanisms. A Delphi consensus programme combined with a pragmatic analysis of primary care data has identified a series of individual and combined therapies that warrant further investigation in pre-clinical and clinical trials. These include treatments which target well-established neurodegeneration pathways and more explorative agents, including hormonal and anti-infective agents, which align to emerging hypotheses relating to endocrine and immune pathways in AD. Whilst caution is critical when considering combined therapy due to the risks of interaction and polypharmacy, this study provides valuable indications of potential synergistic drug pairs that warrant further investigation.}, } @article {pmid41145338, year = {2025}, author = {Cummings, J and Burstein, AH and Fillit, H}, title = {Add-on combination therapy with monoclonal antibodies: Implications for drug development.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {10}, pages = {100359}, pmid = {41145338}, issn = {2426-0266}, support = {P20 GM109025/GM/NIGMS NIH HHS/United States ; R01 NS139383/NS/NINDS NIH HHS/United States ; R25 AG083721/AG/NIA NIH HHS/United States ; R35 AG071476/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Development ; *Antibodies, Monoclonal/therapeutic use ; Drug Therapy, Combination ; Amyloid beta-Peptides ; Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {Three anti-amyloid monoclonal antibodies (MABs) including aducanumab, lecanemab, and donanemab have been approved by the FDA and lecanemab and donanemab are available in the US market and a variety of other national markets. The increasing use of anti-amyloid MABs to treat early AD will require that development of novel agents occur as add-on treatment to MABs. There is limited experience with add-on therapy to anti-amyloid agents. In most cases, it is prudent to initiate novel agents after at least six-months exposure to the MAB at the highest dose. Agents with extensive data on pharmacokinetics and pharmacodynamics and well-known safety may employ alternative approaches. Anti-amyloid MABs have different mechanisms of action, titration, and side effect profiles suggesting that add-on trials include only one type of MAB if possible. Demonstration of clinical benefit with add-on therapy will require showing additional slowing beyond that provided by the anti-amyloid MAB. Anti-amyloid therapies have profound effects on biomarkers including amyloid positron emission tomography and plasma p-tau and plasma GFAP measures. Definition of the biomarker profile of a novel agent prior to initiation of add-on therapies, inclusion of target engagement biomarkers specific to the novel intervention, assessment of biomarkers not known to be affected by anti-amyloid MABs, and interrogation of the magnitude, timing, and trajectory of biomarker change in the add-on context compared to monotherapy with MABs will provide insight into the biological impact of the novel therapy on AD. Patient convenience in terms of formulation and timing of add-on therapies will be important to successful clinical implementation. Add-on therapies are an important step in addressing the complexity of AD and optimizing patient outcomes.}, } @article {pmid41145337, year = {2025}, author = {Cummings, JL and Burstein, AH and Fillit, H}, title = {Alzheimer Combination Therapies: Overview and Scenarios.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {10}, pages = {100328}, pmid = {41145337}, issn = {2426-0266}, mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; Drug Therapy, Combination ; Combined Modality Therapy ; Animals ; }, abstract = {Progress in understanding the complexity of Alzheimer's disease informs the search for combination therapies that can successfully prevent or substantially slow the progression of the disease. Anti-amyloid monoclonal antibodies are the first approved disease targeted therapies; they slow disease progression by approximately 30 %. Building on these agents in add-on therapies is one avenue to designing combination treatments. Development of combination drugs consisting of two or more novel interventions is an alternate pathway for combination treatment development. Combination therapies can involve small molecule drugs, biological agents, devices, stem cells, gene therapies, lifestyle interventions, or cognitive training. Nonclinical assessment of drug combinations may involve animal models or new approach methodologies such as induced pluripotent stem cells or organoids. Phase 1 trials are required to characterize each member of a novel combination. Phase 2 trials may use a 2-by-2 factorial design comparing each drug to placebo and the drug combination. In Phase 3, comparison of the novel combination to standard of care may be sufficient or more complex designs may be required. Targets for combination therapies beyond amyloid-related processes include tau abnormalities, inflammation, neurodegeneration, and co-pathologies such as alpha-synuclein and TDP-43. The choice of combination therapies will depend on the strength of the information regarding the target, biomarkers to guide clinical trials, and a candidate agent with the appropriate mechanism of action. Computational strategies based on network analysis of disease and drugs, validation in non-clinical models, and use of real-world data may facilitate prioritization of candidates for combination treatments.}, } @article {pmid41144509, year = {2025}, author = {Morden, NE and Chyn, D and Meara, E}, title = {Falls and Fractures Among Medicare Beneficiaries Concurrently Receiving Anti-Dementia Drugs and Potentially Risky Medications.}, journal = {Medical care}, volume = {63}, number = {12}, pages = {941-948}, doi = {10.1097/MLR.0000000000002229}, pmid = {41144509}, issn = {1537-1948}, mesh = {Humans ; *Accidental Falls/statistics & numerical data ; United States/epidemiology ; Female ; Male ; *Medicare/statistics & numerical data ; Aged, 80 and over ; Aged ; *Dementia/drug therapy ; *Cholinesterase Inhibitors/adverse effects/therapeutic use ; Analgesics, Opioid/adverse effects ; Memantine/adverse effects/therapeutic use ; Hip Fractures/epidemiology ; }, abstract = {BACKGROUND: Patients with Alzheimer disease and related dementias (ADRD) face risks from medications labeled "potentially inappropriate in older adults" (risky); concurrent receipt of anti-dementia drugs may amplify risk. We studied adverse events among older adults concurrently receiving anti-dementia and risky medications. METHODS: Using 2016-2019 administrative data from a random 40% sample of fee-for-service Medicare beneficiaries receiving anti-dementia medications (acetylcholinesterase inhibitors (AChEI) and/or memantine), we identified days with concurrent receipt of select, risky medications (benzodiazepines, sedative hypnotics, opioids). We measured diagnosed falls, hip fractures, and deaths among person-days with anti-dementia drug receipt comparing person-days with versus without concurrent risky drug receipt. We stratified regression analyses on long-term care (LTC) residence. RESULTS: We studied 633,528 beneficiaries; 64.3% were women, 33.7% met LTC residence criteria. Mean (SD) age was 80.9 (7.6) years. Each beneficiary contributed a mean (SD) of 551.7 (449.2) anti-dementia drug receipt days. Overall, 4.5% of person-days involved receipt of AChEI plus benzodiazepines; 3.8% involved AChEI plus an opioid. Falls, the most common outcome, affected 22.5% of our beneficiaries. Concurrent receipt of AChEI and opioids was associated with the greatest fall risk increase. Among community-dwelling beneficiaries, AChEI and opioid receipt (vs. AChEI alone) was associated with a hazard ratio for falls of 2.25 (95% CI: 2.19, 2.32); among LTC residents the corresponding hazard ratio was 1.46 (95% CI: 1.42, 1.51). CONCLUSIONS: Assessment and treatment of symptoms among people with ADRD is complex; concurrent receipt of opioids and dementia medications is uncommon but seems risky. Efforts to eliminate avoidable opioids may decrease adverse events and associated suffering in this population.}, } @article {pmid41143926, year = {2025}, author = {Shi, Y and Ma, H and Li, H and Wang, Y and Wang, C and Zhang, N and Luo, G and Wang, Y and Gao, X}, title = {Sennoside A alleviating cognitive impairment in APP/PS1 mice via balancing microbiome metabolism.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1659-1676}, doi = {10.1177/13872877251389922}, pmid = {41143926}, issn = {1875-8908}, mesh = {Animals ; *Gastrointestinal Microbiome/drug effects ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism ; *Sennosides/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; Male ; Mice, Transgenic ; Disease Models, Animal ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/genetics ; Brain/drug effects/pathology/metabolism ; }, abstract = {BackgroundThe progression of Alzheimer's disease (AD) is associated with constipation, potentially mediated by gut microbiota. Laxatives have shown potential in improving the cognitive function of AD, but the specific mechanism remains underexplored. Sennoside A (SA), a well-established laxative, is commonly used for treating constipation.ObjectiveThis work used SA as a probe to explore the therapeutic effects and potential mechanisms of laxatives on AD via the gut-brain axis.MethodsFollowing a two-month treatment, behavioral experiments were used to assess the cognitive function. The central pathologies and neuroinflammation were evaluated by histopathology and ELISA. 16S rRNA sequencing, fecal microbiota transplantation and antibiotic treatment were conducted to verify whether SA exerts anti-AD effects via gut microbiota. Further, non-targeted metabolomics coupled with Spearman correlation analysis was employed to elucidate the underlying mechanisms.ResultsSA significantly countered cognitive dysfunction and central pathological damage in APP/PS1 mice. Besides, SA ameliorated gut dysbiosis and affected the metabolic functions of the flora. Furthermore, the therapeutic effects of SA decrease with the depletion of gut microbes and could be transferred with the microbiota. Intriguingly, amino acid metabolism and aminoacyl-tRNA biosynthesis were the main metabolic pathways regulated by SA, consistent with the predicted functions of gut bacteria. Finally, correlation analysis revealed a strong correlation between gut microbes, fecal metabolites, and cognitive ability affected by SA.ConclusionsThe study investigated the efficacy and mechanisms of laxatives represented by SA for AD from the perspective of the gut-brain axis.}, } @article {pmid41143875, year = {2025}, author = {Saak, TM and Tervo, JP and Motter, JN and Overdevest, JB}, title = {Expanding the scope of olfactory evaluation in Alzheimer's disease and related dementias (ADRD): A narrative review of the role for odor memory and recognition in AD/ADRD.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {13872877251389113}, doi = {10.1177/13872877251389113}, pmid = {41143875}, issn = {1875-8908}, abstract = {Olfactory dysfunction (OD) is a well-characterized feature of Alzheimer's disease (AD) and is often one of the earliest functional biomarkers in the disease course. As such, olfactory evaluation shows promise as an important tool in AD screening and may provide insight into pathologic underpinnings and potential treatment pathways. The National Plan to Address Alzheimer's Disease emphasizes the importance of including Alzheimer's disease related dementias (ADRD) in research efforts, and while olfaction is also associated with ADRD, this association is relatively understudied. Additionally, there have been efforts to expand the evaluation of olfactory function to include assessments beyond key domains, such as odor threshold, odor discrimination, and odor identification, which have been the primary focus of most olfaction research in AD/ADRD. Odor recognition memory assessments have been developed primarily for their utility in identifying and stratifying individuals along the AD continuum, although a wide variety of methods have been reported in the literature. In this narrative review, we provide an overview of odor identification, odor threshold, and odor discrimination in AD/ADRD with a specific focus on providing a centralized guide detailing odor recognition memory methods and their utility in AD/ADRD.}, } @article {pmid41143243, year = {2025}, author = {Allué, JA and Sarasa, L and Fandos, N and Gonzalo, R and Sabido-Vera, R and Loscos, J and Romero, J and Sánchez, A and Terencio, J and Matias-Guiu, JA and Piñol-Ripoll, G and Pascual-Lucas, M}, title = {Clinical validation of a plasma-based antibody-free LC-MS method for identifying CSF amyloid positivity in mild cognitive impairment.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1681516}, pmid = {41143243}, issn = {1663-4365}, abstract = {BACKGROUND: The recent approval of monoclonal antibodies for the treatment of Alzheimer's disease (AD) in several countries has accelerated the need for affordable, simple and scalable methods to identify patients who are eligible for treatment with the new disease-modifying therapies (DMT). Blood-based biomarkers offer less invasive alternatives to established gold standards. We have clinically validated a predictive model combining plasma Aβ42/Aβ40, apolipoprotein E (APOE) genotype and age, in two independent real-world cohorts to identify brain amyloid deposition. METHODS: We conducted a clinical validation study involving 450 patients with mild cognitive impairment (MCI) from two real-world cohorts (HCSC, Madrid, Spain and HUSM, Lleida, Spain). Plasma Aβ42/Aβ40 was measured by ABtest-MS, an antibody-free liquid chromatography-mass spectrometry method. CSF Aβ42/Aβ40 and p-tau181/Aβ42 (gold standards) were quantified with the Lumipulse[®] platform. The model was trained in the HCSC cohort and validated in the HUSM cohort. Finally, an overall analysis in the combined population was performed. A dual cutoff approach was used to classify the patients as positive or negative. Statistical analysis included bootstrap resampling and model calibration. RESULTS: In the HCSC, HUSM, external validation and combined analysis, AUCs were 0.89 (95% confidence intervals-CI: 0.84-0.93), 0.88 (0.84-0.93), 0.88 (0.83-0.92) and 0.88 (0.84-0.91), with corresponding accuracies of 82.3, 81.6, 82.3, and 81.1%, respectively. After the combined analysis, positive and negative predictive values (PPV and NPV) were established at 87.5%, resulting in cutoff values of 0.30 and 0.67 for the likelihood of amyloid negativity and positivity, respectively, for a prevalence of 62%. Probability values lower than 0.30 indicate low probability of brain amyloid deposition, while values greater than 0.67 indicate high probability. Less than 28% of the participants fell into the intermediate zone. Additional cutoffs were derived for different prevalence values. Predictive model calibration showed excellent agreement with observed data, confirming accurate predictions (slope = 0.98, intercept = -0.01). CONCLUSION: This predictive model has demonstrated high accuracy for the identification of brain amyloid deposition in patients with MCI. Derived cutoffs enabled over 70% reduction in invasive testing, supporting efficient and cost-effective identification of candidates for DMTs.}, } @article {pmid41141907, year = {2025}, author = {Blazquez-Folch, J and Limones Andrade, M and Calm, B and Auñón García, JM and Alegret, M and Muñoz, N and Cano, A and Fernández, V and García-Gutiérrez, F and De Rojas, I and García-González, P and Olivé, C and Puerta, R and Capdevila-Bayo, M and Muñoz-Morales, Á and Bayón-Buján, P and Miguel, A and Montrreal, L and Espinosa, A and Sanz-Cartagena, P and Rosende-Roca, M and Zaldua, C and Gabirondo, P and Cantero-Fortiz, Y and Gurruchaga, MJ and Tarraga, L and Boada, M and Ruiz, A and Marquié, M and Valero, S}, title = {Federated learning for cognitive impairment detection using speech data.}, journal = {Frontiers in artificial intelligence}, volume = {8}, number = {}, pages = {1662859}, pmid = {41141907}, issn = {2624-8212}, abstract = {INTRODUCTION: In Alzheimer's disease (AD) research, clinical, neuroimaging, genetic, and biomarker data are vital for advancing its understanding and treatment. However, privacy concerns and limited datasets complicate data sharing. Federated learning (FL) offers a solution by enabling collaborative research while preserving data privacy. METHODS: This study analyzed data from patients assessed at the Memory Unit of the Ace Alzheimer Center Barcelona who completed a standardized digital speech protocol. Acoustic features extracted from these recordings were used to distinguish between cognitively unimpaired (CU) and cognitively impaired (CI) individuals. The aim was to evaluate how data heterogeneity impacted the FL model performance across three scenarios: (1) equal contributions and class ratios, (2) unequal contributions, and (3) imbalanced class ratios. In each scenario, the performance of local models trained using an MLP feed-forward neural network on institutional data was analyzed and compared to a global model created by aggregating these local models using Federated Averaging (FedAvg) and Iterative Data Aggregation (IDA). RESULTS: The cohort included 2,239 participants: 221 CU individuals (mean age 66.8, 64.7% female) and 2,018 CI subjects, comprising 1,219 with mild cognitive impairment (mean age 74.3, 61.9% female) and 799 with mild AD dementia (mean age 80.8, 64.8% female). In scenarios 1 and 3, FL provided modest gains in accuracy and AUC. In scenario 2, FL markedly improved performance for the smaller dataset (balanced accuracy rising from 0.51 to 0.80) while preserving 0.86 accuracy in the larger dataset, highlighting scalability across heterogeneous conditions. CONCLUSION: These findings demonstrate the potential of FL to enable collaborative modeling of speech-based biomarkers for cognitive impairment detection, even under conditions of data imbalance and institutional disparity. This work highlights FL as a scalable and privacy-preserving approach for advancing digital health research in neurodegenerative diseases.}, } @article {pmid41141199, year = {2025}, author = {Sorod, P and Chen, GI}, title = {Hearing All About Donepezil: Its Role in the Field of Auditory Processing.}, journal = {Cureus}, volume = {17}, number = {9}, pages = {e93143}, pmid = {41141199}, issn = {2168-8184}, abstract = {Donepezil is a central-acting acetylcholinesterase inhibitor aimed at increasing acetylcholine availability at the neuron synapses to enhance cholinergic transmission. It is often used to assist with cognitive function and is well-known as the first-line treatment for mild to severe dementia of several etiologies. However, its mechanism of action within "top-down" and "bottom-up" neurological pathways continues to be explored. This case reports on a 93-year-old woman in an ambulatory geriatrics clinic with moderate-to-severe dementia. Her significant history of hearing loss with auditory hallucination impressively responded to the initiation of donepezil. There may be potential benefits of donepezil within the peripheral pathways of neuro-cortical reorganization in the field of hearing loss and auditory processing.}, } @article {pmid41140221, year = {2025}, author = {Mastrostefano, A and Alborghetti, M and Tiso, D and Davinelli, S and Medoro, A and Scapagnini, G}, title = {Pleiotropic Actions of Gastrodia Elata Glucosides in the Treatment of Painful Neuropathies and CNS Disorders: Focus on Mitochondrial Dysfunction and Modulation of Ion Channels.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X402568251002112117}, pmid = {41140221}, issn = {1875-6190}, abstract = {Glycosides contained in Gastrodia elata have consistently shown neuroprotective and antiinflammatory activity in preclinical models of neurological disorders, including peripheral neuropathies, cerebrovascular disorders, and chronic neurodegenerative disorders. In a commercial product used in Italy, gastrodin has replaced α-lipoic, the use of which is now limited by unexpected adverse effects, such as severe hypoglycemia. The clinical efficacy of gastrodin in traditional Chinese medicine has been ascribed to a plethora of mechanisms, which involve the modulation of intracellular signaling pathways and membrane ion channels. Moving from the pathophysiology of diabetic neuropathy, Alzheimer's disease, and Parkinson's disease, we now focus on what we consider a key mechanism in the action of gastrodin, i.e., the regulation of mitochondrial quality control. Gastrodin is able to enhance mitochondrial fusion and biogenesis, as shown by the induction of specific biochemical markers, such as mitofusins and mitochondrial transcription factors. This supports mitochondrial health, preventing the loss of energy production and formation of reactive oxygen species associated with disorders of the central and peripheral nervous system. In addition, gastrodin physically interacts with, and restrains the expression and activity of, voltage-sensitive ion channels and acid-sensing ion channels, which play a central role in pain transmission and nociceptive sensitization. Thus, gastrodin and other constituents of Gastrodia elata show promising potential to support first-line treatments, based on preclinical evidence in models of neurological disease.}, } @article {pmid41140219, year = {2025}, author = {Devi, S and Singh, AP}, title = {Novel Therapeutic Approaches to Neuroinflammation in Neurodegenerative Disorders: Aptamers as Central Nervous System Agents.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249392444251002135338}, pmid = {41140219}, issn = {1875-6166}, abstract = {INTRODUCTION: Neurodegenerative disorders (NDDs) like Alzheimer's, Parkinson's, and multiple sclerosis all begin with neuroinflammation. Neuroinflammation targeting has recently gained attention as a potential approach to treating several diseases affecting the central nervous system. The objective of this review is to explore the potential of aptamers as innovative therapeutic agents for targeting neuroinflammation in neurodegenerative disorders, offering a novel approach to CNS treatment. METHODS: The use of aptamers, which are single-stranded nucleic acids, in diagnostic and therapeutic contexts may one day help overcome these obstacles. Myotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders are linked to neuroinflammation. Important regulators of CNS inflammatory responses include microglia and astrocytes. RESULTS: Neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) and neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes) activation of microglia and astrocytes, respectively, is a diverse and complex process. There may be a lack of reflection of the diverse morphologies of microglia and astrocytes in this binary categorisation. In addition to the complexity of the relationships between these activated glial cells, the phenotypic distribution can vary as neurodegenerative illnesses progress. DISCUSSION: To create effective treatments for neurodegenerative illnesses, a deeper knowledge of microglia and astrocyte functions is required. Drug efficacy, safety concerns, and pharmacokinetics are only a few of the topics covered, along with the enormous possibilities and enormous hurdles of employing aptamers as therapeutic agents. CONCLUSION: This review highlights aptamers as a promising genetic tool for treating neuroinflammation and neurodegenerative diseases through targeted delivery to the central nervous system.}, } @article {pmid41140213, year = {2025}, author = {Zhao, R and Che, M and Cui, Y and Peng, J and Chen, M}, title = {The Role of Lipoprotein and Gut Microbiome in Alzheimer's Disease: A Review of Novel Findings and Potential Applications.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050407276251014113234}, pmid = {41140213}, issn = {1875-5828}, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is inadequately comprehended, with hypotheses implicating amyloid-β, tau pathology, mitochondrial dysfunction, and epigenetic factors. Recent research underscores the significance of lipoproteins and the gut microbiota in the etiology of AD. Apolipoprotein E (ApoE), particularly the E4 subtype, emerges as a key genetic risk factor, influencing oxidative stress, synaptic defects, glucose metabolism, and amyloid-β clearance. Lipoprotein receptors, such as LRP-1, also influence the integrity of the blood-brain barrier, indicating potential for therapeutic applications. Novel therapies targeting lipoproteins, such as ALZ-801 and IDOL inhibitors, show promise in preclinical and clinical trials. Concurrently, the gut microbiome's impact on AD is increasingly recognized. Dysbiosis correlates with inflammation, mitochondrial oxidative stress, impaired autophagy, and neurotransmitter imbalances. Gut-derived metabolites, including phenylalanine and isoleucine, promote Th1 cell activation and microglial dysfunction, exacerbating AD pathology. Interventions, like probiotics, GV-971, and polyphenols, demonstrate efficacy in restoring microbial balance and mitigating cognitive decline. Crucially, bidirectional interactions between lipoproteins and the gut microbiome are implicated in AD. ApoE genotypes influence gut microbial composition, while microbiota- derived short-chain fatty acids and endotoxins modulate lipid metabolism and neuroinflammation. These interactions, mediated via the gut-brain axis, highlight novel therapeutic avenues. Current FDA-approved AD drugs face limitations in efficacy and side effects, underscoring the need for innovative strategies targeting lipoprotein-gut microbiome crosstalk. Integrating insights into lipoprotein biology and gut microbiota dynamics may offer transformative potential for AD treatment, emphasizing combinatorial approaches to modulate these interconnected pathways. Further research is warranted to elucidate mechanistic links and translate preclinical findings into clinical applications.}, } @article {pmid41140062, year = {2025}, author = {Abdel-Lah, ES and Hamad, N and Taha, AF and Mohamed, WH and Fawy, MA and Attaai, AH and Abbas, FYA and Sherkawy, HS and Abdelwarith, A and Gamea, MG}, title = {Neuroprotective Effect of Empagliflozin/Rivastigmine in Alzheimer's Disease Rat Model: Optimization of Multifaceted Mechanism of Action.}, journal = {Drug development research}, volume = {86}, number = {7}, pages = {e70180}, doi = {10.1002/ddr.70180}, pmid = {41140062}, issn = {1098-2299}, support = {//The authors received no specific funding for this work./ ; }, mesh = {Animals ; *Rivastigmine/pharmacology/administration & dosage ; *Glucosides/pharmacology/administration & dosage/therapeutic use ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Male ; *Benzhydryl Compounds/pharmacology/administration & dosage/therapeutic use ; Rats ; Disease Models, Animal ; Oxidative Stress/drug effects ; Acetylcholinesterase/metabolism ; Glucose/metabolism ; Brain/drug effects/pathology/metabolism ; Rats, Wistar ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; tau Proteins/metabolism ; Drug Therapy, Combination ; Lipid Peroxidation/drug effects ; }, abstract = {This study assessed the neuroprotective potential of empagliflozin (EMPA) as antidiabetic drug on glucose metabolism, comparing it to rivastigmine (RIVA) as standard treatment for Alzheimer's disease (AD), and their combination. Male rats were sorted into five groups. Group I served as the control, while groups II, III, IV, and V received the scopolamine plus heavy metal mixture for AD induction. Groups III and IV were administered RIVA and EMPA, respectively, and group V received both treatments. Cognitive function was evaluated behaviorally. Subsequently, glucose levels, acetylcholinesterase, oxidative stress, and inflammatory markers were assessed. Alongside the brain histopathological changes, the expression of phosphorylated tau protein was assessed. Moreover, glycolytic enzymes and glucose transporters were assessed using PCR analysis. The findings were attributed to a notable suppressive impact of EMPA on lipid peroxidation, acetylcholinesterase, glucose levels, phosphorylated tau protein, pro-inflammatory cytokines, and neuropathological changes, while enhancing antioxidant and interleukin-10 levels. It also improves glucose metabolism. The findings suggest that EMPA may be a viable candidate for future therapeutic exploration in AD, which has a multifaceted mechanism of action encompassing anti-neuroinflammation, antioxidant stress, and enhanced glucose metabolism, as well as decreased acetylcholinesterase activity and phosphorylated tau protein levels. Interestingly, combined treatment showed a superior effect than EMPA alone.}, } @article {pmid41139687, year = {2025}, author = {Li, X and Singh, S and DeVries, A and Gurwitz, JH}, title = {Lecanemab Therapy Use Patterns for Alzheimer's Disease Among Early Initiators in a Large National Health Plan.}, journal = {Journal of the American Geriatrics Society}, volume = {73}, number = {10}, pages = {3203-3207}, pmid = {41139687}, issn = {1532-5415}, support = {K01 AG073651/AG/NIA NIH HHS/United States ; R33 AG057806/AG/NIA NIH HHS/United States ; K01AG073651/AG/NIA NIH HHS/United States ; 3R33AG057806-07S1/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Female ; Aged ; Male ; United States ; Medicare Part C/statistics & numerical data ; Magnetic Resonance Imaging ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage ; Aged, 80 and over ; }, abstract = {BACKGROUND: Lecanemab, an anti-amyloid monoclonal antibody, has been approved for treatment of early Alzheimer's disease. However, real-world data remain limited regarding use. METHODS: Using data from a large national health plan with primarily Medicare Advantage enrollees, we characterized demographic and clinical characteristics in the 6 months preceding the initial infusion among individuals who initiated lecanemab between 1/1/2023 and 06/30/2024. We also characterized the patterns of infusions and the timing of MRIs for safety monitoring following the initial infusion among initiators who had ≥ 3 months of follow-up. We further assessed trends in lecanemab use between 1/1/2023 and 12/31/2024. RESULTS: Of the 195 lecanemab initiators, the average age was 74.6 (SD = 5.5) years, 62.1% were female, 87.7% were White, 4.1% were Black, 1.5% were Hispanic, and 98.5% were on a Medicare Advantage plan. Almost all initiators resided in nonrural areas (96.4%); 2.6% used anticoagulants, and 1.5% used antiplatelets. Among the 119 initiators who had ≥ 3 months of follow-up, 40 (33.6%) received 7 total infusions, the expected number of infusions based on the recommended schedule of every 2 weeks. From the initial infusion, the average number of days to the first MRI was 47.1 (SD = 15.8), and to the second MRI scan was 73.4 (SD = 12.0) days, consistent with the recommended schedule. During 2023-2024, there were 526 patients who had ever received lecanemab. The increase in new initiators was modest over 2024, with only 43 more initiators during the final (n = 137) versus the first quarter (n = 94) of 2024. CONCLUSIONS: This study demonstrated slow uptake of lecanemab among Medicare Advantage beneficiaries. Adherence to the ideal treatment schedule was less than recommended. Early lecanemab users were not representative of the population likely eligible for treatment nationally. Further research is warranted to track longer-term trends in utilization, as well as reasons for treatment interruption or discontinuation in real-world populations.}, } @article {pmid41139428, year = {2025}, author = {Justo-Henriques, SI and Lemos, R and Rahmatpour, P and Silva, RCG and Carvalho, JO and Ribeiro, O}, title = {Effectiveness of Individual Cognitive Stimulation on Cognition in Mild Alzheimer's Disease: A Multicenter RCT.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {25}, number = {6}, pages = {e70109}, pmid = {41139428}, issn = {1479-8301}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; Male ; Aged ; *Executive Function/physiology ; Neuropsychological Tests ; Treatment Outcome ; *Cognition/physiology ; Aged, 80 and over ; *Cognitive Behavioral Therapy/methods ; Memory ; Portugal ; *Cognitive Dysfunction/therapy ; }, abstract = {BACKGROUND: Alzheimer's Disease (AD) is characterised by impairments across several neurocognitive domains, including memory and executive function. The study explored the effectiveness of a 3-month individual Cognitive Stimulation (iCS) program in older adults with mild AD. METHODS: A multicenter randomised controlled trial was conducted with 62 Portuguese older adults with mild AD. Participants were randomly assigned to either iCS (n = 33; 53%) or treatment as usual (TAU, n = 29; 47%). Cognitive outcomes were assessed at baseline, post-intervention, and 12-week follow-up using standardised tests for global cognition, memory and executive function. RESULTS: The iCS group showed a significant improvement in memory and executive function compared to the TAU group. The analysis of subscales revealed significant improvements in encoding and semantic memory (Memory Alteration Test) and free delayed recall (Free and Cued Selective Reminding Test). Adherence and engagement with the intervention were high. CONCLUSIONS: A 3-month iCS program showed preliminary benefits in specific cognitive domains (memory and executive function) in older adults with mild AD, warranting further research with larger samples and longer follow-up. TRAIL REGISTRATION: Clinicaltrials.gov ID: NCT05433493; Effect of Individual Cognitive Stimulation on Memory and Executive Function in Older Adults With Alzheimer's Disease.}, } @article {pmid41139132, year = {2026}, author = {Sonwani, A and Pathak, A and Jain, K}, title = {Development and characterization of multifunctional dendrimeric nanoconjugates for delivery of rutin: in vitro characterization for potential neuroprotective application.}, journal = {Nanomedicine (London, England)}, volume = {21}, number = {1}, pages = {1-14}, pmid = {41139132}, issn = {1748-6963}, mesh = {*Rutin/chemistry/administration & dosage/pharmacology ; *Dendrimers/chemistry ; *Neuroprotective Agents/chemistry/administration & dosage/pharmacology ; *Nanoconjugates/chemistry ; Humans ; Antioxidants/chemistry/pharmacology ; Animals ; Folic Acid/chemistry ; Drug Liberation ; Cell Survival/drug effects ; Particle Size ; Acetylcysteine/chemistry ; Drug Delivery Systems ; *Drug Carriers/chemistry ; }, abstract = {AIM: In the present research work, multifunctional dendrimeric nanoconjugates were developed, where poly(amidoamine) dendrimer generation 4.0 (G4.0) was conjugated with folic acid and N-acetyl cysteine simultaneously to deliver rutin for potential neuroprotective applications. METHODS: G4.0 was functionalized with folic acid and N-acetyl cysteine by carbodiimide coupling chemistry, and the conjugation was confirmed using [1]H NMR and FTIR spectroscopy. Further, rutin was incorporated within the conjugate, and the rutin-loaded dendrimeric conjugate was evaluated for size, drug release, cytotoxicity, cellular uptake, and antioxidant activity. RESULTS: The results of FTIR and [1]H NMR confirmed the conjugation of folic acid and N-acetyl cysteine over the dendrimeric surface. The particle size of NAC-FA-G4.0 was 163.4 ± 16.63 nm, which was increased to 229.76 ± 14.05 nm following the rutin incorporation. The in vitro drug release study showed an initial burst release of rutin, i.e. 44.27 ± 6.4% from dendrimeric conjugate within 4 h, followed by sustained release up to 72 h. The safety and biocompatibility of the developed nanoconjugate were confirmed by the hemolytic toxicity and cytotoxicity studies. CONCLUSION: The developed rutin-loaded dendrimeric conjugate showed improved antioxidant activity and acetylcholinesterase inhibition, suggesting promising neuroprotection properties and hence may be further explored for the treatment of neurodegenerative diseases, including Alzheimer's disease.}, } @article {pmid41139043, year = {2026}, author = {Yu, C and Liu, L and Lu, Z and Chen, M and Yang, N and Li, Z and Bai, L and Li, C and Zhou, X}, title = {A new approach for treating AD: Guifu Dihuang Pills improves brain insulin resistance by promoting NrCAM to activate the EGFR/PI3K/Akt signaling pathway.}, journal = {Journal of ethnopharmacology}, volume = {356}, number = {}, pages = {120642}, doi = {10.1016/j.jep.2025.120642}, pmid = {41139043}, issn = {1872-7573}, mesh = {Animals ; *Insulin Resistance ; Proto-Oncogene Proteins c-akt/metabolism ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Male ; ErbB Receptors/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; Humans ; Hippocampus/drug effects/metabolism ; Brain/drug effects/metabolism ; Streptozocin ; Mice, Inbred C57BL ; }, abstract = {Guifu Dihuang Pills (GFDHP), a classical Chinese herbal formula originally recorded in the Synopsis of the Golden Chamber (Jingui Yaolüe), significantly ameliorate cognitive dysfunction in patients with Alzheimer's disease (AD). However, the precise molecular mechanisms underlying its therapeutic effects, particularly those involving the regulation of cerebral insulin resistance (IR), are not yet fully elucidated. AIM OF THE STUDY: This study systematically investigated the neuroprotective mechanism of the traditional Chinese medicine (TCM) compound GFDHP in alleviating AD by integrating RNA-seq transcriptomics, surface plasmon resonance (SPR) analysis, and bioinformatic analysis. The aim was to clarify its key targets and signaling pathways involved in the modulation of cerebral IR by in vitro and in vivo experiments. METHODS: The chemical components of GFDHP were characterized using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). An AD model with cerebral IR was established by an intracerebroventricular streptozotocin (ICV-STZ) injection. Cognitive function was assessed using the Morris water maze (MWM) test, while hippocampal damage was evaluated by histological staining. The insulin level in hippocampal tissues was quantified using enzyme-linked immunosorbent assay (ELISA). AD-related proteins were analyzed using immunohistochemistry and Western blot. Integrated transcriptome sequencing, AlphaFold3 prediction, and SPR analysis confirmed the interaction between neuronal cell adhesion molecule (NrCAM) and epidermal growth factor receptor (EGFR). In vitro experiments were performed using HT22 cells treated with dexamethasone (DXM) to induce an IR model, followed by evaluation of IR and AD-related markers. Lentivirus-mediated shRNA knockdown of NrCAM was performed to systematically examine its regulatory effect on the EGFR/PI3K/Akt signaling pathway and GFDHP's therapeutic intervention. RESULTS: GFDHP significantly attenuated ICV-STZ-induced IR and AD-related neuropathological alterations. SPR analysis further revealed that NrCAM mediated the neuroprotective effect through the specific binding to EGFR, thereby activating the downstream PI3K/Akt signaling cascade. NrCAM silencing not only exacerbated both IR and AD pathology but also suppressed the EGFR/PI3K/Akt pathway and reduced the therapeutic effect of GFDHP. CONCLUSIONS: This study demonstrated that GFDHP alleviated IR by upregulating NrCAM expression and subsequently activating the EGFR/PI3K/Akt signaling pathway, thereby ameliorating AD. This is the first report identifying NrCAM as the key molecular target mediating the neuroprotective effect of this herbal formulation, providing a novel therapeutic strategy for AD treatment.}, } @article {pmid41138654, year = {2025}, author = {Ha, TY and Kim, Y and Lim, SM and Hong, Y and Chang, KA}, title = {GPR40 agonist ameliorates neurodegeneration by regulating mitochondria dysfunction and NLRP3 inflammasome in Alzheimer's disease animal models.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {192}, number = {}, pages = {118678}, doi = {10.1016/j.biopha.2025.118678}, pmid = {41138654}, issn = {1950-6007}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Receptors, G-Protein-Coupled/agonists/metabolism ; *Mitochondria/drug effects/metabolism/pathology ; Disease Models, Animal ; *Inflammasomes/metabolism/drug effects ; Mice ; Amyloid beta-Peptides/metabolism ; Male ; Mice, Transgenic ; Neurons/drug effects/metabolism/pathology ; Reactive Oxygen Species/metabolism ; Hippocampus/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; *Phenethylamines/pharmacology ; Autophagy/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction and chronic neuroinflammation. G-protein coupled receptor 40 (GPR40), primarily known for its role in metabolic regulation, has recently emerged as a modulator of neuronal activity and inflammatory signaling. In this study, we investigated the therapeutic potential of the selective GPR40 agonist TUG469 in both in vitro and in vivo models of AD. Treatment with amyloid-β oligomers (AβO) induced mitochondrial dysfunction in primary hippocampal neurons, as evidenced by disrupted mitochondrial morphology and membrane potential. TUG469 treatment restored mitochondrial integrity and membrane potential. Moreover, TUG469 significantly reduced AβO-induced reactive oxygen species (ROS) production. In the 5xFAD mouse model of AD, TUG469 administration improved cognitive performance and reduced Aβ plaque burden. Furthermore, TUG469 rescued impaired autophagy flux, as demonstrated by the regulation of LC3, p62, and LAMP1 expression, and attenuated neuroinflammatory responses by inhibiting NLRP3 inflammasome activation and modulating microglial reactivity. These findings indicate that GPR40 activation mitigates mitochondrial dysfunction and neuroinflammation, thereby alleviating AD-related pathology. Our results highlight the therapeutic potential of TUG469 as a multi-target modulator for AD.}, } @article {pmid41138336, year = {2026}, author = {Waheed, R and Mostafa, Z and Emad, M and Darwish, SS and Purgatorio, R and Miniero, DV and De Palma, A and Cheng, TP and Wang, TY and Chen, YC and El Kerdawy, AM and Gabr, M and Catto, M and Abadi, AH and Hwang, TL and Abdel-Halim, M}, title = {Revisiting COX-2 inhibitors for Alzheimer's disease as multitargeted ligands: Development of 4-hydrazono-pyrazolidinediones with tuned COX selectivity profile and improved cellular potency.}, journal = {European journal of medicinal chemistry}, volume = {302}, number = {Pt 1}, pages = {118261}, doi = {10.1016/j.ejmech.2025.118261}, pmid = {41138336}, issn = {1768-3254}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Cyclooxygenase 2 Inhibitors/pharmacology/chemistry/chemical synthesis ; Structure-Activity Relationship ; *Cyclooxygenase 2/metabolism ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Molecular Structure ; Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Ligands ; Dose-Response Relationship, Drug ; Animals ; *Hydrazones/chemistry/pharmacology/chemical synthesis ; Dogs ; *Pyrazoles/chemistry/pharmacology/chemical synthesis ; Cyclooxygenase 1/metabolism ; }, abstract = {Herein, we expand on our previously synthesized 4-hydrazono-pyrazolidinedione COX-2 inhibitors as multitargeted agents for Alzheimer's disease (AD). Structural modifications of the 4-phenylhydrazono group led to the identification of several highly potent COX-2 inhibitors, with compound 3 exhibiting the strongest COX-2 inhibition (IC50 = 0.07 μM), with a balanced COX-2/COX-1 profile, suggesting lower cardiovascular risk. Compounds 2 and 9 showed high potency and selectivity shift toward COX-1 and displayed strong antiplatelet activity. Several derivatives showed 4-7 times improved submicromolar cellular potency, significantly inhibiting PGE2 release in LPS-stimulated THP-1 cells. Compounds 2, 3, 7, and 9 maintained the multitarget profile and inhibited Aβ and tau aggregation. Compounds 2, 3, and 7 protected against Amyloid-beta (Aβ)- and H2O2-induced cytotoxicity, confirming their neuroprotective activity with high potential for BBB permeability demonstrated via PAMPA and MDCK-MDR1 assays. These results support the potential of multitargeted COX-2 inhibitors as AD therapeutics and suggest a re-evaluation of their role in neurodegenerative disease treatment.}, } @article {pmid41138018, year = {2025}, author = {Hu, L and Qi, L and Lin, Z and Zhu, J and Zhang, M}, title = {Research progress of single cell RNA sequencing in nervous system.}, journal = {Molecular biology reports}, volume = {53}, number = {1}, pages = {9}, pmid = {41138018}, issn = {1573-4978}, support = {82271747//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Single-Cell Analysis/methods ; *Sequence Analysis, RNA/methods ; *Nervous System/metabolism ; Transcriptome/genetics ; *Nervous System Diseases/genetics ; Animals ; Gene Expression Profiling/methods ; }, abstract = {Single-cell RNA sequencing (scRNA-seq) and its integration with multi-omics technologies such as epigenomics and spatial transcriptomics are revolutionizing our traditional understanding of cellular heterogeneity and the microenvironment in the nervous system. While technical reviews abound, translating multi-omics data into biological and clinical insights remains a challenge. This review comprehensively outlines the latest advancements in scRNA-seq technology and its integration with multi-omics approaches and artificial intelligence. We systematically summarize its applications across neuroscience, from unraveling neurodevelopment and evolution to deciphering the mechanisms of neurological diseases such as Alzheimer's disease, Parkinson's disease, and gliomas. By deeply resolving cell-specific expression differences in neurological disorders, scRNA-seq has enabled the discovery of novel cell subtypes and revealed intercellular regulatory mechanisms, thereby facilitating the deconstruction of disease pathogenesis and the identification of new potential therapeutic targets. Furthermore, this technology has demonstrated significant value in drug screening, efficacy evaluation, and the development of novel treatment strategies. However, scRNA-seq still faces multiple technical limitations. Future efforts should focus on reducing its application costs, addressing clinical ethical concerns, and progressively advancing the clinical translation of scRNA-seq technology.}, } @article {pmid41137894, year = {2025}, author = {Gu, X and Yu, SP and Jiang, MQ and Zhong, W and Sastry, A and Wei, L}, title = {Preventive Memantine Treatment at the Preclinical Stage in the Alzheimer's Disease Model of the 5xFAD Mouse.}, journal = {Neuroscience bulletin}, volume = {}, number = {}, pages = {}, pmid = {41137894}, issn = {1995-8218}, abstract = {Neuronal and NMDA receptor (NMDAR) hyperactivities are common pathophysiology in Alzheimer's disease (AD). We recently identified that the deficiency of NMDAR regulatory subunit GluN3A (NR3A) cultivated early psychological and olfactory symptoms, followed by cognitive decline and deferred endogenous amyloid/tau pathologies. NMDAR antagonist memantine (MEM) prevented AD-like progression in GluN3A knockout (KO) mice. We tested the hypothesis that AD development of the 5xFAD mouse can be antagonized by the preemptive MEM treatment. MEM (10 or 20 mg/kg per day in drinking water for 3 months) was started in wild-type (WT) and 5xFAD mice at 3 months old. In this preclinical stage, the 5xFAD mouse displayed psychological and olfactory symptoms, yet exhibited no significant cognitive deficits or Aβ42 deposition. The MEM treatment antagonized early symptoms, abated cognitive decline, and amyloid/tau pathology. Early and persistent maintenance of normal neuronal/NMDAR activities in individuals carrying AD risk factors should be considered as a preventive and a possible disease-modifying therapy.}, } @article {pmid41137616, year = {2025}, author = {Chan, D and de Weck, G and Jackson, BL and Suk, HJ and Milman, NP and Kitchener, E and Avalos, VSF and Quay, MJ and Aoki, K and Ruiz, E and Becker, A and Zheng, M and Philips, R and Firenze, R and Geigenmüller, U and Hammerschlag, B and Arnold, S and Kivisäkk, P and Brickhouse, M and Touroutoglou, A and Brown, EN and Boyden, ES and Dickerson, BC and Klerman, EB and Tsai, LH}, title = {Gamma sensory stimulation in mild Alzheimer's dementia: An open-label extension study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70792}, pmid = {41137616}, issn = {1552-5279}, support = {//Freedom Together Foundation/ ; //Robert A. and Renee E. Belfer Family Foundation/ ; //Eleanor Schwartz Charitable Foundation/ ; //The Dolby Family/ ; //Che King Leo/ ; //Amy Wong and Calvin Chin/ ; //Kathleen and Miguel Octavio/ ; //the Degroof-VM Foundation/ ; //Halis Family Foundation/ ; //Chijen Lee/ ; //Eduardo Eurnekian/ ; //Larry and Debora Hilibrand/ ; //Gary Hua and Li Chen/ ; //Ko Han Family/ ; //Lester Gimpelson/ ; //David B. Emmes/ ; //Joseph P. DiSabato and Nancy E. Sakamoto/ ; //Donald A. and Glenda G. Mattes/ ; //Alan and Susan Patricof/ ; //Carol and Gene Ludwig Family Foundation/ ; //Alex Hu and Anne Gao/ ; //Elizabeth K. and Russell L. Siegelman/ ; //Marc Haas Foundation/ ; //Dave and Mary Wargo/ ; //James D. Cook, and the Nobert H. Hardner Foundation/ ; UDIW8172//NIH Loan Repayment Program/ ; 15367//Doris Duke Clinical Scientist Development Award/ ; //Picower Clinical Fellowship/ ; UL1 TR002541/TR/NCATS NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Acoustic Stimulation/methods ; *Alzheimer Disease/therapy/physiopathology/diagnostic imaging ; Biomarkers/blood ; Brain/diagnostic imaging/physiopathology ; Cognition/physiology ; Electroencephalography ; Magnetic Resonance Imaging ; Mental Status and Dementia Tests ; Neuropsychological Tests ; *Photic Stimulation/methods ; tau Proteins/blood ; }, abstract = {INTRODUCTION: We evaluated the long-term effects of daily 40 Hz (gamma frequency) audiovisual stimulation on cognition and biomarkers in five patients with mild Alzheimer's disease (AD). METHODS: Over 2 years, patients received 1-h daily stimulation. Electroencephalography (EEG) was used to assess neural entrainment; magnetic resonance imaging (MRI) measured brain volumes; actigraphy monitored activity patterns; neuropsychological tests evaluated cognition; and S-PLEX assay measured plasma pTau217. RESULTS: No adverse events occurred over the study period. Three female patients with late-onset AD (LOAD) retained strong EEG entrainment and showed less decline in Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Functional Assessment Scale (FAS) scores compared to matched controls from National Alzheimer's Coordinating Center (NACC), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). Plasma samples were available for only two of five participants - both with LOAD - and both showed pTau217 reductions of 47% and 19%. DISCUSSION: These findings suggest that long-term 40 Hz audiovisual stimulation is safe, feasible, and may offer cognitive and biomarker benefits in some individuals with mild AD, supporting further investigation. ClinicalTrials.gov (NCT04055376). HIGHLIGHTS: Five mild Alzheimer's disease (AD) patients safely used daily 40 Hz audiovisual stimulation for 2 years. Late-onset AD (LOAD) patients showed increased 40 Hz electroencephalography (EEG) power and improved cognitive scores. National Alzheimer's Coordinating Center (NACC) data enhanced early-phase analysis and support precision medicine in AD studies. Plasma pTau217 declined in 2 LOAD patients after 2 years of daily use. This small pilot is the first to link long-term 40 Hz therapy to AD biomarker change.}, } @article {pmid41137085, year = {2025}, author = {Zhang, W and Song, J and Zhong, F and Yu, W and Qin, Z and Yang, Z and Liu, J and Wang, X and Chen, L and Lü, W and Xing, D and Liu, J and Huang, C and Wu, J and Liu, X and Yu, W and Lü, Y}, title = {Computerized cognitive training enhances cognitive function in Alzheimer's disease by downregulating Ruminococcus-TMAO pathway.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {1173}, pmid = {41137085}, issn = {1479-5876}, support = {2022YSZX-JSX0002CSTB//grants from Innovation Programs Led by the Academicians in Chongqing under Project/ ; cstc2022ycjh-bgzxm0184//Chongqing Talent Plan/ ; CSTC2021jscx-gksb-N0020//Jiangsu Provincial Agricultural Science and Technology Independent Innovation Fund/ ; 2021ZD0201802//STI2030-Major Projects/ ; 2018YFC2001700//National Key R&D Program of China/ ; 0201[2023]160 202412//Chongqing Medical Key Discipline and Regional Medical Key Discipline Development Project/ ; }, mesh = {Humans ; Male ; *Alzheimer Disease/microbiology/physiopathology/therapy/blood ; Female ; *Cognition/physiology ; Aged ; *Methylamines/blood/metabolism ; *Down-Regulation ; Gastrointestinal Microbiome ; Cognitive Dysfunction/physiopathology ; Cognitive Training ; }, abstract = {BACKGROUND: The microbiota-gut-brain (MGB) axis is implicated in Alzheimer's disease (AD), but evidence for interventional strategies targeting this axis remains limited. METHODS: In a 24-week, single-blind, randomized controlled trial, 84 individuals with mild cognitive impairment (MCI) or mild AD received either computerized cognitive training (CCT) or treatment as usual (TAU). Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) was the primary outcome. We also assessed functional connectivity (fNIRS), plasma trimethylamine N-oxide (TMAO) levels, and gut microbiota at baseline and 24 weeks. RESULTS: Seventy-four participants completed the study. The CCT group showed significant improvement in ADAS-cog scores compared to controls (Cohen's d = 1.57 by week 24). Notably, CCT also induced a distinct reorganization of prefrontal functional connectivity and significantly reduced plasma TMAO levels. Microbiome analysis revealed that CCT mitigated the expansion of Ruminococcus torques group (R.torques), which was observed in the control group. Crucially, R.torques was the only genus significantly correlated with improvements in cognition (ADAS-cog, r = 0.407), neuropsychiatric symptoms (NPI, r = 0.395), TMAO reduction (r = 0.443), and functional connectivity changes (r = 0.449). CONCLUSION: A 24-week CCT program improves cognitive function in MCI and mild AD, potentially through downregulating the R.torques-TMAO pathway within the MGB axis. This pathway represents a promising novel target for multi-domain intervention in AD.}, } @article {pmid41136359, year = {2025}, author = {Pan, X and Su, Z and Huang, Z and Chen, Y and Li, X and Zheng, X}, title = {N-acetylcysteine (NAC) ameliorates ethanol-induced oxidative stress, neuroinflammation, and cognitive dysfunction in APP/PS1 mouse model.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {435}, pmid = {41136359}, issn = {2158-3188}, mesh = {Animals ; *Acetylcysteine/pharmacology ; *Ethanol/toxicity/adverse effects ; Mice ; *Oxidative Stress/drug effects ; Disease Models, Animal ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroinflammatory Diseases/chemically induced/drug therapy ; Mice, Transgenic ; Male ; Microglia/drug effects ; *Antioxidants/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects ; Disks Large Homolog 4 Protein/metabolism/drug effects ; Amyloid beta-Protein Precursor/genetics ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder that predominantly affects the elderly, leading to a progressive decline in cognitive function. Accumulating evidence suggests that many environmental and dietary factors, especially chronic ethanol exposure, aggravate the risk of this disease. However, its precise influence on AD has not yet been clarified. Here, we show that ethanol exposure caused earlier and severer cognitive behavioral impairments, more beta amyloid (Aβ) depositions, microglia activation, decreased total antioxidant capacity (T-AOC). Moreover, inflammatory mediators, such as Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and Tumor necrosis factor-alpha (TNF-α) increased, while pivotal proteins involved in dendritic and synaptic development, such as Synaptophysin (SYP), postsynaptic density protein 95 (PSD95) and brain-derived neurotrophic factor (BDNF) decreased in APP/PS1 mice. N-acetylcysteine (NAC), a well-known antioxidant, could attenuate cognitive behavioral impairments and neuroinflammatory damage by restoring inflammatory and neurodevelopmental mediators. In general, our study uncovered that chronic ethanol exposure may exacerbate AD progress at the pathological and molecular levels and NAC may act as a potential drug for the treatment of AD patients with chronic ethanol exposure.}, } @article {pmid41135777, year = {2026}, author = {Zhang, S and Fan, Z and Ji, D}, title = {Advances in eye-brain axis: Anatomy, immunity, and association with visual dysfunction.}, journal = {Ageing research reviews}, volume = {113}, number = {}, pages = {102925}, doi = {10.1016/j.arr.2025.102925}, pmid = {41135777}, issn = {1872-9649}, mesh = {Humans ; *Brain/immunology/anatomy & histology/pathology ; Animals ; *Eye/anatomy & histology/immunology ; *Vision Disorders/physiopathology/immunology/pathology ; Glaucoma/physiopathology ; }, abstract = {The "eye-brain axis" refers to the dynamic system of interactions between the eyes and the brain, collectively encompassing the visual signal transmission and integration pathways. The eyes and the brain exhibit structural and functional synergy, and visual dysfunction not only impairs information processing within the eye but also induces structural and functional remodeling of the central nervous system (CNS) via the eye-brain axis. For instance, the effects of glaucoma on the visual cortex are manifested as reduced blood perfusion and decreased efficiency of mitochondrial adenosine triphosphate (ATP) synthesis. Moreover, the eye can serve as an important window and biomarker for the early diagnosis and intervention of neurodegenerative diseases of the CNS. Relevant research findings include the parallelism of beta amyloid (Aβ) and phosphorylated Tau (p-Tau) between the retina and Alzheimer's disease (AD), glaucomatous neurodegeneration with AD-like features, and the role of vascular endothelial growth factor C (VEGF-C) expression along the eye-brain lymphatic pathway in regulating intraocular pressure (IOP) and correcting macular edema. Therefore, eye-brain axis research provides novel perspectives for understanding the pathophysiological mechanisms underlying visual dysfunction and related disorders, while simultaneously supporting the development of cross-organ neuroprotective strategies. This review explores the anatomical foundations, immune regulation, and bidirectional interactions of the eye-brain axis, and evaluates its relevance to the diagnosis and treatment of visual dysfunction and degenerative diseases of the CNS.}, } @article {pmid41135742, year = {2025}, author = {Hu, T and Xi, J and Xie, N and Zhang, X and Huang, N and Cheng, Y}, title = {Multi-omics analysis reveals the protective role of transcriptional enhancer factor and the pathogenic mechanism of monocytes in Parkinson's disease.}, journal = {Brain research bulletin}, volume = {232}, number = {}, pages = {111594}, doi = {10.1016/j.brainresbull.2025.111594}, pmid = {41135742}, issn = {1873-2747}, mesh = {Animals ; *Parkinson Disease/genetics/metabolism ; Humans ; *Monocytes/metabolism/pathology ; Mice ; Mendelian Randomization Analysis ; *Transcription Factors/metabolism/genetics ; Male ; Mice, Inbred C57BL ; Cell Line, Tumor ; Multiomics ; }, abstract = {Parkinson's disease (PD) is a multifactorial neurodegenerative disorder whose pathogenic mechanisms remain incompletely elucidated. This study aimed to systematically identify key regulatory factors involved in PD at the genetic, cellular, and molecular levels. Using univariate Mendelian randomization (UVMR), we identified plasma proteins and genes associated with Alzheimer's disease (AD), PD, and amyotrophic lateral sclerosis (ALS), and validated their causal relationships through colocalization analysis. Cross-validation across multi-omics datasets revealed transcriptional enhancer factor (TEF) as a protective factor for PD, whereas increased counts of CD14[+]CD16[+] monocytes were identified as a risk factor. Single-cell analysis and multivariate Mendelian randomization (MVMR) further suggested potential mediating roles of these factors in PD pathogenesis. In vitro experiments demonstrated that TEF overexpression significantly enhanced the resistance of neuroblastoma cells to rotenone-induced damage, inhibited apoptosis, and preserved tyrosine hydroxylase (TH) expression. In vivo, TEF notably improved motor coordination and exploratory behavior in PD mouse models. Collectively, these findings suggest that TEF may exert neuroprotective effects by modulating immune and neuronal pathways, offering a novel therapeutic target for the prevention and treatment of Parkinson's disease.}, } @article {pmid41134994, year = {2025}, author = {Mullins, CA and Gannaban, RB and Kramer, A and Shah, H and Haque, ZF and Ramezan, M and Dehghani, F and Palaniyappan, AK and Bowers, F and MohanKumar, SM and MohanKumar, PS and Shin, AC}, title = {Early branched-chain amino acid reduction delays the onset of cognitive decline in a mouse model of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1567-1583}, doi = {10.1177/13872877251389236}, pmid = {41134994}, issn = {1875-8908}, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *Amino Acids, Branched-Chain/metabolism/blood ; *Cognitive Dysfunction/prevention & control/metabolism ; Mice ; Male ; Disease Models, Animal ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Peptides/metabolism ; }, abstract = {BackgroundMany Alzheimer's disease (AD) treatments focus on a single variable of AD that have yet demonstrated clinically meaningful and perceived benefits by the patients. We recently showed that lowering plasma branched-chain amino acids (BCAAs) can deliver multiple pro-neuronal effects in APP/PS1 and 5xFAD mouse models.ObjectiveThe main aim was to determine the optimal point in time for the disease-modifying effects of BCAA reduction during AD development.Methods12-month-old, cognitively impaired male WT and APP/PS1 mice were injected with either vehicle or BCAA-lowering compound BT2 (40 mg/kg/day ip) for 30 days. To test if early BT2 during AD progression would have long-lasting beneficial effects, 2-month-old, cognitively intact male 5xFAD mice were treated with BT2 after which they were left alone for a month.ResultsPlasma BCAAs were reduced in BT2-treated APP/PS1 mice. Despite Aβ42 reduction, BT2 did not modify proteins or genes related to AD-related pathology, dendritic density and neurotransmitters in the cortex and hippocampus, or alleviate cognitive deficit. In another experiment, BT2-treated 5xFAD mice had lower plasma BCAAs. Importantly, early BT2, even after treatment cessation for a month, was able to effectively delay cognitive impairment which was associated with a complete restoration of cortical neurotransmitters. These results were observed without any changes in pathology markers in the brain.ConclusionsOur findings suggest that BT2-induced BCAA reduction is a novel strategy to delay AD progression possibly through enhanced neurotransmission. The efficacy is time-dependent such that treating with BT2 before the onset of AD can successfully rescue cognitive function.}, } @article {pmid41134991, year = {2025}, author = {Tseng, P}, title = {Does weak gamma entrainment still work? Rethinking the comfort-efficacy trade-off in 40 Hz sensory stimulation.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1517-1519}, doi = {10.1177/13872877251389153}, pmid = {41134991}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology ; *Gamma Rhythm/physiology ; Electroencephalography ; *Photic Stimulation/methods ; }, abstract = {As 40 Hz sensory stimulation gains attention as a potential treatment for Alzheimer's disease, comfort-focused designs such as invisible spectral flicker and multi-luminaire are increasingly used to promote long-term compliance. However, these systems often produce significantly weaker electroencephalographic entrainment than traditional stroboscopic lights. It is therefore important to question the common assumption that any level of entrainment is sufficient, and consider the possibility of nonlinear or threshold-based mechanisms that may require a minimum entrainment strength for therapeutic effects. The field needs to empirically test the relationship between entrainment strength and outcome, to ensure efficacy is not compromised for comfort.}, } @article {pmid41134085, year = {2026}, author = {Xu, YJ and Wu, T and Lo, LT and Ko, CC and Wang, X and Ma, CHE}, title = {Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {13}, number = {2}, pages = {e05421}, pmid = {41134085}, issn = {2198-3844}, support = {ITS/099/23FP//Innovation and Technology Commission of the Hong Kong Special Administrative Region (HKSAR) Government/ ; R1005-24F//Research Grant Council of the HKSAR Government/ ; CityU11100424//Research Grant Council of the HKSAR Government/ ; 08193956//Health and Medical Research Fund, Food and Health Bureau, HKSAR Government/ ; 32400807//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *Microglia/metabolism ; *Amyloid beta-Peptides/metabolism ; Mice ; *Phagocytosis/genetics ; *tau Proteins/metabolism/genetics ; Disease Models, Animal ; Mice, Transgenic ; Humans ; Male ; }, abstract = {Amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low-dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg-AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H4R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg-AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p-tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF-β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF-β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H4R/cAMP/TGF-β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD.}, } @article {pmid41133841, year = {2025}, author = {Yao, L and Ni, J and Wei, M and Li, T and Li, F and Wang, T and Xiao, W and Shi, J and Tian, J}, title = {Recent Advances in the Application of Artificial Intelligence in Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050410489250930175402}, pmid = {41133841}, issn = {1875-5828}, abstract = {Artificial intelligence (AI) refers to a system that can simulate and execute the processes of human thinking and learning, and make informed decisions. Fueled by the development of AI, the quality and effectiveness of medical work have gained momentum. AI technology plays an increasingly important role in healthcare, exhibiting substantial potential in clinical practice and decision-making processes. In Alzheimer's disease (AD), where early diagnosis and treatment remain challenging due to clinical heterogeneity and insidious progression, AI could offer excellent solutions. AI models can integrate multi-modal data to identify pre-symptomatic biomarkers and stratify high-risk cohorts, improving diagnostic accuracy, assisting with personalizing treatment and care. Furthermore, AI can accelerate drug discovery and development through drug-target identification and predictive modeling of compound efficacy. However, data quality, supervision, transparency, privacy, and ethical concerns need to be addressed. By identifying and retrieving studies for the systematic review, this article provides a comprehensive overview of current progress and related AI applications in AD.}, } @article {pmid41133228, year = {2025}, author = {Wang, S and Shi, Y and Xin, R and Kang, H and Xiong, H and Ren, J}, title = {Exploring the role of insulin resistance in bridging the metabolic syndrome and Alzheimer's disease-a review of mechanistic studies.}, journal = {Frontiers in endocrinology}, volume = {16}, number = {}, pages = {1614006}, pmid = {41133228}, issn = {1664-2392}, mesh = {*Insulin Resistance/physiology ; Humans ; *Alzheimer Disease/metabolism/pathology/etiology ; *Metabolic Syndrome/metabolism/pathology ; Animals ; Oxidative Stress ; Renin-Angiotensin System ; }, abstract = {The association between metabolic syndrome (MetS) and Alzheimer's disease (AD) has attracted widespread attention; nevertheless, the precise mechanism of action between the two is not yet fully elucidated. This review systematically explores the complex mechanisms of insulin resistance (IR) in MetS and AD. We first detail the intrinsic mechanisms of insulin resistance and emphasize its central role in the pathophysiology of MetS. Further, we reveal the underlying mechanisms by which insulin resistance in turn triggers AD through a multidimensional pathway that promotes the accumulation of pathological products, induces blood-brain barrier dysfunction, impairs neuroplasticity, induces neuroinflammatory responses, aberrantly activates the renin-angiotensin-aldosterone system, and exacerbates oxidative stress. In addition, we summarize potential strategies for targeting IR in AD treatment and demonstrate the promising prospects for improving insulin resistance in promoting cognitive recovery. This study offers a novel theoretical framework for elucidating the intricate relationship between MetS and AD. Furthermore, it provides a scientific foundation for the formulation of preventive and therapeutic strategies for metabolic and neurodegenerative diseases.}, } @article {pmid41132583, year = {2025}, author = {Zou, Z and Lei, D and Wang, X and Yin, Y and Li, H and Di, X and Li, X}, title = {Crocin Ameliorates Cognitive Impairment and Pathological Changes in Alzheimer's Disease Model Mice by Regulating Gut Microbiota.}, journal = {Food science & nutrition}, volume = {13}, number = {10}, pages = {e71117}, pmid = {41132583}, issn = {2048-7177}, abstract = {Alzheimer's disease (AD), a primary cause of dementia, places a significant strain on both patients and society due to the absence of effective treatments. Recent research suggests that the gut microbiota may play a role in the development of AD. Crocin, a compound derived from traditional medicine, has demonstrated potential in alleviating neurological disorders and influencing gut microbiota, yet its specific mechanisms in AD remain unclear. In this study, we administered Crocin or saline to 5xFAD mice and wild-type controls. We discovered that Crocin treatment led to notable improvements in cognitive function, as measured by the Morris water maze test, reduced beta-amyloid (Aβ) accumulation, and decreased neuroinflammation, as indicated by reduced microglial and astrocyte activation. Metagenomic sequencing revealed a significant increase in the gut microbiota diversity, specifically the abundance of Firmicutes, Verrucomicrobiota, and Akkermansia. Additionally, Crocin enhanced intestinal barrier function by upregulating tight junction proteins and Secretory immunoglobulin A, while improving the structure of the jejunal mucosa. These results suggest that Crocin may alleviate cognitive deficits and neuropathological changes in 5xFAD mice, possibly through modulation of the gut microbiota and strengthening the gut barrier, presenting it as a promising therapeutic approach for AD.}, } @article {pmid41132573, year = {2025}, author = {Sriramcharan, P and Ahmed, SS and Natarajan, J and Kumar, RR and Antony, J and Kumar, AP and Anjali, PB and Ganganagappa, N and Shah, RM and Madar, IH}, title = {Cerium oxide nanoparticles synthesized via green route exhibit neuroprotective effects in Alzheimer's-induced Albino Wistar rats.}, journal = {3 Biotech}, volume = {15}, number = {11}, pages = {398}, pmid = {41132573}, issn = {2190-572X}, abstract = {UNLABELLED: Green synthesis of cerium oxide nanoparticles emerges as a feasible therapeutic strategy for disorders like Alzheimer's to determine its antioxidant and cytotoxicity in the in vitro environment, following in vivo studies, safety and effectiveness were confirmed. This approach has gained increased reliability compared to physical and chemical methods due to its non-toxic and environmentally friendly nature. The synthesized nanoparticles are then characterized using Fourier transform infrared spectrometry (FTIR), particle size, scanning electron microscopy (SEM), X-ray diffraction (XRD), and Raman spectroscopy. Design optimization was applied to the selected variables to get the best-fit values of the experiment. FTIR spectroscopy revealed amide, carboxyl, and ester groups in the cerium oxide particles produced by Candida albicans, indicating their significance in nanoparticle stabilization. The particle size and zeta potential of cerium oxide nanoparticles were found to be 152 nm and - 15 mV, respectively. Various antioxidant studies, such as 2, 2-Diphenyl-2-Picryl Hydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS), anti-lipid peroxidation, and catalase, were conducted, revealing that synthesized nanoparticles had high antioxidant activity. SEM images produced high-quality, evenly distributed images. Cerium oxide nanoparticles effectively inhibited SK-N-SH human neuroblastoma cells, with an IC50 value of 65 µg/ml. An in vivo study was performed using an amyloid-beta-induced intracerebroventricular rat model. The finding demonstrates the induction of AD in rats led to spatial memory impairments, whereas the treatment with cerium oxide nanoparticles suggests a significant improvement in neuroprotective effect. This outcome was validated through Morris water maze behavioral assessment and histopathological analysis. The results indicated that the synthesized cerium oxide nanoparticles, optimizing using the Box-Behnken design, resulted in strong antioxidant and cytotoxic activities (65%). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04563-4.}, } @article {pmid41131967, year = {2025}, author = {Javed, A and Mandal, P and Khan, I and Singh, A and Akhtar, J and Maheshwari, S and Prajapati, BG}, title = {Liposomal Drug Delivery for Neurological Disorders: Advances and Challenges.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {25}, number = {3}, pages = {245-260}, pmid = {41131967}, issn = {1875-6166}, mesh = {Humans ; *Liposomes/chemistry/administration & dosage/metabolism ; *Drug Delivery Systems/methods/trends ; *Nervous System Diseases/drug therapy/metabolism ; Animals ; Blood-Brain Barrier/drug effects/metabolism ; *Neuroprotective Agents/administration & dosage ; }, abstract = {Liposomal drug delivery methods are becoming increasingly viable options for improving treatment outcomes for neurological illnesses. These systems provide a flexible framework for the formulation of medications intended for delivery to the brain, protecting the medication from enzymatic breakdown and enhancing its bioavailability. To maximize liposome-drug interactions and improve brain-targeted delivery efficiency, a variety of formulation strategies are used, such as surface modification and remote loading. By utilizing various pathways to cross the blood- -brain barrier (BBB), such as passive diffusion and receptor-mediated transcytosis, liposomes facilitate the effective transport of therapeutic drugs to the brain parenchyma. Liposomal formulations show potential for targeted drug delivery, reducing off-target effects, and improving treatment efficacy in neurological conditions like Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis, and brain cancers. For instance, in Parkinson's disease, liposomal delivery of neuroprotective agents can help maintain dopamine levels and protect dopaminergic neurons. In Alzheimer's disease, liposomes can be engineered to deliver drugs that reduce amyloid-beta plaques or tau tangles. For brain cancer, liposomal chemotherapy can target tumor cells more precisely while minimizing damage to surrounding healthy tissue. In stroke, liposomal delivery of neuroprotective agents can reduce the extent of brain damage, while in multiple sclerosis, liposomes can be used to deliver drugs that modulate the immune response. However, the clinical translation of liposomal drug delivery systems for brain diseases faces challenges related to scalability, stability, and immunogenicity, in addition to regulatory barriers. Scalability issues arise from the complex manufacturing processes required to produce liposomes consistently on a large scale. Stability concerns involve maintaining the integrity of liposomes during storage and after administration. Immunogenicity can be a problem if the liposomes trigger an unwanted immune response, potentially reducing their effectiveness or causing adverse effects. To overcome these obstacles, multidisciplinary cooperation is essential. Collaboration among materials scientists, pharmacologists, neurologists, and regulatory experts can drive the development of more robust liposomal formulations. Continuous research is needed to refine liposome designs, such as by optimizing lipid composition, surface charge, and size to improve stability and targeting capabilities. Advanced techniques like PEGylation (coating liposomes with polyethylene glycol) can help reduce immunogenicity and extend circulation time in the bloodstream. Despite these challenges, liposomal methods present intriguing prospects for transforming medication administration to the brain and offering effective treatments for neurological illnesses. The development of more sophisticated liposomal technologies, combined with a deeper understanding of their mechanisms of action, could lead to significant breakthroughs in the treatment of neurological disorders. For example, research into ligand- targeted liposomes, which use specific molecules to bind to receptors on the BBB, holds promise for enhancing delivery specificity and efficiency. To fully realize the therapeutic promise of these novel drug delivery systems, further advancements in liposomal technologies and a deeper understanding of their mechanisms are necessary. This includes not only technical improvements but also comprehensive preclinical and clinical studies to evaluate safety, efficacy, and long-term effects. As our knowledge expands and technology progresses, liposomal drug delivery could become a cornerstone of neurological disease treatment, providing new hope for patients with previously intractable conditions.}, } @article {pmid41131557, year = {2025}, author = {Buchanan, RA and Kramer, AT and Calipari, ES and Bowman, AB and Nobis, WP and Harrison, FE}, title = {Differential impact of manganese on glutamate clearance, electroencephalography, and sleep in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70821}, pmid = {41131557}, issn = {1552-5279}, support = {DK135073/DK/NIDDK NIH HHS/United States ; DK020593/DK/NIDDK NIH HHS/United States ; //FEH and ABB/ ; T32 ES007028/ES/NIEHS NIH HHS/United States ; P50 HD103537/HD/NICHD NIH HHS/United States ; HD103537//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01 ES031401/ES/NIEHS NIH HHS/United States ; R01 ES035518/ES/NIEHS NIH HHS/United States ; ES007028/ES/NIEHS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Manganese/toxicity/metabolism/pharmacology ; Electroencephalography ; *Glutamic Acid/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Sleep/drug effects ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; *Brain/drug effects/metabolism ; Mice, Inbred C57BL ; }, abstract = {INTRODUCTION: Underlying glutamate dysregulation in Alzheimer's disease can be worsened by environmental factors like manganese (Mn) exposure. This study examined how excess Mn affects glutamatergic signaling and neurotransmission in a beta-amyloid mouse model. METHODS: APP/PSEN1 and control mice were exposed to systemic Mn subcutaneously. Gene expression, glutamate clearance dynamics, electroencephalography (EEG) activity, and sleep architecture were analyzed using quantitative polymerase chain reaction (qPCR), Western blot, ex vivo hippocampal slices, and EEG recordings. RESULTS: Mn exposure elevated brain Mn levels and altered glutamate dynamics in both WT and APP/PSEN1 mice. Wild-type (WT) mice showed faster glutamate clearance, increased spiking, disrupted sleep, and brain wave changes. APP/PSEN1 mice exhibited slower glutamate clearance, altered gene expression, increased glial fibrillary acidic protein (GFAP), and changes in non-rapid eye movement (NREM) delta and rapid eye movement (REM) alpha power. DISCUSSION: Mn exposure altered glutamate clearance and brain activity, particularly in WT mice. APP/PSEN1 mice showed impaired clearance, limited gene expression changes, and altered EEG patterns, suggesting distinct or pre-existing compensatory mechanisms. HIGHLIGHTS: Manganese exposure significantly alters glutamate clearance dynamics differentially in wild-type and APP/PSEN1 mouse models of Alzheimer's disease. Acute manganese treatment disrupts sleep architecture, evidenced by changes in electroencephalography (EEG) patterns and vigilance states. APP/PSEN1 mice exhibit slower glutamate clearance and altered gene expression compared to wild-type mice following manganese exposure. Distinct brain wave frequency shifts were observed in response to manganese treatment, particularly affecting delta, theta, and alpha rhythms. Findings suggest a potential exacerbation of excitatory/inhibitory imbalances due to environmental manganese exposure in Alzheimer's pathology.}, } @article {pmid41129981, year = {2026}, author = {Wang, B and Chang, Y and Shen, L and Ma, Y and Zhang, Z and Du, J and Wang, Y and Li, Y and Zhao, F and Wang, J and Pang, X and Fan, W and Du, L and Yan, L}, title = {Multifunctional near-infrared fluorescent probe for imaging of hydrogen peroxide and photodynamic therapy of amyloid-β aggregation in Alzheimer's disease.}, journal = {Talanta}, volume = {298}, number = {Pt B}, pages = {129009}, doi = {10.1016/j.talanta.2025.129009}, pmid = {41129981}, issn = {1873-3573}, mesh = {*Hydrogen Peroxide/analysis/metabolism ; *Alzheimer Disease/drug therapy/metabolism/diagnostic imaging ; *Amyloid beta-Peptides/metabolism/chemistry ; *Photochemotherapy ; *Fluorescent Dyes/chemistry/pharmacology/chemical synthesis ; Animals ; Humans ; *Photosensitizing Agents/chemistry/pharmacology/chemical synthesis/therapeutic use ; Mice ; Infrared Rays ; Protein Aggregates/drug effects ; Optical Imaging ; }, abstract = {Photodynamic therapy (PDT) has shown significant potential in eliminating amyloid-β (Aβ) aggregates, the characteristic pathological marker of Alzheimer's disease (AD). However, traditional photosensitizers have limitations such as off-target oxidation and single functionality, which severely hinder their specificity and therapeutic efficiency in clearing Aβ plaques. Given the complexity of AD's pathological mechanisms, the development of novel photosensitizers with both targeting ability and multifunctionality has become an urgent priority. In this study, a H2O2-responsive near-infrared (NIR) fluorescent probe ENBS-P was designed and synthesized. By integrating the dual functions of H2O2 visualization and precise photodynamic therapy, it has achieved efficient application in both in vitro and in vivo models. ENBS-P could be specifically activated by H2O2 to release ENBS, resulting in a significant enhancement of fluorescence signal at 720 nm (λex = 640 nm), thus realizing highly sensitive in situ detection of H2O2 (LOD = 0.2 μM). In addition, benefiting from a more efficient intersystem crossing (ISC) process from S1 to T1, the therapeutic molecule ENBS, generated after the specific activation of ENBS-P by H2O2, could produce superoxide radical anions (O2[-•], Type I photoreaction) under NIR light excitation. Importantly, through imaging-guided PDT, it could effectively inhibit the aberrant aggregation of Aβ42 and promote the dissociation of formed aggregates. This study overcomes the limitations of traditional photosensitizers by providing an innovative "diagnosis-treatment" integrated strategy for the early diagnosis and therapy of AD, holding significant promise for advancing precision medicine in AD.}, } @article {pmid41129661, year = {2025}, author = {Wu, CS and Huang, WL and Wang, SH and Wu, MS and Chen, KS and Cheng, SH and Chiu, YM}, title = {Association Between Autoimmune Diseases, Treatments, and Dementia Risk: A Population-Based Case-Control Study From Taiwan.}, journal = {The Journal of clinical psychiatry}, volume = {86}, number = {4}, pages = {}, doi = {10.4088/JCP.25m15774}, pmid = {41129661}, issn = {1555-2101}, mesh = {Humans ; Taiwan/epidemiology ; Female ; Male ; *Autoimmune Diseases/epidemiology/drug therapy/complications ; *Dementia/epidemiology/etiology ; Middle Aged ; Aged ; Case-Control Studies ; Comorbidity ; Prevalence ; Aged, 80 and over ; Risk Factors ; Immunosuppressive Agents/therapeutic use ; }, abstract = {Objectives: This study aimed to assess the risk of dementia associated with specific autoimmune diseases and the impact of related pharmacologic treatments. Methods: Patients 55 years or older diagnosed with dementia by neurologists or psychiatrists between 2010 and 2021 were identified using claims data from Taiwan's National Health Insurance program. We examined 22 autoimmune diseases for their associations with dementia, controlling for age, gender, urbanization level, and comorbidities. Results: Dementia prevalence was higher among individuals with autoimmune diseases (10.5% in cases vs. 8.7% in comparisons). Thirteen autoimmune diseases were linked with an elevated dementia risk, particularly Behçet disease, multiple sclerosis, and systemic lupus erythematosus. Associations with vascular dementia were stronger than with Alzheimer disease. Although overall dementia risk was higher in women, no significant sex differences were observed for specific autoimmune diseases. Nonsteroidal anti-inflammatory drugs and corticosteroids did not significantly alter dementia risk among individuals with autoimmune diseases; however, immunosuppressants were associated with a reduced risk when used for more than 180 days. Conclusions: Certain autoimmune diseases are significantly associated with an increased risk of dementia, particularly vascular dementia, highlighting the distinct role of inflammation. Effective prevention or treatment of autoimmune diseases may reduce dementia incidence by 0.8%. While immunosuppressants show potential for risk reduction, further prospective studies are needed to confirm this effect.}, } @article {pmid41128826, year = {2025}, author = {Hoveizi, E and Bijavi, G and Parsa, H}, title = {Advancing Cell Therapy to Enhance Passive Avoidance Memory: Integrative Approaches Combining Neural-Like Cells and Rosmarinic Acid Through Behavioral, Molecular, and Histological Analyses.}, journal = {Neurochemical research}, volume = {50}, number = {6}, pages = {334}, pmid = {41128826}, issn = {1573-6903}, mesh = {Animals ; Rosmarinic Acid ; *Depsides/pharmacology/therapeutic use ; *Cinnamates/pharmacology/therapeutic use ; Male ; *Alzheimer Disease/therapy/metabolism/pathology ; Rats ; *Avoidance Learning/physiology/drug effects ; *Cell- and Tissue-Based Therapy/methods ; *Memory/physiology/drug effects ; Mesenchymal Stem Cells/cytology ; Rats, Sprague-Dawley ; *Neurons/drug effects/metabolism ; Cell Differentiation/physiology/drug effects ; Dental Pulp/cytology ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration, synaptic dysfunction, and cognitive decline. Regenerative strategies aim to replace lost neurons and modulate the inflammatory milieu to restore neural networks. This study examined the effects of neural-like cells (NLCs) derived from dental pulp mesenchymal stem cells (DPSCs) on a chitosan scaffold using rosmarinic acid (RA) in AD rats. In this study, DPSCs were extracted from teeth, characterized and differentiated, induced an AD model by destroying the Meynert nucleus, conducted passive avoidance tests, analyzed histology and immunohistochemistry, and measured inflammatory and oxidative stress markers. The extraction and differentiation of DPSCs were successful. Differentiated DPSCs into neural progenitors showed increased expression of Tuj-1, Map2, Nestin, and NF (RT-PCR, p < 0.001). Behavioral tests confirmed the AD model after seven days, and histology showed neuronal loss and gliosis following Meynert destruction. Histomorphology revealed improved brain tissue and significantly increased choline acetyltransferase (ChAT) expression in the treatment groups. Notable behavioral improvements were observed in the Y‑maze and shuttle box for treated rats compared with the AD group. Biochemical analyses showed a significant decrease in inflammatory markers IL‑1β, IL‑6, and TNF‑α, along with increases in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) in the RA-treated groups. The results provide reliable evidence that DPSCs, in combination with RA, exert a promising therapeutic effect and represent a meaningful advance toward the clinical application of combination therapies for patients with AD.}, } @article {pmid41127243, year = {2025}, author = {Li, G and Li, S and Zhou, W}, title = {Kynurenine pathway: a possible new mechanism for exercise in the prevention and treatment of Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1617690}, pmid = {41127243}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease in clinical practice. The kynurenine pathway (KP) is a potential intersection of factors associated with the development of AD (central nervous inflammation, glutamate excitotoxicity, and tau phosphorylation, among others). Pharmacological modulators targeting KP enzymes, such as inhibitors or agonists, and their major neuroprotective metabolites are beneficial in alleviating AD progression. Exercise significantly improves AD symptoms and also impacts KP pharmacokinetics. Promoting the production of neuroprotective active metabolites by KP may be one of the central mechanisms by which exercise improves AD symptoms. This article reviews the possible role of KP in AD neurodegeneration and AD exercise prevention and treatment.}, } @article {pmid41126950, year = {2025}, author = {Frost, B and Kolb, H and Algeciras-Schimnich, A and Betthauser, TJ and DeVos, S and Edelmayer, RM and Elwood, F and Fleisher, AS and Henley, D and Horie, K and Hyman, B and Kreisl, WC and Kulic, L and Leuzy, A and Palma, JA and Parmentier-Batteur, S and Patru, MM and Rabinovici, GD and Reyderman, L and Sperling, RA and Van Der Geyten, S and Wildsmith, KR and Mahinrad, S and Carrillo, MC and Weber, CJ}, title = {Tau biology, biomarkers, and therapeutics.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {4}, pages = {e70165}, pmid = {41126950}, issn = {2352-8737}, abstract = {UNLABELLED: As Alzheimer's disease (AD) research advances, tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development. The Fall 2024 Alzheimer's Association Research Roundtable convened experts from academia, industry, National Institutes of Health (NIH), and the United States Food and Drug Administration (FDA) to explore current progress and future directions in tau-centered diagnostics and therapeutics. Discussions addressed the integration of tau biomarkers into the 2024 Revised Diagnostic Criteria for AD, updates to amyloid and tau positron emission tomography (PET) imaging, and modeling of biomarker trajectories. Presenters highlighted tau-targeting therapeutics including antisense oligonucleotides, monoclonal antibodies, and small molecules, alongside innovations in drug delivery. The interplay between anti-amyloid and anti-tau therapies and strategic design of combination trials were key themes. Regulatory insights facilitated discussions on drug approval pathways. The meeting highlighted the rapid evolution of tau research and emphasized opportunities to improve diagnostics, trial design, and treatment strategies in AD. HIGHLIGHTS: The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government, to explore current progress and future directions in tau-centered diagnostics and therapeutics.Tau has emerged as both a critical biomarker and a promising therapeutic target, central to understanding disease mechanisms, tracking progression, and guiding treatment development.Discussions addressed the integration of tau biomarkers into the 2024 revised diagnostic criteria for AD, updates to amyloid and tau PET imaging, modeling of biomarker trajectories, tau-targeting therapeutics, and interplay between anti-amyloid and anti-tau therapies and strategic design of combination trials.}, } @article {pmid41126823, year = {2025}, author = {Atkinson, J and Dokiburra, A and Groover, H and Godbout, JP and Segal, BM and Zhang, Y}, title = {Targeting senescent microglia in progressive multiple sclerosis: a geroscience-informed approach.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1681724}, pmid = {41126823}, issn = {1664-3224}, mesh = {Animals ; *Microglia/drug effects/pathology/metabolism/immunology ; Mice ; *Encephalomyelitis, Autoimmune, Experimental/drug therapy/immunology/pathology ; *Cellular Senescence/drug effects ; Humans ; *Multiple Sclerosis/drug therapy/pathology ; *Senotherapeutics/pharmacology/therapeutic use ; Female ; Disease Models, Animal ; Senescence-Associated Secretory Phenotype/drug effects ; *Multiple Sclerosis, Chronic Progressive/drug therapy/pathology ; Mice, Inbred C57BL ; }, abstract = {Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disorder of the central nervous system (CNS). Age is the strongest predictor of disease phenotype, with the majority of older adults transitioning to a progressive form marked by irreversible neurological decline. This clinical progression is associated with smoldering, CNS-compartmentalized inflammation and neurodegeneration, for which there are currently no effective disease-modifying therapies. Cellular senescence, characterized by the secretion of pro-inflammatory mediators collectively known as the senescence-associated secretory phenotype (SASP), increases with age and contributes to tissue injury. In MS, neuroinflammation can further promote cellular senescence, creating a self-reinforcing cycle of damage. Senescent microglia have been identified within MS lesions, where their SASP may impair remyelination and exacerbate neurodegeneration. Senolytic agents selectively target and eliminate senescent cells by disrupting anti-apoptotic pathways. In experimental autoimmune encephalomyelitis (EAE), a widely used model of MS, senolytic treatment reduces senescent microglia burden and attenuates disease severity in an age- and drug-dependent manner. Specifically, here we show that middle-aged mice (40-44 weeks) with EAE exhibit improved clinical outcomes and survival following treatment with either dasatinib plus quercetin (D+Q) or navitoclax. Early-phase clinical trials of senolytics in age-related diseases have demonstrated functional benefits, including improved gait speed in idiopathic pulmonary fibrosis and CNS penetrance in Alzheimer's disease. Translating senolytic therapy to MS will require careful selection of CNS-penetrant and well-tolerated agents, identification of appropriate patient populations, and deployment of responsive biomarkers. Senolytic therapy represents a promising geroscience-based strategy to meet the urgent therapeutic need in progressive MS.}, } @article {pmid41126448, year = {2025}, author = {Biel, D and Steward, A and Dewenter, A and Dehsarvi, A and Zhu, Z and Roemer-Cassiano, SN and Frontzkowski, L and Hirsch, F and Palleis, C and Höglinger, G and Brendel, M and Franzmeier, N and , }, title = {A systematic comparison of ATN biomarkers for monitoring longitudinal cognitive changes in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70783}, pmid = {41126448}, issn = {1552-5279}, support = {EXC2145SyNergy-ID390857198//Munich Cluster for Systems Neurology/ ; AARG-22-973496/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Biomarkers/blood ; *tau Proteins/blood ; Positron-Emission Tomography ; Male ; Female ; Longitudinal Studies ; Aged ; Magnetic Resonance Imaging ; Amyloid beta-Peptides ; Aged, 80 and over ; *Cognitive Dysfunction/diagnostic imaging ; Brain/diagnostic imaging/pathology ; Cognition ; }, abstract = {INTRODUCTION: With anti-amyloid beta (Aβ) therapies approved for Alzheimer's disease (AD), surrogate biomarkers are needed to monitor clinical treatment efficacy. Therefore, we systematically compared longitudinal changes in A/T/N biomarkers (amyloid-positron emission tomography [PET], tau-PET, plasma phosphorylated tau at threonine 217 [p-tau217], and magnetic resonance imaging) for tracking cognitive changes. METHODS: We analyzed longitudinal biomarker and cognitive change rates from the Alzheimer's Disease Neuroimaging Initiative (N = 141) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) (N = 151), estimated using linear mixed models. Using linear models, we tested biomarker changes as predictors of cognitive changes, comparing predictive strengths across biomarkers using bootstrapping. RESULTS: Tau-PET, plasma p-tau217, and cortical thickness changes accurately tracked change rates in Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive Subscale 13-item version, Clinical Dementia Rating-Sum of Boxes, and Preclinial Alzheimer Cognitive Composite scores. In contrast, amyloid-PET change rates were not linked to cognitive changes. DISCUSSION: Plasma p-tau217 offers a cost-effective AD-specific alternative to tau-PET and could potentially be implemented for monitoring cognitive changes in AD trials, while amyloid-PET lacks utility. Cortical thickness changes accurately track cognitive changes but may be confounded by pseudo-atrophy in anti-Aβ treatments. HIGHLIGHTS: Longitudinal changes in tau-PET, plasma p-tau217, cortical thickness - but not amyloid-PET - effectively track cognitive decline. Cortical thickness may be confounded by pseudo-atrophy in anti-Aβ trials. Plasma p-tau217 is a robust and cost-effective alternative to tau-PET as an AD-specific surrogate biomarker for monitoring cognitive changes.}, } @article {pmid41126430, year = {2025}, author = {Alhawarri, MB}, title = {Hypothesis-Driven Insights and Clinical Trial Updates in Alzheimer's Disease Pathogenesis.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273387383250924031644}, pmid = {41126430}, issn = {1996-3181}, abstract = {BACKGROUND: Alzheimer's disease (AD) is the primary cause of dementia and a significant threat to healthy aging. The prevalence of AD and other non-communicable diseases (NCDs) is significantly influenced by the progressive decline in physiological functions that is associated with aging. METHODS: This review summarizes the results of drug interventions for AD that have been conducted in the past five years, with a particular emphasis on Phase I, Phase III, and Phase IV clinical trials. Systematic investigations of clinical trial registries and databases were employed to identify clinical trials. A total of 106 Phase I, 52 Phase III, and 13 Phase IV trials were considered, excluding studies on devices, biologics, and diagnostic tests. RESULTS: This review summarizes a wide range of therapy approaches aimed at different facets of AD pathogenesis, including amyloid-beta aggregation, tau protein dysfunction, neuroinflammation, synapse loss, and metabolic dysregulation. AD's complex nature highlights the need for multi-target treatment strategies, which may encompass combination therapies and innovative targets that show potential in addressing the complex pathogenesis of AD. DISCUSSION: Current clinical studies demonstrate a variety of therapies aimed at various pathogenic processes of AD. Progress in therapeutic discovery, including synthetic molecules and bioactive natural materials, suggests potential strategies for successful AD treatment. The efficacy of natural products as therapeutic agents is especially significant because of their multi-target effects. CONCLUSION: Effective strategies to prevent the progression of AD require a thorough comprehension of its complex pathophysiology. Current clinical studies are essential for discovering viable chemicals and treatment strategies to combat this multifactorial neurodegenerative disorder, AD.}, } @article {pmid41125269, year = {2025}, author = {Lin, DE and Gunaga, S and Mowbray, FI and Isaacs, ED and Markwalter, D and George, N and Hay, AE and Manfredi, R and Westlake, E and Akhter, M and Bowman, JK and Rebollo-Lee, N and Gacioch, B and Ginsburg, AD and Brooten, JK and Pajka, S and Selman, K and Bain, P and Davis, JJ and Liu, S and Ouchi, K}, title = {Emergency department-initiated palliative care screening among older adults: a systematic review and meta-analysis protocol.}, journal = {BMJ open}, volume = {15}, number = {10}, pages = {e095894}, pmid = {41125269}, issn = {2044-6055}, mesh = {Humans ; *Palliative Care/methods ; Systematic Reviews as Topic ; *Emergency Service, Hospital ; Aged ; Meta-Analysis as Topic ; Quality of Life ; Research Design ; Length of Stay/statistics & numerical data ; *Mass Screening/methods ; Hospitalization/statistics & numerical data ; }, abstract = {INTRODUCTION: The rapidly growing population of older adults (individuals aged 65 years and older) presents a new set of challenges for healthcare providers in the emergency department (ED), given the prevalence of severe and life-threatening conditions among this group, such as chronic cancer, Alzheimer's disease/dementia and congestive heart failure. ED encounters often represent a critical point in an older patient's trajectory of care and can thus be an important opportunity for various interventions such as palliative care consultation. Therefore, identifying those who will benefit most from palliative care is of high importance, especially in determining the course of future treatment. Thus, we aim to conduct a systematic review assessing the efficacy of palliative care screening in the ED by assessing inpatient length of stay as the primary outcome and quality of life, percentage of hospitalisation and cost of care as secondary outcomes. METHODS: This study will use Ovid MEDLINE, Embase, EBSCO CINAHL, Web of Science and Cochrane as databases. The study population comprises adults aged 60 years and older, with no focus on any specific clinical specialty or disease. Patients who have not received palliative care screening will serve as the comparator. Only studies with an applicable comparator will be considered. Studies published from 1 January 2000 to 1 July 2025 will be included.All articles will be reviewed independently and in duplicate, and every author will participate in the review, data abstraction and conflict resolution process. ETHICS AND DISSEMINATION: Ethical approval is not required as it is a protocol for a systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42024562389.}, } @article {pmid41124320, year = {2025}, author = {Li, C and Feng, L and Li, M and Dai, C}, title = {Research progress on the regulation of Nrf2/HO-1 signaling pathway by traditional Chinese medicine in the treatment of Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {4}, pages = {1475-1487}, doi = {10.1177/13872877251389011}, pmid = {41124320}, issn = {1875-8908}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *NF-E2-Related Factor 2/metabolism ; *Signal Transduction/drug effects/physiology ; *Medicine, Chinese Traditional/methods ; *Heme Oxygenase-1/metabolism ; Animals ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder with a complex pathogenesis. Oxidative stress, neuroinflammation and apoptosis play key roles in the occurrence and development of AD. The Nrf2/HO-1 signaling pathway, as an important endogenous antioxidant stress pathway in cells, is of great significance in combating oxidative damage and neurodegeneration. In recent years, an increasing number of studies have shown that traditional Chinese medicine can exert therapeutic effects on AD by regulating the Nrf2/HO-1 signaling pathway. This article aims to review the research progress of traditional Chinese medicine in regulating the Nrf2/HO-1 signaling pathway for the treatment of AD, providing new ideas and strategies for the treatment of AD.}, } @article {pmid41124311, year = {2025}, author = {Sosa Pérez, S and Urrutia Amable, N and Viada González, CE and Lorenzo-Luaces, P and Sánchez Valdés, L and Crombet Ramos, T and León Monzón, K and Rodríguez Obaya, TJ and Pérez Ruiz, L}, title = {NeuroEPO plus (NeuralCIM[®]) in Alzheimer's disease: Post-trial observational follow-up study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {3}, pages = {1422-1435}, doi = {10.1177/13872877251386885}, pmid = {41124311}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Male ; Female ; Follow-Up Studies ; Aged ; *Erythropoietin/therapeutic use/administration & dosage ; Treatment Outcome ; Aged, 80 and over ; Neuropsychological Tests ; Double-Blind Method ; Mental Status and Dementia Tests ; Activities of Daily Living ; Middle Aged ; }, abstract = {BackgroundNeuroEPO plus is a recombinant erythropoietin with a sialic acid content like that produced by astrocytes, lacking the hematopoietic activity of conventional erythropoietin.ObjectiveTo evaluate the efficacy and safety of treatment with neuroEPO plus.MethodsIt was a post-trial observational follow-up study with four groups, NE: subjects who continued treatment with neuroEPO plus after trial, PB-NE: subjects who received a placebo during the trial and then receive neuroEPO plus, NE-CTRL: subjects who received neuroEPO plus during the trial and then interrupted treatment and CTRL: subjects who were never treated. NeuroEPO plus was administrated three times a week nasally. The primary outcome was changed from baseline in the score on the11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog11) at 96 weeks. Secondary outcomes included Global Deterioration Scale, Montreal Cognitive Assessment, Neuropsychiatric Inventory, and Lawton Instrumental Activities of Daily Living Scale.ResultsThe adjusted median change from baseline in the ADAS-Cog11 score at 96 weeks was -6.0 in NE group and 11.0 in the CTRL group (difference, 21.0; 95% confidence interval [CI], 14.6-27.4; p = 0.000), -1.0 in the PB-NE (difference, 15.4; 95% CI, 9.0-21.8; p = 0.000) and 4.0 in the NE-CTRL (difference, 8.3; 95% CI, 1.4-15.2; p = 0.011). The results for secondary outcomes showed statistically significant differences.ConclusionsSubjects who continued or started treatment with neuroEPO plus stabilized or slowed down the progression of the disease. These results and the method of drug administration, make neuroEPO plus an attractive option to consider for Alzheimer's disease patients.}, } @article {pmid41124234, year = {2025}, author = {Sun, Y and Jiang, X and Yi, X and Wang, C and Zhang, X and Shen, R and Yang, A and Kou, X}, title = {Novel Biochanin A Carbamate Derivatives as Multifunctional Anti-Alzheimer's Disease Metal Chelators: Design, Synthesis, and Activity Evaluation.}, journal = {Chemistry & biodiversity}, volume = {22}, number = {12}, pages = {e01827}, doi = {10.1002/cbdv.202501827}, pmid = {41124234}, issn = {1612-1880}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Chelating Agents/chemistry/chemical synthesis/pharmacology ; *Genistein/chemistry/pharmacology/chemical synthesis ; *Drug Design ; Humans ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Structure-Activity Relationship ; Animals ; *Carbamates/chemistry/pharmacology/chemical synthesis ; Reactive Oxygen Species/metabolism ; Molecular Structure ; Rats ; Dose-Response Relationship, Drug ; Cell Survival/drug effects ; Acetylcholinesterase/metabolism ; Neuroprotective Agents/chemical synthesis/chemistry/pharmacology ; }, abstract = {Considerable evidence suggests that metal ions play crucial roles in Alzheimer's disease (AD) progression, spurring the development of metal-involved therapeutic strategies. In this study, biochanin A, a bioactive ingredient derived fromTrifolium pratense L. (a traditional Chinese medicine [TCM]), was identified as a lead compound for the rational design of multifunctional metal chelators. A series of biochanin A derivatives (compounds a-e) was synthesized through a one-step carbamate introduction reaction. Their drug-likeness and pharmacokinetic profiles were assessed using an online prediction server. The bioactivities, including metal ion chelation, β-amyloid aggregation regulation, reactive oxygen species elimination, cholinesterase inhibition, and neurocytotoxicity were evaluated. The results indicated that compounds (a-e) possessed favorable pharmacokinetic profiles and potential as multifunctional metal chelators with minimal neurocytotoxicity, with compound d emerging as a particularly promising candidate. These findings may provide meaningful information for developing novel multifunctional metal chelators for AD treatment and innovative drugs derived from TCM.}, } @article {pmid41123015, year = {2026}, author = {Ebbert, KA and Chen, R and Culibrk, RA and Yeisley, DJ and Hahn, MS}, title = {Rapamycin and Suramin Effects on TNF-⍺-Mediated Mast Cell and Brain Microvascular Endothelial Cell Dysfunction.}, journal = {Biotechnology and bioengineering}, volume = {123}, number = {1}, pages = {255-268}, doi = {10.1002/bit.70082}, pmid = {41123015}, issn = {1097-0290}, support = {//This study was supported, in part, by the National Institute of Health R03AG067140 and R03AG067970 to M.S.H./ ; }, mesh = {*Sirolimus/pharmacology ; *Mast Cells/drug effects/metabolism ; *Endothelial Cells/drug effects/metabolism ; Humans ; *Tumor Necrosis Factor-alpha/metabolism ; *Brain/blood supply ; Microvessels/drug effects ; Cell Line ; Blood-Brain Barrier/drug effects ; Cells, Cultured ; Signal Transduction/drug effects ; }, abstract = {Chronic blood-brain barrier (BBB) disruption due to impaired function of brain microvascular endothelial cells (BMECs) is commonly observed in neuroinflammatory and neurodegenerative conditions. Current treatment approaches are generally limited in their capacity to reduce this dysfunction, with the Akt/mTOR/GSK pathway modulator rapamycin showing recent promise in ameliorating neuroinflammatory BBB dysfunction. Understanding the role of early, cellular level BMEC dysfunction, particularly in the context of interplay with immune cells involved in neuroinflammation, such as mast cells (MCs), is important for identifying targets for therapeutic intervention related to BBB disruption. In the present work, we investigate primary human BMECs and human MC line HMC-1.2 dysfunction in response to inflammatory insult with TNF-α and paracrine interactions, with an emphasis on the Akt/mTOR/GSK pathway-an upstream regulator of angiogenesis and MC activation-and associated extracellular and intracellular cytokine production and oxidative stress. We further compare alterations in BMEC-MC paracrine inflammatory crosstalk in response to Akt/mTOR/GSK pathway modulator suramin (100 µM) relative to rapamycin (250 nM). In monoculture, TNF-α stimulation significantly increased oxidative stress-assessed through measuring PGE2-extracellularly in BMECs. Similarly, proangiogenic and pro-inflammatory cytokine and chemokine secretion was increased in both TNF-α stimulated BMEC and MC monocultures. Additionally, TNF-α stimulation increased BMEC levels of the Akt/mTOR/GSK pathway intermediates p-p70S6K and p-RPS6 and MC levels of p-GSK3α and p-GSK3β. Coculture of TNF-α stimulated BMECs and MCs resulted in a modest increase in extracellular PGE2, and effects on extracellular cytokine/chemokine levels were primarily limited to increases in pro-inflammatory CCL2, CCL3 and CCL5 relative to TNF-α-stimulated BMEC monoculture. In contrast, the levels of intracellular cytokines in MCs increased 2-100 fold with TNF-α-stimulated coculture, concomitant with a decrease in MC p-p70S6K levels. Rapamycin treatment of TNF-⍺-stimulated cocultures resulted a modest increase in extracellular PGE2 as well as decreases in extracellular chemokines CCL2 and CCL3. In contrast, suramin treatment significantly decreased extracellular PGE2, GM-CSF, CCL2, and CCL5 while markedly increasing the BBB-stabilizing PDGF-BB. However, suramin also increased intracellular BMEC levels of multiple pro-inflammatory cytokines. Neither rapamycin nor suramin improved the intracellular inflammatory profile of cocultured MCs, indicating that MC activation had not been resolved by either treatment.}, } @article {pmid41122827, year = {2025}, author = {Tang, S and Wu, Y and Wang, R and Li, Y and Li, J and Peng, Y and Liu, S and Men, L and Hou, Z and Liu, Z and Liu, Z}, title = {Revealing the Formula Pattern of Congming Decoction by Ultra-High-Performance Liquid Chromatography Coupled With Quadrupole-Orbitrap Mass Spectrometry From the Perspective of Chemical Constituents, In Vitro, and In Vivo Properties.}, journal = {Journal of separation science}, volume = {48}, number = {10}, pages = {e70306}, doi = {10.1002/jssc.70306}, pmid = {41122827}, issn = {1615-9314}, support = {82274062//National Natural Science Foundation of China/ ; 20240602085RC//Department of Science and Technology of Jilin Province/ ; 20220101289JC//Natural Science Foundation of Jilin Province/ ; }, mesh = {Chromatography, High Pressure Liquid ; Animals ; *Drugs, Chinese Herbal/chemistry/analysis/pharmacokinetics/metabolism ; Rats ; Mass Spectrometry ; Rats, Sprague-Dawley ; Male ; Medicine, Chinese Traditional ; }, abstract = {The Congming decoction (CMD) is a classic traditional Chinese medicine formula, composed of Poria cocos (Schw.) Wolf, Polygalae Radix, and Acori Tatarinowii Rhizoma. The material basis for the rationality of CMD's compatibility remains unclear in both in vitro and in vivo studies. The relationship between its components and therapeutic efficacy still presents a research gap. Therefore, this study aims to reveal the co-extraction dissolution patterns, metabolic regularity in vitro, and absorption and distribution characteristics in vivo of CMD, thereby exploring the scientific connotation of formulation. Utilizing ultra-high-performance liquid chromatography coupled with quadrupole-orbitrap mass spectrometry technology, a total of 183 constituents were identified in CMD, with 72 recognized as differential compounds before and after combination, suggesting that co-boiling enhances the solubility of active ingredients. In vitro intestinal microbiota results indicated that combination reduced metabolism rates, allowing for greater absorption as the prototype. In vivo analysis identified 62 constituents within rat plasma and tissues; comparing content differences among groups found that the combinations regulate hepatic metabolism and enhance distribution of effective components, potentially serving as a significant material basis for treating Alzheimer's disease (AD). Furthermore, a targeted network pharmacology strategy was established to explore the mechanism of CMD in treating AD. This study clarified the chemical composition, metabolic patterns in vitro, and distribution rules in vivo regarding CMD, and also compared variations before and after composition. It provided new insights into the rationality of CMD's compatibility in the treatment of AD from multiple dimensions and levels.}, } @article {pmid41122812, year = {2025}, author = {Dodge, HH and Chen, L and Wu, CY and Cutter, G and Bowman, GL and Feldman, HH and Arnold, SE}, title = {Seeking optimal repeated fluid biomarker assessments to enhance precision and statistical power in clinical trials: SLIM method.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70787}, pmid = {41122812}, issn = {1552-5279}, support = {//the Epstein Family Collaboration of Powder for Pennies/ ; P30AG062421/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; *Alzheimer Disease/blood/cerebrospinal fluid ; *Clinical Trials as Topic/methods ; *Research Design ; Computer Simulation ; }, abstract = {INTRODUCTION: Plasma biomarkers are increasingly used as surrogate outcomes in clinical trials for Alzheimer's disease and related dementias (ADRD) due to their non-invasive nature. In early-phase trials designed to evaluate mechanisms of action and biological efficacy, assessing pre-post changes in plasma biomarkers within the same individuals - using a single-arm placebo lead-in design - offers a potentially cost-effective alternative to parallel-group designs by minimizing between-subject variability. However, plasma biomarkers are also subject to within-individual variability, which can obscure true treatment effects. METHODS: One strategy to address this limitation is to collect repeated measures during each study period. This approach can improve measurement precision, enhance the signal-to-noise ratio, and increase statistical power, even with modest sample sizes. RESULTS: We propose an innovative early-phase trial design, Single-arm Lead-In with Multiple measures (SLIM), which incorporates repeated biomarker assessments over a short follow-up period. DISCUSSION: Using simulation studies, we demonstrate that the SLIM design can substantially reduce required sample sizes. HIGHLIGHTS: SLIM involves repeated biomarker assessments during both the lead-in and post-treatment periods. It minimizes between-subject variability and improves the precision of within-subject estimates. It is well suited for early-phase, short-duration trials. It is not suitable for cognitive tests or other outcomes prone to practice or placebo effects. SLIM design can be an alternative to the traditional parallel design by reducing required sample sizes, thereby lowering the recruitment burden.}, } @article {pmid41122803, year = {2025}, author = {Chaunsali, L and Li, J and Fleischel, E and Prim, CE and Kasprzak, I and Jiang, S and Hou, S and Escalante, M and Cope, EC and Olsen, ML and Tewari, BP and Sontheimer, H}, title = {Degradation of perineuronal nets in hippocampal CA2 explains the loss of social cognition memory in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70813}, pmid = {41122803}, issn = {1552-5279}, support = {R01NS123069/NH/NIH HHS/United States ; R01 NS123069/NS/NINDS NIH HHS/United States ; R01 NS036692/NS/NINDS NIH HHS/United States ; R01NS036692/NH/NIH HHS/United States ; R01 AG065836/AG/NIA NIH HHS/United States ; R01AG065836/NH/NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/psychology/genetics ; Mice ; Disease Models, Animal ; *CA2 Region, Hippocampal/metabolism/pathology ; *Extracellular Matrix/metabolism ; Mice, Transgenic ; Matrix Metalloproteinases/metabolism ; *Social Behavior ; *Memory Disorders ; }, abstract = {INTRODUCTION: Loss of social cognition memory impairs Alzheimer's disease (AD) patients to recognize family members, friends, and caregivers. We investigate the role of perineuronal nets (PNNs), specialized coats of extracellular matrix around hippocampal CA2 neurons in AD-associated social memory impairments. METHODS: We utilized 5XFAD mouse model of AD and employed immunohistochemistry, microscopy, bulk RNA-sequencing, animal behavior, gene-knockout, and drug-treatment approaches. RESULTS: AD mice showed profound disruption of CA2 PNNs with concomitant impairment of social cognition memory. Genetic or enzymatic CA2 PNN disruption in wild-type mice mimicked these impairments. Transcriptomic analysis shows upregulation of PNN-cleaving matrix metalloproteinases (MMP) in AD mice causing disequilibrium of PNN synthesis and remodeling. Chronic inhibition of MMPs retains CA2 PNN and delays social memory impairments in 5XFAD mice. DISCUSSION: AD-associated social memory impairments are caused by loss of CA2 PNNs. Inhibition of PNN proteolysis by MMPs preserves social memory, suggesting PNN as a promising therapeutic target. HIGHLIGHTS: Perineuronal nets (PNNs) are disrupted in the CA2 area of the hippocampus in 5XFAD Alzheimer's disease (AD) mice at 6 months of age and beyond. Social memory deficits in 5XFAD mice coincide with the disruption of CA2 PNNs and PNN loss alone is sufficient to cause loss of social memory. Bulk RNA sequencing of hippocampal CA2 tissue reveals alterations in PNN remodeling enzymes. Inhibition of matrix metalloproteinase (MMP) activity with GM6001 prevents PNN disruption and protects against social memory deficits in the 5XFAD AD mouse model.}, } @article {pmid41122453, year = {2025}, author = {Jangid, K and Devi, B and Dahiya, R and Mishra, J and Kumar, V and Bhatti, JS and Thareja, S and Kumar, V}, title = {Investigation of the multifunctional profile of dihydroquinazoline derivatives as potential therapeutics for Alzheimer's disease.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {41122453}, issn = {2632-8682}, abstract = {Multitarget directed ligands represent an innovative strategy in the management of Alzheimer's disease (AD) by addressing its multifactorial etiology. These agents are designed to simultaneously modulate multiple key targets involved in the disease progression, offering a holistic approach for the effective treatment of AD. The current work presents the synthesis and evaluation of novel dihydroquinazoline-based multitargeting agents for the management of Alzheimer's disease. Most of the compounds showed good selectivity for AChE and MAO-B, and two compounds, viz.K2V-9 and K2V-12, emerged as potent inhibitors against both the targets. Compound K2V-9 displayed IC50 values of 1.72 ± 0.01 μM and 0.950 ± 0.52 μM against AChE and MAO-B, respectively. Compound K2V-12 showed IC50 values of 1.10 ± 0.078 μM and 1.68 ± 0.25 μM against AChE and MAO-B, respectively. Moreover, amyloid β self-aggregation inhibition studies were performed, where K2V-9 and K2V-12 showed percentage inhibitions of 37.34% and 48.10%, respectively, after 48 h. Both compounds were found to be non-toxic and neuroprotective and showed the capability of reducing the ROS levels in SHSY-5Y cells. Reversibility and kinetic studies of these lead compounds showed that both molecules produced reversible and mixed-type of inhibition against the targeted enzymes. In the docking and molecular dynamics simulation studies, K2V-9 and K2V-12 were found to be well accommodated in the active cavity with good thermodynamic stability.}, } @article {pmid41122344, year = {2025}, author = {Casey, CS and Patel, N and Vasileva-Metodiev, SZ and Cotton, S and Walker, C and Nilforooshan, R}, title = {Real-world diagnosis and management of mild cognitive impairment and Alzheimer's disease dementia in the United Kingdom.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251370708}, pmid = {41122344}, issn = {2542-4823}, abstract = {BACKGROUND: Timely diagnosis of Alzheimer's disease (AD) remains challenging in the United Kingdom and improvements are needed with the introduction of new therapies. OBJECTIVE: To examine the United Kingdom diagnostic and current treatment journey for people with mild cognitive impairment (MCI) and AD dementia to identify future opportunities for new treatments. METHODS: Physician-reported data were drawn from the Adelphi Real World Dementia Disease Specific Programme™, a cross-sectional survey of physicians treating patients with MCI or AD dementia in the United Kingdom between 2022 and 2024. Analyses were descriptive. RESULTS: Physicians (n = 109) reported data for 717 patients with MCI or AD dementia (including 264 with MCI or mild dementia). Overall median (interquartile range) time from symptom onset to first consultation was 26.0 (9.1-52.9) weeks. Time from consultation to diagnosis, for patients not diagnosed at initial consultation, was 15.2 (5.1-21.0) weeks for patients who first consulted and were diagnosed by a general practitioner and 21.9 (12.6-39.0) weeks for those who consulted a general practitioner and were diagnosed by a specialist. Few patients (4.9%) had a biomarker-confirmed diagnosis. Delays due to waiting for specialist referrals and diagnostic tests were reported for 57.6% and 26.9% of patients, respectively. Acetylcholinesterase inhibitors were the most common first-line treatment (82.0%). CONCLUSIONS: Our data highlighted delays in AD diagnosis and potential areas for United Kingdom health system improvement. Expediting timely diagnosis through increased public awareness, expanded biomarker use and addressing disparities in services is crucial to maximize access to emerging new therapies.}, } @article {pmid41121478, year = {2025}, author = {Hsieh, CY and Chuang, CH and Gomez, MC and Tayo, LL and Huang, SM and Tsai, PW}, title = {Computational Analysis and in vitro Verification Insights into Quercetin's Suppression of Neuroinflammation in BV-2 Microglia through NF-κB Pathway Inhibition.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673395813250901012530}, pmid = {41121478}, issn = {1875-533X}, abstract = {INTRODUCTION: Neuroinflammation, primarily mediated by activated microglia, is a significant contributor to neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Quercetin (QCT), a dietary flavonoid, has demonstrated anti-inflammatory and neuroprotective properties; however, the detailed molecular mechanisms behind these effects remain unclear. This study aimed to investigate the anti-inflammatory actions of QCT, particularly focusing on its potential to suppress the activation of microglia and subsequent neuroinflammation. METHODS: BV-2 microglial cells were stimulated with lipopolysaccharide (LPS) to induce an inflammatory response and were subsequently treated with various concentrations of QCT. Cell viability was assessed using the MTT assay. Levels of pro-inflammatory cytokines (IL-6, TNF- α) and nitric oxide (NO) were quantified through ELISA and Griess reaction methods, respectively. Western blot analysis was conducted to examine inducible nitric oxide synthase (i- NOS), NF-κB, IκBα, and phosphorylated IκBα protein expressions. In silico approaches, including protein-protein interaction (PPI) network analysis and molecular docking, were employed to explore potential molecular mechanisms involving NF-κB signaling pathways. RESULTS: Treatment with QCT significantly reduced the secretion of IL-6 (96%) and TNF-α (87%), as well as NO production (42%), in a dose-dependent manner. Western blot results demonstrated a marked reduction in iNOS expression and inhibition of NF-κB activation through reduced phosphorylation of IκBα following QCT treatment. Molecular docking indicated a strong binding affinity between QCT and IKKβ, suggesting inhibition of the NF-κB pathway. DISCUSSION: The findings indicated QCT to exert potent anti-inflammatory effects in LPS-stimulated BV-2 cells by modulating key proteins involved in the NF-κB signaling pathway. Specifically, the docking results implied QCT's direct interaction with the catalytic subunit IKKβ, inhibiting IκBα phosphorylation and subsequent NF-κB activation. The results have been found to be consistent with previous literature, reinforcing QCT's role in reducing neuroinflammation through specific molecular targets and pathways. Further in vivo studies are necessary to validate the findings. CONCLUSION: Quercetin effectively suppressed neuroinflammation in microglial cells through inhibition of the NF-κB signaling pathway, reducing levels of critical pro-inflammatory mediators. The outcomes have highlighted the potential of quercetin as a preventive nutraceutical for neurodegenerative diseases, necessitating future in vivo investigations to confirm its therapeutic efficacy.}, } @article {pmid41121098, year = {2025}, author = {Afolayan, O and Nwaogu, V and Idowu, O and Dosumu, O}, title = {Differential oxido-reductive activities of aged garlic extract and S-allyl-cysteine in genetically modified Drosophila model of Alzheimer's disease.}, journal = {BMC complementary medicine and therapies}, volume = {25}, number = {1}, pages = {392}, pmid = {41121098}, issn = {2662-7671}, abstract = {Alzheimer’s disease (AD) is a progressive neurodegenerative disorder frequently associated with ageing. It is characterised by the loss of neurons in the hippocampus and cortex, leading to declines in cognitive function and memory. Recent research has spotlighted Aged Garlic Extract (AGE) and its bioactive component, S-allyl-cysteine (SAC), as promising candidates for the treatment of AD due to their potent antioxidant, anti-inflammatory, and neuroprotective properties. These features help mitigate oxidative stress and neuronal damage associated with the disease. The present study aimed to evaluate the neuroprotective effects of AGE and SAC using a Drosophila melanogaster (Drosophila) model of Alzheimer’s disease. The Drosophila (UAS-Aβ > Elav-GAL4) were reared on a diet supplemented with varying concentrations of AGE (10 µL, 20 µL, and 40 µL) and SAC (at doses of 25, 50, and 75 mg/kg). Key parameters measured included larval motility, negative geotaxis, and oxidative stress markers. The AD models exhibited reduced motor abilities, decreased antioxidant levels, increased oxidative stress, and elevated acetylcholinesterase (AChE) activity. However, treatment with different concentrations of AGE and SAC significantly improved locomotor function and modulated redox activities, along with a reduction in AChE activity. This study highlights the neuroprotective potential of AGE and its active component, SAC, in the Drosophila AD model, indicating that the beneficial effects of AGE are primarily attributed to SAC.}, } @article {pmid41120520, year = {2025}, author = {Rahman, MO and Ahmed, SS and Alqahtani, AS and Rehman, MT and Sultana, N and Bouhrim, M and Ali, MA and Lee, J}, title = {Identification of stigmasterol derived AChE inhibitors for Alzheimer's disease using high throughput virtual screening and molecular dynamics simulations.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {36676}, pmid = {41120520}, issn = {2045-2322}, support = {ORF-2025-132//King Saud University/ ; }, mesh = {*Stigmasterol/chemistry/analogs & derivatives/pharmacology ; *Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Molecular Dynamics Simulation ; *Alzheimer Disease/drug therapy ; Humans ; High-Throughput Screening Assays ; Molecular Docking Simulation ; *Acetylcholinesterase/metabolism/chemistry ; Neuroprotective Agents/chemistry ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, poses a significant global health burden due to its intricate pathology and the absence of curative treatments. Current therapies primarily offer symptomatic relief, often with limited efficacy and complications, thereby underscoring the urgent need for innovative, safer, and more effective interventions. Stigmasterol, a plant-derived phytosterol, has demonstrated neuroprotective properties, including anti-inflammatory and antioxidant effects, which positions this sterol as a compelling candidate for further investigation in AD treatment. In this investigation, high-throughput virtual screening of 972 stigmasterol analogs (SAs) was conducted to identify potential acetylcholinesterase (AChE) inhibitors, followed by ADMET filtering, molecular dynamics (MD) simulations, MM/GBSA free binding energy estimations, and DFT calculations. Three lead compounds, including SA4 (-10.9 kcal/mol), SA12 (-10.6 kcal/mol), and SA15 (-10.5 kcal/mol), demonstrated superior binding affinities compared to stigmasterol (-9.6 kcal/mol) and the control drug donepezil (-8.6 kcal/mol). Docking interaction analysis revealed strong binding by hydrogen bonds and hydrophobic interactions, whereas pharmacokinetic, pharmacodynamic, and toxicity assessments confirmed the favorable characteristics of these compounds. MD simulations (200 ns) demonstrated the structural compactness of the compounds, which was further supported by principal component analysis and Gibbs free energy landscape experiments. MM/GBSA identified SA4 as the most potent analog (-82.21 kcal/mol), followed by SA15 (-80.40 kcal/mol) and SA12 (-69.72 kcal/mol). A DFT-based molecular reactivity analysis revealed decreased reactivity and increased kinetic stability of the lead candidates in their transition from free to bound states. These findings provide insights into the therapeutic potential of stigmasterol analogs as AChE inhibitors, thus offering the groundwork for in vivo and in vitro validation for advancing AD treatment.}, } @article {pmid41120130, year = {2025}, author = {Marziliano, A and Babar, H and Patel, P and Gieniusz, M and Mongelli, J and Burns, E and Applebaum, AJ and Pessin, H and Breitbart, W and Sinvani, L and Perissinotto, C and Diefenbach, MA}, title = {The adaptation of meaning centered psychotherapy to develop RELOAD-C: a web-based tool to reduce loneliness in caregivers of persons with Alzheimer's disease and related dementias.}, journal = {Translational behavioral medicine}, volume = {15}, number = {1}, pages = {}, doi = {10.1093/tbm/ibaf059}, pmid = {41120130}, issn = {1613-9860}, support = {K01AG076888//National Institute on Aging (NIA) of the National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Caregivers/psychology ; *Alzheimer Disease/psychology/nursing ; *Psychotherapy/methods ; Male ; Female ; *Loneliness/psychology ; *Dementia/nursing/psychology ; Middle Aged ; Internet ; Aged ; Internet-Based Intervention ; }, abstract = {BACKGROUND: More than 60% of caregivers of persons with Alzheimer's disease and related dementias (AD/ADRD) are lonely. Meaning and purpose in life is associated with reduced feelings of loneliness, but has not yet been systematically fostered among caregivers of patients with AD/ADRD. Adapting meaning-centered psychotherapy (MCP), an evidence-based treatment for increasing meaning and purpose in life in cancer caregivers, might decrease loneliness in the dementia caregiver population. PURPOSE: The purpose of this manuscript is to report on the development, usability, and acceptability testing of REducing LOneliness in Alzeheimer's Disease-Care Partners (RELOAD-C), a web-based platform that features six brief videos and aims to reduce loneliness in caregivers of patients with dementia through introducing major concepts and principles adapted from meaning centered psychotherapy. METHOD: Within 12 months, RELOAD-C was developed through two rounds of one-on-one interviews with 15 dementia caregivers to obtain feedback on video scripts, recording of videos, and placement of videos and written content (e.g. thought exercises) on the website. Following this, RELOAD-C underwent rigorous usability and acceptability testing by another 16 dementia caregivers. RESULTS: Quantitative assessments show that RELOAD-C is deemed usable by caregivers (mean = 1.69 on system usability scale, where possible range is 1-5 and lower scores indicate more favorable views of the website; and more than 90% of the usability sample correctly engaged in ≥8 of 10 discreet tasks). Qualitative data indicate acceptability of the intervention with feedback such as "love that the videos are clear and load fast." CONCLUSIONS: RELOAD-C is a web-based intervention focused on reducing loneliness in dementia caregivers. It contains six therapist-narrated videos and written content, reinforcing MCP principles. It is currently undergoing pilot testing in preparation for a large-scale randomized controlled clinical trial evaluating its efficacy in reducing loneliness in dementia caregivers.}, } @article {pmid41118083, year = {2025}, author = {Kopi, TA and Shanehbandpour-Tabari, F and Arani, RM and Ataie, A and Pouramir, M and Khaleghzadeh-Ahangar, H}, title = {Piperine Prevents Scopolamine-Induced Cognitive Impairment via its Antioxidant and Anti-Inflammatory Roles; Suggesting Potential Modulation of Necroptosis-Related Genes Including MLKL and TNF-α.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {4}, pages = {142}, pmid = {41118083}, issn = {1559-1166}, support = {724133561//Babol University of Medical Science/ ; }, mesh = {Animals ; *Benzodioxoles/pharmacology/therapeutic use ; *Piperidines/pharmacology/therapeutic use ; Male ; *Alkaloids/pharmacology/therapeutic use ; *Polyunsaturated Alkamides/pharmacology/therapeutic use ; Rats, Wistar ; Rats ; Tumor Necrosis Factor-alpha/genetics/metabolism ; *Cognitive Dysfunction/prevention & control/drug therapy/metabolism/chemically induced ; Necroptosis ; Hippocampus/metabolism/drug effects ; *Antioxidants/pharmacology/therapeutic use ; Scopolamine/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; Protein Kinases/genetics/metabolism ; NF-E2-Related Factor 2/genetics/metabolism ; Heme Oxygenase-1/genetics/metabolism ; Caspase 8/genetics/metabolism ; }, abstract = {Alzheimer's disease (AD) is the leading cause of dementia, characterized by cognitive decline and neurodegeneration. Given the limitations of current treatments, research has turned to natural substances such as piperine, which is known for its neuroprotective properties. This study investigates the effects of piperine on cognitive function and genes associated with oxidative stress, inflammation, and necroptosis-related genes in a rat model of cognitive impairment. Fifty adult male Wistar rats were used, divided into five groups: an intact group, a control group (vehicle solution followed by scopolamine), and three experimental groups receiving piperine (5, 10, and 20 mg/kg) followed by scopolamine during the training period. Behavioral assessment was conducted using the Morris Water Maze (MWM) test. Hippocampal tissue was collected after euthanasia for gene expression analysis of Nrf2, HO‑1, TNF‑α, Fas, TRAIL, MLKL, and Caspase‑8. Spatial learning and memory improved significantly in piperine-treated groups, with no impact on swimming velocity, indicating cognitive enhancement without affecting motor functions in the scopolamine-induced cognitive impairment model. Piperine pretreatment prevented oxidative stress and inflammation, as evidenced by the restoration of Nrf2, HO-1, and Caspase-8 and the reduction of TNF-α, Fas, TRAIL, and MLKL expression levels. These findings suggest that piperine has antioxidative, anti‑inflammatory, and cognitive‑enhancing effects, with particular effects possibly on necroptosis, and could be a valuable addition to the current AD treatment paradigm, warranting further investigation in clinical trials.}, } @article {pmid41118046, year = {2025}, author = {Aswinanand, B and Palani, KN and Santhanam, SD and Ramamurthy, K and Palaniappan, S and Arasu, MV and Guru, A and Muthuramamoorthy, M and Kumaradoss, KM and Arockiaraj, J}, title = {Pyrimidine Derivative, (E)-N-[4-(4-Chlorophenyl)-6-(4-Methylphenyl)Pyrimidin-2-yl]-1-(Furan-2-yl)Methanimine, Named BN5 Ameliorates Cognitive Dysfunction and Regulates esr1 and esr2b Expression in Female In Vivo Zebrafish Alzheimer Model.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {20}, number = {1}, pages = {94}, pmid = {41118046}, issn = {1557-1904}, mesh = {Animals ; Female ; Zebrafish ; *Pyrimidines/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Cognitive Dysfunction/drug therapy/metabolism ; *Estrogen Receptor alpha/biosynthesis/genetics ; *Estrogen Receptor beta/biosynthesis/genetics ; Disease Models, Animal ; *Furans/pharmacology/therapeutic use ; *Imines/pharmacology/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia, characterized by a progressive decline in cognitive functions. It is more prevalent in women, especially after menopause, likely due to factors like longer life expectancy and hormonal changes. Current therapies focus on cholinesterase inhibitors, but recent studies suggest that pyrimidine derivatives hold promise as multi-target agents targeting complex mechanisms of AD. This study evaluated the potential of a pyrimidine derivative, (E)-N-[4-(4-chlorophenyl)-6-(4-methylphenyl)pyrimidin-2-yl]-1-(furan-2-yl)methanimine (named BN5), in a scopolamine (SCO)-induced female zebrafish model. SCO induces cognitive dysfunction mimicking AD conditions. BN5, particularly at a 60 µM concentration, significantly improved AD-related parameters, including anxiety, memory, shoaling, and social behaviour in vivo. Biochemical analyses supported these findings, as BN5 reversed SCO-induced changes in acetylcholinesterase (AChE) activity and oxidative stress markers, such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), malondialdehyde (MDA), and γ-Aminobutyric acid (GABA) levels. Additionally, BN5 demonstrated positive regulation of neurotransmitter-related genes such as appb, bdnf, mbpa, and il-1β, essential for neural function and cognitive processes. It also upregulated estrogen receptor genes esr1 and esr2b, which have neuroprotective roles but are often downregulated in postmenopausal women due to hormonal changes. These results highlight the therapeutic potential of BN5, as it alleviates cognitive impairments through Aβ aggregation inhibition and addresses the decline in estrogen receptor activity, providing a targeted treatment option particularly beneficial for females, who are at greater risk of developing AD.}, } @article {pmid41117350, year = {2025}, author = {Khachaturian, Z}, title = {History of Alzheimer's Disease Research Centers: From inception in 1984 to evolution beyond 2025.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70778}, pmid = {41117350}, issn = {1552-5279}, support = {1975-1982/AG/NIA NIH HHS/United States ; 1983-1991/AG/NIA NIH HHS/United States ; 1978-1995/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/history/therapy ; Humans ; History, 20th Century ; United States ; *Biomedical Research/history ; History, 21st Century ; }, abstract = {This paper reviews the history of the so-called Alzheimer Movement in the United States, the origins of the Alzheimer's Disease Research Centers (ADRC) program, and their critical role in shaping the National Plan to Address Alzheimer's Disease by 2035. The long narration unfolds in three parts: (1) Beginnings, (2) Accomplishments, and (3) Charting the Next Step. HIGHLIGHTS: This paper reviews the history of the Alzheimer movement in the United States, the origins of the ADRC program, and the centers' critical role in shaping the National Plan to Address Alzheimer's Disease by 2035. The long narration unfolds in three parts: (1) Beginnings: Establishing a Foothold, (2) Accomplishments: Key Achievements and Future Lessons, and (3) Charting the Next Step: Rethinking the ADRC's role after 2035. This perspective offers a high-level view of the scientific landscape during the inception of programmatic research in aging and dementia. The story covers the significant challenges involved in starting such an undertaking. It recounts the rationale, intent, achievements, and structure of the ADRCs. The narrative focuses on the politics of science that shaped programs like the ADRC and NACC, particularly through earmarked funding. It explains why the program prioritized the creation of infrastructure and building capacity for longitudinal clinical studies. The discussion of future directions will (1) explain the reasoning for reformulating the mission and structure of the ADRC's concept to accommodate a comprehensive range of emerging needs and (2) explore the role of the re-engineered centers as a catalyst to promote and maintain brain health to prevent cognitive impairments. It will suggest some possible options to restructure some current centers into comprehensive regional centers as instruments to deal with new challenges.}, } @article {pmid41116989, year = {2025}, author = {Lei, L and Mei, SY and Lü, Y and Huang, GQ and Lü, PR and Liu, Q and Zhang, N}, title = {[Effect of moxibustion on synaptic plasticity in mice with Alzheimer's disease based on the CaMKⅡ/RyR3 pathway].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {50}, number = {10}, pages = {1161-1168}, doi = {10.13702/j.1000-0607.20240673}, pmid = {41116989}, issn = {1000-0607}, mesh = {Animals ; *Alzheimer Disease/therapy/genetics/metabolism/physiopathology/enzymology/psychology ; *Moxibustion ; Mice ; *Neuronal Plasticity ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism/genetics ; Male ; Mice, Inbred C57BL ; Humans ; *Ryanodine Receptor Calcium Release Channel/metabolism/genetics ; Acupuncture Points ; Hippocampus/metabolism ; Female ; }, abstract = {OBJECTIVES: To explore the mechanism by which moxibustion promotes synaptic plasticity of hippocampal neurons and improves learning and memory in mice with Alzheimer's disease (AD) based on the calmodulin-dependent protein kinase Ⅱ (CaMKⅡ)/ryanodine receptor (RyR)3 pathway. METHODS: Forty APP/PS1 mice were randomly divided into the model (n=15), moxibustion (n=25) groups, and 15 C57BL/6J mice served as the blank control group. The mice in the moxibustion group were given moxibustion at the "Baihui"(GV20) and "Yongquan"(KI1) acupoints, 30 minutes each time, once a day. A course of treatment lasted for 5 days, and there were a total of 4 courses of treatment. Ten mice from the moxibustion group were randomly selected as the moxibustion+inhibitor group, and were intraperitoneally injected with the CaMKⅡ protein inhibitor KN-93 (2 mg/100 g) one day before sample collection on the basis of moxibustion. After the treatment, the shuttle box test was used to evaluate the learning and memory ability of the mice. Transmission electron microscopy was used to detect the changes in the ultrastructure of synapses in the CA1 region of the hippocampus. Western blot was used to detect the expression levels of β-amyloid protein (Aβ) and CaMKⅡ protein in the hippocampus of the mice. Immunofluorescence staining was used to detect the positive expression of CaMKⅡ in the hippocampus and the co-expression of RyR3/PSD95. RESULTS: Compared with the blank control group, the number of active avoidance responses, the protein expression and positive expression of CaMKⅡ in the hippocampus, and the percentage of the co-expression area of RyR3/PSD95 of the mice in the model group were decreased (P<0.01, P<0.05), and the number of synaptic vesicles in the CA1 region of the hippocampus was decreased;while the expression of Aβ protein in the hippocampus was increased (P<0.01). Compared with the model group, the number of active avoidance responses, the protein expression and positive expression of CaMKⅡ in the hippocampus, and the co-expression area percentage of RyR3/PSD95 of the mice in the moxibustion group were increased significantly (P<0.01), and the number of synaptic vesicles in the CA1 region of the hippocampus was increased;while the expression of Aβ protein was decreased (P<0.05). Compared with the moxibustion group, the number of active avoidance, the positive expression of CaMKⅡ and the co-expression area percentage of RyR3/PSD95 in the moxibustion+inhibitor group were decreased (P<0.01), and the number of synaptic vesicles in the CA1 region of the hippocampus was decreased. CONCLUSIONS: Moxibustion can improve the learning and memory ability of AD model mice, and its mechanism may be related to up-regulating the expression of CaMKⅡ, activating the endoplasmic reticulum RyR3 channel, inducing the release of Ca[2+], and then promoting neuronal synaptic plasticity.}, } @article {pmid41114448, year = {2025}, author = {Sato, K and Niimi, Y and Ihara, R and Iwata, A and Nemoto, K and Arai, T and Higashi, S and Igarashi, A and Kasuga, K and Akiyama, H and Awata, S and Ikeda, M and Iwatsubo, T}, title = {Real-world lecanemab adoption in Japan 1 year after launch: Insights from 311 specialists on infrastructure and reimbursement barriers.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70652}, pmid = {41114448}, issn = {1552-5279}, support = {JPMH23CA2008//MHLW Health Labour Sciences Research Grant/ ; 24GB1001//MHLW Health Labour Sciences Research Grant/ ; JP24K10653//JSPS KAKENHI/ ; JP25K19014//JSPS KAKENHI/ ; JP23dk0207048//AMED Research and Development Grants for Dementia/ ; JP24dk0207054//AMED Research and Development Grants for Dementia/ ; JP24dk0207068//AMED Research and Development Grants for Dementia/ ; //Japan Agency for Medical Research and Development/ ; }, mesh = {Humans ; Japan ; *Alzheimer Disease/drug therapy ; Surveys and Questionnaires ; Male ; *Insurance, Health, Reimbursement ; Female ; }, abstract = {INTRODUCTION: Lecanemab was approved for early Alzheimer's disease in Japan, with ≈ 6000 patients treated in the first year post approval. This study explores real-world practices, challenges, and potential solutions. METHODS: We conducted an anonymized online survey of clinical specialists authorized to prescribe lecanemab, obtaining responses from 311 specialists who collectively treated 3259 patients with lecanemab. RESULTS: A majority of respondents (79%) reported wait times of ≤ 3 months from first consultation to initial infusion. One fourth reported tight outpatient space and staffing and significantly lower capacity of treatment than anticipated. Safety concerns were limited, with amyloid imaging-related abnormality-related interruptions in 3.5%. More than half highly supported additional reimbursement for infusion-related services and insurance coverage for apolipoprotein E (APOE) testing. DISCUSSION: Early access to lecanemab appears feasible, yet infrastructure and financial hurdles remain. Dedicated reimbursement and insurance coverage for APOE testing may be essential for ensuring safer, more accessible, and sustainable use of this therapy in Japan. HIGHLIGHTS: Results from an online survey of 311 Japanese specialists prescribing lecanemab in its first year are reported. Majority of wait times from first consultation to initial infusion were 1 to 3 months. Tight affordability of infusion space and staffing was reported by one quarter. Establishing additional medical fee for infusion management was highly expected. Reimbursement of apolipoprotein E test in Japanese health insurance system was also demanded.}, } @article {pmid41113923, year = {2025}, author = {Shine, S and Chandrapragasam, V}, title = {Acetylcholinesterase inhibitory potency of Lactobacillus plantarum fermentation extracts, and antioxidant scavenging effects against LPS-induced nitric oxide production in PC12 cell lines.}, journal = {3 Biotech}, volume = {15}, number = {11}, pages = {393}, pmid = {41113923}, issn = {2190-572X}, abstract = {Nutrient optimization of Lactobacillus plantarum MTCC 1325 with cinnamon (40 µg/mL) and pantothenic acid (4 µg/mL) resulted in a chloroform extract of Media D that exhibited a strong activity profile relevant to the therapeutic approach to Alzheimer's disease. Across 20-100 µg/mL extracts were non-cytotoxic to undifferentiated PC12 cells. Chloroform extract of Media D showed potent radical scavenging [IC50(superoxide) = 41.7 ± 2.1 µg/mL, IC50(NO) = 33.4 ± 1.1 µg/mL], high total phenolics (68.6 ± 1.1 mg GAE/g), and acetylcholinesterase inhibition [IC50 = 33.2 ± 4.2 µg/mL, galantamine (standard) = 22.5 ± 3.2 µg/mL]. Pre-treatment with chloroform extract of Media D reduced LPS-induced cytotoxicity [IC50 = 32.6 ± 3.6 µg/mL] and lowered nitrite accumulation up to 1.69-fold versus LPS. GC-MS of the active fraction resolved six constituents, consistent with lipid and aromatic metabolites. Together, these results support a nutrient-first media design strategy, demonstrating that selective modulation of media composition under fixed incubation parameters can enrich L. plantarum culture-derived metabolites with antioxidants, anti-inflammatory, and AChE inhibitory activities related to the medical management of AD. This is a preliminary in vitro study using one strain and a single-cell model, Extract were crude and tested with modest replication, and library matched GC-MS identification. Mechanistic markers were not quantified, and in vivo validation is warranted.}, } @article {pmid41111974, year = {2025}, author = {Woo, HG and Park, MS and Park, JY and Chun, H and Song, TJ}, title = {Association of hemorrhoidal disease with dementia risk: a nationwide cohort study.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1655944}, pmid = {41111974}, issn = {1664-2295}, abstract = {INTRODUCTION: Research on the association between hemorrhoidal diseases (HDs) and dementia is limited. We explored this relationship in a population-based longitudinal cohort and proposed that individuals with HD may experience a higher incidence of dementia. METHODS: Our study included 381,031 participants drawn from results from the South Korean health-screening cohort database, between 2005 and 2010. HD was identified based on at least two claims using the International Classification of Diseases, Tenth Revision (ICD-10) code I84. We used propensity score matching (PSM) to categorize the participants into two groups based on the presence or treatment of HD. The primary outcome was the incidence of all-cause dementia as determined by two or more claims with ICD-10 codes (F00-03, G30, and G31). Secondary outcomes included the occurrence of Alzheimer's (F00 or G30) and vascular dementia (F01). RESULTS: Over a median follow-up period of 15.49 years (interquartile range: 12.21-18.77 years), the cumulative incidence of all-cause dementia was 80,488 cases (22.47%). Multivariate analysis showed that the group with HD consistently had a higher incidence of all-cause dementia than the group without HD after PSM (hazard ratio [HR], 1.243; 95% confidence interval [CI], 1.199-1.288). Participants who underwent surgical procedures or treatment for HD revealed a significantly lower incidence of all-cause dementia after PSM (HR, 0.925; 95% CI, 0.872-0.981). DISCUSSION: This study revealed a significantly higher incidence of all-cause dementia among participants with hemorrhoidal disease, suggesting that while hemorrhoidal disease may not directly cause dementia, it may serve as a marker of an underlying systemic condition that increases dementia risk.}, } @article {pmid41111606, year = {2025}, author = {Wu, X and Zhang, R and Chen, W and Mei, Y and Hu, Q and Lan, W and Zhang, Y and Ye, Z and Huang, C and Zhu, B}, title = {Preoperative perivascular space burden predicts treatment response to deep cervical lymphovenous anastomosis in Alzheimer's disease: A pilot study.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251387366}, pmid = {41111606}, issn = {2542-4823}, abstract = {BACKGROUND: Deep cervical lymphovenous anastomosis (DLVA) shows promise for Alzheimer's disease (AD) treatment, but patient selection criteria remain undefined. Perivascular spaces (PVS) may predict glymphatic enhancement potential. OBJECTIVE: To investigate whether preoperative magnetic resonance imaging (MRI) measures of PVS burden can predict treatment response to DLVA in AD patients and explore potential mechanisms through longitudinal glymphatic function assessment. METHODS: Retrospective analysis of 10 AD patients undergoing DLVA. Preoperative T1-weighted MRI quantified PVS volumes using Frangi filtering. Treatment response was assessed at one month using Mini-Mental State Examination/Montreal Cognitive Assessment improvements ≥2 points. RESULTS: Total PVS volume demonstrated perfect predictive accuracy for treatment response (AUC = 1.000) with an optimal cut-off of 5150 mm³ (sensitivity 100%, specificity 100%). White matter PVS volume also showed strong predictive performance (AUC = 0.875, cut-off 3630 mm³, sensitivity 75%, specificity 100%). The improved group had significantly higher preoperative PVS volumes (total PVS: p = 0.012, Cohen's d = 2.631; white matter PVS: p = 0.050, Cohen's d = 1.689). Preliminary longitudinal analysis revealed divergent Analysis Along the Perivascular Space (ALPS) index changes: the improved group showed mean increase (+0.0276), while the non-improved group demonstrated decrease (-0.0252). CONCLUSIONS: Preoperative PVS burden serves as a powerful predictor of DLVA response, with higher volumes indicating sufficient anatomical reserve for therapeutic benefit. These findings establish PVS volume as clinically actionable biomarkers for precision patient selection in glymphatic-targeted AD interventions.}, } @article {pmid41110764, year = {2025}, author = {Tagad, A and Galatage, ST and Hankuntimath, N and Hugar, S and Raikar, SR and Patil, VP and Manjappa, AS}, title = {Neuroprotective potential of green-synthesized silver nanoparticles from Psidium guajava in a scopolamine-induced rat model of Alzheimer's disease.}, journal = {Annales pharmaceutiques francaises}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.pharma.2025.10.006}, pmid = {41110764}, issn = {2772-803X}, abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative condition marked by progressive memory decline and cognitive dysfunction, and oxidative stress, with no definitive cure currently available. The present study aimed to develop a plant-based nanotherapeutic approach for AD by synthesizing silver nanoparticles (AgNPs) using the ethanolic leaf extract of Psidium guajava (PG) via a green synthesis method. Formation of PG-AgNPs was confirmed by a characteristic surface plasmon resonance (SPR) peak observed in UV-Visible spectroscopy and a visible colour change to dark brown. The synthesized nanoparticles exhibited a mean particle size of 107±4nm, a polydispersity index (PDI) of 0.364±0.08, and a zeta potential of -30.7±2.3mV, indicating good colloidal stability. Energy-dispersive X-ray diffraction (E-XRD) confirmed the crystalline nature and elemental composition of silver. In a scopolamine-induced rat model of AD, treatment with PG-AgNPs significantly improved cognitive performance. Rats treated with PG-AgNPs showed a statistically significant increase (P<0.001) in spontaneous alternation behaviour, prolonged step-through latency in the passive avoidance test (P<0.001), and a significant reduction in escape latency time in the Morris Water Maze test (P<0.001) compared to the disease control group. Biochemical analyses revealed that PG-AgNPs significantly reduced lipid peroxidation (LPO) levels (P<0.001) and significantly increased catalase (CAT) activity (P<0.001), indicating strong antioxidant potential. In conclusion, P. guajava leaf extract and its green-synthesized silver nanoparticles demonstrated statistically significant neuroprotective, antioxidant, and cognitive-enhancing effects, supporting their potential as a novel therapeutic strategy for the treatment of Alzheimer's disease. Further research is needed to explore and conform their clinical applicability.}, } @article {pmid41110751, year = {2025}, author = {Wang, Y and Deng, L and Wang, L and Liu, W}, title = {Schisandrin B combined with vitamin D inhibits NLRP3 inflammasome to improve cognitive dysfunction and Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1007}, number = {}, pages = {178268}, doi = {10.1016/j.ejphar.2025.178268}, pmid = {41110751}, issn = {1879-0712}, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/antagonists & inhibitors ; Male ; *Alzheimer Disease/drug therapy/metabolism/psychology ; *Cognitive Dysfunction/drug therapy/metabolism/psychology ; *Inflammasomes/metabolism/antagonists & inhibitors ; *Polycyclic Compounds/pharmacology/therapeutic use ; *Vitamin D/pharmacology/therapeutic use ; Rats ; Rats, Sprague-Dawley ; *Lignans/pharmacology/therapeutic use ; Hippocampus/drug effects/metabolism ; Cyclooctanes/pharmacology ; Cognition/drug effects ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Behavior, Animal/drug effects ; }, abstract = {PURPOSE: This study investigates the therapeutic effects of Schisandrin B (Sch B) combined with vitamin D (VD) on cognitive dysfunction and Alzheimer's disease (AD)-like pathology in aged rats induced by a high-fat and high-sugar (HFHS) diet, with a focus on the inhibition of NLRP3 inflammasome activation as a potential mechanism. METHODS: Eighteen-week-old male Sprague-Dawley rats were randomly assigned to five groups: Control, HFHS, HFHS + Sch B, HFHS + VD, and HFHS + Sch B + VD. After 20 weeks of treatment, metabolic parameters (body weight, fasting blood glucose, insulin resistance, lipid profiles), inflammatory markers, and hippocampal protein expression were assessed. Cognitive function was evaluated using the Morris water maze, novel object recognition, open field, and elevated plus maze tests. RESULTS: Combined Sch B and VD markedly attenuated body weight gain, fasting blood glucose, fasting serum insulin, and homeostatic model assessment of insulin resistance (HOMA-IR), while improving lipid profiles (TG, TC, LDL-C). Behavioral tests revealed significant improvements in spatial learning, memory, and object recognition (p < 0.01), with combined therapy outperforming monotherapy. Additionally, the combination downregulated hippocampal NLRP3 inflammasome components (ASC, cleaved caspase-1, IL-1β, IL-18) and reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). CONCLUSION: In this HFHS diet-induced aging rat model, Sch B combined with VD improved cognitive performance and reduced AD-like lesions, likely via inhibition of NLRP3 inflammasome-mediated neuroinflammation. These findings provide mechanistic insights and support further preclinical evaluation of this combination as a potential strategy for AD prevention and intervention.}, } @article {pmid41110688, year = {2025}, author = {Qin, RZ and Peng, SY and Huang, ZX and Zhang, BF and Tang, RN and Zhao, YC and Jiang, FS and Xu, XH and Pan, JL and Li, MY}, title = {Coelonin, an active component extract from Bletilla striata (Thunb.) Reichb.f., alleviates lipopolysaccharide-induced acute lung injury by increasing the expression of non-coding RNA Gm27505 and inhibiting the M1 polarization of macrophages caused by inflammatory responses.}, journal = {The international journal of biochemistry & cell biology}, volume = {189}, number = {}, pages = {106871}, doi = {10.1016/j.biocel.2025.106871}, pmid = {41110688}, issn = {1878-5875}, mesh = {Animals ; *Lipopolysaccharides/toxicity ; *Acute Lung Injury/chemically induced/drug therapy/pathology/genetics/immunology/metabolism ; Mice ; *Orchidaceae/chemistry ; RAW 264.7 Cells ; *Macrophages/drug effects/metabolism/pathology ; *Inflammation/drug therapy/pathology/chemically induced/genetics ; *RNA, Untranslated/genetics ; Male ; *Plant Extracts/pharmacology/chemistry ; *Phenanthrenes/pharmacology ; Anti-Inflammatory Agents/pharmacology ; }, abstract = {Coelonin is a dihydrophenanthrene compound derived from the traditional Chinese medicine Bletilla striata (Thunb.) Reichb.f., which exhibits significant anti-inflammatory activity and effectively inhibits lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 cells. Although previous studies have demonstrated the protective effect of Bletilla striata against LPS-induced acute lung injury (ALI), the potential protective role and underlying molecular mechanisms of its major active component, Coelonin, in ALI remain unclear. In this study, an LPS-induced mouse ALI model was established to systematically evaluate the protective effects of Coelonin on ALI. Furthermore, transcriptomic analysis was utilized to investigate the anti-inflammatory mechanisms mediated by Coelonin through the regulation of non-coding RNA (ncRNA)-associated inflammatory pathways. The results indicated that Coelonin significantly ameliorated LPS-induced pathological damage in lung tissues and markedly reduced the levels of inflammatory markers in bronchoalveolar lavage fluid (BALF). In vitro experiments using the murine alveolar macrophages (MH-S) cell line further confirmed the anti-inflammatory activity of Coelonin. Transcriptome analysis revealed that Coelonin markedly upregulates the expression of the ncRNA Gm27505, which was previously found to be downregulated in a mouse model of Alzheimer's disease. To date, there have been no reports on the biological functions of Gm27505. Bioinformatics analysis and real-time quantitative fluorescence PCR (qPCR) confirmed that this ncRNA is primarily localized within the nucleus. Overexpression of Gm27505 in MH-S cells significantly downregulated the expression of inflammation-related genes such as Il6, Tnfα, Il27, and Ccl3 induced by LPS stimulation. Moreover, overexpression of Gm27505 promoted macrophage polarization toward the M2 phenotype while suppressing M1 polarization. These findings suggest that the ncRNA Gm27505 plays an important biological role and is critically involved in the regulation of inflammatory responses. Coelonin may alleviate LPS-induced ALI in mice by up-regulating Gm27505 expression and modulating macrophage polarization. Therefore, Gm27505 may represent a potential target for the prevention and treatment of ALI, providing new research directions for future therapeutic strategies against related diseases.}, } @article {pmid41110565, year = {2025}, author = {Lv, H and Liu, Y and Yang, X and Xu, X and Zhou, J and Yu, W}, title = {Research progress on the role of oxidative stress in the pathogenesis of vascular dementia and its treatment.}, journal = {Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association}, volume = {34}, number = {12}, pages = {108475}, doi = {10.1016/j.jstrokecerebrovasdis.2025.108475}, pmid = {41110565}, issn = {1532-8511}, mesh = {Humans ; *Oxidative Stress/drug effects ; *Dementia, Vascular/metabolism/physiopathology/drug therapy/pathology/therapy/psychology ; Animals ; *Antioxidants/therapeutic use/adverse effects ; Signal Transduction/drug effects ; Reactive Oxygen Species/metabolism ; *Brain/metabolism/drug effects/pathology/physiopathology ; Cognition/drug effects ; *Neuroprotective Agents/therapeutic use/adverse effects ; Mitochondria/metabolism/drug effects/pathology ; }, abstract = {BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease, imposing a substantial burden on global health. Accumulating evidence indicates that oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defense, plays a pivotal role in the pathogenesis of VaD. OBJECTIVE: This review aims to summarize the latest research progress on the involvement of oxidative stress in the pathogenesis of VaD and explore emerging therapeutic strategies targeting oxidative stress. RESULTS: Oxidative stress is deeply involved in multiple pathological processes of VaD. Its root cause lies in chronic cerebral hypoperfusion (CCH), which leads to mitochondrial dysfunction and excessive ROS production. Such oxidative damage exacerbates blood-brain barrier (BBB) disruption, neuroinflammation, and neuronal apoptosis, ultimately resulting in cognitive decline. Key molecular mechanisms include the activation of NADPH oxidase, impairment of the Nrf2 antioxidant pathway, and dysregulation of SIRT1. Therapeutic strategies have evolved from traditional antioxidants (e.g., α-lipoic acid) to novel approaches, including targeting the Nrf2/HO-1 pathway (e.g., using saffron-rich GJ-4 extract), regulating mitochondrial function, utilizing natural compounds (e.g., resveratrol acting via SIRT1 activation), and non-pharmacological interventions such as acupuncture. These strategies alleviate oxidative stress through multi-target mechanisms and have demonstrated significant efficacy. CONCLUSION: The central role of oxidative stress in VaD provides new targets for treatment, but a shift from single-target antioxidant therapy to multi-level intervention is required. Future research should focus on developing targeted antioxidant therapies, exploring combination treatment regimens, and validating biomarkers applicable for early detection and therapeutic efficacy assessment.}, } @article {pmid41110363, year = {2026}, author = {Kuyrukcu Ozturk, O and Oyardi, O and Ilikci Sagkan, R and Dundar, Y}, title = {Synthesis and biological evaluation of some pyrimidine derivatives as multifunctional ligands for the treatment of Alzheimer's disease.}, journal = {Bioorganic & medicinal chemistry}, volume = {132}, number = {}, pages = {118445}, doi = {10.1016/j.bmc.2025.118445}, pmid = {41110363}, issn = {1464-3391}, mesh = {*Pyrimidines/pharmacology/chemical synthesis/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; Structure-Activity Relationship ; Horses ; Acetylcholinesterase/metabolism ; Butyrylcholinesterase/metabolism ; Bacillus cereus/enzymology/drug effects ; Electrophorus ; Molecular Docking Simulation ; Ligands ; Humans ; Molecular Structure ; Dose-Response Relationship, Drug ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder and acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and sphingomyelinase (SMase) enzymes are among its therapeutic targets. In this study, a series of tetrahydropyrimidine and hexahydropyrimidine derivatives were synthesized and evaluated for their inhibition of Bacillus cereus SMase, electric eel AChE (EeAChE), and equine BuChE (eqBuChE) as potential agents against AD. Among the synthesized compounds, 4-oxo-6-(pyridin-2-yl)-2-thioxohexahydropyrimidine-5‑carbonitrile (compound 24) was found to be the most active compound against B. cereus SMase, with an IC50 value of 1.61 μM. In addition, 2-(benzylthio)-4-octyl-6-oxo-1,6-dihydropyrimidine-5‑carbonitrile (compound 14) and 4-octyl-6-oxo-2-(phenethylthio)-1,6-dihydropyrimidine-5‑carbonitrile (compound 16) exhibited selective eqBuChE inhibition with IC50 values of 3.68 and 1.65 μM, respectively. The mode of inhibition of the selected compounds was determined by enzyme kinetic study. These compounds were also examined for their metal-chelating properties with various biometals and effect of B. cereus-induced hemolysis on sheep erythrocytes. Additionally, compound 24 showed no cytotoxic effect on the HUVEC cell line at its IC50 concentration. The biological data were supported by the results of molecular docking studies, and in-silico physicochemical properties/ADME predictions of the selected compounds were determined.}, } @article {pmid41109840, year = {2026}, author = {Davidson, MH and Szarek, M and Scheltens, P and Vijverberg, E and Hsieh, A and Ditmarsch, M and Kling, D and Curcio, D and Nicholls, SJ and Ray, KK and Cummings, JL and Kastelein, JJ}, title = {Effect of obicetrapib, a potent cholesteryl ester transfer protein inhibitor, on p-tau217 levels in patients with cardiovascular disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {1}, pages = {100394}, doi = {10.1016/j.tjpad.2025.100394}, pmid = {41109840}, issn = {2426-0266}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Anticholesteremic Agents/therapeutic use/pharmacology ; Biomarkers/blood ; *Cardiovascular Diseases/drug therapy/blood ; *Cholesterol Ester Transfer Proteins/antagonists & inhibitors ; Cholesterol, LDL/blood ; Double-Blind Method ; *tau Proteins/blood ; }, abstract = {BACKGROUND: Cholesteryl ester transfer protein (CETP) inhibition reduces low density lipoprotein-cholesterol (LDL-C) while simultaneously increasing high density lipoprotein-cholesterol (HDL-C) levels and improving HDL-particle functionality. These lipoprotein modifications may provide a novel pathway for Alzheimer disease (AD) prevention through effects on lipid modulation, antioxidant activity, and neuro-inflammation. This approach could prove particularly beneficial for APOE4 carriers, who face elevated risks for both AD and atherosclerotic cardiovascular disease (ASCVD). OBJECTIVES: To examine the effects of obicetrapib, an oral CETP inhibitor, on biomarker changes indicative of AD pathology among patients with ASCVD DESIGN: This was a pre-specified substudy of the BROADWAY trial, a phase 3, double-blind, placebo-controlled pivotal registration trial to evaluate the LDL-C lowering efficacy of obicetrapib in adult patients with established ASCVD and/or heterozygous familial hypercholesterolemia (HeFH), whose LDL-C was not adequately controlled, despite being on maximally tolerated lipid-lowering therapy. SETTING: The trial was conducted across 188 sites in China, Europe, Japan, and the United States. Participants were recruited from cardiology clinics and lipid specialty centers from 2021 to 2024. PARTICIPANTS: Participants with ASCVD in BROADWAY who had known ApoE status and phosphorylated tau-217 (p-tau217) measured at baseline and 12 months. INTERVENTION: Participants in BROADWAY were randomized 2:1 to receive oral obicetrapib 10 mg daily or placebo for 12 months. MEASUREMENTS: AD plasma biomarkers were measured at baseline and 12 months using standardized SIMOA assays. The key outcome measure of interest was change in plasma p-tau217 from baseline to 12 months. Other outcome measures included changes in p-tau217/(Aβ42:40), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). RESULTS: The analysis population consisted of 1535 (61 %) of the 2530 BROADWAY participants. Median age was 67 years and 67.0 % were male. Baseline p-tau217 levels varied significantly by ApoE subgroups, with ApoE4 carriers generally having higher concentrations and ApoE4/E4 participants exhibiting the highest median concentration (0.56 pg/mL). Obicetrapib significantly attenuated p-tau217 increases compared to placebo (adjusted mean 2.09 % vs 4.94 %; P = 0.025). Treatment differences were most pronounced in ApoE4 carriers, where adjusted mean increases were 1.92 % and 6.91 %, for obicetrapib and placebo, respectively (P = 0.041). Furthermore, among ApoE4/E4 participants, there was a 7.81 % adjusted mean decrease in p-tau217 with obicetrapib compared to a 12.67 % increase with placebo, representing a 20.48 % treatment difference (P = 0.010). Positive trends were observed across secondary biomarkers, with obicetrapib also significantly limiting increases in the p-tau217/Aβ42:40 ratio compared to placebo (2.51 % vs 6.55 %; P = 0.004). In addition, among ApoE4/E4 participants, obicetrapib demonstrated significant effects on GFAP (-6.39 % vs +8.85 %; P = 0.006) and NfL (-10.49 % vs +6.82 %; P = 0.020). Strong correlations were observed between end-of-study obicetrapib plasma concentrations and biomarker improvements (r=-0.64), suggesting CETP inhibition as a potential mechanism, although other drug effects may also contribute to these changes. CONCLUSIONS: Obicetrapib significantly slowed AD biomarker progression over 12 months in participants with ASCVD, with the greatest effects in ApoE4 carriers. Among ApoE4/E4 participants, obicetrapib reduced p-tau217 levels by a placebo-adjusted 20.48 % and demonstrated consistent effects across multiple AD biomarkers. These findings represent the first demonstration of an oral intervention capable of reducing both beta-amyloid and tau pathology biomarkers in ApoE4 carriers, offering a potential preventive strategy for this high-risk population who currently have no effective prevention options. Future research will need to establish whether these biomarker changes translate to clinical benefits in dedicated AD prevention trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05142722.}, } @article {pmid41109234, year = {2025}, author = {Boon, BDC and Piura, YD and Moloney, CM and Chalk, JL and Lincoln, SJ and Rutledge, MH and Rothberg, DM and Kouri, N and Hinkle, KM and Roemer, SF and Johnson, DR and Burkett, BJ and Lowe, VJ and Petersen, RC and Dickson, DW and Reichard, RR and Nguyen, AT and Graff-Radford, J and Knopman, DS and Graff-Radford, NR and Murray, ME}, title = {Neuropathological changes and amyloid-related imaging abnormalities in Alzheimer's disease treated with aducanumab versus untreated: a retrospective case-control study.}, journal = {The Lancet. Neurology}, volume = {24}, number = {11}, pages = {931-944}, pmid = {41109234}, issn = {1474-4465}, support = {R01 AG069052/AG/NIA NIH HHS/United States ; RF1 AG069052/AG/NIA NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; R01 AG075802/AG/NIA NIH HHS/United States ; P50 NS072187/NS/NINDS NIH HHS/United States ; R01 AG073282/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; U19 AG069701/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/pathology/metabolism/genetics ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Aged ; Retrospective Studies ; Case-Control Studies ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; *Brain/pathology/diagnostic imaging/drug effects ; Middle Aged ; Aged, 80 and over ; }, abstract = {BACKGROUND: Understanding the neuropathological effects of amyloid β (Aβ)-targeting therapies and amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease is critical for optimising treatment efficacy and patient outcomes. Comparing Aβ PET imaging with neuropathological assessments provides context for evaluating the extent of Aβ clearance and interpreting in-vivo biomarkers. We aimed to assess clinicopathological changes and ARIA-related effects in aducanumab-treated versus untreated Alzheimer's disease. METHODS: This retrospective case-control study included five aducanumab-treated participants from clinical trials conducted at the Mayo Clinic (2016-21) who underwent autopsy (2020-23). Treated participants were matched by autosomal dominant Alzheimer's disease mutation or APOE genotype, age at cognitive symptom onset, and sex to 12 untreated participants from the Mayo Clinic Alzheimer's Disease Research Center and Mayo Clinic Study of Aging cohorts in the Mayo Clinic brain bank (Jacksonville, FL, USA). Cognitive, imaging, and neuropathological outcomes were compared using descriptive analyses and Mann-Whitney U tests. FINDINGS: Aducanumab-treated participants comprised four males and one female, all carrying at least one APOE ∊4 allele, with two harbouring a PSEN1 mutation. Cumulative dosages of aducanumab ranged from 5 mg/kg to 241 mg/kg; all participants cognitively declined during treatment, and two exhibited ARIA. Reductions in [[18]F]florbetapir PET Centiloid values ranged from -6% to -81% compared with baseline. Treatment-to-death intervals ranged from 5 months to 41 months. Neuropathological analyses revealed clearance of Aβaa1-8 and Aβ42 localised to cortical layer I in treated participants, with no significant clearance in deeper cortical layers. Regions corresponding to ARIA on MRI showed microinfarcts with haemosiderin, complement activation, and CD68-positive vessel walls originating from Aβ-laden leptomeningeal and penetrating vessels. INTERPRETATION: Disproportionate Aβ clearance and ARIA-associated neuropathology localised to superficial cortical layers suggest a distinctive pattern of target engagement by aducanumab. These findings inform understanding and monitoring of similar Aβ-targeting therapies. FUNDING: Alzheimer Nederland, National Institute on Aging, and Alzheimer's Association.}, } @article {pmid41109226, year = {2025}, author = {Iwatsubo, T}, title = {Neuropathology of Alzheimer's disease after anti-amyloid β antibody treatment.}, journal = {The Lancet. Neurology}, volume = {24}, number = {11}, pages = {897-899}, doi = {10.1016/S1474-4422(25)00348-5}, pmid = {41109226}, issn = {1474-4465}, } @article {pmid41107348, year = {2025}, author = {Zeng, Z and Zhou, F and Zheng, Y and Shi, W and Hu, W and Wang, X and Ye, M and Zhou, J and Ye, P and Yuan, F and Zou, Y and Yan, Q and Dai, Y and Tang, D}, title = {Comprehensive analysis of LncRNA-miRNA-mRNA CeRNA network associated with umbilical cord blood PBMC in down syndrome.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {36352}, pmid = {41107348}, issn = {2045-2322}, support = {No. 2017B020209001//Science and Technology Planning Project of Guangdong Province/ ; }, mesh = {Humans ; *RNA, Messenger/genetics/metabolism ; *Down Syndrome/genetics/blood ; *MicroRNAs/genetics ; *RNA, Long Noncoding/genetics ; *Fetal Blood/metabolism/cytology ; *Gene Regulatory Networks ; *Leukocytes, Mononuclear/metabolism ; Female ; Computational Biology/methods ; Gene Expression Profiling ; Gene Expression Regulation ; RNA, Competitive Endogenous ; }, abstract = {Down syndrome (DS), a typical chromosomal disease caused by all or part of an extra genomic copy of chromosome 21. Few reports have investigated roles of competing endogenous RNA (ceRNA)-mediated regulatory mechanisms in DS pathogenesis. RNA from PBMCs of cord blood from DS and non-DS fetuses was used for RNA-Seq to profile lncRNAs, miRNAs, and mRNAs. Bioinformatics revealed DS-associated differential gene expression. Predicted miRNA-mRNA/lncRNA interactions were used to build and visualize ceRNA networks in Cytoscape. A total of 216 DEmiRNAs, 651 DElncRNA and 15,789 DEmRNA transcripts were identified in umbilical cord blood PBMC RNA preparations from DS and non-DS control subjects. KEGG pathway enrichment analysis showed that DEmRNAs were involved in pathways such as Huntington's disease, Alzheimer's disease, Parkinson's disease, etc., which are closely related to DS. The 11 mRNAs corresponding to the highest degree PPI network nodes (RPS27A, UBA52, UBC, RPL11, RPS27, MRPS7, RPL23, RPL9, NFKB1, RBX1, and RELA) may play important roles in expression of DS-associated phenotypic characteristics. Finally, we constructed upregulated and downregulated lncRNA-miRNA-mRNA ceRNA sub-networks and found several pairs of ceRNAs that might be involved in DS. MIAT might serve as a ceRNA to sponge hsa-miR-378c and ultimately regulate the expression of RBX1 to affect the cell cycle and lead to DS occurrence. In this study, we comprehensively analysed gene regulatory mechanisms associated with DS progression. The lncRNA-associated ceRNAs identified here may contribute to DS diagnosis and treatment.}, } @article {pmid41107250, year = {2025}, author = {Chang, JS and Huang, HZ and Yuan, M and Zhou, Y and Liu, D and Zhan, KB and Zhu, LQ}, title = {Alcohol addiction and Alzheimer's disease: a molecular collision course.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {410}, pmid = {41107250}, issn = {2158-3188}, mesh = {Humans ; *Alzheimer Disease/metabolism/etiology ; *Alcoholism/complications/metabolism/therapy ; Oxidative Stress ; *Brain/metabolism ; Cognitive Dysfunction ; Neuroprotective Agents/therapeutic use ; }, abstract = {Chronic alcohol consumption is increasingly recognized as a risk factor for Alzheimer's disease (AD), contributing to cognitive decline through multiple biological pathways. Excessive alcohol intake accelerates neurodegeneration by impairing the brain's ability to clear toxic proteins, disrupting neurotransmitter balance, and exacerbating inflammation and oxidative stress. These effects collectively weaken neuronal resilience, making the brain more vulnerable to AD-related damage. Emerging therapeutic strategies focus on mitigating alcohol-induced harm through neuroprotective drugs, inflammation-targeting treatments, and neurotransmitter modulators. Lifestyle-based interventions, including early abstinence, cognitive training, and precision nutrition, also show promise in reducing risk and slowing disease progression. Future research should prioritize personalized treatment approaches and novel drug delivery methods to improve outcomes for individuals affected by both conditions.}, } @article {pmid41106565, year = {2026}, author = {Sun, T and Li, Z and Xiao, B and Yang, J and Han, M and Zhang, J and Liu, S and Ma, H and Song, J and Su, Y and Cao, B and Zhang, X and Xie, Z and Zhu, H and Chen, Y and Ma, J and Wang, P and Zhang, Z}, title = {Multi-target neuroprotection of Atractylodes macrocephala ethyl acetate extract against Alzheimer's disease: from bioactivity-guided screening to mechanistic validation.}, journal = {Journal of ethnopharmacology}, volume = {355}, number = {Pt B}, pages = {120735}, doi = {10.1016/j.jep.2025.120735}, pmid = {41106565}, issn = {1872-7573}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/isolation & purification/therapeutic use ; *Plant Extracts/pharmacology/therapeutic use/isolation & purification ; Caenorhabditis elegans ; Amyloid beta-Peptides/metabolism ; *Atractylodes/chemistry ; Mice ; Acetates/chemistry ; Humans ; Disease Models, Animal ; Antioxidants/pharmacology/isolation & purification ; Cell Line ; Neurons/drug effects ; Anti-Inflammatory Agents/pharmacology/isolation & purification ; Microglia/drug effects ; Peptide Fragments ; }, abstract = {Atractylodes macrocephala (AM) has traditionally been used for treating inflammatory conditions, edema, and digestive issues. It is now being explored for its potential in treating Alzheimer's disease (AD), which is characterized by cognitive decline and impairments in learning and memory. While AM shows promise as a potential treatment for AD, further research is needed to identify its specific bioactive components and understand its mechanisms of action. AIM OF THE STUDY: This study aim to identify and evaluate bioactive fractions from AM for their potential to treat AD. The research focused on assessing the antioxidant, anti-inflammatory, and neuroprotective properties of these fractions to determine the most effective one. The ultimate goal was to find a basis for isolating active neuroprotective components from AM that could be used to develop new AD therapies. MATERIALS AND METHODS: To identify AM fractions with potential against AD, the study began with in vitro assessments of their ability to inhibit amyloid-β (Aβ) aggregation and their antioxidant capacity. The neuroprotective effects of these fractions were then evaluated against Aβ1-42 and D-galactose-induced toxicity in neuronal and microglial cell lines. A C. elegans AD model (CL4176 strain) was employed to assess the impact on Aβ-induced neurodegeneration (paralysis). Based on this comprehensive screening, the ethyl acetate extract (AMEA) emerged as the most promising fraction. Its mechanism of action was investigated using network pharmacology and validated in vivo using APP/PS1 transgenic mice. Finally, key compounds within AMEA were isolated and characterized. RESULTS: Compared to other extracts, AMEA showed stronger antioxidant, anti-inflammatory, and neuroprotective effects. In AD model mice, AMEA treatment protected the hippocampal neuronal structure, reduced damage to the pyramidal cell layer, and prevented dendritic spine loss. AMEA also significantly lowered the levels of key pro-inflammatory cytokines (IL-6, TNF-α, IL-1β) and reduced markers of microglial (IBA-1) and astrocyte (GFAP) activation, indicating reduced neuroinflammation. AMEA inhibited Aβ aggregation and improved cognitive function by reducing Aβ deposition in APP/PS1 transgenic mice. Network pharmacology analysis showed that AMEA is associated with neurodegenerative disease pathways and can regulate inflammatory mediators. UPLC-OE/MS analysis tentatively identified thirty-three phytochemicals in AMEA, including sesquiterpenoids, phenylpropanoids, coumarins, and flavonoids. Molecular docking revealed high binding affinity of compounds 3, 9, and 11 towards TNF-α, IL-6, and IL-1β, and ELISA results confirmed that compounds 3 and 11 markedly downregulated the expression of key neuroinflammatory factors. Structural isolation and bioactivity analysis of AMEA revealed that it contains bioactive components capable of protecting nerve cells from Aβ toxicity. CONCLUSIONS: This research concludes that the AMEA fraction of AM demonstrates significantly superior neuroprotective effects against the primary pathological features of AD compared to other solvent fractions. AMEA exhibited greater efficacy in inhibiting Aβ aggregation, neutralizing free radicals, protecting nerve cells, and reducing brain inflammation across various models, including C. elegans and AD mice. Furthermore, chemical component isolation and structural identification of the AMEA fraction yielded compounds such as atractylenolide and atractylenolactam, along with their dimers, many of which possess neuroprotective properties. In conclusion, this study establishes a basis for the future identification and development of neuroprotective compounds from AM.}, } @article {pmid41106076, year = {2025}, author = {Yang, G and Li, J and Guo, J and Liu, Y and Yan, J and Huang, H and Liu, J and Peng, C and Gan, M and Shu, J}, title = {Monoterpenoids from Verbena officinalis exert anti-neuroinflammatory effect through suppression of the NF-κB/MAPK signaling cascades.}, journal = {Bioorganic chemistry}, volume = {166}, number = {}, pages = {109098}, doi = {10.1016/j.bioorg.2025.109098}, pmid = {41106076}, issn = {1090-2120}, mesh = {Animals ; Mice ; *Anti-Inflammatory Agents/pharmacology/chemistry/isolation & purification ; Cell Line ; Cytokines/antagonists & inhibitors/biosynthesis/metabolism ; Dose-Response Relationship, Drug ; Lipopolysaccharides/pharmacology/antagonists & inhibitors ; *MAP Kinase Signaling System/drug effects ; Microglia/drug effects/metabolism ; Mitogen-Activated Protein Kinases/metabolism/antagonists & inhibitors ; Molecular Structure ; *Monoterpenes/pharmacology/chemistry/isolation & purification ; *NF-kappa B/metabolism/antagonists & inhibitors ; Nitric Oxide/antagonists & inhibitors/biosynthesis ; Signal Transduction/drug effects ; Structure-Activity Relationship ; Alzheimer Disease/drug therapy ; }, abstract = {Using bioactivity-guided isolation, we identified 11 monoterpenoids from V. officinalis, including 7 previously undescribed compounds (1-3, 5, and 8-10), two of which feature a rare C4-4'/C5-2' skeleton. At 12.5 μM, all isolated compounds significantly suppressed NO and pro-inflammatory cytokine production in LPS-stimulated BV2 microglial cells. Notably, compound 5 demonstrated the most potent anti-neuroinflammatory effects by modulating the NF-κB/MAPK signaling pathway, positioning it as a potential lead compound for AD treatment. These findings not only underscore the therapeutic value of V. officinalis but also broaden the pharmacological understanding of its monoterpenoid constituents.}, } @article {pmid41105718, year = {2025}, author = {Lara-Simon, E and Gispert, JD and Garcia-Ojalvo, J and Villoslada, P and , }, title = {Multiscale networks in Alzheimer's disease identify brain hypometabolism as central across biological scales.}, journal = {PLoS computational biology}, volume = {21}, number = {10}, pages = {e1013583}, pmid = {41105718}, issn = {1553-7358}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism/diagnostic imaging ; Humans ; *Brain/metabolism/diagnostic imaging ; Positron-Emission Tomography ; Biomarkers/metabolism/cerebrospinal fluid ; Systems Biology ; Aged ; Magnetic Resonance Imaging ; Male ; Amyloid beta-Peptides/metabolism ; Female ; tau Proteins/metabolism ; Computational Biology ; Aged, 80 and over ; }, abstract = {Alzheimer's disease encompasses multiple biological scales, spanning molecular factors, cells, tissues, and behavioral manifestations. The interplay among these scales in shaping the clinical phenotype is not yet fully comprehended. In particular, there is great interest in understanding the heterogeneity of the clinical aspects of AD in order to improve treatment and prevention, by targeting those aspects most susceptible to the disease. Here we employed a systems biology approach to address this issue, utilizing multilayer network analysis and deep phenotyping. This integrative analysis incorporated genomics, cerebrospinal fluid biomarkers, tau and amyloid beta (Aβ) PET imaging, brain MRI data, risk factors, and clinical information (cognitive tests scores, Clinical Dementia Rating and clinical diagnosis) obtained through the ADNI collaboration. Multilayer networks were built based on mutual information between the elements of each layer and between layers. Boolean simulations allowed us to identify paths that transmit dynamic information across layers. The most prominent path for predicting variables in the cognitive phenotype layer included the PET radiotracer fluorodeoxyglucose (FDG) in the posterior cingulate. Combinations of different symptomatic variables, mainly related to mental health (depression, mood swings, drowsiness) and vascular features (hypertension, cardiovascular history), were also part of the paths explaining the average phenotype. Our results show that integrating the flow of information across biological scales reveals relevant paths for AD, which can be subsequently explored as potential biomarkers or therapeutic targets. In particular, our results point for paths related with brain hypometabolism as a key feature in AD.}, } @article {pmid41105605, year = {2025}, author = {Bi, X and Xiao, X and Zhou, L and Liu, Q and Liu, Y and Tu, Q and Zhou, Y}, title = {Exploring multitarget molecular mechanisms of cannabidiol in Alzheimer's disease treatment using molecular simulations and modeling.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {3}, pages = {1287-1301}, doi = {10.1177/13872877251386440}, pmid = {41105605}, issn = {1875-8908}, mesh = {*Cannabidiol/pharmacology/therapeutic use/metabolism/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; tau Proteins/metabolism ; Glycogen Synthase Kinase 3 beta/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; *Amyloid beta-Peptides/metabolism ; Phosphorylation/drug effects ; }, abstract = {BackgroundAlzheimer's disease is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaque deposition and neurofibrillary tangles composed of hyperphosphorylated tau. Dysregulation of glycogen synthase kinase-3β (GSK3β) promotes tau hyperphosphorylation and amplifies Aβ-induced neurotoxicity, driving pathogenesis. Despite extensive research, current therapies targeting these core mechanisms remain largely ineffective at halting disease progression.ObjectiveBased on prior clinical and preclinical evidence, we hypothesize that cannabidiol (CBD), a non-psychoactive phytocannabinoid, may exert multitarget therapeutic effects in AD by modulating Aβ aggregation, tau hyperphosphorylation, and GSK3β activity.MethodsWe investigated CBD's interactions with Aβ-42/40, tau, and GSK3β using molecular docking, molecular dynamics simulations and ADMET predictions.ResultsOur results show that CBD binds to Aβ with binding free energies of -7.81 kcal/mol, -7.46 kcal/mol, and -7.25 kcal/mol, disrupting aggregation by interacting with key residues (HIS6, HIS13, HIS14, GLU14, GLU22, ASP15, and ASP23). MD simulations confirm that CBD destabilizes Aβ's β-sheet structure, preventing fibril formation. CBD binds tau with binding free energies of -9.91 kcal/mol, -9.70 kcal/mol, and -9.66 kcal/mol, disrupting tau aggregation and preventing neurofibrillary tangle formation. MD simulations show that CBD induces structural changes in tau, reducing β-sheet packing and inhibiting tau-tau interactions. CBD also binds to GSK3β with binding energies of -8.94 kcal/mol, -8.51 kcal/mol, and -8.41 kcal/mol, competing with ATP to inhibit its kinase activity and reduce tau phosphorylation. ADMET analysis indicates CBD's favorable oral bioavailability and low toxicity.ConclusionsThese findings support CBD as a promising multitarget therapeutic for AD, warranting further preclinical and clinical investigations.}, } @article {pmid41105579, year = {2025}, author = {Zhu, X and Liu, S and Wang, L and Liu, J and Gu, D and Huang, C}, title = {Predicting the conversion time from normal cognition to mild cognitive impairment based on dual attention convolutional networks.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {3}, pages = {1115-1131}, doi = {10.1177/13872877251386078}, pmid = {41105579}, issn = {1875-8908}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis/psychology ; Disease Progression ; Aged ; *Neural Networks, Computer ; Male ; *Cognition/physiology ; Female ; *Attention/physiology ; Early Diagnosis ; Aged, 80 and over ; Neuropsychological Tests ; Time Factors ; }, abstract = {BackgroundDementia, a progressive neurological disorder, is a leading cause of disability and death globally, often underdiagnosed in its early stages. Early diagnosis, prevention, and treatment are crucial for mitigating its impact on individuals and society.ObjectiveThis study aimed to predict the exact conversion time from normal cognition (NC) to mild cognitive impairment (MCI), and to provide insights for early diagnosis and treatment of dementia.MethodsA novel dual attention convolutional network model was proposed to handle high-dimensional features and limited patients' records in short-sequence time series data. It integrated feature and temporal attention modules to capture dependencies and used a custom loss function to enhance clinical interpretability.ResultsThe model significantly reduced mean squared error (MSE) by 9.67% and mean absolute error (MAE) by 26.24%, while increasing the r-square (R2) by 16.71% compared to a basic convolutional model. It effectively predicted NC to MCI conversion, offering valuable guidance for early intervention.ConclusionsThe dual attention convolutional network model effectively predicted NC to MCI conversion, providing a valuable tool for early dementia diagnosis and treatment.}, } @article {pmid41104322, year = {2025}, author = {Hyung, H and Jang, S and Kim, SY and Bae, JE and Park, JY and Lim, SG and Ko, J and Jang, S and Kim, JB and Chae, HY and Park, S and Yi, J and Choi, DK and Kim, MO and Lee, HS and Cho, DH and Young Ryoo, Z}, title = {Down-regulation of HSPA9 reduces tyrosine hydroxylase-positive neurons in mouse substantia nigra and induces Parkinson's disease-like motor impairments.}, journal = {Animal cells and systems}, volume = {29}, number = {1}, pages = {615-627}, pmid = {41104322}, issn = {1976-8354}, abstract = {Parkinson's disease (PD) is a progressive neurological disorder characterized by the degeneration of midbrain dopaminergic neurons and disabling motor impairments. Heat shock protein family A member 9 (HSPA9) play a crucial role in neuronal homeostasis by regulating the import of various mitochondrial proteins. HSPA9 is down-regulated in neurodegenerative diseases such as Alzheimer's disease and PD, and its loss leads to excessive mitochondrial fragmentation with oxidative stress, which subsequently causes damage to dopaminergic neurons. Moreover, HSPA9 interacts with multiple PD-associated proteins, including Pink1, DJ-1, and α-synuclein, however precise roles of HSPA9 in PD pathophysiology remain unclear. To further explore the contributions of HSPA9 in PD pathogenesis, we developed an HSPA9 knockout mouse. Haploinsufficiency of Hspa9 (Hspa9 [+/-]) was associated with the loss of tyrosine hydroxylase-positive neurons in the striatum and substantia nigra. Furthermore, Hspa9 haploinsufficiency induced excessive mitochondrial fission, enhanced apoptotic signaling, and resulted in diminished motor performance during the rotarod test. Administration of the mitochondrial neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Hspa9 [+/-] mice further exacerbated the loss of dopaminergic neurons, aggravated motor impairments, and enhanced activation of apoptosis effector caspase-3. These results suggest that down-regulation of HSPA9 may contribute to the development and progression of PD, potentially offering a new therapeutic strategy for PD treatment.}, } @article {pmid41104248, year = {2025}, author = {Kasaei, A and Forouzanfar, M and Jafarinia, M}, title = {Neuroprotection by Resveratrol in Chronic Cerebral Hypoperfusion: A Study on Synaptogenesis Enhancement and Apoptosis Inhibition.}, journal = {Iranian journal of pharmaceutical research : IJPR}, volume = {24}, number = {1}, pages = {e162425}, pmid = {41104248}, issn = {1726-6890}, abstract = {BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a key contributor to vascular dementia (VaD) and Alzheimer's disease. Resveratrol (RSV), a polyphenol with potential neuroprotective properties, may mitigate CCH-induced neuronal damage, but its mechanisms remain unclear. OBJECTIVES: This study investigated RSV's effects on memory enhancement through synaptogenesis and apoptosis inhibition in the hippocampus in a rat CCH model. METHODS: Forty male rats were randomly divided into four groups: Sham, 2-VO (bilateral carotid artery occlusion), 2-VO+RSV (2.5 mg/kg), and 2-VO+RSV (5 mg/kg). Initial group sizes (n = 10 each) were maintained by replacing deceased animals (2-VO: 7, 2-VO+RSV2.5: 4, 2-VO+RSV5: 6 deaths). The RSV was administered via intraperitoneal injection (ip) for 35 days post-surgery. Cognitive function was assessed using Morris water maze (MWM) and shuttle box tests. Hippocampal mRNA/protein levels of B-cell lymphoma 2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase-3, Ras homolog family member A (RhoA), Rho-associated coiled-coil containing protein kinase 2 (ROCK2), calcium/calmodulin-dependent protein kinase II alpha (CaMKII-α), and N-methyl-D-aspartate receptor subunit 2B (NMDAR2B) were measured. RESULTS: The RSV (5 mg/kg) significantly improved spatial memory in the MWM. Also, RSV at doses of 2.5 and 5 mg/kg significantly increased the entrance latency to the dark compartment (P < 0.05 and P < 0.01 vs 2-VO, respectively). There was a downregulation of pro-apoptotic markers (Bax, Caspase-3) and Rho/ROCK gene expressions, and an upregulation of anti-apoptotic Bcl-2 gene expression and synaptic proteins (CaMKII-α, NMDAR2B) after RSV treatment. The RSV at 5 mg/kg significantly reduced the Bax/Bcl-2 ratio compared to the 2-VO group. CONCLUSIONS: The RSV protects against CCH-induced neuronal damage by inhibiting apoptosis and enhancing synaptic plasticity. These findings highlight RSV's therapeutic potential for vascular cognitive impairment.}, } @article {pmid41103911, year = {2025}, author = {Bhansali, PR and Sonkusare, SM and Savale, SS and Wijayasinghe, YS and Liao, Y and Sloan, DC and Chaturbhuj, GU and Muntean, BS}, title = {Comprehensive medicinal chemistry survey highlights a portfolio of lead molecules for Alzheimer's disease therapy.}, journal = {Frontiers in chemistry}, volume = {13}, number = {}, pages = {1642190}, pmid = {41103911}, issn = {2296-2646}, abstract = {The World Health Organization reports 10 million new patients with dementia each year. The most common form of dementia is Alzheimer's disease (AD), which constitutes up to 70% of cases. AD is mainly characterized by loss of memory, which, in addition to its debilitating individual effect, represents a burden of 1.3 trillion US dollars globally. The staggering scale of hardship has spurred intense investigations from the scientific community in search of therapeutic solutions. Recent advances to combat AD involve the identification of numerous neural targets and concomitant chemical interventions as nodes of therapy. Due to disparate biological and chemical facets of AD therapy, a comprehensive perspective covering both arenas is currently missing from the literature. This perspective aims to provide an extensive understanding of anti-AD mechanics alongside small-molecule drug design efforts from a medicinal chemist viewpoint. We are confident that this survey of the literature will provide a resourceful motivation to propel future research efforts towards successful Alzheimer's disease therapy.}, } @article {pmid41103096, year = {2025}, author = {Bulut, Z and Karaküçük-Iyidoğan, A and Bilge, M and Sicak, Y and Turgut-Solak, ZD and Oruç-Emre, EE}, title = {Structure-Based Design of Chiral Thioureas as Anticholinesterase Inhibitors Using Enantiopure α-Methylbenzylamines: Synthesis, Enzyme Inhibition, and In Silico Studies.}, journal = {Archiv der Pharmazie}, volume = {358}, number = {10}, pages = {e70124}, doi = {10.1002/ardp.70124}, pmid = {41103096}, issn = {1521-4184}, support = {//This study was funded by the Scientific and Technological Research Council of Türkiye (TUBITAK) with project number 222Z293./ ; }, mesh = {*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; *Thiourea/pharmacology/chemistry/chemical synthesis/analogs & derivatives ; Structure-Activity Relationship ; Butyrylcholinesterase/metabolism ; *Drug Design ; Acetylcholinesterase/metabolism ; Stereoisomerism ; Molecular Docking Simulation ; Molecular Structure ; Humans ; Dose-Response Relationship, Drug ; *Benzylamines/chemistry/pharmacology/chemical synthesis ; Animals ; Computer Simulation ; }, abstract = {A detailed analysis of the research on the treatment of Alzheimer's disease indicates that selective inhibition of butyrylcholinesterase (BChE) is the most promising strategy for identifying a drug target. According to this perspective, in this study, a new series of potential BChE inhibitors (1a-8a and 1b-8b) were designed using a structure-based design approach and synthesized as enantiomer pairs based on the benzyl thiourea attached to a chiral moiety. The in vitro anticholinesterase activity studies against acetylcholinesterase (AChE) and BChE consistently demonstrated that the majority of the designed compounds exhibited selective and potent BChE inhibition. Also, the present results of the study reveal that compound 6b, which has a methyl group at the para position of the phenyl ring and has an S configuration, was the most potent compound against BChE with an IC50 value of 1.46 ± 1.99 μM (SI = 8.47). In contrast, the chiral thioureas (8a and 8b) bearing a cyclohexyl group demonstrated higher selectivity toward AChE, with SI values of 2.10 and 2.32, respectively. Notably, compounds 2a and 2b showed dual inhibitory effects with similar potency for AChE and greater potency for BChE, compared to the standard drug galantamine. The molecular docking method, which showed a good correlation with our in vitro anticholinesterase activity results, was used to predict the interactions of all chiral thioureas within the binding pockets of AChE and BChE. Further structural improvement of these molecules in future studies may lead to the emergence of more potent AChE and BChE inhibitors.}, } @article {pmid41102960, year = {2025}, author = {Agarwal, U and Kapoor, G and Tonk, RK}, title = {A Review on the Pathophysiology of Alzheimer's Disease.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037416859250915091846}, pmid = {41102960}, issn = {1875-5550}, abstract = {INTRODUCTION: Alzheimer's disease is characterized by a complex and multifactorial pathogenesis, involving key features such as amyloid-beta plaques, tau tangles, and neuron loss. Understanding the disease requires investigating its underlying causes, as these hallmarks reflect the intricate physiological processes involved. Identifying the root factors driving AD is essential for developing effective treatments. METHOD: This literature review was conducted using PubMed and Scopus databases, covering studies published from October 1999 to April 2025. The review included 190 references focused on the pathophysiology of Alzheimer's disease (AD). The selected studies analysed the primary pathophysiology leading to AD, particularly the accumulation of amyloid-beta plaques, tau tangles, and neuronal loss. RESULT: The study highlights several key biological factors associated with Alzheimer's Disease (AD). These include genetic mutations, mitochondrial dysfunction, hormonal imbalances, inflammation, oxidative stress, cellular division abnormalities, and reduced levels of dopamine-related neurotransmitters. It also highlights issues with calcium regulation and the imbalance of metals, such as copper, iron, lead, and zinc, in the body. Lifestyle choices such as drinking alcohol and smoking, along with changes in blood vessels and problems with the blood-brain barrier, were also found to play a role in how the disease develops. Additionally, the presence of certain pathogens was suggested as a possible factor in the disease's underlying mechanisms. DISCUSSION: The results indicate that a complex combination of genetic, biochemical, and environmental factors shapes the development and progression of Alzheimer's disease. Genetic mutations seem to play a significant role in affecting enzyme functions, which can disrupt vital biological processes. Problems with mitochondria and hormonal imbalances contribute to the deterioration of nerve cells, while oxidative stress and neuroinflammation are key mechanisms that worsen cellular damage. Disruptions in calcium signalling and imbalances in bio-metals further disturb neuronal stability. Lifestyle choices, blood vessel issues, and blood-brain barrier problems highlight the multifaceted nature of the disease. The study also highlights the close relationship between oxidative stress and neuroinflammation, suggesting that they may form a feedback loop that accelerates disease progression. Additionally, the possible involvement of infectious agents adds another layer of complexity, indicating that infections might trigger or worsen neurodegeneration in vulnerable individuals. CONCLUSION: To better understand and address Alzheimer's disease, it is essential to examine the fundamental processes that trigger its development. The various and interconnected factors involved- such as genetic mutations, cellular problems, environmental factors, and exposure to pathogens- require a comprehensive and integrated approach to research and treatment. Recognizing that neuroinflammation and oxidative stress play key roles in the progression of the disease can help guide future efforts toward early detection and more precise interventions.}, } @article {pmid41102777, year = {2025}, author = {Lin, Y and Yoo, JM and Li, Y and Heo, Y and Okumura, M and Won, HS and Vendruscolo, M and Lim, MH and Lee, YH}, title = {Disease-disease interactions: molecular links of neurodegenerative diseases with cancer, viral infections, and type 2 diabetes.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {52}, pmid = {41102777}, issn = {2047-9158}, support = {A439200//Korea Basic Science Institute/ ; C539200//Korea Basic Science Institute/ ; C512120//Korea Basic Science Institute/ ; C523200//Korea Basic Science Institute/ ; A412580//Korea Basic Science Institute/ ; A423310//Korea Basic Science Institute/ ; CCL22061-100//National Research Council of Science & Technology/ ; RS-2022-NR069719//National Research Foundation of Korea/ ; RS-2022-NR070709//National Research Foundation of Korea/ ; RS-2021-NR057690//National Research Foundation of Korea/ ; RS-2023-00221332//National Research Foundation of Korea/ ; RS-2024-00356469//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/metabolism ; *Neurodegenerative Diseases/metabolism ; Animals ; *Neoplasms/metabolism ; *Virus Diseases/metabolism ; }, abstract = {Neurodegenerative disorders, notably Alzheimer's and Parkinson's diseases, are unified by progressive neuronal loss and aberrant protein aggregation. Growing evidence indicates that these conditions are linked to cancer, infectious diseases, and type 2 diabetes through convergent molecular processes. In this review, we examine the mechanistic foundations of these links, focusing on shared features such as protein misfolding and aggregation, chronic inflammation, and dysregulated signalling pathways. We integrate cellular, animal, and human data to illustrate how pathogenic proteins may influence one another through cross-seeding and co-aggregation, and assess the implications of such interactions for disease susceptibility, progression, and treatment response. Understanding these underlying mechanisms may provide a conceptual framework for developing therapeutic approaches that target the molecular basis of multiple complex disorders.}, } @article {pmid41102562, year = {2025}, author = {, and Cao, H and Song, Z and Duggan, MR and Erus, G and Srinivasan, D and Tian, YE and Bai, W and Rafii, MS and Aisen, P and Belsky, DW and Walker, KA and Zalesky, A and Ferrucci, L and Davatzikos, C and Wen, J}, title = {MRI-based multi-organ clocks for healthy aging and disease assessment.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {41102562}, issn = {1546-170X}, support = {RF1AG092412//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; }, abstract = {Biological aging clocks across organ systems and tissues have advanced understanding of human aging and disease. In this study, we expand this framework to develop seven magnetic resonance imaging-based multi-organ biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney and pancreas. Using data from 313,645 individuals curated by the MULTI Consortium, we link the seven MRIBAGs to 2,923 plasma proteins, 327 metabolites and 6,477,810 common genetic variants. Genome-wide associations identify 53 MRIBAG-locus pairs (P < 5 × 10[-8]). Genetic correlation and Mendelian randomization analyses support organ-specific and cross-organ interconnection, including 24 non-MRI biological aging clocks and 525 disease endpoints. Through functional gene mapping and Bayesian co-localization multi-omics evidence, we prioritize nine druggable genes as targets for future anti-aging treatments. Furthermore, the seven MRIBAGs are linked to future risk of systemic disease endpoints (for example, diabetes mellitus) and all-cause mortality. Finally, participants with more youthful versus more aged brain profiles exhibited distinct cognitive decline trajectories over 240 weeks of treatment with the Alzheimer's disease drug solanezumab, although this heterogeneity cannot be fully attributed to the drug. In summary, we developed seven MRIBAGs that enhance the existing multi-organ biological aging framework, and we demonstrate their clinical potential to advance aging research.}, } @article {pmid41101301, year = {2025}, author = {Sasidharan, A and Somayaji, Y and Fernandes, R}, title = {Shifting Microglial Phenotypes: Targeting Disease-Associated Microglia in Neurodegeneration.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {21}, pages = {4147-4158}, doi = {10.1021/acschemneuro.5c00159}, pmid = {41101301}, issn = {1948-7193}, mesh = {Humans ; *Microglia/metabolism/pathology/immunology ; *Neurodegenerative Diseases/metabolism/pathology/immunology ; Animals ; Phenotype ; Neuroinflammatory Diseases/metabolism ; Phagocytosis/physiology ; }, abstract = {Neurodegenerative disorders are marked by the gradual degeneration of neurons and deterioration of cognitive function. One key underlying factor in these diseases is neuroinflammation. An essential component of this process is microglia, which are the innate immune cells that maintain homeostasis in the brain. A common outcome of microglial dysregulation in neurodegenerative diseases is chronic neuroinflammation, which exacerbates neuronal damage and impairs synaptic function. This review focuses on the dual roles that disease-associated microglia (DAMs) play in neural inflammation and neuroprotection as well as their distinct transcriptional profile in neurodegenerative diseases. DAMs engage in phagocytosis to remove debris, in addition to releasing cytokines that promote inflammation. To create an effective medicine, it is imperative to comprehend these dual functions. The roles of DAMs in Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are discussed, along with the mechanisms (such as the TREM2-APOE pathway) causing their activation. This review attempts to highlight the important aspects that could direct future investigations and treatment development by clarifying the interactions between DAMs and neurodegenerative diseases.}, } @article {pmid41099783, year = {2025}, author = {Alavian, F and Hajimohammadi, A}, title = {Interplay between gut Microbiome and glymphatic system in cognitive function and memory regulation.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {1038}, pmid = {41099783}, issn = {1573-4978}, mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Cognition/physiology ; *Glymphatic System/metabolism/physiology ; *Memory/physiology ; Animals ; Brain/metabolism ; Neurodegenerative Diseases/metabolism ; Dysbiosis ; Aquaporin 4/metabolism ; }, abstract = {The glymphatic system, a network of perivascular channels in the brain, clears toxins and metabolic products such as amyloid-β (Aβ), supporting cognitive function and preventing neurodegenerative diseases. The gut microbiome also affects brain health and cognitive functions by producing anti-inflammatory metabolites and neurotransmitters. In this narrative review study, recently published articles from reputable scientific databases were collected and analyzed. Characteristics related to the gut microbiome, its metabolites, and their impact on the glymphatic system and ultimately cognitive function were examined. These findings indicate that microbial metabolites such as short-chain fatty acids (SCFAs) and neurotransmitters such as serotonin and melatonin reduce brain inflammation and improve sleep quality and synaptic plasticity, which are essential for memory stabilization. Disruption of the gut microbiome (dysbiosis) leads to increased inflammation and dysfunction of the glymphatic system, resulting in the accumulation of toxic proteins and decreased cognitive function. Proper polarization of aquaporin-4 (AQP4), a water channel protein critical for fluid homeostasis in the brain, in astrocytes is essential for the effective functioning of this system, and its disruption is associated with diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Understanding the interaction between the gut microbiome and the glymphatic system presents a new pathway for regulating memory and cognitive health, which could be an important target for the prevention and treatment of neurodegenerative diseases. Enhancing the gut microbiome through probiotics and a healthy diet may improve glymphatic system function and brain health, thereby preventing cognitive disorders.}, } @article {pmid41099201, year = {2025}, author = {Bolzetta, F and Durante, G and Tessari, A and Lazzarin, M and Busonera, F and Pontarin, A and Villanova, M and Vernuccio, L and Saccaro, C and Custodero, C and Portincasa, P and Barbagallo, M and Veronese, N}, title = {A simple nomogram to predict the onset of dementia in mild cognitive impairment: A retrospective study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {834-843}, pmid = {41099201}, issn = {1875-8908}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis/complications/psychology ; Male ; Female ; Aged ; *Dementia/diagnosis/etiology/psychology ; Retrospective Studies ; *Nomograms ; Neuropsychological Tests ; Aged, 80 and over ; Disease Progression ; Mental Status and Dementia Tests ; Follow-Up Studies ; Predictive Value of Tests ; }, abstract = {BackgroundCurrently there is no effective treatment to reverse Alzheimer's disease, thus prevention is crucial. Patients with mild cognitive impairment (MCI) have higher rate of progression to dementia. Two commonly used cognitive tests, Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT), have only modest accuracy at predicting conversion from MCI to dementia, whereas other potentially predicting factors are difficult to implement in clinical practice.ObjectiveThe aim of this study was to assess the performance of a combination of simple cognitive tests and routine clinical data to predict onset clinical dementia over 3-year follow-up in a cohort of outpatients with MCI.MethodsMedical history was collected, and an advanced neuropsychological assessment was performed at baseline and at follow-up.Results98 participants were included (mean age 76.6 ± 4.5 years), and 49 developed dementia. Participants who developed dementia had significantly lower MMSE and CDT scores, as well as higher presence of hypercholesterolemia at the baseline evaluation. In the multivariate binary logistic regression analysis, the OR were 0.71 (CI95% 0.58-0.87) for MMSE, 0.77 (CI95% 0.65-0.93) for CDT, and 3.9 (CI95% 1.4-10.9) for hypercholesterolemia. The ROC curve combining these three factors obtained a value of AUC of 0.825 (CI95% 0.74-0.91). A nomogram was then developed for the risk of evolution from MCI to dementia at 3 years.ConclusionsCombining history of hypercholesterolemia with CDT and MMSE tests, may result in a simple prediction model to predict the onset of dementia over 3 years.}, } @article {pmid41099145, year = {2025}, author = {García Ribas, G and Ferrer-Picón, E}, title = {Tolerability of rivastigmine transdermal patch in patients with Alzheimer's disease: a narrative review.}, journal = {Expert opinion on drug safety}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/14740338.2025.2576520}, pmid = {41099145}, issn = {1744-764X}, abstract = {INTRODUCTION: The rivastigmine transdermal patch was developed to provide similar efficacy to oral rivastigmine in the treatment of Alzheimer's disease (AD), but with improved tolerability. AREAS COVERED: Randomized clinical trials and observational studies reporting on the tolerability of the rivastigmine transdermal patch in patients with AD, identified through a systematic literature search. EXPERT OPINION: Rivastigmine was the first cholinesterase inhibitor for which a transdermal formulation was developed; consequently, there is a substantial body of evidence on its efficacy and tolerability. The incidence of gastrointestinal AEs is markedly reduced with the transdermal patch compared with oral rivastigmine, while the efficacy of the patch remains similar to that of the oral formulation. Application site reactions are generally mild and do not cause much discomfort for the patient, and the risk of can be reduced by simple measures such as site rotation and good skin care. Tolerability of the patch improves over time, including at the highest dose level. Overall, the available evidence supports transdermal rivastigmine being generally well tolerated at doses up to 13.3 mg/24 h in patients with AD.}, } @article {pmid41098825, year = {2025}, author = {Zhang, X and Huang, S and Xu, H and Hu, Y and Gao, L}, title = {Research progress on plant-derived natural compounds regulating the MAPK signaling pathway for the prevention and therapy of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1666082}, pmid = {41098825}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder. It is characterised by the following: amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation and oxidative stress. Unfortunately, there is no curative treatment available. Recently, natural products have attracted growing interest as potential therapeutic agents for AD, thanks to their multi-target actions and favourable safety profiles. This review highlights recent advances in the use of various natural compounds, including flavonoids, phenolic compounds, saponins, terpenoids, alkaloids and coumarins, with a particular focus on how they modulate the mitogen-activated protein kinase (MAPK) signaling pathway. Representative agents such as myricetin, nobiletin, resveratrol, gallic acid, paeoniflorin, ganoderic acid A, huperzine A, triptolide, berberine, crocin, and ginsenosides have been shown to regulate MAPK subpathways (ERK, JNK, p38), thereby attenuating oxidative stress, neuroinflammation, synaptic dysfunction, and neuronal apoptosis. Preclinical studies suggest that these compounds improve cognitive function and ameliorate AD-related pathology, thereby supporting the idea that MAPK signaling is a critical therapeutic target. Nevertheless, current evidence is limited by short-term animal experiments, insufficient toxicological evaluations, and challenges related to bioavailability and blood-brain barrier penetration. Future studies should emphasize long-term efficacy, safety assessments, optimized drug delivery systems, and high-quality clinical trials. Overall, natural products represent a valuable source for AD drug discovery, and targeting MAPK signaling offers promising opportunities for novel therapeutic development.}, } @article {pmid41097927, year = {2025}, author = {Kowa, H and Sato, S and Kamiki, E and Nishimoto, T}, title = {[Significance of Amyloid Plaque Removal in Alzheimer's Disease Treatment: Development of Amyloid β-Targeting Antibody Drugs Based on the Amyloid Cascade Hypothesis].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {10}, pages = {1129-1136}, doi = {10.11477/mf.188160960770101129}, pmid = {41097927}, issn = {1881-6096}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Plaque, Amyloid/drug therapy/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies/therapeutic use ; }, abstract = {In a hyper-aging society, taking measures against dementia, especially against dementia due to Alzheimer's disease, which accounts for about two thirds of dementia cases, is an important task socially and economically. Forty years have passed since amyloid β was isolated from a patient, 30 years have passed since the amyloid cascade hypothesis was proposed and antibody drugs based on this hypothesis have emerged, which has led to the new era of Alzheimer's disease treatment. This article reviews the significance of amyloid plaque removal with amyloid β-targeting antibody treatment for Alzheimer's disease. (Recieved October 17, 2024; Accepted June 6, 2025; Published October 1, 2025).}, } @article {pmid41097350, year = {2025}, author = {Chakhari, S and Marco-Contelles, J and Iriepa, I and Carreiras, MDC and Chabchoub, F and Ismaili, L and Refouvelet, B}, title = {Multicomponent Synthesis of Multi-Target Quinazolines Modulating Cholinesterase, Oxidative Stress, and Amyloid Aggregation Activities for the Therapy of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {19}, pages = {}, pmid = {41097350}, issn = {1420-3049}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *Quinazolines/chemical synthesis/pharmacology/chemistry ; *Amyloid beta-Peptides/metabolism/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Humans ; Antioxidants/pharmacology/chemical synthesis/chemistry ; Protein Aggregates/drug effects ; Acetylcholinesterase/metabolism ; *Cholinesterases/metabolism ; Peptide Fragments/metabolism/chemistry ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta (Aβ) peptide, intracellular neurofibrillary tangles (NFTs), severe neuronal loss, and a marked decline in cholinergic function. Due to the limited efficacy of currently available therapies, the search for new chemical scaffolds able to target multiple pathological mechanisms remains an urgent priority. Among the most promising strategies are heterocyclic frameworks that can simultaneously interact with cholinesterase (ChE) enzymes and inhibit amyloid-β (Aβ) aggregation while also exhibiting antioxidant activity. In this context, we report a series of quinazoline derivatives synthesized via a sequential, one-pot multicomponent reaction, in good yields. Several of these compounds demonstrated notable antioxidant properties, as well as inhibitory effects on ChE activity and Aβ1-42 self-aggregation, highlighting their potential as multifunctional agents for the treatment of neurodegenerative disorders. Notably, 2-ethyl-4-(3,4-Dimethoxyphenyl)aminoquinazoline (3h) demonstrated the most balanced biological profile among the tested compounds, exhibiting an ORAC value of 5.73 TE, an acetylcholinesterase (AChE) inhibition IC50 = 6.67 μM, and 36.68% inhibition of Aβ1-42 aggregation, closely approaching the activity of curcumin. These findings highlight compound 3h as a promising quinazoline-based hit for the development of multifunctional agents targeting AD.}, } @article {pmid41097203, year = {2025}, author = {Mohib, O and Bomans, S and Jimenez Garcia, B and Leemans, L and Ligneel, C and De Waele, E and Beckwée, D and Janssens, P}, title = {Clinical Benefits of Exogenous Ketosis in Adults with Disease: A Systematic Review.}, journal = {Nutrients}, volume = {17}, number = {19}, pages = {}, pmid = {41097203}, issn = {2072-6643}, support = {G075423N//Research Foundation - Flanders/ ; }, mesh = {Humans ; *Ketosis ; *Ketone Bodies/therapeutic use/administration & dosage ; Adult ; Cardiovascular Diseases ; *Metabolic Diseases ; COVID-19 ; Mental Disorders/drug therapy ; Nervous System Diseases ; }, abstract = {BACKGROUND/OBJECTIVES: Ketone bodies are increasingly studied for their potential therapeutic effects, particularly through exogenous ketosis, in a variety of diseases. This systematic review aimed to rigorously assess the clinical efficacy of exogenous ketosis in adults with medical conditions. METHODS: Following PRISMA guidelines, we systematically searched MEDLINE and Scopus databases. Our inclusion criteria were defined according to the PICOS framework, focusing on studies involving exogenous ketosis in adult patients with specific diseases. The study is registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42023492846). RESULTS: After a stringent selection process, fifty-one studies were analyzed. Twenty-two studies focused on neurological disorders, one on psychiatric disorders, twenty-two on metabolic disorders, five on cardiovascular disorders, and one on an inflammatory disorder. Exogenous ketosis demonstrated potential benefits across multiple conditions, including Alzheimer's disease, mild cognitive impairment, McArdle's disease, various forms of heart failure, cardiogenic shock, pulmonary hypertension, and COVID-19-related acute respiratory distress syndrome, although evidence is mostly limited to surrogate endpoints with insufficient hard outcome data. Subtherapeutic ketone concentrations induced by medium-chain triglycerides and limited follow-up periods often precluded firm conclusions regarding clinically meaningful outcomes. CONCLUSIONS: Exogenous ketosis shows potential in neurological, metabolic, and cardiovascular disorders, while evidence in psychiatric and inflammatory conditions remains scarce and preliminary. Ketone esters appear preferable for effective and tolerable ketosis. Future research should focus on identifying responsive patient populations, optimizing treatment regimens, and conducting long-term clinical trials with hard endpoints to validate these findings.}, } @article {pmid41097011, year = {2025}, author = {Campagnoli, LIM and Varesi, A and Fahmideh, F and Hakimizad, R and Petkovic, P and Barbieri, A and Marchesi, N and Pascale, A}, title = {From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41097011}, issn = {1422-0067}, mesh = {Humans ; *Metformin/therapeutic use/pharmacology ; *Hypoglycemic Agents/therapeutic use/pharmacology ; *Diabetes Mellitus, Type 2/drug therapy/metabolism ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; AMP-Activated Protein Kinases/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; }, abstract = {Metformin, an oral antihyperglycemic drug, represents the cornerstone of pharmacological treatment for type 2 diabetes mellitus (T2DM). Its primary glucose-lowering effects are well established, predominantly mediated through the activation of AMP-activated protein kinase (AMPK). This activation leads to a reduction in hepatic glucose production (primarily by inhibiting gluconeogenesis and glycogenolysis) and an increase in peripheral glucose uptake and utilization. Beyond its direct impact on glucose metabolism, metformin also improves insulin sensitivity and has beneficial effects on lipid profiles. Increasingly, research shows that metformin has pleiotropic effects. In addition to its recognized antihyperglycemic action, metformin is emerging as a regulator of cellular processes implicated in aging. Indeed, emerging evidence suggests a potential role of metformin in modulating pathways associated with longevity and ameliorating the symptoms of age-related diseases, including neurodegenerative disorders (such as Alzheimer's and Parkinson's diseases), cardiovascular diseases, age-related macular degeneration, and osteoporosis. The proposed mechanisms for these broader effects involve AMPK activation, modulation of the mTOR pathway, reduction of oxidative stress, and promotion of autophagy. After exploring the established role of metformin in T2D, this review provides a comprehensive investigation of its promising applications in the context of age-related diseases, offering valuable insights into its multifaceted therapeutic potential beyond glycemic control.}, } @article {pmid41097004, year = {2025}, author = {Daponte, A and Koros, C and Skarlis, C and Siozios, D and Rentzos, M and Papageorgiou, SG and Anagnostouli, M}, title = {Neurofilament Biomarkers in Neurology: From Neuroinflammation to Neurodegeneration, Bridging Established and Novel Analytical Advances with Clinical Practice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41097004}, issn = {1422-0067}, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Neurofilament Proteins/metabolism/blood ; *Neurodegenerative Diseases/metabolism/diagnosis ; *Neuroinflammatory Diseases/metabolism/diagnosis ; Animals ; }, abstract = {Neuroaxonal damage underlies permanent disability in various neurological conditions, both neuroautoimmune and neurodegenerative. It is crucial to accurately quantify and monitor axonal injury using biomarkers to evaluate disease progression and treatment effectiveness and offer prognostic insights. Neurofilaments (NFs), and especially neurofilament light chain (NfL), show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. Recent advances in ultrasensitive immunoassays enable the reliable detection of NFs in blood, transforming them from research tools into clinically applicable measures. In multiple sclerosis (MS), serum NfL correlates with disease activity, treatment response, and long-term disability, and may complement MRI in monitoring subclinical progression. In MS, NfL is primarily emerging as a marker of disease activity and treatment response; in amyotrophic lateral sclerosis (ALS), it has progressed further, being integrated into clinical trials as a pharmacodynamic endpoint and considered by regulatory agencies as a drug development tool. Additionally, NFs are increasingly being investigated in Alzheimer's disease, frontotemporal dementia, and other neurodegenerative disorders, though their disease specificity is limited. Ongoing challenges include older and novel assay harmonization, normative range interpretation, biological and analytical variability, and integration with other molecular and imaging biomarkers. This critical narrative review synthesizes the existing literature on NFs as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers and discusses their role in therapeutic development and precision medicine in neuroautoimmune and neurodegenerative diseases.}, } @article {pmid41096835, year = {2025}, author = {Nairuz, T and Heo, JC and Park, HJ and Lee, JH}, title = {Photobiomodulation at 660 nm Alleviates Alzheimer's Disease Pathology Through Amyloid-β Reduction and SIRT1 Upregulation in the Hippocampus of 5xFAD Mice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096835}, issn = {1422-0067}, support = {DBSD1-06,NRF-2022R1I1A307278, RS-2023-00237791,HI21C0977, RS-2021-KH118978, RS-2024-00433896,RS-2022-00166898,2020R1A6C101B189//Korea government (MSIT and Daegu Metropolitan City), the Basic Research Program through the National Research Foundation of Korea,Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), the Korea government (th/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/radiotherapy/genetics/therapy ; *Sirtuin 1/metabolism/genetics ; *Hippocampus/metabolism/radiation effects/pathology ; *Low-Level Light Therapy/methods ; Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; Mice ; Disease Models, Animal ; Up-Regulation/radiation effects ; Male ; Humans ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, synaptic dysfunction, and cognitive decline. Current pharmacological treatments provide only symptomatic relief without altering disease progression. Photobiomodulation therapy (PBMT), a light-based intervention, has shown neuroprotective potential, although its exact neurobiological mechanisms in AD pathogenesis remain obscure. In this study, we investigated the effects of PBMT using a 660 nm wavelength light-emitting diode (LED) in 5xFAD transgenic mouse, a well-established model of early-onset AD. Mice were subjected to once daily PBMT sessions over a defined treatment period and outcomes were assessed through immunohistochemical analysis of hippocampal regions (CA1, CA2, CA3, and dentate gyrus) alongside behavioral testing using the Y-maze spontaneous alternation task. PBMT significantly reduced Aβ plaque load across hippocampal regions, accompanied by improved preservation of neuronal morphology. Furthermore, PBMT significantly upregulated SIRT1 expression, a critical regulator of synaptic plasticity and memory processes. Behaviorally, PBMT-treated mice displayed enhanced spatial working memory compared with controls, indicating a functional benefit linked to the observed molecular and structural changes. These findings suggest that 660 nm PBMT attenuates hallmark AD pathology, promotes neuroprotective pathways, and improves cognition, highlighting its potential as a disease-modifying therapy that warrants further preclinical and clinical investigation.}, } @article {pmid41096792, year = {2025}, author = {Athanasaki, A and Tsantzali, I and Theodorou, A and Michalopoulou, A and Constantinides, VC and Boufidou, F and Tzartos, JS and Tsalouchidou, PE and Zompola, C and Paraskevas, SG and Bonakis, A and Giannopoulos, S and Tsivgoulis, G and Kapaki, E and Paraskevas, GP}, title = {The Biomarker Profile of Alzheimer's Disease for Disease-Modifying Treatment Eligibility: Questions and Debates.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096792}, issn = {1422-0067}, mesh = {*Alzheimer Disease/metabolism/diagnosis/drug therapy/therapy/blood ; Humans ; *Biomarkers/blood/metabolism ; tau Proteins/metabolism/blood ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common cause of cognitive decline; currently, anti-amyloid monoclonal antibodies are available for clinical use as disease-modifying treatments, while many other substances are being tested in clinical trials. Molecular biomarkers for AD have been studied for more than two decades, and various guidelines and diagnostic recommendations have been published. However, there are still questions and controversies about the biomarker profile needed to confirm AD and the eligibility for such established treatments and clinical trials. Is amyloid positivity sufficient for eligibility, or is a biomarker for tau biochemistry/pathology also needed? What is the role of hybrid ratios combining amyloid and tau? Should we rely on plasma biomarkers alone? This review aimed to describe and discuss such questions and controversies.}, } @article {pmid41383699, year = {2024}, author = {Huang, S and Zhang, M}, title = {The role of angiotensin II type 1 receptor pathway in cerebral ischemia‒reperfusion injury: Implications for the neuroprotective effect of ARBs.}, journal = {Neuroprotection (Chichester, England)}, volume = {2}, number = {2}, pages = {100-119}, pmid = {41383699}, issn = {2770-730X}, abstract = {Cerebral ischemia-reperfusion (I/R) injury is a crucial factor that impacts the prognosis of recanalization therapy for acute ischemic stroke (AIS). It has been found that the brain renin-angiotensin system, especially the angiotensin II type 1 receptor (AT1R) pathway, plays a significant role in cerebral I/R injury. This pathway is involved in processes such as oxidative stress, neuroinflammation, apoptosis, and it affects cerebrovascular autoregulation and the maintenance of blood-brain barrier. AT1R blocker (ARB), widely used as an antihypertensive agent, has demonstrated stroke prevention capabilities in numerous prospective studies, independent of its antihypertensive characteristics. Studies focusing on neurological diseases like Alzheimer's disease, Parkinson's disease, and cognitive impairment have confirmed that ARBs exhibit neuroprotective effects and aid in improving neurological functions. Preclinical studies have shown that ARBs can reduce infarct volume and brain edema, inhibit multiple signaling pathways associated with I/R injury, restore energy levels in damaged brain regions, and rescue the penumbra by promoting neovascularization in cerebral I/R models. These findings suggest that ARBs have potential to become a novel category of neuroprotecting agents for clinical treatment of AIS. Therefore, this review primarily provides a theoretical foundation and practical evidence for the future clinical utilization of ARBs as neuroprotective agents following reperfusion therapy for AIS. It outlines the role of cerebral I/R injury through the AT1R pathway and highlights the research progress made on ARBs in I/R models.}, } @article {pmid41341247, year = {2024}, author = {Lefkovitz, I and Walsh, S and Blank, LJ and Jetté, N and Kummer, BR}, title = {Direct Clinical Applications of Natural Language Processing in Common Neurological Disorders: Scoping Review.}, journal = {JMIR neurotechnology}, volume = {3}, number = {}, pages = {e51822}, pmid = {41341247}, issn = {2817-092X}, abstract = {BACKGROUND: Natural language processing (NLP), a branch of artificial intelligence that analyzes unstructured language, is being increasingly used in health care. However, the extent to which NLP has been formally studied in neurological disorders remains unclear. OBJECTIVE: We sought to characterize studies that applied NLP to the diagnosis, prediction, or treatment of common neurological disorders. METHODS: This review followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) standards. The search was conducted using MEDLINE and Embase on May 11, 2022. Studies of NLP use in migraine, Parkinson disease, Alzheimer disease, stroke and transient ischemic attack, epilepsy, or multiple sclerosis were included. We excluded conference abstracts, review papers, as well as studies involving heterogeneous clinical populations or indirect clinical uses of NLP. Study characteristics were extracted and analyzed using descriptive statistics. We did not aggregate measurements of performance in our review due to the high variability in study outcomes, which is the main limitation of the study. RESULTS: In total, 916 studies were identified, of which 41 (4.5%) met all eligibility criteria and were included in the final review. Of the 41 included studies, the most frequently represented disorders were stroke and transient ischemic attack (n=20, 49%), followed by epilepsy (n=10, 24%), Alzheimer disease (n=6, 15%), and multiple sclerosis (n=5, 12%). We found no studies of NLP use in migraine or Parkinson disease that met our eligibility criteria. The main objective of NLP was diagnosis (n=20, 49%), followed by disease phenotyping (n=17, 41%), prognostication (n=9, 22%), and treatment (n=4, 10%). In total, 18 (44%) studies used only machine learning approaches, 6 (15%) used only rule-based methods, and 17 (41%) used both. CONCLUSIONS: We found that NLP was most commonly applied for diagnosis, implying a potential role for NLP in augmenting diagnostic accuracy in settings with limited access to neurological expertise. We also found several gaps in neurological NLP research, with few to no studies addressing certain disorders, which may suggest additional areas of inquiry. TRIAL REGISTRATION: Prospective Register of Systematic Reviews (PROSPERO) CRD42021228703; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=228703.}, } @article {pmid41383445, year = {2024}, author = {Zhu, Y and Liao, L and Gao, S and Tao, Y and Huang, H and Fang, X and Yuan, C and Gao, C}, title = {Neuroprotective effects of repetitive transcranial magnetic stimulation on Alzheimer's disease: Undetermined therapeutic protocols and mechanisms.}, journal = {Neuroprotection (Chichester, England)}, volume = {2}, number = {1}, pages = {16-32}, pmid = {41383445}, issn = {2770-730X}, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by gradual deterioration of cognitive functions, for which an effective treatment is currently unavailable. Repetitive transcranial magnetic stimulation (rTMS), a well-established noninvasive brain stimulation method, is utilized in clinical settings to address various neuropsychiatric conditions, such as depression, neuropathic pain, and poststroke dysfunction. Increasing evidence suggests that rTMS may enhance cognitive abilities in individuals with AD. However, its optimal therapeutic protocols and precise mechanisms are currently unknown, impeding its clinical implementation. In the present review, we aimed to summarize and discuss the efficacy-related parameters in rTMS treatment, encompassing stimulus frequency, stimulus pattern, stimulus intensity, and the configuration of the stimulus coil. Furthermore, we reviewed promising rTMS therapeutic protocols involving various combinations of these factors, that were examined in clinical studies. Based on our analysis, we propose that a multisite high-frequency rTMS (HF-rTMS) regimen has value in AD therapy, and that promising single-site protocols, such as HF-rTMS, applied over the left dorsolateral prefrontal cortex, precuneus, or cerebellum are required to be validated in larger clinical studies. Lastly, we provide a comprehensive review of the potential mechanisms underlying the neuroprotective effects of rTMS on cognition in AD in terms of brain network modulation as well as cellular and molecular reactions. In conclusion, the interaction of diverse mechanisms may be responsible for the total therapeutic effect of rTMS on AD. This review provides theoretical and practical evidence for the future clinical application and scientific research of rTMS in AD.}, } @article {pmid41141948, year = {2023}, author = {Sarko, L and Saha, K}, title = {Harnessing chimeric antigen receptor (CAR)-T cells as a potential treatment for Alzheimer's disease.}, journal = {Cell & gene therapy insights}, volume = {9}, number = {7}, pages = {1003-1010}, pmid = {41141948}, issn = {2059-7800}, support = {R35 GM119644/GM/NIGMS NIH HHS/United States ; T32 GM135119/GM/NIGMS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) significantly burdens global healthcare systems given limited treatment options to delay or stop disease progression. Chimeric antigen receptor (CAR) T cell therapy, an immunotherapeutic approach that has produced remarkably effective responses in cancer, offers a potential avenue for the treatment of AD. Here, we discuss three significant challenges of adapting CAR-T cell therapy for AD: (i) identifying a suitable antigen target; (ii) limited permeability of the blood-brain barrier; and (iii) long-term persistence and durability of manufactured CAR-T cell products. Potential strategies to overcome these hurdles provide an attractive opportunity to revolutionize the treatment for AD and potentially other neurodegenerative disorders.}, } @article {pmid41096715, year = {2025}, author = {Mima, Y and Yamamoto, M and Iozumi, K}, title = {Review of Promising Off-Label Use of Deucravacitinib.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096715}, issn = {1422-0067}, mesh = {Humans ; *Off-Label Use ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; Animals ; *TYK2 Kinase/antagonists & inhibitors/metabolism ; Signal Transduction/drug effects ; Clinical Trials as Topic ; Psoriasis/drug therapy ; Bridged-Ring Compounds ; Pyrimidines ; }, abstract = {Tyrosine kinase 2 (TYK2) mediates the signaling pathways of proinflammatory cytokines such as interleukin (IL)-12, IL-23, and type I interferons (IFNs) and plays a pivotal role in the pathogenesis of psoriasis and various other immune-mediated diseases. Deucravacitinib, a selective oral TYK2 inhibitor, has been approved for the treatment of psoriasis and demonstrated high efficacy and a favorable safety profile. This review summarizes the potential for expanding deucravacitinib indications based on case reports, clinical trials, and preclinical studies. Diseases in which TYK2 pathway has been demonstrated to be involved and for which clinical benefit of deucravacitinib has been reported include discoid lupus erythematosus, systemic lupus erythematosus, alopecia areata, lichen planus, palmoplantar pustulosis, psoriatic arthritis, systemic sclerosis, interstitial pneumonia, inflammatory bowel disease, and chronic recurrent multifocal osteomyelitis. Furthermore, emerging research suggests potential therapeutic applications in neurodegenerative diseases such as Alzheimer's disease, and malignancies such as type 1 diabetes, vascular calcification in chronic kidney disease, T-cell acute lymphoblastic leukemia, and multiple sclerosis. Deucravacitinib may exert therapeutic effects by broadly suppressing cytokine signaling in a diverse range of inflammatory disorders. Ongoing clinical trials and mechanistic studies are required to clarify the efficacy and support its future indications.}, } @article {pmid41096667, year = {2025}, author = {Skarlis, C and Angelopoulou, E and Rentzos, M and Papageorgiou, SG and Anagnostouli, M}, title = {Monoclonal Antibodies as Therapeutic Agents in Autoimmune and Neurodegenerative Diseases of the Central Nervous System: Current Evidence on Molecular Mechanisms and Future Directions.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096667}, issn = {1422-0067}, mesh = {Humans ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/immunology ; Animals ; *Central Nervous System Diseases/drug therapy/immunology ; Neuromyelitis Optica/drug therapy ; Central Nervous System/drug effects/immunology ; Multiple Sclerosis/drug therapy ; }, abstract = {Monoclonal antibodies (mAbs) have revolutionized the treatment landscape for neurological diseases, providing targeted, mechanism-based therapies for conditions ranging from autoimmune demyelinating disorders to neurodegenerative diseases. In multiple sclerosis (MS), mAbs against CD20, CD52, and α4-integrins offer disease-modifying efficacy by altering immune responses, depleting B cells, or blocking leukocyte migration into the central nervous system (CNS). Similarly, novel agents under investigation, such as frexalimab and foralumab, modulate T and B cell interactions and regulatory immunity. In neuromyelitis optica spectrum disorder (NMOSD), mAbs targeting IL-6, the complement cascade, and B cell lineage have demonstrated significant clinical benefit in preventing relapses and disability. In Alzheimer's disease (AD), several anti-amyloid mAbs have gained regulatory approval. Anti-tau and anti-α-synuclein antibodies, though promising, have shown limited efficacy to date in AD and parkinson's disease (PD), respectively. The evolving armamentarium of mAbs reflects a paradigm shift toward personalized neuroimmunology and neurodegeneration-targeted treatments, based on ongoing clarification of molecular and neuroinflammatory mechanisms. In this context, the present review summarizes current evidence on mAbs used in CNS disorders, with an emphasis on their pathophysiological targets, molecular mechanisms, clinical efficacy, and safety.}, } @article {pmid41096666, year = {2025}, author = {Świątek, G and Nowakowska-Gołacka, J and Słomińska-Wojewódzka, M and Glac, W and Harackiewicz, O and Kurowska-Rucińska, E and Wrona, D}, title = {Minocycline Treatment Improves Memory and Reduces Anxiety by Lowering Levels of Brain Amyloid Precursor Protein and Indoleamine 2,3-Dioxygenase in a Rat Model of Streptozotocin-Induced Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096666}, issn = {1422-0067}, mesh = {Animals ; *Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Male ; *Minocycline/pharmacology/therapeutic use ; Rats ; *Anxiety/drug therapy/metabolism ; Streptozocin ; Rats, Wistar ; Disease Models, Animal ; *Memory/drug effects ; *Amyloid beta-Protein Precursor/metabolism ; Brain/metabolism/drug effects ; Hippocampus/metabolism/drug effects ; Maze Learning/drug effects ; }, abstract = {Minocycline (MINO), a classic antibiotic, may have psychotropic activity related to the modulation of the tryptophan-kynurenine pathway. In this study, we investigated the effects of MINO on (1) memory and anxiety behaviors, (2) the modulation of brain levels of amyloid precursor protein (APP) and 2,3-indoleamine dioxygenase (IDO1) levels, and (3) peripheral inflammatory markers in a streptozotocin (STZ)-induced rat model of sporadic Alzheimer's disease (sAD). After repeated treatment with a dose of 35 mg/kg MINO for seven consecutive days, male Wistar rats with sAD showed (1) improvements in early (29 days after injection, probe test) reference memory (decreased latency to reach the platform, increased time in the critical quadrant of the Morris water maze) and anxiety disorders (increased time in the open arms of the elevated plus maze; increased exploration and entrances in the center of the white-light illuminated open field) 45-46 and 90-91 days after STZ injection; (2) reduced APP and IDO1 levels in the hippocampus and prefrontal cortex; and (3) induction of anti-inflammatory response in blood (increased TCD4[+] lymphocyte number and interleukin-10 production). This suggests that MINO, due to its anti-inflammatory action, improves memory and anxiety behavior related to sAD, indicating its neuroprotective and psychotropic properties.}, } @article {pmid41096642, year = {2025}, author = {Mochol, M and Jablonowski, L and Pawlik, A and Rasławska-Socha, J and Chamarczuk, A and Lipski, M and Mazurek-Mochol, M}, title = {The Role of Vitamin C in Selected Autoimmune and Immune-Mediated Diseases: Exploring Potential Therapeutic Benefits.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096642}, issn = {1422-0067}, mesh = {Humans ; *Autoimmune Diseases/drug therapy/metabolism/immunology ; *Ascorbic Acid/therapeutic use/pharmacology ; Antioxidants/therapeutic use ; Animals ; Dietary Supplements ; *Immune System Diseases/drug therapy ; Oxidative Stress/drug effects ; }, abstract = {Autoimmune diseases are characterized by immune response dysregulation against self-components, leading to chronic inflammation and tissue damage. Vitamin C (VitC), a water-soluble vitamin with established functions in antioxidant defence and collagen synthesis, has also been of interest based on its potential immunomodulatory effects. This review discusses the role of VitC in the course and progression of (A) autoimmune diseases (multiple sclerosis, rheumatoid arthritis, Sjögren's disease, type 1 diabetes, Hashimoto's thyroiditis, pernicious anaemia, antiphospholipid syndrome), (B) other immune-mediated diseases (Crohn's disease, periodontitis), and (C) Alzheimer's disease, a neurodegenerative disorder with autoimmune features. Results from clinical, observational, and experimental trials show that VitC deficiency is common in many of these diseases and may contribute to increased oxidative stress and immune disequilibrium. Supplementation has been associated with improved antioxidant levels, control of inflammatory mediators, and, in some cases, clinical outcomes like disease activity decrease or symptom load. Although findings vary across conditions and few large, randomized trials are available, the overall evidence indicates that maintaining good VitC status can be useful in maintaining immune homeostasis and reducing inflammation. VitC should be viewed as an adjunct to be employed safely, perhaps and ideally within larger treatment regimens, but not in place of effective therapies. Further research, including large-scale clinical trials, will be required to determine more clearly optimal dosing, timing of treatment, and patient population most likely to benefit. By integration of current knowledge, this review recognizes both promise in VitC for treatment of autoimmune/immune-mediated disease and promise in its potential use within future treatment regimens.}, } @article {pmid41096572, year = {2025}, author = {Zhang, X and Fu, Y and Li, X and Zhang, Y and Li, L and Yi, T and Jiang, H and Lu, Y}, title = {Phlorizin Ameliorates Amyloid-β Toxicity and Enhances Fatty Acid β-Oxidation in Caenorhabditis elegans via NHR-49-Dependent Pathway.}, journal = {International journal of molecular sciences}, volume = {26}, number = {19}, pages = {}, pmid = {41096572}, issn = {1422-0067}, support = {7252230//Beijing Municipal Science & Technology Commission/ ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/drug effects/genetics ; *Amyloid beta-Peptides/toxicity/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Fatty Acids/metabolism ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species/metabolism ; Alzheimer Disease/metabolism/drug therapy ; Lipid Metabolism/drug effects ; Longevity/drug effects ; Signal Transduction/drug effects ; Disease Models, Animal ; Receptors, Cytoplasmic and Nuclear ; }, abstract = {Phlorizin (PHZ) is a glucoside of phloretin, belonging to the dihydrochalcone class within flavonoids; It is one of the active ingredients of the plant Cynomorium, and it has been shown that PHZ can regulate lipid metabolism disorders as well as having anti-aging properties. However, no studies have investigated whether PHZ ameliorates Aβ-induced toxicity in Alzheimer's disease (AD) by regulating fatty acid β-oxidation. This study aims to investigate the effects of PHZ on the regulation of fatty acid β-oxidation and resistance to Aβ-associated toxicity on the AD Caenorhabditis elegans and the mechanisms of action. Wild-type N2 and AD model CL4176 C. elegans were used; lifespan, heat stress resistance, chronic paraquat stress, reactive oxygen species (ROS), behavioral performance, and lipofuscin accumulation assays were examined to evaluate the anti-aging effects; and non-esterified fatty acid (NEFA), triglyceride (TG) and lipidomic contents were quantified after PHZ treatment. The detection of genes related to fatty acid β-oxidation pathways was performed using qRT-PCR. nhr-49 knockout mutant RB1716; and GFP-binding mutants PMD150 WBM170 were used to observe the effect of PHZ on NHR-49 pathways, and molecular docking studies were performed by combining PHZ with NHR-49 proteins. Results showed that PHZ improved worms' survival and delayed senescence, as demonstrated by enhanced performance in lifespan, heat stress, ROS, and paraquat assays and chronic paraquat assays; PHZ also reduced lipid accumulation in worms, affected the unsaturated fatty acid pathway, and significantly increased the expression of fatty acid metabolism-related genes nhr-49, acs-2, and cpt-5, and can be tightly coupled to NHR-49 targets. PHZ may play an anti-Aβ toxicity role by regulating lipid metabolism disorders through the NHR-49-related pathway and anti-aging in AD worms.}, } @article {pmid41096196, year = {2025}, author = {Siwecka, N and Golberg, M and Świerczewska, D and Filipek, B and Pendrasik, K and Bączek-Grzegorzewska, A and Stasiołek, M and Świderek-Matysiak, M}, title = {Sleep Disorders in Neurodegenerative Diseases with Dementia: A Comprehensive Review.}, journal = {Journal of clinical medicine}, volume = {14}, number = {19}, pages = {}, pmid = {41096196}, issn = {2077-0383}, abstract = {Dementia is a growing problem of global relevance, currently affecting over 55 million people worldwide. The number of new dementia cases is still increasing, primarily due to the aging of society. Dementia is defined as a substantial decline in cognitive function, and it is inherently associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, and vascular dementia. Of note, most patients suffering from neurodegenerative conditions, in addition to cognitive impairment, often experience various types of sleep disorders, including insomnia, rapid eye movement sleep behavior disorder, sleep-disordered breathing, and circadian rhythm disturbances. There is increasing evidence of a bidirectional interaction between sleep disturbances and mental health. Disrupted sleep may directly aggravate neuropsychiatric symptoms, like depression, anxiety, agitation, and hallucinations, and conversely, such symptoms can make sleeping more difficult. This creates a feedback loop that inevitably leads to disease progression and deterioration in quality of life. In this review, we provide an up-to-date overview of the nature and mechanisms behind sleep disorders in major neurodegenerative diseases, summarize treatment strategies for handling sleep disturbances, and discuss the clinical relevance of sleep-mental health interactions in the context of neurodegeneration-associated dementia. Neurodegeneration is a complex problem on the border between neurology and psychiatry, and it poses a challenge to the healthcare system, as it requires multidisciplinary approaches for optimal management. Understanding the connection between sleep and neuropsychiatric symptoms offers further opportunities for better symptom control, improved quality of life, and slower cognitive decline.}, } @article {pmid41094207, year = {2025}, author = {Chen, Z and Ma, S and Wang, C and Liu, J and Yang, X}, title = {A ratio electrochemiluminescence sensor for monitoring amyloid-beta based on g-C3N4-heme with luminol as the internal standard.}, journal = {Mikrochimica acta}, volume = {192}, number = {11}, pages = {737}, pmid = {41094207}, issn = {1436-5073}, support = {ZR2023MB083//Natural Science Foundation of Shandong Province/ ; }, mesh = {*Luminol/chemistry ; *Amyloid beta-Peptides/analysis/blood ; *Electrochemical Techniques/methods ; *Biosensing Techniques/methods ; Aptamers, Nucleotide/chemistry ; *Luminescent Measurements/methods ; Humans ; Graphite/chemistry ; Limit of Detection ; *Nitriles/chemistry ; Metal Nanoparticles/chemistry ; Electrodes ; Gold/chemistry ; Aniline Compounds/chemistry ; Tin Compounds/chemistry ; }, abstract = {Monitoring of the amyloid-beta (Aβ) peptide is crucial for the diagnosis and treatment of Alzheimer's disease. Here, a label-free, signal-on ratiometric electrochemiluminescence (ECL) aptasensor was fabricated for the detection of Aβ peptide. Specifically, graphite-like carbon nitride (g-C3N4) nanosheets and luminol served as the cathodic and anodic ECL emitters, respectively. K2S2O8 and H2O2 were used as the coreactants for the two emitters. Luminol was first coated on the indium tin oxide (ITO) electrode and used as the internal standard in the ratiometric biosensor. Polyaniline was then electrodeposited on the surface of the luminol-modified electrode to improve the biocompatibility and conductivity of the sensing interfaces. Gold nanoparticles were subsequently modified on the surface of polyaniline to immobilize a DNA aptamer. g-C3N4-heme incubated with different concentrations of Aβ solution to form g-C3N4-heme-Aβ complex, in which Aβ could specifically bind to the DNA aptamer and thus introduce g-C3N4 into the system. As a result, it was observed that the ratio value of ECL intensity (I1/I2) significantly increased with the increase of Aβ concentration. Under the optimized conditions, the biosensor has a good linear response in the range 10 fM to 10 nM with a detection limit of 4.2 fM. Consequently, the ratiometric ECL sensor, characterized by high sensitivity and favorable stability, offers a reliable method for the determination of Aβ.}, } @article {pmid41094020, year = {2025}, author = {Makinde, IA and Hammed, SO and Kumar, N and Kuthi, NA and Umar, HI and Hassan, TA and Kehinde, IO and Bello, RO and Aborode, AT and Jimoh, TO and Mahamat, AO and Khalid, M and Almohammed, OA}, title = {Identification of novel DYRK1A inhibitors as treatment options for alzheimer's disease through comprehensive in silico approaches.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {36114}, pmid = {41094020}, issn = {2045-2322}, support = {ORF-2025-77//King Saud University/ ; }, mesh = {Dyrk Kinases ; *Protein-Tyrosine Kinases/antagonists & inhibitors/chemistry/metabolism ; *Protein Serine-Threonine Kinases/antagonists & inhibitors/chemistry/metabolism ; *Alzheimer Disease/drug therapy ; Quantitative Structure-Activity Relationship ; *Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; Humans ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Benzimidazoles/pharmacology/chemistry ; Computer Simulation ; Aminopyridines/pharmacology/chemistry ; }, abstract = {This study aims to identify potential DYRK1A inhibitors from a curated database and utilize a QSAR model to predict the bioactivity of drug compounds in inhibiting the enzyme involved in tau protein oligomerization, a key process in AD pathology. 192 compounds were sourced from the SuperNatural 3.0 database and docked against DYRK1A using Maestro 12.5. The top five lead compounds and the reference drug Abemaciclib underwent ADMET profiling via the AI Drug Lab Server and a 200 nanosecond molecular dynamics simulation using Desmond. A machine learning-based Quantitative Structure-Activity Relationship (QSAR) analysis was then performed to predict their biological activity based on pIC50 values. The top five compounds, identified as 45,934,388, CNP0344929, CNP0360040, CNP0309850, and CNP0426983, demonstrated binding affinities of -13.337, -12.746, -11.712, -11.656, and - 11.416 kcal/mol, respectively, outperforming Abemaciclib (-6.528 kcal/mol). None of the compounds violated Lipinski's Rule of Five, and all exhibited favorable ADMET profiles, including optimal blood-brain barrier penetration and structural stability. The QSAR model successfully predicted the pIC50 values of the hit compounds (6.16, 5.758, 5.752, 6.003, 5.982), comparable to Abemaciclib (6.32). These findings highlight five promising DYRK1A inhibitors with potential therapeutic applications for AD.}, } @article {pmid41093210, year = {2025}, author = {Manzoor, SI and Ahanger, IA and Kamli, MR and Malik, MA and Dar, TA}, title = {Nano-conjugation of small molecule modulators of protein aggregation: Enhancing the therapeutic precision.}, journal = {International journal of biological macromolecules}, volume = {331}, number = {Pt 2}, pages = {148293}, doi = {10.1016/j.ijbiomac.2025.148293}, pmid = {41093210}, issn = {1879-0003}, mesh = {Humans ; *Protein Aggregates/drug effects ; *Protein Aggregation, Pathological/drug therapy/metabolism ; *Small Molecule Libraries/chemistry/pharmacology/therapeutic use ; Animals ; *Nanoparticles/chemistry ; Precision Medicine ; }, abstract = {Protein aggregation is a central hallmark of several neurodegenerative and systemic diseases, including Alzheimer's, Parkinson's, cataract and type 2 diabetes. Consequently, targeting protein aggregation is emerging as a promising therapeutic strategy for these diseases. Small molecule modulators have exhibited considerable potential in stabilizing native protein conformations and promoting the dissolution of toxic aggregates, leading to delayed disease progression. Some also target proteostatic pathways, promoting clearance of misfolded proteins to prevent further aggregation. Despite being promising, their clinical efficacy often faces challenges due to poor bioavailability, limited stability, and lack of specificity. Recent advances in nanotechnology have introduced nano-conjugation as a potential strategy for maximizing the therapeutic efficacy of these small molecule modulators. By ensuring targeted delivery, increased availability, improved stability and controlled tissue release, nano-conjugation has not only overcome the limitations but also acts as a future pathway to precision medicine in protein aggregation diseases. The present review article provides a comprehensive overview of small molecule modulators of protein aggregation and explores how nano-conjugation enhances their therapeutic efficacy. Moreover, it highlights emerging clinical trials and explores future directions in the application of nano-conjugated small molecule modulators as a potential treatment strategy for protein aggregation diseases.}, } @article {pmid41093142, year = {2026}, author = {Marizzoni, M and Mombelli, E and Alboni, S and Rosa, M and Moretti, DV and Mirabelli, P and Coppola, L and Luongo, D and Salamone, D and Saleri, S and Piazza, F and Begni, V and Salvatore, M and Frisoni, GB and Cattaneo, A}, title = {Microbiota-gut-brain axis dysregulation in Alzheimer's disease and its modulation through probiotic supplementation.}, journal = {Brain, behavior, and immunity}, volume = {131}, number = {}, pages = {106138}, doi = {10.1016/j.bbi.2025.106138}, pmid = {41093142}, issn = {1090-2139}, mesh = {Humans ; *Probiotics/administration & dosage/therapeutic use/pharmacology ; *Alzheimer Disease/microbiology/metabolism ; *Gastrointestinal Microbiome/physiology/drug effects ; Male ; Female ; Aged ; *Brain/metabolism ; *Brain-Gut Axis/physiology ; Middle Aged ; Dietary Supplements ; Inflammation/metabolism ; Feces/microbiology ; Aged, 80 and over ; }, abstract = {BACKGROUND: The microbiota-gut-brain axis (MGBA) has been implicated in the pathophysiology of Alzheimer's Disease (AD).Probiotics reduced the progression of ADin different mouse models, possibly through MGBA modulation, but human data are still limited. OBJECTIVE: Here, we evaluated whether differences in the gut microbiome (GM), pro-inflammatory markers and other MGBA mediators were associated with probable AD (pAD). We also assessed the impact of a 12-week probiotic treatment on MGBA. METHODS: Forty-five pAD patients and 47 healthy subjects (HC) were recruited at IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli of Brescia (Italy). An uncontrolled clinical investigation was performed to test the effects of 12-week probiotic supplementation in the pAD group. Fecal microbiota composition, intestinal and blood inflammatory markers, and microbiota-related metabolites were assessed before supplementation in all participants and after only in pAD. RESULTS: pAD patients showed intestinal inflammation, an altered GM profile, blood changes in the tryptophan metabolism, and reduced glutamate levels compared with HC (p-value < 0.049). Probiotic supplementation partially modulated these alterations, determining a reduction in several pro-inflammatory mediators, and an increase of GM-related protective factors, such as butyrate (p-value < 0.040) in pAD. CONCLUSIONS: These findings confirmed the presence of MGBA alterations in AD and suggested a potential beneficial effect of probiotic supplementation through modulation of GM functionality rather than composition. Further research is required to confirm these results and their clinical relevance.}, } @article {pmid41093115, year = {2026}, author = {Shen, Z and Wu, M and Sun, S and Ling, Y and Chen, X and Zhang, J and Zhou, X and Zhou, C}, title = {Lingguizhugan decoction improves cognitive impairment in APP/PS1 mice by promoting meningeal lymphatic drainage based on fatty acid degradation pathway.}, journal = {Journal of ethnopharmacology}, volume = {355}, number = {Pt B}, pages = {120748}, doi = {10.1016/j.jep.2025.120748}, pmid = {41093115}, issn = {1872-7573}, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Fatty Acids/metabolism ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Male ; *Alzheimer Disease/drug therapy/metabolism ; Disease Models, Animal ; Presenilin-1/genetics ; Mice, Inbred C57BL ; *Lymphatic Vessels/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Brain/drug effects/metabolism ; Molecular Docking Simulation ; Cognition/drug effects ; }, abstract = {Lingguizhugan Decoction (LGZG), a classic traditional Chinese medicine formula, has been demonstrated in numerous studies to possess therapeutic potential for Alzheimer's disease (AD). However, it remains unclear whether its mechanism of action involves the meningeal lymphatic system. AIM OF THE STUDY: Investigate if LGZG improves cognition in APP/PS1 mice by restoring meningeal lymphatic vessels (mLVs) drainage. MATERIALS AND METHODS: Assessed cognitive behavior and pathology in LGZG-treated APP/PS1 mice. Used tracers and immunofluorescence (LYVE-1/TR-d3) to evaluate mLVs drainage and markers. Conducted untargeted brain metabolomics and dura mater micro-proteomics. Performed molecular docking and functional analysis focusing on fatty acid pathways. RESULTS: LGZG ameliorated cognitive impairment and Aβ deposition in mice. Improved Aβ clearance correlated with enhanced mLVs function (confirmed by tracing). Metabolomics and micro-proteomics identified impaired fatty acid degradation as a key pathological factor. LGZG, at clinically relevant doses, restored mLVs drainage and rescued cognition by activating the fatty acid degradation pathway. CONCLUSION: Lingguizhugan Decoction ameliorates AD-like pathologies and cognitive deficits in APP/PS1 mice by enhancing Aβ clearance via regulating the "fatty acid degradation-meningeal lymphatic axis." This finding reveals a novel multi-target mechanism of LGZG and offers a fresh perspective on metabolic intervention for AD treatment.}, } @article {pmid41093093, year = {2025}, author = {Tuo, C and Sui, X and Cui, C and Han, F and Jiao, J and Cai, H and Wu, M}, title = {Pramipexole improves cognitive deficits and synaptic plasticity impairments in 3xTg-AD mice through enhancing autophagy.}, journal = {Experimental neurology}, volume = {395}, number = {}, pages = {115503}, doi = {10.1016/j.expneurol.2025.115503}, pmid = {41093093}, issn = {1090-2430}, abstract = {Autophagy dysfunction plays important roles in the pathogenesis of Alzheimer's disease (AD), and activation of autophagy might be a potential strategy in AD treatment. Although some autophagy inducers play beneficial roles in AD, no autophagy inducer has been available in AD clinical treatment due to lack of efficacy or obvious side effects. A recent study demonstrated that pramipexole (PPX) can activate autophagy in the brain without interfering with protein synthesis, thereby avoiding the side effects associated with prolonged use of an autophagy inducer. However, whether PPX can exert neuroprotective effects on AD and whether its potential mechanism is related to autophagy remains unclear. In the present study, the effects of PPX on the cognitive function of 3xTg-AD mice were observed using multiple behavioral tests, then synaptic plasticity was evaluated through in vivo hippocampal electrophysiological recordings and by measuring synaptic proteins, while Aβ and tau pathologies were detected using immunofluorescence staining and western blot. Finally, autophagy was detected and the potential target was predicted using bioinformatics analysis, qRT-PCR and molecular docking. Results demonstrated that PPX significantly improved cognitive deficits and hippocampal long-term potentiation (LTP) depression, increased the expression of PSD95, reduced Aβ deposition and tau hyperphosphorylation, activated autophagy by increasing LC3-II/LC3-I ratios and decreasing p62 levels, and restored Beclin1 expression. Bioinformatics analysis identified MAPK1 as a key target in PPX-ameliorated AD by enhancing autophagy. These findings suggest that PPX alleviates AD-related cognitive deficits and neuropathologies through increased autophagy, emphasising its potential as a disease-modifying therapeutic strategy for AD.}, } @article {pmid41091591, year = {2025}, author = {Magham, SV and Shanavas, S and Pindiprolu, SSSKS and Nagappan, K and More, S and Chaudhury, D and Ramakkamma, AR and Singh, MT and Wadhwani, A and Bose, B and Thaggikuppe Krishnamurthy, P}, title = {Targeting GSK-3β to Modulate the Wnt Pathway: A Promising Neuroprotective Strategy for Alzheimer's Disease.}, journal = {Molecular pharmaceutics}, volume = {22}, number = {11}, pages = {6561-6574}, doi = {10.1021/acs.molpharmaceut.5c00329}, pmid = {41091591}, issn = {1543-8392}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; Nanoparticles/chemistry ; *Neuroprotective Agents/pharmacology/pharmacokinetics/administration & dosage ; *Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; Rats, Wistar ; *Indoles/pharmacology/chemistry/pharmacokinetics/administration & dosage ; *Wnt Signaling Pathway/drug effects ; Humans ; Male ; Tissue Distribution ; *Oximes/pharmacokinetics/chemistry/pharmacology/administration & dosage ; Brain/metabolism/drug effects ; Stearic Acids/chemistry ; Cell Line, Tumor ; Drug Delivery Systems/methods ; Particle Size ; Liposomes ; }, abstract = {Alzheimer's disease (AD) is marked by amyloid-β plaques and neurofibrillary tangles. Glycogen synthase kinase-3β (GSK-3β) is a promising therapeutic target for mitigating several AD-related pathologies via modulation of the Wnt pathway. However, nonspecific GSK-3β inhibition by indirubin-3'-oxime (IMX) may result in significant off-target effects, necessitating the development of brain-targeted delivery systems. Solid lipid nanoparticles (SLNs) are biocompatible nanocarriers for brain-targeted delivery of therapeutics. Polysorbate 80 (PS80) and stearic acid (SA)-modified SLNs encapsulating IMX (PS80-SA SLNs-IMX) were prepared using the solvent injection method. The formula was optimized using full factorial design (FFD). The optimized formulation was biophysically characterized. The neuroprotective efficacy of PS80-SA SLNs-IMX was then evaluated in vitro using cell lines (IMR-32 & N2a). Biodistribution study was carried out in Wistar rats to evaluate the site-specific distribution of IMX and SLNs. The optimized PS80-SA SLNs-IMX exhibited a particle size of 185.7 ± 2.7 nm, a polydispersity index of 0.22 ± 0.01, a ζ potential of -21.02 ± 1.53 mV, and an entrapment efficiency of 99.4 ± 0.12%. Surface morphology analysis revealed that they are spherical in shape, and in vitro release study revealed the sustained release of PS80-SA SLNs-IMX until 48 h. Accelerated stability study results revealed the formulation stability with negligible changes in the PS, PDI, and ZP up to 6 months. MTT assay results have shown that PS80-SA SLNs-IMX has a negligible cytotoxic effect. ROS and neuroprotective assays have demonstrated antioxidant and neuroprotective effects of PS80-SA SLNs-IMX against OKA-induced neurotoxicity. ELISA depicted a significant reduction in Aβ1-42 and p-tau upon treatment with PS80-SA SLNs-IMX. Western blot analysis confirmed the effect of PS80-SA SLNs-IMX on the inhibition of GSK-3β and the activation of the Wnt pathway. Biodistribution study results revealed that PS80-SA SLNs-IMX has a significant increase in brain concentration when compared to naïve IMX, indicating the brain-specific distribution of PS80-SA SLNs-IMX. In conclusion, PS80-SA SLNs-IMX demonstrated enhanced neuronal cell uptake and significant neuroprotective activity in vitro. To our knowledge, this is the first report of PS80-SA SLNs-IMX with high entrapment and robust neuroprotection in an okadaic acid (OKA)-induced tauopathy model, underscoring the translational potential for AD therapy.}, } @article {pmid41090735, year = {2025}, author = {Shen, X and Li, H and Zhang, B and Li, Y and Zhu, Z}, title = {Tau-Targeted Therapeutic Strategies: Mechanistic Targets, Clinical Pipelines, and Analysis of Failures.}, journal = {Cells}, volume = {14}, number = {19}, pages = {}, pmid = {41090735}, issn = {2073-4409}, support = {A126H5//University of Nottingham/ ; }, mesh = {Humans ; *tau Proteins/metabolism/antagonists & inhibitors ; *Molecular Targeted Therapy ; Animals ; *Alzheimer Disease/metabolism/drug therapy ; Protein Processing, Post-Translational ; *Tauopathies/drug therapy/metabolism ; Phosphorylation ; }, abstract = {Tau protein, a neuron-enriched microtubule-associated protein encoded by the MAPT gene, plays pivotal roles in microtubule stabilisation, axonal transport, and synaptic plasticity. Aberrant post-translational modifications (PTMs), hyperphosphorylation, acetylation, ubiquitination, oxidative stress and neuroinflammation disrupt tau's normal functions, drive its mislocalization, and promote aggregation into neurofibrillary tangles, a hallmark of Alzheimer's disease (AD) and related tauopathies. Over the past two decades, tau-targeted therapies have advanced into clinical development, yet most have failed to demonstrate efficacy in human trials. This review synthesises mechanistic insights into tau biology and pathology, highlighting phosphorylation and acetylation pathways, aggregation-prone motifs, and immune-mediated propagation. We analyse the current therapeutic landscape, including kinase and phosphatase modulators, O-GlcNAcase inhibitors, aggregation blockers, immunotherapies, and microtubule-stabilising agents, while examining representative clinical programs and the reasons underlying their limited success. By combining mechanistic understanding with clinical experience, this review outlines emerging opportunities for rational treatment development, aiming to inform future tau-targeted strategies for AD and other tauopathies.}, } @article {pmid41090155, year = {2025}, author = {Li, JM and Huang, J and Liao, Y and Hu, T and Wang, CL and Zhang, WZ and Huang, CW}, title = {Gene and RNA Editing: Revolutionary Approaches to Treating Diseases.}, journal = {MedComm}, volume = {6}, number = {10}, pages = {e70389}, pmid = {41090155}, issn = {2688-2663}, abstract = {Gene editing and RNA editing technologies are advancing modern medicine by enabling precise manipulation of genetic information at the DNA and RNA levels, respectively. The third-generation gene editing tools, particularly Clustered regularly interspaced shortpalindromic repeats (CRISPR)/CRISPR-associated (Cas) system, have transformed genetic disease treatment with high efficiency, precision, and cost effectiveness, while RNA editing, via adenosine deaminase acting on RNA (ADAR) enzymes and CRISPR-Cas13, offers reversible regulation to avoid genomic integration risks. Despite advancements, challenges persist in delivery efficiency, tissue specificity, and long-term safety, limiting their clinical translation. This review systematically discusses the molecular mechanisms and technological evolution of these tools, focusing on their promising applications in treating nervous system disorders (e.g., Alzheimer's, Parkinson's), immune diseases (e.g., severe combined immunodeficiency, lupus), and cancers. It compares their technical attributes, analyzes ethical and regulatory issues, and highlights synergies between the two technologies. By bridging basic research and clinical translation, this review provides critical insights for advancing precision medicine, reshaping disease diagnosis, prevention, and treatment paradigms.}, } @article {pmid41089659, year = {2025}, author = {Xu, B and Ding, S and Xu, W and Fredericks, C and Zhao, Y}, title = {GenCPM: a toolbox for generalized connectome-based predictive modeling.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1627497}, pmid = {41089659}, issn = {1662-4548}, abstract = {Understanding brain-behavior relationships and predicting cognitive and clinical outcomes from neuromarkers are central tasks in neuroscience. Connectome-based Predictive Modeling (CPM) has been widely adopted to predict behavioral traits from brain connectivity data; however, existing implementations are largely restricted to continuous outcomes, often overlook essential non-imaging covariates, and are difficult to apply in clinical or disease cohort settings. To address these limitations, we present GenCPM, a generalized CPM framework implemented in open-source R software. GenCPM extends traditional CPM by supporting binary, categorical, and time-to-event outcomes and allows the integration of covariates such as demographic and genetic information, thereby improving predictive accuracy and interpretability. To handle high-dimensional data, GenCPM incorporates marginal screening and regularized regression techniques, including LASSO, ridge, and elastic net, for efficient selection of informative brain connections. We demonstrate the utility of GenCPM through analyses of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Study and the Alzheimer's Disease Neuroimaging Initiative (ADNI), showing enhanced predictive performance and improved signal attribution compared to standard methods. GenCPM offers a flexible, scalable, and interpretable solution for predictive modeling in brain connectivity research, supporting broader applications in cognitive and clinical neuroscience.}, } @article {pmid41089460, year = {2025}, author = {Gerasimov, E and Berg, M and Bolshakova, A and Bezprozvanny, I and Vlasova, O}, title = {Chemogenetic Modulation of Astrocytic Activity Rescues Hippocampus Associated Neurodegeneration in Alzheimer's Disease Mice Model 5xFAD.}, journal = {Neural plasticity}, volume = {2025}, number = {}, pages = {9880933}, pmid = {41089460}, issn = {1687-5443}, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy/genetics/physiopathology ; *Astrocytes/drug effects/metabolism ; Mice ; *Hippocampus/drug effects/pathology/metabolism/physiopathology ; *Clozapine/analogs & derivatives/pharmacology ; Mice, Transgenic ; Disease Models, Animal ; Male ; Long-Term Potentiation/drug effects ; Chemogenetics ; }, abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by Aβ-amyloid accumulation and cognitive decline. Despite extensive research, effective treatments remain elusive. Astrocytes, the most abundant glial cells, play a crucial role in synaptic transmission, neuronal excitability, and plasticity. In AD, astrocytes become reactive, exhibiting aberrant calcium signaling and altered neurotransmitter release, making them promising targets for disease-modifying therapies. To address this, we explored designer receptors exclusively activated by designer drugs (DREADDs), specifically the hM3D(Gq) receptor, which selectively modulates intracellular Ca[2+] levels in astrocytes upon activation by clozapine-N-oxide (CNO). Using daily CNO administration in 8-month-old 5xFAD mice, we observed a significant enhancement of impaired long-term potentiation formation, accompanied by cognitive improvements in the fear conditioning (FC) and Morris water maze (MWM) tests. Additionally, anxiety levels and social preference deficits in 5xFAD mice were fully restored following astrocytic activity modulation. Importantly, this approach reduced Aβ-amyloid plaque burden and demonstrated a trend toward mitigating astrocytic reactivity, further highlighting its therapeutic potential. Our findings suggest that targeting astrocytic activity via Gq-coupled receptors represents a novel and promising strategy for AD treatment, offering a noninvasive and effective approach to mitigating disease progression.}, } @article {pmid41088943, year = {2025}, author = {Haseeb, M and Hatiboglu, MA}, title = {Carbon Dot Nanoparticle-based Therapeutic Approaches in Major Neurological Disorders.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575398775250811070903}, pmid = {41088943}, issn = {1875-5607}, abstract = {Neurological disorders (NDs) are diseases that arise due to deformities mainly in the central nervous system (CNS) and also affect the nerves throughout the human body. NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple Sclerosis (MS), and a variety of brain malignancies, pose a major healthcare challenge and are the main cause of mortality on the global scale. There are very limited treatment options for the majority of the NDs, and the currently available drugs commonly fail to penetrate the BBB and deliver the drug to the target effectively. These challenges have necessitated the advent of new drug delivery methods that can cross the BBB with ease and deliver the drug by accurately targeting the diseased area in a safe and biocompatible manner. Nanoparticle-based drug delivery strategies offer significant advantages in BBB penetration and drug delivery due to their unique properties. Carbon dots, among nanoparticles with a size below 10 nm, are highly biocompatible, fluorescent molecules that offer ease of functionalization, drug conjugation, and effective detection within biological systems. The literature is rich in reviews on the synthesis, characterization, and application of CDs. However, a review specifically focused on the therapeutic potential of CDs in major NDs is missing. This review aims to fill that gap by presenting a detailed account of the carbon dot-based therapeutic approaches in the treatment of major NDs. It briefly discusses the properties of CDs, the main routes of synthesis, major raw materials, and key synthesis parameters that affect their properties, while placing a greater emphasis on their therapeutic potential. The review provides a detailed assessment of literature from the past 15 years on the development and current challenges in the application of CDs as therapeutic and drug delivery agents. Our analysis reveals that limited research has been conducted on CD-based therapeutics in NDs, particularly in MS and brain tumors, where original research is scarce. This review article highlights the major developments in the therapeutic uses of carbon dots in NDs, addresses a critical research gap, and provides a comprehensive overview of various studies related to carbon-dot-based therapeutic approaches for major NDs.}, } @article {pmid41088853, year = {2025}, author = {Collij, LE and Mattsson-Carlgren, N and Janelidze, S and Ossenkoppele, R and Hansson, O}, title = {Complementary utility of plasma biomarkers and Aβ-PET for diagnosis, risk-stratification, and treatment monitoring in Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70763}, pmid = {41088853}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/blood/therapy/diagnosis ; *Positron-Emission Tomography ; *Biomarkers/blood ; *Amyloid beta-Peptides/blood/metabolism ; Risk Assessment ; }, abstract = {With the rapid development of blood biomarkers (BBMs) related to amyloid-β (Aβ) pathology in Alzheimer's disease (AD), the question arises whether these can replace the accepted reference standard, positron emission tomography (PET), for assessing Aβ burden. BBMs can differentiate Aβ status reliably in cognitively impaired patients, but two-threshold strategies to further improve their performance demonstrate the need for pathological confirmation by Aβ-PET in a non-negligible portion of individuals (∼10%-40%), especially in early-stage disease where BBM performance declines due to lower AD prevalence, reducing the test's positive predictive value (PPV) and increasing the risk for false-positives. This may be increasingly relevant in the future, considering the development of (very) early interventions against AD. Further, BBMs do not accurately reflect the actual Aβ load or change after immunotherapy. Consequently, there are clear remaining needs for Aβ-PET in several clinically important settings as (i) a confirmatory test and (ii) to determine treatment response. HIGHLIGHTS: When used as stand-alone tests, blood biomarkers (BBMs) demonstrate good sensitivity and specificity (84%-90%) relative to amyloid-β positron emission tomography (Aβ-PET). Two-threshold strategies improve BBM performance but require confirmatory testing by, for example, Aβ-PET in a non-negligible portion of patients that fall in an intermediate range or "gray-zone" (∼10%-40%). In early/preclinical populations, BBM performance declines due to lower AD prevalence, reducing the test's positive predictive value (PPV) and increases the gray-zone population. Currently available BBMs cannot reliably estimate Aβ-PET burden or track Aβ-plaque removal post-immunotherapy.}, } @article {pmid41088262, year = {2025}, author = {Ritchie, M and Hussen, K and Langford, O and Navarro, C and Kotadiya, Z and Donohue, MC and Aisen, P and Sperling, RA and Grill, JD and Raman, R}, title = {Recruitment and retention in a preclinical AD trial: comparisons between academic and non-academic sites.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {222}, pmid = {41088262}, issn = {1758-9193}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; *Patient Selection ; Female ; Aged ; Patient Dropouts/statistics & numerical data ; Academic Medical Centers ; Middle Aged ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) clinical trials enroll participants at various site types including research-focused academic institutions and independent non-academic sites. Limited research has examined the impact of site type on recruitment and retention outcomes. METHODS: To evaluate potential differences between site types, we used data from the Anti-Amyloid Treatment for Asymptomatic AD (A4) trial, the largest completed preclinical AD trial to date. We first compared the frequency of varying recruitment sources between site types. We then examined potential differences in participant- and site-level characteristics. To assess potential site type differences in retention, we fit a multivariable logistic regression model adjusting for variables associated with site type. For participants who prematurely discontinued, we examined potential differences by site type in reasons for dropout. RESULTS: One thousand and fifty-eight participants were randomized at 50 academic (N = 835) and 15 non-academic (N = 223) sites in North America. Academic sites had higher proportions of participants recruited through earned media and organizational referrals and lower proportions recruited through internal referrals and advertisements, compared to non-academic sites. Participant-level characteristics differed between site types. Compared to non-academic sites, academic sites had higher proportions of participants with a family history of dementia and a professional degree (highest education category), but lower proportions of individuals with a history of diabetes, a CDR-SB score above 0, and belonging to a racial and ethnic underrepresented group. Though the results were not statistically significant, non-academic sites had a higher screening rate (number of participants screened/site/month), but a lower randomization rate (randomized/screened) compared to academic sites. No site type differences in completion rates were observed. When examining reasons for discontinuation, we found that among the 72 participants who discontinued the trial at non-academic sites, 56 (77.8%) withdrew consent or were lost to follow up. In contrast, 140 out of 243 (57.6%) participants who discontinued the trial in academic sites withdrew consent or were lost to follow up. CONCLUSION: Our findings shed light on important site type differences that investigators should consider when making choices around site, design, and conduct in multisite preclinical AD trials.}, } @article {pmid41087559, year = {2025}, author = {Alghamdi, AM and Ashraf, MU and Bahaddad, AA and Almarhabi, KA and Al Shehri, WA and Daraz, A}, title = {A novel approach hybrid of ensemble learning and 3-D CNN mechanism: early-stage diagnosis of Alzheimer's disease using EEG signals.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {35893}, pmid = {41087559}, issn = {2045-2322}, support = {UJ-24-SUCH-1247//University of Jeddah/ ; }, mesh = {*Alzheimer Disease/diagnosis/physiopathology ; Humans ; *Electroencephalography/methods ; *Neural Networks, Computer ; *Deep Learning ; Early Diagnosis ; Male ; Aged ; Female ; *Diagnosis, Computer-Assisted/methods ; Ensemble Learning ; }, abstract = {Alzheimer's disease (AD) is a progressive neurological disorder that causes brain cell degeneration and leads to dementia. Early and accurate detection of AD is crucial, as it allows timely treatment before the brain suffers permanent damage. In recent years, computer-aided methods using Artificial Intelligence (AI) have shown promise in improving the diagnosis of AD, healthy cognition (HC), and other types of dementia. However, distinguishing between AD and HC using Electroencephalography (EEG) signals remains challenging, mainly due to difficulties in identifying meaningful features from the signals. To address this issue, we propose a novel method called EDL3DCNN, which combines Ensemble Deep Learning (EDL) with a 3D Convolutional Neural Network (3D-CNN). This model is designed to diagnose and classify AD and HC subjects accurately. We trained and evaluated the model using two publicly available EEG datasets related to AD. The EDL3DCNN model, leveraging multiple 3D-CNN classifiers, achieved a high classification accuracy of 99.02%. Our results demonstrate that integrating EDL with 3D-CNN offers a robust and scalable solution for computer-aided AD diagnosis.}, } @article {pmid41087268, year = {2026}, author = {Liang, T and Liu, S and Dang, B and Luan, X and Guo, Y and Steimbach, RR and Hu, J and Lu, L and Yue, P and Wang, R and Zheng, M and Gao, J and Yin, X and Chen, X}, title = {Corrigendum to 'Multimechanism biological profiling of tetrahydro-β-carboline analogues as selective HDAC6 inhibitors for the treatment of Alzheimer's disease' [Eur. J. Med. Chem. 275 (2024) 116624].}, journal = {European journal of medicinal chemistry}, volume = {301}, number = {}, pages = {118254}, doi = {10.1016/j.ejmech.2025.118254}, pmid = {41087268}, issn = {1768-3254}, } @article {pmid41086934, year = {2025}, author = {Piekarczyk, N and Berezka, P and Majkutewicz, I and Myślińska, D and Kaczor, JJ}, title = {Combined vitamin D3 and dimethyl fumarate treatment alleviates cognitive dysfunction, oxidative stress, and inflammation in a rat model of sporadic Alzheimer's disease.}, journal = {Free radical biology & medicine}, volume = {241}, number = {}, pages = {748-759}, doi = {10.1016/j.freeradbiomed.2025.10.259}, pmid = {41086934}, issn = {1873-4596}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/pathology/metabolism ; Oxidative Stress/drug effects ; Rats ; *Cholecalciferol/pharmacology/administration & dosage ; *Dimethyl Fumarate/pharmacology/administration & dosage ; Male ; *Cognitive Dysfunction/drug therapy/pathology/metabolism/chemically induced ; Rats, Wistar ; Disease Models, Animal ; Streptozocin/toxicity ; Hippocampus/drug effects/metabolism/pathology ; *Inflammation/drug therapy/pathology ; tau Proteins/metabolism/genetics ; Glutathione/metabolism ; Antioxidants ; Neuroprotective Agents/pharmacology ; Drug Therapy, Combination ; }, abstract = {Alzheimer's disease (AD) concerns early oxidative and inflammatory disturbances that accelerate tau pathology and cognitive decline. We investigated whether combined treatment with vitamin D3 (VitD3) and dimethyl fumarate (DMF), two agents with complementary antioxidant and immunomodulatory actions, provides additive neuroprotection in the intracerebroventricular streptozotocin (ICV-STZ) rat model of sporadic AD. Male Wistar rats (n = 50) were divided into SHAM, STZ, VITD (STZ + VitD3 2000 IU/kg), DMF (STZ + DMF 50 mg/kg), or COMBO (STZ + VitD3+DMF) groups and treated orally for 90 days. Spatial learning and memory were assessed in the Morris Water Maze. Hippocampal oxidative stress indices (8-isoprostanes (8-Izo)), glutathione (GSH), glutathione disulfide (GSSG), and -SH groups and tau phosphorylation (pTau Ser396) were measured, and circulating vitamin D metabolites quantified by LC-MS/MS. STZ-induced cognitive impairment, elevated lipid peroxidation, increased the GSSG/GSH ratio, and raised pTau in CA1-CA3. VitD3 or DMF each improved acquisition and attenuated the 8-Izo increase; DMF normalized glutathione redox parameters, whereas VitD3 alone decreased GSH despite reducing lipid peroxidation. The COMBO provided the most consistent behavioral improvement and mitigated region-specific pTau elevations while maintaining redox balance. VitD3 treatment increased 25(OH)D3 and 3-epi-25(OH)D3 and reduced the 24,25(OH)2D3/25(OH)D3 ratio, indicating altered vitamin D metabolism. All treated groups showed a decrease in plasma TNF-α. These findings suggest that simultaneous modulation of vitamin D signaling and DMF may synergistically target oxidative, inflammatory, and tau-related mechanisms involved in sporadic AD. Future research should clarify brain-region vitamin D metabolite dynamics and the long-term impacts on protein thiol levels and cognitive function.}, } @article {pmid41085546, year = {2025}, author = {Chander, R and Sharma, R and Agnihotri, VK}, title = {Natural β-citronellol derivatives as potential dual enzyme inhibitors for the treatment of type 2 diabetes and Alzheimer's diseases.}, journal = {Natural product research}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/14786419.2025.2572038}, pmid = {41085546}, issn = {1478-6427}, abstract = {Effective strategies for treating type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) involve inhibition of α-amylase, α-glucosidase for T2DM and block acetylcholinesterase (AChE) enzymes for treating AD. To explore this potential natural β-citronellol, isolated from Dracocephalum heterophyllum Benth essential oil, was derivatized to yield three derivatives (Compounds 2-4), analysed using NMR and GC-MS techniques. The results showed that compounds 2 and 4 had the most significant α-glucosidase and AChE inhibition. Parent compound 1, along with 3 and 4, displayed the highest α-amylase inhibition. Network pharmacology identified CXCR4 (score: 14) and PIK3CA (score: 12) as top-ranked targets. These findings suggest that PIK3CA, which regulates glucose metabolism, insulin signalling, and cell survival, while CXCR4 suggests potential for neuroprotective and anti-inflammatory roles. Structure-activity relationship indicated that alkoxy group functionalization at β-carbon of β-citronellol is essential for activity. It highlights, a single β-citronellol derivative can manage dual T2DM and AD diseases.}, } @article {pmid41085520, year = {2025}, author = {Mathai, A and Kannoth, S and Nambiar, V and Gopinath, S and Thevarkalam, M and Anandakuttan, A and Kalingavarman, S and Mony, U and Raj, M and Bhaskaran, R}, title = {Immune system modifications in atypical parkinsonism related to autoimmunity - a case control study.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-6}, doi = {10.1080/17582024.2025.2573597}, pmid = {41085520}, issn = {1758-2032}, abstract = {BACKGROUND: Inflammation is known in atypical parkinsonism (AP), but the role of autoimmunity is unclear. This study evaluates immune system modifications suggesting autoimmunity in AP. METHODS: Included patients with AP diagnosed at Amrita Institute of Medical Sciences, Kochi (December 2018-May 2019), and age- and sex-matched controls. Fifteen immune parameters, including T regulatory cells, RORγt, and cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IL-21, IL-22, IL-23, TNF, IFN-γ, GM-CSF, NF-κB, TGF-β), were assessed in peripheral blood (flow cytometry and ELISA). RESULTS: Twenty-six cases (mean age 67.8 ± 7.5 years; 16 males) and 15 controls (mean age 68.1 ± 3.5 years; 10 males) studied. Diagnoses included progressive supranuclear palsy (n = 15), multiple system atrophy (n = 1), frontotemporal dementia with parkinsonism (n = 2), and unspecified AP (n = 8). AP cases had significantly higher RORγt (p = 0.041), IL-6 (p = 0.004), TNF (p = 0.020), IL-10 (p = 0.027), and IL-4 (p = 0.048). CONCLUSIONS: Elevated RORγt and cytokines suggest immune dysregulation and possible autoimmune mechanisms in AP, warranting further investigation.}, } @article {pmid41085169, year = {2025}, author = {Ismail, Z and Sivananthan, S and Main, S and Ménard, A and McLaren-Beato, J and Chambers, LW and Welch, V and Vedel, I and Smith, EE and Ewa, V and Feldman, S}, title = {Culturally sensitive CLEAR guidelines on disclosing and communicating a diagnosis of dementia.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70744}, pmid = {41085169}, issn = {1552-5279}, support = {P004637//Public Health Agency of Canada/ ; BMS-20-002//Academic Health Science Centre (AHSC)/ ; //University of Toronto Academic Health Science Centre (AHSC) Alternative Funding Plan (AFP) Innovation Fund./ ; }, mesh = {Humans ; *Dementia/diagnosis/psychology/ethnology ; Canada ; *Communication ; *Disclosure ; *Cultural Competency ; *Physician-Patient Relations ; *Truth Disclosure ; Primary Health Care ; *Practice Guidelines as Topic ; *Culturally Competent Care ; }, abstract = {Providing a dementia diagnosis is challenging, especially in primary care and considering diverse patient backgrounds. The Alzheimer Society of Canada (ASC), the College of Family Physicians of Canada, and the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD) guideline group partnered with patients, care partners, and clinicians to generate contemporaneous guidance for primary care practitioners. While relevant to all communities, Black and Chinese Canadians were formally represented in working groups. A literature review identified needs areas. Informed by Guidelines International Network (GIN) principles and through iterative group meetings with all partners, these needs were explored and incorporated into guidance. The Compassionate Language and Empathetic Approaches for Respectful Dementia Disclosure (CLEAR) offers recommendations on: holistic engagement, fostering hope, acknowledging care partners, identifying disclosing clinicians, appointment structure and environment, person-centered communication, specific discussion topics, and emotional supports, all through a cultural competence lens. These guidelines address communication challenges in disclosing a dementia diagnosis and enhancing care and support for persons living with dementia and their care partners. HIGHLIGHTS: Healthcare practitioners (HCPs) struggle with disclosing and communicating dementia diagnoses. Guidance is limited in primary care and different patient ethnocultural groups. We developed culturally sensitive guidelines with scripts and practical materials. Appropriate communication techniques and terminology are recommended in Compassionate Language and Empathetic Approaches for Respectful Dementia Disclosure (CLEAR). Patient-centered and holistic approaches for the patient and care partner are emphasized.}, } @article {pmid41085158, year = {2025}, author = {Fischer, DL and Grinberg, LT and Ahrendsen, JT and Beach, TG and Bieniek, KF and Castellani, RJ and Chkheidze, R and Cobos, I and Cohen, M and Crary, JF and Dickson, DW and Dugger, BN and Dunlop, SR and Farrell, K and Ghetti, B and Haeri, M and Harrison, W and Head, E and Hiniker, A and Huang, EJ and Huttner, A and Jamshidi, P and Kapasi, A and Keene, CD and Kofler, J and Latimer, CS and McKee, AC and Mente, K and Miller, MB and Montine, TJ and Morris, M and Murray, ME and Nelson, PT and Newell, KL and Perrin, RJ and Ramani, B and Reichard, RR and Roy, S and Schlachetzki, JCM and Seeley, WW and Serrano, GE and Spina, S and Teich, AF and Wang, SJ and Wisniewski, T and Lee, EB}, title = {Celebrating neuropathology's contributions to Alzheimer's Disease Research Centers.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70734}, pmid = {41085158}, issn = {1552-5279}, support = {UE5NS070680/GF/NIH HHS/United States ; R01AG075802/GF/NIH HHS/United States ; P30AG072976/GF/NIH HHS/United States ; P30AG019610/GF/NIH HHS/United States ; P30AG072980/GF/NIH HHS/United States ; P30AG072977/GF/NIH HHS/United States ; P30AG066515/GF/NIH HHS/United States ; P30AG066514/GF/NIH HHS/United States ; R01AG054008/GF/NIH HHS/United States ; R01NS095252/GF/NIH HHS/United States ; R01AG062348/GF/NIH HHS/United States ; P30AG062677/GF/NIH HHS/United States ; R01AG062517/GF/NIH HHS/United States ; U24NS133949/GF/NIH HHS/United States ; P30AG072972/GF/NIH HHS/United States ; K01AG070326/GF/NIH HHS/United States ; RF1NS128908/GF/NIH HHS/United States ; P30AG066508/GF/NIH HHS/United States ; P30AG072947/GF/NIH HHS/United States ; R24AG073199/GF/NIH HHS/United States ; P30AG066509/GF/NIH HHS/United States ; P30AG062715/GF/NIH HHS/United States ; U19AG066567/GF/NIH HHS/United States ; U19AG060909/GF/NIH HHS/United States ; UM1MH130981/GF/NIH HHS/United States ; UM1MH134812/GF/NIH HHS/United States ; U24AG072458/GF/NIH HHS/United States ; U24NS133945/GF/NIH HHS/United States ; U24NS135651/GF/NIH HHS/United States ; R24AG073137/GF/NIH HHS/United States ; U01NS137500/GF/NIH HHS/United States ; U01NS137484/GF/NIH HHS/United States ; U01AG082350/GF/NIH HHS/United States ; R01AG082730/GF/NIH HHS/United States ; R01AG087226/GF/NIH HHS/United States ; R01AG088656/GF/NIH HHS/United States ; R01AG060942/GF/NIH HHS/United States ; R01AG080585/GF/NIH HHS/United States ; R01NS129609/GF/NIH HHS/United States ; R01AG069912/GF/NIH HHS/United States ; P30AG066468/GF/NIH HHS/United States ; U19AG068054/GF/NIH HHS/United States ; R01MH116046/GF/NIH HHS/United States ; R01AG090551/GF/NIH HHS/United States ; P30AG072959/GF/NIH HHS/United States ; DP2AG086138/GF/NIH HHS/United States ; R01AG082346/GF/NIH HHS/United States ; P30AG066507/GF/NIH HHS/United States ; P01AG003991/GF/NIH HHS/United States ; P30AG066444/GF/NIH HHS/United States ; U19AG024904/GF/NIH HHS/United States ; U19AG032438/GF/NIH HHS/United States ; R01AG068319/GF/NIH HHS/United States ; R01AG053267/GF/NIH HHS/United States ; R01NS111978/GF/NIH HHS/United States ; UF1NS120463/GF/NIH HHS/United States ; P50AG023501/GF/NIH HHS/United States ; P01AG019724/GF/NIH HHS/United States ; U01AG057195/GF/NIH HHS/United States ; U19AG063911/GF/NIH HHS/United States ; P30AG072958/GF/NIH HHS/United States ; P30AG066512/GF/NIH HHS/United States ; R01AG077422/GF/NIH HHS/United States ; U01OH012486/GF/NIH HHS/United States ; U24NS135568/GF/NIH HHS/United States ; R01AG087280/GF/NIH HHS/United States ; R13AG059336/GF/NIH HHS/United States ; P30AG072979/GF/NIH HHS/United States ; P01AG066597/GF/NIH HHS/United States ; P01AG084497/GF/NIH HHS/United States ; RF1AG065341/GF/NIH HHS/United States ; P30AG062429/GF/NIH HHS/United States ; P30AG062421/GF/NIH HHS/United States ; P30AG066530/GF/NIH HHS/United States ; P30AG066518/GF/NIH HHS/United States ; P30AG066462/GF/NIH HHS/United States ; P30AG072975/GF/NIH HHS/United States ; P30AG072978/GF/NIH HHS/United States ; P30AG066519/GF/NIH HHS/United States ; P30AG079280/GF/NIH HHS/United States ; P30AG062422/GF/NIH HHS/United States ; P30AG066511/GF/NIH HHS/United States ; P30AG072946/GF/NIH HHS/United States ; P30AG072973/GF/NIH HHS/United States ; P30AG066506/GF/NIH HHS/United States ; P30AG072931/GF/NIH HHS/United States ; P30AG066546/GF/NIH HHS/United States ; P30AG086401/GF/NIH HHS/United States ; P30AG086404/GF/NIH HHS/United States ; P20AG068082/GF/NIH HHS/United States ; /ALZ/Alzheimer's Association/United States ; //The Fred and Barbara Erb Family Foundation/ ; //Rainwater Charitable Trust/Tau Consortium/ ; //Karen Strauss Cook Research Scholar Award/ ; //Rainwater Charitable Trust/ ; SG-25-1416824//Alzheimer's Association Florida Gulf Coast/ ; 2024-351073//Chan Zuckerberg Initiative/ ; //Silicon Valley Community Foundation/ ; 685-2023-06//CurePSP/ ; //Allen Institute for Brain Science/ ; //Nancy and Buster Alvord Endowment/ ; //Shanahan Family Foundation/ ; //Barrist Family Foundation/ ; W81XWH-21-S-TBIPH2//U.S. Department of Defense/ ; //Stuart Katz and Dr. Jane Martin/ ; //10,000 Brains NeuroAI Inc/ ; //DeCrane Family Fund for PPA Research/ ; //Bluefield Project to Cure FTD/ ; }, mesh = {Humans ; *Alzheimer Disease/pathology ; *Biomedical Research/history ; History, 20th Century ; History, 21st Century ; National Institute on Aging (U.S.) ; *Neuropathology/history ; United States ; }, abstract = {Our understanding of Alzheimer's disease (AD) and related dementias (ADRD) has grown exponentially, thanks to significant investments by the National Institute on Aging (NIA). This article celebrates the 40th anniversary of the NIA's Alzheimer's Disease Research Centers, highlighting the pivotal role of neuropathology as the bedrock for neurodegeneration research. Neuropathology has championed the key principles of proteinopathy, selective vulnerability, and stereotypic spread. Furthermore, neuropathologic studies advanced our understanding of ADRD prevalence, heterogeneity, clinical-pathological correlations, and genetic underpinnings, spurring biomarker development for target engagement and disease monitoring. Disease-modifying therapies for AD were inspired and informed by neuropathology. The neuropathology community is poised to refine diagnostics, leveraging digital pathology and integrating genetics and pathomics to enhance subtyping for novel precision medicine approaches. Despite some common misconceptions and logistical challenges, neuropathology continues to be a critical component of the ADRD research infrastructure, serving as a key bridge between allied basic and clinical sciences. HIGHLIGHTS: We celebrate 40 years of NIA-funded ADRCs and their contributions through neuropathology studies that have significantly advanced our understanding and treatment of ADRD. Neuropathology uncovers principles of neurodegenerative disease: proteinopathy, selective vulnerability, and stereotypic spread, informing diagnostics and therapies. Development of AD biomarkers with reference to neuropathology enhances accuracy in diagnosis and monitoring, paving the way for targeted disease-modifying therapies. Integration of digital pathology, genetics, and novel tools in neurodegeneration research promises advanced precision medicine approaches and refined diagnostics. Misconceptions and logistical challenges to neuropathological research are addressed to improve understanding and collaboration.}, } @article {pmid41085151, year = {2025}, author = {Zhu, CW and Flournoy, C and Raman, R and Sano, M}, title = {Employment, volunteering, and health-related resource use in pre-symptomatic AD: Results from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70641}, pmid = {41085151}, issn = {1552-5279}, support = {P30 AG066514/AG/NIA NIH HHS/United States ; U19AG010483/AG/NIA NIH HHS/United States ; R01AG063689/AG/NIA NIH HHS/United States ; U24AG057437/AG/NIA NIH HHS/United States ; //Eli Lilly/ ; NIRG-12-243012/ALZ/Alzheimer's Association/United States ; //GHR Foundation/ ; //C.W.Z. and M.S. are also supported by the Department of Veterans Affairs, Veterans Health Administration/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Female ; *Employment/statistics & numerical data ; Aged ; Longitudinal Studies ; *Volunteers/statistics & numerical data ; Prodromal Symptoms ; }, abstract = {INTRODUCTION: Little is known about productive time use and health-related resource use during "pre-symptomatic" AD, defined by the presence of brain amyloid in the absence of cognitive symptoms. We compared changes in resource use and participation in paid employment and/or volunteering in cognitively unimpaired older adults with amyloid accumulation (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease [A4] study, N = 1165) to otherwise matched participants without amyloid accumulation (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration [LEARN] study, N = 507). METHODS: Health-related resource use was self-reported using the Resource Use Inventory (RUI). Longitudinal analyses examined effect on RUI from study (A4 vs LEARN), time, and their interaction, controlling for Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (ADCS-PACC) and the Clinical Dementia Rating (CDR) scale, and their change scores from baseline. RESULTS: Over time, paid employment and volunteering decreased, and unpaid help and hospitalization increased. Results showed clear associations between ADCS-PACC and CDR with RUI. DISCUSSION: Little detectable impact of amyloid levels on RUI was found in pre-symptomatic AD that has been identified as an ideal stage to target for dementia prevention. HIGHLIGHTS: Using data from a cohort of cognitively unimpaired older adults with evidence of amyloid accumulation enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study and otherwise matched participants who did not meet subthreshold levels of amyloid accumulation enrolled in the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study, this study showed clear associations between clinical variables and resource use and participation in paid employment and volunteering but suggested little detectable impact of amyloid levels on rate of change during the preclinical stage. Our results suggest that economic benefits from currently available treatment that effectively removes amyloid may not be immediately or concurrently observed during the short timeline of clinical trials. It is critical that our examination of economic consequence of treatment include broad ranges of items on resource use and productivity loss, longer time horizon, and that we balance between cost of detection, treatment, and burden and benefit.}, } @article {pmid41085131, year = {2025}, author = {Bauer, A and Rabe, C and Schiffman, C and Rose, F and Respondek, G and Gullotta, F and Schlieker, L and Jethwa, A and Schrurs, I and Manuilova, E and Ostrowitzki, S and Bittner, T}, title = {Blood-based pre-screening in the SKYLINE secondary prevention Ph3 gantenerumab study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70676}, pmid = {41085131}, issn = {1552-5279}, support = {//F. Hoffmann-La Roche Ltd/ ; //Roche Diagnostics International Ltd (Rotkreuz, Switzerland)/ ; }, mesh = {Humans ; *Alzheimer Disease/blood/drug therapy/diagnosis/prevention & control ; *tau Proteins/blood ; Female ; Biomarkers/blood/cerebrospinal fluid ; Male ; Retrospective Studies ; Aged ; *Secondary Prevention/methods ; Amyloid beta-Peptides/blood ; Apolipoprotein E4/blood ; Positron-Emission Tomography ; *Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {INTRODUCTION: SKYLINE was a secondary prevention study that used blood-based biomarker (BBBM) pre-screening to screen out participants with a low likelihood of amyloid positivity by positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. METHODS: This retrospective analysis used data from SKYLINE (ClinicalTrials.gov: NCT05256134; terminated prematurely) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study to compare predicted and actual clinical performance characteristics of various biomarker combinations using prototype Elecsys[®] plasma immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). RESULTS: In >3500 participants screened in SKYLINE, tau phosphorylated at threonine 181 (pTau181) and apolipoprotein E4 protein (ApoE4p) was the highest-performing BBBM combination. Actual clinical performance of the BBBM pre-screening in SKYLINE was similar to predictions based on A4 in terms of screen-out rate, positive predictive value, and 1-negative predictive value. DISCUSSION: BBBM pre-screening in SKYLINE using prototype plasma pTau181 and ApoE4p immunoassays effectively alleviated participant burden by avoiding unnecessary PET or CSF testing. HIGHLIGHTS: We compared blood-based biomarker (BBBM) performance in SKYLINE and Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4). Pre-screening improved amyloid positivity (defined by positron emission tomography/cerebrospinal fluid) screen failure rate. Tau phosphorylated at threonine 181 (pTau181) and apolipoprotein E4 protein was the highest-performing combination among BBBMs tested. Pre-screening eased participant burden by reducing subsequent screening procedures.}, } @article {pmid41084412, year = {2025}, author = {Lee, A and Al-Dahwi, S and Angell, T and Arulalagan, A and Bloxsom, R and Clarkson, H and Faure, R and Goodarzi, S and Gupta, M and Kale, A and Lam, K and Mahon-Daly, F and Parry, C and Pradhan, V and Ryan-Phillips, F and Shah, S and Sidhu, S and Smiddy, J and Sridhar, A and Tahmid, SF and Wight, R and Roberts, N and Topiwala, A}, title = {A systematic review of brain health in adults with chronic pain.}, journal = {Anaesthesia}, volume = {}, number = {}, pages = {}, doi = {10.1111/anae.70021}, pmid = {41084412}, issn = {1365-2044}, abstract = {INTRODUCTION: Recent research has linked chronic pain with an increased risk of clinical dementia diagnosis. Yet structural and functional brain changes associated with chronic pain and their potential role in accelerating brain ageing have not been characterised comprehensively. Understanding these effects is crucial to developing targeted prevention and management strategies. METHODS: We conducted a systematic review of all English language articles in MEDLINE and Embase. Studies were eligible if they compared neuroimaging, clinical, biological, cognitive or mental health outcomes in adults with chronic pain to healthy controls. Following screening, data were extracted and the risk of bias was assessed. RESULTS: Of 5805 identified studies, 365 met the inclusion criteria. Most were cross-sectional studies with small sample sizes; conducted in middle-aged populations in China or the USA; had moderate to high risk of bias; and represented > 30 distinct pain phenotypes. Magnetic resonance imaging was the most common method for assessing brain health. Key findings in patients with chronic pain included: lower grey matter volumes and reduced fractional anisotropy; evidence of accelerated brain ageing including older brain age and higher white matter hyperintensities; mixed results in resting state functional connectivity; increased power densities and connectivity on electroencephalography; and higher levels of serum brain-derived neurotrophic factor. The most consistently affected brain regions across magnetic resonance imaging studies were the insula; anterior and posterior cingulate; thalamus; hippocampus; primary motor cortex; and cerebellum. DISCUSSION: Adults with chronic pain exhibit widespread alterations in brain health compared with healthy controls. Several observed features overlap with biomarkers of Alzheimer's disease and other forms of neurodegeneration. These findings highlight the need for larger, well-designed studies incorporating clearly defined pain phenotypes, multimodal imaging and causal inference methods to clarify the role of chronic pain in brain ageing and dementia risk.}, } @article {pmid41084258, year = {2025}, author = {Raabe, AC and Correa, RAS and Rodrigues, CCPR and Vieira, RP}, title = {History, Challenges, and Perspectives of CNS-Targeted Transdermal Formulations.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128409331250915220233}, pmid = {41084258}, issn = {1873-4286}, abstract = {Central nervous system (CNS) disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Schizophrenia (Sch) present significant challenges for healthcare systems, both in terms of prevalence and the complexity of pharmacological treatment. While current therapies offer symptomatic relief, there is a high rate of failure in addressing the full spectrum of clinical symptoms and patient adherence issues, especially in long-term care. Since ancient times, various civilizations, including the Chinese, Egyptians, and indigenous South African cultures, have investigated and utilized the transdermal route for therapeutic and medicinal applications. Recent advances in transdermal drug delivery systems (TDS) offer a promising alternative to traditional routes of administration, enhancing drug absorption and minimizing side effects, such as gastrointestinal distress. This review explores the potential of TDS for improving the pharmacotherapy of AD, PD, and Sch. We also highlight the ongoing challenges in optimizing TDS formulations, such as drug absorption through the skin, skin irritation, and maintaining therapeutic efficacy. Furthermore, the review discusses the progress in prodrug design strategies aimed at enhancing skin permeation and bioavailability, particularly in the context of CNS-targeted drugs. The need for continued research into TDS technology is emphasized, as it holds promise for improving treatment adherence, patient quality of life, and caregiver burden, thereby advancing therapeutic options for CNS disorders.}, } @article {pmid41084249, year = {2025}, author = {Tamaddon-Abibigloo, Y and Dastmalchi, S and Mahdipanah, F and Asadi, E and Khezrpour, S and Valizadeh, P and Shahbazi-Mojarrad, J}, title = {Isatin Derivatives as Emerging Promising Anti-Alzheimer Agents: Focusing on Their Chemical Structure and Biological Targets.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266394265250828164308}, pmid = {41084249}, issn = {1873-4294}, abstract = {Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder with a complex pathology. Until now, there is no generally effective treatment for AD. Isatin is a natural alkaloid whose derivatives have shown a wide spectrum of biological activities. This molecule is also the basic scaffold for several compounds with useful biological properties against AD. In this review, for the first time, we focus on the anti-AD properties of isatin derivatives. We tried to present comprehensive data about their structure and mechanism of action. Results showed that indirubins, isatin Schiff Bases, and spiro derivatives of isatin were the most studied molecules. The most studied targets were the glycogen synthase kinase-3, cholinesterases, and amyloid beta aggregation. It was concluded that isatin could be considered an important scaffold for the development of new anti-AD compounds.}, } @article {pmid41082949, year = {2025}, author = {Ye, Q and Gast, G and Holmes, TC and Xu, X}, title = {Hippocampal neural circuit mechanisms in Alzheimer's disease revealed by viral-genetic circuit mapping.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107139}, doi = {10.1016/j.nbd.2025.107139}, pmid = {41082949}, issn = {1095-953X}, mesh = {*Alzheimer Disease/genetics/pathology/physiopathology ; Animals ; *Hippocampus/pathology/physiopathology/virology ; Humans ; Disease Models, Animal ; *Nerve Net/pathology/physiopathology ; Mice ; Rabies virus/genetics ; Neural Pathways/pathology/physiopathology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts in countries with aging populations. Existing therapeutic approaches that have been based on neurochemical and neuropathological findings are largely ineffective. This lack of progress suggests we require a new framework for future AD therapies. The examination of neural circuit mechanisms in AD mouse models is an emerging focus for identifying new AD treatment strategies. We now know there are neural circuit-level maladaptive alterations in AD brains, some of which appear very early in the disease process before neuropathological features are detectable. Recent advancements in viral-genetic technologies allow us to quantitatively map the cell-type-specific neural circuit connections in AD mouse models. Monosynaptic rabies virus mapping reveals age-progressive changes in both long-range and local hippocampal neural circuit connectivity in AD mouse models - and provides explanations for human AD behavioral defects, such as sex differences and higher level visual deficits. These recent developments in neural circuits level concepts and technology present new opportunities for studying AD pathogenesis for early identification of the disease and for developing novel therapeutic interventions.}, } @article {pmid41082483, year = {2025}, author = {Hao, X and Ding, N and Zhang, Y and Wu, M and Ning, Y and Wang, Z and Li, Z}, title = {Acupuncture Strategies in a Mouse Model of Alzheimer's Disease.}, journal = {Journal of visualized experiments : JoVE}, volume = {}, number = {223}, pages = {}, doi = {10.3791/68809}, pmid = {41082483}, issn = {1940-087X}, mesh = {*Alzheimer Disease/therapy/microbiology ; Animals ; *Acupuncture Therapy/methods/instrumentation ; Mice ; Disease Models, Animal ; Brain ; Male ; Gastrointestinal Microbiome/physiology ; Mice, Inbred C57BL ; Intestines/microbiology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease. Numerous studies have demonstrated that alterations in intestinal flora can influence the central nervous system (CNS) through multiple pathways, ultimately contributing to the onset and progression of AD. Recent research suggests the limitations of pharmacological therapies, emphasizing the need for multi-targeted interventions in AD treatment. Traditional Chinese medicine (TCM) highlights the physiological and pathological relationship between the brain and the intestine. Therefore, therapeutic strategies targeting gastrointestinal regulation to enhance brain function are of great importance for delaying the pathological progression of AD. This protocol introduces a brain-intestine coordination acupuncture method. The experimental results showed that this acupuncture protocol could modulate intestinal flora, suppress intestinal inflammation and neuroinflammation in AD model mice, thereby achieving bidirectional therapeutic effects on brain-intestine regulation. Moreover, a mouse bag fixation device for acupuncture treatment was described in this study, which can reduce stress reaction and improve experimental efficiency.}, } @article {pmid41082320, year = {2025}, author = {Verrienti, G and Lombardozzi, G and Albergo, G and De Filippis, S}, title = {Trazodone in neurology, a new life for an old molecule - an updated, comprehensive, systematic review of clinical trials.}, journal = {International journal of psychiatry in clinical practice}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/13651501.2025.2572291}, pmid = {41082320}, issn = {1471-1788}, abstract = {INTRODUCTION: The triazolopyridine derivative trazodone is approved for the treatment of major depressive disorder (MDD) in adults; according to the available literature, this molecule, through a specific dose-dependent profile of action, was found to be a potential therapeutic option in some neurological conditions. This systematic review aimed to synthesise the available evidence on the use of trazodone in neurological patients. METHODS: PubMed was searched for articles published from inception until March 2025. Article reference lists were screened, and relevant articles were retrieved for consultation. Clinical trials specifically investigating trazodone in neurological populations were included, following PRISMA guidelines for systematic reviews. RESULTS: Out of 69 records initially retrieved, 14 studies met the inclusion criteria, comprising 13 randomised controlled trials and 1 retrospective study, with a total of 608 patients. Most of the included studies focused on individuals with dementia, while others explored its use in different neurological disorders. CONCLUSIONS: Despite being an older antidepressant, trazodone remains widely prescribed. Beyond treating depression in neurological patients, it may may be useful in the treatment of some neurological aspects. However, current evidence remains limited. Further high-quality research is necessary to better define the therapeutic potential of trazodone in the management of neurological conditions.}, } @article {pmid41082199, year = {2025}, author = {Lu, M and Kim, MJ and Collins, EC and Shcherbinin, S and Ellinwood, AK and Yokoi, Y and Brooks, DA and Hansson, O and Knopman, DS and Sims, JR and Mintun, MA}, title = {Posttreatment Amyloid Levels and Clinical Outcomes Following Donanemab for Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ 2 Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {82}, number = {12}, pages = {1251-1256}, pmid = {41082199}, issn = {2168-6157}, mesh = {Humans ; Aged ; Female ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; Male ; Aged, 80 and over ; Middle Aged ; tau Proteins/metabolism ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; Double-Blind Method ; Treatment Outcome ; Biomarkers/blood ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Plaque, Amyloid/drug therapy/metabolism ; }, abstract = {IMPORTANCE: Accumulation of amyloid plaque drives pathogenesis of Alzheimer disease (AD). Reduction of amyloid via amyloid-targeting therapies may result in clinical benefit. OBJECTIVE: To assess the correlation of posttreatment amyloid levels with clinical outcomes and biomarkers in AD. This was a post hoc exploratory analysis from the randomized, placebo-controlled phase 3 trial, TRAILBLAZER-ALZ 2, conducted June 2020 through April 2023 at 277 medical research centers/hospitals in 8 countries. A total of 8240 participants aged 60 to 85 years with early symptomatic AD with amyloid and tau pathology based on positron emission tomography (PET) imaging were assessed for eligibility. Of these, 6504 participants were excluded predominantly due to inadequate amyloid or tau pathology. The current analysis included 1582 participants (766 in the donanemab group and 816 in the placebo group) with baseline and at least 1 posttreatment assessment. Data analysis took place from July 2024 to March 2025. INTERVENTIONS: Participants were randomized 1:1 to receive donanemab (700 mg for the first 3 doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks, with outcomes assessed through 76 weeks. MAIN OUTCOMES AND MEASURES: Participants were categorized into 1 of 10 groups (deciles) based on their lowest amyloid value observed posttreatment. Clinical progression was assessed via changes in integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores. Plasma biomarkers measured included phosphorylated tau 217 (p-tau217), p-tau181, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Correlations between the median amyloid level in each decile were assessed with 76-week least-squares mean changes in each outcome and biomarker. RESULTS: Analyses included 1582 participants, including 766 treated with donanemab and 816 with placebo. The mean (SD) age was 72.9 (6.2) years, and 900 participants (56.9%) were female. Participants who received donanemab had lower posttreatment amyloid values than those in the placebo group. Across the trial population, lower posttreatment amyloid levels were correlated with slower clinical progression as measured by iADRS score (R2, 0.73 [95% CI, 0.37-0.97]) and CDR-SB score (R2, 0.87 [95% CI, 0.70-0.97]) and with decreases in p-tau217 (R2, 0.86 [95% CI, 0.73-0.97]), p-tau181 (R2, 0.88 [95% CI, 0.77-0.97]), and GFAP (R2, 0.87 [95% CI, 0.76-0.97]). There was no correlation between posttreatment amyloid value and NfL (R2, 0.03 [95% CI, 0.00-0.54]). CONCLUSIONS AND RELEVANCE: The findings in this secondary analysis of a randomized clinical trial demonstrating a correlation between posttreatment amyloid plaque level and clinical benefit support amyloid plaque removal as the mechanism of action for donanemab treatment and the level of amyloid plaque as a potential surrogate biomarker in amyloid-targeting therapies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04437511.}, } @article {pmid41082159, year = {2025}, author = {Ntondini, TL and Naki, T and Alven, S}, title = {The therapeutic efficacy of nanoparticles in the treatment of alzheimer's disease.}, journal = {Acta neurologica Belgica}, volume = {}, number = {}, pages = {}, pmid = {41082159}, issn = {2240-2993}, abstract = {The build-up of beta-amyloid plaques in the brain leads to Alzheimer's disease (AD), a neurodegenerative condition. AD affects more than 30 million individuals globally every year. No cure for AD has been discovered yet. The available therapeutic options are administered to slow down the progress of the disease. The currently available treatment plans are used to relieve symptoms and improve cognitive abilities, thus slowing progression. Nanotechnology is highly effective and has demonstrated significant benefits across various medical applications. Nanoparticles have been explored as promising drug delivery systems for the targeted delivery of anti-AD therapeutics and for the precise diagnosis of the condition. Nanoparticles, such as dendrimers, lipid-based nanoparticles, polymer-based nanoparticles, and metal-based nanoparticles, have been designed and reported to inhibit Aβ aggregation, fibril formation, and disaggregating mature fibrils, prevent neuroinflammation and Aβ1-42-induced cell damage, treat oxidative stress and lower hallmark of Aβ, and display excellent capability to bypass blood-brain barrier (BBB). This review is focused on the preclinical therapeutic outcomes of nanoparticles and the challenges encountered in the treatment of AD. This review highlights the significant advancements of nanoparticles that are currently undergoing clinical trials for management of AD.}, } @article {pmid41081549, year = {2025}, author = {Bellio, TA and Krunic, A and Campion, MS and Dupaguntla, R and Labadorf, A and Stein, TD and Lin, H and Mellott, TJ and Blusztajn, JK}, title = {Perinatal Choline Supplementation Promotes Resilience Against Progression of Alzheimer's Disease-Like Brain Transcriptomic Signatures in App[NL-G-F] Mice.}, journal = {Aging cell}, volume = {24}, number = {11}, pages = {e70148}, pmid = {41081549}, issn = {1474-9726}, support = {RF1 AG057768/AG/NIA NIH HHS/United States ; //NIH Office of Dietary Supplements/ ; R21 AG056901/NH/NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; R21 AG059195/AG/NIA NIH HHS/United States ; RF1 AG057768/NH/NIH HHS/United States ; RF1 AG078299/NH/NIH HHS/United States ; R01 AG045031/AG/NIA NIH HHS/United States ; R21 AG056901/AG/NIA NIH HHS/United States ; R01 AG045031/NH/NIH HHS/United States ; R21 AG 059195/NH/NIH HHS/United States ; RF1 AG078299/AG/NIA NIH HHS/United States ; P30 AG072978/NH/NIH HHS/United States ; }, mesh = {Animals ; *Choline/pharmacology/therapeutic use/administration & dosage ; *Alzheimer Disease/genetics/pathology/metabolism ; Mice ; *Dietary Supplements ; *Transcriptome/drug effects ; Female ; *Brain/metabolism/drug effects/pathology ; Disease Models, Animal ; Disease Progression ; Mice, Transgenic ; Humans ; Male ; }, abstract = {Alzheimer's disease (AD)-the leading cause of dementia-has no cure, inadequate treatment options, and a limited understanding of prevention measures. We have previously shown that perinatal dietary supplementation with the nutrient choline ameliorates cognitive deficits and reduces amyloidosis across the brain in App[NL-G-F] AD model mice. Here, we analyzed transcriptomic abnormalities in these mice and tested the hypothesis that they may be attenuated by perinatal choline supplementation (PCS). Wild-type (WT) and App[NL-G-F] dams consumed a diet containing 1.1 (control) or 5 g/kg (supplemented) of choline chloride from 2 weeks prior to mating until weaning. At 3, 6, 9, or 12 months of age, the offspring RNA was sequenced in the hippocampus and cerebral cortex. As compared to WT, the App[NL-G-F] mice reared on the control diet had age-dependent upregulation of expression of mRNAs and lncRNAs related to inflammation and reduced expression of mRNAs related to neuronal function. As compared to App[NL-G-F] mice on the control diet, PCS App[NL-G-F] mice increased expression of synaptic genes and downregulated inflammation-related genes starting at 6 months in the cortex; increased expression of GABAergic function and ATP metabolism genes, and decreased expression of inflammatory genes in the hippocampus at 12 months. These changes counteracted the effects of App[NL-G-F] genotype seen in mice on the control diet. The expression of many of these choline-protected genes correlated with clinical dementia rating, inflammation, and tauopathy in human postmortem dorsolateral prefrontal cortex AD samples, indicating their relevance to the disease process. The results suggest that adequate choline intake could be a preventive strategy for AD.}, } @article {pmid41080679, year = {2025}, author = {Mishra, K and Tripathi, S and Tiwari, AK and Rana, R and Yadav, P and Chourasia, MK}, title = {Cerium-based nanoparticles for neurodegeneration: emerging redox therapeutics beyond pharmaceuticals.}, journal = {RSC advances}, volume = {15}, number = {45}, pages = {37540-37569}, pmid = {41080679}, issn = {2046-2069}, abstract = {Delivering therapeutic agents across the blood-brain barrier (BBB) remains a formidable hurdle in the treatment of neurodegenerative diseases, which are primarily driven by mitochondrial dysfunction, oxidative stress, and neuroinflammation. Although our understanding of these disease mechanisms has advanced, effective treatments are still limited due to the restrictive nature of the BBB. In this context, nanotechnology has emerged as a promising approach, offering engineered nanocarriers capable of traversing the BBB and enabling targeted drug delivery to the brain. Amongst the various nanomaterials explored, cerium-based nanoparticles have gained particular attention as promising candidates for neurodegenerative disease therapy. Their multifunctionality stemming from reversible redox behaviour, enzyme-mimicking activity, sustained antioxidant effects, and anti-inflammatory properties, combined with their ability to penetrate the BBB and provide neuroprotection, positions them as a powerful platform for future therapeutic strategies. This review begins with a concise overview of the shared pathological mechanisms underlying neurodegenerative diseases, highlights BBB-related drug delivery challenges, and discusses nanocarrier strategies for brain targeting, focusing on cerium-based nanoparticles. We then delved into the structural features, synthesis techniques, and distinctive redox properties of cerium-based nanomaterials, with emphasis on cerium oxide and cerium vanadate. Their therapeutic potential is explored across Alzheimer's and Parkinson's diseases, as well as in stroke, multiple sclerosis, and glioblastoma. Key insights into their physicochemical properties, BBB permeability, and neuroprotective mechanisms are provided. We also address current limitations, including nanoparticle stability, toxicity, and translational barriers, and conclude with future directions for optimizing cerium-based nanozymes in neurotherapeutics.}, } @article {pmid41079916, year = {2025}, author = {Alba, LCO and Anlacan, VMM and Navarra, CJA and Jamora, RDG}, title = {YouTube as an educational resource: Evaluating the quality and reliability of videos for family caregivers of persons living with Alzheimer's disease dementia.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251368887}, pmid = {41079916}, issn = {2542-4823}, abstract = {BACKGROUND: YouTube is increasingly used by patients and caregivers as a source of health information. However, the quality and reliability of content on Alzheimer's disease dementia (ADD) remain uncertain. OBJECTIVE: This study aimed to determine whether YouTube videos on ADD provide reliable and high-quality information for caregivers and to assess whether the most popular videos are also the most trustworthy. METHODS: In December 2024, YouTube was systematically searched for ADD-related videos. Two independent physicians reviewed each video, scoring it using modified DISCERN (mDISCERN) for reliability and the Global Quality Scale (GQS) for content quality. Videos were categorized by goal and assessed for quality, accuracy, comprehensiveness, and specific content. RESULTS: There were 117 videos included in the study. Using the mDISCERN scale, 70 videos (59.8%) were deemed with good reliability, 33 videos (28.2%) have moderate reliability, and 14 videos (12%) have poor reliability. Using the GQS, 61 videos (51.1%) have high quality, 16 videos (28%) were assessed as excellent quality, 34 videos (29%) as moderate quality, and 7 videos (6%) as low quality. Videos from academic institutions, news agency and physicians exhibited higher mDISCERN and GQS scores compared to other groups and a significant correlation was seen between mDISCERN and GQS (p < 0.001). CONCLUSIONS: The videos on ADD produced by healthcare professionals and academic institutions have high quality and good reliability, covering disease properties, treatment choices, and patient experiences. However, video popularity does not significantly correlate with content reliability and quality.}, } @article {pmid41078387, year = {2025}, author = {Zapata-Restrepo, LM and Miller, BL and Rivas, J and Possin, K and Valcour, V and Piña-Escudero, SD and Ibañez, A and Kosik, KS}, title = {Case of early onset Alzheimer's disease associated with a novel PSEN1 variant identified in Colombia.}, journal = {NPJ dementia}, volume = {1}, number = {1}, pages = {31}, pmid = {41078387}, issn = {3005-1940}, abstract = {Early-onset Alzheimer's disease (EOAD) is a rare form of dementia that often progresses more quickly than late-onset cases, and is more commonly associated with autosomal dominant mutations. A 47-year-old male presented with progressive cognitive and behavioral decline, a family history of EOAD, and was later found to have a novel pathogenic PSEN1 variant (c.519 G > T, p.Leu173Phe). Initial evaluations, including neuroimaging and laboratory tests, were unremarkable. Neuropsychological testing later revealed memory impairment, executive dysfunction, and neuropsychiatric symptoms. These features, alongside the identified mutation, are consistent with phenotypic presentations of EOAD involving the third transmembrane domain of PSEN1. Pharmacological treatment with cholinesterase inhibitors and antipsychotics yielded limited benefit. Notably, the extended follow-up time, of more than 10 years from the early symptomatic stage, is a unique and valuable feature of this case study, providing rare longitudinal insight into the natural course of genetically confirmed EOAD.}, } @article {pmid41078145, year = {2025}, author = {Wang, F and Liu, J and Bai, D and Li, L and Fedgchin, M and Henley, D and Li, H and Zhang, F}, title = {A Phase 1 Study of the Pharmacokinetics, Safety, and Tolerability of Posdinemab (JNJ-63733657) in Healthy Chinese Adults.}, journal = {Journal of clinical pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1002/jcph.70116}, pmid = {41078145}, issn = {1552-4604}, support = {//Johnson & Johnson/ ; }, abstract = {Posdinemab, a humanized immunoglobulin G1/κ monoclonal antibody, binds with high affinity to phosphorylated tau protein which is associated with Alzheimer's disease (AD) pathophysiology. Posdinemab reduced tau seeding in murine models and was well tolerated in Phase-1 clinical studies. This open-label, single-arm, Phase-1 study examined the effects of posdinemab with single intravenous dose (60 mg/kg) in healthy adults from China. The main objectives were to assess posdinemab serum pharmacokinetics (PK, primary), safety and tolerability (secondary), and presence of anti-drug antibodies (ADAs; secondary). Results were compared with Phase-1 European first-in-human (NCT03375697) and Japanese (NCT03689153) studies. Healthy Chinese participants (N = 10), mean age 60.0 (SD 3.80) years and 60% female, received posdinemab. Mean posdinemab serum Cmax was 1401 µg/mL, median tmax was 0.08 days, mean AUCinf was 18162 µg·day/mL, mean CL was 3.36 mL/day/kg, and mean elimination t1/2 was 17.5 days. Most participants (n = 8; 80%) experienced ≥1 treatment-emergent adverse event (TEAEs), most common (20%) of which were arthralgia and back pain. Four participants (40.0%) were positive for posdinemab ADAs post-dose with peak titers of 1:22.5 (n = 3) and 1:360 (n = 1). Serum posdinemab concentrations in ADA-positive and ADA-negative participants were generally comparable. In conclusion, PK profile of posdinemab in healthy participants from China was in the expected range and comparable to previous Phase-1 studies in Europe and Japan. There were no new safety concerns. These results support further global development of posdinemab in AD.}, } @article {pmid41077117, year = {2025}, author = {Elamin, SA and Al Shibli, AN and Shaito, A and Al-Maadhadi, MJMB and Zolezzi, M and Pedersen, S}, title = {Anti-amyloid monoclonal antibody therapies in Alzheimer's disease - a scoping review.}, journal = {Neuroscience}, volume = {589}, number = {}, pages = {50-61}, doi = {10.1016/j.neuroscience.2025.10.011}, pmid = {41077117}, issn = {1873-7544}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide, and with advancements in the medical field, Anti-amyloid monoclonal antibodies (AA mAbs) targeting amyloid-β have emerged as potential disease-modifying agents altering AD pathology. This scoping review mapped the characteristics, patterns, and gaps in clinical trials investigating the efficacy and safety of AA mAbs in AD treatments, with focus on cognitive, functional, biochemical, imaging, and safety outcomes. It highlighted patterns, gaps, and limitations of the existing literature. A systematic search of PubMed/MEDLINE, Embase, Scopus, and Web of Science was conducted for studies published since inception to February 2022, and eligible studies that investigated efficacy and safety outcomes of AA mAbs in treatment of AD were included. A majority of the included trials reported a combination of cognitive, functional, biochemical, and imaging outcomes. Across the sample, reductions in amyloid burden were frequently reported (10 trials), with a smaller subset of studies reporting significant cognitive and functional improvements (4 trials), primarily lecanemab and aducanumab in addition to one pooled analysis of solanezumab. ARIA-E and ARIA-H were frequently reported among the safety concerns, particularly in high-dose and APOE ε4 carrier populations. Notable limitations were observed in the reviewed literature including a disconnect between biomarker changes and consistent clinical benefits and, importantly, limited population diversity and patient-reported outcomes. This review highlights the need for rigorous, diverse, and patient-centered research. Addressing these gaps is critical in ensuring safe, effective, and equitable treatment for all patients living with Alzheimer's disease.}, } @article {pmid41076749, year = {2025}, author = {Kunath, N and Ramfjord, HAB and Kvisvik, EV and Konyves-Kolonics, M and Rolfseng Grøntvedt, G and Serysheva, II and Komorowski, L and Wildemann, B and Jarius, S}, title = {ITPR1 autoantibody-associated autoimmunity as a cause of newly emerging cognitive decline mimicking Alzheimer's disease: Case report and brief review of the literature.}, journal = {Journal of neuroimmunology}, volume = {409}, number = {}, pages = {578774}, doi = {10.1016/j.jneuroim.2025.578774}, pmid = {41076749}, issn = {1872-8421}, mesh = {Humans ; Middle Aged ; *Alzheimer Disease/diagnosis/immunology/diagnostic imaging ; *Autoantibodies/blood/immunology ; *Autoimmunity/immunology ; *Cognitive Dysfunction/immunology/blood/diagnosis/etiology/diagnostic imaging ; Diagnosis, Differential ; *Inositol 1,4,5-Trisphosphate Receptors/immunology ; }, abstract = {BACKGROUND: Since its first description in 2014, anti-inositol 1,4,5-trisphosphate receptor type 1 (ITPR1, also termed IP3R1) autoimmunity has been recognized as causing a clinically heterogeneous spectrum of symptoms. While first described in patients with autoimmune cerebellar ataxia, this facultative paraneoplastic disease has been associated also with peripheral neuropathy, dysautonomia, sleep disorders, neuropsychiatric/psychotic symptoms, and cognitive decline. METHODS: Retrospective case study. RESULTS: We report the case of a 58-year-old patient who was admitted with acute confusion, rapidly progressive cognitive decline, and hallucinations. A history of mild cognitive impairment over several years and low cerebrospinal fluid (CSF) amyloid beta-42 and elevated CSF tau protein were suggestive of Alzheimer's disease (AD). However, pleocytosis, intrathecal IgG synthesis and blood-CSF barrier dysfunction prompted screening for antineuronal antibodies, which revealed ITPR1-IgG1/anti-Sj antibodies in both serum and CSF. Brain MRI showed limbic hyperintensities and hippocampal atrophy. No neoplastic disease was found. Immunosuppressive treatment stabilized the disease course but did not lead to symptom improvement. CONCLUSIONS: This case underscores the clinical importance of CSF analysis and testing for anti-neural autoantibodies, including less common reactivities, in case of rapid cognitive decline even in patients with known or suspected neurodegenerative disease, such as AD, with ITPR1 representing a novel autoimmune target antigen.}, } @article {pmid41076604, year = {2025}, author = {Ebadpour, N and Abavisani, M and Karav, S and Kesharwani, P and Sahebkar, A}, title = {Exosome/Extracellular Vesicles-Based Therapeutics in Alzheimer's Disease: Neuroprotective Roles and Future Perspectives.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {4}, pages = {137}, pmid = {41076604}, issn = {1559-1166}, mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; *Exosomes/metabolism/transplantation ; *Extracellular Vesicles/metabolism/transplantation ; Animals ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is marked by memory loss, cognitive decline, and characteristic pathological features including β-amyloid (Aβ) plaques, tau tangles, and neuroinflammation. Despite extensive research, effective therapies remain elusive. Exosome/EVs-based therapeutics have emerged as a promising avenue for AD treatment. Neuron-derived exosomes/extracellular vesicles (EVs) (NDEs) and stem cell-derived exosomes/EVs exhibit neuroprotective effects by promoting Aβ degradation, modulating tau pathology, and reducing inflammation. Notably, NDEs carry insulin-degrading enzyme (IDE) and cellular prion proteins (PrPC), aiding Aβ clearance. However, exosomes also present challenges, such as the potential propagation of pathogenic tau and complement-mediated neurotoxicity. Neural and mesenchymal stem cell-derived exosomes further demonstrate therapeutic efficacy by altering amyloid precursor protein processing and activating PI3K/Akt/mTOR signaling to reduce AD pathology. Despite these advancements, clinical translation requires a deeper understanding of exosome/EVs biology, improved isolation techniques, and personalized strategies. Continued research may establish exosomes as a transformative approach in AD therapy.}, } @article {pmid41076002, year = {2025}, author = {Pantiya, P and Chattipakorn, N and Chattipakorn, SC}, title = {Exploring the role of CD147 in cerebrovascular and Alzheimer's pathologies: Insights into mechanisms and interventions.}, journal = {Experimental neurology}, volume = {395}, number = {}, pages = {115498}, doi = {10.1016/j.expneurol.2025.115498}, pmid = {41076002}, issn = {1090-2430}, abstract = {Cluster of Differentiation 147 (CD147), a multifunctional transmembrane glycoprotein, has been identified as a key regulator in the pathophysiology of cerebrovascular diseases and Alzheimer's disease (AD). In cerebrovascular diseases, CD147 contributes to neurological dysfunction by modulating pathways related to extracellular matrix remodeling, angiogenesis, and neuroinflammation. In AD, CD147 exhibits a complex, context-dependent role. Upregulation of CD147 has been implicated in increased amyloid-beta (Aβ) production and impaired energy metabolism, both of which contribute to cognitive decline. Paradoxically, other studies suggest that CD147 may exert neuroprotective effects by promoting Aβ degradation and preserving blood-brain barrier (BBB) integrity. These contradictory findings highlight the dualistic nature of CD147's functions, suggesting it may act as both a pathogenic and protective factor in AD. As evidence regarding its roles continues to grow, a more integrated understanding is needed to determine whether CD147 should be pursued as a viable biomarker or therapeutic target in cerebrovascular and neurodegenerative diseases. Therefore, this review aims to comprehensively synthesize current findings from clinical data, animal models, and in vitro studies to elucidate CD147's functions in cerebrovascular disease and AD. Additionally, we explore emerging therapeutic strategies targeting CD147-related pathways, which may offer promising avenues for neuroprotection.}, } @article {pmid41075815, year = {2025}, author = {Wu, JY and Lin, YM and Hsu, WH and Liu, TH and Tsai, YW and Huang, PY and Chuang, MH and Yu, T and Lai, CC}, title = {Glucagon-Like Peptide-1 Receptor Agonists and Dementia Risk Reduction in Older Adults With Type 2 Diabetes: A Retrospective Cohort Study.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {12}, pages = {105901}, doi = {10.1016/j.jamda.2025.105901}, pmid = {41075815}, issn = {1538-9375}, mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy ; Aged ; Retrospective Studies ; Male ; Female ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Dementia/prevention & control/epidemiology ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Aged, 80 and over ; *Hypoglycemic Agents/therapeutic use ; Propensity Score ; *Risk Reduction Behavior ; }, abstract = {OBJECTIVE: To evaluate the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on dementia risk compared with dipeptidyl peptidase-4 inhibitors (DPP-4is) among older adults with type 2 diabetes (T2D). DESIGN: Retrospective cohort study using an active-comparator, new-user design with propensity score matching. SETTING AND PARTICIPANTS: Data were obtained from the TriNetX Global Collaborative Network, which includes electronic health records from 134 health care organizations worldwide. Participants were adults aged ≥65 years with T2D who initiated GLP-1RA or DPP-4i therapy between January 2017 and November 2024. METHODS: Eligible participants were matched 1:1 on baseline characteristics using propensity score matching (PSM). The primary outcome was incident dementia. Secondary outcomes included prescriptions for dementia-related drugs, Alzheimer's disease, and vascular dementia. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, and subgroup and sensitivity analyses were performed. RESULTS: After PSM, 82,689 patients were included in each treatment group. GLP-1RA use was associated with a lower risk of dementia compared with DPP-4i (HR, 0.58; 95% CI, 0.55-0.61; P < .0001). Stratified analyses revealed consistent risk reductions across age, sex, and GLP-1RA type. In addition, GLP-1RA was also associated with lower risks of dementia-related drug prescriptions (HR, 0.76; 95% CI, 0.70-0.81), Alzheimer's disease (HR, 0.62; 95% CI, 0.56-0.70), and vascular dementia (HR, 0.62; 95% CI, 0.55-0.70). Sensitivity analyses supported the robustness of these findings. CONCLUSIONS AND IMPLICATIONS: GLP-1RA use in older adults with T2D is associated with a significantly lower risk of dementia compared with DPP-4i. These findings suggest the potential neuroprotective benefits of GLP-1RAs and highlight their importance in managing T2D with a view toward reducing dementia risk. Further studies are warranted to explore the underlying mechanisms and validate these observations in randomized controlled trials.}, } @article {pmid41075024, year = {2025}, author = {Abedimanesh, N and Miri, SA and Mohammadi, A and Shahmohammadi, F and Danafar, H and Eskandari, MR and Hejazi, S and Andalib, S and Motlagh, B}, title = {Protective and therapeutic effects of betanin nanoparticles in an alzheimer's rat model: modulation of behavior and expression of AQP4, BDNF, SIRT6, and Seladin-1.}, journal = {Metabolic brain disease}, volume = {40}, number = {7}, pages = {286}, pmid = {41075024}, issn = {1573-7365}, support = {A-12-898-19//The Vice Chancellor for Research of Zanjan University of Medical Sciences, Zanjan, Iran/ ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/genetics/metabolism/biosynthesis ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; *Nanoparticles/administration & dosage ; *Sirtuins/genetics/biosynthesis/metabolism ; *Neuroprotective Agents/administration & dosage/pharmacology/therapeutic use ; Male ; *Aquaporin 4/genetics/biosynthesis/metabolism ; *Betacyanins/administration & dosage/therapeutic use/pharmacology ; *Nerve Tissue Proteins/biosynthesis/genetics/metabolism ; Disease Models, Animal ; Hippocampus/metabolism/drug effects ; Microfilament Proteins/biosynthesis/genetics/metabolism ; Antioxidants ; Behavior, Animal/drug effects ; Maze Learning/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, oxidative stress, and neuroinflammation. Betanin, a natural antioxidant, has shown neuroprotective potential, but its clinical use is limited by poor bioavailability. This study investigates the effects of betanin-loaded nanomicelles, designed to enhance brain delivery, in a scopolamine-induced rat model of AD. Nanomicelles were synthesized and characterized using TEM, DLS, and FT-IR. Rats received either pre- or post-treatment with betanin nanomicelles, free betanin, donepezil, or saline. Cognitive performance was assessed using the Morris Water Maze. Gene expression levels of AQP4, BDNF, SIRT6, and Seladin-1 were measured using real-time PCR, and antioxidant activity was evaluated by assessing glutathione (GSH) and glutathione reductase (GR) in hippocampal tissue. Betanin nanomicelles improved spatial memory, increased BDNF and SIRT6 expression, and reduced AQP4 levels, indicating potential neuroprotection. Seladin-1 expression was notably elevated in the pre-treatment group, suggesting support for neuronal survival. Antioxidant assays showed restoration of GSH and GR activity. These findings suggest that betanin nanomicelles may enhance cognitive function and modulate neuroprotective pathways more effectively than free betanin, supporting their potential as a novel therapeutic strategy for AD.}, } @article {pmid41074172, year = {2025}, author = {Chen, J and Zhang, X and Sun, J and Zhi, Y and Xie, Z and Guan, Y and Zhang, Z and Wu, C}, title = {Photothermal nano-agents: an innovative trident weapon for accurate and effective treatment of alzheimer's disease.}, journal = {Journal of nanobiotechnology}, volume = {23}, number = {1}, pages = {650}, pmid = {41074172}, issn = {1477-3155}, support = {82404876//National Natural Science Foundation of China/ ; 2024M760845//China Postdoctoral Science Foundation/ ; 2025T181064//China Postdoctoral Special Funding Project/ ; 232301420087//The Joint Fund of Science and Technology Development Program of Henan Province/ ; HN2025064//Postdoctoral funding in Henan Province/ ; }, mesh = {*Alzheimer Disease/therapy ; Humans ; *Photothermal Therapy/methods ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Infrared Rays ; *Nanoparticles/chemistry/therapeutic use ; Brain/metabolism ; Phototherapy/methods ; }, abstract = {Alzheimer's disease (AD) is a degenerative neurological illness for which effective therapy alternatives are currently lacking. Photothermal therapy (PTT) employs the localized thermal effects of nano-photothermal agents (NPTAs) under near-infrared (NIR) light for the treatment of diverse conditions. PTT presents numerous benefits for AD therapy, including operational flexibility, non-invasiveness, spatiotemporal modulation, and synergistic multimodal treatment approaches. The primary mechanisms of PTT for AD treatment encompass the following facets: Initially, localized heat impacts may transiently disrupt the blood-brain barrier (BBB), facilitating the trans-BBB transport of therapeutic medicines. Secondly, the photothermal action can efficiently dissociate Aβ aggregates and Tau protein while inhibiting Aβ aggregation, hence diminishing neurotoxicity and reinstating cognitive function. Third, during PTT, NPTAs can achieve imaging of biomarkers such as Aβ and Tau at the site of AD lesions and actively monitor the therapy process. Despite being in its nascent stages for AD treatment and encountering numerous challenges, such as poor biocompatibility, inadequate penetration of deep brain tissue by NIR light, and cumulative toxicity risks, PTT remains a promising therapeutic strategy to overcome the limitations of AD treatment. This study elucidates the pathophysiology of AD, the processes by which NPTAs enter the brain, and the mechanism of NPTAs in AD theranostics, with a particular focus on current developments in NIR-activated NPTAs for AD treatment. It further discusses the challenges in this emerging field and proposes future research directions, thereby facilitating the clinical translation of PTT-based strategies in AD treatment.}, } @article {pmid41073674, year = {2025}, author = {Woo, MS and Therriault, J and Hosseini, SA and Wang, YT and Macedo, AC and Rahmouni, N and Aumont, É and Servaes, S and Tissot, C and Fernandez-Arias, J and Trudel, L and Hall, B and Bezgin, G and Quispialaya-Socualaya, K and Goncalves, M and Chan, T and Stevenson, J and Zheng, Y and Mitchell, S and Hopewell, R and Pola, I and Tan, K and Di Molfetta, G and Lussier, FZ and Massarweh, G and Vitali, P and Soucy, JP and Gauthier, S and Ashton, NJ and Blennow, K and Pascoal, TA and Zetterberg, H and Benedet, AL and Rosa-Neto, P}, title = {Glia inflammation and cell death pathways drive disease progression in preclinical and early AD.}, journal = {EMBO molecular medicine}, volume = {17}, number = {11}, pages = {3064-3079}, pmid = {41073674}, issn = {1757-4684}, support = {MOP-11-51-31; RFN 152985, 159815, 162303//Canadian Government | Canadian Institutes of Health Research (CIHR)/ ; MOP-11-51-31 -team 1//Canadian Consortium of Neurodegeneration and Aging/ ; NIRG-12-92090, NIRP-12-259245//Alzheimer's Association (AA)/ ; #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C//Alzheimer's Association (AA)/ ; ZEN-21-848495, SG-23-1038904 QC//Alzheimer's Association (AA)/ ; CFI Project 34874; 33397//Brain Canada Foundation/ ; 2020-VICO-279314//FRQ | Fonds de Recherche du Québec - Santé (FRQS)/ ; IT27627//Mitacs Graduate Fellowship/ ; F225864C02//Max E Binz Fellowship-Medicine/ ; M159875C51//Grad Excellence Award in Neurology and Neurosurgery/ ; 2023_EKMS.03//Else Kröner Fresenius Foundation/ ; WO 2835/1-1//Deutsche Forschungsgemeinschaft (DFG)/ ; S0199/10110/2025//Corona-Stiftung (Corona Foundation)/ ; #2023-00356, #2022-01018 and #2019-02397//Swedish Research Council/ ; #2017-00915 and #2022-00732//Swedish Research Council/ ; 101053962//European Union Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//Alzheimer Drug Discovery Foundation, USA/ ; #22HLT07//European Partnership on Metrology (EPM)/ ; #FO2022-0270//Swedish State/ ; #ALZ2022-0006, #FO2024-0048-TK-130 and FO2024-0048-HK-24//Swedish State/ ; 860197//European Union's Horizon 2020 research and innovation programme Marie Sklodowska-Curie grant/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//UK Dementia Research Institute (UK DRI)/ ; #AF-930351, #AF-939721, #AF-968270, and #AF-994551//Swedish Alzheimer Foundation/ ; #ALFGBG-965240 and #ALFGBG-1006418//ALF agreement/ ; JPND2019-466-236//European Union Joint Programme for Neurodegenerative Disorders/ ; }, mesh = {Humans ; *Neuroglia/pathology/metabolism ; *Alzheimer Disease/pathology ; Disease Progression ; *Cell Death ; *Inflammation/pathology ; Amyloid beta-Peptides/metabolism ; Female ; Male ; Proteomics ; Brain/pathology/diagnostic imaging ; Aged ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; *Neuroinflammatory Diseases/pathology ; }, abstract = {Accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are followed by the activation of glia cells and infiltration of peripheral immune cells that collectively accelerate neurodegeneration in preclinical AD models. Yet, the role of neuroinflammation for neuronal injury and disease progression in preclinical and early symptomatic AD remains elusive. Here, we combined multiplexed immunoassays and SomaScan proteomics of the cerebrospinal fluid (CSF) with MRI and PET brain imaging of people across the AD continuum to identify pathways that are associated with AD progression. Unbiased clustering revealed that glia-mediated inflammation, activation of cell death pathways (CDPs) and synaptic pathologies were among the earliest Aβ-induced changes, and were associated with disease progression in preclinical AD. Mediation analysis revealed that activation of CDPs were decisive drivers of inflammation in early symptomatic AD. The cycle of glia-mediated neuroinflammation and neuronal injury characterizes preclinical AD and has implications for novel treatment approaches.}, } @article {pmid41073581, year = {2025}, author = {Lanskey, JH and Jafarian, A and Hughes, LE and Karadag, M and Kocagoncu, E and Rouse, MA and Adams, NE and Naessens, M and Raymont, V and Woolrich, M and Singh, KD and Henson, RN and Rowe, JB}, title = {Alzheimer's disease and memantine effects on NMDA-receptor blockade: non-invasive in vivo insights from magnetoencephalography.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {41073581}, issn = {1476-5578}, support = {ARUK-PG2017B-19//Alzheimer's Research UK (ARUK)/ ; 220258/WT_/Wellcome Trust/United Kingdom ; SUAG/092 G116788; SUAG/096 G116788//RCUK | MRC | Medical Research Foundation/ ; }, abstract = {To accelerate new treatments for Alzheimer's disease, there is the need for human pathophysiological biomarkers that are sensitive to treatment and disease mechanisms. In this proof-of-concept study, we assess new biophysical models of non-invasive human MEG imaging to test the pharmacological and disease modulation of NMDA-receptor inhibition. Magnetoencephalography was recorded during an auditory mismatch negativity paradigm from (1) neurologically-healthy people on memantine or placebo (n = 19, placebo-controlled crossover design); (2) people with Alzheimer's disease at baseline and 16-months (n = 42, amyloid-biomarker positive, longitudinal observational design). Optimised dynamic causal models inferred voltage-dependent NMDA-receptor blockade using Parametric Empirical Bayes to test group effects. The mismatch negativity amplitude was attenuated when Alzheimer's disease was more severe (lower baseline mini-mental state examination) and after follow-up (versus baseline). Memantine increased NMDA-receptor inhibition, compared to placebo. Alzheimer's disease reduced NMDA-receptor inhibition in proportion to severity and over time. In line with preclinical studies, we confirm in humans that memantine and Alzheimer's disease have opposing effects on NMDA-receptor inhibition. The ability to infer such receptor dynamics and pharmacology from non-invasive physiological recordings has wide applications, including the assessment of other neurological disorders and novel drugs intended for symptomatic or disease-modifying treatments.}, } @article {pmid41073019, year = {2025}, author = {Li, A and Yu, Y and Zhang, Z and Wufuer, R and Wang, D and Zhang, L}, title = {Pd-modified MXene enabled electrochemical sensing platform for ratiometric detection of acetylcholinesterase inhibitors via modulation effect of Prussian blue.}, journal = {Analytica chimica acta}, volume = {1376}, number = {}, pages = {344625}, doi = {10.1016/j.aca.2025.344625}, pmid = {41073019}, issn = {1873-4324}, mesh = {*Ferrocyanides/chemistry ; *Electrochemical Techniques/methods ; *Cholinesterase Inhibitors/analysis ; *Palladium/chemistry ; Acetylcholinesterase/metabolism ; Humans ; Limit of Detection ; *Nanocomposites/chemistry ; *Metal Nanoparticles/chemistry ; Electrodes ; Nitrites ; Transition Elements ; }, abstract = {BACKGROUND: Sensitive detection of acetylcholinesterase (AChE) inhibitors is crucial for pharmaceutical screening, managing neurodegenerative diseases, and drug development. However, their therapeutic use is often limited by toxicity and side effects. Current detection methods for AChE inhibitors suffer from issues like low sensitivity, high cost, and interference from complex biological matrices. Therefore, there is a growing and urgent demand for sensitive, reliable, and cost-effective sensors that enable early diagnosis, accurate monitoring of drug efficacy, and personalized treatment plans in various clinical settings. RESULTS: In this work, a novel ratiometric electrochemical sensor was developed using Pd-modified MXene integrated with Prussian blue (PB) nanocomposites for AChE inhibitor detection. The Pd-modified MXene provides high electrical conductivity and abundant surface sites for nanoparticle immobilization, enhancing electron transfer and signal strength. Pd nanoparticles improve the electrocatalytic activity of the electrode, boosting electron transfer. PB acted as a redox mediator that oxidized thiocholine (TCh), the enzymatic product of AChE-catalyzed hydrolysis of ATCh, and was reoxidized to generate a stable redox potential serving as an internal reference. This enabled dual-signal ratiometric detection, improving accuracy and resistance to background interference. Using berberine as a model inhibitor, the sensor exhibited a linear range of 0.13-41 μmol/L and a detection limit of 10.0 nmol/L. The sensor demonstrated excellent reproducibility, retaining 93.1 % of its initial response after 28 days, and detected berberine in tablet and serum samples with high recovery, showing broad applicability. SIGNIFICANCE: This work highlights the synergistic effects of Pd-MXene and PB, offering a portable, cost-effective strategy for highly sensitive AChE inhibitor detection. The dual-signal ratiometric detection system enhances both sensitivity and accuracy, making it ideal for biomedical and pharmaceutical applications, with significant potential for early diagnosis and monitoring of neurodegenerative diseases.}, } @article {pmid41072129, year = {2026}, author = {Guo, G and Wen, G and Liu, L and Song, R and Cao, P and Yang, J and Zaiane, OR}, title = {BrainOSM: Outlier screening for multi-view functional brain network analysis.}, journal = {Computer methods and programs in biomedicine}, volume = {273}, number = {}, pages = {109092}, doi = {10.1016/j.cmpb.2025.109092}, pmid = {41072129}, issn = {1872-7565}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/physiopathology ; *Autism Spectrum Disorder/diagnostic imaging/physiopathology ; *Brain/diagnostic imaging/physiopathology ; Magnetic Resonance Imaging ; Algorithms ; Neuroimaging ; }, abstract = {PURPOSE: Identifying biomarkers for mental diseases is vital for understanding their underlying mechanisms, facilitating early diagnosis, and enabling more personalized treatment strategies. In this study, we focus on diagnosing autism spectrum disorder (ASD) and alzheimer's disease (AD) by analyzing functional brain networks (FBNs), which are represented as graphs capturing the functional connectivity patterns of the brain. The primary challenges in modeling FBNs for this disorder stem from two key issues: (i) the heterogeneity among graphs, and (ii) the disease-unrelated information within graphs. METHOD: We introduce a two-stage framework, BrainOSM, which combines outlier screening in datasets with a multi-view graph pooling module for enhanced graph classification. Specifically, the first stage employs progressive uncertainty-based outlier screening to reduce the interference of inter-graph heterogeneity. The second stage integrates multi-graph pooling, multi-view learning, and prior subnetwork regularization to refine graph structures, effectively tackling the challenge of disease-unrelated information within graphs. RESULTS: To validate the effectiveness of our method, we assess its performance on two public datasets: the Autism Brain Imaging Data Exchange (ABIDE) dataset and the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. On the ABIDE dataset, BrainOSM achieved an average accuracy of 70.23% and an AUC of 70.42%, corresponding to improvements of 8.55% and 7.74% over the traditional GCN method. On the ADNI dataset, it reached an average accuracy of 82.29% and an AUC of 83.23%, showing gains of 8.97% and 11.78%, respectively. Our code is publicly available at https://github.com/guoguiliang111/BrainOSM. CONCLUSION: Our extensive experiments confirm the generalizability and the effectiveness of BrainOSM for mental disease classification. Visual analyses further demonstrate that the model effectively identifies subnetworks associated with mental diseases, highlighting its potential for clinical interpretation. Moreover, our findings indicate that outlier screening plays a crucial role in improving classification accuracy when dealing with heterogeneous datasets.}, } @article {pmid41071446, year = {2025}, author = {Li, S and Gao, Y and Zhang, Y and Zhang, J and Zhao, Y and Chang, C and Gao, X and Zhang, J and Yang, G}, title = {Picroside II Alleviates the Progression of Alzheimer's Disease via the NLRP3/Caspase-1/GSDMD Pathway.}, journal = {Neuromolecular medicine}, volume = {27}, number = {1}, pages = {68}, pmid = {41071446}, issn = {1559-1174}, support = {Grant No. 20220997//the Medical Science Research Project of Hebei Provincial Health Commission/ ; Grant No. 21377745D//the Key Research and Development Plan of Hebei Province/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology ; *NLR Family, Pyrin Domain-Containing 3 Protein/physiology/genetics ; Mice ; *Cinnamates/therapeutic use/pharmacology ; *Caspase 1/physiology/genetics ; Signal Transduction/drug effects ; *Iridoid Glucosides/therapeutic use/pharmacology ; Male ; Disease Progression ; Mice, Transgenic ; *Neuroprotective Agents/therapeutic use/pharmacology ; Plaque, Amyloid ; Mice, Inbred C57BL ; Cytokines ; Disease Models, Animal ; Amyloid beta-Protein Precursor/genetics ; Inflammasomes ; }, abstract = {Alzheimer's disease (AD), an irreversible, degenerative disorder, affects the central nervous system. However, its accurate pathology remains unclear, and studies on treatment modalities are ongoing. Picroside II (PII) is an active compound in the medicinal herb Rhizoma coptis. It has strong effects, including antioxidation, anti-inflammatory, antiapoptotic, and neuroprotective effects. In this study, we analyzed how PII affects cognitive impairment in mice with AD and its underlying mechanism. PII at doses of 20 or 40 mg/kg was given to APP/PS1 mice through intraperitoneal injection for 2 months. Moreover, we carried out the Morris water maze test to evaluate cognitive function. Immunofluorescence analysis was performed to observe cortical Aβ plaque deposition, neuronal loss, and inflammatory cell expression. An enzyme-linked immunosorbent assay (ELISA) was performed to measure the levels of the cortical inflammatory factors tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Western blotting and quantitative polymerase chain reaction (qPCR) were performed to measure NLRP3, ASC, GSDMD, and caspase-1 expression. PII improved cognitive function, reduced Aβ plaque deposition and glial activation, and alleviated cortical neuronal loss in APP/PS1 mice. Furthermore, PII decreased the levels of cortical inflammatory factors (TNF-α, IL-6, and IL-1β). In addition, it suppressed NLRP3, ASC, GSDMD, and caspase-1 expression at the mRNA and protein levels. PII enhances the cognitive function of APP/PS1 mice by reducing inflammation and pyroptosis via the suppression of the NLRP3/caspase-1/GSDMD pathway. Therefore, PII is a candidate anti-AD therapeutic agent.}, } @article {pmid41070709, year = {2025}, author = {Chen, S and Ou, R and Wei, Q and Li, C and Song, W and Zhao, B and Yang, J and Fu, J and Ma, Y and Liu, J and Wang, X and Fang, D and Hu, T and Xiao, L and Zhang, S and Huang, R and Guo, X and Feng, F and Chen, X and Shang, H}, title = {Lecanemab treatment for Alzheimer's Disease of varying severities and associated plasma biomarkers monitoring: A multi-center real-world study in China.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70750}, pmid = {41070709}, issn = {1552-5279}, support = {82271272//National Natural Science Foundation of China/ ; 2023YFQ0098//Science and Technology Bureau Fund of Sichuan Province of China/ ; YCXJ-JZ-2022-007//Beijing E town Coorperation & Development Foundation/ ; 2025-108//the Sichuan Provincial Cadre Healthcare Research Project/ ; No.2022ZD0211605//the Sci-Tech Innovation 2023 "Brain Science and Brain-like Research/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/blood ; Male ; Female ; Biomarkers/blood ; China ; Aged ; Prospective Studies ; tau Proteins/blood ; Middle Aged ; Treatment Outcome ; Amyloid beta-Peptides ; Neuropsychological Tests ; Aged, 80 and over ; Severity of Illness Index ; }, abstract = {INTRODUCTION: We investigated real-world efficacy, safety, and plasma biomarker dynamics of Lecanemab in Chinese patients with Alzheimer's disease (AD). METHODS: A multi-center prospective cohort study enrolled 68 AD patients. Cognitive scales and plasma biomarkers were assessed at baseline (V0), 2.5 months (V1), and 7 months (V2). RESULTS: Alzheimer's Disease Assessment Scale-Cognitive Subscale 14-item version (ADAS-cog14) scores improved significantly at both follow-ups, and plasma p-tau181 consistently declined. Both p-tau181 and p-tau217 correlated with cognition and partially predicted treatment response (area under the curve [AUC] = 0.734 and 0.713). Mixed-effects modeling confirmed their dynamic association with ADAS-cog14 scores. Subgroup analyses indicated benefits across sex and apolipoprotein E4 status, while moderate-to-severe cases showed limited response. Lecanemab was well tolerated, with asymptomatic amyloid-related imaging abnormalities in 17.65% and mild infusion reactions in 5.88%. DISCUSSION: These findings support the short-term efficacy and safety of Lecanemab in early AD and highlight plasma biomarkers as a treatment-responsive biomarker. HIGHLIGHTS: Lecanemab improved cognitive function in Chinese patients with mild cognitive impairment due to Alzheimer's disease (AD-MCI) and mild AD over a short period. Plasma p-tau181 and p-tau217 showed significant correlation with cognitive scores, and their baseline level could partially predict the efficacy of lecanemab. Lecanemab showed a favorable safety profile with low, manageable rates of amyloid-related imaging abnormalities (ARIA) and infusion reactions.}, } @article {pmid41070364, year = {2025}, author = {Igarashi, A and Kimura, N and Ataka, T and Ito, T and Sasaki, K and Kobayashi, C and Tani, M and Sakata, Y and Azuma, M and Chida, A and Takeshima, T and Iwasaki, K and Matsubara, E}, title = {Simulation of Alzheimer's diagnostic flows with blood biomarker test options in Japan.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {4}, pages = {e70157}, pmid = {41070364}, issn = {2352-8737}, abstract = {INTRODUCTION: This study projected the diagnostic testing landscape for lecanemab treatment in Japan under different workflows. METHODS: A dynamic simulation estimated wait times and treatment-eligible patient numbers under four scenarios: current diagnostic workflow, blood biomarker (BBM) tests as triage tools, BBM tests for confirmatory diagnostics, and both combined. Willingness-to-pay (WTP) and intangible costs were assessed via an online survey to estimate testing demand. RESULTS: The maximum mean wait time under the current workflow was projected at 6.4 months, decreasing with BBM integration. The number of treatment-eligible patients increased considerably with BBM-based confirmatory diagnostics. BBM triage testing reduced wait times but temporarily increased treatment-eligible patients. DISCUSSION: Replacing positron emission tomography (PET) or cerebrospinal fluid with BBM-based diagnostics may increase treatment eligibility because of lower costs, driving higher demand for testing. HIGHLIGHTS: A dynamic simulation models Alzheimer's diagnostic workflows in Japan.Blood biomarker (BBM) tests reduce diagnostic wait times for Alzheimer's in Japan.Implementing BBM tests improves access to Alzheimer's diagnostics.Study quantifies demand for diagnostic testing based on costs and accessibility.Testing costs impact the number of treatment-eligible Alzheimer's patients.}, } @article {pmid41070139, year = {2025}, author = {Weber, DM and Stroh, MA and Taylor, SW and Lagier, RJ and Louie, JZ and Clarke, NJ and Vaillancourt, DE and Rayaprolu, S and Duara, R and Racke, MK}, title = {Development and Clinical Validation of Blood-Based Multibiomarker Models for the Evaluation of Brain Amyloid Pathology.}, journal = {Neurology. Clinical practice}, volume = {15}, number = {6}, pages = {e200546}, pmid = {41070139}, issn = {2163-0402}, abstract = {BACKGROUND AND OBJECTIVES: Plasma biomarkers provide new tools for evaluating patients with mild cognitive impairment (MCI) for Alzheimer disease (AD) pathology. Such tools are needed for anti-amyloid therapies that require efficient and accurate diagnostic evaluation to identify potential treatment candidates. This study sought to develop and evaluate the clinical performance of a multimarker combination of plasma beta-amyloid 42/40 (Aβ42/40), ptau-217, and APOE genotype to predict amyloid PET positivity in a diverse cohort of patients at a memory clinic and evaluate >4,000 results from "real-world" specimens submitted for high-throughput clinical testing. METHODS: Study participants were from the 1Florida AD Research Center. Demographics, clinical evaluations, and amyloid PET scan data were provided along with plasma specimens for model development in the intended-use cohort (MCI/AD: n = 215). Aβ42/40 and ApoE4 proteotype (reflecting high-risk APOE ɛ4 alleles) were measured by mass spectrometry and ptau-217 by immunoassay. A likelihood score model was determined for each biomarker separately and in combination. Model performance was optimized using 2 cutpoints, 1 for high and 1 for low likelihood of PET positivity, to attain ≥90% specificity and sensitivity. These cutpoints were applied to categorize 4,326 real-world specimens and an expanded cohort stratified by cognitive status (normal cognition [NC], MCI, AD). RESULTS: For the intended-use cohort (46.0% prevalence of PET positivity), a combination of Aβ42/40, ptau-217, and APOE4 allele count provided the best model with a receiver operating characteristic area under the curve of 0.942 and with 2 cutpoints fixed at 91% sensitivity and 91% specificity, yielding a high cutpoint with 88% positive predictive value and 87% accuracy and a low cutpoint with 91% negative predictive value and 85% accuracy. Incorporating the APOE4 allele count also reduced the percentage of patients with indeterminate risk from 15% to 10%. The cutpoints categorized the real-world clinical specimens as having 42% high, 51% low, and 7% indeterminate likelihood of PET positivity and differentiated between NC, MCI, and AD dementia cognitive status in the expanded cohort. DISCUSSION: Combining plasma biomarkers Aβ42/40, ptau-217, and APOE4 allele count is a scalable approach for evaluating patients with MCI for suspected AD pathology.}, } @article {pmid41069980, year = {2025}, author = {Ghaleb, J and Khouzami, KK and Nassif, N and Attieh, P and Ajlani, MFA and Sleiman, JB and Khalouf, A and Harb, F and Azar, S and Kannan, A and Ghadieh, HE}, title = {Unveiling Tirzepatide's Therapeutic Spectrum: A Dual GIP/GLP-1 Agonist Targeting Metabolic, Neurological, and Cardiovascular Health.}, journal = {International journal of endocrinology}, volume = {2025}, number = {}, pages = {2876156}, pmid = {41069980}, issn = {1687-8337}, abstract = {Tirzepatide, a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as a groundbreaking treatment for Type 2 diabetes mellitus (T2DM) and obesity. Initially developed for glycemic control, recent clinical and preclinical data reveal its broader therapeutic potential across a range of metabolic and systemic conditions. This review explores tirzepatide's mechanisms of action, clinical efficacy, and safety profile, with particular attention to its impact on T2DM, obesity, cardiovascular health, metabolic-associated fatty liver disease (MAFLD), chronic kidney disease (CKD), and neurological disorders such as Alzheimer's and Parkinson's diseases. By addressing multiple pathophysiological pathways, including insulin resistance, inflammation, and oxidative stress, Tirzepatide presents a unique opportunity to redefine treatment paradigms beyond glycemic management. Our review also synthesizes recent evidence on the efficacy and safety of tirzepatide for obesity management specifically in Asian populations; a group frequently underrepresented in global trials. This demographic focus introduces a valuable dimension to the existing body of knowledge. As ongoing trials continue to evaluate its long-term effects, tirzepatide stands at the forefront of a new era in integrated cardiometabolic and neuroprotective therapeutics.}, } @article {pmid41069798, year = {2025}, author = {Stites, SD and Lee, BN and Kuz, C and Adams, M and Harkins, K and Xie, SX and Walke, L and Sankar, P and Hamilton, R}, title = {An online vignette study of diagnostic testing: Racial and ethnic differences in Alzheimer's disease diagnosis confidence and stigma.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {4}, pages = {e70178}, pmid = {41069798}, issn = {2352-8729}, abstract = {INTRODUCTION: Understanding how biomarker testing affects Alzheimer's disease (AD) diagnosis confidence and AD stigma among race and ethnicity groups is essential for supporting early diagnosis and treatment. METHODS: Adults (N = 3548) rated confidence in an AD diagnosis based on four diagnostic evaluations and answered questions about AD stigma based on a clinical vignette. The sample reflects response and completion rates of 53% and 91.3%, respectively. Bivariate and multivariable regression analyses were conducted. RESULTS: Black participants showed the smallest increase (11.86 points) in diagnosis confidence of all race groups when a brain scan was included in the diagnostic evaluation. AD diagnosis confidence changed across diagnostic evaluation categories based on level and type of AD stigma domain and race group. DISCUSSION: Use of brain scans in evaluations can heighten diagnosis confidence in all race groups. Yet, no group had 100% confidence in an AD diagnosis with any evaluation. Recommendations are discussed. HIGHLIGHTS: Confidence in an Alzheimer's disease (AD) diagnosis varies across racial groups.Within racial groups, AD diagnosis confidence differs with diagnostics.Even with cutting-edge biomarker testing, no racial group had 100% confidence in an AD diagnosis.Patient-centered care and systemic changes are needed to widen distribution of diagnostic technologies and improve access to care.}, } @article {pmid41069328, year = {2025}, author = {Tettevi, EJ and Simpong, DL and Maina, M and Adjei, S and Asuming-Brempong, E and Osei-Atweneboana, MY and Ocloo, A}, title = {Antibiotic-Induced Gut Dysbiosis Modulates Alzheimer's Disease-Associated Gene Expression and Protein Aggregation in 3xTg-AD Mice via the Gut-Brain Axis.}, journal = {Brain and behavior}, volume = {15}, number = {10}, pages = {e70946}, pmid = {41069328}, issn = {2162-3279}, support = {//Council for Scientific and Industrial Research - Water Research Institute/ ; }, mesh = {Animals ; *Dysbiosis/chemically induced/metabolism ; *Alzheimer Disease/metabolism/genetics/microbiology ; Mice ; *Gastrointestinal Microbiome/drug effects/physiology ; *Anti-Bacterial Agents/pharmacology/adverse effects ; Female ; *Brain/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *Brain-Gut Axis/drug effects/physiology ; Amyloid beta-Peptides/metabolism ; Gene Expression/drug effects ; tau Proteins/metabolism ; Anxiety/metabolism ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that poses a major global health challenge due to its increasing prevalence and lack of effective treatments. Emerging evidence suggests the gut-brain axis may play a pivotal role in AD pathogenesis. However, causal links between dysbiosis and late-stage AD pathology remain unclear. METHODS: This study evaluated the effects of antibiotic-induced gut dysbiosis in aged 3xTg-AD mice (46-48 weeks). Female mice were randomly assigned to control or treatment groups and administered a broad-spectrum antibiotic cocktail (ampicillin, vancomycin, and neomycin) for 14 days. Behavioral tests (Y-maze, elevated plus maze) were performed to assess cognitive and anxiety-like behaviors. Gut microbiota composition was assessed via 16S rRNA qPCR. Gene expression of Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), and Tumor Necrosis Factor-Alpha (TNF-α) was analyzed via qRT-PCR, and cerebral amyloid-β1-42 and tau protein levels were quantified by ELISA. RESULTS: Antibiotic treatment induced significant dysbiosis, with > 90% reduction in Firmicutes and Bacteroidetes. Dysbiotic mice displayed impaired spatial working memory, heightened anxiety-like behavior, and reduced locomotor activity. Molecular analyses revealed region-specific dysregulation of cholinergic genes: AChE was upregulated in the hippocampus but downregulated in the cortex, while BChE showed the opposite trend. TNF-α was significantly elevated in both regions, indicating neuroinflammation. Dysbiosis also led to increased brain levels of amyloid-β1-42 and tau. CONCLUSION: Gut microbiome disruption exacerbates late-stage AD pathology, driving cognitive deficits, neuroinflammation, and hallmark protein aggregation. These findings support the gut-brain axis as a critical modulator of AD and highlight the microbiome as a potential therapeutic target.}, } @article {pmid41069042, year = {2025}, author = {Kennemer, AA and Gao, Z and Davis, PB and Kaelber, DC and Xu, R}, title = {Timing of neurorehabilitation and subsequent Alzheimer's disease risk in patients with moderate to severe traumatic brain injury: A nationwide retrospective cohort study in the United States.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {3}, pages = {1155-1165}, pmid = {41069042}, issn = {1875-8908}, support = {R01 AG057557/AG/NIA NIH HHS/United States ; R01 AG076649/AG/NIA NIH HHS/United States ; R01 AA029831/AA/NIAAA NIH HHS/United States ; R56 AG062272/AG/NIA NIH HHS/United States ; R01 AG061388/AG/NIA NIH HHS/United States ; RF1 AG076649/AG/NIA NIH HHS/United States ; UM1 TR004528/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/epidemiology/etiology ; Male ; Female ; Retrospective Studies ; Aged ; *Brain Injuries, Traumatic/rehabilitation/epidemiology/complications ; Middle Aged ; United States/epidemiology ; Aged, 80 and over ; *Neurological Rehabilitation/methods ; Cohort Studies ; Cognitive Dysfunction/epidemiology ; Time Factors ; *Time-to-Treatment ; }, abstract = {BackgroundTraumatic brain injury (TBI) is associated with an increased risk of Alzheimer's disease (AD). It is unknown if prompt neuro-rehabilitative treatment following moderate or severe TBI mitigates this risk compared with delayed treatment.ObjectiveTo determine whether immediate neuro-rehabilitative treatment following moderate or severe TBI reduces the risk of AD and related cognitive outcomes compared with delayed treatment.MethodsWe conducted a retrospective cohort using the TriNetX Analytics Platform, which includes health records from over 100 million US patients. Adults aged 50-90 years with moderate or severe TBI were included if they received immediate treatment (within 1 week) or delayed treatment (>1 week). Outcomes were AD risk at 3- and 5-year follow-up, with additional outcomes of mild cognitive impairment (MCI), dementia, and AD-related medication prescriptions. Cox proportional hazards models were applied to propensity score-matched cohorts, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated.ResultsOf 37,081 eligible patients, 17,636 remained after propensity score matching. Immediate treatment was associated with lower AD risk compared with delayed treatment (HR, 0.59; 95% CI, 0.41-0.86 at 3 years; HR, 0.70; 95% CI, 0.52-0.94 at 5 years). Similar risk reductions were observed for MCI, dementia, and AD-related medication use.ConclusionsImmediate treatment following moderate or severe TBI was associated with significantly reduced risk of AD and related cognitive decline. These findings suggest that prompt intervention may mitigate long-term neurodegenerative consequences of TBI.}, } @article {pmid41069006, year = {2025}, author = {Kang, W and Gao, C and Li, X and Wang, X and Zhong, H and Wei, Q and Tang, Y and Huang, P and Shen, R and Chen, L and Zhang, J and Fang, R and Wei, W and Zhang, F and Zhou, G and Yuan, W and Chen, X and Yang, Z and Wu, Y and Xu, W and Zhu, S and Zhang, L and He, N and Fang, W and Zhang, M and Zhang, Y and Ju, H and Bai, Y and Liu, J}, title = {Safety and effectiveness of lecanemab in Chinese patients with early Alzheimer's disease: Evidence from a multidimensional real-world study.}, journal = {Chinese medical journal}, volume = {138}, number = {22}, pages = {2907-2916}, pmid = {41069006}, issn = {2542-5641}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Cognitive Dysfunction/drug therapy ; Aged, 80 and over ; Amyloid beta-Peptides/blood/metabolism ; Biomarkers ; East Asian People ; }, abstract = {INTRODUCTION: Lecanemab has shown promise in treating early Alzheimer's disease (AD), but its safety and efficacy in Chinese populations remain unexplored. This study aimed to evaluate the safety and 6-month clinical outcomes of lecanemab in Chinese patients with mild cognitive impairment (MCI) or mild AD. METHODS: In this single-arm, real-world study, participants with MCI due to AD or mild AD received biweekly intravenous lecanemab (10 mg/kg). The study was conducted at Hainan Branch, Ruijin Hospital Shanghai Jiao Tong University School of Medicine. Patient enrollment and baseline assessments commenced in November 2023. Safety assessments included monitoring for amyloid-related imaging abnormalities (ARIA) and other adverse events. Clinical and biomarker changes from baseline to 6 months were evaluated using cognitive scales (mini-mental state examination [MMSE], montreal cognitive assessment [MoCA], clinical dementia rating-sum of boxes [CDR-SB]), plasma biomarker analysis, and advanced neuroimaging. RESULTS: A total of 64 patients were enrolled in this ongoing real-world study. Safety analysis revealed predominantly mild adverse events, with infusion-related reactions (20.3%, 13/64) being the most common. Of these, 69.2% (9/13) occurred during the initial infusion and 84.6% (11/13) did not recur. ARIA-H (microhemorrhages/superficial siderosis) and ARIA-E (edema/effusion) were observed in 9.4% (6/64) and 3.1% (2/64) of participants, respectively, with only two symptomatic cases (one ARIA-E presenting with headache and one ARIA-H with visual disturbances). After 6 months of treatment, cognitive scores remained stable compared to baseline (MMSE: 22.33 ± 5.58 vs . 21.27 ± 4.30, P = 0.733; MoCA: 16.38 ± 6.67 vs . 15.90 ± 4.78, P = 0.785; CDR-SB: 2.30 ± 1.65 vs . 3.16 ± 1.72, P = 0.357), while significantly increasing plasma amyloid-β 42 (Aβ42) (+21.42%) and Aβ40 (+23.53%) levels compared to baseline. CONCLUSIONS: Lecanemab demonstrated a favorable safety profile in Chinese patients with early AD. Cognitive stability and biomarker changes over 6 months suggest potential efficacy, though high dropout rates and absence of a control group warrant cautious interpretation. These findings provide preliminary real-world evidence for lecanemab's use in China, supporting further investigation in larger controlled studies. REGISTRATION: ClinicalTrials.gov , NCT07034222.}, } @article {pmid41068898, year = {2025}, author = {Climacosa, FMM and Ornos, EDB and Gapaz, NCLL and Guantia, MGR and Cruz, JMC and Manalo, RVM and Yu, ML and Qureshi, AP and Carampel, AC and Asis, JLB and Reyes, JCB and Dacasin, AB and Anlacan, VMM}, title = {The role of genetic polymorphisms on drug response in Alzheimer's disease: a systematic review.}, journal = {BMC medical genomics}, volume = {18}, number = {1}, pages = {154}, pmid = {41068898}, issn = {1755-8794}, abstract = {UNLABELLED: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting over 32 million people globally. The variability in treatment response to AD medications is influenced by genetic factors, sex, comorbidities, and medication history. Pharmacogenomics, the study of how an individual’s genetic makeup influences drug response, offers a promising approach to understanding these differences. This systematic review investigated the role of genetic polymorphisms in affecting treatment outcomes in AD. Following PRISMA guidelines, we systematically searched PubMed, Scopus, Cochrane, and PharmGKB databases for studies on AD, pharmacogenomics, and treatment response. Ten researchers independently screened the articles, with two independent reviewers resolving conflicts. A total of 1126 records were identified, and after removing duplicates and screening, 58 studies met inclusion criteria. APOE emerged as the most consistently studied gene, with ε2 and ε3 alleles generally associated with better responses to acetylcholinesterase inhibitors (AChEIs) and NMDA receptor antagonists, while ε4 carriage predicted poorer outcomes. The CYP2D610 allele, common in East Asian populations, was linked to enhanced donepezil response due to slower drug metabolism. Other genes, including ABCA1, A2M, CHRNA7, CHRFAM7A, and CHAT, showed potential associations with treatment response, particularly with AChEIs, though results varied across populations and study designs. Polymorphisms in inflammatory, metabolic, and vascular genes such as IL6, IDE, and ACE were also associated with cognitive outcomes, but findings were largely exploratory. In conclusion, APOE and CYP2D6 remain the most promising pharmacogenetic markers in AD, particularly for guiding donepezil therapy. However, evidence remains inconsistent due to varying study designs, populations, and clinical metrics. Additional genes show potential but require further validation. Larger, multiethnic studies with standardized treatment protocols and outcomes are needed to establish the clinical utility of pharmacogenomics in AD therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12920-025-02225-1.}, } @article {pmid41068796, year = {2025}, author = {Mu, Z and Chen, Y and Hu, Y and Wang, H and Li, J}, title = {Tailored brain metastatic tumor cells-derived apoptotic bodies ameliorate Alzheimer's disease by promoting microglia efferocytosis and neuroinflammation mitigation.}, journal = {Journal of nanobiotechnology}, volume = {23}, number = {1}, pages = {633}, pmid = {41068796}, issn = {1477-3155}, support = {No. KYCX25_3261//Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; No. 81502997//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Microglia/metabolism/drug effects ; Mice ; *Brain Neoplasms/secondary/pathology/metabolism ; Liposomes/chemistry ; Humans ; Cell Line, Tumor ; Manganese Compounds/chemistry/pharmacology ; Sirolimus/pharmacology/chemistry ; Apoptosis ; *Neuroinflammatory Diseases ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Nanocomposites/chemistry ; Brain/pathology ; Male ; Phagocytosis/drug effects ; Efferocytosis ; Oxides ; }, abstract = {Neuroinflammation, characterized by microglial overactivation and oxidative stress, plays a critical role in the initiation and progression of Alzheimer's disease (AD). In this study, we focus on simulating the natural efferocytosis process to reprogram microglial and mitigate chronic neuroinflammation for combinational AD therapy. To achieve this goal, engineered apoptotic bodies derived from brain metastatic tumor cells (LAbs) are successfully developed. Specifically, LAbs-based nanocomposites were fabricated by hybridizing LAbs with liposomes co-loaded with manganese dioxide nanoenzyme (BMn) and autophagy-activating rapamycin (Rapa), referred to as LAbs@Lip@BMn/Rapa. LAbs@Lip@BMn/Rapa exhibits efficient BBB penetration via LAbs-associated brain metastasis propensity of apoptotic bodies. Within the AD microenvironment, oxygen produced through BMn catalyzation in response to H2O2 triggers the structural disintegration of LAbs-camouflaged liposomes and their reassembly into ultra-small vesicles, thereby significantly enhancing intracranial delivery efficiency. In vitro and in vivo experiments confirm that this multi-target strategy effectively normalizes microglia toward anti-inflammatory M2 phenotype, scavenges reactive oxide species (ROS) accumulation, promotes β-amyloid and phosphorylated tau clearance through synergistic intervention, restores the pathological microenvironment in the brain, and enhances cognitive functions in AD model mice. This study demonstrates a novel LAbs-based biomimetic construction strategy that effectively penetrates the BBB and regulates microglia functions, offering a promising approach for AD treatment.}, } @article {pmid41066687, year = {2025}, author = {Reichau, K and Scheiner, M and Poeta, E and Bringmann, G and Monti, B and Decker, M}, title = {Total Syntheses of the Amaryllidaceae Alkaloids Carltonines A-C and the Neuroprotective and Immunomodulatory Evaluation of Carltonine B.}, journal = {Journal of natural products}, volume = {88}, number = {10}, pages = {2460-2471}, doi = {10.1021/acs.jnatprod.5c00841}, pmid = {41066687}, issn = {1520-6025}, mesh = {*Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; *Amaryllidaceae Alkaloids/pharmacology/chemical synthesis/chemistry ; Animals ; Mice ; *Amaryllidaceae/chemistry ; Molecular Structure ; Alzheimer Disease/drug therapy ; Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Butyrylcholinesterase/metabolism ; *Immunomodulating Agents/pharmacology/chemical synthesis ; }, abstract = {The inhibition of butyrylcholinesterase (BChE) represents an emerging approach for the treatment of Alzheimer's disease (AD). In 2020, three previously undescribed Amaryllidaceae alkaloids, carltonines A-C (1-3), were isolated, and their inhibitory activity on BChE was reported. Herein, we describe the first, nonstereoselective total synthesis of carltonine A-C (1-3) and confirmed their inhibitory activity using Ellman's assay, with nanomolar BChE inhibition by carltonine B (2). Further kinetic studies revealed that carltonine B (2) acts as a reversible, competitive inhibitor of BChE. In addition, racemic carltonine B (2) was evaluated in a phenotypic screening using murine hippocampal nerve cells, where it demonstrated protective effects against glutamate-induced oxytosis and ferroptosis at concentrations ranging from 5 to 10 μM and against iodoacetic acid-induced ATP depletion. Finally, in studies using lipopolysaccharide-activated microglial N9 cells, carltonine B (2) exhibited immunomodulatory effects by downregulating pro-inflammatory markers such as NOS2 and IL-1β without affecting anti-inflammatory signaling pathways.}, } @article {pmid41066449, year = {2025}, author = {Hanson, M and Liu, Y and Ozawa, T and Yin, H and Mattke, S}, title = {Potential barriers to timely Alzheimer's disease diagnosis and treatment: Tracer delivery and patient travel to amyloid PET scanners in the United States.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {3}, pages = {1023-1028}, doi = {10.1177/13872877251385118}, pmid = {41066449}, issn = {1875-8908}, mesh = {*Alzheimer Disease/diagnostic imaging/therapy ; Humans ; United States/epidemiology ; *Positron-Emission Tomography/methods ; *Travel ; *Health Services Accessibility ; Aged ; *Amyloid/metabolism ; }, abstract = {Several disease-modifying Alzheimer's disease treatments are available or in clinical trials. Participation in these trials and access to approved treatments often require amyloid positron emission tomography (PET) scans. Amyloid PET requires a radioactive tracer with a short half-life so PET scanner must be near a cyclotron facility that produces and delivers viable tracers. We examined the size and composition of the US population that faces likely geographic obstacles due to travel time constraints. Our estimate that 1.5 million older Americans would drive more than one hour to a qualifying PET site raises concern for differences in access to memory care.}, } @article {pmid41066226, year = {2025}, author = {Weiss, S and Harris, K and Carney, OL and Maza, VI and Wickline, S and Henderson, A and Widjaja, T and Garrett, B and Hill, DL and Liskovec, L and Chen, P and LeRoy, AS}, title = {Initial development of the writing to heal app: A structured writing series for caregivers of spouses living with Alzheimer's disease and related dementias.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {552-570}, pmid = {41066226}, issn = {1875-8908}, support = {K01 AG073824/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Caregivers/psychology ; *Writing ; *Spouses/psychology ; Female ; Male ; *Mobile Applications ; *Alzheimer Disease/psychology/nursing ; Aged ; Middle Aged ; *Dementia/psychology/nursing ; *Stress, Psychological/psychology/therapy ; Focus Groups ; }, abstract = {BackgroundCaregiving for a spouse living with Alzheimer's disease and related dementias (ADRD) is incredibly stressful, which puts caregivers at risk for developing health problems themselves.ObjectiveTo develop an intervention that supports caregivers and helps mitigate the stress associated with caregiving.MethodsIn Part I, we used qualitative methods (e.g., data collected via focus groups with people caring for a spouse living with ADRD) to identify opportunities for targeted treatment and potential barriers to a cognitive-based online expressive writing (EW) intervention tailored to spousal caregivers. In Part IIa, we conducted a second wave of focus groups, throughout which we iteratively adapted a mobile app-based writing intervention for stress and grief among spousal caregivers, while continuously monitoring caregivers' perceived acceptability and feasibility of each proposed feature. Finally, to prepare for app development, we conducted preliminary usability testing (Part IIb), during which caregivers interacted with a prototype of the future app to complete a number of proposed task flows.ResultsCaregivers reported having dynamic needs and requested an intervention that was efficient, mobile, and readily accessible. Further, people caregiving for a spouse living with ADRD have specific motivations for writing (e.g., needing an outlet to release their emotions) as well as unique barriers to the intervention (e.g., lack of time, security concerns).ConclusionsA mobile-based writing intervention catering to the specific needs of these individuals may be a helpful coping resource for caregivers.}, } @article {pmid41066175, year = {2025}, author = {Toyoda, H and Kim, D and Koh, BG and Sano, T and Kanematsu, T and Oh, SB and Kang, Y}, title = {Chronic stress impairs autoinhibition in neurons of the locus coeruleus to increase asparagine endopeptidase activity.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {41066175}, issn = {2050-084X}, support = {20K06926//Japan Society for the Promotion of Science/ ; 23K06346//Japan Society for the Promotion of Science/ ; 26290006//Japan Society for the Promotion of Science/ ; 21K06441//Japan Society for the Promotion of Science/ ; Brain Pool Program//Ministry of Science and ICT/ ; Naito Grant//Naito Foundation/ ; RS-2023-00264409//Ministry of Science and ICT/ ; RS-2023-00302281//Ministry of Science and ICT/ ; }, mesh = {Animals ; *Locus Coeruleus ; *Neurons/physiology/enzymology/metabolism ; Mice ; *Cysteine Endopeptidases/metabolism ; Male ; Monoamine Oxidase/metabolism ; Norepinephrine/metabolism ; *Stress, Physiological ; Mice, Inbred C57BL ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism ; }, abstract = {Impairments of locus coeruleus (LC) are implicated in anxiety/depression and Alzheimer's disease (AD). Increases in cytosolic noradrenaline (NA) concentration and monoamine oxidase A (MAO-A) activity initiate the LC impairment through production of NA metabolite, 3,4-dihydroxyphenyl-glycolaldehyde (DOPEGAL), by MAO-A. However, how NA accumulates in soma/dendritic cytosol of LC neurons has never been addressed despite the fact that NA is virtually absent in cytosol while NA is produced exclusively in cytoplasmic vesicles from dopamine by dopamine-β-hydroxylase. Since reuptake of autocrine-released NA following spike activity is the major source of NA accumulation, we investigated whether and how chronic stress can increase the spike activity accompanied by NA autocrine. Overexcitation of LC neurons is normally prevented by the autoinhibition mediated by activation of α2A-adrenergic receptor (AR)-coupled inwardly rectifying potassium-current (GIRK-I) with autocrine-released NA. Patch-clamp study revealed that NA-induced GIRK-I in LC neurons was decreased in chronic restraint stress (RS) mice, while a similar decrease was gradually caused by repeated excitation. Chronic RS caused internalization of α2A-ARs expressed in cell membrane in LC neurons and decreased protein/mRNA levels of α2A-ARs/GIRKs in membrane fraction. Subsequently, chronic RS increased the protein levels of MAO-A, DOPEGAL-induced asparagine endopeptidase (AEP), and tau N368. These results suggest that chronic RS-induced overexcitation due to the internalization of α2A-ARs/GIRK is accompanied by [Ca[2+]]i increases, subsequently increasing Ca[2+]-dependent MAO-A activity and NA autocrine. Thus, it is likely that internalization of α2A-AR increased cytosolic NA, as reflected in AEP increases, by facilitating reuptake of autocrine-released NA. The suppression of α2A-AR internalization may have a translational potential for anxiety/AD treatment.}, } @article {pmid41066060, year = {2025}, author = {Jeevanandam, J and Tsenov, G and Danquah, MK and Ruiz-Molena, D and Boussios, S and Ovsepian, SV}, title = {Smart Nanomedicines for Neurodegenerative Diseases: Empowering New Therapies with Molecular Imaging and Artificial Intelligence.}, journal = {Molecular diagnosis & therapy}, volume = {}, number = {}, pages = {}, pmid = {41066060}, issn = {1179-2000}, abstract = {Neurodegenerative diseases (NDDs) remain among the most challenging disorders to treat, owing to their multifactorial pathology, limited drug delivery across the blood-brain barrier, and lack of effective disease-modifying therapies. Smart nanomedicines are emerging as powerful tools to overcome these challenges by enabling targeted delivery, controlled release, and enhanced bioavailability of therapeutics. In parallel, advances in molecular imaging, combined with machine learning (ML) and artificial intelligence (AI), are transforming the design, validation, and optimization of nanomedicines. This article integrates the rapidly evolving fields of nanomedicine and AI/ML-driven imaging to evaluate their synergistic potential toward NDD therapy. The capabilities of AI-aided imaging for mapping nanomedicine biodistribution, predicting therapeutic outcomes, guiding nanoparticle design, and ensuring quality control at preclinical and clinical stages in NDDs are discussed. This synergistic approach opens new avenues for precision medicine, enabling personalized and adaptive treatment strategies for Alzheimer's, Parkinson's, and other NDDs by linking smart nanocarriers with intelligent imaging analytics. Hence, this article presents a roadmap for translating AI-guided nanomedicine-integrated imaging platforms into clinically viable solutions, marking a paradigm shift in the diagnosis and treatment of NDDs.}, } @article {pmid41064738, year = {2025}, author = {Niu, L and Li, Y and Wu, H and Zhao, L and Zhang, J and Lu, F and Zhao, G and Jia, F and Zhu, J and Liu, M}, title = {Causal effect of serum lipopolysaccharide activity levels and inflammatory proteins on Alzheimer's disease: A Mendelian randomization study combined with meta-analysis in a large-scale cohort.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251385589}, pmid = {41064738}, issn = {2542-4823}, abstract = {BACKGROUND: Neuroinflammation represents a central pathological mechanism in Alzheimer's disease (AD). Lipopolysaccharide (LPS) is a potent inducer of neuroinflammation and demonstrates elevated circulating levels in AD patients. OBJECTIVE: This study aims to investigate the genetic association between serum LPS activity level, inflammatory proteins and AD. METHODS: A two-sample mendelian randomization (MR) analysis was performed to explore the causal effect of serum LPS activity level and 91 inflammatory proteins on AD, including 1, 260, 136 sporadic AD and 2, 838, 825 familial AD patients, respectively. Meta-analysis was conducted on multiple datasets to determine statistically significant results that was initially observed in one dataset. RESULTS: Serum LPS activity level is a risk factor for early onset sporadic AD with OR = 1.392, 95% CI: 1.038-1.869. In most other sporadic AD datasets, LPS shows a trend of increasing the risk of AD onset. After meta-analysis in 10 independent datasets, no association between LPS and sporadic AD was observed. In most familial AD datasets, LPS level demonstrated a trend of decreasing AD risk in MR analysis, however, meta-analysis of the combined 8 datasets showed no statistically significant difference. Two inflammatory proteins, AXIN1 and IL-1 alpha, were identified as significant risk factors for sporadic AD. CONCLUSIONS: This study suggested that serum LPS activity level may present a risk effect in early onset sporadic AD. Two inflammatory proteins AXIN1 and IL-1 alpha were associated with the risk of sporadic AD. These findings provide a new perspective for the early diagnosis and treatment of sporadic and familial AD.}, } @article {pmid41064556, year = {2025}, author = {Ota, M and Nakayama, K and Kitabatake, A and Takahashi, T and Nemoto, K and Arai, T}, title = {Spatial Patterns of Cerebral Blood Flow in Alzheimer's Disease Identified by the Subtype and Stage Inference Algorithm.}, journal = {Dementia and geriatric cognitive disorders extra}, volume = {15}, number = {1}, pages = {108-118}, pmid = {41064556}, issn = {1664-5464}, abstract = {INTRODUCTION: Much research has focused on the deposition of amyloid and tau proteins in the Alzheimer's disease (AD) brain, but many amyloid and tau models assumed a single spatial progression of amyloid and tau accumulation. We estimated the changing patterns of an indirect biomarker, i.e., the cerebral blood flow (CBF), in AD, and we discuss the pathological process of AD. METHODS: The participants were 341 patients who visited our hospital's outpatient department for memory loss (146 males, 195 females): 115 diagnosed with AD, 176 diagnosed with mild cognitive impairment, and 50 diagnosed with subjective cognitive decline. For the evaluation of disease-related changes in their CBF, the patients underwent 99mTc-ethyl cysteinate dimer single-photon emission computed tomography scans. We differentiated the subtypes of CBF in AD by using a machine-learning algorithm called the "Subtype and Stage Inference (SuStaIn)"algorithm. RESULTS: When we divided the data into two groups, the SuStaIn algorithm identified two different CBF subtypes: the typical AD pattern and a cortical pattern with hippocampal sparing. CONCLUSION: We observed two subtypes of the pattern of change in the CBF of individuals with AD, and these subtypes were highly similar to previous findings derived from SuStaIn algorithm applied differing neuroimaging modalities. Such subtyping derived from CBF imaging might have clinical utility in the treatment of AD.}, } @article {pmid41064234, year = {2025}, author = {Rodríguez-Romero, A and Belachew, S and Bartholomé, E and Mazzà, C and Reyes, Ó and Luque, C and Pless, S and Bernasconi, C}, title = {Biomarkers of Alzheimer's disease modification using adaptive cognitive assessments to improve responsiveness-a simulation study.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1653261}, pmid = {41064234}, issn = {1662-4548}, abstract = {INTRODUCTION: Clinical studies assessing cognition in Alzheimer's and other neurodegenerative diseases require endpoints that are sensitive to treatment response across a broad range of cognitive abilities. However, responsiveness of conventional cognitive assessments typically varies with the performance level, especially due to non-linearities such as floor or ceiling effects. Here, we evaluate 6 newly developed smartphone-based and gamified Adaptive Cognitive Assessments (ACAs) entailing a system of dynamic difficulty adaptation to individual performance, which is expected to improve adherence but also measurement properties. Deployment of such ACAs to maximize their discriminative ability in comparative studies requires exploration of many free parameters and complex dynamics. METHODS: In simulations of cohorts of patients with cognitive impairment, we compared two ACAs paradigms: after 14 daily tests allowing performance-based difficulty adaptation, the difficulty level was either (1) fixed or (2) kept adaptive for a period of 4 years with weekly testing. Sensitivity to between-group effects was assessed in cohorts characterized by cognitive decline observed in neurodegenerative diseases. RESULTS: The discriminative ability of the two paradigms depends on features of the study design and subjects. At study end, the adaptive difficulty paradigm clearly outperformed the fixed-difficulty paradigm in terms of responsiveness for cognitive decline rates >2.5% per year. DISCUSSION: ACA can increase biomarker responsiveness to treatment effects over fixed difficulty. ACA deployment should be guided by study and assessment features, including duration, expected cognitive decline rates and effect size. In the high-dimensional parameter space of ACA instruments, study simulations are indispensable to identify suitable deployment strategies.}, } @article {pmid41063670, year = {2025}, author = {Seyyedabadi, B and Babataheri, S and Naseri, M and Laher, I and Soraya, H}, title = {Ivermectin and non-parasitic disorders: An update.}, journal = {Current opinion in pharmacology}, volume = {85}, number = {}, pages = {102574}, doi = {10.1016/j.coph.2025.102574}, pmid = {41063670}, issn = {1471-4973}, mesh = {Humans ; *Ivermectin/therapeutic use/pharmacology/adverse effects ; Animals ; *Antiparasitic Agents/therapeutic use/pharmacology/adverse effects ; Neuroprotective Agents/therapeutic use/pharmacology/adverse effects ; }, abstract = {Ivermectin, a broad-spectrum anti-parasitic agent, demonstrates potential therapeutic benefits in treating non-parasitic ailments, particularly in neurological, respiratory, inflammatory, dermal, cardiovascular, and neoplastic disorders. For instance, ivermectin targets both DNA and RNA viruses, inhibits angiogenesis, and has anti-cancer properties, which result from inhibiting RNA helicase, inducing mitochondrial dysfunction, apoptosis, necrosis, and autophagy, as well as promoting oxidative stress. While the precise neurological impacts of ivermectin are not fully understood, it also has anticonvulsant properties in rats. Recent discoveries have revealed the neuroprotective effects of ivermectin in cerebral ischemia/reperfusion and Alzheimer's disease. Although there is limited research on the influence of ivermectin on the cardiovascular system, some studies have reported cardioprotective effects of ivermectin. However, a recent study suggested that ivermectin pre-treatment may have detrimental effects on myocardial ischemia. Consequently, numerous questions regarding the therapeutic/adverse effects of ivermectin remain unanswered and necessitate further investigation. We review the effects of ivermectin in non-parasitic diseases with an emphasis on current research in this field.}, } @article {pmid41062840, year = {2025}, author = {Youssef, B and Ibrahim, EA and Moselhy, SS and ElShebiney, S and Elabd, WK}, title = {Phytochemical based on nanoparticles for neurodegenerative alzheimer disease management: Update review.}, journal = {Discover nano}, volume = {20}, number = {1}, pages = {176}, pmid = {41062840}, issn = {2731-9229}, abstract = {Alzheimer's disease (AD) is one of the most common chronic neurodegenerative diseases and dementia, with about 46 million cases worldwide and going to become tripled by 2050. It is characterized by formation and aggregation of amyloid-β plaques, tau tangles, and inflammatory mediators. The treatment protocol poses challenging obstacles particularly, effectiveness drug delivery to the brain. However, the available therapies with low potency and blood-brain barrier (BBB) are most challenges for developing novel treatments. New delivery systems that interact with biological systems at the molecular level, such as nanotechnology can overcome these problems and open new therapeutic avenues. Nanoparticles showed different applications in medicine due to its bioavailability, transport and low toxicity. This review explored the therapeutic potential of natural phytochemical nanomedicine that important in AD treatment through improving drug delivery system across BBB, increasing bioavailability and minimizing neurotoxicity.}, } @article {pmid41061790, year = {2025}, author = {Li, S and Zheng, F and Liu, S and Wu, R and Zhang, L and He, X and Li, M and Li, L}, title = {Physical exercise protects neurons from energy deficit and improves cognitive function by upregulating astrocytic Slc2a1 in Alzheimer's disease.}, journal = {Experimental neurology}, volume = {395}, number = {}, pages = {115493}, doi = {10.1016/j.expneurol.2025.115493}, pmid = {41061790}, issn = {1090-2430}, abstract = {Alzheimer's disease (AD) has been associated with impaired energy metabolism and neuronal mitochondrial dysfunction, which contribute to the development of anxiety-like behaviors and spatial memory deficits. Astrocytes are recognized as a critical source of metabolites for neurons, supporting mitochondrial respiration. Although physical exercise (PE) has shown therapeutic potential in AD models, the molecular mechanisms linking PE to metabolic reprogramming remain elusive. In a 5xFAD mouse model, this study shows that PE increased the expression of solute carrier family 2 member 1 (Slc2a1) and decreased the expression of GFAP in astrocytes. We demonstrate that both PE and the overexpression of astrocytic Slc2a1 alleviated neuronal mitochondria damage and neuron death, shifts astrocytes to an anti-inflammatory phenotype and reduced Aβ accumulation. Conversely, knockdown of Slc2a1 abrogated the protective effects of PE. In vitro, we established an AD glucose-deficiency cell model by incubating cells with 5.5 mM glucose and oligomeric Aβ (oAβ). Our results showed that Slc2a1 overexpression increased lactate secretion in the supernatant of C8-D1A astrocytes. Furthermore, both Slc2a1 overexpression in C8-D1A cells and lactate treatment rescued oAβ-induced mitochondrial oxidative stress and membrane potential alterations in energy-deficient HT22 neurons, thereby enhancing lactate secretion from astrocytes and promoting the lactate shuttle to neuron for energy supply. Collectively, our findings indicate that PE ameliorates anxiety-like behavior and spatial memory deficits, mitigates mitochondrial damage in neurons, and reduces Aβ accumulation in 5xFAD mice through the upregulation of Slc2a1 in astrocytes. Our findings identify Slc2a1 as a pivotal mediator of metabolic support induced by PE and highlights astrocyte-neuron lactate shuttling as a promising therapeutic target for AD.}, } @article {pmid41061335, year = {2025}, author = {Shahsavari, F and Eidi, A and Sotoodehnejadnematalahi, F}, title = {Neuroprotective effects of sodium molybdate in a beta-amyloid-induced rat model of Alzheimer's disease: An In Vivo preclinical study.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {92}, number = {}, pages = {127774}, doi = {10.1016/j.jtemb.2025.127774}, pmid = {41061335}, issn = {1878-3252}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/chemically induced/metabolism ; *Molybdenum/pharmacology/therapeutic use/administration & dosage ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Rats, Wistar ; Disease Models, Animal ; Rats ; *Amyloid beta-Peptides/toxicity ; Hippocampus/drug effects/metabolism/pathology ; }, abstract = {BACKGROUND: Molybdenum, as a trace element, exhibits various pharmacological properties, including antioxidant, anti-inflammatory, and free radical-scavenging activities. This study aimed to evaluate the effects of sodium molybdate on neurotoxicity induced by beta-amyloid (Aβ) in adult male Wistar rats. METHODS: Forty-eight rats were randomly divided into eight groups: Healthy control group, Experimental groups receiving sodium molybdate (0.1, 0.2, and 0.4 mg/kg intragastrically daily), Alzheimer's control group (intrahippocampal injection of Aβ bilaterally), and Alzheimer's experimental groups receiving sodium molybdate (0.1, 0.2, and 0.4 mg/kg intragastrically daily) for 30 consecutive days following Aβ injection. Histopathological changes in the hippocampus were assessed using Hematoxylin and Eosin staining, and amyloid plaques were evaluated via Congo Red staining. The expression levels of GFAP and S100 proteins were investigated by immunohistochemistry, and changes in the expression level of Bax/Bcl2 ratio were evaluated by Real-time PCR in the hippocampus. FINDINGS: Our results revealed a dose-dependent attenuation of neuronal degeneration, and reduced amyloid plaque formation in the Alzheimer's experimental groups following sodium molybdate administration. Treatment with sodium molybdate at doses of 0.2 and 0.4 mg/kg significantly reduced the levels of both S100 and GFAP proteins (P < 0.05 and P < 0.001 respectively) compared to the Alzheimer's control group. Furthermore, sodium molybdate administration at a dose of 0.1 mg/kg significantly reduced the Bax/Bcl2 expression ratio (P < 0.05), with greater reductions observed at 0.2 and 0.4 mg/kg doses (P < 0.01). CONCLUSION: The results of this study suggest that sodium molybdate may exert protective effects against neurological disorders caused by Aβ in a rat model of Alzheimer's disease.}, } @article {pmid41061323, year = {2025}, author = {Zhang, J and Zhang, L and Sun, X and Yang, Y and Kong, L and Lu, C and Lv, G and Wang, T and Wang, H and Fu, F}, title = {Corrigendum to "Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation" [The Journal of Pharmacology and Experimental Therapeutics 359 (2016) 374-382].}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {392}, number = {10}, pages = {103699}, doi = {10.1016/j.jpet.2025.103699}, pmid = {41061323}, issn = {1521-0103}, } @article {pmid41058018, year = {2025}, author = {Pascual-Lucas, M and Lacosta, AM and Montañés, M and Canudas, J and Loscos, J and Monleón, I and Allué, JA and Sarasa, L and Fandos, N and Romero, J and Sarasa, M and Torres, M and Whyms, D and Terencio, J and Piñol-Ripoll, G and Boada, M}, title = {Safety, tolerability, immunogenicity, and efficacy of ABvac40 active immunotherapy against Aβ40 in patients with mild cognitive impairment or very mild Alzheimer's disease: A randomized, double-blind, placebo-controlled phase 2 study.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70776}, pmid = {41058018}, issn = {1552-5279}, support = {//Araclon Biotech-Grifols/ ; }, mesh = {Humans ; Double-Blind Method ; *Alzheimer Disease/therapy/immunology/drug therapy ; Male ; *Amyloid beta-Peptides/immunology ; Female ; Aged ; *Cognitive Dysfunction/therapy/immunology/drug therapy ; *Immunotherapy, Active/methods ; Treatment Outcome ; *Peptide Fragments/immunology ; *Alzheimer Vaccines/therapeutic use/adverse effects ; Middle Aged ; Aged, 80 and over ; }, abstract = {INTRODUCTION: ABvac40 is an investigational active immunotherapy (vaccine) targeting Aβ40. This study assessed the safety and immunogenicity of ABvac40 in patients with amnestic mild cognitive impairment or very mild Alzheimer's disease. METHODS: AB1601 was a multicenter, randomized, double-blind, placebo-controlled phase 2 study. Patients (n = 124) received five monthly injections plus a 10-month booster of ABvac40 or placebo, with 18-24 months of follow-up. Primary endpoints included safety, tolerability, and immunogenicity. Secondary endpoints assessed immune response, neuropsychological changes, and disease biomarkers. RESULTS: Treatment-emergent adverse events (TEAEs) and serious TEAEs were comparable between ABvac40 (90.6% and 26.6%) and placebo (93.3% and 26.7%). Amyloid-related imaging abnormalities-hemorrhage (ARIA-H) were similar (12.5% ABvac40; 15.0% placebo), with no ARIA-edema (ARIA-E) or meningoencephalomyelitis. ABvac40 induced a specific, sustained immune response in plasma, with detectable antibodies in CSF. DISCUSSION: These findings support further investigation of ABvac40 as a potential disease-modifying therapy. NCT03461276 (ClinicalTrials.gov) HIGHLIGHTS: ABvac40 was safe and well-tolerated in early-stage Alzheimer's disease patients. No amyloid-related imaging abnormalities-edema (ARIA-E) or encephalitis observed; ARIA-hemorrhage (ARIA-H) rates were similar across groups. Specific, sustained immune response to ABvac40 in plasma, with cerebrospinal fluid (CSF) antibody penetration. Cognitive scales and magnetic resonance imaging (MRI) volumetric data favored ABvac40 over placebo. Results support further development of ABvac40 as a disease-modifying therapy.}, } @article {pmid41057918, year = {2025}, author = {Erichsen, JM and Register, TC and Sutphen, C and Ma, D and Gaussoin, SA and Rudolph, M and Rundle, M and Bateman, JT and Lockhart, SN and Sai, KKS and Whitlow, C and Craft, S}, title = {A phase 2A/B randomized trial of metabolic modulators intranasal insulin and empagliflozin for MCI and early AD.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70704}, pmid = {41057918}, issn = {1552-5279}, support = {//Aptar Pharma/ ; //National Institute of Aging/ ; T32 AG033534/AG/NIA NIH HHS/United States ; PTC-22-975243/ALZ/Alzheimer's Association/United States ; //Kulynych Cente for Memory and and Cognition/ ; //Kulynych Center for Memory and Cognition/ ; P30 AG072947/AG/NIA NIH HHS/United States ; T32 AG0333534/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Glucosides/administration & dosage/therapeutic use ; *Cognitive Dysfunction/drug therapy ; *Benzhydryl Compounds/administration & dosage/therapeutic use ; Male ; Administration, Intranasal ; Female ; *Alzheimer Disease/drug therapy ; *Insulin/administration & dosage/therapeutic use ; Aged ; Double-Blind Method ; *Sodium-Glucose Transporter 2 Inhibitors/administration & dosage/therapeutic use ; Biomarkers/cerebrospinal fluid ; Treatment Outcome ; }, abstract = {INTRODUCTION: Agents targeting metabolic/vascular disorders are promising candidates to treat Alzheimer's disease (AD) and enhance safety and efficacy of other therapies. METHODS: In a 2×2 factorial double-blinded randomized trial, participants with mild cognitive impairment (MCI), early AD, or who were amyloid positive received intranasal insulin (INI; 40 IU q.i.d.), the sodium-glucose cotransporter-2 inhibitor empagliflozin (10 mg q.d. oral tablet), both, or placebo for 4 weeks. The primary outcome was treatment-related adverse events (TRAEs). Secondary outcomes included the modified Preclinical Alzheimer's Cognitive Composite-5 (mPACC5), fluid biomarkers, cerebral blood flow (CBF), and fractional anisotropy (FA). RESULTS: TRAEs were mild and similar for all groups. INI increased mPACC5, modulated FA and CBF, and reduced plasma glial fibrillary acidic protein. Empagliflozin lowered cerebrospinal fluid tau and modulated CBF. Both agents moderated immune/inflammatory/neurovascular markers. DISCUSSION: INI and empagliflozin treatment was safe with promising effects on cognition, fluid, and imaging biomarkers. A longer and larger trial is needed to confirm these results. CLINICAL TRIAL REGISTRATION: NCT05081219 HIGHLIGHTS: Agents targeting metabolic or vascular disorders are promising candidates to prevent or treat Alzheimer's disease (AD). Intranasal insulin and empagliflozin were safe alone or in combination for mild cognitive impairment/AD. Insulin improved cognition and markers of inflammation and immune function. Empagliflozin reduced markers of vascular injury and neurodegeneration. A longer, larger trial is needed to validate these results.}, } @article {pmid41056473, year = {2025}, author = {Crump, C and Wei, J and Vickrey, BG and Edwards, AC and Schulz, PE and Sieh, W and Sundquist, J and Sundquist, K}, title = {Risk of major depression in partners of people with Alzheimer's disease: a national cohort study.}, journal = {Age and ageing}, volume = {54}, number = {10}, pages = {}, pmid = {41056473}, issn = {1468-2834}, support = {R03 AG083596/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/psychology/epidemiology/diagnosis ; Female ; *Depressive Disorder, Major/epidemiology/psychology/diagnosis ; Male ; Aged ; Sweden/epidemiology ; Risk Factors ; Incidence ; Aged, 80 and over ; Middle Aged ; Cohort Studies ; Risk Assessment ; *Spouses/psychology ; *Caregivers/psychology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) may cause significant psychosocial distress not only in the patient but also their partner. However, long-term risks of major depression in partners of AD patients are largely unknown. METHODS: A national cohort study was conducted of all 145 289 partners of people diagnosed with all-cause dementia, including 57 113 partners of people diagnosed with AD, in Sweden during 1998-2017, and 1 300 561 population-based controls. Cox regression was used to compute hazard ratios (HRs) for subsequent risk of major depression identified from nationwide outpatient and inpatient diagnoses through 2018, adjusting for sociodemographic factors and prior mental disorders. RESULTS: The 10-year cumulative incidence of major depression was 5.4% in partners of people with AD, 5.6% in partners of people with all-cause dementia, and 3.9% in controls. The adjusted relative rate of major depression was increased ~1.5-fold in partners of people with AD (HR, 1.53; 95% CI, 1.35-1.72) or all-cause dementia (1.45; 1.34-1.57), compared with controls. These risks were elevated among both women (AD: HR, 1.41; 95% CI, 1.22-1.64; all-cause dementia: 1.36; 1.24-1.50) and men (AD: 1.81; 1.46-2.25; all-cause dementia: 1.73; 1.48-2.01). Risks remained significantly elevated ≥3 years later in both women (1.3- to 1.5-fold) and men (1.5-fold). Risks were generally highest in partners aged ≥85 years. CONCLUSIONS: In this large national cohort, partners of people diagnosed with AD or all-cause dementia had ~1.5-fold risks of major depression, which remained elevated several years later. Partners of people with dementia need psychosocial support and long-term follow-up for timely detection and treatment of depression.}, } @article {pmid41056389, year = {2025}, author = {Sharma, M and Deshmukh, S and Thakre, T and Waskar, R and Pardhekar, A}, title = {Ayurvedic Management of Alzheimer's Disease: A Clinical Case Study.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {41056389}, issn = {1078-6791}, abstract = {ABSTRACT: Alzheimer's disease is a progressive neurodegenerative disorder that primarily affects memory, cognition, and behavior, often leading to severe functional decline. A 55-year-old male patient came with complaints of confusion in daily activities, forgetting names, misplacing objects, frequent episodes of crying, and loss of communication skills for the past 1 year. He was clinically diagnosed with Alzheimer's Disease. The patient was treated with an Ayurvedic treatment protocol, involving internal administration of Brahmi ghrit, Saraswatarishta with gold, Ashwagandha powder, and Rasona Ksheerpaka, along with Panchakarma therapies including Nasya with Panchendriya taila, Shirobasti, and Abhyanga with Balashwagandha taila. After the treatment, the patient showed marked improvements in memory retention, orientation, and mood stability. This case showed that Ayurvedic interventions aid in slowing cognitive decline and improving daily functioning in Alzheimer's patients, highlighting the need for integrative and individualized treatment approaches in neurodegenerative disorders. KEYWORDS: neurodegeneration, Alzheimer's disease, Dementia, Ayurvedic medicines, Brahmi ghrit, case report.}, } @article {pmid41055317, year = {2025}, author = {Li, J and Sun, W and Wang, X and Ding, F and Li, L and Lin, X and Zhao, Y}, title = {Astaxanthin Suppresses Amyloid-Beta-Induced Toxicity in AD Transgenic Caenorhabditis elegans via Promoting Skn-1-Dependent Proteasomal Activity.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {20}, pages = {3954-3963}, doi = {10.1021/acschemneuro.5c00130}, pmid = {41055317}, issn = {1948-7193}, mesh = {Animals ; Caenorhabditis elegans ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Amyloid beta-Peptides/toxicity/metabolism ; Xanthophylls/pharmacology ; Animals, Genetically Modified ; *Proteasome Endopeptidase Complex/metabolism/drug effects ; *Transcription Factors/metabolism/genetics ; *Alzheimer Disease/metabolism/drug therapy ; *DNA-Binding Proteins/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; }, abstract = {Astaxanthin is a ketocarotenoid that exhibits a variety of bioactivities, including neuroprotection, but the detailed mechanisms by which astaxanthin exerts neuroprotection remain unclear. In the present study, the effects of astaxanthin on amyloid-beta (Abeta)-induced toxicity were investigated in a Caenorhabditis elegans (C. elegans) model of Alzheimer's disease (AD). It is demonstrated that astaxanthin treatment significantly alleviated the Abeta-induced paralytic phenotype in AD C. elegans while reducing the production of reactive oxygen species and restoring the level of glutathione. Further analyses revealed that astaxanthin treatment resulted in a decrease in Abeta accumulation in AD C. elegans. Moreover, astaxanthin restored the proteasomal activity in AD C. elegans by elevating the expression of genes encoding the central subunits of the 20S proteasome. Therefore, astaxanthin might reduce Abeta accumulation via promoting proteasomal function. In addition, astaxanthin treatment increased the expression of skinhead-1 (skn-1), while knockdown of skn-1 expression by RNA interference diminished the inhibition of astaxanthin on Abeta-induced toxicity in AD C. elegans. The elevation of the expression of proteasome subunit genes and the enhancement of proteasomal activity by astaxanthin were also dependent on SKN-1. Overall, these findings indicated that astaxanthin exerted its protection against Abeta-induced toxicity in AD C. elegans via maintaining redox balance and promoting SKN-1-mediated proteasomal activity.}, } @article {pmid41054805, year = {2025}, author = {Teipel, S and Singh, D and Dubbelman, MA and Pan, G and Tang, Y and König, A}, title = {Early detection of Alzheimer's disease: From multiplex assays and imaging to point of care devices and AI-based functional monitoring.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1_suppl}, pages = {S5-S7}, doi = {10.1177/13872877251383339}, pmid = {41054805}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging ; Early Diagnosis ; *Artificial Intelligence ; *Point-of-Care Systems ; Biomarkers ; Neuroimaging/methods ; }, abstract = {The advent of disease-modifying treatments and risk-reduction strategies in the clinic have increased the demand for biomarkers for early disease detection, prediction of clinical course of disease, individual risk prediction and monitoring of treatment effects. The studies in this special issue span ultra-sensitive fluid assays and automated laboratory platforms, structural and molecular neuroimaging, electrophysiology, digital cognitive and behavioral monitoring, multi-omics, neuromodulation, and the computational frameworks necessary to integrate these diverse data.}, } @article {pmid41054216, year = {2025}, author = {Sánchez de Muniain, L and Escalada, P and Ramírez, MJ and Solas, M}, title = {Astrocytes as Metabolic Sensors Orchestrating Energy-Driven Brain Vulnerability in Alzheimer's Disease.}, journal = {Journal of neurochemistry}, volume = {169}, number = {10}, pages = {e70252}, pmid = {41054216}, issn = {1471-4159}, support = {PID2021-128737NB-I00//MCIN/AEI/10.13039/501100011033/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Astrocytes/metabolism/pathology ; *Energy Metabolism/physiology ; *Brain/metabolism/pathology ; Animals ; Oxidative Stress/physiology ; }, abstract = {Alzheimer's disease (AD), the leading neurodegenerative disorder linked to aging, emerges within a paradoxical metabolic landscape. Despite rising cellular energy demands due to accumulated damage and stress, overall energy expenditure remains stable or declines with age. The brain, acting as the central regulator, responds to hypermetabolic signals from aged tissues by activating energy-conserving mechanisms. In this scenario, astrocytes, strategically located between blood vessels and neurons, play a pivotal role as energy sensors, adapting to systemic stress and modulating brain metabolism. This review explores how astrocytes undergo metabolic reprogramming in the early stages, potentially becoming maladaptive over time, fueling neuroinflammation, oxidative stress, and accelerating AD. By understanding astrocyte energetics, we uncover new avenues for biomarkers and therapies that could transform AD treatment.}, } @article {pmid41053519, year = {2025}, author = {Amiri, M and Afshary, H and Bezaatpour, A and Hatamikia, S and Wei, J and Boukherroub, R and Szunerits, S}, title = {A critical review on neurodegenerative biomarker diagnostics: where is the field heading to?.}, journal = {Analytical and bioanalytical chemistry}, volume = {417}, number = {24}, pages = {5435-5448}, pmid = {41053519}, issn = {1618-2650}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Biomarkers/analysis ; Nanotechnology/methods ; }, abstract = {Neurodegenerative diseases (NDD), a collection of disorders with different underlying causes and clinical presentations, are recognized as a major area of concern of our society today. The most common NDD are Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease, each one of them being characterized by the progressive degradation of nerve cells and accumulation of misfolded and aggregated proteins in the affected brain region. Diagnosing NDD is challenging, due to the heterogeneity of the disease and the overlap of symptoms. Yet, early detection and accurate diagnosis are crucial for effective NDD management. With the emergence of disease-modifying therapies for AD, monitoring disease progression and treatment success is becoming essential. The future of NND diagnostics is focusing on developing less invasive, cost-effective strategies that enable early NDD identification and detection with improved patient outcomes. The integration of biotechnology and nanotechnology is seen as crucial for advancing the analytical science aspect of NDD. The creation of these innovative tools and methodologies is on the verge of enabling new possibilities for clinical diagnostics, but is also faced with several hurdles that will be critically evaluated.}, } @article {pmid41053038, year = {2025}, author = {Ficchì, S and Cauzzi, E and La Barbera, L and De Paolis, ML and Loffredo, G and Spoleti, E and Ferrari, I and Saba, L and Biamonte, F and Nobili, A and Krashia, P and D'Amelio, M}, title = {Optogenetic stimulation of midbrain dopaminergic neurons rescues hippocampal synaptic plasticity deficits in a mouse model of Alzheimer's disease.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {371}, pmid = {41053038}, issn = {2158-3188}, support = {AARG-21-851219/ALZ/Alzheimer's Association/United States ; }, mesh = {Animals ; *Alzheimer Disease/physiopathology/therapy ; *Dopaminergic Neurons/physiology ; *Optogenetics ; Disease Models, Animal ; Mice ; *Mesencephalon/physiopathology ; *Neuronal Plasticity/physiology ; *Hippocampus/physiopathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Oxidopamine ; *Long-Term Potentiation/physiology ; Male ; Synaptic Transmission ; }, abstract = {We previously demonstrated that the Tg2576 mouse model of Alzheimer's Disease (AD) exhibits degeneration of midbrain dopaminergic neurons, resulting in reduced dopamine (DA) outflow in the hippocampus. These impairments temporally coincide with synaptic plasticity deficits at CA3-CA1 synapses. Notably, systemic administration of dopaminergic agents/drugs rescues the hippocampal deficits in Tg2576 mice. However, whether direct stimulation of the remaining midbrain dopaminergic neurons can restore glutamatergic transmission and rescue plasticity dysfunctions in the context of AD remains unexplored. Here, using both 6-hydroxydopamine (6-OHDA) neurotoxic lesion and optogenetic stimulation in C57BL/6N and DATCre/Tg2576 mice, respectively, we demonstrate that midbrain DA is essential for hippocampal High-Frequency Stimulation-induced Long-Term Potentiation (HFS-LTP) in CA3-CA1 synapses. Indeed, lesioning midbrain DA neurons with 6-OHDA abolishes HFS-LTP and impairs novel object recognition memory. Conversely, optogenetic activation of the midbrain-hippocampal dopaminergic pathway in DATCre/Tg2576 mice enhances glutamatergic transmission and rescues plasticity deficits. Our results highlight the phase-specific role of DA in HFS-LTP, since 6-OHDA lesion affects the late but not the early phase, aligning with prior studies on D1/D5 receptor involvement in protein synthesis-dependent plasticity. Furthermore, we provide novel insights into midbrain DA neuron regulation, demonstrating that phasic, but not prolonged, optogenetic stimulation effectively engages DA neuron activity, restoring hippocampal function in Tg2576 mice. Notably, phasic DA release induces "DA-LTP" via D1/D5 receptors, and restores HFS-LTP in CA3-CA1 synapses of AD mice, underscoring a potential compensatory mechanism counteracting plasticity deficits induced by DA neuron degeneration in Tg2576 mice. These findings support targeting the dopaminergic midbrain as a promising strategy for AD treatment, complementing pharmacological and non-invasive neuromodulatory approaches.}, } @article {pmid41052971, year = {2025}, author = {Chen, J and Xiang, P and Duro-Castano, A and Cai, H and Guo, B and Liu, X and Yu, Y and Lui, S and Luo, K and Ke, B and Ruiz-Pérez, L and Gong, Q and Tian, X and Battaglia, G}, title = {Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport.}, journal = {Signal transduction and targeted therapy}, volume = {10}, number = {1}, pages = {331}, pmid = {41052971}, issn = {2059-3635}, support = {769798 CheSSTag//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; }, mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; *Amyloid beta-Peptides/genetics/metabolism ; Mice ; *Alzheimer Disease/genetics/drug therapy/pathology/metabolism ; Humans ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics ; *Cognition/drug effects ; Receptors, LDL/genetics ; Disease Models, Animal ; Transcytosis ; }, abstract = {The blood‒brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer's disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques. We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1 (LRP1) on the BBB. Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport, biasing LRP1 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβ removal. In AD model mice, this intervention significantly reduced brain Aβ levels by nearly 45% and increased plasma Aβ levels by 8-fold within 2 h, as measured by ELISA. Multiple imaging techniques confirmed the reduction in brain Aβ signals after treatment. Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory, with performance levels comparable to those of wild-type mice. These cognitive benefits persisted for up to 6 months post-treatment. This work pioneers a new paradigm in drug design, where function arises from the supramolecular nature of the nanomedicine, harnessing multivalency to elicit biological action at the membrane trafficking level. Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective. We establish a compelling case for BBB modulation and LRP1-mediated Aβ clearance as a transformative foundation for future AD therapies.}, } @article {pmid41052930, year = {2025}, author = {Emami Naeini, S and Bhandari, B and Hill, B and Perez-Morales, N and Rogers, HM and Khodadadi, H and Young, N and Maciel, LM and Yu, JC and Hess, DC and Morgan, JC and Lopes Salles, É and Wang, LP and Baban, B}, title = {Rethinking Alzheimer's: Harnessing Cannabidiol to Modulate IDO and cGAS Pathways for Neuroinflammation Control.}, journal = {eNeuro}, volume = {12}, number = {10}, pages = {}, pmid = {41052930}, issn = {2373-2822}, mesh = {*Cannabidiol/pharmacology/administration & dosage ; Animals ; *Alzheimer Disease/metabolism/drug therapy/immunology ; *Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism/drug effects ; Mice ; Male ; Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism/drug therapy ; *Nucleotidyltransferases/metabolism/drug effects ; Disease Models, Animal ; Signal Transduction/drug effects ; }, abstract = {Alzheimer's disease (AD) has traditionally been associated with amyloid-β plaques, but growing evidence underscores the role of neuroinflammation in disease progression. The autoinflammatory hypothesis of AD suggests chronic immune dysfunction contributes to neuronal damage, making immune modulation a promising therapeutic strategy. Cannabidiol (CBD), a phytocannabinoid with anti-inflammatory properties, may offer therapeutic potential. This study investigates how CBD independently influences two key neuroinflammatory regulators in AD: the indoleamine 2,3-dioxygenase (IDO) pathway and the cyclic GMP-AMP synthase (cGAS) pathway. Though mechanistically distinct, both shape CNS immune responses. Targeting these immune-metabolic axes provides a mechanistic alternative to amyloid- or tau-based approaches by addressing upstream drivers of neuroinflammation and immune dysregulation. Using the male 5XFAD transgenic AD mouse model, we administered CBD via inhalation and assessed IDO and cGAS expression using flow cytometry, immunofluorescence (IF), and gene expression analysis. We evaluated cytokine levels and used STRING-based bioinformatics to identify CBD-target interactions. CBD treatment significantly reduced IDO and cGAS expression, correlating with decreased proinflammatory cytokines, including TNF-α, IL-1β, and IFN-γ. Bioinformatics identified potential interactions between CBD and immune targets such as AKT1, TRPV1, and GPR55. These targets were prioritized based on their roles in neuroinflammatory signaling and high-confidence interactions with CBD. AKT1 regulates inflammatory signaling and cell survival, TRPV1 modulates nociception and neuroinflammation, and GPR55 influences immune cell activation. These findings support CBD as a potential monotherapy or adjunctive treatment for AD by targeting distinct neuroinflammatory pathways, including IDO and cGAS. Further studies are warranted to fully explore its therapeutic potential.}, } @article {pmid41052547, year = {2025}, author = {Ajoolabady, A and Kim, B and Abdulkhaliq, AA and Ren, J and Bahijri, S and Tuomilehto, J and Borai, A and Khan, J and Pratico, D}, title = {Dual role of microglia in neuroinflammation and neurodegenerative diseases.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107133}, doi = {10.1016/j.nbd.2025.107133}, pmid = {41052547}, issn = {1095-953X}, mesh = {*Microglia/metabolism/immunology ; Humans ; *Neurodegenerative Diseases/immunology/metabolism/pathology ; *Neuroinflammatory Diseases/immunology/metabolism/pathology ; Animals ; HMGB1 Protein/metabolism ; Brain/immunology/metabolism ; }, abstract = {Microglia are the principal innate immune cells of the central nervous system, playing cardinal roles in regulating immunity and mediating neuroinflammation - a chronic inflammatory response occurring in the brain and spinal cord. Microglia exhibit a dual role in this process: they can suppress neuroinflammation through anti-inflammatory polarization or inhibition of proinflammatory intracellular signaling, or conversely, they can exacerbate neuroinflammation via activation of proinflammatory pathways and phenotypes. This seemingly binary behavior is further complicated by a network of internal and external molecular effectors that influence microglial polarization and function, guiding them toward either neuroprotection or neurotoxicity. In this narrative review, we aimed to elucidate the dual role of microglia in neuroinflammation, particularly in the context of neurodegenerative diseases and other brain pathologies. Special emphasis is placed on the most recent findings related to key proteins such as TREM2 (triggering receptor expressed on myeloid cells 2) and HMGB1 (high mobility group box 1 protein). By examining the molecular mechanisms and pathways involving these proteins, we highlight promising therapeutic targets for modulating neuroinflammation and advancing developing novel treatment strategies for neurodegenerative and other brain-related disorders.}, } @article {pmid41052542, year = {2025}, author = {Hansen, N and Wiltfang, J}, title = {[Disease-modifying therapy with lecanemab for early Alzheimer's dementia].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {93}, number = {11}, pages = {453-460}, pmid = {41052542}, issn = {1439-3522}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a severe and progressive neurodegenerative disease of the brain that has so far been treated with symptomatic drug and non-drug therapies as standard treatment. Following the approval of the monoclonal anti-amyloid antibody by the FDA, AD therapy has changed, as this therapy has made it possible to attenuate the biological disease process of AD. Lecanemab has been recommended by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for approval in patients with early AD under two conditions. Firstly, homozygous ApoE4 carriers and secondly, patients receiving oral anticoagulants should not receive lecanemab. The following narrative review explains the mechanism of action, safety and side effects of lecanemab. Furthermore, risk factors for side effects are described. Finally, the first experiences with lecanemab are reported and the efficacy and financial aspects are discussed. Lecanemab leads to a temporary reduction in amyloid-ß deposits and to a benefit that can be reflected in everyday competence, cognition and quality of life and can be described as a breakthrough in AD's therapy due to its demonstrable biological and clinical efficacy.}, } @article {pmid41051912, year = {2025}, author = {Hickman, LB and Pandey, B and Fish, A and Bandla, M and Husein, A and Allas, C and Kottakota, H and Herzog, L and Vossel, K and Stern, JM}, title = {Late-onset epilepsy of unknown etiology is more treatment-responsive than acquired lesional late-onset epilepsy.}, journal = {Epilepsia open}, volume = {10}, number = {6}, pages = {1847-1859}, pmid = {41051912}, issn = {2470-9239}, support = {UE5 NS065723-16/NS/NINDS NIH HHS/United States ; R01 AG058820/AG/NIA NIH HHS/United States ; R01 AG075955/NS/NINDS NIH HHS/United States ; R01 AG058820/NS/NINDS NIH HHS/United States ; UH2 AG083254/AG/NIA NIH HHS/United States ; R56 AG074473/AG/NIA NIH HHS/United States ; UH2 AG083254/NS/NINDS NIH HHS/United States ; UE5 NS065723/NS/NINDS NIH HHS/United States ; R56 AG074473/NS/NINDS NIH HHS/United States ; R01 AG075955/AG/NIA NIH HHS/United States ; R01 NS033310/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; *Epilepsy/etiology/drug therapy/diagnostic imaging/physiopathology ; Electroencephalography ; Age of Onset ; Magnetic Resonance Imaging ; *Anticonvulsants/therapeutic use ; Aged, 80 and over ; }, abstract = {OBJECTIVE: Late-onset epilepsy of unknown etiology (LOEU) carries an elevated risk of dementia, suggesting that it may represent an early manifestation of neurodegenerative or cerebrovascular disease. Direct comparisons between LOEU and acquired lesional late-onset epilepsy (LOE) may elucidate clinical features specific to LOEU. METHODS: We performed a retrospective chart review of patients with LOE, with first documented seizure at age 55 or older, whose evaluation included an epilepsy-protocol brain MRI and/or inpatient video-EEG evaluation. Etiology was determined from neuroimaging lesions and medical history. Patients without an identified etiology were categorized as LOEU. Analyses were performed controlling for sex, age of onset, and epilepsy duration. RESULTS: We identified 75 LOEU (mean onset: 64.9 years, 38.7% female) and 57 acquired lesional LOE cases with etiologies including cortical stroke, hemorrhage, neoplasm, trauma, or infection (mean onset: 66.5 years, 36.8% female). LOEU was less likely to have a history of status epilepticus (6.7% vs. 21.1%, aOR: 0.28, p < 0.03) or to have undergone inpatient video-EEG monitoring (13.3% vs. 24.6%, aOR: 0.34, p < 0.04). LOEU was prescribed fewer ASMs compared to acquired lesional LOE (aOR: 0.43, p < 0.02), and LOEU patients prescribed multiple ASMs had lower average 12-month seizure frequency than acquired lesional LOE (median: 0.2 vs. 1.0, p < 0.01). LOEU had lower rates of vascular comorbidities than acquired lesional LOE, though rates of subsequent dementia were not significantly different (5-year risk: 16.6% vs. 17.7%). An exploratory cluster analysis demonstrated an LOEU subgroup with older onset, higher prevalence of white matter hyperintensities, cerebral atrophy, epileptiform discharges, and greater epilepsy severity. SIGNIFICANCE: LOEU was associated with fewer proxies for epilepsy severity, signifying that LOEU is more often treatment-responsive than acquired lesional LOE. LOEU has lower rates of comorbid vascular disease compared to acquired lesional LOE, suggesting that occult cerebrovascular disease is not overrepresented in LOEU relative to other forms of LOE. PLAIN LANGUAGE SUMMARY: People who develop epilepsy after age 55 without a known cause usually respond well to treatment and need fewer antiseizure medications than people with epilepsy from a known brain injury. In this study, they had fewer hospital stays for seizure monitoring and fewer vascular problems. Dementia risk was high in patients with late-onset epilepsy, both when the cause was known and when it was unknown. Late-onset epilepsy without a known cause is often less severe but still needs regular monitoring for memory and thinking problems.}, } @article {pmid41051689, year = {2025}, author = {Azam, HMH and Mumtaz, M and Rödiger, S and Schierack, P and Hussain, N and Aisha, A}, title = {MicroRNAs in neurodegenerative diseases: from molecular mechanisms to clinical biomarkers, detection methods and therapeutic strategies-advances and challenges.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {12}, pages = {6277-6319}, pmid = {41051689}, issn = {1590-3478}, mesh = {Humans ; *MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/diagnosis/therapy/genetics/metabolism ; Biomarkers/metabolism ; Animals ; }, abstract = {Neurodegenerative diseases (NDDs) pose significant challenges in early detection and treatment due to their complex pathophysiology and heterogeneous clinical presentations. MicroRNAs (miRNAs), small noncoding RNAs that regulate gene expression, have emerged as promising diagnostic biomarkers and therapeutic targets in NDDs. Pathological examination of affected tissues reveals early synaptic dysfunction, protein misfolding, and neuroinflammation occur prior to overt clinical symptoms, highlighting the importance of sensitive diagnostics approaches in prodromal stages. This review summarizes for researchers on the role of miRNAs in NDDs by examining their diagnostic potential in biofluids such as blood and cerebrospinal fluid, and their therapeutic applicability through inhibition or replacement strategies. Literature from peer-reviewed databases was assessed with a focus on recent advances in molecular detection platforms, computational modeling of miRNA-mRNA interactions, and preclinical/clinical investigations.More than 2600 human miRNAs have been identified, collectively regulating over half of mammalian protein-coding genes. Quantitative methodologies, particularly reverse transcription quantitative PCR (RT-qPCR), enable reliable miRNA profiling, facilitating early diagnosis and prognosis of NDDs. Therapeutic strategies, including antagomirs, mimics, sponges and viral or non-viral delivery systems, show promise in modulating disease pathways. However, significant challenges remain, including variability in miRNA extraction and quantification protocols, off-target effects, delivery barriers across the blood brain barrier and limited reproducibility across studies. MiRNAs represent a class of molecular tools with potential to transform diagnostics and therapeutics in NDDs. Future research should prioritize methodological standardization, validation in large multicenter cohorts, and improved computational approaches to elucidate miRNA-mediated regulatory networks in NDDs. Replication studies and translational research are essential harnessing the the full clinical utility of miRNAs in the management of Alzheimer disease, Parkinson disease and other NDDs. Graphical Abstract.}, } @article {pmid41051550, year = {2025}, author = {Yang, T}, title = {Molecular Mechanisms of EDC-Induced Alzheimer's Disease and of Traditional Chinese Medicine Active Substances in Treating AD and Antagonizing EDC-Induced Effects.}, journal = {Neurochemical research}, volume = {50}, number = {5}, pages = {319}, pmid = {41051550}, issn = {1573-6903}, mesh = {*Alzheimer Disease/chemically induced/drug therapy/metabolism ; Molecular Docking Simulation/methods ; *Medicine, Chinese Traditional/methods ; Humans ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Animals ; Network Pharmacology ; Ginsenosides/therapeutic use/pharmacology ; Protein Interaction Maps/drug effects ; }, abstract = {AD, a progressive neurodegenerative disorder, imposes an increasingly heavy burden on global public health, with its pathogenesis remaining incompletely understood. Meanwhile, EDCs-widely present in the environment, food, and consumer products-have emerged as a significant public health concern due to their diverse health risks, including potential contributions to neurodegenerative processes such as AD by disrupting neurohomeostasis. Furthermore, as natural compounds, ginsenosides and other AS have been the focus of numerous studies exploring their role in treating AD, thanks to their advantages of multi-target properties and low side effects. However, the specific molecular pathways through which EDCs induce AD, as well as the mechanisms by which AS may counteract EDC-induced toxicity and intervene in AD, remain unclear. Against this background, this study sought to: (1) explore the molecular pathways through which EDCs may induce AD by disrupting neurohomeostasis; (2) preliminarily investigate the potential of AS in treating AD and antagonizing EDC-induced AD at the molecular level. To achieve these goals, we integrated network toxicology, network pharmacology, and molecular docking to construct a multi-dimensional interaction network among EDCs, AD, and AS. By establishing intersecting target sets for EDCs-AD and AS-AD, core targets were identified via topology analysis of protein-protein interaction (PPI) networks. GO and KEGG enrichment analyses highlighted key pathways, including serotonergic synapse and neuroactive ligand-receptor interaction. Molecular docking further explored interactions between EDCs/AS and core target proteins. The results suggest that EDCs may drive neurodegeneration in AD by impairing synaptic function, while AS may counteract these effects by enhancing synaptic activity, stabilizing membrane microenvironments, inhibiting Aβ aggregation, alleviating neuroinflammation, and restoring metabolic homeostasis. Further analysis indicated that AS exhibit stronger binding ability to core targets compared to EDCs, implying a potential antagonistic effect of AS against EDCs. This study provides insights into the molecular mechanisms underlying EDC-induced AD and establishes a multi-target theoretical framework for AS-mediated antagonism of EDC toxicity, offering a reference for the prevention and treatment of neurodegenerative diseases.}, } @article {pmid41051385, year = {2025}, author = {Xie, D and Zheng, Q and Lv, J and Zhang, Q and Cui, Z and Huang, S and Yu, W and Chen, B and Que, W and Fu, S and Xi, Y and Chen, J and Ye, X and Chen, S and Zhao, H and Yamamoto, T and Koyama, H and Wang, X and Cheng, J}, title = {Uric Acid Functions as an Endogenous Modulator of Microglial Function and Amyloid Clearance in Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {48}, pages = {e10270}, pmid = {41051385}, issn = {2198-3844}, support = {82370895//National Natural Science Foundation of China/ ; U01 AG024904/AG/NIA NIH HHS/United States ; W81XWH-12-2-0012//DOD ADNI/ ; 82271451//National Natural Science Foundation of China/ ; 82260163//National Natural Science Foundation of China/ ; 2020J01018//Natural Science Foundation of Fujian Province/ ; 2022Y4007//Fujian Provincial Industry-University-Research Collaborative Innovation Project Plan/ ; }, mesh = {*Alzheimer Disease/metabolism ; *Uric Acid/metabolism/pharmacology ; *Microglia/metabolism/drug effects ; Animals ; Mice ; *Amyloid beta-Peptides/metabolism ; Humans ; Phagocytosis/drug effects ; Disease Models, Animal ; Mice, Transgenic ; Male ; Plaque, Amyloid/metabolism ; }, abstract = {Epidemiological studies have linked uric acid (UA), the end product of purine metabolism in humans, with reduced Alzheimer's disease (AD) risk. Decreased serum UA levels are observed in AD patients versus age-matched controls, while upstream purine metabolites remained unchanged. In 5×FAD mice, two months of UA supplementation improved cognitive function and reduced amyloid plaque burden. Mechanistically, UA enhances microglial amyloid-β (Aβ) phagocytosis and induces transcriptional reprogramming in AD mouse microglia, characterized by upregulated phagocytic pathways and attenuated inflammatory responses. UA treatment restored the recycling of Aβ receptors CD36 and TREM2 in microglia, enhanced lysosomal biogenesis, and facilitated Aβ degradation. These findings identify UA as a critical endogenous modulator of microglial Aβ processing and suggest exploring UA supplementation as a therapeutic strategy for AD.}, } @article {pmid41051231, year = {2025}, author = {Paul, S and Guruprasad, L}, title = {Hexagonal Boron Nitride Nanoparticles for Inhibition of Small Fragment Tau Aggregation.}, journal = {The journal of physical chemistry. B}, volume = {129}, number = {41}, pages = {10752-10764}, doi = {10.1021/acs.jpcb.5c04935}, pmid = {41051231}, issn = {1520-5207}, mesh = {*Nanoparticles/chemistry ; *Boron Compounds/chemistry/pharmacology ; *tau Proteins/chemistry/metabolism/antagonists & inhibitors ; Protein Aggregates/drug effects ; Humans ; Molecular Dynamics Simulation ; }, abstract = {The aberrant folding of the Tau protein is correlated with several neurodegenerative diseases, such as Alzheimer's and other tauopathies. Recent studies on the neurotoxic species of Tau have identified some smaller nucleating domains of the full-length protein to initiate Tau aggregation and are shown as potential therapeutic targets in Tau pathology. Two hexapeptides, namely, PHF6 ([306]VQIVYK[311]) and PHF6* ([275]VQIINK[280]), have been recognized as the most important aggregation-prone Tau fragments among all. Currently, low-dimensional nanomaterials have shown a plethora of applications in bionanomedicine, including the treatment of amyloid diseases. Hexagonal boron nitride (h-BN) nanoparticles, analogous to carbon nanomaterials, have become potential candidates in this field due to their lower cytotoxicity compared to carbon nanoparticles and biocompatibility. In this study, we have explored the aggregation pattern of PHF6 and PHF6* and the effects of a two-dimensional (2D) h-BN nanosheet (BNNS) on these peptide oligomerizations. Atomistic simulations reveal that the PHF6-PHF6 homomer aggregation is highly favored due to the aromatic π-π interaction between the Tyr residues; furthermore, the heteromeric interaction between PHF6 and PHF6* is stronger than the self-association of PHF6* homomers. In the presence of BNNS, the peptides get absorbed on the nanosurface through weak hydrophobic interactions and aromatic π-π stacking and remain in their monomeric random coil structure. Also, the h-BN nanosheet can destabilize the preformed oligomers of the hexapeptides, hence providing a new direction toward the use of h-BN and other related nanomaterials as potential antiaggregating agents against amyloid deposition.}, } @article {pmid41051040, year = {2025}, author = {Agarwal, U and Paliwal, S and Yadav, V and Pannu, A and Tonk, RK and Verma, S}, title = {Pathological Insights into Neurodegenerative and Neurodevelopmental Disorders: Perspectives for the Development of Novel Treatment Approaches.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273402657250905055635}, pmid = {41051040}, issn = {1996-3181}, abstract = {Neurodegenerative and neurodevelopmental disorders represent a significant global health burden, characterized by progressive neuronal dysfunction and loss. Both diseases, despite their diverse etiologies and mechanisms, share a complex interplay of genetic, environmental, and biological factors. Neurodegenerative diseases are caused by multiple factors, including aging, mitochondrial dysfunction, oxidative stress, inflammation, genetic mutations, and protein misfolding. In contrast, neurodevelopmental disorders are primarily influenced by epigenetic alterations, neurotransmitter imbalances, early brain damage, environmental factors, and genetic variations. Despite extensive research, effective treatments remain unavailable due to the complexity of their pathologies and the biochemical pathways involved. A deep understanding of the complexities and individual differences associated with these disorders is crucial for developing effective treatments. In this background, this review provides a comprehensive overview of neurodegenerative and neurodevelopmental disorders, including their clinical symptoms, etiology, pathogenesis, underlying mechanisms, potential drug targets, reported drugs, advanced treatment options, and challenges in the drug discovery process. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to April 2025. By understanding the complexities of these disorders, researchers can develop novel therapeutic approaches, including potential drugs and advanced treatment methods, to mitigate their devastating impact.}, } @article {pmid41050964, year = {2025}, author = {Zhou, Z and Chen, X and Kou, W and Meng, F and Yu, L and Wen, J and Boey, J and Shah, V and Malagón, P}, title = {Modified Dynamic Lymphaticovenular Anastomosis for Surgical Management of Alzheimer Disease.}, journal = {Plastic and reconstructive surgery. Global open}, volume = {13}, number = {10}, pages = {e7082}, pmid = {41050964}, issn = {2169-7574}, abstract = {Alzheimer disease (AD) is a neurodegenerative disorder that frequently results in progressive cognitive decline. Despite the extensive research conducted on AD, there is presently no solution available due to its increasing prevalence. Recent research has suggested cervical lymphaticovenular anastomosis (LVA) as a therapeutic strategy to improve lymphatic outflow and potentially reduce AD symptoms. We established an amended LVA protocol to mitigate the risk of venous reflux, a prevalent issue associated with the original LVA methodology. A 64-year-old man of Chinese descent exhibited the typical signs and symptoms of AD. The absence of substantial progress with standard medical treatment led to the consideration of LVA. We used a lower limb vein graft for the LVA, anastomosing it to the cervical lymphatic vessels and external jugular vein. The cognitive function of the patient got better after LVA, as shown by higher Mini Mental State Examination and Montreal Cognitive Assessment scores. Fewer β-amyloid and tau protein deposits were observed on positron emission tomography/computed tomography scans. No adverse occurrences or issues were observed. The success in this case demonstrated the potential role of LVA in the management of AD. However, further thorough research is required to evaluate the efficacy of our technique.}, } @article {pmid41050469, year = {2025}, author = {Wang, Y and Liu, T and He, Y and Tang, Y and Tan, P and Huang, L and Huang, D and Wen, T and Shao, L and Wang, J and Wang, Y and Han, Z}, title = {Identifying Alzheimer's disease-related pathways based on whole-genome sequencing data.}, journal = {Computational and structural biotechnology journal}, volume = {27}, number = {}, pages = {4132-4144}, pmid = {41050469}, issn = {2001-0370}, abstract = {Alzheimer's disease (AD) is a highly inheritable neurodegenerative disorder for which pathway-specific genetic profiling provides insights into its key biological mechanisms and potential treatment targets. Traditional disease-pathway analyses for AD have certain limitations, such as environmental interference and arbitrary sample division. We present a comprehensive framework that starts with genome data, avoiding these drawbacks and offering intrinsic pathway-specific genetic profiling for AD. Whole genome sequencing data from 173 individuals were used to quantify transcriptomes in 14 brain regions, estimate individual-level pathway variant scores, and analyze AD risk for each patient. These results were combined to identify AD-related pathways and quantify their interactions. The predicted expression levels were consistent with previous findings, and the estimated AD risk showed a significant correlation with Braak/Thal scores. A total of 3798 pathways were identified as potentially associated with AD, with about 19.7 % previously reported. The pathways identified as AD risk related primarily address six core biological themes, including: Immunity and inflammation, Metabolism, Protein homeostasis, DNA/RNA and Epigenetics, Synapse and structure, Cell cycle. Specifically, key pathways, such as NF-κB signaling and GSK3β activation, were linked to AD pathogenesis. The interactions among pathways highlighted shared gene functions in AD. In summary, we provided an effective framework for disease-pathway analysis, revealing the interdependence or compensatory effects of pathways in AD.}, } @article {pmid41050397, year = {2025}, author = {Liu, W and Zhao, Y and Liu, T and Wang, Y and Yin, D and Zou, S and Zou, C and Zhang, Z and Zhi, H and Wang, Y}, title = {Kaixin San Jiawei granule improves cognitive function and alleviates neuronal damage in Alzheimer's disease via multi-component and multi-target mechanisms.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1650534}, pmid = {41050397}, issn = {1663-9812}, abstract = {BACKGROUND: Kaixin San Jiawei Granule (KSG) is a traditional Chinese medicine formulation derived from classical prescriptions. Although it has shown promise in treating Alzheimer's disease (AD), its precise mechanisms of action remain unclear. This study aimed to systematically investigate the molecular mechanisms underlying KSG's therapeutic effects on AD through an integrative approach combining network pharmacology with experimental validation. METHODS: An in vivo AD model was established in male KM mice via intraperitoneal injection of scopolamine. Cognitive function was assessed using the Morris water maze, and hippocampal levels of acetylcholine (ACh), acetylcholinesterase (AChE), glutathione peroxidase (GSH-Px), and reactive oxygen species (ROS) were measured using ELISA. In vitro, PC12 cells were exposed to Aβ25-35 to induce apoptosis. Immunofluorescence staining, Western blotting, and qPCR were used to assess the expression of amyloid-beta (Aβ), apoptosis-related protein caspase-3, and inflammatory cytokines (TNF-α, IL-1β). Active components of KSG and their potential targets and pathways were identified using mass spectrometry and network pharmacology, while partial validation was performed using molecular docking and Western blotting. RESULTS: In vivo, KSG significantly alleviated scopolamine-induced cognitive deficits in mice. Treatment increased hippocampal levels of ACh and GSH-Px while reducing AChE and ROS. In vitro, KSG mitigated Aβ25-35-induced cytotoxicity in PC12 cells, decreased Aβ accumulation, and downregulated the expression of TNF-α and IL-1β. However, KSG had no significant effect on telomerase activity, telomere length, or the expression of the telomere-associated protein POT1. Mass spectrometry and network pharmacology analyses identified genistein, quercetin, and apigenin as key active compounds with TP53, AKT1, PTGS2, and CNR2 identified as core targets. Molecular docking validation confirmed the favorable binding activity between them. The calcium signaling, PI3K-Akt, and MAPK pathways emerged as the primary enriched pathways. CONCLUSION: KSG improves cognitive function and attenuates Aβ-induced neuronal damage in AD through multi-component, multi-target synergistic mechanisms. These effects appear to be mediated by modulation of the cholinergic system, inhibition of oxidative stress and inflammation, and suppression of neuronal apoptosis. These findings provide a theoretical basis and experimental support for developing novel AD therapies based on traditional Chinese medicine.}, } @article {pmid41049759, year = {2025}, author = {Meden, A and Žnidaršič, N and Knez, D and Wang, Y and Xu, Z and Yang, H and Zhang, W and Pišlar, A and Perdih, A and Brezar, SK and Grgurevič, N and Pajk, S and Sun, H and Gobec, S}, title = {Pleiotropic prodrugs for both symptomatic and disease-modifying treatment of Alzheimer's disease.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {9}, pages = {4807-4828}, pmid = {41049759}, issn = {2211-3835}, abstract = {The inherent complexity of Alzheimer's disease (AD) and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology. Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action. Pseudo-irreversible inhibition of the first therapeutic target, human butyrylcholinesterase (hBChE), enhances cholinergic transmission, and thereby provides symptomatic treatment, same as the standard therapeutics in use for AD. Simultaneously, this step also functions as a metabolic activation that liberates a nanomolar selective α 2-adrenergic antagonist atipamezole, which blocks pathological amyloid β (Aβ)-induced and noradrenaline-dependent activation of GSK3β that ultimately leads to hyperphosphorylation of tau, thus achieving a disease-modifying effect. Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition, metabolic activation in human plasma, blood-brain barrier permeability, and p.o. bioavailability in mice. Multi-day in vivo treatment with 8 in an Aβ-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine, the current drug of choice for AD therapy. Furthermore, decreased GSK3β activation and lowered tau phosphorylation were observed in APP/PS1 mice. This surpasses the symptomatic-only treatment with cholinesterase inhibitors, as it directly blocks an essential pathological cascade in AD. Therefore, these multifunctional α 2-adrenergic antagonists-butyrylcholinesterase inhibitors, exemplified by lead compound 8, present an innovative, small molecule-based, disease-modifying approach to treatment of AD.}, } @article {pmid41049755, year = {2025}, author = {Yang, Y and Diao, Y and Jiang, L and Li, F and Chen, L and Ni, M and Wang, Z and Fang, H}, title = {A computational medicine framework integrating multi-omics, systems biology, and artificial neural networks for Alzheimer's disease therapeutic discovery.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {9}, pages = {4411-4426}, pmid = {41049755}, issn = {2211-3835}, abstract = {The translation of genetic findings from genome-wide association studies into actionable therapeutics persists as a critical challenge in Alzheimer's disease (AD) research. Here, we present PI4AD, a computational medicine framework that integrates multi-omics data, systems biology, and artificial neural networks for therapeutic discovery. This framework leverages multi-omic and network evidence to deliver three core functionalities: clinical target prioritisation; self-organising prioritisation map construction, distinguishing AD-specific targets from those linked to neuropsychiatric disorders; and pathway crosstalk-informed therapeutic discovery. PI4AD successfully recovers clinically validated targets like APP and ESR1, confirming its prioritisation efficacy. Its artificial neural network component identifies disease-specific molecular signatures, while pathway crosstalk analysis reveals critical nodal genes (e.g., HRAS and MAPK1), drug repurposing candidates, and clinically relevant network modules. By validating targets, elucidating disease-specific therapeutic potentials, and exploring crosstalk mechanisms, PI4AD bridges genetic insights with pathway-level biology, establishing a systems genetics foundation for rational therapeutic development. Importantly, its emphasis on Ras-centred pathways-implicated in synaptic dysfunction and neuroinflammation-provides a strategy to disrupt AD progression, complementing conventional amyloid/tau-focused paradigms, with the future potential to redefine treatment strategies in conjunction with mRNA therapeutics and thereby advance translational medicine in neurodegeneration.}, } @article {pmid41049729, year = {2025}, author = {Ren, F and Wei, J and Chen, Q and Hu, M and Yu, L and Mi, J and Zhou, X and Qin, D and Wu, J and Wu, A}, title = {Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {9}, pages = {4327-4385}, pmid = {41049729}, issn = {2211-3835}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, with few effective treatments currently available. The multifactorial nature of AD, shaped by genetic, environmental, and biological factors, complicates both research and clinical management. Recent advances in artificial intelligence (AI) and multi-omics technologies provide new opportunities to elucidate the molecular mechanisms of AD and identify early biomarkers for diagnosis and prognosis. AI-driven approaches such as machine learning, deep learning, and network-based models have enabled the integration of large-scale genomic, transcriptomic, proteomic, metabolomic, and microbiomic datasets. These efforts have facilitated the discovery of novel molecular signatures and therapeutic targets. Methods including deep belief networks and joint deep semi-non-negative matrix factorization have contributed to improvements in disease classification and patient stratification. However, ongoing challenges remain. These include data heterogeneity, limited interpretability of complex models, a lack of large and diverse datasets, and insufficient clinical validation. The absence of standardized multi-omics data processing methods further restricts progress. This review systematically summarizes recent advances in AI-driven multi-omics research in AD, highlighting achievements in early diagnosis and biomarker discovery while discussing limitations and future directions needed to advance these approaches toward clinical application.}, } @article {pmid41048559, year = {2025}, author = {Ma, X and Wang, F and Wang, G and Zhao, M and Zheng, Y and Guo, Y and Wu, J and Liu, Y and Liu, Y and He, G and Ren, L and Gong, Z and Wang, J and Chen, L and Hu, S and Chu, Q and Li, Z and Wu, J and Li, R and Zhang, X and Shi, Q and Lian, H and Ye, J}, title = {A surgical therapy for Alzheimer's disease with lymphaticovenular anastomosis.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251384244}, pmid = {41048559}, issn = {2542-4823}, abstract = {BACKGROUND: Deep cervical lymphaticovenular anastomosis (dcLVA) surgery is able to control aging-associated Alzheimer's disease in patients. However, the efficacy rate remains unknown. OBJECTIVE: This study is designed to test the surgery efficacy in the treatment of mild-to-moderate AD patients. METHODS: This is a single-center retrospective study of dcLVA treatment of mild-to-moderate AD for 3 months. A total of 41 patients received the surgery, in which lymph vessels and lymph nodes in the district III of cervical area were identified using indocyanine fluorescence dye. The afferent lymphatics of the obstructed lymph nodes were connected to the jugular vein to fix the lymphatic blockage under a fluorescent microscope. The efficacy rate was examined at 3-month post-surgery by clinical scores and biomarkers. RESULTS: Lymph flow obstruction was observed on both sides of cervical area in the AD patients. The obstruction was successfully resolved through the surgery, and AD progression was attenuated or even reversed in the patients according to improvement in the scales of MMSE, ADL, NPI, CDR-SB, and CGI-EI. The average effectiveness rate was 50% by the CDR-SB score improvement. The efficacy was higher with shorter disease duration but not influenced by age and APOE4 genotype. Aβ42/40 ratio and p-tau181 were improved in more than 67% patients. There were 2 cases of mild adverse reactions that were controlled immediately by regular treatments. CONCLUSIONS: The data demonstrate that dcLVA surgery is an effective and safe therapy for AD in mild-to-moderate patients with 50% efficacy rate as measured by improvement of the CDR-SB score.}, } @article {pmid41048557, year = {2025}, author = {Jeong, H and Kang, D and Kim, JE and Lim, J and Lee, HW}, title = {Preliminary study on the feasibility of virtual reality-based cognitive training on patients with mild to moderate Alzheimer's disease.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251385901}, pmid = {41048557}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that causes a decline in cognitive functions, considerably affecting a patient's life. Recently, virtual reality (VR) technology has emerged as a new tool used in the cognitive training of patients with AD. OBJECTIVE: This study aimed to investigate the safety, feasibility, and clinical efficacy of VR-based cognitive training for patients with mild to moderate AD. METHODS: Thirteen participants diagnosed with mild to moderate AD underwent VR training sessions by using the MentiTree software. Each session was conducted for 30 min twice a week for 9 weeks (total of 540 min). Cognitive functions were assessed before and after the intervention. RESULTS: Although 1 of the 13 participants experienced adverse effects, the 9-week cognitive training was well tolerated and had a high feasibility of 93%±24.65%. A tendency toward improvement was observed in the visual recognition memory of the participants (p = 0.034), but other domains did not significantly change. CONCLUSIONS: VR-based cognitive training is safely accepted by patients with mild to moderate AD. The potential of VR in AD treatment should be further explored using a randomized control group.}, } @article {pmid41048330, year = {2025}, author = {Puducheri, S and Zhou, OT and Kapadia, K and Romano, MF and Yalamanchili, S and Agrawal, A and Carlota Andreu-Arasa, V and Farris, CW and Mian, AZ and Paul, AB and Rohatgi, S and Setty, BN and Small, JE and Kolachalama, VB}, title = {Augmenting radiological assessment of imaging evident dementias with radiomic analysis.}, journal = {NPJ dementia}, volume = {1}, number = {1}, pages = {27}, pmid = {41048330}, issn = {3005-1940}, abstract = {Accurate differential diagnosis of dementia is essential for guiding timely treatment, particularly as anti-amyloid therapies become more widely available and require precise patient characterization. Here, we developed a radiomics-based machine learning (ML) approach to enhance neuroimaging assessments in distinguishing Alzheimer's disease (AD) from other imaging-evident dementias (OIED). We retrospectively analyzed 1041 individuals from the National Alzheimer's Coordinating Center with confirmed dementia diagnoses and at least one T1 or T2/FLAIR MRI scan. Using FastSurfer and a Lesion Prediction Algorithm, we extracted volumetric and lesion features, which were then used to train ML models. Model performance was compared to the independent evaluations of seven fellowship-trained neuroradiologists. The classifier achieved an AUROC of 0.79 ± 0.01 for AD and 0.66 ± 0.03 for OIED, performing comparably to expert assessments. Interpretation using SHAP values showed strong alignment with imaging features known to align with AD or OIED, respectively. These findings highlight the potential of radiomics to augment neuroimaging workflows.}, } @article {pmid41047765, year = {2025}, author = {Jayarathne, H and Manchanayake, DH and Sullivan, R and Chimienti, N and Kadri, O and Gurdziel, K and Kim, S and Jang, H and Ginsburg, BC and Miller, RA and Yakar, S and Sadagurski, M}, title = {Canagliflozin Reprograms the Aging Hippocampus in Genetically Diverse UM-HET3 Mice and Attenuates Alzheimer's-Like Pathology.}, journal = {Aging cell}, volume = {24}, number = {12}, pages = {e70255}, pmid = {41047765}, issn = {1474-9726}, support = {R01 ES033171/ES/NIEHS NIH HHS/United States ; P30 ES036084/ES/NIEHS NIH HHS/United States ; P30ES036084//CURES/ ; P30ES020957/ES/NIEHS NIH HHS/United States ; P30CA022453/GF/NIH HHS/United States ; P30 CA022453/CA/NCI NIH HHS/United States ; P30 ES020957/ES/NIEHS NIH HHS/United States ; R01ES033171/ES/NIEHS NIH HHS/United States ; S10 OD030484/OD/NIH HHS/United States ; //Impetus Grants for Longevity Research/ ; RF1AG078170/AG/NIA NIH HHS/United States ; RF1 AG078170/AG/NIA NIH HHS/United States ; S10OD030484/GF/NIH HHS/United States ; P30ES036084/GF/NIH HHS/United States ; }, mesh = {Animals ; *Hippocampus/drug effects/pathology/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; *Canagliflozin/pharmacology/therapeutic use ; Male ; Female ; *Aging/drug effects ; Disease Models, Animal ; Mice, Transgenic ; }, abstract = {Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana's potential to combat brain aging and AD through sex-specific mechanisms.}, } @article {pmid41047763, year = {2025}, author = {Pinto, A and Haytural, H and Loss, CM and Alvarez, C and Ertas, A and Curtis, O and Williams, AR and Murphy, G and Salleng, KJ and Gografe, S and Visavadiya, NP and Khamoui, AV and Altıntaş, A and Kafri, T and Barres, R and Deshmukh, AS and van Praag, H}, title = {Muscle Cathepsin B Treatment Improves Behavioral and Neurogenic Deficits in a Mouse Model of Alzheimer's Disease.}, journal = {Aging cell}, volume = {24}, number = {11}, pages = {e70242}, pmid = {41047763}, issn = {1474-9726}, support = {NNF18CC0034900//Novo Nordisk Fonden/ ; NNF23SA0084103//Novo Nordisk Fonden/ ; NNF19SA0059305//Novo Nordisk Fonden/ ; R01 HL155986/HL/NHLBI NIH HHS/United States ; 9AZ02//Florida Department of Health/ ; RO1HL155986/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Cathepsin B/pharmacology/therapeutic use/metabolism ; Mice ; Disease Models, Animal ; *Neurogenesis/drug effects ; *Muscle, Skeletal/metabolism/drug effects ; Hippocampus/metabolism ; *Behavior, Animal/drug effects ; Male ; Mice, Transgenic ; }, abstract = {Increasing evidence indicates skeletal muscle function is associated with cognition. Muscle-secreted protease Cathepsin B (Ctsb) is linked to memory in animals and humans, but has an unclear role in neurodegenerative diseases. To address this question, we utilized an AAV-vector-mediated approach to express Ctsb in skeletal muscle of APP/PS1 Alzheimer's disease (AD) model mice. Mice were treated with Ctsb at 4 months of age, followed by behavioral analyses 6 months thereafter. Here we show that muscle-targeted Ctsb treatment results in long-term improvements in motor coordination, memory function, and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment normalizes hippocampal, muscle, and plasma proteomic profiles to resemble that of wildtype (WT) controls. In AD mice, Ctsb increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes. In muscle, Ctsb treatment elevates protein translation in AD mice, whereas in WT mice mitochondrial proteins decrease. In WT mice, Ctsb treatment causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.}, } @article {pmid41047679, year = {2025}, author = {Wang, R and Yang, X}, title = {Research Progress on the Pathogenesis, Therapeutic Strategies, and Phthalocyanine Compounds for Alzheimer's Disease.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050406141250822082635}, pmid = {41047679}, issn = {1875-5828}, abstract = {Alzheimer's disease (AD) is a formidable and complex neurodegenerative disorder driven by multifactorial interactions, including amyloid-beta (Aβ) aggregation, neurofibrillary tangles, and neuroinflammation etc. Current therapies mainly consist of cholinesterase inhibitors and NMDA receptor antagonists, which can alleviate symptoms but fail to reverse disease progression. In recent years, emerging approaches such as immunotherapy and gene therapy have shown potential but remain in clinical exploration. Phthalocyanine (Pc) compounds, with their ability to inhibit Aβ fibril formation, favorable biocompatibility, and optical properties, have demonstrated potential in AD diagnosis and treatment. This review discusses the pathogenesis, therapeutic strategies, and research progress of Pc compounds in AD. Furthermore, the elucidation of their mechanisms of action, the optimization of blood-brain barrier penetration, and the promotion of clinical translation are needed to provide new directions for AD therapy.}, } @article {pmid41047654, year = {2025}, author = {Shichijo, F}, title = {[Precautions for Neurosurgeons in Administering Anti-Amyloid β Antibody Therapy].}, journal = {No shinkei geka. Neurological surgery}, volume = {53}, number = {5}, pages = {1000-1012}, doi = {10.11477/mf.030126030530051000}, pmid = {41047654}, issn = {0301-2603}, mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy ; *Amyloid beta-Peptides/immunology ; *Antibodies, Monoclonal/therapeutic use ; *Neurosurgeons ; }, abstract = {In Japan, anti-amyloid β (Aβ) monoclonal antibodies, including lecanemab and donanemab, have recently been approved as disease-modifying therapies for early-stage Alzheimer's disease (AD). These drugs, developed based on the amyloid cascade hypothesis, target toxic Aβ aggregates: lecanemab selectively binds to soluble protofibrils, while donanemab targets Aβ plaques. The Ministry of Health, Labour and Welfare (MHLW) has issued Optimal Use Guidelines that specify criteria for administration: informed consent from both patients and caregivers; cognitive assessments (MMSE and CDR); confirmation of Aβ pathology via amyloid PET or cerebrospinal fluid (CSF) testing; and MRI screening to assess the risk of amyloid-related imaging abnormalities (ARIA). ARIA is a significant adverse event and requires regular MRI monitoring. Initial administration is limited to certified facilities staffed by experienced specialists and equipped with the necessary diagnostic infrastructure. After six months, treatment may be continued at collaborating institutions. The APOEε4 genotype is a known risk factor for ARIA but is not covered by insurance. Caution is advised when co-administering anticoagulants or antiplatelet agents. The guidelines also require the use of official treatment cards to inform healthcare providers. This article summarizes the clinical precautions, diagnostic requirements, and facility standards necessary for implementing anti-Aβ antibody therapy in accordance with current MHLW Guidelines in Japan.}, } @article {pmid41047650, year = {2025}, author = {Miyajima, M and Kawai, Y and Bandai, H}, title = {[Hydrocephalus and Dementia].}, journal = {No shinkei geka. Neurological surgery}, volume = {53}, number = {5}, pages = {969-974}, doi = {10.11477/mf.030126030530050969}, pmid = {41047650}, issn = {0301-2603}, mesh = {Humans ; *Dementia/etiology/diagnosis/surgery ; *Hydrocephalus, Normal Pressure/complications/surgery/diagnosis ; Neuropsychological Tests ; }, abstract = {Idiopathic normal pressure hydrocephalus (iNPH), also known as Hakim's disease, is a major cause of reversible dementia in adults. iNPH primarily affects frontal lobe-related cognitive functions, including attention, executive function, and working memory, even in early stages. Although memory impairment is also present, recognition memory is often preserved, distinguishing iNPH from Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD), especially apathy, depression, and anxiety, are common in iNPH and are generally less active than those seen in AD. Neuropsychological assessments reveal significant impairments in frontal lobe tests such as the Frontal Assessment Battery and Trail Making Test-B. Shunt surgery leads to substantial improvement in attention and executive function, reflecting the reversible nature of iNPH. However, memory functions, particularly delayed recall, show limited recovery, indicating possible overlap with neurodegenerative mechanisms. Early surgical intervention is associated with better outcomes, while delayed treatment or advanced brain atrophy may reduce effectiveness. Comprehensive cognitive evaluation is essential for assessing treatment response, planning rehabilitation, and providing appropriate patient and family guidance.}, } @article {pmid41047647, year = {2025}, author = {Ota, M and Arai, T}, title = {[Pharmacological Interventions in Dementia].}, journal = {No shinkei geka. Neurological surgery}, volume = {53}, number = {5}, pages = {943-950}, doi = {10.11477/mf.030126030530050943}, pmid = {41047647}, issn = {0301-2603}, mesh = {Humans ; Cholinesterase Inhibitors/therapeutic use ; *Dementia/drug therapy ; }, abstract = {Pharmacological interventions for dementia include medications aimed at alleviating its core symptom: cognitive dysfunction. These medicines are known as anti-dementia drugs. As our understanding of Alzheimer's disease (AD) has advanced, the amyloid hypothesis stating that amyloid proteins are involved in the pathogenesis of AD has been proposed. To date, anti-dementia drugs such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists have focused on symptomatic treatment. In recent years, based on the amyloid hypothesis, the development of medicines that target either (1) the enzyme that produces amyloid beta (Aβ) or (2) Aβ itself, has been promoted as a treatment strategy for AD. In 2021, the first drug targeting Aβ, aducanumab, was launched in the USA. In Japan, lecanemab and donanemab are now available as monoclonal antibodies targeting Aβ. Additionally, medications have been used to manage the behavioral and psychological symptoms of dementia (BPSD), Parkinsonism, and rapid eye movement sleep behavior disorder. Furthermore, dementia is a major risk factor for delirium, which often occurs during the course of dementia. In this study, we introduce pharmacotherapy with anti-dementia drugs, BPSD treatment, and delirium.}, } @article {pmid41047645, year = {2025}, author = {Ishiguro, T and Kasuga, K}, title = {[Current Status and Future Perspectives of Biomarkers in Alzheimer's Disease Diagnosis].}, journal = {No shinkei geka. Neurological surgery}, volume = {53}, number = {5}, pages = {923-931}, doi = {10.11477/mf.030126030530050923}, pmid = {41047645}, issn = {0301-2603}, mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; *Biomarkers/cerebrospinal fluid/blood ; Amyloid beta-Peptides ; tau Proteins/blood ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia, characterized by the pathological accumulation of amyloid-β (Aβ) and phosphorylated tau in the brain. Recent advances in biomarker technology have significantly improved AD diagnosis and treatment. Cerebrospinal fluid biomarkers and amyloid positron emission tomography imaging are now available in clinical settings and serve as key tools in identifying early-stage AD, especially when considering anti-Aβ monoclonal antibody therapies. In 2024, the Alzheimer's Association proposed revised diagnostic criteria that integrate both biomarker-based and clinical staging systems. This framework introduces a classification of "core biomarkers" that reflect AD-specific pathology and defines biological and clinical symptom stages. Furthermore, blood-based biomarkers, such as plasma p-tau217 and MTBR-tau243, are gaining attention as minimally invasive tools for early diagnosis and disease staging. As these biomarkers become more accessible, proper interpretation within a clinical context remains essential. In Japan, biomarker testing is currently recommended only for symptomatic individuals, and its use requires careful judgment regarding indications and relevance to the clinical setting. This review outlines the evolution of diagnostic criteria, current and emerging biomarkers, and their implications for personalized AD care while emphasizing the need for expert clinical interpretation to ensure responsible and patient-centric use.}, } @article {pmid41047224, year = {2025}, author = {Graham, N and Zimmerman, K and Hain, J and Rooney, E and Lee, Y and Del Giovane, M and Parker, T and Wilson, M and Patel, M and Veleva, E and Swann, O and Heslegrave, AJ and Li, LM and Zetterberg, H and Friedland, D and Sylvester, R and Sharp, D}, title = {Midlife plasma proteomic profiles indicate altered amyloid and tau processing in former elite rugby players.}, journal = {Journal of neurology, neurosurgery, and psychiatry}, volume = {}, number = {}, pages = {}, doi = {10.1136/jnnp-2025-336593}, pmid = {41047224}, issn = {1468-330X}, abstract = {BACKGROUND: Contact sports, including rugby union, are associated with higher rates of neurodegenerative dementia, due to various underlying pathologies such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). New ultrasensitive multiplexed immunoassays may clarify disease mechanisms after repetitive head impacts (RHI) and traumatic brain injury, potentially aiding risk-stratification, early diagnosis and dementia treatment. METHODS: Midlife participants in the ABHC cohort underwent plasma biomarker quantification (NULISA - NUcleic acid Linked Immuno-Sandwich Assay; n=124 markers), 3T MRI, trauma exposure ascertainment and phenotyping. Regressions quantified exposure-specific protein expression, relationship to trauma (including position) and brain atrophy, using cluster analysis to test correlates of traumatic encephalopathy syndrome (TES). RESULTS: 197 former elite rugby players and 33 controls were assessed. 24 (12.2%) met criteria for TES but none had dementia. Ex-players returned reduced plasma glial fibrillary acidic protein (GFAP), kallikrein-6 (KLK6) and synaptosomal-associated protein 25 (SNAP25). Ex-forwards specifically showed reduced plasma beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid beta-38 (Aβ38), and increased phospho-tau181 (p-tau181). KLK6 was lower in ex-backs than controls. No biomarkers related to career duration, concussion load or regional brain volume, nor did clustering relate to TES. CONCLUSIONS: Ex-players showed distinctive plasma biomarker changes, more prominently in ex-forwards, possibly reflecting greater RHI exposure. Plasma KLK6, an endothelial serine protease, was reduced across the ex-player group, with potential diagnostic or prognostic utility in future. Reduced GFAP and SNAP25 in ex-forwards has an uncertain basis, while elevated p-tau-181 more so than p-tau217 points towards non-AD tau pathology. Our findings motivate longitudinal characterisation, including comparison with other neurodegenerative diseases.}, } @article {pmid41047041, year = {2025}, author = {Fan, X and Wang, H and Ping, J and Li, M and Gu, J and Qian, W}, title = {Synaptic scaffold protein PSD-95: a therapeutic target for Alzheimer's disease.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 3}, pages = {117401}, doi = {10.1016/j.bcp.2025.117401}, pmid = {41047041}, issn = {1873-2968}, mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Disks Large Homolog 4 Protein/metabolism/antagonists & inhibitors/genetics ; Animals ; *Synapses/metabolism/drug effects ; *Drug Delivery Systems/methods ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder marked by gradual cognitive deterioration and distinct neuropathological characteristics. The abnormal accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are the hallmarks of AD. In fact, synaptic loss and damage occur earlier than amyloid plaques and NFTs in the progression of AD and are most closely associated with the cognitive deficits exhibited by AD patients. In this review, we discuss the expression level, localization, posttranslational modification and interaction proteins of PSD-95, as well as their roles in synaptic plastisity. We also review the mechanisms through which PSD-95 contributes to synaptic dysfunction in AD. Moreover, the potential of PSD-95 as an early biomarker for AD is also discussed, along with the therapeutic approaches that target PSD-95 for patients afflicted with the disease. The objective of this review is to offer comprehensive insights into the early pathogenesis of Alzheimer's disease and to aid in the development of novel diagnostic and treatment methodologies grounded in this understanding.}, } @article {pmid41046825, year = {2025}, author = {Manful, EE and Adu-Amankwaah, F and Madhvi, A and Bubb, K and Pietersen, RD and Baker, B}, title = {Therapeutic potential of IFIT2 in human diseases.}, journal = {Cytokine}, volume = {196}, number = {}, pages = {157049}, doi = {10.1016/j.cyto.2025.157049}, pmid = {41046825}, issn = {1096-0023}, mesh = {Humans ; Neoplasms/metabolism ; Animals ; Autoimmune Diseases/metabolism ; RNA-Binding Proteins/metabolism ; Adaptor Proteins, Signal Transducing ; *Intracellular Signaling Peptides and Proteins/metabolism ; Apoptosis Regulatory Proteins ; }, abstract = {The interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is a crucial member of the interferon-stimulated gene (ISG) family, widely acknowledged for its antiviral activity. IFIT2 functions primarily through AU-rich RNA binding, aiding in viral suppression by inhibiting protein translation and promoting apoptosis via mitochondrial pathways. While traditionally known for its role in antiviral defence, emerging research highlights its broader significance in cancer, bacterial and fungal infections, autoimmune diseases, neurological disorders, and metabolic and cardiovascular conditions. Notably, IFIT2 is the only IFIT family member with established tumour suppressor properties, demonstrating anti-proliferative effects in multiple cancers, including lung, renal, colorectal, breast, and gallbladder cancers. Beyond oncology, IFIT2 has been implicated in the host response to Mycobacterium tuberculosis, Plasmodium spp., Candida albicans, and Treponema pallidum, where it modulates immune responses and infection outcomes. It is upregulated in several autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, and multiple sclerosis, suggesting its potential as a diagnostic and therapeutic biomarker. Furthermore, transcriptomic analyses have linked IFIT2 to disease progression and treatment response in conditions like diabetic ulcers, gestational diabetes, ischaemic cardiomyopathy, schizophrenia, and Alzheimer's disease. This review thoroughly examines the molecular structure, regulatory mechanisms, and diverse roles of IFIT2 in human diseases. It addresses its interaction with key immune pathways, its ability to modulate apoptosis and inflammation, and its potential as a prognostic marker and therapeutic target. Although its mechanistic functions in numerous diseases remain only partly understood, IFIT2 emerges as a versatile immune effector with considerable translational promise. Further investigation into its biological roles will be crucial for utilising its therapeutic potential across infectious, inflammatory, metabolic, and neoplastic diseases.}, } @article {pmid41046632, year = {2026}, author = {Fuh, JL and Wang, SJ and Wang, PN and Wu, HM and Su, WS and Lin, HM and Yang, FY}, title = {Safety and efficacy of transcranial ultrasound stimulation for the treatment of Alzheimer's disease: A randomized, double-blind, placebo-controlled trial.}, journal = {Ultrasonics}, volume = {159}, number = {}, pages = {107844}, doi = {10.1016/j.ultras.2025.107844}, pmid = {41046632}, issn = {1874-9968}, mesh = {Humans ; *Alzheimer Disease/therapy ; Aged ; Double-Blind Method ; Male ; Female ; Aged, 80 and over ; Middle Aged ; *Ultrasonic Therapy/methods/adverse effects ; Pilot Projects ; Treatment Outcome ; Magnetic Resonance Imaging ; }, abstract = {Transcranial ultrasound stimulation (TUS) has emerged as a potential neuromodulatory intervention for Alzheimer's disease (AD). This pilot randomized, double-blind, placebo-controlled trial evaluated TUS's safety and preliminary efficacy in patients with mild AD. Patients aged 50-90 years were enrolled and randomly assigned at a 2:1 ratio to receive TUS treatment for 30 sessions (15 min/day, 5 days/week for 6 weeks) or a placebo procedure. Safety was monitored through magnetic resonance imaging, adverse event reporting, and laboratory assessments. Efficacy was assessed with the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Mini-Mental State Examination (MMSE). Nine of 30 patients screened were enrolled (six TUS, three placebo). All patients completed the study, and no serious clinical or radiographic adverse events related to TUS were observed. At 52 weeks, the change in ADAS-cog score from baseline remained relatively stable in the TUS group compared to worsening in the placebo group (0.5 ± 4.7 vs. 5.0 ± 4.0, p = 0.237), particularly in the memory domain. The change in MMSE score from baseline showed a significant benefit in the TUS group at 24 weeks compared to placebo (2.2 ± 2.2 vs. -3.0 ± 2.6, p < 0.05), and this improvement persisted to 52 weeks. This study demonstrates the safety and feasibility of repeated TUS sessions in AD and suggests potential benefits in preserving cognitive function. Larger, adequately powered trials are required to validate these preliminary findings and further define the therapeutic potential of TUS in AD.}, } @article {pmid41046322, year = {2025}, author = {Wu, KC and Lin, CY and Tran, T and Lin, JH and Yeh, HH and Ho, CJ and Chern, Y and Lin, CJ}, title = {Preclinical Evaluation of a Novel Molecule Targeting Nucleoside Homeostasis to Restore Energy Metabolism and Cognitive Function in Alzheimer's Disease.}, journal = {Pharmacology research & perspectives}, volume = {13}, number = {5}, pages = {e70176}, pmid = {41046322}, issn = {2052-1707}, support = {AS-BRPT-110-11//Academia Sinica, Taiwan/ ; AS-KPQ-111-KNT//Academia Sinica, Taiwan/ ; MOST 110-3111-Y-001-002//Ministry of Science and Technology, Taiwan/ ; MOST 110-3111-Y-001-003//Ministry of Science and Technology, Taiwan/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Energy Metabolism/drug effects ; Mice ; Disease Models, Animal ; *Nucleosides/metabolism ; Homeostasis/drug effects ; Brain/metabolism/drug effects ; Mice, Transgenic ; *Cognition/drug effects ; Male ; Equilibrative Nucleoside Transporter 1/metabolism ; Mice, Inbred C57BL ; Humans ; Cognitive Dysfunction/drug therapy ; Positron-Emission Tomography ; }, abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia, characterized by progressive cognitive decline and cerebral metabolic impairment. Yet, the therapeutic options for addressing the disease pathogenesis are limited. Here, we report an approach by targeting brain nucleoside homeostasis and energy metabolism to alleviate AD-associated cognitive deficits. A compound, J4, was designed to modulate nucleoside homeostasis by interacting with the equilibrative nucleoside transporter-1 (ENT1). The effects of J4 on brain nucleoside homeostasis and energy metabolism were examined in mice. Two AD animal models, THY-Tau22 and APP/PS1 mice, were used to evaluate the translational potential of J4 for the treatment of AD. Cognitive function and functional ability were assessed using the Morris water maze, Y-maze, and nesting behavior tests. The pharmacodynamic marker was explored, and the pharmacokinetic and safety properties of J4 were evaluated. As a result, being administered after disease onset, oral J4 administration rescued memory and cognitive dysfunction in both tau and amyloid AD mouse models. Metabolomic analysis showed that J4 increased brain nucleoside levels and facilitated brain primary metabolism, including glucose metabolism and the pentose phosphate pathway. The [[18]F]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging further demonstrated that glucose metabolism can be used as a pharmacodynamic biomarker for the target engagement of J4 on ENT1. The nonclinical studies also demonstrated the ideal pharmacokinetic and safety profiles of J4, supporting that targeting nucleoside homeostasis can improve brain energy metabolism and is a promising approach for AD treatment.}, } @article {pmid41046244, year = {2025}, author = {Chatterjee, S and Soria, M and Norville, ZC and Thompson, KR and Lillie, J and Kreitzer, AC and Wood, MW}, title = {Preclinical efficacy of the muscarinic agonist ML-007 in psychosis models depends on both M1 and M4 receptors.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {41046244}, issn = {1740-634X}, abstract = {Muscarinic agonists represent a new class of treatments for psychosis with a mechanism distinct from typical and atypical antipsychotics. The muscarinic subtype M4 has been proposed as the primary mediator of efficacy but results from recent clinical trials with M4-selective compounds have drawn this hypothesis into question. Instead, activation of both M1 and M4 receptor subtypes may be required for robust treatment effects. Here, we characterize the clinical-stage muscarinic agonist ML-007 in preclinical models and explore its therapeutic potential for treating psychosis in schizophrenia and Alzheimer's disease. ML-007 is a potent brain-penetrant agonist at both M1 and M4 muscarinic receptors that has demonstrated compelling efficacy across a range of preclinical models of psychosis in schizophrenia including amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, and conditioned avoidance response. Moreover, ML-007 is approximately ten-fold more potent than the comparator xanomeline in all animal models. Dose-response experiments in M1 and M4 knockout mice reveal that the efficacy of ML-007 is dependent on both M1 and M4 receptors. Taken together, our data suggest that both M1 and M4 receptors contribute to the potent efficacy of ML-007 in preclinical rodent models of psychosis.}, } @article {pmid41046022, year = {2025}, author = {Zhou, X and Lin, X and He, Y and Huang, N and Luo, Y}, title = {TDP-43 in Alzheimer's disease: Pathophysiology and therapeutic strategies.}, journal = {Pharmacological research}, volume = {221}, number = {}, pages = {107977}, doi = {10.1016/j.phrs.2025.107977}, pmid = {41046022}, issn = {1096-1186}, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/physiopathology ; *DNA-Binding Proteins/metabolism/genetics/antagonists & inhibitors ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Brain/metabolism/drug effects/pathology/physiopathology ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the dysregulation of multiple molecular mechanisms. In recent years, transactive response DNA-binding protein 43 kDa (TDP-43) has increasingly been recognized as a critical pathological protein and has become a prominent focus in AD research. TDP-43 is involved not only in physiological processes such as RNA metabolism, protein quality control, and mitochondrial regulation but also in AD pathology through abnormal aggregation, dysregulated nucleocytoplasmic transport, and aberrant posttranslational modifications, leading to neurotoxicity, mitochondrial dysfunction, and disrupted protein homeostasis. Studies have shown that TDP-43 closely interacts with two core pathological hallmarks of AD, β-amyloid (Aβ) and tau. By promoting Aβ oligomerization and tau hyperphosphorylation, TDP-43 accelerates the pathological progression of this disease. Given the multifaceted role of TDP-43 in AD, therapeutic strategies targeting TDP-43 have shown great potential. Approaches such as modulating its RNA splicing activity, inhibiting pathological aggregation, restoring the balance of nucleocytoplasmic transport, and preventing its mitochondrial localization offer new avenues for AD treatment. This review systematically summarizes the pathological mechanisms of TDP-43 in AD and its interactions with Aβ and tau and discusses the feasibility of targeting TDP-43 as a therapeutic strategy. Future studies should further elucidate the role of TDP-43 in the early stages of AD and develop specific therapeutic agents that target TDP-43, with the aim of providing new insights for precision treatment of AD.}, } @article {pmid41045719, year = {2025}, author = {Swerdlow, NR and Sprock, J and Gonzalez, CE and Din, JM and Minhas, J and Talledo, J and Molina, JL and Joshi, YB and Léger, GC and Powell, L and Rana, B and Delano-Wood, L and Light, GA}, title = {Do cognitive and neurophysiological effects of acute memantine "challenge" predict its clinical benefits in Alzheimer's Disease?.}, journal = {Psychiatry research}, volume = {353}, number = {}, pages = {116740}, doi = {10.1016/j.psychres.2025.116740}, pmid = {41045719}, issn = {1872-7123}, abstract = {"Personalized" interventions based on patients' "biomarkers" may be valuable for treatments that benefit only subsets of patients. The NMDA antagonist, memantine, slows clinical progression of Alzheimer's disease (AD); this effect is heterogeneous in magnitude and duration. This study tested whether acute cognitive or neurophysiological responses to memantine challenge predicted sensitivity to memantine's therapeutic effects. Thirty individuals with mild-to-moderate severity AD (M:F = 13:17) and 24 comparably aged healthy subjects (HCS) (M:F = 12:12) were enrolled. Participants with AD were characterized on 9 experimental measures and their changes after acute memantine "challenge" (20 mg). We then assessed whether acute memantine effects on these measures predicted clinical change over a 24-week open-label trial of memantine. Baseline cognitive (Repeatable Battery for the Assessment of Neuropsychological Status) and neurophysiological measures (prepulse inhibition, P3a latency and auditory steady state response power and coherence) were impaired in participants with AD (p's<0.05-0.0001); neurophysiological deficits were modestly reduced by acute memantine challenge. As a group, participants with AD showed no significant clinical changes across 24 weeks of memantine treatment; subgroups exhibited either small gains or deterioration. With one exception (mismatch negativity latency, p < 0.017), sensitivity of experimental measures to acute memantine challenge did not significantly predict clinical sensitivity to memantine. In summary, a challenge dose design identified neurophysiological measures sensitive to memantine in mild-to-moderate severity AD; acute memantine effects on one measure weakly predicted clinical outcomes over 24 weeks. Impairment in specific measures among participants with AD, and their opposition by memantine, might inform future efforts to identify treatment biomarkers in AD.}, } @article {pmid41045350, year = {2025}, author = {Alsaadi, T and Almadani, A and AlRukn, S and Hassan, A and Sarathchandran, P and Shatila, A and Szolics, M and Benito, D and Ince, S and Krieger, DW}, title = {Expert Guidance on Cognitive Impairment in Alzheimer's Disease: A Practical Seven-Step Approach from the United Arab Emirates.}, journal = {Neurology and therapy}, volume = {14}, number = {6}, pages = {2507-2535}, pmid = {41045350}, issn = {2193-8253}, abstract = {INTRODUCTION: Cognitive impairment (CI) spans a spectrum from mild CI to severe dementia, with Alzheimer's disease (AD) the most prevalent cause of CI and dementia. Although dementia burden and prevalence in Arab countries reflect general global trends, the United Arab Emirates (UAE) differs from Western countries both culturally and regarding management resources. Further guidance is therefore needed for the diagnosis and management of CI in the UAE. METHODS: A task force of eight neurologists and two non-voting collaborators with special dementia expertise was convened to develop evidence-based position statements/recommendations to guide the diagnosis and management of AD, including the use of amyloid-targeting therapies (ATTs), in the UAE clinical setting. A modified Delphi survey method was chosen to obtain a consensus, ensuring that drafted expert statements reflected diverse perspectives and experiences. Discordance was predefined as > 25% of panelists rating an expert statement as ≤ 3 on the Likert scale. Consensus was predefined as a median rating ≥ 7 without discordance. Expert statements achieving consensus were adopted. RESULTS: A seven-step framework for diagnosing and managing CI in the UAE was developed, with consensus achieved on all statements. Recommendations largely aligned with international guidelines on AD dementia management and treatment, combined with UAE-specific guidance. The framework spans the full patient journey from initial symptoms to diagnosis (including biomarker use), initial treatment (including ATTs where appropriate), and subsequent monitoring and management as the disease progresses. CONCLUSIONS: Management of CI and dementia in UAE requires consideration of international guidelines in the context of regional and local cultural sensitivities and healthcare resources. A holistic approach is recommended, combining appropriate pharmacological treatment with lifestyle interventions, education, and support for patients and care partners. Patients require ongoing monitoring to ensure the approach is tailored to the disease stage and provides optimal quality of life and reduced burden for patients and care partners.}, } @article {pmid41044993, year = {2025}, author = {Yan, Q and Qin, Q and Zhang, S and Chen, F and Ru, Y and Zhong, Y and Wu, G}, title = {Glial cell nutrient sensing: mechanisms of nutrients regulating Alzheimer's pathogenesis and precision intervention.}, journal = {Critical reviews in food science and nutrition}, volume = {}, number = {}, pages = {1-17}, doi = {10.1080/10408398.2025.2568606}, pmid = {41044993}, issn = {1549-7852}, abstract = {Modern nutrition is a core element of clinical treatment. Although some literature addresses neuro-nutrition's effects on Alzheimer's disease (AD), a systematic discussion of how the body's six essential nutrients impact AD is lacking. Moreover, neural glial cells directly participate in the pathological regulation of AD. A novel conceptual framework linking "essential nutrients - glial cells - AD" needs to be summarized. Therefore, this review examines the regulatory roles of glial cells (astrocytes, microglia, and their networks) in AD and explores how essential nutrients impact AD via glial cells. Specifically, vitamins (NR, NMN, etc.), minerals (copper, iron, selenium, etc.), proteins and amino acids (arginine, citrulline, methionine, etc.), lipids (fatty acids, phosphatidylinositol, etc.), and carbohydrates (trehalose, oligosaccharides, plant polysaccharides, etc.) can influence important functions such as brain energy metabolism remodeling, inflammatory factor secretion, and phagocytic clearance by regulating microglia and astrocytes. Moreover, a significant strength of this review is its clear exposition of nutrient alterations observed in AD patients, coupled with detailed recommendations for nutritional interventions targeting AD prevention and management. Furthermore, it also investigated beneficial dietary patterns for improving AD. In conclusion, this review explores the "essential nutrients -glial cell" molecular interactions, laying the foundation for precision nutrition-based AD strategies.}, } @article {pmid41042852, year = {2025}, author = {Bellaflor, S and Barfoot, MK and Boddy, J and Wallace, PJ and Baranowski, RW and Cheung, SS and Fajardo, VA and MacPherson, REK}, title = {Heat therapy increases brain HSP70 and BDNF content in male mice.}, journal = {Journal of neurophysiology}, volume = {134}, number = {5}, pages = {1445-1452}, doi = {10.1152/jn.00301.2025}, pmid = {41042852}, issn = {1522-1598}, support = {2017-03904//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; 2019-05833//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; 2018-04077//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; Male ; *HSP70 Heat-Shock Proteins/metabolism ; Mice ; *Hyperthermia, Induced ; *Hippocampus/metabolism ; *Prefrontal Cortex/metabolism ; Pilot Projects ; *Brain/metabolism ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Aspartic Acid Endopeptidases/metabolism ; }, abstract = {Heat shock proteins (HSPs) are molecular chaperones that play important roles in protein homeostasis, with HSP70 linked to a role in neuroprotection. HSP70 is upregulated in response to various stressors, such as heat therapy (HT), which has been shown to increase brain-derived neurotrophic factor (BDNF) content. BDNF reduces the activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the rate-limiting enzyme responsible for the generation of amyloid-β (Aβ) peptides that form the characteristic Aβ plaques observed in Alzheimer's disease brains. The current pilot study examined whether 4 wk of HT can increase HSP70 and BDNF content (pro and mature forms) in the brain, and alter markers of amyloid precursor protein (APP) processing. Male mice had their core temperature maintained between 37.0 and 38.0°C in Control (CON, n = 16) and 40.5 and 41.5°C in Heat Therapy (HT, n = 16) for 20 min every 72 h over 4 wk. Seventy-two hours after the last treatment, the prefrontal cortex (PFC) and hippocampus (HIP) were collected. HT significantly increased HSP70 levels in both the hippocampus and prefrontal cortex compared with controls (P = 0.0007, PFC CON = 1.001 [0.314], PFC HT = 1.546 [0.948], HIP CON = 1.000 [0.356], HIP HT = 2.207 [0.756]). In the HIP, proBDNF levels were also higher in the HT group relative to both the control group and the PFC (P < 0.05, PFC CON = 1.000 [0.156], PFC HT = 0.984 [0.607], HIP CON = 1.001 [0.242], HIP HT = 1.575 [0.482]. There were no differences in mature BDNF in either PFC or HIP regions (P > 0.05, PFC CON = 1.000 [0.273], PFC HT = 1.174 [0.266], HIP CON = 0.999 [0.130], HIP HT = 0.971 [0.207]), The findings from our pilot study suggest that HT enhances the expression of HSP70 and BDNF, indicating the potential to modulate key neuroprotective proteins. Future studies in dedicated preclinical mouse models of Alzheimer's disease using the heat therapy regimen are warranted.NEW & NOTEWORTHY Four weeks of heat therapy increases heat shock protein (HSP)70 and brain-derived neurotrophic factor (BDNF) levels in the hippocampus and prefrontal cortex of mice, regions crucial for memory and cognition. These findings highlight the promise of heat therapy as a nonpharmacological strategy to enhance brain resilience against neurodegenerative diseases.}, } @article {pmid41042837, year = {2025}, author = {Boongird, C and Anothaisintawee, T and Tearneukit, W and Wongpipathpong, W and Suthutvoravut, U and Thongpan, M and Pongsettakul, N and Attia, J and McKay, GJ and Rattanasiri, S and Thakkinstian, A}, title = {Bridging the gap: Efficacy of combined therapies for cognitive, behavioral, and functional outcomes in Alzheimer's disease - results from a systematic review and network meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {509-521}, pmid = {41042837}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology/drug therapy ; Cognition ; *Cognitive Behavioral Therapy/methods ; Combined Modality Therapy ; Donepezil/therapeutic use ; Randomized Controlled Trials as Topic ; Rivastigmine/therapeutic use ; Treatment Outcome ; }, abstract = {BackgroundEvidence regarding efficacy of combined pharmaco- and non-pharmacotherapies and their comparative effectiveness for Alzheimer's disease (AD) is limited.ObjectiveTo estimate the comparative efficacy of pharmacotherapies, non-pharmacotherapies, and combined therapies for improving cognitive, behavioral, and functional outcomes in patients with AD.MethodsRelevant studies were identified from Medline via PubMed and Scopus databases (March 2021-December 2022). Randomized-controlled trials were eligible if they assessed the efficacy of pharmacotherapies, non-pharmacotherapies, or combined therapies in patients aged 60 years or older, and measuring cognitive, behavioral, or functional outcomes. A network meta-analysis was conducted to estimate relative treatment effects, and interventions were ranked using surface under the cumulative ranking (SUCRA) curve. Confidence in the findings was evaluated using the Confidence in Network Meta-Analysis (CINeMA) framework.ResultsA total of 153 randomized-controlled trials were analyzed. Compared to placebo/usual care, donepezil plus cognitive therapy and rivastigmine plus cognitive rehabilitation significantly improved Mini-Mental State Examination scores. Behavioral outcomes were improved by rivastigmine plus cognitive stimulation, brain stimulation plus exercise, and occupational therapy. Functional status improved significantly with rivastigmine plus cognitive stimulation and exercise. Based on SUCRA ranking, rivastigmine plus cognitive rehabilitation ranked highest for cognitive improvement (92.8%), brain stimulation plus exercise ranked highest for the behavioral outcome (93.1%), and rivastigmine plus cognitive stimulation ranked highest for functional improvement (94.1%).ConclusionsDonepezil plus cognitive therapy and rivastigmine plus cognitive rehabilitation were the most effective treatments for improving cognitive outcomes. Rivastigmine plus cognitive stimulation ranked highest for both behavioral and functional outcomes, while exercise remains an important strategy for supporting daily functioning in patients with AD.}, } @article {pmid41042700, year = {2025}, author = {Xu, X and Tan, H and Yin, K and Xu, S and Wang, Z and Serrano, GE and Beach, TG and Wang, X and Peng, J and Wu, R}, title = {Comprehensive and Site-Specific Characterization of Protein N-Glycosylation in AD Samples Reveals Its Potential Roles in Protein Aggregation and Synaptic Dysfunction.}, journal = {Analytical chemistry}, volume = {97}, number = {40}, pages = {21873-21882}, pmid = {41042700}, issn = {1520-6882}, support = {P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; R35 GM156318/GM/NIGMS NIH HHS/United States ; RF1 AG064909/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Glycosylation ; *Alzheimer Disease/metabolism/pathology ; *Protein Aggregates ; *Glycoproteins/metabolism/chemistry/analysis ; Proteomics ; *Synapses/metabolism ; Male ; Female ; Brain/metabolism ; Aged ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Emerging evidence strongly suggests that protein glycosylation is strongly related to this disease. However, the extent and functional consequences of site-specific N-glycosylation alterations in AD remain to be further explored. Here, we employed a dendrimer boronic acid (DBA)-based enrichment strategy combined with multiplexed proteomics to systematically analyze protein N-glycosylation in post-mortem human brain tissues. We identified 3,105 N-glycosylation sites on 1,299 glycoproteins from nine AD cases and nine healthy controls, and performed a systematic and site-specific investigation of glycosylation alterations in AD. Glycoproteins involved in cholesterol efflux were upregulated, whereas those associated with chemical synaptic transmission and ion transport were significantly downregulated in AD compared to control brain samples. We observed widespread dysregulation of N-glycosylation across multiple protein domains, particularly in the ConA-like lectins/glucanases and Zn-dependent exopeptidases domains. Notably, we identified 161 N-glycosylation sites located within aggregation-prone regions (APRs), and reduced glycosylation at APRs on plaque-associated glycoproteins may be associated with protein aggregation and plaque formation. Additionally, downregulated N-glycosylation sites were enriched in synaptic membrane proteins, such as Ca[2+] ion channels, GABA-gated chloride channels, and glutamate receptors, implicating glycosylation loss in synaptic dysfunction. Our findings suggest that the loss of N-glycosylation may contribute to the pathogenesis of AD through impairing synaptic transmission and promoting protein aggregation. This study provides novel insights into glycosylation-dependent mechanisms of neurodegeneration, highlighting N-glycosylation as a potential therapeutic target for AD treatment.}, } @article {pmid41042497, year = {2025}, author = {Schreiber, CP and Kovacik, A and Bishop, J and Helman, J}, title = {Amyloid-related Imaging Abnormalities (ARIA) in the Context of Alzheimer's Disease and Amyloid-targeting Therapies: An Introduction for Advanced Practice Providers.}, journal = {Drugs & aging}, volume = {42}, number = {12}, pages = {1103-1111}, pmid = {41042497}, issn = {1179-1969}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; Brain/diagnostic imaging/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the accumulation of amyloid-beta (Aβ) and neurofibrillary tangles of hyperphosphorylated tau in the brain. Amyloid-targeting therapies (ATTs) are the first available disease-modifying treatments shown to slow cognitive and functional decline for patients with mild cognitive impairment owing to AD and early symptomatic AD. Currently two ATTs are commercially available, donanemab (Kisunla™) and lecanemab (Leqembi[®]). The main potential side effect and safety concern of ATT treatment is amyloid-related imaging abnormalities (ARIA). ARIA can be categorized into two types that can co-occur: ARIA-E (edema/sulcal effusion) and ARIA-H (hemorrhage/superficial siderosis). Although both are often asymptomatic and ARIA-E typically resolves radiographically over time, both forms can be radiologically and/or clinically serious. Treating clinicians should be equipped with a comprehensive understanding of ARIA. This review aims to provide advanced practice providers, who are pivotal to patient care in AD, with critical insights into ARIA to safely identify risk factors, understand treatment guidelines, and gain familiarity with appropriate management strategies. It emphasizes the importance of understanding APOE genotype and vascular factors in ARIA risk and recognizing the clinical and radiographic manifestations of ARIA. Practical recommendations are provided for monitoring and managing ARIA, including dose management strategies and education on symptom awareness. By fostering a comprehensive understanding of ARIA and its monitoring and management, this review aims to support the safe and effective implementation of ATTs, contributing to optimized patient care for those treated with ATTs.}, } @article {pmid41042431, year = {2025}, author = {Shah, N and Natesan, G and Gupta, R}, title = {Uncovering Necroptosis in Alzheimer's Disease: A Systematic Review of Evidence Across Experimental Models.}, journal = {Cellular and molecular neurobiology}, volume = {45}, number = {1}, pages = {83}, pmid = {41042431}, issn = {1573-6830}, mesh = {*Necroptosis/physiology ; *Alzheimer Disease/pathology/metabolism ; Humans ; Animals ; Disease Models, Animal ; Signal Transduction ; }, abstract = {Alzheimer's disease (AD), one of the most challenging neurodegenerative disorders, with high prevalence worldwide, is characterized by progressive cognitive decline and accumulation of amyloid-β plaques and neurofibrillary tau tangles. Despite significant research, the limited efficacy of current treatments underscores the critical need to identify novel pathogenic mechanisms and therapeutic targets. Necroptosis, a regulated and highly inflammatory form of programmed cell death, has emerged as one of the key contributors to AD pathogenesis. This systematic review comprises 25 high-quality in vivo, in vitro, and autopsy studies, published between 2015 and 2025, extracted from PubMed, Scopus, and Science Direct databases. The keywords include "necroptosis", "RIPK1", "RIPK3", "MLKL", "pMLKL", "necroptosis inhibitors", "Alzheimer's disease", and "neurodegeneration". The review summarizes the multiple molecular mechanisms, including TNF-α/TNFR1 signaling, TRIF-mediated RIPK3 activation, and RHIM-dependent MLKL phosphorylation, associated with necroptosis in the pathogenesis of AD. All the studies converge on necroptosis as a central pathogenic pathway linking key molecular and cellular abnormalities observed in AD. The accumulated evidence strongly supports prioritizing the development of brain-penetrant necroptosis inhibitors and clinical validation of associated biomarkers. These insights signal a significant shift in AD therapeutics, moving from symptomatic treatment to mechanistically targeted interventions that can alter disease progression.}, } @article {pmid41041548, year = {2025}, author = {Trigiani, L and Chernavsky, N and Kim, R and Hong, N and Hawkins, R and Le, E and Bahninameh, Z and Yamaguchi, K and Bernard, J and Huang, A and Rivera, D and Allan-Rahill, N and Lamont, M and Marongiu, R and Iadecola, C and Nishimura, N and Schaffer, C}, title = {Memory deficits in hypertensive ApoE4 mice reversed by P2Y12 inhibition via different mechanisms in males and perimenopausal females.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41041548}, issn = {2693-5015}, support = {R01 NS108472/NS/NINDS NIH HHS/United States ; R21 AG064455/AG/NIA NIH HHS/United States ; R01 NS095441/NS/NINDS NIH HHS/United States ; R01 NS127156/NS/NINDS NIH HHS/United States ; R01 NS126467/NS/NINDS NIH HHS/United States ; RF1 AG049952/AG/NIA NIH HHS/United States ; }, abstract = {Apolipoprotein E4 (ApoE4) genotype, hypertension, and biological sex are critical risk factors for Alzheimer's disease and related dementias. Yet, their combined impact on early cerebrovascular dysfunction, brain inflammation, and memory impairment remains poorly understood. We developed a translational mouse model incorporating human ApoE4, hypertension via angiotensin II infusion, and induced accelerated ovarian failure (AOF) to mimic perimenopause in females to investigate these interactions. Hypertensive ApoE4 mice of both sexes exhibited impaired spatial working memory, decreased cerebral blood flow, increased neuroinflammation, and decreased blood brain barrier integrity, recapitulating key early clinical features observed in human populations with these risk factors. Brain blood flow reduction was associated with an increased incidence of capillary stalling, with notable sex differences in the extent and cellular composition of stalls: in males, stalling was strongly elevated and mostly due to red blood cell arrest, while stalling was modestly elevated in peri-AOF females with most stalls including leukocytes. Treatment with prasugrel, a P2Y12 receptor inhibitor, improved memory performance in both sexes but was correlated with different physiological effects - restored cerebral blood flow in males and reduced microglia motility and inflammation in peri-AOF females. Platelet depletion mimicked prasugrel's blood flow and cognitive benefits in males, while microglia depletion selectively rescued memory in females. Our work emphasizes the necessity of including translationally relevant female mouse models in neurodegenerative disease studies, and our findings highlight the importance of risk profile-specific interventions and demonstrate that early vascular dysfunction may be a key, sex-dependent driver of cognitive decline.}, } @article {pmid41040848, year = {2025}, author = {Kumar, A and Pichet Binette, A and Bali, D and Janelidze, S and Stomrud, E and Palmqvist, S and Vogel, JW and Hansson, O and Mattsson-Carlgren, N}, title = {Cell-weighted polygenic risk scores are associated with β-amyloid and tau biomarkers in Alzheimer's disease.}, journal = {Brain communications}, volume = {7}, number = {5}, pages = {fcaf353}, pmid = {41040848}, issn = {2632-1297}, abstract = {The molecular pathways influencing the build-up of β-amyloid and tau pathology in Alzheimer's disease are unclear. To investigate how the involvement of different cell types influences β-amyloid and tau, we utilized single-cell RNA-seq data to derive cell-weighted polygenic risk scores. We included participants from the BioFINDER-1 study, including cognitively unimpaired (N = 734) individuals and patients with mild cognitive impairment (N = 235), Alzheimer's diseasedementia (N = 97) or non-Alzheimer's disease neurodegenerative diseases (N = 227). We developed seven polygenic risk scores, including six cell-weighted (for astrocytes, excitatory neurons, inhibitory neurons, microglia, oligodendrocyte precursor cells and oligodendrocytes) and one full polygenic risk score without cell specificity. For each of the polygenic risk score models, we calculated seven scores (polygenic risk score 1-7) based on different P-value thresholds (ranging from P-value < 0.05 to P-value < 5e-08) of variants from an independent large Alzheimer's disease genome-wide association study. We tested associations between the polygenic risk scores with β-amyloid [using cerebrospinal fluid (CSF) β-amyloid1-42/β-amyloid1-40], tau (using CSF pTau217) and cognitive measures (Mini-Mental State Examination score and Preclinical Alzheimer Cognitive Composite) using regression models adjusting for age, sex and the top genotype principal components. We also replicated the polygenic risk score association with β-amyloid (CSF β-amyloid1-42/β-amyloid1-40) and tau (CSF pTau217) in an independent cohort (BioFINDER-2), including cognitively unimpaired (N = 773) individuals and patients with mild cognitive impairment (N = 358), Alzheimer's disease dementia (N = 286) or non-Alzheimer's disease neurodegenerative diseases (N = 319). We observed differential cellular effects on β-amyloid, pTau217 and cognitive measures. There are substantial effects of neuronal-specific polygenic risk scores on β-amyloid, pTau217 and cognitive measures. The microglial-polygenic risk scores showed more significant effects on pTau217 than on β-amyloid. β-Amyloid positivity partly mediated the associations between polygenic risk scores and pTau217, with the lowest mediation effect observed for the microglial-polygenic risk scores (on average 33%). Cell-weighted gene expression has differential effects on pathological β-amyloid and tau metabolism, as well as cognitive decline. Cell-weighted gene expression related to microglia is preferentially relevant for the metabolism of soluble phosphorylated tau through partly β-amyloid-independent mechanisms. Cell-weighted gene expression related to neurons shows the strongest associations with cognition. These findings inform further studies that address specific cell types for various aspects of Alzheimer's disease, including the development of novel treatment strategies.}, } @article {pmid41040192, year = {2025}, author = {Scheidemantel, LP and Lopes, KP and Gaiteri, C and Menon, V and De Jager, PL and Schneider, JA and Buchman, AS and Wang, Y and Tasaki, S and Raittz, RT and Bennett, DA and Vialle, RA}, title = {Integration of aged brain multi-omics reveals cross-system mechanisms underlying Alzheimer's disease heterogeneity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41040192}, issn = {2692-8205}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; U01 AG079847/AG/NIA NIH HHS/United States ; }, abstract = {The molecular correlates of Alzheimer's disease (AD) are increasingly being defined by omics. Yet, the findings from different data types or cohorts are often difficult to reconcile. Collecting multiple omics from the same individuals allows a comprehensive view of disease-related molecular mechanisms, while addressing conflicting findings derived from single omics. Such same-sample multi-omics can reveal, for instance, when changes observed in the transcriptome share distinct but coordinated signals in epigenetics and proteomics, relationships otherwise unclear. Here, we apply a data-driven multi-omic framework to integrate epigenomic, transcriptomic, proteomic, metabolomic, and cell-type-specific population data from up to 1,358 aged human brain samples from the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). We demonstrate the existence of sprawling cross-omics cross-system biological factors that also relate to AD phenotypes. The strongest AD-associated factor (factor 8) involved elevated immune activity at the epigenetic level, decreased expression of heat shock genes in the transcriptome, and disrupted energy metabolism and cytoskeletal dynamics in the proteome. We also showed immune-related factors (factors 2 and 3) with discordant enrichments, reflecting reactive-like glial subpopulations and protective contributions from surveillance microglia. Both were negatively associated with AD pathology, suggesting potential immune resilience mechanisms. Finally, unsupervised clustering of participants revealed eleven molecular subtypes of the aging brain, including three clusters strongly associated with AD but displaying distinct molecular signatures and phenotypic characteristics. Our findings provide a comprehensive map of molecular mechanisms underlying AD heterogeneity, highlighting the complex role of neuroinflammatory processes, and yielding potential novel biomarkers and therapeutic targets for precision medicine approaches to AD treatment.}, } @article {pmid41039568, year = {2025}, author = {Wu, H and Qiu, Z and Mu, J and Wang, Y and Wang, J and Han, Y and Yang, R and Yuan, S and Yuan, M and Yang, R and Chen, X and Sun, Q and Li, F and Xiao, L and Zhang, M and Xu, J}, title = {Salt-sensitive hypertension promotes neuronal mitochondrial stress and neurodegenerative alterations via neuro-vascular metabolic reprogramming and local RAS signaling.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {220}, pmid = {41039568}, issn = {1742-2094}, support = {XJTU1AF-CRF-2023-021//The First Affiliated Hospital of Xi'an Jiaotong University/ ; 32271016//National Natural Science Foundation of China/ ; 81803026//National Natural Science Foundation of China/ ; 82071879//National Natural Science Foundation of China/ ; 82100454//National Natural Science Foundation of China/ ; 2023PT-09//the Health Research and Innovation Capacity Strengthening Platform Program of Shaanxi Province/ ; }, abstract = {UNLABELLED: Hypertension increases risks for cognitive impairment and Alzheimer’s disease (AD). In renal patients with both hypertension and cognitive decline, via rest-state fMRI, their cerebral cortical region showed maintained cerebral blood flow (CBF), but reduced signals of blood-oxygen-level-dependent (BOLD). In mice, although CBF was unchanged, deoxycorticosterone acetate (DOCA)-salt treatment markedly reduced cerebrovascular reactivity, with altered transcriptomic pattern in cortical endothelial cells (ECs) and astrocytes, showing downregulated expression of glucose transport 1 (GluT1) but upregulated metabolic reprogramming. Lipidomic analysis using prefrontal cortex (PFC) further revealed enhanced catabolism of glycerophospholipids and accumulation of free fatty acids. In the PFC of hypertensive mice, neurodegenerative alterations were observed, including reduced number of neuronal dendritic spines and more expression of phosphorylated Tau (p-Tau). Via both morphological and molecular tests, we identified that DOCA-salt hypertension was associated with significant mitochondrial injury and upregulated lysine succinylation in the PFC neurons. Upregulated lysine succinylation was largely mitochondria-located, and they were functionally enriched in gluconeogenesis-related energy metabolic pathways, the tricarboxylic acid (TCA) cycle, oxidative stress, and neurodegenerative diseases. In hypertensive mice, angiotensinogen (Agt) expression was markedly upregulated in most astrocytes, together with neuronal expression of Agtr1a. In cultured neuronal cells, angiotensin II (ang II) elevated mitochondrial membrane potential and ATP biosynthesis. In mice with neuronal AT1aR knockout (AT1N), DOCA-salt failed to induce cognitive impairment. Additionally, DOCA-salt-associated reduction of acetylcholine, accumulation of p-Tau, and upregulation of lysine succinylation were not observed in AT1N mice. Direct anti-hypertensive treatment did not abolish DOCA-salt-related pathological phenotypes, and enhanced lysine succinylation was not detected in hypertension models induced by norepinephrine or L-NAME. Our data provide evidence that hypertension induced metabolic rearrangement (enhanced energy metabolism from non-glucose source and upregulated mitochondrial oxidative phosphorylation) in the neuro-vascular unit, due to downregulated glucose uptake in ECs. Increased neuronal energy consumption, via local ang II/AT1R signaling, further exacerbated mitochondrial stress and neurodegenerative alterations. Together, by multi-omics analysis, this study provided novel insights regarding how hypertension increases the risk for age-related cognitive impairment. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03533-0.}, } @article {pmid41039514, year = {2025}, author = {El-Nagah, SMA and Abdel-Halim, M and Heikal, OA and AbdelKader, RM}, title = {Neuroprotective role of rice bran extract and its constituents in a neuroinflammatory mouse model.}, journal = {BMC complementary medicine and therapies}, volume = {25}, number = {1}, pages = {351}, pmid = {41039514}, issn = {2662-7671}, mesh = {Animals ; Mice ; *Neuroprotective Agents/pharmacology ; *Oryza/chemistry ; *Plant Extracts/pharmacology/chemistry ; Disease Models, Animal ; PPAR gamma/metabolism ; Male ; *Neuroinflammatory Diseases/drug therapy ; Brain/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; Alzheimer Disease/drug therapy ; }, abstract = {BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor known to play a critical role in regulating neuroinflammation and neurodegenerative processes, including Alzheimer's disease. Prior studies from our group demonstrated that rice bran extract (RBE) enhances cognitive function and increases PPARγ DNA-binding activity in the brain, effects that were abolished by PPARγ antagonism. These findings suggest that bioactive constituents within RBE may modulate PPARγ signaling. The current study aimed to provide additional evidence for the involvement of PPARγ activation in the neuroprotective effects of RBE and to identify key RBE-derived components that may contribute to these effects. METHODS: A neuroinflammatory mouse model was treated orally for 21 consecutive days with RBE. The brain CD36 and amyloid-beta (Aβ) protein levels were measured. HPLC and GC were used to assess the levels of RBE components. To measure alterations in fatty acid content after treatment with RBE, brain levels of DHA, EPA and AA were assessed using UHPLC/MS-MS. RESULTS: RBE treatment increased the brain levels of CD36, the direct PPARγ target, and decreased Aβ levels. A strong correlation was detected between the Aβ and CD36 protein levels. As RBE was found to be rich in linolenic acid (ALA), linoleic acid (LA) and oleic acid, their metabolites concentrations in mice brain were measured, and results indicated higher concentration of EPA and DHA after RBE treatment. CONCLUSIONS: RBE exerts neuroprotective effects potentially through activation of the PPARγ pathway, as evidenced by CD36 upregulation and Aβ reduction. The enrichment of RBE in polyunsaturated fatty acids (PUFAs), along with the observed increase in their brain-penetrant metabolites (EPA and DHA), suggests these lipids may contribute to the cognitive benefits of RBE.}, } @article {pmid41038644, year = {2025}, author = {Rohatgi, S and Zhu, S and Calle Cadavid, E and Ford, JN and Kozak, BM and Ganem Chagui, O and Vejdani-Jahromi, M and Griffin, HR and Farzaneh, H and Huang, RY and Seah, JC and Omid-Fard, N and Gomez-Isla, T and Dickson, JR and Ramírez Gómez, L and Romero, JM}, title = {Are Deep White Matter Hyperintensities Associated with Amyloid-Related Imaging Abnormalities in Patients with Alzheimer Disease Treated with Lecanemab?.}, journal = {AJNR. American journal of neuroradiology}, volume = {46}, number = {11}, pages = {2324-2329}, pmid = {41038644}, issn = {1936-959X}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/pathology ; Male ; Female ; Aged ; Retrospective Studies ; *White Matter/diagnostic imaging/pathology/drug effects ; *Magnetic Resonance Imaging/methods ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; Aged, 80 and over ; Glymphatic System/diagnostic imaging ; }, abstract = {BACKGROUND AND PURPOSE: Amyloid-related imaging abnormalities (ARIA) are common complications of antiamyloid immunotherapy for Alzheimer disease (AD). Identifying imaging biomarkers that predict ARIA risk may help guide treatment decisions. This study investigates the relationship between deep white matter hyperintensities (DWMH), perivascular spaces (PVS), and ARIA incidence in patients with AD treated with lecanemab. MATERIALS AND METHODS: This retrospective cohort study included 27 ARIA-positive patients identified between November 2023 and November 2024, and 27 age- and sex-matched ARIA-negative controls. Baseline MRI was assessed for DWMH burden (Fazekas score) and PVS grades in the basal ganglia and centrum semiovale. Simple logistic regression was performed to evaluate associations between imaging markers and ARIA risk. RESULTS: ARIA-positive patients had significantly higher Fazekas scores compared with ARIA-negative patients (1.37 versus 1.0; P = .0262), indicating a greater DWMH burden. PVS grades in the basal ganglia were numerically higher in ARIA-positive patients (1.81 versus 1.56, P = .0733) but did not reach statistical significance. Simple logistic regression identified the Fazekas score as a significant predictor of ARIA (OR: 2.812; 95% CI, 1.076-8.438; P = .0343). The area under the receiver operating characteristic curve for the model was 0.640 (95% CI, 0.492-0.788; P = .078). CONCLUSIONS: Higher DWMH burden, as quantified by the Fazekas score, is significantly associated with ARIA risk in patients with AD treated with lecanemab. These findings suggest that DWMH may serve as a potential imaging biomarker for ARIA risk stratification. Larger studies incorporating additional vascular biomarkers, including cerebral amyloid angiopathy markers, are warranted to refine risk prediction models.}, } @article {pmid41038490, year = {2025}, author = {Naghib, SM and Khorasani, MA and Sharifianjazi, F and Tavamaishvili, K}, title = {Bifunctional chitosan-based nanocarriers as promising therapeutic approach for brain disease therapy: A critical review focusing on multiple sclerosis over emerging strategies, technologies and applications.}, journal = {International journal of biological macromolecules}, volume = {330}, number = {Pt 3}, pages = {148003}, doi = {10.1016/j.ijbiomac.2025.148003}, pmid = {41038490}, issn = {1879-0003}, mesh = {Humans ; *Chitosan/chemistry/therapeutic use ; *Multiple Sclerosis/drug therapy ; Animals ; *Drug Carriers/chemistry ; Blood-Brain Barrier/drug effects/metabolism ; *Nanoparticles/chemistry ; *Brain Diseases/drug therapy ; Drug Delivery Systems ; Neuroprotective Agents/chemistry/therapeutic use/pharmacology ; }, abstract = {Chitosan (CS) has appeared as a promising candidate in brain disease (BD) (such as Alzheimer's, Parkinson's, and Multiple sclerosis (MS)) therapy due to its anti-inflammatory, antioxidative, and neuroprotective properties. CS's capacity to interact with the blood-brain barrier (BBB) enhances the central nervous system (CNS) drug permeability, offering new avenues for effective treatment strategies aimed at overcoming the limitations of conventional therapies. Furthermore, CS's role in regenerative medicine extends beyond drug delivery, as it fosters neural repair by providing a supportive microenvironment for oligodendrocyte proliferation and neuronal regeneration. Studies have shown that CS-based scaffolds, when combined with neurotrophic factors and stem cells, can enhance remyelination and neuroprotection in BD models. The immunomodulatory effects of CS further contribute to reducing neuroinflammation by shifting immune responses toward an anti-inflammatory phenotype, thereby mitigating the progression of BD-associated damage. This review provides a comprehensive analysis of the latest advancements in CS-based BD therapies, exploring its multifunctional applications in drug delivery, immune modulation, and tissue engineering. The discussion also addresses the current challenges in clinical translation, including variability in CS formulations, regulatory considerations, and potential safety concerns. Future research directions should focus on optimizing CS derivatives, improving its bioavailability, and integrating it with emerging therapeutic approaches such as gene therapy and biomimetic nanocarriers.}, } @article {pmid41038475, year = {2025}, author = {Zhou, J and Guo, X and Yu, W and Bu, H and Du, Y and Li, S and Kuang, H and Wu, L}, title = {Pharmacological action, mechanism and structure-activity relationship of traditional Chinese medicine polysaccharide in the treatment of Alzheimer's disease: A review.}, journal = {International journal of biological macromolecules}, volume = {330}, number = {Pt 2}, pages = {148017}, doi = {10.1016/j.ijbiomac.2025.148017}, pmid = {41038475}, issn = {1879-0003}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Polysaccharides/chemistry/therapeutic use/pharmacology ; Structure-Activity Relationship ; *Medicine, Chinese Traditional ; *Drugs, Chinese Herbal/chemistry/therapeutic use/pharmacology ; Animals ; }, abstract = {Alzheimer's disease (AD) is a significant neurodegenerative disorder characterized by a progressive decline in cognitive functions. The pathogenesis of AD remains largely elusive, resulting in Western medications that often exhibit limited efficacy and frequent side effects. In contrast, traditional Chinese medicine (TCM) has been utilized for managing AD, recognized for its favorable safety profile and multi-target therapeutic potential. Polysaccharides, which are essential bioactive components found in TCM extracts, have attracted considerable interest due to their safety and ability to target multiple biological pathways. This article examines the pharmacological effects and mechanisms of TCM polysaccharides in the treatment of AD, focusing on research conducted over the past decade. Additionally, it explores the structure-activity relationships of these polysaccharides, providing a foundation for further investigation into polysaccharide-based interventions for AD and suggesting potential avenues for future studies aimed at structural enhancements.}, } @article {pmid41037798, year = {2025}, author = {Park, HJ and Kim, J and Choi, J and Ryou, C and Shin, E and Lee, JY}, title = {Targeted genome editing of ZKSCAN3 mitigates the neurotoxicity caused by mutant HTT (huntingtin) in a Huntington disease animal model and three-dimensional cell culture of Huntington disease.}, journal = {Autophagy}, volume = {21}, number = {12}, pages = {3398-3412}, pmid = {41037798}, issn = {1554-8635}, mesh = {Animals ; *Huntington Disease/genetics/pathology ; Humans ; Disease Models, Animal ; Induced Pluripotent Stem Cells/metabolism ; Autophagy/genetics ; *Huntingtin Protein/genetics/metabolism/toxicity ; *Gene Editing/methods ; CRISPR-Cas Systems/genetics ; *Transcription Factors/genetics/metabolism ; Spheroids, Cellular/metabolism ; Mice ; *Mutation/genetics ; Lysosomes/metabolism ; Neurons/metabolism/pathology ; }, abstract = {Huntington disease (HD) is a neurodegenerative disease caused by the expression of a mutant form of HTT (huntingtin; mHTT), caused by an abnormal expansion of polyglutamine in HTT. In HD, macroautophagy/autophagy dysfunction can cause mHTT accumulation. Moreover, the promotion of autophagy is considered a therapeutic strategy for the treatment of HD. ZKSCAN3 (zinc finger with KRAB And SCAN domains 3) has been identified as a transcriptional repressor of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal functions. In this study, we conducted CRISPR-Cas9-based gene ablation to disrupt ZKSCAN3 in HD animal models and HD patient-induced pluripotent stem cell (iPSC) -derived three-dimensional (3D) spheroids. In animal models of HD, targeted in vivo zkscan3 ablation via a single adeno-associated virus (AAV) mediated CRISPR-Cas9 approach resulted in reduced mHTT levels, leading to improvements in both behavioral symptoms and the brain environment. Furthermore, CRISPR-Cas9 mediated ablation of ZKSCAN3 in 3D spheroids from HD patient-derived iPSC resulted in increased autophagy and lysosomal function, along with reduced mHTT accumulation. Specifically, in iPSC-derived neurons from HD patients, ZKSCAN3-depleted neurons demonstrated increased lysosomal function and reduced oxidative stress compared to controls. Additionally, transcriptional analysis of ZKSCAN3-edited neurons revealed an increased expression of genes involved in synaptic function and transporter activity. Taken together, these results suggest that in HD treatment strategies for improving neuronal function and the brain environment, ZKSCAN3 downregulation in neurons by autophagy activation may improve the brain environment through neuronal self-repair.Abbreviations: 2D: two-dimensional; 3D: three-dimensional; 4-HNE: 4-hydroxynonenal; AAV: adeno-associated virus; AD: Alzheimer disease; Aβ: beta-amyloid; DAPI: 4,6-diamidino-2-phenylindole; GFP: green fluorescent protein; HD: Huntington disease; HTT: huntingtin; IXMC: ImageXpress microconfocal high-content imaging system; Indel: insertion or deletion; iPSC: induced pluripotent stem cell; LAMP1: lysosomal-associated membrane protein 1; mHTT: mutant huntingtin; NPCs: neural precursor cells; RBFOX3/NeuN: RNA binding fox-1 homolog 3; PD: Parkinson disease; RNP: ribonucleoprotein; sgRNAs: single guide RNAs; ST: striatum; TFEB: transcription factor EB; TUBB3/Tuj-1: tubulin beta 3 class III; ZKSCAN3: zinc finger with KRAB and SCAN domains 3.}, } @article {pmid41036749, year = {2025}, author = {Bartolomeu, PF and Fortes, IS and Zimmer, AR and Lopes, MS and de Andrade, SF}, title = {8-Hydroxyquinoline Derivatives as Drug Candidates for the Treatment of Alzheimer's Disease.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673409645250823055140}, pmid = {41036749}, issn = {1875-533X}, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia among older adults worldwide. Amidst several hypotheses to explain the pathobiology of the disease are biochemical indicators such as β-amyloid (Aβ) plaques; neurofibrillary tangles, caused by hyperphosphorylated tau protein; oxidative stress; metal dyshomeostasis; low levels of acetylcholine, and neuroinflammation. Considering the multifactorial nature of AD, there has been an increase in research for novel multitarget compounds, mainly utilizing molecular hybridization for drug design. In this review, we focus on the 8-hydroxyquinoline moiety, a privileged metal-binding agent with Aβ antiaggregating properties, and its derivatives, aiming to have an effect on multiple molecular targets. Furthermore, the most prominent structure-activity relationships found on the analyzed compounds, along with the most promising strategies explored by researchers, are discussed. That way, we hope to provide a comprehensive perspective on the development of anti- Alzheimer agents based on the 8-hydroxyquinoline moiety in the last decade.}, } @article {pmid41035985, year = {2025}, author = {Ghaliby, FAKA and Alhasan, L}, title = {Histopathological study of the neuroprotective effects of Gum Arabic and Fenchol on neuronal cells in an Alzheimer's disease rat model.}, journal = {Open veterinary journal}, volume = {15}, number = {8}, pages = {3871-3877}, pmid = {41035985}, issn = {2218-6050}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/chemically induced ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Rats ; *Gum Arabic/pharmacology/therapeutic use ; Disease Models, Animal ; *Neurons/drug effects ; Interleukin-6/blood ; Brain/drug effects/pathology ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder influenced by environmental and genetic factors. It is primarily characterized by beta-amyloid plaque deposition, neurofibrillary tangles, and impaired neuronal signaling. Given the lack of a definitive cure, research has increasingly focused on identifying natural compounds with neuroprotective and therapeutic potential. AIM: This study evaluates the effects of natural compounds (Fenchol and Gum Arabic) on immune modulation and neuroinflammatory markers, specifically interleukin-6 (IL-6), in a rat model of AD. By examining the effects of these natural products on the immune response and brain tissue pathology, this research aims to provide new insights into their potential therapeutic benefits for slowing AD progression. METHODS: In this study, 36 adult male rats were randomly assigned to five groups: (1) a negative control group received standard feed and water, (2) a positive control group treated with aluminum chloride (17 mg/kg/day orally), (3) a Gum Arabic-treated group (2 ml, 10 g/100 ml orally) post-induction, (4) a Fenchol-treated group (2 ml, 5 mg/80 ml orally), and (5) a memantine-treated group (2 ml, 1.57 g/25 ml orally). After 1 month, histopathological assessments were performed to evaluate neuronal integrity, granule cell density, and beta-amyloid accumulation in the hippocampus. Additionally, serum IL-6 concentrations were measured via ELISA to assess systemic neuroinflammatory responses. Data were statistically analyzed using analysis of variance followed by least significant difference (LSD) post hoc tests. RESULTS: Histopathological analysis revealed significant neurodegeneration in the positive control group, characterized by cytoplasmic vacuolation, reduced granule cell density, and elevated beta-amyloid levels. The Gum Arabic-treated group exhibited a partial neuroprotective effect, with a notable reduction in neurodegeneration, increased granule cell density, and a 50% decrease in amyloid plaques. The Fenchol-treated group demonstrated improved neuronal integrity and a marked reduction in beta-amyloid aggregates. The memantine-treated group exhibited the most substantial neuroprotective effect, significantly preserving granule cells and minimizing beta-amyloid deposition. Biochemical analysis revealed that IL-6 levels were markedly elevated in the positive control group (85.00 ± 3.00 ng/l) compared to the negative control (60.00 ± 2.00 ng/l). All treatment groups showed significant reductions in IL-6 levels. Memantine and combined treatments restored IL-6 levels close to normal. Fenchol and Gum Arabic alone reduced IL-6 levels, though to a lesser extent, indicating partial inflammatory effects. CONCLUSION: The findings suggested that Gum Arabic and Fenchol possess neuroprotective properties, suggesting their potential as therapeutic agents for AD, with efficacy comparable to that of memantine. Their ability to downregulate IL-6 further highlights their potential in mitigating neuroinflammation associated with Alzheimer's pathology. Further investigations are warranted to elucidate their underlying mechanisms and evaluate their potential clinical applications.}, } @article {pmid41035827, year = {2025}, author = {Cai, M and Cai, K and Wei, Z and Zhou, J and Shu, J and Wang, W and Sun, W and Hu, J}, title = {Exercise-mediated cerebrovascular repair in Alzheimer's disease: from pathophysiology to therapeutic precision.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1632365}, pmid = {41035827}, issn = {1663-4365}, abstract = {Cerebrovascular dysfunctions, encompassing changes in cerebrovascular microstructure, blood-brain barrier (BBB) integrity, cerebrovascular reactivity, and cerebral blood flow (CBF), accelerate the pathological progression of Alzheimer's disease (AD). Exercise emerges as a promising non-pharmacological intervention that enhances cerebrovascular repair for the treatment of AD. This review summarizes the pathological vascular changes in AD pathology, such as pericyte loss, endothelial dysfunction, and capillary fibrosis, which exacerbate hypoperfusion, hypoxia, and amyloidogenesis. We further discuss the contributing vascular factors and underlying signaling mechanisms to explore potential targets for AD diagnosis and therapy. Finally, we present evidence concerning the impact of exercise on cerebral vascular signaling and the cells involved in vascular plasticity. We also address the impact of various exercise patterns on cerebrovascular health. This work aims to uncover the potential and intervention effects of exercise on cerebrovascular non-malignant alterations and will provide exercise strategies for treating AD.}, } @article {pmid41035821, year = {2025}, author = {Noto, NM and Speth, RC and Robison, LS}, title = {Cerebral amyloid angiopathy: a narrative review.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1632252}, pmid = {41035821}, issn = {1663-4365}, abstract = {Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the accumulation of amyloid-beta (Aβ) in the walls of cerebral vessels. It is commonly associated with cognitive decline, cerebral hemorrhage, and other neurological pathologies. Despite its prevalence and impact, there are currently no approved treatments for CAA. CAA frequently co-occurs with Alzheimer's disease (AD), but affected patients are often excluded from anti-amyloid therapies due to increased risks of cerebral edema and hemorrhage, underscoring the urgent need for alternative and safe approaches for treating individuals with CAA. Over the years, various animal models have been developed to investigate the pathophysiology of CAA and evaluate potential treatments. Recent studies have demonstrated that certain repurposed drugs, originally approved for other conditions, show promise for treating CAA. Additionally, it has been shown that positive lifestyle changes may benefit vascular health, reduce amyloid burden and neuroinflammation, and improve cognitive resilience in individuals with CAA. In this review, we summarize the current knowledge on CAA, its relationship with AD, insights from preclinical and clinical studies, and emerging evidence supporting the potential of drug repurposing and lifestyle modification in managing CAA.}, } @article {pmid41035200, year = {2025}, author = {Gaffour, A and Bakker, M and Bera, K and Pavlíková Přecechtělová, J}, title = {Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops.}, journal = {Biophysical journal}, volume = {124}, number = {21}, pages = {3800-3810}, pmid = {41035200}, issn = {1542-0086}, mesh = {*tau Proteins/metabolism/chemistry ; Molecular Dynamics Simulation ; Protein Binding ; *Adaptor Proteins, Signal Transducing/metabolism/chemistry ; *Tumor Suppressor Proteins/metabolism/chemistry ; *Phosphates/metabolism ; *Nuclear Proteins/metabolism/chemistry ; Humans ; *src-Family Kinases/metabolism/chemistry ; Static Electricity ; src Homology Domains ; Phosphorylation ; }, abstract = {Within the disordered tangles of Tau is a proline-rich region, which is selectively targeted by the SH3 domain of BIN1, a known genetic factor for Alzheimer disease, and may hold the key to understanding the disorder and treatment strategies. Hyperphosphorylation of Tau is known to disrupt complex formation, providing researchers with excellent preventative or remediative targets. This work compiles an extensive (>60 μs) collection of all-atomistic molecular dynamics simulations of the Tau(210-240) fragment, representing the majority of the P2 subdomain of the proline-rich region, benchmarking various force fields, phosphorylations, and modifications against experimental NMR chemical shifts and spin-spin coupling for comparison. Additionally, several simulations of the binding complex were analyzed for their binding energies by MMGBSA calculations and computational alanine scanning to pinpoint the exact residues involved and the disruptions caused by the phosphate group. We noted that the additional charges decrease salt bridges formed by positive residues in Tau, particularly on R221, and negative residues in BIN1 by up to 32%, and a strong preference in Tau, particularly in the latter half, for contact toward the distal and n-Src loops instead of residues in the RT-Src loop.}, } @article {pmid41034564, year = {2025}, author = {Makarov, N and Bordukova, M and Quengdaeng, P and Garger, D and Rodriguez-Esteban, R and Schmich, F and Menden, MP}, title = {Large language models forecast patient health trajectories enabling digital twins.}, journal = {NPJ digital medicine}, volume = {8}, number = {1}, pages = {588}, pmid = {41034564}, issn = {2398-6352}, support = {U19 AG024904/AG/NIA NIH HHS/United States ; 950293 - COMBAT-RES//European Union's Horizon 2020 Research and Innovation Programme/ ; }, abstract = {Generative artificial intelligence is revolutionizing digital twin development, enabling virtual patient representations that predict health trajectories, with large language models (LLMs) showcasing untapped clinical forecasting potential. We developed the Digital Twin-Generative Pretrained Transformer (DT-GPT), extending LLM-based forecasting solutions to clinical trajectory prediction. DT-GPT leverages electronic health records without requiring data imputation or normalization and overcomes real-world data challenges such as missingness, noise, and limited sample sizes. Benchmarking on non-small cell lung cancer, intensive care unit, and Alzheimer's disease datasets, DT-GPT outperformed state-of-the-art machine learning models, reducing the scaled mean absolute error by 3.4%, 1.3% and 1.8%, respectively. It maintained distributions and cross-correlations of clinical variables, and demonstrated explainability through a human-interpretable interface. Additionally, DT-GPT's ability to perform zero-shot forecasting highlights potential advantages of LLMs as clinical forecasting platforms, proposing a path towards digital twin applications in clinical trials, treatment selection, and adverse event mitigation.}, } @article {pmid41034513, year = {2025}, author = {Zhuo, Y and Lu, Y and Zhu, Y and Wen, N and Zou, G and Lu, H and Pei, X and Zhang, Y and Zhang, Q and Wang, X and Zhang, W and Zhang, Q and Wang, Z and Xie, S and Li, CQ and Tan, W and Qiu, L}, title = {Targeted clearance of extracellular Tau using aptamer-armed monocytes alleviates neuroinflammation in mice with Alzheimer's disease.}, journal = {Nature biomedical engineering}, volume = {}, number = {}, pages = {}, pmid = {41034513}, issn = {2157-846X}, support = {21991080//National Natural Science Foundation of China (National Science Foundation of China)/ ; 92253304//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {Extracellular Tau determines the progression of Alzheimer's disease, yet therapeutic strategies targeting it are hindered by poor brain delivery and limited clearance. Here we developed a Tau-clearing cell therapy based on monocytes functionalized with a high-affinity Tau-specific aptamer. The aptamer was covalently conjugated to the surface of monocytes (derived from bone marrow leucocytes and cultured under monocyte-inducing conditions) via bioorthogonal chemistry without affecting their viability or function. Upon intravenous administration in mice expressing mutant and disease-relevant human Tau, the engineered monocytes actively crossed the blood-brain barrier and accumulated in Tau-rich brain regions such as the hippocampus and striatum. They efficiently phagocytosed extracellular Tau, leading to a significant reduction in Tau burden. As a result, glial activation was suppressed, neuroinflammation was alleviated, and neuronal and mitochondrial integrity was preserved. Long-term treatment improved memory and spatial learning, without inducing toxicity or behavioural side effects. These results demonstrate that aptamer-guided monocytes can achieve targeted delivery, effective clearance and sustained neuroprotection, offering a promising strategy for therapeutic intervention in Alzheimer's disease.}, } @article {pmid41032155, year = {2025}, author = {Gao, X and Yang, K and Yuan, X and Song, M and Wang, T and Shen, C}, title = {Research progress of exosomes used in the Alzheimer's disease treatment.}, journal = {Discover nano}, volume = {20}, number = {1}, pages = {173}, pmid = {41032155}, issn = {2731-9229}, support = {82402735//National Natural Science Foundation of China/ ; 2023NSFSC1481//Natural Science Foundation of Sichuan Province/ ; 2023HXBH122//Postdoctoral Research Foundation of West China Hospital of Sichuan University/ ; }, abstract = {Alzheimer's disease (AD) is a common form of dementia characterized by memory loss, cognitive and linguistic abilities declining and self-care capabilities diminishment. With the aging population globally, AD poses a significant threat to public health. Current treatments for AD aim to alleviate symptoms and slow down disease progression, but due to the limited understanding of underlying disease mechanisms, AD is still impossible to be cured yet. In recent years, there has been an exponential growth in exosome-related research because of their excellent biocompatibility ability, loading capacity and cellular internalization, making exosome to be one of the hotspots and a promising strategy in AD therapy research. This comprehensive review systematically explores the potential roles of various exosome-based nanotherapeutic strategy in AD treatment, with a particular focus on their specific biological mechanisms of action. Firstly, we elaborated on the pathological mechanisms of AD formation as well as the mechanisms related to the formation, secretion and function of exosome. Additionally, we highlighted the research progress in the development of exosome-based nanotherapeutic strategies for AD treatment and their corresponding biological mechanisms. Furthermore, we delved into the challenges and opportunities these strategies facing in clinical application. Looking forward to future research directions and trends, our review aims to provide a more comprehensive understanding and guidance with the application of exosome in AD treatment. Exosome-based nanotherapeutic strategies, as a new therapeutic approach, have opened up new possibilities for the treatment of AD and brought new light to patients.}, } @article {pmid41032080, year = {2025}, author = {Khatun, P and Li, X and Xiaoxi, Z and Zhai, J and Ullah, A and Bo, Y and Lyu, Q}, title = {Effect of Omega-3 Polyunsaturated Fatty Acid Supplements on Cognitive Performance in Patients with Mild Cognitive Impairment or Alzheimer's Disease: A Systematic Review and Meta-Analysis.}, journal = {Nutrition reviews}, volume = {}, number = {}, pages = {}, doi = {10.1093/nutrit/nuaf167}, pmid = {41032080}, issn = {1753-4887}, support = {YJ20220181//2022 International Postdoctoral Exchange Fellowship Program/ ; 232102310069//Henan Medical Science and Technology Research Program/ ; //Preferential support for scientific research of overseas persons in Henan Province/ ; }, abstract = {CONTEXT: A positive effect of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on brain activity has been observed within subjects who have Alzheimer's disease (AD) or mild cognitive impairment (MCI). However, inconsistent findings have been reported regarding the efficacy or ineffectiveness of an n-3 PUFA dietary intervention for cognitive improvement. OBJECTIVE: To address this problem, our thorough investigation and statistical analysis sought to assess the impact of n-3 PUFA dietary intake on cognitive function among persons diagnosed with AD or MCI. DATA SOURCES: The databases consulted included PubMed, PubMed Central Library, and the Cochrane Library. DATA EXTRACTION: Nine articles reporting on the findings of randomized controlled trials that looked at the link between n-3 PUFA intake and cognitive performance-related outcomes were included in the comprehensive evaluation, with the meta-analysis utilizing 7 of these. Key details such as author, publication year, study area, research type, pathology (MCI or AD), were incorporated into the data extraction procedure. DATA ANALYSIS: Evaluation of the included studies used Cochrane risk-of-bias instruments, a random-effects model, standardized mean differences (SMDs) and 95% CIs. RESULTS: Our findings have provided evidence of the effectiveness of an n-3 PUFA treatment in improving Full-Scale IQ (FSIQ) (SMD -0.82; 95% CI: -1.57, -0.08; P = .000), information processing (SMD -2.90; 95% CI: -5.25, -0.56; P = .000), and digit span/working memory/attention aspects of cognitive functioning (SMD -1.89; 95% CI: -3.27, -0.51; P = .000). No evidence was found for the effectiveness of an n-3 PUFA treatment in improving image completion (SMD -0.07; 95% CI: -0.50, 0.35; P = .000), picture layout (SMD -0.08; 95% CI: -0.32, 0.16; P = .075), block design SMD -0.15; 95% CI: -0.37, 0.03; P = .123), or arithmetic aspects of cognitive functioning (SMD -0.33; 95% CI: -0.61, 0.04; P = .007). CONCLUSION: In summary, n-3 PUFAs have been found to significantly affect some domains of cognitive function, such as FSIQ, information processing, and digit span/working memory/attention in subjects with MCI. However, no significant effect was observed for some domains, such as picture completion, picture arrangement, or block design.}, } @article {pmid41031197, year = {2025}, author = {Wang, Q and Wang, DL and Zhang, XC and Jiang, XY and Jiang, HN and Yang, XY and Zhang, T and Lv, YY and Li, Q}, title = {Efficacy and safety of traditional Chinese medicine and Western medicine in Alzheimer's disease: a systematic review and meta-analysis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1607945}, pmid = {41031197}, issn = {1664-2295}, abstract = {OBJECTIVE: This study aimed to compare the efficacy and safety of traditional Chinese medicine (TCM) compounds with single Western medicines in treating Alzheimer's disease (AD) through a systematic review and meta-analysis. METHODS: In this study, we searched for randomized controlled trials on the treatment of AD with TCM compounds published before March 2025 in Chinese and English databases (PubMed, Embase, Cochrane, China National Knowledge Infrastructure, VIP, and Wanfang) and conducted a meta-analysis using Stata15.0 software. RESULTS: A total of 23 studies were included, involving 2,035 participants (1,173 in the experimental group and 862 in the control group). Traditional Chinese herbal compounds showed good clinical efficacy and maintenance effects in the treatment of AD. The effective rate of TCM compounds in treating AD was higher than that of Western medicine (relative risk ratio = 1.19, 95% CI: 1.04-1.37, p = 0.009). In terms of the Alzheimer's Disease Assessment Scale-Cognitive and Hierarchic Dementia Scale-Revised scores, TCM compounds were superior to Western medicine (standardized mean difference = -0.22, 95% CI: -0.40--0.05). There were no significant differences between the two groups in the Mini-Mental State Examination or Activities of Daily Living scores. Additionally, there were no significant differences in adverse reactions between the TCM compounds and Western medicine groups. CONCLUSION: The present research indicates that TCM compounds could be a promising therapeutic option for AD, demonstrating encouraging results in terms of efficacy and safety, particularly regarding certain cognitive functions.}, } @article {pmid41030887, year = {2025}, author = {Pan, Q and Lu, J and Xiao, Z and Zhang, H and Liu, G and Li, Y}, title = {Construction of a Rat Model of Hemilateral Parkinson's Disease Induced by Human Wild-Type α-Synuclein Overexpression.}, journal = {Neuropsychiatric disease and treatment}, volume = {21}, number = {}, pages = {2183-2194}, pmid = {41030887}, issn = {1176-6328}, abstract = {OBJECTIVE: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease. The precise etiology and pathogenesis of PD remain unclear. Human wild-type α-synuclein has been implicated in PD pathogenesis. The objective of this study is to examine the role of α-synuclein in PD by establishing a rat model of substantia nigra degeneration and Motor behavioral changes through the induced overexpression of human α-synuclein. METHODS: Rats were randomly assigned to either the Negative control group or the adeno-associated virus serotype 9 (AAV9) treatment group. Animals in the AAV9 group received 2.5 μL of AAV9 expressing human wild-type α-synuclein, while those in the Negative control group received an equal volume of AAV9 expressing green fluorescent protein via stereotactic unilateral injection into the substantia nigra pars compacta. Behavioral assessments were conducted at 1-, 3-, and 8-weeks following virus administration. Tyrosine hydroxylase and human α-synuclein expression in the substantia nigra pars compacta were analyzed. Additionally, dopamine, dihydroxyphenylacetic acid, and homovanillic acid levels in the striatum were quantified. RESULTS: After 3 weeks of virus induction, neurodegeneration of the right substantia nigra was observed, with a reduction in the number of tyrosine hydroxylase-immunopositive neurons in the AAV9 group. By 8 weeks, substantia nigra neurodegeneration had further progressed, and animals in the AAV9 group exhibited apomorphine-induced asymmetrical rotation and altered forelimb use. CONCLUSION: Overexpression of human wild-type α-synuclein led to substantia nigra degeneration and Motor behavioral changes in rats, providing a viable model for exploring the pathogenesis of Parkinson's disease. Limitations include the 8-week observation window and the absence of neuroinflammation markers.}, } @article {pmid41030378, year = {2025}, author = {Gazes, Y and Suzuki, H and Morris, LA and Lee, S and Jin, Z and Huey, ED and Chen, BB and Le Heron, C and Heibronner, SR and Vanegas-Arroyave, N}, title = {A transdiagnostic, multi-modal approach to understanding apathy: Methodological and analytical framework.}, journal = {Neuroimage. Reports}, volume = {5}, number = {4}, pages = {100289}, pmid = {41030378}, issn = {2666-9560}, abstract = {Apathy is characterized by loss of motivation and manifests as a reduction of goal-directed behavior. Apathy is highly prevalent across neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD), and is an important contributor to the disability and reduce quality of life in these conditions. The treatment of apathy remains challenging due to a lack of specific therapies, largely attributed to an incomplete understanding of its cognitive and neuroanatomical underpinnings, crucial for developing targeted interventions. Apathy can be mechanistically studied through effort-based decision-making (EBDM) paradigms, where individuals choose between low- and high-effort tasks for varying reward magnitudes. Anatomically, apathy has been associated with alterations in brain regions previously implicated in EBDM. Using a novel transdiagnostic study design in individuals with AD and PD, we aim to: (1) evaluate the independent effects of reward and effort sensitivity as a mechanistic link between apathy and neurodegeneration of basal ganglia-frontal networks and, (2) in a subset of PD patients receiving deep brain stimulation (DBS) surgery, determine whether electrical manipulation of subthalamic nucleus and/or DBS connectivity, directly alter reward and effort information processing and, consequently, goal-directed behavior. Understanding how neurodegeneration-alone or in combination with neuromodulatory interventions-drives apathy, is essential for guiding clinical decision-making and therapeutic development. Given its prevalence across neurodegenerative disorders, apathy provides a unique framework for investigating shared and disease-specific neuroanatomical, functional, and behavioral mechanisms. In this protocol paper, we describe the rationale and methodology of our proposed multimodal approach, to investigate apathy in a transdiagnostic cohort of individuals with AD and PD.}, } @article {pmid41029918, year = {2025}, author = {Agarwal, M and Singhal, M and Basist, P and Tamta, N and Kumar, S and Saha, S}, title = {Evaluation of Hordenine's Therapeutic Potential in Alzheimer's Disease-Induced Cognitive and Oxidative Impairments.}, journal = {Recent advances in food, nutrition & agriculture}, volume = {}, number = {}, pages = {}, doi = {10.2174/012772574X389943250908070348}, pmid = {41029918}, issn = {2772-5758}, abstract = {INTRODUCTION: This research aimed to investigate the potential of Hordenine (HR) against Alzheimer's Disease (AD) induced by Streptozotocin (STZ) in Wistar rats by evaluating its impact on cognitive function, oxidative stress, inflammatory cytokines, and neuroprotective biomarkers in comparison to donepezil. METHODS: The study involved five groups of Wistar rats: a control group, a group with STZinduced AD, and three treatment groups receiving varying doses of HR (50 mg/kg and 75 mg/kg) and donepezil (5 mg/kg). Over 28 days, the animals underwent various behavioural tests to assess cognitive function, along with biochemical analyses to measure A+cetylcholinesterase (AChE) activity, oxidative stress markers, inflammatory cytokines (IL-1β, TNF-α), and nuclear factor kappa B (NF-κB) levels, and histological examination. Additionally, molecular docking studies were performed to assess the interaction of HR with AChE. RESULTS: STZ administration caused significant cognitive decline, oxidative stress, and elevated inflammatory markers. HR supplementation, particularly at 75 mg/kg, significantly improved cognition, reduced oxidative stress, and decreased pro-inflammatory cytokines (IL-1β, TNF-α), as well as NF-κB levels, while increasing Brain-Derived Neurotrophic Factor (BDNF) expression. Molecular docking studies revealed strong binding of HR to AChE, suggesting potential inhibitory effects. DISCUSSION: Hordenine demonstrated promising neuroprotective effects against STZ-induced neurotoxicity by improving cognition and reducing oxidative stress and inflammation, suggesting HR's potential as an adjunct therapy for Alzheimer's disease, offering a protective mechanism that may complement existing treatments like donepezil. CONCLUSION: The research shows that the medicinal plant HR exhibits neuroprotective potential against AD induced by STZ. Further research involving clinical trials is warranted to fully establish the efficacy and safety of HR in the treatment of AD.}, } @article {pmid41029885, year = {2025}, author = {Zhou, J and Zhong, Y and Jin, C and Dong, L and Zhou, R and Wang, Y and Fan, Z and Zheng, X and Xing, X and Wang, J and Tian, M and Zhang, H}, title = {A novel electric field approach for improving cognitive function through ameliorating cell-specific pathology in P301S tauopathy mice.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {210}, pmid = {41029885}, issn = {1758-9193}, support = {82394433//National Natural Science Foundation of China/ ; 82030049//National Natural Science Foundation of China/ ; 2022YFE0118000//National Key Research and Development Program of China/ ; 226-2024-00059//Fundamental Research Funds for the Central Universities/ ; }, mesh = {Animals ; *Tauopathies/pathology/therapy/genetics ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Microglia/pathology/metabolism ; *Cognition/physiology ; Brain/pathology/metabolism ; Neurons/pathology/metabolism ; tau Proteins/genetics/metabolism ; *Cognitive Dysfunction/therapy/pathology ; Male ; Mice, Inbred C57BL ; Oxidative Stress/physiology ; *Electric Stimulation Therapy/methods ; }, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder, with no effective treatment currently available. Recently, non-pharmacological therapy, especially gamma frequency stimulation has shown promising therapeutic effects in Alzheimer's disease (AD) mouse models. Electric field (EF) is a non-invasive biophysical approach for neuronal protection. However, whether EF is beneficial in AD neuropathology remains unknown. In this study, we exposed the P301S tauopathy mouse model to EF at gamma frequency on the head. We demonstrated that EF treatment significantly improved the cognitive impairments in the P301S mice. This was accompanied by reduced tau pathologies, suppressed microglial activation, neuroinflammation and oxidative stress in the tauopathy mouse brain. Moreover, EF treatment induced cell-specific responses in neural cells, with neurons being more susceptible, followed by microglia and oligodendrocytes. EF also had favorable effects on synaptic protein in neurons, inflammatory response and complement signaling in microglia, and myelination in oligodendrocytes. This study provides strong evidence that EF at gamma frequency may have great potential to be a novel therapeutic intervention for P301S by attenuating neuropathology and offering neuroprotection.}, } @article {pmid41028047, year = {2025}, author = {Khan, MI and Jeong, ES and Tasreen, G and Khan, MZ and Shin, JH and Kim, JD}, title = {The therapeutic potential of beta-carotene against neuroinflammation and amyloid beta in SH-SY5Y cells.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {33803}, pmid = {41028047}, issn = {2045-2322}, support = {NRF-2018R1D1A1B07047021//National Research Foundation of Korea/ ; }, mesh = {Humans ; *beta Carotene/pharmacology ; *Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; Apoptosis/drug effects ; *Neuroprotective Agents/pharmacology ; Antioxidants/pharmacology ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Alzheimer Disease/drug therapy/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; }, abstract = {Neurodegenerative diseases, particularly Alzheimer's disease (AD), represent a significant public health challenge due to their increasing prevalence and the lack of effective treatments. In this study, we explored the neuroprotective effects of beta-carotene, a naturally occurring carotenoid, by investigating its ability to inhibit or reduce apoptosis and inflammation while enhancing antioxidant potential in SH-SY5Y neuroblastoma cells. Beta-carotene was extracted from Chlorella vulgaris using high-performance liquid chromatography (HPLC). We utilized SH-SY5Y cells, a widely employed in vitro model for studying neurodegenerative processes, to evaluate these therapeutic effects. A combination of colorimetric assays, enzyme-linked immunosorbent assays (ELISA), and quantitative real-time PCR (qRT-PCR) was used to assess the impact of beta-carotene on enzyme activity, cytokine production, and gene expression. The caspase assay results demonstrated that beta-carotene effectively reduced the activity of pro-apoptotic caspases and downregulated the expression of pro-apoptotic genes such as Bax, Bak and caspases, thereby inhibiting apoptosis in SH-SY5Y cells. Additionally, beta-carotene exhibited potent antioxidant properties by upregulating NRF2 and superoxide dismutase (SOD), along with enhancing ABTS and DPPH radical scavenging activities.showed antiinflamatory effects reduce the concentrations of proinflamatory cytokines TNFα, IL-1 β and IFN-γ, and supress the inflamtion patway by supressing the expression of Akt, PIK3, STAT1 and NF-kB, Akt etc. Importantly, beta-carotene treatment led to the suppression of β-secretase (BACE1), γ-secretase and acetylcholinesterase (AChE) activities, and the downregulation of genes involved in amyloid-beta production, including BACE1, and PECN1 eventualy resulted in dcerase concentration o Aβ peptides. These findings suggest that β-carotene could be a promising therapeutic candidate for the prevention and treatment of neurodegenerative diseases, particularly Alzheimer's disease, however further investigations are recomended in animal models and clinical trials before incorporating beta-cerotene into pharmaceutical formulations for AD treatment.}, } @article {pmid41027951, year = {2025}, author = {Sriram, S and Nivethitha, V and Arun Kaarthic, TP and Archita, S and Murugan, T}, title = {Advanced MRI based Alzheimer's diagnosis through ensemble learning techniques.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {33840}, pmid = {41027951}, issn = {2045-2322}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Magnetic Resonance Imaging/methods ; Deep Learning ; Neural Networks, Computer ; *Brain/diagnostic imaging ; *Machine Learning ; Aged ; Male ; Female ; Ensemble Learning ; }, abstract = {Alzheimer's Disease is a condition that affects the brain and causes changes in behavior and memory loss while making it hard to carry out tasks properly. It's vital to spot the illness early, for effective treatment. MRI technology has advanced in detecting Alzheimer's by using machine learning and deep learning models. These models use neural networks to analyze brain MRI results automatically and identify key indicators of Alzheimer's disease. In this study, we used MRI data to train a CNN for diagnosing and categorizing the four stages of Alzheimer's disease with deep learning techniques, offering significant advantages in identifying patterns in medical imaging for this neurodegenerative condition compared to using a CNN exclusively trained for this purpose. They evaluated ResNet50, InceptionResNetv2 as well as a CNN specifically trained for their study and found that combining the models led to highly accurate results. The accuracy rates for the trained CNN model stood at 90.76%, InceptionResNetv2 at 86.84%, and ResNet50 at 90.27%. In this trial run of the experiment conducted by combining all three models collaboratively resulted in an accuracy rate of 94.27% compared to the accuracy rates of each model working individually.}, } @article {pmid41027737, year = {2025}, author = {Dimitrov, D and Raja, S and Noor, H and Takahashi, T}, title = {Common Mechanism Underlying Synaptic Dysfunction Caused by Preformed Fibril-Induced Accumulation of α-Synuclein or Tau in a Culture Propagation Model.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {45}, number = {45}, pages = {}, pmid = {41027737}, issn = {1529-2401}, mesh = {*alpha-Synuclein/metabolism ; Animals ; *tau Proteins/metabolism ; Mice ; Humans ; *Synapses/metabolism/pathology ; Male ; Cells, Cultured ; Female ; Mice, Inbred C57BL ; *Neurons/metabolism ; }, abstract = {In sporadic neurodegenerative diseases, the endogenous proteins α-synuclein in Parkinson's disease and tau in Alzheimer's disease undergo pathogenic prion-like propagation over many years, accumulating in both soluble and insoluble forms in neurons including synapses, where they impair synaptic transmission and potentially cause various neuronal symptoms. To investigate the functional outcome of such synaptic accumulation, we induced accumulation of endogenous proteins in murine and human synapses by incubating mouse (of either sex) neuronal cultures with pathogenic preformed fibrils (pffs). Two weeks after treatment with human α-synuclein or tau pff, the respective endogenous proteins accumulated in neurons including presynaptic terminals, where we also observed tubulin accumulation, suggesting microtubule over-assembly. These were not associated with mRNA upregulation and were prevented by pharmacological stimulation of autophagy. Both pffs caused accumulation of p62 in cell bodies, suggesting compromised protein degradation. pHluorin imaging in synapses indicated a marked prolongation of vesicular endocytic time, which was rescued by pharmacological depolymerization of microtubules or by the overexpression of full-length dynamin 1. Since dynamin is a high-affinity binding partner of microtubules as well as an endocytic key molecule, over-assembled microtubules can sequester dynamin, thereby inhibiting endocytosis. We conclude that pff-induced accumulation of α-synuclein or tau in presynaptic terminals can disrupt vesicle endocytosis through a common mechanism. Since endocytosis-dependent vesicle recycling is critical for maintaining neurotransmitter release, its disruption can affect the neurocircuitry operations involved, thereby causing diverse symptoms associated with neurodegenerative diseases. Thus, our data suggest a common molecular mechanism underlying synaptic dysfunctions associated with Parkinson's and Alzheimer's diseases.}, } @article {pmid41025909, year = {2025}, author = {Sajimon, M and Wheeler, CJ and Foley, AR and Chan, K and Griffin, MN and Dinakarapandian, DM and Holberton, A and Joy, J and Paravastu, AK and Wood, LB and Raskatov, JA}, title = {Asparagine Deamidation Attenuates Toxicity, Aggregation, and Microglial Responses of Alzheimer's Amyloid-β.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {20}, pages = {4076-4085}, doi = {10.1021/acschemneuro.5c00544}, pmid = {41025909}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; *Microglia/metabolism/drug effects ; *Asparagine/metabolism ; *Alzheimer Disease/metabolism ; Animals ; *Peptide Fragments/metabolism/toxicity ; Humans ; Mice ; }, abstract = {Alzheimer's disease (AD) is a growing global challenge that imposes a tremendous burden on society and economies. Though recently approved anti-amyloid β (Aβ) immunotherapies show effectiveness in clearing amyloid and slowing cognitive decline, the removal of cerebral Aβ can also cause serious adverse events (SAEs). Therefore, decreasing the detrimental effects of Aβ in the brain without promoting SAEs is an unmet need in AD treatment. Here, we show that deamidation of Asparagine 27(N27) in Aβ1-42 can significantly reduce Aβ's neurotoxicity and decrease selective microglial pro-inflammatory cytokine production. We also show that deamidation of N27 produces a pronounced decrease in Aβ's aggregation propensity and decreases soluble oligomer formation, suggesting a potential mechanism for its mitigation of Aβ's detrimental cellular effects. Modulation of these Aβ properties by N27 deamidation represents a proof of concept for a potential strategy to alter the detrimental effects of Aβ that may not require its removal from the brain. Our findings on reducing Aβ's toxic properties by N27 deamidation may provide a basis for future therapeutic interventions.}, } @article {pmid41024939, year = {2024}, author = {Saleh, AY and Valentina, R and Susanto, TD and Saputra, DAY}, title = {Beyond stroke therapy, neuroaid (a chinese herbal) has an effect on cognition and neurogenesis, a bibliometric study.}, journal = {F1000Research}, volume = {13}, number = {}, pages = {799}, pmid = {41024939}, issn = {2046-1402}, mesh = {Humans ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Cognition/drug effects ; *Stroke/drug therapy ; Bibliometrics ; *Neurogenesis/drug effects ; Animals ; }, abstract = {INTRODUCTION: NeuroAiD, also known as MLC601 or MLC901, is a Chinese herbal combination used worldwide for stroke treatment. It contains herbal components and five hewan components. MLC601 contains herbal components and hewan components, while MLC901 has a similar herbal composition. NeuroAiD is used to support neurologic recovery after stroke and to aid cognitive function in Alzheimer's disease. Studies show that NeuroAiD has potential in treating Alzheimer's disease and is beneficial in both local and global stroke models and in the Kortikal culture. However, there is limited bibliometric research on NeuroAiD, which is a method of collecting data from published articles to analyze developments and trends in the field of research. This research contributes significantly to the literature and helps develop more effective stroke treatment strategies. METHODS: In this work, a literature review methodology is employed to gather data from the Scopus database using the keywords neuroaid. Data were analyzed using Biblioshiny and VOSviewer software to produce visualizations and bibliometric maps. We conducted quantitative and qualitative analysis. RESULTS: The research trend found are documents by year, most relevant sources, factorial map of the most cited documents, factorial map of The documents with the highest contributes, documents by author, documents by country or territory, documents by subject area, documents by affiliation, network visualization, overlay visualization of scopus database using vosviewer, density visualization, thematic map, thematic evolution, topic dendogram, and world cloud. CONCLUSIONS: The study investigates the potential of Neuroaid, a neuroprotective drug, for stroke prevention and cognitive function enhancement. It uses terms like "cognition" and "neurogenesis" to highlight its potential. While the study's focus may be limited, it provides valuable insights into research direction and potential areas of neuroaid for stroke treatment.}, } @article {pmid41024926, year = {2025}, author = {Bitar, I and Alabdalrazzak, M and Zamzam, M and Desai, Y and Abushaban, K}, title = {Clinically Silent Amyloid-Related Imaging Abnormality With Edema Following Lecanemab Therapy: A Case Report.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e91230}, pmid = {41024926}, issn = {2168-8184}, abstract = {Amyloid-related imaging abnormalities with edema (ARIA-E) are a known complication of anti-amyloid monoclonal antibody therapies such as lecanemab. ARIA-E represents vasogenic cerebral edema resulting from treatment-related disruption of vascular amyloid and appears on MRI as cortical or gyriform T2 fluid-attenuated inversion recovery (FLAIR) hyperintensities. Clinically, ARIA-E ranges from asymptomatic radiologic findings to symptomatic events such as headache, confusion, or seizures, making routine surveillance important during therapy. We present the case of a 60-year-old woman with biomarker-confirmed AD who developed radiographically evident ARIA-E following six biweekly infusions of lecanemab. Surveillance MRI revealed new cortically based and gyriform T2 FLAIR hyperintensities in the posterior occipital and bilateral temporal lobes, consistent with parenchymal and sulcal edema. Notably, the patient remained neurologically asymptomatic throughout the episode. Lecanemab therapy was discontinued, and she was managed conservatively with close outpatient follow-up. This case highlights the importance of routine imaging during anti-amyloid therapy and demonstrates that conservative management may be appropriate in select asymptomatic cases of ARIA-E.}, } @article {pmid41023855, year = {2025}, author = {Zou, M and Xu, SS and Zhu, SG and Yuan, CX and Huang, JF and Zhu, JH and Zhang, X and Wang, JY}, title = {Elevated D-dimer levels after lecanemab infusions: a case report.}, journal = {BMC geriatrics}, volume = {25}, number = {1}, pages = {742}, pmid = {41023855}, issn = {1471-2318}, support = {2023RC215//Zhejiang Provincial Medical Technology Program/ ; }, mesh = {Humans ; *Fibrin Fibrinogen Degradation Products/metabolism ; Aged, 80 and over ; Male ; *Alzheimer Disease/drug therapy/blood ; Infusions, Intravenous ; Biomarkers/blood ; }, abstract = {BACKGROUND: Lecanemab is a disease-modifying immunotherapy for Alzheimer's disease (AD) and has been increasingly prescribed to the patients in the world. It has a definite therapeutic effect in slowing cognitive decline in AD patients, but its adverse drug reactions should not be ignored. CASE PRESENTATION: We reported an 82-year-old Chinese AD patient who developed recurrent D-dimer elevation after lecanemab infusions. His D-dimer levels were positively correlated with activated partial thromboplastin time, C-reactive protein, and neutrophil percentage, but negatively correlated with platelet count. CONCLUSIONS: Elevated D-dimer levels may be associated with the enhanced phagocytic response to vascular amyloid β upon lecanemab treatment. Our report expands knowledge on lecanemab's adverse drug reactions, suggesting that D-dimer levels and potential thromboembolic events should be monitored during treatment. CLINICAL TRIAL NUMBER: not applicable.}, } @article {pmid41023476, year = {2025}, author = {Bhatt, K and Jayanthi, N and Kumar, M}, title = {FHESA: fourier decomposition and hilbert transform based EEG signal analysis for Alzheimer's disease detection.}, journal = {Physical and engineering sciences in medicine}, volume = {48}, number = {4}, pages = {2043-2058}, pmid = {41023476}, issn = {2662-4737}, mesh = {*Alzheimer Disease/diagnosis/physiopathology ; Humans ; *Electroencephalography ; *Fourier Analysis ; *Signal Processing, Computer-Assisted ; Algorithms ; Machine Learning ; Aged ; Male ; }, abstract = {Alzheimer's Disease (AD) is a chronic neurological disorder that impairs the cognitive and behavioral abilities of older people. Early detection and treatment are crucial for minimizing the progression of the disease. Electroencephalogram (EEG) makes it possible to investigate the brain activities linked to various forms of disabilities experienced by individuals with AD. Nevertheless, the EEG signals are non-linear and non-stationary in nature making it difficult to retrieve the concealed information from the EEG signals. Therefore, a Fourier Decomposition Method (FDM) and Hilbert Transform (HT) based EEG signals analysis (FHESA) method is developed in this paper for the automated detection of AD. The FHESA method aims to efficiently analyze the EEG data to identify the important brain regions vulnerable to AD, and to assess the impact of various EEG channels for the timely and early detection of AD. The proposed FHESA method is divided into three primary stages. The first stage deals with the decomposition of the EEG signals into a finite number of Fourier Intrinsic Band Functions (FIBFs). In the second stage, HT is applied to all FIBFs to obtain instantaneous amplitude, frequency, and phase, that are then used to construct feature vectors. In the last stage, various Machine Learning (ML) algorithms are used to classify these feature vectors for efficient AD detection. Two distinct data sets are employed to assess the effectiveness of the proposed FHESA method. The outcome demonstrates that with dataset-I and dataset-II, the proposed methodology can detect AD with 98% and 99% accuracy, respectively. The performance of the proposed FHESA method is compared to other state-of-the-art methods used for AD detection. The promising results show that the proposed FHESA method can assist neurological experts in identifying and utilizing EEG signals for AD detection.}, } @article {pmid41023471, year = {2025}, author = {Wang, Y and Yang, J and Jiang, X and Yuan, R and Cheng, R and Lu, N and Gao, A and Liu, S}, title = {Potential new drug sources for the treatment of Parkinson's disease: flavonoid O-glycosides.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {966}, pmid = {41023471}, issn = {1573-4978}, support = {82274125//National Natural Science Foundation of China/ ; }, mesh = {*Parkinson Disease/drug therapy ; *Flavonoids/therapeutic use/pharmacology/chemistry ; Humans ; *Glycosides/therapeutic use/pharmacology/chemistry ; Animals ; Biological Products/therapeutic use/pharmacology ; }, abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. With the increase in the global aging population, the global prevalence of PD has soared, and the burden of global medical resources is increasingly heavy. Although modern medicine has progressed in treating PD, existing drugs still have drawbacks regarding Mechanism and efficacy, intensifying the urgency of developing new drugs. Researchers have favored natural treatments for their safety in recent years and have increasingly become an essential source for developing new drugs. Flavonoid O-glycoside compounds are one of the main active ingredients of natural products and have shown satisfactory efficacy in treating PD, thus becoming potential drugs for treating neurodegenerative diseases. In this study, we systematically evaluated the Mechanism of several specific flavonoid O-glycoside compounds in the treatment of PD, conducted a relatively in-depth summary and discussion of their biological activities, and compared them with other flavonoid O-glycoside compounds. This provides a theoretical basis for further future mechanism research on flavonoid O-glycoside compounds. And lay the foundation and set an example for the development and application of natural products. This review indicates that flavonoid O-glycoside compounds are up-and-coming new therapeutic drugs for Parkinson's disease (PD) and can be used in PD prevention and treatment strategies.}, } @article {pmid41021789, year = {2025}, author = {Huang, M and Su, X and Bian, L and Xu, L and Pang, H and Song, Z and Sun, L and Zhang, H and Ma, Y}, title = {Preliminary efficacy analysis of middle meningeal artery embolization using Glubran 2 for chronic subdural hematoma.}, journal = {Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences}, volume = {}, number = {}, pages = {15910199251380388}, pmid = {41021789}, issn = {2385-2011}, abstract = {ObjectiveTo preliminarily conclude the safety and efficacy of middle meningeal artery embolization (MMAE) with Glubran 2 in treating chronic subdural hematoma (CSDH).MethodsThis retrospective analysis was performed on 40 consecutive CSDH patients who received MMAE with Glubran 2 between 2021 and 2023. The patients were followed up for 3 years post-operationally. Surgical procedures included burr hole drainage (BHD) and MMAE, both of which were performed under local anesthesia. MMAE with Glubran 2 was performed through transfemoral access. Postoperative recurrence was defined as an increase in hematoma volume based on computed tomography (CT) and/or magnetic resonance imaging (MRI) accompanied by clinical symptoms, which require further treatment within 3 years postoperatively.ResultsIn this study, 40 CSDH patients (34 male and six female) with a mean age of 68.2 ± 13.2 years were included. Of these, 38 patients underwent MMAE-assisted BHD. Two patients received MMAE alone. A single-branch embolization was performed on 20 hematomas in 18 patients, and a double-branch on 27 hematomas in 22 patients. At the three-year follow-up, 33 patients were successfully contacted, and 24 patients showed significant improvement or were asymptomatic after treatment. Three patients passed away owing to non-CSDH-related reasons. One patient developed decompensated liver cirrhosis, one experienced Alzheimer's disease, and four patients experiencing deteriorated functions were unclear but non-CSDH related as demonstrated by absorbed hematomas on head CT or MRI during return visits. The median follow-up time was 35 (IQR 27-40) months, and the median mRS score was 0 (IQR 0-0).ConclusionMMAE-assisted BHD with Glubran 2 is feasible, safe, and effective in treating CSDH, with no associated complications.}, } @article {pmid41020462, year = {2025}, author = {Lee, YC and Tai, YC}, title = {Seronegative but Cerebrospinal Fluid-positive NMDA Receptor Encephalitis in an Alzheimer's Dementia Patient with Good Treatment Outcome: A Case Report.}, journal = {Acta neurologica Taiwanica}, volume = {34}, number = {3}, pages = {161-164}, doi = {10.4103/ANT.ANT_113_0041}, pmid = {41020462}, issn = {1028-768X}, mesh = {Humans ; Female ; Aged ; *Alzheimer Disease/complications ; *Anti-N-Methyl-D-Aspartate Receptor Encephalitis/cerebrospinal fluid/complications/therapy ; Immunoglobulins, Intravenous/therapeutic use ; Treatment Outcome ; Electroencephalography ; Autoantibodies/cerebrospinal fluid ; }, abstract = {We present a rare case of elderly-onset anti-N-methyl-D-aspartate (NMDA) receptor encephalitis combined with underlying Alzheimer dementia, characterized by seronegativity but cerebrospinal fluid (CSF) antibody positivity, which showed a significant improvement following intravenous immunoglobulin (IVIG) treatment. The case highlights serial electroencephalogram (EEG) changes. We focus the discussion on factors contributing to favorable recovery. A 78-year-old woman with Alzheimer's dementia and hypertension experienced rapid onset of further cognitive decline over 1 week, presenting with disorientation, irrelevant speech, and disorganized behaviors. Myoclonus of both upper limbs and focal seizures 10 days later which lead her into intensive care unit (ICU) admission. Test results revealed positive anti-NMDA antibodies in CSF but negative in serum. Serial electroencephalograms (EEG) exhibited extreme delta brush activity transitioning to excess beta activity. Initial treatment with a 5-day course of steroid pulse therapy showed limited efficacy. Subsequently, 5 days of IVIG therapy provided marked improvement in consciousness and cognitive function and also normalized the EEG. This patient presented with severe neurological dysfunction, the need for ICU management, and presence of extreme delta brush EEG pattern. Generally, the prognosis was unfavorable. However, advanced age onset and anti-NMDA antibody positivity in CSF with seronegativity in serum may imply better prognosis. Thus, testing anti-NMDA receptor antibody in both serum and CSF is mandatory and under this complicated situation, timely immunotherapy may be the influencing factors of good prognosis.}, } @article {pmid41020412, year = {2025}, author = {Villeneuve, S and Poirier, J and Breitner, JCS and Tremblay-Mercier, J and Remz, J and Raoult, JM and Yakoub, Y and Gallego-Rudolf, J and Qiu, T and Fajardo Valdez, A and Mohammediyan, B and Javanray, M and Metz, A and Sanami, S and Ourry, V and Wearn, A and Pastor-Bernier, A and Edde, M and Gonneaud, J and Strikwerda-Brown, C and Tardif, CL and Gauthier, CJ and Descoteaux, M and Dadar, M and Vachon-Presseau, É and Baril, AA and Ducharme, S and Montembeault, M and Geddes, MR and Soucy, JP and Rajah, N and Laforce, R and Bocti, C and Davatzikos, C and Bellec, L and Rosa-Neto, P and Baillet, S and Evans, AC and Collins, DL and Chakravarty, MM and Blennow, K and Zetterberg, H and Spreng, RN and Pichet Binette, A and , }, title = {The PREVENT-AD cohort: Accelerating Alzheimer's disease research and treatment in Canada and beyond.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70653}, pmid = {41020412}, issn = {1552-5279}, support = {R01AG068563/AG/NIA NIH HHS/United States ; //Canada Foundation for Innovation/ ; PJT-367122/CAPMC/CIHR/Canada ; SG-23-1038904QC/ALZ/Alzheimer's Association/United States ; PJT-463677/CAPMC/CIHR/Canada ; P30 AG048785/AG/NIA NIH HHS/United States ; JPND2019-466-236//EU Joint Programme Neurodegenerative Disease Research/ ; PJT-410106/CAPMC/CIHR/Canada ; PJT-165921/CAPMC/CIHR/Canada ; AARG-22-927100/ALZ/Alzheimer's Association/United States ; R01 AG068563/AG/NIA NIH HHS/United States ; //Fonds de recherche du Québec - Santé/ ; PJT-178210/CAPMC/CIHR/Canada ; PJT-438655/CAPMC/CIHR/Canada ; //Fondation de la Famille Lemaire/ ; R01 EB026299/EB/NIBIB NIH HHS/United States ; 3R01AG068563-04S1/AG/NIA NIH HHS/United States ; PJT-451830/CAPMC/CIHR/Canada ; 2022-00732//Vetenskapsrådet/ ; //Fondation Brain Canada/ ; PJT-153287/CAPMC/CIHR/Canada ; //Fondation Jean-Louis Lévesque/ ; NIG-17-08//Alzheimer Society of Canada/ ; 2017-00915//Vetenskapsrådet/ ; //Canada First Research Excellence Fund/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/therapy ; Canada ; Aged ; Female ; Magnetic Resonance Imaging ; Male ; Disease Progression ; Longitudinal Studies ; Biomarkers/blood/cerebrospinal fluid ; Positron-Emission Tomography ; Cohort Studies ; Amyloid beta-Peptides ; Neuroimaging ; }, abstract = {The PResymptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) is an investigator-driven study that was created in 2011 and enrolled cognitively normal older adults with a family history of sporadic AD. Participants are deeply phenotyped and have now been followed annually for more than 12 years (median follow-up 8.0 years, SD 3.1). Multimodal magnetic resonance imaging (MRI), genetic, neurosensory, clinical, cerebrospinal fluid, and cognitive data collected until 2017 on 348 participants who agreed to open sharing with the neuroscience community were already available. We now share a new release including 6 years of additional follow-up cognitive data, and additional MRI follow-ups, clinical progression, new longitudinal behavioral and lifestyle measures (questionnaires, actigraphy), longitudinal AD plasma biomarkers, amyloid-beta and tau positron emission tomography (PET), magnetoencephalography, as well as neuroimaging analytic measures from all MRI modalities. We describe the PREVENT-AD study, the data shared with the global research community, as well as the model we created to sustain longitudinal follow-ups while also allowing new innovative data collection. HIGHLIGHTS: The PResymptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) is a single-site longitudinal study that started in 2011 with annual follow-up data collection on individuals at risk of Alzheimer's disease who were all cognitively normal at enrolment. All 387 participants were enrolled between 2011 and 2017 and 306 (79%) of these participants were still in the study as of December 2023. While the PREVENT-AD dataset was not originally planned to be shared with the global research community, 348 participants retrospectively consented for their data to be shared with researchers worldwide. The first release of data was in 2019. We now share a second release that includes 6 years of additional follow-up visits, information on clinical progression and novel cognitive, behavioral, genetic, plasma and neuroimaging (amyloid and tau positron emission tomography [PET], magnetoencephalography [MEG], and new magnetic resonance imaging [MRI] sequences) data. It also includes analytic outputs for neuroimaging modalities.}, } @article {pmid41019419, year = {2025}, author = {Punsawad, C and Kaewman, P and Techarang, T and Sketriene, D and Lalert, L}, title = {Low-Dose Paracetamol Treatment Protects Neuronal Oxidative Stress and Neuroinflammation in D-Galactose-Induced Accelerated Aging Model.}, journal = {Scientifica}, volume = {2025}, number = {}, pages = {5559483}, pmid = {41019419}, issn = {2090-908X}, abstract = {Aging increases the risk of neurodegenerative diseases such as Parkinson's and Alzheimer's (PD and AD) which are potentially linked to increased oxidative stress and inflammation. Paracetamol (APAP) is known for its antioxidant and anti-inflammatory properties; however, its potential neuroprotective effects against age-related oxidative stress and neuroinflammation remain inadequately investigated. Therefore, we aimed to examine whether low-dose APAP could mitigate oxidative stress and neuroinflammation in a D-galactose (D-gal)-induced aging model. In our study, fifty adult male ICR mice were divided into five groups (n = 10). Except for the normal control group, all mice received D-gal subcutaneous injections (200 mg/kg) and were fed vehicle, 15 or 50 mg/kg APAP, or 100 mg/kg vitamin E daily for six weeks. After treatment, liver function was assessed by serum liver enzyme analysis. The liver and brain pathologies were examined using hematoxylin and eosin staining. Brain oxidative stress was evaluated through malondialdehyde (MDA) measurement. Additionally, immunohistochemistry was used to determine levels of inflammatory cytokines (TNF-α, IL-1β, TGF-β, and IL-10) and the oxidative stress marker, NADPH Oxidase 4 (NOX4). The study found no significant changes in serum liver enzymes or liver morphology among the experimental groups. However, the D-gal group exhibited increased neuronal cell loss, along with elevated levels of MDA and NOX4 in the frontal cortex and hippocampus. Moreover, D-gal mice showed elevated levels of TNF-α, IL-1β, and TGF-β, accompanied by decreased IL-10 levels. Notably, treatment with low-dose APAP and vitamin E mitigated neuronal cell loss, decreased MDA levels, and attenuated NOX4 expression induced by D-gal injection. Furthermore, low-dose APAP, particularly at 50 mg/kg, and vitamin E reversed the alterations in TNF-α, IL-1β, and IL-10 induced by D-gal, while TGF-β was unaffected. We suggest that low-dose APAP exerts antioxidant and anti-inflammatory activities to protect against neurodegeneration in a mouse model of brain aging induced by chronic D-gal injection.}, } @article {pmid41019272, year = {2025}, author = {Fernandes, JVA and Ramos, JVO and Vilar, LADS and Holanda, MMA}, title = {Brexpiprazole for agitation in alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials.}, journal = {Indian journal of psychiatry}, volume = {67}, number = {9}, pages = {852-861}, pmid = {41019272}, issn = {0019-5545}, abstract = {BACKGROUND: Agitation in Alzheimer's disease (AD) severely affects patients and caregivers. Brexpiprazole, a serotonin-dopamine modulator, is the potential treatment; however, recent trials and variations in dosing have raised questions about its optimal efficacy and safety. AIM: To evaluate the efficacy and safety of brexpiprazole in the treatment of agitation associated with AD, with a focus on dose-specific outcomes. METHODS: A systematic search was conducted in PubMed, Embase, and the Cochrane Library for Randomized Controlled Trials (RCT) comparing brexpiprazole with placebo in AD-related agitation. Primary efficacy outcomes included changes in the Cohen-Mansfield Agitation Inventory (CMAI) and Clinical Global Impression-Severity (CGI-S) scores. Safety outcomes encompassed treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and mortality. Meta-analyses were performed using a random-effects model, with mean differences (MD) and odds ratios (OR) reported with 95% confidence intervals (CI). RESULTS: Four RCTs with 1,710 participants were included. Brexpiprazole 2 mg significantly reduced CMAI scores (MD: -5.618; 95% CI: -7.884, -3.351; P < 0.001) and CGI-S scores (MD: -0.513; 95% CI: -0.890, -0.135; P = 0.008) compared to placebo. Lower doses (0.5-1 mg) demonstrated limited efficacy. TEAEs were more frequent with brexpiprazole 2 mg (OR: 1.554; 95% CI: 1.045, 2.312; P = 0.030), while SAEs (OR: 1.389; P = 0.384) and mortality (OR: 2.189; P = 0.301) did not significantly differ from placebo. CONCLUSION: Brexpiprazole 2 mg is effective in reducing agitation symptoms in AD with an acceptable safety profile.}, } @article {pmid41018231, year = {2025}, author = {Tziveleka, LA and Cascione, M and Pellegrino, P and Bianco, A and Leporatti, S and De Matteis, V}, title = {Immunomodulatory natural polysaccharide-based nanoparticles for the treatment of neurodegenerative diseases.}, journal = {Ibrain}, volume = {11}, number = {3}, pages = {277-296}, pmid = {41018231}, issn = {2769-2795}, abstract = {Polysaccharide-based nanoparticles offer significant potential for the treatment of neurodegenerative diseases and the modulation of inflammatory responses in the central nervous system. These biopolymers, when derived from natural sources, possess inherent immunomodulatory properties, which can be leveraged to regulate immune activity, positioning them as promising candidates for both prophylactic and therapeutic strategies. Furthermore, when integrated with other materials, polysaccharides form nanocomposites with enhanced structural, physicochemical, and biological properties, making them highly versatile platforms for drug delivery in the central nervous system. This review provides a comprehensive analysis of polysaccharide-based nanoparticles, focusing on their application in the treatment of three major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Emphasis is placed on optimizing these nanomaterials for targeted drug delivery and immune modulation, underscoring their potential to improve therapeutic outcomes in neurodegenerative disorders. The review also examines the structural, chemical, and biological characteristics of key polysaccharides, and explores their innovative roles in combating neuroinflammation and neurodegeneration.}, } @article {pmid41017736, year = {2025}, author = {Laouini, SE and Bouafia, A and Azzi, M and Laib, I and Fellah, M and Abdullah, MMS and Al-Lohedan, HA and Abdullah, JAA}, title = {Synthesis and Characterization of Amoxicillin-Functionalized Ag/AgCl Nanoparticles: A Promising Multifunctional Platform for Next-Generation Nanomedicine.}, journal = {Journal of biomedical materials research. Part B, Applied biomaterials}, volume = {113}, number = {10}, pages = {e35661}, doi = {10.1002/jbm.b.35661}, pmid = {41017736}, issn = {1552-4981}, support = {ORF-2025-54//Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia, Ongoing Research Funding program/ ; }, mesh = {*Amoxicillin/chemistry/pharmacology ; *Silver/chemistry/pharmacology ; *Silver Compounds/chemistry/pharmacology ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Metal Nanoparticles/chemistry ; Escherichia coli/growth & development ; Animals ; *Nanomedicine ; Antioxidants/chemistry/pharmacology ; *Biofilms/drug effects/growth & development ; Cholinesterase Inhibitors/chemistry/pharmacology ; }, abstract = {This study synthesized and characterized amoxicillin-functionalized Ag/AgCl nanoparticles (Amoxicillin@Ag/AgCl NPs) for biomedical applications. The nanoparticles were prepared via a coprecipitation method and functionalized with amoxicillin to enhance therapeutic potential. Characterization techniques (X-ray diffraction [XRD], Fourier-transform infrared (FTIR), scanning electron microscopy [SEM], and UV-Vis) confirmed successful functionalization and improved physicochemical properties. The crystallite size increased from 17.29 ± 3.44 to 20.47 ± 4.17 nm, while the bandgap widened from 2.33 to 2.40 eV, indicating enhanced electronic interactions. Antioxidant activity was significantly improved, with 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging reaching 97.87% and β-carotene bleaching inhibition at 95.47% (175 μg/mL). The antibiofilm efficacy was notable, with inhibition rates of 90.24% for E. coli (250 μg/mL), 81.47% for S. typhimurium (175 μg/mL), and 87.68% for B. subtilis (250 μg/mL). In enzymatic inhibition studies, Amoxicillin@Ag/AgCl NPs showed neuroprotective potential, inhibiting acetylcholinesterase (AChE) (93.74% at 160 μg/mL) and butyrylcholinesterase (BChE) (97.41% at 80 μg/mL), highlighting their potential in Alzheimer's treatment. Additionally, they exhibited anti-inflammatory effects, inhibiting lipoxygenase (LOX) by 90.47% (120 μg/mL). To the best of our knowledge, this is the first report on the synthesis of Amoxicillin@Ag/AgCl NPs that simultaneously demonstrate strong antioxidant, antibiofilm, neuroprotective, and anti-inflammatory properties, underscoring their novelty as next-generation nanomedicines.}, } @article {pmid41017725, year = {2025}, author = {Zhang, J and He, S and Xiao, Q and Jiang, W and Wang, B and Lu, J and Gu, H and Liao, Y and Wang, Z and Xu, Y and Wang, D and Tang, X and Qi, L}, title = {Engineered mesenchymal stem cell-derived extracellular vesicles overexpressing miR-146a alleviate neuroinflammation in Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00404}, pmid = {41017725}, issn = {1673-5374}, abstract = {Alzheimer's disease is an inflammatory neurodegenerative disease for which no effective clinical treatment currently exists. We have previously reported that mesenchymal stem cell.derived extracellular vesicles delay retinal degeneration by exerting anti-inflammatory effects though the miR-146a.nuclear receptor subfamily 4 group A member 3 axis; however, it remains unclear how NR4A3 drives inflammation. Herein, we engineered mesenchymal stem cell. derived extracellular vesicles overexpressing miR-146a to explore their possible neuroprotective effects and the underlying mechanisms in both cell and animal models of Alzheimer's disease. In HT22 cells co-cultured with lipopolysaccharide-induced RAW264.7/BV2 cells, extracellular vesicles overexpressing miR- 146a significantly reduced the number of apoptotic cells and inhibited proinflammatory cytokine expression, nuclear factor (NF)-κB activation, and caspase-3/ apoptosis regulator BAX signaling. These effects of extracellular vesicles overexpressing miR-146a were replicated in 5×FAD mice. In addition, extracellular vesicles overexpressing miR-146a inhibited the activation of microglia and astrocytes, reduced amyloid-β and phosphorylated tau expression, lowered the number of apoptotic cells in the hippocampus, and improved the cognitive function of these Alzheimer's disease model mice. Mechanistically, miR-146a negatively regulated the expression of nuclear receptor subfamily 4 group A member 3 and suppressed the expression of proinflammatory cytokines and nuclear factor-κB signaling. Furthermore, NR4A3 overexpression promoted nuclear factor-κB and proinflammatory cytokine expression as well as nuclear factor-κB signaling. The upregulation of NR4A3 and the inflammatory response was reversed by miR-146a overexpression. Finally, NR4A3 was identified as a transcriptional activator of nuclear factor-κB using chromatin immunoprecipitation polymerase chain reaction. Collectively, these findings indicate that extracellular vesicles overexpressing miR-146a may alleviate the progression of Alzheimer's disease by exerting anti-inflammatory effects via the NR4A3. nuclear factor-κB axis. They are thus a potential therapeutic candidate for the clinical treatment of neurodegenerative diseases.}, } @article {pmid41017722, year = {2025}, author = {Xu, X and Li, J and Wang, F and Xue, K and He, J and Meng, X and Shen, Y}, title = {Genetic and pathway complexity in Alzheimer's disease: Insights from multi-omic data about the immune response and mitochondrial function.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00184}, pmid = {41017722}, issn = {1673-5374}, abstract = {Despite recent developments, the genetics and biology of Alzheimer's disease remain insufficiently characterized. As an important first step toward developing effective treatment strategies to slow or prevent Alzheimer's disease onset, the identification of relevant genetic markers is crucial. In the present study, we analyzed transcriptomic and multi-omic datasets across multiple cohorts (the Alzheimer's Disease Neuroimaging Initiative, Religious Orders Study and Rush Memory and Aging Project, Mount Sinai Brain Bank, and Mayo Clinic Alzheimer's Disease Genetics Studies) using gene set enrichment analysis, machine learning algorithms, and polygenic risk scoring to identify gene sets relevant to Alzheimer's disease risk and pathological features. For prioritized gene sets, we performed epigenome-wide association studies to assess DNA methylation patterns, and used multi-omic mediation analysis to characterize the causal gene regulatory networks. Overall, we identified several key gene sets relevant to Alzheimer's disease pathology-particularly, those related to immune system function and mitochondrial dysfunction. Upregulated pathways, including neutrophil degranulation and tumor necrosis factor-α signaling pathways, correlated strongly with aspects of neuroinflammation in Alzheimer's disease. By contrast, downregulated oxidative phosphorylation pathways further suggested mitochondrial dysfunction. Gene sets that contained mitochondrially located genes (e.g., SGK1 and LRRK1) were identified as significantly contributing to neurodegeneration. Moreover, genes such as CXCL1, TGFB2, and DUSP1 were consistently implicated in all datasets, thus emphasizing their involvement in immune modulation and mitochondrial function. The multimodal investigation outlined in the current study represents useful steps toward comprehending the genetic architecture of Alzheimer's disease, including an expanded understanding of the spatial interactions of genes associated with disease susceptibility. Mitochondrial dysfunction and immune modulation were pathological pathways that converged on Alzheimer's disease and future treatment novel options. Using the frameworks provided in the current comprehensive study, we present opportunities to explore targeted treatment strategies that may alter immune systems and mitochondrial function to optimize treatment outcomes for individuals at increased risk of or living with Alzheimer's disease.}, } @article {pmid41017717, year = {2025}, author = {Yuan, H and Shi, J and Gu, C and Yuan, J and Huang, C and Li, X and Zhou, K and Qi, J}, title = {Akkermansia muciniphila: A next-generation gut probiotic supporting neurorepair and functional recovery.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00701}, pmid = {41017717}, issn = {1673-5374}, abstract = {The brain-gut axis is a bidirectional signal transduction system between the gastrointestinal tract and the central nervous system that integrates neural, endocrine, and immune functions. In recent years, the role of the intestinal flora in regulating neural function and affecting the progression of different neurological diseases has received increasing attention. Akkermansia muciniphila is a mucindegrading bacterium of the intestinal flora present in the intestinal mucus layer that can regulate host immunity, the intestinal barrier and neuroimmune homeostasis. In recent years, a growing body of literature has suggested that Akkermansia muciniphila may play beneficial roles in nerve injury and regeneration by regulating brain-gut axis signalling. This review comprehensively summarizes the latest research results on the role of Akkermansia muciniphila in neurological diseases such as spinal cord injury, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The mechanisms by which Akkermansia muciniphila regulates inflammatory cytokines, neurotransmitters, and shortchain fatty acids are also highlighted. Various Akkermansia muciniphila-based interventions, such as those involving outer membrane proteins, extracellular vesicles, and pasteurized Akkermansia muciniphila, are discussed, and their therapeutic potential in restoring intestinal homeostasis, alleviating neuroinflammation, and supporting neuronal repair is explored. Although promising results from animal models have been reported, significant challenges remain in translating these findings into clinical practice and therapeutic applications. The differences in Akkermansia muciniphila colonization efficiency, host responses, and intervention strategies in different disease states limit the results of these studies. In addition, Akkermansia muciniphila may exhibit different mechanisms of action in acute and chronic neurodegenerative diseases, and thus more targeted mechanistic studies are needed. Despite these limitations, Akkermansia muciniphila represents a novel and potent pathway for the modulation of the brain-gut axis to support neural repair and functional recovery. By enhancing intestinal barrier integrity and regulating neuroimmunity, Akkermansia muciniphila has broad prospects as a microbial candidate for the treatment of central nervous system diseases. Future research should focus on optimizing the administration method and clinical trials to verify its efficacy, ultimately providing new treatment options in the field of neural regeneration and microbial therapy.}, } @article {pmid41017705, year = {2025}, author = {Wang, H and Wei, Y and Wang, J and Liu, J and Ou, S and Wang, J}, title = {Structure and function of voltage-gated sodium channel Nav1.6: Involvement in the pathological process of neural injury.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00354}, pmid = {41017705}, issn = {1673-5374}, abstract = {The voltage-gated sodium channel Nav1.6, encoded by the sodium voltage-gated channel alpha subunit 8 gene, is a crucial regulator of neuronal excitability, with widespread expression throughout the central and peripheral nervous systems. Recent breakthroughs in structural biology, particularly the elucidation of the cryo-EM architecture of Nav1.6 at a resolution of 0.31 nm, have provided unprecedented insights into its molecular organization and functional modulation. As a key mediator of action potential initiation and propagation, Nav1.6 possesses unique biophysical properties, including persistent and resurgent sodium currents that critically influence neuronal firing patterns. This comprehensive review synthesizes current knowledge on the physiological functions and pathological roles of Nav1.6 in multiple neurological conditions. Key findings include the following: (1) Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype-phenotype correlations, where gain-of-function variants lead to severe epileptic encephalopathies, while loss-of-function variants are associated with generalized epilepsy, highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967. (2) In Alzheimer's disease, Nav1.6 mediates amyloid-β oligomer-induced neuronal hyperexcitability through amyloid precursor protein-dependent membrane trafficking and regulates beta-secretase 1 expression via nuclear factor of activated T cells 1 signaling, suggesting novel disease-modifying strategies. (3) Parkinson's disease research has demonstrated that Nav1.6 upregulation in reactive astrocytes in the globus pallidus contributes to motor deficits through calcium-mediated abnormalities in neuronal synchronization. (4) Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration, with riluzole showing partial efficacy through sodium current modulation. (5) Multiple sclerosis pathophysiology features Nav1.6 redistribution in demyelinated axons, which drives calcium-dependent axonal injury via reverse Na+/Ca2+ exchange. (6) Chronic pain mechanisms involve Nav1.6 overexpression in dorsal root ganglia neurons, regulated by the p38 mitogen-activated protein kinase and tumor necrosis factor-α signaling pathways. (7) Traumatic brain injury models show that exercise-induced cognitive improvement is correlated with the normalization of Nav1.6-mediated excitability. Therapeutic development has progressed from nonselective sodium channel blockers to precision approaches, including state-dependent pore blockers designed using structural insights; allosteric modulators targeting specific conformations; gene therapy strategies using clustered regularly interspaced short palindromic repeats and antisense oligonucleotides; and miRNA-based regulation of channel expression. Current challenges include achieving sufficient subtype selectivity, optimizing blood-brain barrier penetration, and developing clinically relevant biomarkers for patient stratification. Future directions emphasize the integration of advanced technologies-such as singlecell multiomics to map neuronal subtype-specific expression patterns, patient-derived organoids for personalized drug testing, and machine learning-assisted drug design-to accelerate translation. Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.}, } @article {pmid41017698, year = {2025}, author = {Li, Y and Zhang, Y and Wang, Y and Ye, K and Liu, L and Tian, M and Han, X and Chen, X and Zheng, T and Li, F and Gao, X and Xia, Q and Wang, D}, title = {N6-methyladenosine modification regulates cell death in cognitive impairment.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00813}, pmid = {41017698}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are characterized by a decline in brain structure and function. Their pathology involves multiple cell death pathways, including ferroptosis, cuproptosis, and pyroptosis. These pathways are intricately linked to genes associated with metabolism, antioxidant defense, lipid metabolism, chronic inflammation, and nerve regeneration processes. Key regulators of atypical cell death pathways show aberrant N6-methyladenosine modification levels under pathological conditions. As the most abundant and dynamic RNA modification in brain tissue, N6-methyladenosine plays crucial functional roles. Notably, there exists an intricate interplay between N6-methyladenosine modifications and these cell death pathways, both of which are robustly associated with the pathogenesis of neurodegenerative diseases. However, the molecular mechanisms underlying this association remain unclear. This paper reviews the correlation between N6-methyladenosine and various cell death patterns in neurodegenerative diseases, with emphasis on the molecular mechanisms underlying the interaction between N6-methyladenosine epigenetic regulation and ferroptosis, cuproptosis, and pyroptosis in cognitive impairment. N6- methyladenosine-modified ferroptosis plays an important role in neurodegenerative diseases. There is also a close association between N6-methyladenosine modification and key molecules related to cuproptosis, which may promote the deposition of copper in the brain. Chronic inflammation, a hallmark of neurodegenerative diseases, is related to pyroptosis and N6-methyladenosine modification. It is widely thought that ferroptosis, cuproptosis, and pyroptosis are interconnected processes that may share a common pathway affecting the pathogenesis of neurodegenerative diseases, and are related to key molecules involved in N6-methyladenosine epigenetic modification. This suggests a great potential for future neurodegenerative diseases treatment strategies regulated by N6-methyladenosine modification. N6-methyladenosine modification plays a dual role in nerve injury and regeneration by dynamically regulating processes such as ferroptosis, cuproptosis, and pyroptosis and their key molecules. It maintains the "death-regeneration" balance in oxidative stress and inflammation while selectively promoting axon regeneration through the modulation of methylases. This mechanism indicates a considerable therapeutic target for neurological disorders.}, } @article {pmid41017390, year = {2025}, author = {Chen, JD and Chen, SY and Liao, CC and Fang, CY and Yen, GC}, title = {Enhancing cognitive memory function using Phyllanthus emblica polysaccharides via modulating autophagy and reshaping the gut microbiota.}, journal = {Food & function}, volume = {16}, number = {20}, pages = {8140-8159}, doi = {10.1039/d5fo03048j}, pmid = {41017390}, issn = {2042-650X}, mesh = {Animals ; *Gastrointestinal Microbiome/drug effects ; *Autophagy/drug effects ; Rats ; *Polysaccharides/pharmacology/administration & dosage/chemistry ; *Phyllanthus emblica/chemistry ; Male ; *Memory/drug effects ; Rats, Sprague-Dawley ; Alzheimer Disease/prevention & control ; Cognitive Dysfunction ; Plant Extracts/pharmacology ; *Cognition/drug effects ; Oxidative Stress/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by neuroinflammation, oxidative stress, amyloid-beta (Aβ) plaque buildup, Tau hyperphosphorylation, and gut microbiota imbalance. Natural polysaccharides have been shown to mitigate cognitive decline by regulating the microbiota-gut-brain axis and autophagy, inhibiting neuroinflammation, enhancing Aβ efflux, and facilitating the clearance of Tau protein. Phyllanthus emblica polysaccharides (PEP) exhibit anti-inflammatory, antioxidant, and gut microbiota-modulating properties in colitis and obese mice. However, the potential of PEP in AD prevention remains unclear, prompting the need to investigate the underlying mechanisms of PEP in AD prevention. Physicochemical analysis characterized PEP (MW: 1.182 × 10[3] kDa) as a non-crystalline, heat-stable α-acidic pyran heteropolysaccharide composed of galactose and arabinose monosaccharides. In vivo results showed that PEP administration significantly alleviated cognitive decline by reducing neuroinflammatory cytokines (TNF-α, IL-6, and IL-1β) and MDA levels while increasing anti-inflammatory factors (IL-4 and IL-10) and antioxidants (SOD, catalase, and GPx) in AlCl3-treated rats. Mechanistically, PEP upregulated autophagy-related proteins (Atg5, Beclin1, and LC3B) and LRP1 expression while downregulating AD-related proteins (BACE1, APP, Aβ, and phospho-Tau[Ser404]). Additionally, PEP treatment elevated short-chain fatty acids (SCFAs) and SCFA-producing bacteria, particularly the Christensenellaceae_R-7_group. In summary, PEP demonstrated preventive effects by exerting antioxidant, anti-inflammatory, autophagy-inducing, AD-related protein-suppressing, and microbiota-modulating properties, alleviating cognitive impairment in rats subjected to AlCl3 treatment.}, } @article {pmid41017285, year = {2026}, author = {Guo, S and Wei, F and Sun, H and Jin, H and Cheng, W and Fu, C and Wang, H and Yin, Y}, title = {Astrocyte-Specific Nrf2 Expression Transforms Neurotoxic Reactive Astrocytes to Neuroprotective Phenotype in 3xTg-AD Mice.}, journal = {Glia}, volume = {74}, number = {1}, pages = {e70087}, doi = {10.1002/glia.70087}, pmid = {41017285}, issn = {1098-1136}, support = {82472014//National Natural Science Foundation of China/ ; 81974270//National Natural Science Foundation of China/ ; 24ZR1450000//Natural Science Foundation of Shanghai Municipality/ ; 23ZR1441200//Natural Science Foundation of Shanghai Municipality/ ; }, mesh = {Animals ; *NF-E2-Related Factor 2/genetics/metabolism/biosynthesis ; *Astrocytes/metabolism/pathology/drug effects ; Mice, Transgenic ; Mice ; *Alzheimer Disease/pathology/metabolism/genetics ; Hippocampus/metabolism/pathology ; Phenotype ; tau Proteins/metabolism/genetics ; *Neuroprotection/physiology ; Male ; Disease Models, Animal ; Cells, Cultured ; Mice, Inbred C57BL ; Amyloid beta-Peptides/metabolism ; }, abstract = {Astrocyte reactivity is a common feature of Alzheimer's disease (AD), with reactive astrocytes traditionally subdivided into neurotoxic or neuroprotective phenotypes. It's crucial to transform neurotoxic reactive astrocytes to neuroprotective phenotypes for the treatment of AD, particularly during the progression of the disease. In this study, we evaluated the role of nuclear factor E2-related factor 2 (Nrf2) in facilitating the phenotype transformation of reactive astrocytes in vivo and in vitro by overexpressing Nrf2 in hippocampal astrocytes of 3xTg-AD mice using adeno-associated virus (AAV) vectors, as well as treating neurotoxic reactive astrocytes with dimethyl fumarate (a Nrf2 activator). We also evaluated the therapeutic effect of astrocyte-specific Nrf2 in 3xTg-AD mice with coexpression of Aβ and tau pathologies. Our findings indicate that Nrf2 could facilitate the conversion of neurotoxic reactive astrocytes to neuroprotective phenotypes in vivo and in vitro. AAV-mediated astrocyte-specific Nrf2 expression improved cognitive function, reduced Aβ and tau pathologies, rescued the loss of neurons and synapses, and ameliorated neuroinflammation in 3xTg-AD mice. These findings highlighted the role of Nrf2 in modulating reactive astrocyte phenotypes and suggested the potential for utilizing AAV to target astrocyte-specific Nrf2 as a promising therapeutic strategy for AD.}, } @article {pmid41016794, year = {2025}, author = {Huang, Y and Wei, F and Cheng, X and Shi, Y and Liu, Z and Ye, L}, title = {Neurotropin alleviates Alzheimer's disease pathology by inhibiting FUS-mediated Calhm2 transcription, blocking the Calhm2/EFhd2 interaction, to improve mitochondrial dysfunction-associated microglia polarization.}, journal = {Bioscience trends}, volume = {19}, number = {5}, pages = {566-580}, doi = {10.5582/bst.2025.01220}, pmid = {41016794}, issn = {1881-7823}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Microglia/drug effects/metabolism ; *Mitochondria/drug effects/metabolism ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Calcium-Binding Proteins/metabolism ; Humans ; *Membrane Glycoproteins/metabolism/genetics ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Transcription Factors/metabolism ; *Polysaccharides/pharmacology/therapeutic use ; Transcription, Genetic/drug effects ; Male ; }, abstract = {Neurotropin, a non-protein extract widely used for the treatment of neuropathic pain, has recently been reported to protect against ischemic brain injury, enhance remyelination in demyelinating diseases, and ameliorate neuroinflammation and memory deficits. However, its role in microglial polarization and mitochondrial dysfunction in Alzheimer's disease (AD) remains poorly understood. In this study, we investigated the therapeutic potential of Neurotropin in the 5xFAD mouse model of AD. Neurotropin administration alleviated cognitive decline, reduced amyloid-β (Aβ) deposition, suppressed neuroinflammation, and preserved neuronal density. Mechanistically, Neurotropin improved mitochondrial morphology, restored ATP production, increased mitochondrial DNA copy number, and reduced oxidative stress while promoting a shift in microglial polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype. Transcriptomic and molecular analyses revealed that calcium homeostasis modulator family member 2 (Calhm2) was markedly upregulated in 5xFAD mice, colocalized with microglia, and transcriptionally regulated by fused in sarcoma (FUS), while Calhm2 interacted with EF-hand domain containing protein D2 (EFhd2). Neurotropin suppressed FUS-mediated Calhm2 transcription and attenuated Calhm2-EFhd2 interaction. Importantly, overexpression of Calhm2 in both microglial cells and 5xFAD mice abolished the beneficial effects of Neurotropin, leading to exacerbated mitochondrial dysfunction, oxidative stress, and inflammatory cytokine release. Together, these findings identify Calhm2 as a critical mediator of Neurotropin's neuroprotective effects and demonstrate that Neurotropin alleviates AD pathology by suppressing FUS-dependent Calhm2 transcription and blocking the Calhm2/EFhd2 interaction. This study provides new insights into the mechanism of Neurotropin action and highlights its therapeutic potential for AD.}, } @article {pmid41016150, year = {2025}, author = {Bautista-Aguilera, ÓM and Manik, A and Diez-Iriepa, D and Szałaj, N and Zaręba, P and Więckowska, A and Żmudzki, P and Honkisz-Orzechowska, E and Knez, D and Gobec, S and Sałat, K and Martínez-Alonso, B and Guarnizo-Herrero, V and Durán, GT and Torrado-Salmerón, C and Bellver-Sanchis, A and Nsiona-Defise, I and Ribalta-Vilella, M and Pallàs, M and López-Muñoz, F and Griñán-Ferré, C and Marco-Contelles, J and Iriepa, I}, title = {N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {192}, number = {}, pages = {118603}, doi = {10.1016/j.biopha.2025.118603}, pmid = {41016150}, issn = {1950-6007}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; Mice ; Disease Models, Animal ; Male ; *Benzimidazoles/pharmacology/pharmacokinetics/chemistry/therapeutic use ; Amnesia/drug therapy/chemically induced ; Scopolamine ; Humans ; Neuronal Plasticity/drug effects ; *Piperidines/pharmacology/chemistry/pharmacokinetics ; }, abstract = {As part of a project aimed at the pharmacological optimization of Contilisant, herein we describe molecular modelling studies that led to the identification of MBA-159 as a new polyfunctionalized, multitarget-directed ligand and a promising drug candidate for the treatment of Alzheimer's disease. We synthesized MBA-159 and conducted comprehensive in vitro and in vivo evaluations. In in vivo studies MBA-159 demonstrated favourable pharmacokinetics, anti-amnesic properties and significantly improved non-spatial memory (contextual and recognition memory) in a mouse model of scopolamine-induced amnesia. Additionally, MBA-159 showed a tendency to increase synaptic plasticity biomarkers and reduce neuroinflammatory trends (assessed by qPCR), as well as cognitive enhancement in a senescence-accelerated prone mouse 8 model.}, } @article {pmid41015981, year = {2025}, author = {Abushakra, S and Power, A and Watson, D and Porsteinsson, A and Sabbagh, M and MacSweeney, E and Cohen, S and Boada Rovira, M and Doraiswamy, PM and Liang, E and Flint, S and Kesslak, JP and McLaine, R and Albayrak, A and Schaefer, J and Yu, J and Tolar, L and Dickson, S and Hey, JA and Tolar, M}, title = {Clinical Efficacy, Safety and Imaging Effects of Oral Valiltramiprosate in APOEε4/ε4 Homozygotes with Early Alzheimer's Disease: Results of the Phase III, Randomized, Double-Blind, Placebo-Controlled, 78-Week APOLLOE4 Trial.}, journal = {Drugs}, volume = {85}, number = {11}, pages = {1455-1472}, pmid = {41015981}, issn = {1179-1950}, support = {R01 AG065253/AG/NIA NIH HHS/United States ; R01-AG065253/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Double-Blind Method ; Female ; *Alzheimer Disease/drug therapy/genetics/diagnostic imaging ; Aged ; Male ; *Apolipoprotein E4/genetics ; Aged, 80 and over ; Middle Aged ; Magnetic Resonance Imaging ; Administration, Oral ; Homozygote ; Treatment Outcome ; Cognitive Dysfunction/drug therapy ; Brain/drug effects/diagnostic imaging ; }, abstract = {BACKGROUND: The apolipoprotein E ε4 (APOE ε4) allele is the strongest genetic risk factor for Alzheimer's disease (AD), with homozygotes accumulating a high burden of cerebral beta-amyloid (Aβ) pathology. Valiltramiprosate/ALZ-801 is a small-molecule potent inhibitor of Aβ-oligomer formation. The efficacy, safety/tolerability, and brain volume effects of oral valiltramiprosate were evaluated in this phase III, randomized, double-blind, placebo-controlled, multi-center, 78-week trial in homozygotes with early symptomatic AD. METHODS: The study enrolled eligible APOE4/4 subjects aged 50-80 years with Early AD (Mini-Mental State Examination [MMSE] 22-30), which included mild cognitive impairment (MCI) and mild dementia, Clinical Dementia Rating-Global Score (CDR-G) of 0.5 or 1, who were randomized 1:1 to valiltramiprosate (265 mg twice/day) or placebo. The primary outcome was AD Assessment Scale-Cognitive Subscale (ADAS-Cog13); the key secondary outcomes were CDR-Sum of Boxes (CDR-SB) and Amsterdam-Instrumental Activities of Daily Living (IADL), and a secondary outcome was Disability Assessment for Dementia (DAD). The main imaging outcome was hippocampal volume on MRI; diffusion tensor imaging (MRI-DTI) assessed microstructural tissue integrity. Amyloid-related imaging abnormalities (ARIA) were monitored with MRIs every 26 weeks. RESULTS: A total of 325 participants enrolled and received study drug. At 78 weeks, the overall efficacy population did not show significant effects on ADAS-Cog13 or other clinical outcomes compared with placebo (ADAS-Cog13: 11% slowing; p = 0.607, N = 320), but showed significant slowing of hippocampal atrophy (18%, p = 0.017, N = 290). Prespecified analyses by disease severity (stratification variable) showed no significant clinical effects in mild AD (MMSE ≤26, N = 195). The prespecified MCI group (MMSE >26, N = 125) showed nominally significant positive effects on ADAS-Cog13 (52%, nominal p = 0.041) and DAD (96%, nominal p = 0.016), positive trend on CDR-SB (102%, nominal p = 0.053), with significant hippocampal atrophy slowing (26%, p = 0.004), and positive grey/white matter effects on MRI-DTI. In the MCI group, positive ADAS-Cog13 drug effects showed significant subject-level correlations with positive effects on imaging outcomes. The most common adverse events were nausea, vomiting, and decreased appetite (more than double placebo rate), with no increased risk of brain edema or microhemorrhages. CONCLUSIONS: The APOE4/4 Early AD population did not show significant clinical efficacy at 78 weeks but showed significant brain atrophy slowing. Prespecified analyses at the MCI stage showed nominally significant slowing of clinical decline with significant hippocampal atrophy slowing. Oral valiltramiprosate may provide a favorable benefit-risk profile and simple treatment paradigm for homozygotes with MCI. These results will inform the design of future MCI trials. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04770220; EudraCT Number: 2020-005755-20.}, } @article {pmid41015797, year = {2025}, author = {Shuang, NI and Xiaofei, L and Xiaoyan, G and Zuxi, GU and Panqing, WU and Chao, C and Shengnan, LI and Xianwei, G and Lianwei, XU}, title = {Mechanism of Tiaogeng decoction in a cognitive dysfunction mouse model.}, journal = {Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan}, volume = {45}, number = {5}, pages = {987-997}, pmid = {41015797}, issn = {2589-451X}, support = {81874482//Natural Science Foundation-funded Project: Mechanism of Tiaogeng Decoction improving Cognitive Function via Regulating Nuclear Factor-erythroid 2-related Factor 2/c-Jun N-terminal kinase/Aβ Oxidative Stress Network in Hippocampus Neurons/ ; }, mesh = {Animals ; *Drugs, Chinese Herbal/administration & dosage ; Mice ; *Cognitive Dysfunction/drug therapy/genetics/metabolism/psychology ; Female ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Oxidative Stress/drug effects ; Mice, Inbred C57BL ; Mice, Transgenic ; Humans ; Amyloid beta-Peptides/metabolism/genetics ; Apoptosis/drug effects ; NF-E2-Related Factor 2/metabolism/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; }, abstract = {OBJECTIVE: To explore the mechanism of action of Tiaogeng decoction (, TG) in alleviating oxidative stress damage in the hippocampus of a mouse model of cognitive impairment. METHODS: Amyloid precursor protein/presenilin-1 (APP/PS1) transgenic female mice were randomly divided into model, estradiol valerate, low-, medium-, and high-dose TG groups, female C57 mice were used as the control group (n = 12/group). After 12 weeks of treatment, the behavior of mice was tested with the Morris water maze, and brain tissue samples were collected, and changes in hippocampal neurons were observed using electron microscopy. The deposition of beta-amyloid protein (Aβ) amyloid plaques in the hippocampus was determined by light microscopy. Aβ1-42 protein levels were detected through immunofluorescence. Oxidative stress indicators in the hippocampus were detected by enzyme linked immunosorbent assay. The expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2), c-Jun N-terminal kinase (JNK), phospho-JNK (p-JNK), B-cell lymphoma-2 (Bcl-2), caspase-9, and cleaved caspase-9 were detected by Western blot. Hippocampal cell apoptosis was detected using the terminal deoxynucleotidyl transferase-mediated nick end Labeling. RESULTS: TG improved the cognitive function of APP/PS1 mice, as judged by improvements in several indices from the Morris water maze test. TG increased Nrf2, superoxide dismutase, and heme oxygenase-1 protein expression and reduced malondialdelyde and reactive oxygen species expression. TG also inhibited the expression of JNK proteins, upregulated the expression of Bcl-2, and downregulated the expression of caspase-9, reducing cell apoptosis. TG decreased the percentage of the hippocampal cornu ammonis 1 area positive for Aβ1-42, reducing mitochondrial damage caused by oxidative stress and Aβ protein deposition. CONCLUSIONS: TG may improve memory ability while reducing oxidative stress and apoptosis. It also reduces Aβ protein deposition in the hippocampus, protecting the central nervous system and improving memory function. TG may reduce the risk of AD.}, } @article {pmid41015375, year = {2025}, author = {Afridi, MB and Ali Shah, SW and Hussain, H and Elhenawy, AA and Mujtaba, M and Al-Otaibi, JS and Khan, H}, title = {Exploring Anticholinergic and anti-amnesic potential of methyl substituted monocarbonyl curcumin derivatives.}, journal = {European journal of pharmacology}, volume = {1007}, number = {}, pages = {178193}, doi = {10.1016/j.ejphar.2025.178193}, pmid = {41015375}, issn = {1879-0712}, mesh = {Animals ; *Curcumin/pharmacology/analogs & derivatives/therapeutic use/chemistry/metabolism ; Acetylcholinesterase/metabolism/chemistry ; Mice ; Butyrylcholinesterase/metabolism/chemistry ; Molecular Docking Simulation ; *Amnesia/drug therapy/chemically induced/metabolism ; *Cholinergic Antagonists/pharmacology/chemistry/therapeutic use/metabolism ; Male ; *Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/metabolism ; Scopolamine ; Maze Learning/drug effects ; Behavior, Animal/drug effects ; Structure-Activity Relationship ; }, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia or amnesia, characterized primarily by loss of acetylcholine (ACh), due to increased activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), both of which accelerate ACh degradation, and exacerbate cholinergic dysfunction. In this regard, the synthetic methyl-substituted monocarbonyl curcumin derivatives (BL1-BL3) were analyzed for AChE and BChE inhibition, followed by molecular docking studies. Scopolamine (1 mg/kg) was used to induce amnesia in mice. The results of BL1-BL3 demonstrated a significant inhibitory effect especially against AChE compared to BChE enzymes, with IC50 of 128.4, 118.4, 170.9 μg/mL against AChE and 334.3, 1168, 288.2 μg/mL against BChE, respectively. These compounds exhibited strong binding affinities to both target proteins in docking studies. Scopolamine administration induced significant memory deficits in mice, that was significantly (P < 0.001) mitigated by pretreatment with BL1-BL3 in the Y-maze test at both 7.5 and 15 mg/kg doses by restoring spontaneous alternation performance (SAP). In the novel object recognition test (NORT), a prominent (P < 0.001) improvement in memory retention was seen during the test phase, and enhanced the discrimination index (DI) at both tested doses. Biochemical analyses of hippocampal tissue further supported the behavioral data. Treatment with BL1-BL3 effectively decreases AChE and malondialdehyde (MDA) levels while increasing catalase (CAT) and superoxide dismutase (SOD) levels. Overall, BL2 was found to be most significant. In short, BL1-BL3 emerged as potential therapeutic agents for AD due to significant effects in vitro and in vivo experimental models, and are also equally supported by in silico studies.}, } @article {pmid41014665, year = {2025}, author = {Wei, H and Zhang, G and Yan, X and Zhao, A and Zheng, Y and Shao, Y and Yang, L and Wang, J and Jiang, X}, title = {Plant-derived natural products modulate astrocyte function: Therapeutic strategies for Alzheimer's disease.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {148}, number = {}, pages = {157238}, doi = {10.1016/j.phymed.2025.157238}, pmid = {41014665}, issn = {1618-095X}, mesh = {*Alzheimer Disease/drug therapy ; *Astrocytes/drug effects ; Humans ; *Biological Products/pharmacology ; Animals ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Alkaloids/pharmacology ; tau Proteins/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a gradually worsening neurodegenerative condition with limited treatment options, highlighting the need for novel therapies. Astrocytes play key roles in AD pathogenesis. Natural products show promise for treating AD through modulating amyloid-beta (Aβ) and tau pathology, inhibiting neuroinflammation and oxidative stress, and protecting cellular organelles. Preclinical evidence supports their efficacy in targeting astrocyte-related mechanisms, enhancing cognition, and reducing neuronal damage. PURPOSE: Systematically summarize and evaluate the medicinal benefits of plant-derived natural products in modulating astrocyte-mediated processes to attenuate AD progression. METHODS: A comprehensive literature review was performed in PubMed and Web of Science, utilizing targeted keywords such as "natural products", "active compounds", "Alzheimer's disease", and "astrocytes". The review primarily focused on studies published between 2013 and 2024, with the selected literature systematically categorized and analyzed. RESULTS: This review highlights the medicinal benefits of plant-derived natural products, such as flavonoids, alkaloids, polyphenols, and terpenes in targeting astrocyte morphology and function to combat AD. These bioactive compounds modulate key pathological processes, including neuroinflammation, oxidative stress, Aβ metabolism, tau hyperphosphorylation, mitochondrial dysfunction, and ER stress, outlining pathways to alleviate AD through astrocytic effects. The review also summarizes clinical progress and major challenges in translating these compounds, such as variability, low bioavailability, and delivery limitations. CONCLUSION: This study addresses a critical gap by systematically elucidating the relationship between astrocytes and AD, and therapeutic potential of plant-derived natural products. It aims to expand treatment options for patients and advance the development of therapeutic strategies in the field of AD management.}, } @article {pmid41013881, year = {2025}, author = {Jastrzębski, MK and Wójcik, P and Mudgal, A and Woźniak, S and Targowska-Duda, KM and Wronikowska-Denysiuk, O and Michalak, A and Jeleniewicz, W and Karcz, T and Raczek, J and Stepulak, A and Kaczor, AA}, title = {Unveiling the Therapeutic Potential of D2AAK1 and Its Derivatives: Mechanistic Insights and Applications in Neurodegenerative Disease Treatment.}, journal = {Journal of neurochemistry}, volume = {169}, number = {10}, pages = {e70232}, doi = {10.1111/jnc.70232}, pmid = {41013881}, issn = {1471-4159}, support = {2017/27/B/NZ7/01767//Narodowe Centrum Nauki/ ; 2021/43/B/NZ7/01732//Narodowe Centrum Nauki/ ; }, mesh = {Animals ; Mice ; Male ; *Neurodegenerative Diseases/drug therapy/metabolism ; Cell Survival/drug effects/physiology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Humans ; Oxidative Stress/drug effects ; }, abstract = {The global rise in life expectancy has been accompanied by a growing prevalence of neurodegenerative diseases, such as Alzheimer's disease (AD). These complex disorders arise from multiple pathogenic factors and biological pathways, necessitating the development of multi-target therapeutic strategies. D2AAK1, discovered by our group, has emerged as a promising candidate due to its cytoprotective, antioxidant, and procognitive properties. This study aimed to further elucidate the mechanisms underlying the action of D2AAK1 and its derivatives, with a focus on their potential for neuroprotection and cognitive enhancement. The effect of D2AAK1 on cell viability was evaluated under normal conditions and during H2O2-induced oxidative stress using the resazurin assay. p38 MAPK activity was measured through cell-based ELISA. mRNA expression was analyzed using a two-step quantitative PCR method, and enzymatic effects were assessed via photometric, fluorescence, and luminescence techniques. Behavioral studies in murine models were performed to investigate the influence of the compounds on memory processes. It was found that D2AAK1 and its derivatives significantly enhanced cell viability, with some derivatives exhibiting greater potency than D2AAK1. In vivo, one derivative notably improved memory performance and reversed scopolamine-induced memory impairment in the novel object recognition test in male Swiss mice. Mechanistic studies revealed that D2AAK1 increased the expression of cytoprotective proteins such as Bcl-2 and HO-1, while concurrently reducing the expression and activity of pro-apoptotic factors, including caspase-3, p38 MAPK, and MAO-B. These dual actions culminated in enhanced cellular resilience and viability, translating into improved cognitive outcomes. The findings suggest that D2AAK1 and its derivatives, through their multi-factor mechanism of action, hold promise as therapeutic agents for the treatment of neurodegenerative diseases.}, } @article {pmid41013670, year = {2025}, author = {Sharma, N and Kim, D and Sharma, H and Kim, MI and Lee, H and Kim, M and Ryoo, N and Kang, MJ and Pyun, JM and Park, YH and Ryu, J and Oh, HJ and Yang, HS and Kim, HR and Kim, GH and Han, S and Yang, Y and Youn, YC and Teunissen, C and Zetterberg, H and Scheltens, P and An, SSA and Kim, YB and Kim, S and , }, title = {Bridging the barrier: insights into blood biomarkers and therapeutic strategies targeting choroid plexus and BBB dysfunction in alzheimer's disease.}, journal = {Biomarker research}, volume = {13}, number = {1}, pages = {116}, pmid = {41013670}, issn = {2050-7771}, support = {RS-2023-00251396//National Research Foundation of Korea (NRF)/ ; RS-2025-02292973//Korea Institute of Marine Science and Technology promotion/ ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia and accounts for approximately 60-80% of total dementia patients. Currently, accurate diagnosis for AD relies on cerebrospinal fluid (CSF) sampling or a positron emission tomography (PET) scan, methods that cannot be done in primary care centers where most people go with cognitive complaints. This Limitation calls for the urgent need to develop blood-related diagnostic tests that could facilitate early detection and enable timely treatment. Recent CSF proteomic research categorized AD into five molecular subtypes with discrete Genetic risk profiles. Subtypes 1-3, namely neuronal hyperplasticity, innate immune activation, and RNA dysregulation, were characterized by more classical AD-related changes, like accumulation of amyloid/tau and synaptic and immune dysfunction, respectively. On the contrary, non-traditional AD mechanisms in subtypes 4-5 were choroid plexus (CP) dysfunction and blood-brain barrier (BBB) dysfunction, emphasizing clearance deficits in association with brain barrier dysfunction. The unchanged tau levels later may be explained by an alternate disease mechanism (clearance dysfunction). These subtypes included BBB and CP dysfunction. Biomarker identification based on the mechanism of disease progression would increase the precision of diagnoses, allowing for tailored interventions and aiding in the creation of novel therapies for subtypes that might not react favorably to conventional amyloid/tau-targeting strategies. Finding biomarkers specific to each subtype would aid in patient classification, resulting in more individualized therapy as opposed to a "one-size-fits-all" strategy. The present review emphasized the importance of identifying blood-based biomarkers (BBMs) related to brain barrier dysfunction from CSF studies and personalized treatment strategies to streamline the diagnostic workup, and may be utilized in standard clinical practice for the early detection of AD.}, } @article {pmid41012536, year = {2025}, author = {Chen, BH and Jen, CT and Wang, CC and Pan, MH}, title = {Improving Alzheimer's Disease and Parkinson's Disease in Rats with Nanoemulsion and Byproducts Prepared from Cinnamon Leaves.}, journal = {Pharmaceutics}, volume = {17}, number = {9}, pages = {}, pmid = {41012536}, issn = {1999-4923}, support = {Grant no. 7100474//Tou-Fu Investment Co, Taipei, Taiwan/ ; }, abstract = {Background/Objectives: Cinnamon leaves, an important source of the functional compound cinnamaldehyde (CA), have been shown to be effective in improving type II diabetes and Parkinson's disease (PD) in rats following the incorporation of cinnamon leaf extract into a nanoemulsion. However, the effect of a cinnamon leaf extract nanoemulsion (CLEN) on improving Alzheimer's disease (AD), the most prevalent type of dementia, remains unexplored. The objectives of this study were to determine functional compounds in cinnamon leaves by UPLC-MS/MS, followed by the preparation of a nanoemulsion and its byproducts to study their effects on AD and PD in rats. Methods: Oven-dried (60 °C for 2 h) cinnamon leaf powder and hydrosol, obtained by steam distillation of cinnamon leaf powder, were stored at 4 °C. After determination of basic composition (crude protein, crude fat, carbohydrate, moisture and ash) of cinnamon leaf powder, it was extracted with 80% ethanol with sonication at 60 °C for 2 h and analyzed for bioactive compounds by UPLC-MS/MS. Then, the CLEN was prepared by mixing cinnamon leaf extract rich in CA with lecithin, soybean oil, tween 80 and ethanol in an optimal ratio, followed by evaporation to form thin-film and redissolving in deionized water. For characterization, mean particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency, and surface morphology were determined. Animal experiments were done by dividing 90 male rats into 10 groups (n = 9), with groups 2-8 being subjected to mini-osmotic pump implantation surgery in brain to infuse Amyloid-beta 40 (Aβ40) solution in groups 2-8 for induction of AD, while groups 9 and 10 were pre-fed respectively with cinnamon powder in water (0.5 g/10 mL) and in hydrosol for 4 weeks, followed by induction of AD as shown above. Different treatments for a period of 4 weeks included groups 1-9, with group 1 (control) and group 2 feeding with sterilized water, while groups 3, 4 and 5 were fed respectively with high (90 mg/kg), medium (60 mg/kg) and low (30 mg/kg) doses of cinnamon leaf extracts, groups 6, 7 and 8 fed respectively with high (90 mg/kg), medium (60 mg/kg) and low (30 mg/kg) doses of nanoemulsions, groups 9 and 10 fed respectively with 10 mL/kg of cinnamon powder in water and hydrosol (0.5 g/10 mL). Morris water maze test was conducted to determine short-term memory, long-term memory and space probing of rats. After sacrificing of rats, brain and liver tissues were collected for determination of Aβ40, BACE1 and 8-oxodG in hippocampi, and AchE and malondialdehyde (MDA) in cortices, antioxidant enzymes (SOD, CAT, GSH-Px) and MDA in both cortices and livers, and dopamine in brain striata by using commercial kits. Results: The results showed that the highest level of CA (18,250.7 μg/g) was in the cinnamon leaf powder. The CLEN was prepared successfully, with an average particle size of 17.1 nm, a polydispersity index of 0.236, a zeta potential of -42.68 mV, and high stability over a 90-day storage period at 4 °C. The Morris water maze test revealed that the CLEN treatment was the most effective in improving short-term memory, long-term memory, and spatial probe test results in AD rats, followed by the cinnamon leaf extract (CLE), powder in hydrosol (PH), and powder in water (PW). Additionally, both CLEN and CLE treatments indicated a dose-dependent improvement in AD rats, while PH and PW were effective in preventing AD occurrence. Furthermore, AD occurrence accompanied by PD development was demonstrated in this study. With the exception of the induction group, declines in Aβ40, BACE1, and 8-oxodG in the hippocampi and AchE and MDA in the cortices of rats were observed for all the treatments, with the high-dose CLEN (90 mg/kg bw) exhibiting the highest efficiency. The antioxidant enzyme activity, including that of SOD, CAT, and GSH-Px, in the cortices of rats increased. In addition, dopamine content, a vital index of PD, was increased in the striata of rats, accompanied by elevations in SOD, CAT, and GSH-Px and decreased MDA in rat livers. Conclusions: These outcomes suggest that the CLEN possesses significant potential for formulation into a functional food or botanical drug for the prevention and treatment of AD and/or PD in the future.}, } @article {pmid41012495, year = {2025}, author = {Sivamaruthi, BS and Kesika, P and Sisubalan, N and Chaiyasut, C}, title = {Advances in Gold Nanoparticles for the Diagnosis and Management of Alzheimer's Disease.}, journal = {Pharmaceutics}, volume = {17}, number = {9}, pages = {}, pmid = {41012495}, issn = {1999-4923}, abstract = {Alzheimer's disease (AD) presents a significant challenge in modern healthcare, prompting exploration into novel therapeutic strategies. This review clearly classifies different types of gold (Au) nanoparticles (NPs) (AuNPs), links them to the gut-brain axis, highlights recent advances, and points out future research needs, offering a more updated perspective than earlier reviews. Diverse approaches have emerged from single to hybrid and functionalized AuNPs, including innovative nanotherapeutic agents like Au nanorods-polyethylene glycol-angiopep-2 peptide/D1 peptide and noninvasive dynamic magnetic field-stimulated NPs. AuNPs have been reported for the neuroprotective properties. Clinical applications of AuNPs highlight their promise in diagnosis and therapeutic monitoring. However, challenges persist, notably in overcoming blood-brain barrier limitations and refining drug delivery systems. Furthermore, the incomplete understanding of AD's physiological and pathological mechanisms hinders therapeutic development. Future research directions should prioritize elucidating these mechanisms and optimizing AuNPs physicochemical properties for therapeutic efficacy. Despite limitations, nanomaterial-based therapies hold promise for revolutionizing AD treatment and addressing other central nervous system disorders. It also emphasizes the importance of further investigation into the potential of AuNPs, envisioning a future where they serve as a cornerstone in advancing neurological healthcare.}, } @article {pmid41011288, year = {2025}, author = {Łomankiewicz, D and Pilawa, B and Chodurek, E and Zdybel, M}, title = {Interactions of Extracts from Selected Plant Materials Supporting the Treatment of Alzheimer's Disease with Free Radicals-EPR and UV-Vis Studies.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {9}, pages = {}, pmid = {41011288}, issn = {1424-8247}, support = {BNW-1-073/K/3/F, PCN-2-015/N/1/F//Medical University of Silesia/ ; }, abstract = {Background/objectives: Interactions of infusions of Ginkgo biloba, ginseng, Yerba Mate, and green tea, with free radicals, were examined. The aim of these studies was to determine quenching of free radicals by the extracts from the selected plant raw materials that are useful in the treatment of Alzheimer's disease. Methods: The interactions were tested by an X-band (9.3 GHz) EPR spectroscopy and UV-Vis spectrophotometry. The model DPPH free radicals were used. The magnitude and changes with time of EPR and UV-Vis spectra of DPPH by the tested extracts were measured. Results: EPR and UV-Vis lines of DPPH free radicals decrease with increasing time of interactions of the extracts with DPPH, and after reaching the minimum value, it does not change with time. Ginseng infusion quenched free radicals the least. Ginkgo biloba extract quenches free radicals a little stronger than ginseng extract. Taking into account the tested extracts, Ginkgo biloba and ginseng extracts interact with free radicals less effectively compared to extracts of Yerba mate and green tea. Ginkgo biloba and ginseng extracts quench free radicals weaker than Yerba Mate and green tea extracts. Conclusions: Yerba Mate extract definitely had the strongest antioxidant properties. This extract quenches free radicals most effectively, what can be useful in the case of Alzheimer's disease. Given its strong antioxidant properties, green tea extract can also be particularly recommended in the case of Alzheimer's disease.}, } @article {pmid41010812, year = {2025}, author = {Yang, HM}, title = {Vascular Dementia: From Pathophysiology to Therapeutic Frontiers.}, journal = {Journal of clinical medicine}, volume = {14}, number = {18}, pages = {}, pmid = {41010812}, issn = {2077-0383}, support = {03-2025-0200//Seoul National University Hospital/ ; }, abstract = {Vascular dementia (VaD) represents the second-most common dementia type after Alzheimer's disease since it results from complications of cerebrovascular disease. Mixed pathologies combining vascular and neurodegenerative processes are the rule rather than exception in elderly dementia patients. The condition known as VaD includes various types of vascular damage that affect both large and small blood vessels in the brain which results in cerebral hypoperfusion, blood-brain barrier disruption, glymphatic dysfunction, and molecular cascades causing neuronal damage. The mechanisms of VaD include endothelial dysfunction, oxidative stress, chronic neuroinflammation, impaired glymphatic clearance, white matter demyelination, and synaptic failure. The disease susceptibility of individuals depends on genetic factors which include NOTCH3 mutations and vascular risk polymorphisms. The diagnostic field uses neuroimaging tools and fluid biomarkers such as neurofilament light chain, inflammatory markers, and Aβ/tau ratios for mixed pathology. The current practice of vascular risk management combines with new therapeutic approaches that use phosphodiesterase inhibitors for cerebral perfusion and NLRP3 inflammasome inhibitors for neuroinflammation, senolytics for cellular senescence, and remyelination agents for white matter repair. However, the majority of new treatment methods remain investigational with limited Phase III data. Future medical treatment development will depend on precision medicine approaches which use biomarker-guided treatment selection and combination strategies targeting multiple pathological mechanisms.}, } @article {pmid41010553, year = {2025}, author = {Matuszewski, W and Tomaszek, L and Szklarz, M and Górny, JM and Kordas, B and Rutkowska, J and Juranek, J}, title = {Beyond the Cardio-Renal-Metabolic Axis: Emerging Therapeutic Targets and Novel Mechanisms of Action of Flozins.}, journal = {Journal of clinical medicine}, volume = {14}, number = {18}, pages = {}, pmid = {41010553}, issn = {2077-0383}, abstract = {Contemporary diabetes management is progressively moving away from a glucocentric approach, with growing expectations that novel antidiabetic agents offer benefits beyond glycaemic control. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a cornerstone in the treatment of type 2 diabetes mellitus (T2DM). In addition to reducing blood glucose levels by promoting renal glucose excretion, these agents contribute significantly to cardio-renal-metabolic protection and are associated with improved cardiovascular outcomes and prolonged survival. Although SGLT2 inhibitors do not exhibit a class effect in all clinical aspects, growing evidence suggests their potential in a variety of additional therapeutic areas. We conducted an in-depth review of current scientific literature and clinical studies regarding this class of drugs. SGLT2 inhibitors demonstrate neuroprotective properties and may provide benefits in neurodegenerative disorders such as Alzheimer's and Parkinson's disease, potentially through the improvement of mitochondrial function and attenuation of inflammatory responses. Their anti-inflammatory and antioxidative effects are closely linked to reductions in cardiac and renal fibrosis. Other observed benefits include weight loss, improved insulin sensitivity, normalization of serum uric acid, and a reduction in hepatic steatosis-each with important metabolic implications. Furthermore, SGLT2 inhibitors have been shown to positively influence iron metabolism and improve erythrocyte indices. Emerging data also indicate beneficial effects in women with polycystic ovary syndrome. Another promising area of investigation involves the modulation of Klotho protein expression and support of vascular homeostasis. In oncology, SGLT2 inhibitors are gaining attention, with encouraging preclinical results observed in malignancies such as pancreatic, thyroid, breast, and lung cancers. Based on a comprehensive evaluation of the existing body of evidence, it is anticipated that the clinical indications for SGLT2 inhibitors will expand beyond the cardio-renal-metabolic axis in the near future.}, } @article {pmid41010550, year = {2025}, author = {Pacheco-Sánchez, B and Verheul-Campos, J and Vargas, A and Tovar, R and Rodríguez-Pozo, M and Navarro, JA and López-Gambero, AJ and Baixeras, E and Serrano-Castro, PJ and Suárez, J and Sanjuan, C and Rivera, P and Rodríguez de Fonseca, F}, title = {Early Oral Administration of D-Chiro-Inositol Reverses Hippocampal Insulin and Glutamate Signaling Deficits in the 3×Tg Humanized Mouse Model of Alzheimer's Disease.}, journal = {Nutrients}, volume = {17}, number = {18}, pages = {}, pmid = {41010550}, issn = {2072-6643}, support = {DTS22/00021//Instituto de Salud Carlos III. Proyectos de desarrollo tecnológico/ ; PI22/00427//Instituto de Salud Carlos III. Proyectos de Investigación en Salud/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Hippocampus/metabolism/drug effects ; *Insulin/metabolism ; Disease Models, Animal ; *Signal Transduction/drug effects ; Male ; Female ; Mice, Transgenic ; Mice ; Administration, Oral ; *Glutamic Acid/metabolism ; Humans ; }, abstract = {Background and Objective: Humanized models of Alzheimer's disease (AD) provide valuable tools for investigating the mechanisms of this neurodegenerative disorder, the leading cause of dementia. These models enable the study of AD progression and the potential disease-modifying properties of drugs or dietary nutrients delivered through nutrition. Here, we examine molecular markers of metabolic and synaptic dysfunction in the hippocampus of 6-month-old 3×Tg-AD mice and assess whether a dietary insulin sensitizer can delay synaptic decline. Methods: First we characterized the molecular phenotype of 3×Tg-AD at 12 months using shotgun proteomics and phosphoproteomics to assess metabolic and synaptic changes in the hippocampus. Then, we characterized the effects of early daily oral D-chiro-inositol (DCI, Gyneos[®]) for three months, starting at 3 months of age, to test restoration of insulin signaling and glutamatergic synaptic markers. To this end we evaluated a) insulin signaling pathway components (insulin receptor, IRS1, PI3K, AKT, GSK3β) at mRNA, protein, and phosphorylation levels, and b) the expression of glutamate receptors (mGluR5, GluR1, GluR2, NMDAR1, NMDAR2A, NMDAR2B). Sex effects were explored. Results: 12-month 3×Tg-AD mice exhibit metabolic and synaptic dysfunction in the hippocampus, with phosphoproteomic changes suggesting altered glutamatergic synapses. At 6 months, disruptions in insulin signaling were evident, including altered expression and phosphorylation of insulin pathway components, and changes in glutamate receptor subunits. Early DCI treatment largely reversed these alterations. Several effects showed sex dependency. Conclusions: Early insulin-sensitizing intervention via DCI can restore insulin signaling and counteract hippocampal synaptic impairments in this AD model, supporting the potential for nutrient-based strategies to delay synaptic decline. Sex differences underscore the need to tailor therapeutic approaches in modifying AD progression.}, } @article {pmid41010527, year = {2025}, author = {Barros, MI and Brandão, T and Irving, SC and Alves, P and Gomes, F and Correia, M}, title = {Omega-3 Polyunsaturated Fatty Acids and Cognitive Decline in Adults with Non-Dementia or Mild Cognitive Impairment: An Overview of Systematic Reviews.}, journal = {Nutrients}, volume = {17}, number = {18}, pages = {}, pmid = {41010527}, issn = {2072-6643}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Cognition/drug effects ; *Cognitive Dysfunction/prevention & control/drug therapy ; *Dietary Supplements ; *Fatty Acids, Omega-3/administration & dosage/therapeutic use/pharmacology ; Quality of Life ; Systematic Reviews as Topic ; }, abstract = {BACKGROUND/OBJECTIVES: As global aging accelerates, prevalence of mild cognitive impairment (MCI) continues to rise, challenging healthcare systems and diminishing older adults' quality of life. There is great interest in better understanding the neuroprotective/anti-inflammatory properties of omega-3 polyunsaturated fatty acids but the results from many published studies in humans come to different conclusions. This review aims to clarify the efficacy of n-3 fatty acids as a preventive or therapeutic strategy for cognitive health and to inform future clinical recommendations within aging populations. METHODS: Following PRISMA guidelines and a registered PROSPERO protocol, we reviewed systematic reviews (SRs) from 2014 to 2024 assessing exclusive n-3 fatty acid supplementation and cognitive outcomes via MMSE. Data were extracted on intervention details and cognitive scores. Meta-analyses used fixed and random-effects models, with Hedges' estimating overall impact. Quality was assessed using AMSTAR-2, and statistical analyses were performed (SPSS 28). RESULTS: A total of nine SRs incorporating 14 RCTs were included, representing 26,881 participants aged 40 years or older. The pooled random-effects meta-analysis showed a statistically significant but modest improvement in MMSE scores (effect size: 0.16; 95% CI: 0.01-0.32). Heterogeneity was moderate (I[2] = 42.8%), and no publication bias was detected. Further analyses revealed no significant associations between treatment duration or dosage and cognitive outcomes, suggesting a threshold effect rather than a dose-response relationship. CONCLUSIONS: These findings support n3-PUFA supplementation as a complementary approach to lifestyle-based strategies for cognitive health, including diet, physical activity, sleep optimization, and cognitive training. While benefits appear modest, consistent effects across studies warrant further high-quality research and well-designed studies to strengthen clinical recommendations.}, } @article {pmid41010145, year = {2025}, author = {Zahariev, N and Boyuklieva, R and Penkov, D and Lukova, P and Katsarov, P}, title = {Functionalized Magnetic Nanoparticles: Can They Revolutionize the Treatment of Neurodegenerative Disorders?.}, journal = {Materials (Basel, Switzerland)}, volume = {18}, number = {18}, pages = {}, pmid = {41010145}, issn = {1996-1944}, support = {BG-RRP-2.004-0007-C01//European Union-NextGenerationEU/ ; }, abstract = {Neurodegenerative disorders (NDs), including Alzheimer's disease and Parkinson's disease, pose a significant global health challenge characterized by progressive neuronal loss and limited therapeutic options. Early diagnosis remains a considerable hurdle due to the absence of reliable biomarkers and the restrictive nature of the blood-brain barrier (BBB), which complicates effective drug delivery. Magnetic nanoparticles (MNPs), particularly those based on iron oxide, have emerged as promising tools for both diagnostic and therapeutic applications in NDs, thanks to their superparamagnetism, biocompatibility, and customizable surfaces. This review examines various synthesis strategies for MNPs, encompassing physical methods (such as lithography, ball milling, and laser ablation) and chemical approaches (co-precipitation, thermal decomposition, hydrothermal synthesis, sol-gel processes, and polyacrylamide gel techniques), while highlighting how these techniques influence particle properties. This review also explores recent advancements in surface functionalization using polymers and coatings to enhance circulation time in the bloodstream and improve BBB penetration for targeted delivery. Furthermore, it emphasizes both in vitro and in vivo applications, showcasing MNPs' effectiveness in enhancing imaging sensitivity and enabling targeted drug and gene delivery. By linking synthesis methods, functionalization techniques, and biomedical outcomes, this review illustrates the transformative potential of MNPs as next-generation theranostic agents in precision medicine for neurodegenerative diseases.}, } @article {pmid41009662, year = {2025}, author = {Mironenko, IV and Kryukova, OV and Buianova, AA and Churov, AV and Arbatsky, MS and Kubrikova, AA and Petrusenko, YS and Repinskaia, ZA and Shmitko, AO and Ilyina, GA and Kost, OA and Dudek, SM and Strazhesko, ID and Isaev, RI and Mkhitaryan, EA and Tkacheva, ON and Rebrikov, DV and Danilov, SM}, title = {ACE-Dependent Alzheimer's Disease: Circulating ACE Phenotypes in Heterozygous Carriers of Rare ACE Variants.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009662}, issn = {1422-0067}, support = {075-15-2019-1789//Ministry of Science and Higher Education of the Russian Federation/ ; 125022602916-4//Ministry of Healthcare of Russian Federation/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/blood/enzymology ; Male ; Female ; Heterozygote ; Aged ; *Peptidyl-Dipeptidase A/genetics/blood ; Mutation ; Phenotype ; Aged, 80 and over ; Middle Aged ; Adult ; Genetic Predisposition to Disease ; }, abstract = {Damaging mutations of the Angiotensin I-converting enzyme (ACE) that result in low ACE levels may increase the risk of developing late-onset Alzheimer's disease (AD). We quantified blood ACE levels in EDTA-plasma from 147 subjects with 23 different heterozygous ACE mutations (and 70 controls) and estimated the effect of these mutations on ACE phenotype, using a set of monoclonal antibodies (mAbs) to ACE and two ACE substrates. We identified several mutations in both ACE domains (including the most frequent ACE mutation, Y215C), which led to decreased ACE levels in the blood, and thus could be considered as putative risk factors for late-onset AD. The precipitation of several ACE mutants (Q259R, A725P, C734Y) by specific mAbs changed significantly, and therefore, these mAbs could be markers of these mutations. Analysis of 50 of the most frequent ACE mutations demonstrates that more than 1.5% of the adult population may have mutations which lead to decreased ACE levels, and thus, the role of low ACE levels in the development of AD may be underappreciated. Intriguingly, statistical and cluster analyses of longevity patients revealed trends towards higher frequency of cognitive impairment among affected individuals with damaging ACE mutations. Systematic analysis of blood ACE levels in patients with various ACE mutations identifies individuals with low blood ACE levels who may be at increased risk for late-onset AD. Patients with transport-deficient ACE mutations theoretically could benefit from therapeutic treatment with a combination of chemical and pharmacological chaperones and proteasome inhibitors, as was demonstrated previously on a cell model of the transport-deficient ACE mutation Q1069R. Moreover, clinical association analysis suggests a trend linking damaging ACE mutations with increased risk of cognitive impairment.}, } @article {pmid41009529, year = {2025}, author = {Krasauskas, L and Veiveris, D and Žiaunys, M and Šulskis, D and Sakalauskas, A and Smirnovas, V}, title = {Tau Enhances Aggregation of S100A9 Protein and Further Association of Its Fibrils.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009529}, issn = {1422-0067}, support = {S-MIP-22-34//This research was funded by the Research Council of Lithuania/ ; }, mesh = {*tau Proteins/metabolism/genetics/chemistry ; *Calgranulin B/metabolism/chemistry/genetics ; Humans ; *Amyloid/metabolism/chemistry ; Protein Aggregates ; *Protein Aggregation, Pathological/metabolism ; Alzheimer Disease/metabolism/pathology ; Protein Binding ; }, abstract = {The formation and accumulation of amyloid fibrils is implicated as one of the main reasons for the onset and progression of several widespread neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Decades of effort to unravel the intricate mechanisms of amyloid aggregation have only led to limited success in developing potent treatment modalities. Generally, this failure is considered to be the result of our incomplete understanding of the processes governing protein transitions into these insoluble fibrillar structures. Recently, a growing number of studies have reported that multiple amyloidogenic proteins, including ones related to the most debilitating disorders, can cross-interact during aggregation. This process leads to different nucleation and fibril elongation rates, aggregate structures, and even their cytotoxicity. Despite this revelation, the entire amyloid interactome remains largely unexplored. In this work, we investigate the cross-interaction between the Alzheimer's disease-related Tau protein and a pro-inflammatory S100A9 protein, which has recently been implicated as a possible modulator of amyloid aggregation. We show that Tau 2N4R enhances the amyloid aggregation propensity of S100A9 and mediates the self-association of the resulting fibrils, demonstrating this pairing's potential role in the onset of neurodegenerative disorders.}, } @article {pmid41009493, year = {2025}, author = {Dwamena, A and Beragama-Arachchi, R and Wang, H}, title = {Boosting Neurogenesis as a Strategy in Treating Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009493}, issn = {1422-0067}, support = {RF1 AG072510/AG/NIA NIH HHS/United States ; AG072510//NIH/NIA/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/pathology ; *Neurogenesis ; Animals ; Neural Stem Cells/metabolism/cytology ; Epigenesis, Genetic ; Genetic Therapy ; }, abstract = {Alzheimer's disease (AD) causes progressive cognitive decline and neuronal loss, partly due to the buildup of amyloid-β (Aβ) plaques and tau tangles. Despite years of research, treatments targeting these hallmark pathologies have yielded only modest clinical success, prompting interest in regenerative approaches to restore the brain's ability to repair itself. One such approach focuses on adult hippocampal neurogenesis, the process by which neural stem cells (NSCs) produce new neurons throughout life. In AD, this process is impaired, worsening cognitive deficits. In this review, we examine the molecular pathways that control adult neurogenesis, including transcriptional, epigenetic, inflammatory, and metabolic mechanisms, and how they become dysregulated in AD. We also highlight various therapeutic strategies aimed at boosting neurogenesis, such as pharmacological treatments, stem cell therapy, gene therapy, and epigenetic modulation. Preclinical studies indicate that enhancing neurogenesis can improve cognition and reduce brain pathology in AD models. Several of these treatments are now being tested in clinical trials. Ultimately, promoting neurogenesis may offer a promising avenue to complement current AD therapies and help restore lost neural function.}, } @article {pmid41009371, year = {2025}, author = {Tyng, V and Kellman, ME}, title = {Kinetic Model with Feedback Cycle for Age-Dependent Amyloid Beta Accumulation in Mice.}, journal = {International journal of molecular sciences}, volume = {26}, number = {18}, pages = {}, pmid = {41009371}, issn = {1422-0067}, mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; Mice ; *Alzheimer Disease/metabolism/pathology ; Kinetics ; *Aging/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *Models, Biological ; Feedback, Physiological ; Humans ; }, abstract = {Amyloid beta (Aβ) is believed to play a key role in Alzheimer's disease (AD), whose causes, progression, diagnosis, and treatment nonetheless remain poorly understood despite decades of research. Recent studies suggest that Aβ in its various forms participates in multiple mutual feedback loops ("vicious cycles") including tauopathy, oxidative stress, inflammation, calcium dysregulation, excitotoxicity, and probably many others, eventually leading to neurodegeneration and cognitive decline. Here, as an initial quantitative step toward modeling this vast complexity, we explore a simple kinetic model of a coupled feedback vicious cycle for Aβ buildup based on literature data for Tg2576 mice. The model is used to examine the efficacy of various hypothetical therapeutic approaches, either singly or in combination, to mitigate Aβ buildup. While our computational results support the possible efficacy of combination interventions, they also suggest caution, inasmuch as clear synergy is not found. This kinetic approach highlights the essential importance of the vicious cycle of positive feedback in a quantitative model.}, } @article {pmid41008652, year = {2025}, author = {Bilski, R and Dąbkowski, S and Kozieł, I and Kozicki, M and Małachowska, A and Przygocki, M and Tyska, O}, title = {Perspectives on Alzheimer's Disease Treatment Based on Counteracting Oxidative Stress.}, journal = {Biomolecules}, volume = {15}, number = {9}, pages = {}, pmid = {41008652}, issn = {2218-273X}, mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; Humans ; *Oxidative Stress/drug effects ; *Antioxidants/therapeutic use/pharmacology ; Reactive Oxygen Species/metabolism ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism ; Monoamine Oxidase Inhibitors/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder and one of the most pressing global health challenges. Increasing evidence highlights oxidative stress as a key factor in its pathogenesis, contributing to amyloid-β accumulation, tau hyperphosphorylation, neuroinflammation, and mitochondrial dysfunction. Oxidative stress markers, detected in the bodily fluids of AD patients, are considered promising diagnostic and prognostic tools. Despite extensive research, currently available therapies remain largely symptomatic, which emphasizes the need to develop novel, disease-modifying strategies. The aim of this review is to summarize current knowledge on the role of oxidative stress in the pathogenesis of AD and to evaluate therapeutic approaches aimed at its reduction. We discuss molecular mechanisms linking reactive oxygen species to neurodegeneration and present pharmacological strategies such as monoamine oxidase inhibitors and multifunctional agents, as well as natural antioxidants, dietary interventions, and novel therapeutic technologies. We pay particular attention to their efficacy, limitations, and translational challenges. A more profound understanding of oxidative stress-related mechanisms may facilitate the development of combined antioxidant, anti-inflammatory, and neuroprotective approaches, offering new perspectives for delaying disease progression and improving patient outcomes.}, } @article {pmid41008347, year = {2025}, author = {Scuderi, G and Fagone, P and Petralia, MC and Nicoletti, F and Basile, MS}, title = {Multifaceted Role of Nef in HIV-Associated Neurocognitive Disorder: Histopathological Alterations and Underlying Mechanisms.}, journal = {Brain sciences}, volume = {15}, number = {9}, pages = {}, pmid = {41008347}, issn = {2076-3425}, abstract = {Although antiretroviral regimens achieve durable suppression of human immunodeficiency virus (HIV) replication, individuals living with HIV remain at an increased risk of developing chronic comorbidities, such as HIV-associated neurocognitive disorder (HAND). In the absence of definitive biomarkers or curative treatments, HAND impacts the survival and quality of life in up to 50% of individuals with HIV. Therefore, novel strategies are highly warranted to improve the diagnosis, monitoring, and treatment of individuals with HAND and a deeper characterization of the still poorly understood pathogenesis of HAND is fundamental to this aim. The pathogenesis, progression, and clinical outcomes of HAND are influenced by different factors, including viral proteins like negative factor (Nef). Among HIV proteins, Nef emerges as a potential key contributor to HAND pathogenesis. Nef could drive specific histopathological alterations in the brain and could be involved in HAND through different interconnected pathogenetic mechanisms. These include: immune dysregulation, oxidative stress, mitochondrial dysfunction, disruption of autophagy, myelin damage and oligodendrocytes dysfunction, blood-brain barrier disruption, alterations of cholesterol homeostasis, and certain potential converging mechanisms with Alzheimer's disease. Both extracellular and intracellular Nef can contribute to the development of HAND. Interestingly, it has been proposed that Nef may participate in HAND through its incorporation into extracellular vesicles. This review explores the multifaceted role of Nef in HAND, highlighting the histopathological alterations and the pathogenetic mechanisms potentially involved and the potential emerging relevance of Nef as a diagnostic and therapeutic target in HAND.}, } @article {pmid41008294, year = {2025}, author = {Zeppieri, M and Visalli, F and Musa, M and Avitabile, A and Giglio, R and Tognetto, D and Gagliano, C and D'Esposito, F and Cappellani, F}, title = {Beyond the Eye: Glaucoma and the Brain.}, journal = {Brain sciences}, volume = {15}, number = {9}, pages = {}, pmid = {41008294}, issn = {2076-3425}, abstract = {Glaucoma is traditionally classified as an ocular disease characterized by progressive retinal ganglion cell (RGC) loss and optic nerve damage. However, emerging evidence suggests that its pathophysiology may extend beyond the eye, involving trans-synaptic neurodegeneration along the visual pathway and structural changes within central brain regions, including the lateral geniculate nucleus and visual cortex. In this narrative review, we have used the phrase 'brain involvement' to underscore central changes that accompany or follow retinal ganglion cell loss; we have not intended to redefine glaucoma as a primary cerebral disorder. Neuroimaging studies and neurocognitive assessments in adult glaucoma patients, primarily older individuals with primary open-angle glaucoma reveal that glaucoma patients may exhibit alterations in brain connectivity and cortical thinning, aligning it more closely with neurodegenerative disorders such as Alzheimer's and Parkinson's disease. This evolving neurocentric perspective raises important questions regarding shared mechanisms-such as mitochondrial dysfunction, chronic inflammation, and impaired axonal transport-that may link glaucomatous optic neuropathy to central nervous system (CNS) pathology. These insights open promising therapeutic avenues, including the repurposing of neuroprotective and neuroregenerative agents, targeting not only intraocular pressure (IOP) but also broader CNS pathways. Furthermore, neuroimaging biomarkers and brain-targeted interventions may play a future role in diagnosis, prognosis, and individualized treatment. This review synthesizes current evidence supporting glaucoma as a CNS disease, explores the mechanistic overlap with neurodegeneration, and discusses the potential clinical implications of glaucoma within a neuro-ophthalmologic paradigm.}, } @article {pmid41007711, year = {2025}, author = {Aljadaan, AM and AlSaadi, AM and Shaikh, IA and Whitby, A and Ray, A and Kim, DH and Carter, WG}, title = {Characterization of the Anticholinesterase and Antioxidant Properties of Phytochemicals from Moringa oleifera as a Potential Treatment for Alzheimer's Disease.}, journal = {Biomedicines}, volume = {13}, number = {9}, pages = {}, pmid = {41007711}, issn = {2227-9059}, support = {PhD scholarship to Adel Aljadaan//Cultural Bureau and Najran University PhD scholarship/ ; }, abstract = {Background/Objectives: Alzheimer's disease (AD) is the most prevalent form of dementia and is characterized by a decline in cognition that may be due, in part, to deficient cholinergic signalling. Cholinesterase inhibitors (ChEIs) are the first-line pharmacotherapies for treating the diminished cholinergic function in AD patients. Plant phytochemicals may provide useful ChEIs and mitigate other elements of AD pathology, including oxidative stress. Methods: Herein, the phytochemicals present in Moringa oleifera aqueous and methanolic extracts were identified by LC-MS/MS and the potential of several phytochemicals (4-O-caffeoylquinic acid (4-CQA), quercetin 3-β-D-glucoside (Q3-β-D), chlorogenic acid (CGA), and rutin) to act as ChEIs and antioxidants was assessed. Results: The phytochemicals inhibited human acetylcholinesterase (AChE) in the following order of potency: 4-CQA > Q3-β-D > CGA > rutin; for AChE from Electrophorus electricus, the order of potency was Q3-β-D > 4-CQA > CGA > rutin. For human butyrylcholinesterase (hBuChE), the order of potency was rutin > 4-CQA > Q3-β-D > CGA and for equine serum BuChE, it was 4-CQA > Q3-β-D > rutin > CGA. Molecular docking validated the binding of the phytochemicals to cholinesterases, with binding affinities comparable to or higher than those of ChEI drugs. All the phytochemicals displayed potent radical-scavenging and antioxidant activities across six assays. 4-CQA was the most effective antioxidant in three of the assays. Conclusions: M. oleifera contains phytochemicals with weak ChEI activity and potent antioxidant capacity, with potential use as nutraceuticals to treat the cholinergic signalling deficit and oxidative stress that typifies AD pathology.}, } @article {pmid41007671, year = {2025}, author = {Okła, E and Hołota, M and Michlewska, S and Zawadzki, S and Miłowska, K and Sánchez-Nieves, J and Gómez, R and De la Mata, FJ and Bryszewska, M and Ionov, M}, title = {Crossing Barriers: PEGylated Gold Nanoparticles as Promising Delivery Vehicles for siRNA Delivery in Alzheimer's Disease.}, journal = {Biomedicines}, volume = {13}, number = {9}, pages = {}, pmid = {41007671}, issn = {2227-9059}, support = {2018/30/Z/NZ1/00911//Polish National Science Centre/ ; 2024/00300/001-GP2024-02//Universidad de Alcalá/ ; CIBER-BBN, CB06/01/1021//Centro de Investigación Biomédica en Red/ ; }, abstract = {Background: The proportion of people suffering from neurodegenerative conditions, such as Alzheimer's disease (AD), is increasing in the population year on year. Despite the constant effort of researchers, these conditions remain incurable and can only be managed by alleviation or delaying of symptoms. The lack of suitable treatment is caused by constricted access to the brain, limited by the brain-blood barrier. The aim of this work was to investigate two pegylated gold nanoparticles as potential carriers of therapeutic siRNA and their impact on the cellular functions of Human Brain Endothelial Cells. Methods and Results: Nanoparticles AuNP14a and AuNP14b complexed with siRNA were internalized by HBEC-5i cells and located in the cytoplasm. The genotoxicity assay proved that the nucleus was not affected and complexed nanoparticles did not cause DNA damage. The reactive oxygen species formation and mitochondrial membrane potential changes were measured and showed an adaptive response of cells after compound administration. Results obtained in a cytotoxicity assay conducted on astrocytes and pericytes, which are components of the blood-brain barrier, confirmed the biosafety of tested nanoparticles. Conclusions: In summary, it was shown that AuNP14a and AuNP14b are promising candidates as nanocarriers for therapeutic nucleic acids through biological barriers.}, } @article {pmid41007667, year = {2025}, author = {Dziedziak, M and Mytych, A and Szyller, HP and Lasocka, M and Augustynowicz, G and Szydziak, J and Hrapkowicz, A and Dyda, M and Braksator, J and Pytrus, T}, title = {Gut Microbiota in Psychiatric and Neurological Disorders: Current Insights and Therapeutic Implications.}, journal = {Biomedicines}, volume = {13}, number = {9}, pages = {}, pmid = {41007667}, issn = {2227-9059}, abstract = {Recent studies increasingly highlight the complex interaction between gut microbiota and mental health, drawing attention to the role of the microbiota-gut-brain axis (MGBA) in the pathophysiology of mental and neurodevelopmental disorders. Changes in the composition of the gut microbiota-dysbiosis-are associated with conditions such as depression, schizophrenia, bipolar disorder (BD), autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), and neurodegenerative diseases such as Parkinson's and Alzheimer's. These microbial imbalances can affect brain function through a variety of mechanisms, including activation of the immune system, alteration of intestinal permeability, modulation of the digestive and central nervous systems, and changes in the production of neuroactive metabolites such as short-chain fatty acids, serotonin, and tryptophan derivatives. The aim of this paper is to review the current state of knowledge on therapeutic strategies targeting the gut microbiome-including probiotics, prebiotics, synbiotics, personalized dietary interventions, and fecal microbiota transplantation (FMT)-which are becoming promising adjuncts or alternatives to conventional psychopharmacology, offering a forward-looking and individualized approach to mental health treatment. Understanding the bidirectional and multifactorial nature of MGBA may pave the way for new, integrative treatment paradigms in psychiatry and neurology, requiring further research and exploration of their scope of application.}, } @article {pmid41007636, year = {2025}, author = {Abdalla, M and Ibrahim, M and Alkorbi, N and Alkuwari, S and Pedersen, S and Rathore, HA}, title = {Epoxide Hydrolase Inhibitors for the Treatment of Alzheimer's Disease and Other Neurological Disorders: A Comprehensive Review.}, journal = {Biomedicines}, volume = {13}, number = {9}, pages = {}, pmid = {41007636}, issn = {2227-9059}, abstract = {Alzheimer's disease is the most common form of dementia, yet current treatments only offer symptomatic relief, with little preventative, therapeutic, or disease-modifying properties. As a result, there has been growing interest in targeting various disease mechanisms. One promising target is soluble epoxide hydrolase (sEH), an enzyme found in many organs, playing an important role in metabolism and detoxification. In the brain, sEH is mainly present in astrocytes, oligodendrocytes, and neuronal cell bodies, with higher concentrations in the cerebral cortex and striatum. The main function of sEH is the hydrolysis of epoxyeicosatrienoic acids (EETs), which are important anti-inflammatory molecules derived from arachidonic acid. Deletion of EPHX2, the encoding gene of sEH, maintains EET levels in the brain and helps mitigate inflammation. Multiple studies have found links between sEH function, inflammation, and neurodegeneration in Alzheimer's disease. Several compounds, including TPPU, benzohomoadamantane derivatives, and natural products, have shown significant beneficial effects, including reduction of amyloid-beta plaques, tau fibrils, and inflammation, while improving cognition and neuronal structure and function. sEH inhibitors have also been explored for their potential in the management of Parkinson's disease, vascular dementia, stroke, and other neurodegenerative conditions. Although these preclinical findings are promising, efficacy and safety concerns still need to be addressed, and further clinical trials are needed to translate these therapeutic agents into clinical practice.}, } @article {pmid41007258, year = {2025}, author = {Guan, Q and Cao, Y and Zou, J and Zhang, L}, title = {Bone-Derived Factors: Regulating Brain and Treating Alzheimer's Disease.}, journal = {Biology}, volume = {14}, number = {9}, pages = {}, pmid = {41007258}, issn = {2079-7737}, support = {82272608//National Natural Science Foundation of China/ ; No//Shanghai Oriental Talent Program Youth/ ; 11DZ2261100//Shanghai Key Laboratory of Human Performance/ ; }, abstract = {In recent years, the bidirectional regulatory mechanism of the bone-brain axis has become a hotspot for interdisciplinary research. In this paper, we systematically review the anatomical and functional links between bone and the central nervous system, focusing on the regulation of brain function by bone-derived signals and their clinical translational potential. At the anatomical level, the blood-brain barrier permeability mechanism and the unique structure of the periventricular organs establish the anatomical basis for bone-brain information transmission. Innovative discoveries indicate that the bone cell network (bone marrow mesenchymal stem cells, osteoblasts, osteoclasts, and bone marrow monocytes) directly regulates neuroplasticity and the inflammatory microenvironment through the secretion of factors such as osteocalcin, lipid transporter protein 2, nuclear factor κB receptor-activating factor ligand, and fibroblast growth factor 23, as well as exosome-mediated remote signaling. Clinical studies have revealed a bidirectional vicious cycle between osteoporosis and Alzheimer's disease: reduced bone density exacerbates Alzheimer's disease pathology through pathways such as PDGF-BB, while AD-related neurodegeneration further accelerates bone loss. The breakthrough lies in the discovery that anti-osteoporotic drugs, such as bisphosphonates, improve cognitive function. In contrast, neuroactive drugs modulate bone metabolism, providing new strategies for the treatment of comorbid conditions. Additionally, whole-body vibration therapy shows potential for non-pharmacological interventions by modulating bone-brain interactions through the mechano-osteoclast signaling axis. In the future, it will be essential to integrate multiple groups of biomarkers to develop early diagnostic tools that promote precise prevention and treatment of bone-brain comorbidities. This article provides a new perspective on the mechanisms and therapeutic strategies of neuroskeletal comorbidities.}, } @article {pmid41006538, year = {2025}, author = {Falvey, A and Palandira, SP and Chaudhry, S and Tynan, A and Consolim-Colombo, FM and Metz, CN and Brines, M and Chang, EH and Chavan, SS and Tracey, KJ and Pavlov, VA}, title = {The cholinergic drug galantamine ameliorates acute and subacute peripheral and brain manifestations of acute respiratory distress syndrome in mice.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {33217}, pmid = {41006538}, issn = {2045-2322}, support = {R01 GM121102/GM/NIGMS NIH HHS/United States ; R35 GM118182/GM/NIGMS NIH HHS/United States ; RO1GM128008/NH/NIH HHS/United States ; R35GM118182/NH/NIH HHS/United States ; R01 GM128008/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Galantamine/pharmacology/therapeutic use ; *Respiratory Distress Syndrome/drug therapy/pathology/metabolism/chemically induced ; Mice ; Disease Models, Animal ; Male ; *Cholinergic Agents/pharmacology/therapeutic use ; Bronchoalveolar Lavage Fluid/chemistry ; Acute Lung Injury/drug therapy/pathology ; Lipopolysaccharides ; Cytokines/metabolism/blood ; *Brain/drug effects/pathology ; Lung/pathology/drug effects ; Inflammation/drug therapy ; }, abstract = {Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute lung injury (ALI), which is a common cause of respiratory failure and high mortality in critically ill patients. Long-term mortality and cognitive impairment have been documented in ARDS patients after hospital discharge. Inflammation plays a key role in ALI/ARDS pathogenesis. Neural cholinergic signaling regulates cytokine responses and inflammation. Here, we studied the effects of galantamine, an approved cholinergic drug (for Alzheimer's disease) on ALI/ARDS severity and inflammation in mice, using a clinically relevant mouse model induced by intratracheal administration of hydrochloric acid and lipopolysaccharide. Mice were treated 30 min prior to each insult with vehicle or galantamine (4 mg/kg, i.p.). Galantamine treatment significantly decreased bronchoalveolar lavage (BAL) and serum TNF, IL-1b, and IL-6 levels, as well as BAL total protein and myeloperoxidase (MPO) and lung histopathology in ALI/ARDS mice. In addition, galantamine improved the functional state of mice with ALI/ARDS during a 10-day monitoring and attenuated lung injury and indices of brain inflammation at 10 days. These findings support further studies utilizing this approved cholinergic drug in therapeutic strategies for ALI/ARDS and its subacute sequelae.}, } @article {pmid41005603, year = {2025}, author = {Ramachandran, AK and Govindula, A and Ranadive, N and Birangal, SR and Bhat, V and Fayaz, SM and Shenoy, GG and Mudgal, J}, title = {Design, synthesis, and preclinical evaluation of novel 1-benzylpiperidine derivatives as multitarget agents against Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1006}, number = {}, pages = {178192}, doi = {10.1016/j.ejphar.2025.178192}, pmid = {41005603}, issn = {1879-0712}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology/physiopathology ; Animals ; *Piperidines/pharmacology/chemical synthesis/therapeutic use/chemistry/metabolism ; *Drug Design ; Mice ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/therapeutic use/chemistry/metabolism ; Acetylcholinesterase/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Drug Evaluation, Preclinical ; *Neuroprotective Agents/pharmacology/chemical synthesis/therapeutic use ; Microglia/drug effects/metabolism ; Maze Learning/drug effects ; Humans ; Structure-Activity Relationship ; Disease Models, Animal ; }, abstract = {Small molecules targeting pathologies of Alzheimer's disease (AD) is a promising approach. Identification of potential molecules using computational techniques and their synthesis provides potential applications in the treatment of AD. 2D fingerprint similarity screening, using the Tanimoto coefficient, identified structurally similar molecules to donepezil for lead identification. A molecule with a Tanimoto coefficient of 0.7 was chosen, and derivatives were synthesized. In silico screening of the synthesized compounds indicated strong binding to acetylcholinesterase (AChE). All molecules met drug-likeness criteria and showed 100 % oral absorption. Key interactions with AChE were observed, crucial for inhibitory activity. Molecular dynamics simulations over 100 ns showed stable binding conformations. In vitro assays for AChE and amyloid β (Aβ) inhibition were conducted after the cytotoxicity testing in microglial cells for all four synthesized compounds. Among the tested compounds at 5 μM, (E)-2-(((1-benzylpiperidin-4-yl)imino)methyl)-4-methylphenol (5MeSA4ABP) with AChE (57.46 ± 2.140 %) and Aβ inhibition (57.83 ± 0.08 %), was selected for lipopolysaccharide-induced AD-like mouse model. Behavioural analysis using Morris water maze and open field tests revealed memory impairment in mice. Brain estimations were performed to study the effect of treatments on AD markers such as interleukin-6 (IL-6), Aβ and AChE. In mice with AD pathology, oral administration of 5MeSA4ABP resulted in improved cognitive function without any impact on locomotor activity. Except brain AChE activity, treatment with 5MeSA4ABP significantly reversed the elevated brain IL-6 and Aβ levels. Thus, synthesized hybrid pharmacophores, 5MeSA4ABP, exert its activity via reducing neuroinflammation and plaque deposition. Future investigation are warranted for safety and efficacy mechanisms of 5MeSA4ABP against AD.}, } @article {pmid41005404, year = {2025}, author = {Wang, G and Duan, J and Sun, L and Pan, S and Liu, Q and Fu, K and Zhang, D and Yuan, X and Fan, B and Hu, B and Huang, B}, title = {Multi-omics integration reveals key miRNAs, immune inflammation, and signaling pathways in Alzheimer's disease: Implications for targeted therapy.}, journal = {International journal of biological macromolecules}, volume = {329}, number = {Pt 2}, pages = {147874}, doi = {10.1016/j.ijbiomac.2025.147874}, pmid = {41005404}, issn = {1879-0003}, mesh = {*Alzheimer Disease/genetics/immunology/metabolism/therapy/pathology ; *MicroRNAs/genetics ; Humans ; *Signal Transduction/genetics ; *Inflammation/genetics/immunology ; Gene Expression Profiling ; Gene Regulatory Networks ; Transcriptome ; Gene Expression Regulation ; Male ; Female ; Molecular Targeted Therapy ; Multiomics ; }, abstract = {Alzheimer's disease (AD), a common neurodegenerative disorder, has unclear molecular mechanisms and therapeutic targets. In this study, multi-omics analysis and experimental validation were performed. By integrating three miRNA-seq, four differentially expressed miRNAs (miR-339-3p, miR-28-3p, miR-423-3p, miR-144-5p) were identified, closely related to synaptic function and immune-inflammatory responses. By integrating blood RNA-seq data, we found 725 mRNAs linked to AD, immune, and apoptosis pathways. Peripheral blood single-cell transcriptomics showed altered immune cell proportions in AD patients, indicating systemic immunodysregulation. Integrating the three omics datasets identified 388 key genes involved in JAK-STAT, PI3K-Akt, and MAPK pathways. Experimental validation showed that combining candidate miRNAs significantly reduced AD marker expression and promoted neuronal progenitor cell marker expression, but had limited effect on mature neuronal markers (MAP2, NeuN). However, providing a suitable neuronal environment could induce neuronal differentiation, showing neuronal induction potential. These findings reveal the dual role of synaptic dysfunction and neuroinflammation in AD progression, offering new insights into AD's molecular network and proposing a treatment framework combining immunomodulation and neuroregeneration.}, } @article {pmid41004623, year = {2025}, author = {Mukesha, D and Sarter, M and Dubray, M and Durand, F and Boutillier, S and Pham-Van, LD and Halter, D and Kul, S and Blanc, F and Gürvit, H and Demiralp, T and Dubois, B and Gabelle, A and Marizzoni, M and Frisoni, GB and Pasquier, F and Sellal, F and Ivanoiu, A and Bier, JC and David, R and Démonet, JF and Magnin, E and Sacco, G and Firat, H}, title = {Targeted serum metabolomic profiling and machine learning approach in Alzheimer's disease using the Alzheimer's disease diagnostics clinical study (ADDIA) cohort.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {824-833}, pmid = {41004623}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/genetics ; *Machine Learning ; Male ; Female ; *Metabolomics/methods ; Aged ; Biomarkers/blood ; Cohort Studies ; Middle Aged ; Aged, 80 and over ; Apolipoproteins E/genetics ; }, abstract = {BackgroundMetabolic biomarkers can potentially be used for early diagnosis, prognostic risk stratification and/or early treatment and prevention of individuals at risk to develop Alzheimer's disease (AD).ObjectiveOur goal was to evaluate changes in metabolite concentration levels associated with AD to identify biomarkers that could support early and accurate diagnosis and therapeutic interventions by using targeted mass spectrometry and machine learning approaches.MethodsSerum samples collected from a total of 107 individuals, including 55 individuals diagnosed with AD and 52 healthy controls (HC) enrolled previously to ADDIA cohort were analyzed using the biocrates AbsoluteIDQ[®] p400 HR kit metabolite and lipid panel. Several machine learning models including Least Absolute Shrinkage and Selection Operator (LASSO), Partial Least Squares (PLS), Random Forest, and XGBoost were trained to classify AD and HC. Repeated cross-validation was used to ensure performance evaluation.ResultsThe LASSO and PLS models showed the strongest classification performance on the test set, achieving area under the ROC curve (AUC) values of 0.84 and 0.90, respectively. A refined model based on only the top 5 metabolites maintained strong performance, and the inclusion of Apolipoprotein E (APOE) genotype information notably improved classification accuracy, particularly by reducing false negatives in AD cases.ConclusionsThese results highlight important metabolic signatures that could help to reduce misdiagnosis and support the development of metabolomic panels to detect AD. The combination of multiple serum metabolic biomarkers and APOE genotyping can significantly improve classification accuracy and potentially assist in making non-invasive, cost-effective diagnostic approach.}, } @article {pmid41004106, year = {2025}, author = {Hwang, DJ and Cho, JY}, title = {Exercise as a Therapeutic Intervention for Alzheimer's Disease.}, journal = {Advances in neurobiology}, volume = {44}, number = {}, pages = {297-316}, pmid = {41004106}, issn = {2190-5215}, mesh = {Humans ; *Alzheimer Disease/therapy/prevention & control/physiopathology ; *Exercise Therapy/methods ; *Exercise/physiology ; Animals ; }, abstract = {Alzheimer's disease (AD) is a common form of dementia characterized by cognitive decline and abnormal accumulation of proximate neurotoxins in older adults. It accounts for up to 80% of all dementia cases. AD is not exclusively attributed to aging; rather, it involves complex and multifactorial brain changes that can lead to severe functional dependence and ultimately death. Although there has been progress in the development of novel treatments for AD, they are yet to yield disease-modifying effects. Early detection and therapeutic interventions are critical for preventing or delaying the onset of AD. We aimed to provide an overview of emerging evidence on physical exercise as a therapeutic strategy for the prevention and treatment of AD. Studies have demonstrated the potential of exercise in improving cognitive function, reducing the risk of AD, and slowing disease progression by promoting various neuroplastic changes. Therefore, regular exercise should be considered as a disease-modifying intervention for AD and included in comprehensive treatment protocols. Further studies are warranted to establish the optimal exercise regimen for individuals with AD; nonetheless, incorporating exercise into daily routines may contribute toward the prevention and management of AD.}, } @article {pmid41003796, year = {2025}, author = {Raza, A and Saleem, S and Imran, S and Rahman, S and Haroon, M and Razzaq, A and Hussain, A and Iqbal, J and Sathian, B}, title = {From metabolic dysregulation to neurodegenerative pathology: the role of hyperglycemia, oxidative stress, and blood-brain barrier breakdown in T2D-driven Alzheimer's disease.}, journal = {Metabolic brain disease}, volume = {40}, number = {7}, pages = {276}, pmid = {41003796}, issn = {1573-7365}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Oxidative Stress/physiology ; *Blood-Brain Barrier/metabolism/pathology ; *Diabetes Mellitus, Type 2/metabolism/pathology/complications ; Animals ; *Hyperglycemia/metabolism/pathology ; Insulin Resistance/physiology ; Brain/metabolism/pathology ; }, abstract = {Type 2 Diabetes (T2D) and Alzheimer's Disease (AD) share common risk factors that can be seen through T2D nearly doubling an individual's likelihood of developing AD. Some AD patients show signs of metabolic dysfunction as well. This review focuses on the potential mechanisms associated with these two diseases, like insulin resistance, inflammation, oxidative damage, mitochondrial injury, and cell death. One of the notable elements in this connection is the "brain insulin resistance," most frequently named as "type 3 diabetes," which impairs glucose metabolism and facilitates amyloid beta (Aβ) plaque synthesis while reducing the action of insulin-degrading enzyme (IDE). Moreover, the overactivity of glycogen synthase kinase-3 beta (GSK-3β) also triggers taurine protein pathology. Raised concentrations of glucose in blood can produce advanced glycation end products (AGEs), which further exacerbate neuroinflammation in tandem with the mitigation of neurotoxic Aβ oligomers. Inflammation and subsequent damage to mitochondria lead to the dissolution of synapses. Current vascular insults include the breakdown of the blood-brain barrier (BBB) and decreased brain perfusion, along with other contributory factors to conditions conducive to neurotoxicity. Recently, novel therapies are emerging, including GLP-1 agonists, intranasal insulin, and mitochondrial antioxidants, that show surprising results for treating both conditions, but on the contrary, bioavailability and the timing of interventions remain a big challenge in the management of these diseases. Eventually, further research should center on understanding the mechanisms of integration along with the development of molecular biology, neuroimaging, and outcome-driven treatment strategies. Comprehensive strategies that exist between T2D-AD for integration and preservation of brain and metabolic health are addressed in this review.}, } @article {pmid41003702, year = {2025}, author = {Salarinasab, S and Asgari Taei, A and Kaveh, N and Karima, S and Nikzamir, A and Dargahi, L}, title = {Regorafenib modulates glucose metabolism, insulin/GLP-1 signaling, and tau pathology in an STZ-induced model of Alzheimer's disease.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {41003702}, issn = {1432-1912}, support = {43006607//The authors declare that this study was funded by the Research Affairs of Shahid Beheshti University of Medical Sciences./ ; }, abstract = {PURPOSE: Alzheimer's disease (AD), often described as "type 3 diabetes" due to its metabolic and neuroendocrine features, is marked by impaired glucose metabolism and insulin signaling. This study aimed to investigate whether regorafenib, a multi-kinase inhibitor, could modulate glucose metabolism, insulin/glucagon-like peptide-1 (GLP-1) pathways, and tau pathology in a streptozotocin (STZ)-induced rat model of AD. METHODS: Male rats (n = 5-8/group) received intracerebroventricular STZ to induce AD-like pathology and were subsequently treated with regorafenib for two weeks. Cognitive function was assessed using the Y-maze and novel object recognition (NOR) tests. Glucose metabolism was evaluated via 18F-FDG micro-PET imaging and glucose tolerance tests. Serum and hippocampal markers of insulin, GLP-1, and tau phosphorylation were measured. RESULTS: Regorafenib-treated rats exhibited significant improvement in recognition memory in the NOR test, while enhancement in spatial working memory in the Y-maze did not reach statistical significance. Regorafenib improved glucose metabolism in both the brain and periphery, as demonstrated by imaging and tolerance testing. Treatment significantly increased serum insulin and GLP-1 levels, and reduced hippocampal hyperphosphorylated tau, although hippocampal gene expression of insulin and GLP-1 signaling pathways remained unchanged. CONCLUSION: Regorafenib may provide neuroprotective benefits in AD by improving glucose metabolism and reducing tau pathology. These findings suggest regorafenib as a potential novel therapeutic strategy for AD, though further research is needed to confirm its efficacy, assess long-term outcomes, and elucidate underlying mechanisms.}, } @article {pmid41003140, year = {2025}, author = {Alkhalifa, AE and Al Mokhlf, A and Ali, H and Al-Ghraiybah, NF and Syropoulou, V}, title = {Anti-Amyloid Monoclonal Antibodies for Alzheimer's Disease: Evidence, ARIA Risk, and Precision Patient Selection.}, journal = {Journal of personalized medicine}, volume = {15}, number = {9}, pages = {}, pmid = {41003140}, issn = {2075-4426}, abstract = {Alzheimer's disease (AD) is the most common cause of dementia, pathologically defined by extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Recent U.S. Food and Drug Administration (FDA) approvals of anti-amyloid monoclonal antibodies (mAbs) aducanumab, lecanemab, and donanemab represent the first disease-modifying therapies for early AD. These therapies have generated both optimism and controversy due to modest efficacy and safety concerns, particularly amyloid-related imaging abnormalities (ARIAs). This review synthesizes current evidence on the efficacy, safety, and biomarker-guided use of anti-Aβ mAbs in AD. Methods: We searched PubMed, Scopus, Web of Science, and Google Scholar to 31 July 2025 for studies on anti-amyloid mAbs in AD. Sources included peer-reviewed articles and regulatory reports. The extracted data covered study design, population, amyloid confirmation, dosing, outcomes, biomarkers, ARIA incidence, and management. Results: Anti-amyloid mAbs consistently demonstrated robust amyloid clearance and modest slowing of clinical decline in early symptomatic AD. Differences emerged across agents in efficacy signals, safety profiles, and regulatory outcomes. Lecanemab and donanemab showed more consistent cognitive benefits, while aducanumab yielded mixed findings, leading to its withdrawal. ARIAs were the most frequent adverse events, occurring more often in APOE ε4 carriers and typically during early treatment. Biomarker analyses also revealed favorable downstream effects, including reductions in phosphorylated tau and markers of astroglial injury, supporting engagement of disease biology. Conclusions: Anti-amyloid mAbs provide proof of concept for AD modification, with the greatest benefit in early disease stages and moderate tau burden. Optimal use requires biomarker confirmation of the amyloid, careful tau staging, and genetic risk assessment. While limitations remain, these therapies represent a pivotal step toward precision neurology and may serve as a foundation for multimodal strategies targeting tau, neuroinflammation, and vascular pathology.}, } @article {pmid41003116, year = {2025}, author = {Kalyvas, AC and Smyrni, N and Ioannidis, P and Grigoriadis, N and Afrantou, T}, title = {Bridging Epilepsy and Cognitive Impairment: Insights from EEG and Clinical Observations in a Retrospective Case Series.}, journal = {Journal of personalized medicine}, volume = {15}, number = {9}, pages = {}, pmid = {41003116}, issn = {2075-4426}, abstract = {Background: Epilepsy and cognitive impairment frequently coexist, yet their relationship remains complex and insufficiently understood. This study aims to explore the clinical and electrophysiological features of patients presenting with both conditions in order to identify patterns that may inform more accurate diagnosis and effective management within a personalized medicine framework. Methods: We retrospectively analyzed 14 patients with late-onset epilepsy and coexisting cognitive impairment, including mild cognitive impairment and Alzheimer's disease. Clinical history, cognitive assessments, neuroimaging, and electroencephalographic recordings were reviewed. EEG abnormalities, seizure types, and treatment responses were systematically documented. Results: Patients were categorized into two groups: (1) those with established Alzheimer's disease who later developed epilepsy and (2) those in whom epilepsy preceded cognitive impairment. Temporal lobe involvement was a key feature, with EEG abnormalities frequently localizing to the frontal-temporal electrodes and manifesting as background slowing, focal multiform slow waves, and epileptiform discharges. Levetiracetam was the most commonly used antiseizure medication, and it was effective across both groups. Conclusions: This case series highlights the value of EEG in characterizing patients with subclinical and overt epileptic activity and cognitive impairment comorbidity. The inclusion of a substantial number of cases with documented EEG abnormalities provides valuable insight into the interplay between epilepsy and neurodegenerative diseases. By integrating neurophysiological data with clinical and cognitive trajectories, this work aligns with the principles of precision medicine, facilitating a more comprehensive evaluation and tailored management approach. Further longitudinal studies are required to validate prognostic markers and guide optimal therapeutic strategies.}, } @article {pmid41002746, year = {2025}, author = {Iliuta, FP and Manea, M and Mares, AM and Varlam, CI and Ciobanu, CA and Ciobanu, AM and Lacau, RM and Manea, MC}, title = {Unraveling Dual Cognitive Disorders: A Case Report and Literature Review on Marchiafava-Bignami Disease and Possible Alzheimer's Disease.}, journal = {Diseases (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {41002746}, issn = {2079-9721}, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, particularly in those aged 65 and older. Dementia can also occur under age 45, known as young-onset dementia (YOD), although this is rarer. Marchiafava-Bignami disease (MBD) is a rare disorder characterized by demyelination and necrosis of the corpus callosum, primarily affecting individuals with chronic alcohol use. We present the case of a 49-year-old woman admitted for psychiatric and neurological evaluation due to a multidomain cognitive disorder with a sudden onset approximately four years prior, which progressed rapidly, resulting in complete dependence on others for daily activities. Her medical history included moderate depression, chronic alcohol consumption, and professional exhaustion. Psychological assessments revealed severe neurocognitive impairment. MRI scans highlighted significant bilateral parietal atrophy, hippocampal atrophy, and demyelinating lesions in the corpus callosum, consistent with MBD. Despite initial inconsistencies in biomarkers, later tests showed elevated tau protein, phosphorylated tau, and amyloid-beta, supporting an AD diagnosis. Clinical presentation, combined with neuroimaging findings and chronic alcohol consumption history, led to a diagnosis of AD with young onset and chronic MBD. This case illustrates the complexities involved in diagnosing overlapping neurodegenerative disorders. The coexistence of MBD and AD complicates the treatment plan, requiring a multifaceted approach addressing both neurodegenerative and nutritional aspects.}, } @article {pmid41002740, year = {2025}, author = {Bardhan, M and Anand, A and Javed, A and Chilo, MA and Khan, N and Garg, T and Surana, A and Huang, H and Samim, MM and Suresh, V and Khare, A and Menon, B and Kundu, T}, title = {Polymorphism of Melanocortin Receptor Genes-Association with Inflammatory Traits and Diseases.}, journal = {Diseases (Basel, Switzerland)}, volume = {13}, number = {9}, pages = {}, pmid = {41002740}, issn = {2079-9721}, abstract = {Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, α-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases.}, } @article {pmid41002439, year = {2025}, author = {Lanza, M and Basilotta, R and Caccamo, A and Casili, G and Repici, A and Oddo, S and Esposito, E}, title = {PF-04691502, a PI3K/mTOR Dual Inhibitor, Ameliorates AD-like Pathology in a Mouse Model of AD.}, journal = {Cells}, volume = {14}, number = {18}, pages = {}, pmid = {41002439}, issn = {2073-4409}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; Disease Models, Animal ; Mice ; Female ; Male ; Mice, Transgenic ; *Phosphoinositide-3 Kinase Inhibitors/pharmacology/therapeutic use ; Phosphatidylinositol 3-Kinases/metabolism ; Amyloid beta-Peptides/metabolism ; *MTOR Inhibitors/pharmacology/therapeutic use ; *Pyrimidines/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Mice, Inbred C57BL ; Brain/pathology/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that significantly impacts the lives of patients and their families. The pathological features of AD include the accumulation of amyloid-β (Aβ) and Tau, which disrupt neuronal function and communication, ultimately leading to neuronal loss and brain atrophy. Efforts to understand the molecular mechanisms underlying these pathological changes have led to advancements in diagnostic techniques and potential therapeutic interventions. However, the complexity of AD necessitates further research to develop more effective treatments and, ideally, preventive measures. Extensive research suggests that diminishing mTOR signaling increases lifespan and health span across various species. Increased PI3K/mTOR signaling has been linked to the progression of AD pathology, leading to neuronal degeneration and impairments in cognitive function. In this study, we explored the therapeutic potential of PF-04691502, a dual PI3K/mTOR inhibitor, in Alzheimer's disease (AD)-like pathology using male and female B6.Cg-Tg(APPswe, PSEN1dE9)85Dbo/Mmjax mice (APP/PS1), a well-established transgenic model of AD. Eighteen-month-old APP/PS1 and wild-type mice received oral administration of PF-04691502 at a dose of 1 mg/kg for 12 weeks. Following the treatment period, spatial learning and memory were evaluated using the Morris water maze. Subsequently, the mice brains were collected for neuropathological and biochemical assessments. Our findings showed that PF-04691502 enhanced cognitive performance in APP/PS1 mice and significantly reduced insoluble Aβ accumulation in the brain. Mechanistically, these effects were associated with enhanced autophagy induction. Treatment with PF-04691502 increased the LC3-II/LC3-I ratio, upregulated Beclin-1, and elevated LAMP-2 levels, indicative of stimulated autophagosome formation and lysosomal activity. Overall, these preclinical results suggest that PF-04691502 holds promise as a potential therapeutic agent for AD and other aging-related neurodegenerative diseases involving mTOR pathway dysregulation.}, } @article {pmid41002390, year = {2025}, author = {Katsipis, G and Tzekaki, EE and Iasonidou, S and Pantazaki, AA}, title = {The Diagnostic and Therapeutic Potential of Oligonucleotide Aptamers in Alzheimer's Disease.}, journal = {Cells}, volume = {14}, number = {18}, pages = {}, pmid = {41002390}, issn = {2073-4409}, mesh = {*Alzheimer Disease/diagnosis/drug therapy/therapy ; Humans ; *Aptamers, Nucleotide/therapeutic use ; Biomarkers/metabolism ; MicroRNAs/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; Biosensing Techniques ; }, abstract = {Alzheimer's disease (AD) is the neurodegenerative condition with the outmost future challenges, with timely diagnosis and treatment being the most urgent. Discovery of more and more biomarkers is widely attempted; however, current diagnostic methods often lack sensitivity, specificity, and accessibility. Nucleotide aptamers-short, highly specific oligonucleotide or ligands-are now recognized as highly promising molecular agents for both measuring and targeting key AD biomarkers, with the most notorious being amyloid-beta (Aβ), tau protein, and disease-associated microRNAs (miRNAs). This review provides a comprehensive analysis of nucleotide aptamers related to AD, detailing their mechanisms of selection, recent advances in biosensing applications, and therapeutic potential. Aptamers, targeting the most significant biomarkers of AD, are mainly discussed, as well as ones interacting with novel, promising biomarkers, with a special aim on miRNAs. Additionally, aptamers are compared with conventional antibody-based approaches, highlighting their advantages in terms of stability, cost-effectiveness, and ease of modification. By elucidating the role of aptamers in AD diagnosis and treatment, this review underscores their promise as next-generation tools for precision medicine and neurodegenerative disease management.}, } @article {pmid41001643, year = {2025}, author = {Zhang, Z and Lv, M and Xu, J and Liu, Y and Qin, J and Fan, Z and Du, J}, title = {A Metal-Peptide Framework as a Nanozyme for the Attenuation of Amyloid‑β Aggregation and Reactive Oxygen Species.}, journal = {JACS Au}, volume = {5}, number = {9}, pages = {4346-4360}, pmid = {41001643}, issn = {2691-3704}, abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by abnormal performance in memory, cognition, and language, and it imposes a heavy economic burden worldwide. Amyloidosis and oxidative stress are highly associated with AD progression, yet limited clinical drugs are available at present. Nanozymes exhibit diverse enzyme-mimetic activities and have attracted widespread attention as a promising alternative candidate for scavenging reactive oxygen species to maintain the oxidation-antioxidation balance in cells. Neurotoxic amyloid-β (Aβ) aggregation is also a critical event in AD pathology. The development of dual-targeting nanomaterials with antiamyloidosis ability and enzyme-mimicking activity is expected to be a promising strategy for the treatment of amyloidosis and reactive oxygen species-mediated AD progression. Here, bimetallic-peptide framework nanozymes (CuZn-PEP NZs) with amyloid-β (Aβ) attenuating ability, multiple enzyme-mimicking properties, and broad-spectrum reactive oxygen species scavenging capacity were endowed to inhibit Aβ fibrillization, disaggregate Aβ fibrils, and scavenge Aβ fibril-induced reactive oxygen species. An obvious inhibitory effect on Aβ fibrillization and a disaggregation effect on Aβ fibrils were observed after treatment with CuZn-PEP NZs. Meanwhile, the cytotoxicity of Aβ fibrils toward PC12 cells was significantly reduced by CuZn-PEP NZs. Meanwhile, CuZn-PEP NZs with multiple redox pairs exhibit superoxide dismutase, catalase, and glutathione peroxidase-mimicking enzyme properties simultaneously, which further display cytoprotective effects against Aβ fibril-induced reactive oxygen species and mitochondrial damage. Besides, cellular studies verified that CuZn-PEP NZs possess excellent biocompatibility and blood-brain barrier penetration capacity. Overall, these bimetallic-peptide framework nanozymes represent a promising perspective for attenuation of amyloid-β aggregation and reactive oxygen species simultaneously, which highlights the potential of nanozymes for the treatment of amyloidosis and reactive oxygen species-mediated AD progression.}, } @article {pmid41001460, year = {2025}, author = {Qi, YS and Miller, LR and D'Ascenzo, MD and Berndt, JD and Whitney, GA and Duffy, F and Danziger, SA and Peskind, E and Li, G and Masters, CL and Fowler, C and , and Lipshutz, R and Aitchison, JD and Smith, JJ}, title = {An Indicator Cell Assay-based Multivariate Blood Test for Early Detection of Alzheimer's Disease.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41001460}, support = {R44 CA203455/CA/NCI NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R43 CA203455/CA/NCI NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P50 NS062684/NS/NINDS NIH HHS/United States ; R43 AG056215/AG/NIA NIH HHS/United States ; R44 AG051282/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; }, abstract = {The indicator cell assay platform (iCAP) is a novel next-generation approach for blood-based diagnostics that uses standardized cells as biosensors to amplify weak disease signals in blood. We developed an Alzheimer's disease iCAP (AD-iCAP) for early detection at the mild cognitive impairment/mild dementia stages. To develop the assay, patient plasma is incubated with standardized neurons, which transduce complex circulating signals into gene-expression readouts used to train multivariate disease classifiers via machine learning. We applied systems biology analyses (e.g., GSEA, PCA, correlation/network analyses) to optimize analytical and computational parameters, and then evaluated a locked model in a study with retrospectively collected samples. Performance was AUC 0.64 (95% CI 0.51-0.78, n=82) on an independent external-validation set and AUC 0.77 (95% CI 0.57-0.96, n=23) on a blind set, supporting prospective confirmation in a larger cohort. To overcome pre-analytical noise and reduce bias in feature-selection, modeling was done using a fixed panel of 84 candidate genes chosen a priori from an external AD-iCAP dataset generated with 5XFAD mouse plasma. Despite using no AD-specific prior knowledge in this approach, the assay readout was enriched for Alzheimer's-relevant pathways, including cholesterol biosynthesis, synaptic structure/neurotransmission and PIK3/AKT activation. Because the assay senses a multivalent cellular response, which is orthogonal to circulating amyloid or tau measurements, AD-iCAP may complement existing blood tests, and its multivariate readout offers a path to precision-medicine applications such as patient stratification for treatment response.}, } @article {pmid41001450, year = {2025}, author = {Digma, LA and Young, CB and Winer, JR and Cody, KA and Younes, K and Sheng, J and Insel, PS and Rissman, RA and Sperling, R and Mormino, EC}, title = {Continuum of Core 1 Biomarkers in Preclinical Alzheimer's Disease.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41001450}, support = {K01 AG078443/AG/NIA NIH HHS/United States ; K99 AG071837/AG/NIA NIH HHS/United States ; U24 AG074855/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: Biological Staging for Alzheimer's disease (AD) in clinically unimpaired (CU) individuals is critical for early detection efforts. In this study, we evaluated whether Core 1 biomarkers (plasma ptau-217 and amyloid-PET) within Biological Stage A, the earliest biological stage of AD, predicts progression of downstream biomarkers and cognition. METHODS: We used baseline plasma ptau-217 and amyloid-PET, and longitudinal tau-PET, atrophy, and cognition data from the recently completed Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study. PET data were used to identify participants within AD Biological Stage A (amyloid-PET positive and medial temporal tau-PET negative). Within these Stage A participants, linear mixed effects models were used to examine associations between continuous baseline levels of plasma p-tau217 and amyloid-PET burden with longitudinal regional tau-PET, atrophy, and cognition. We additionally evaluated whether continuous p-tau217 and amyloid-PET burden within this group was associated with higher risk of progression to Biological Stage B+ (tau-PET positive in the medial temporal lobe). In our statistical models, we included covariates for age, sex, and APOE4 carriage. RESULTS: Of 335 A4 participants with complete biomarker data, 222 were identified as being in Biological Stage A. Among Biological Stage A CU, continuous baseline plasma p-tau217 and amyloid-PET burden were independently associated with faster tau-PET accumulation and atrophy in AD-relevant regions (mean follow-up time for both tau-PET and MRI: 4.2 years), as well as faster cognitive decline (mean follow-up time for PACC: 5.7 years) (all p<0.05). Plasma p-tau217 and amyloid-PET burden were independently associated with higher risk of progression to Biological Stage B+. DISCUSSION: In CU individuals, early changing AD biomarkers during the initial stage of AD (Biological Stage A) provide prognostic information of downstream markers of disease. Evaluation of the utility of these continuous measures in a real-world setting is warranted. CLINICAL TRIAL INFORMATION: The A4 study was submitted for registration to clinicaltrials.gov on December 6th, 2023. The study is registered with ID NCT02008357. Screening and data collection for the study began in April 2014.}, } @article {pmid41001445, year = {2025}, author = {Orlichenko, A and Ding, S and Johns, E and Gu, Z and Tian, X and Li, X and Zhao, Y}, title = {Intervention on Modifiable Lifestyle and Physiological Factors via Variational Autoencoder Reveals Changes in Functional Connectivity-Mediated Risk for Alzheimer's Disease.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41001445}, support = {R01 AG068191/AG/NIA NIH HHS/United States ; R01 EB034720/EB/NIBIB NIH HHS/United States ; RF1 AG081413/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) remains without effective treatment, largely due to the fact that clinical symptoms emerge only after decades of silent pathological progression. It is urgently needed to identify modifiable risk factors in earlier life stages, when preventive interventions may still be effective. Functional connectivity (FC) has emerged as a promising neuromarker for both neurodegenerative processes and behavioral traits, making it a potential bridge between early-life health profiles and late-life AD risk. In this work, we introduce a novel integrative framework that models how early-life lifestyle and physiological factors influence AD risk through their impact on brain FC. Our approach combines a modified variational autoencoder (VAE) that simulates FC changes under interventions with a predictive model that estimates AD risk based on FC patterns. This design enables training of the generative and predictive components under different datasets and populations, with FC acting as the bridge between early-life modifiable factors and late-life disease risk. Applying our framework to data from the Human Connectome Project (HCP), UK Biobank (UKB), and Alzheimer's Disease Neuroimaging Initiative (ADNI), we validate its ability to capture known risk factors, such as age and polygenic risk score, on FC-mediated AD risk. We also identify earlier-life modifiable factors including tobacco use, sleep quality, physical activity and weight/BMI that significantly influence AD risk. Notably, we observe a U-shaped relationship between blood pressure and AD risk, and highlight the brain visual and somatomotor networks as key mediators of risk through FC. Our approach provides a powerful tool for investigating the effect pathways linking early-life interventions to neurodegenerative outcomes, with broad applicability to other brain-related disorders.}, } @article {pmid41001289, year = {2025}, author = {Uchida, K and Maruta, J and Kurozumi, H and Inoue, K}, title = {Motivation Through Treatment: How Lecanemab Initiation Facilitated Alcohol Cessation and Cognitive Stability in a Patient With Early Alzheimer's Disease.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e90907}, pmid = {41001289}, issn = {2168-8184}, abstract = {Excessive alcohol use can complicate the management of individuals in the early stages of cognitive decline, as memory impairment may limit the awareness of harmful habits and reduce motivation for behavioral change. Anti-amyloid therapies such as lecanemab have recently become available for early Alzheimer's disease (AD), but their use in individuals with a history of heavy alcohol consumption remains uncommon. Furthermore, the combined impact of abstinence and disease-modifying therapy on clinical outcomes is not well understood. We report the case of a woman in her early 80s initially diagnosed with mild cognitive impairment (MCI), who later progressed to mild AD. Despite repeated counseling, she had persistent difficulties reducing alcohol intake. As her cognitive symptoms worsened, psychiatric intervention and inpatient care were needed to achieve alcohol cessation. With structured support and lifestyle changes, including the involvement of her daughter, her daily routine stabilized. Following the initiation of lecanemab therapy, she maintained abstinence, experienced no significant treatment-related adverse effects, and showed no imaging abnormalities on follow-up MRI. Her Mini-Mental State Examination (MMSE) scores improved after the combined lifestyle and pharmacologic interventions. This case suggests that lifestyle stabilization and lecanemab therapy can work synergistically in individuals with early AD and prior excessive alcohol use. The initiation of regular infusions may have provided both therapeutic and motivational support for maintaining abstinence and daily structure.}, } @article {pmid41001105, year = {2025}, author = {Ali-Jerman, H and Somani, S and Al-Quraishi, Z and Maeyouf, K and Merkler, M and Gerasimou, S and Tate, RJ and Sakata, S and Mullin, M and Irving, C and Anderson, GJ and Bame, JR and MacKenzie, G and McNeill, G and Dufès, C}, title = {Intravenous Delivery of Angiopep-Functionalized Polypropylenimine Dendriplex Enhances Gene Expression in the Brain.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {11569-11591}, pmid = {41001105}, issn = {1178-2013}, mesh = {Animals ; *Dendrimers/chemistry/administration & dosage ; *Brain/metabolism ; Blood-Brain Barrier/metabolism ; Mice, Inbred BALB C ; Mice ; *Gene Transfer Techniques ; Genetic Therapy/methods ; DNA/administration & dosage/chemistry/genetics ; Administration, Intravenous ; Endothelial Cells/metabolism ; Cell Line ; Particle Size ; Gene Expression ; Endocytosis ; Peptides ; Polypropylenes ; }, abstract = {BACKGROUND: The application of gene therapy for treating neurological disorders, including brain cancer, Parkinson's, and Alzheimer's disease, is significantly limited by the current shortage of gene vectors that can effectively cross the blood-brain barrier (BBB) following intravenous administration. Recent studies demonstrated that angiopep-2 can enhance the delivery of therapeutic agents across the BBB through receptor-mediated endocytosis. This study therefore explores the potential of angiopep-2-conjugated generation-3 diaminobutyric polypropylenimine (DAB) dendrimer (DAB-Ang) as nanocarrier for brain-targeted gene delivery. METHODS: Angiopep-2 was conjugated to DAB dendrimer and evaluated in terms of DNA condensation ability, particle size, surface charge, and structural morphology. The cellular uptake was studied in vitro using bEnd.3 brain endothelial cells, and the in vivo efficacy of DAB-Ang dendriplexes for brain gene expression was evaluated in BALB/c mice following intravenous administration. RESULTS: DAB-Ang dendrimer successfully condensed up to 90% of DNA, forming stable spherical dendriplexes with sizes under 240 nm and positive zeta potentials. In vitro, DAB-Ang dendriplex achieved a 9-fold higher cellular uptake in brain endothelial cells in comparison to the unmodified complex, predominantly through clathrin-mediated endocytosis and macropinocytosis. In vivo studies showed significantly increased gene expression in the brain following DAB-Ang dendriplex treatment, achieving 1.8-fold and 3.2-fold higher expression in comparison to DAB dendriplex and naked DNA, respectively, with minimal off-target effects. CONCLUSION: Angiopep-2-conjugated DAB dendrimer demonstrated high specificity and efficacy in facilitating gene delivery to the brain, offering a promising platform for therapeutic applications in neurological disorders.}, } @article {pmid41000798, year = {2025}, author = {Stanton, AE and Pinals, RL and Choi, A and Truong, N and Kang, E and Jiang, A and Lozano Cruz, CF and Hawkins, S and Sarcar, R and Volkova, A and King, O and Agbas, E and Nakano, M and Chiu, CC and Bubnys, A and Wright, S and Staab, C and Bikdash, R and Forden, E and Langer, R and Tsai, LH}, title = {Vascular-Perfusable Human 3D Brain-on-Chip.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.09.18.676925}, pmid = {41000798}, issn = {2692-8205}, abstract = {UNLABELLED: Development and delivery of treatments for neurological diseases are limited by the tight and selective human blood-brain barrier (BBB). Although animal models have been important research and preclinical tools, the rodent BBB exhibits species differences and fails to capture the complexity of human genetics. Microphysiological systems incorporating human-derived cells hold great potential for modeling disease and therapeutic development, with advantages in screening throughput, real-time monitoring, and tunable genetic backgrounds when combined with induced pluripotent stem cell (iPSC) technology. Existing 3D BBB-on-chip systems have incorporated iPSC-derived endothelial cells but not the other major brain cell types from iPSCs, each of which contributes to brain physiology and disease. Here we developed a 3D Brain-Chip system incorporating endothelial cells, pericytes, astrocytes, neurons, microglia, and oligodendroglia from iPSCs. To enable this multicellular 3D co-culture in-chip, we designed a GelChip microfluidic platform using a 3D printing-based approach and dextran-based engineered hydrogel. Leveraging this platform, we co-cultured and characterized iPSC-derived brain-on-chips and modeled the brain microvasculature of APOE4 , the strongest known genetic risk factor for sporadic Alzheimer's disease. These 3D brain-on-chips provide a versatile system to assess BBB vascular morphology and function, investigate downstream neurological effects in disease, and screen therapeutics to optimize delivery to the brain. SIGNIFICANCE STATEMENT: The blood-brain barrier (BBB) is both a contributing factor to neurological disease and a major obstacle to its treatment, yet human-relevant models remain limited. Most existing brain-on-chip systems incorporate only subsets of BBB cell types and cannot capture the full cellular complexity of the human neurovascular unit. Here, we establish a vascular-perfusable 3D Brain-Chip using human induced pluripotent stem cell-derived brain cells including endothelial cells, pericytes, astrocytes, neurons, microglia, and oligodendroglia. This system enables systematic analysis of human genetic risk factors, such as APOE4 in Alzheimer's disease, and provides a powerful platform to investigate BBB function and dysfunction and accelerate the development of more effective neurological therapies.}, } @article {pmid41000621, year = {2025}, author = {Shaaban, D and Seerley, A and Crew, L and Kaylor, C and McElroy, S and Guter, E and Pounder, J and Panter, AG}, title = {The Impact of Formic Acid Treatment on Brain Tissues for Prion Inactivation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41000621}, issn = {2692-8205}, support = {P20 GM152335/GM/NIGMS NIH HHS/United States ; }, abstract = {There are significant risks in clinical, diagnostic, and research settings to those who investigate prion diseases, due to the difficult nature of inactivating prion proteins with standard decontamination methods. Formic acid treatment has been shown to be effective for decontaminating infectious prions and commonly used in biosafety practice to prevent occupational exposure. However, the impact of formic acid protocols on the morphology of tissue samples has not been adequately documented. The goal of this study is to examine morphologic effects of formic acid treatment on central nervous system tissue, using mouse model brain hemisphere tissues that exhibit varying degrees of neurodegeneration as a model. This study included normal, non-diseased wild-type tissues and a 5xFAD model, which recapitulates aspects of Alzheimer's Disease (AD). A model exhibiting Chronic Wasting Disease (CWD), a prion disease of deer and elk, was also used to analyze the effects of formic acid on tissues with spongiform changes. Tissues from both formic acid and untreated control treatment groups were embedded in paraffin, sectioned, stained, and imaged microscopically. Anatomical regions were analyzed and evaluated quantitatively to determine the width, area, and structural integrity of the tissue between treatment groups. Our findings demonstrated that while formic acid has been previously reported to effectively inactivate prions, it compromised the morphology of mouse brain tissues. Furthermore, the effects of formic acid were not distributed equally between regions of the brain. Age did not play a role in the morphologic changes seen in the formic acid treatment group. Interestingly, the presence of neurodegeneration in the tissues did not appear to exacerbate the effects of morphological changes post-formic acid treatment. These results emphasize the need to explore alternative prion inactivation methods that ensure the safety and reliability of handling prion-infected tissues without compromising the integrity of tissues.}, } @article {pmid41000001, year = {2025}, author = {Abdel-Aal, RA and Hareedy, MS and Badary, DM and Abdelnabi, S and Hussein, AMR}, title = {Neuroprotective Effects of Liraglutide and/or Rivastigmine Combination on the Rat Hippocampus.}, journal = {Drug development research}, volume = {86}, number = {7}, pages = {e70160}, doi = {10.1002/ddr.70160}, pmid = {41000001}, issn = {1098-2299}, support = {//The authors gratefully thank the Assiut Medical School Grants Office for the financial support, grant code 2022-12-20-001./ ; }, mesh = {Animals ; *Rivastigmine/pharmacology/administration & dosage ; *Neuroprotective Agents/pharmacology/administration & dosage/therapeutic use ; Male ; *Liraglutide/pharmacology/administration & dosage/therapeutic use ; *Hippocampus/drug effects/metabolism/pathology ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Rats ; Drug Therapy, Combination ; Aluminum Chloride ; tau Proteins/metabolism ; Acetylcholinesterase/metabolism ; Aspartic Acid Endopeptidases/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Disease Models, Animal ; Sequestosome-1 Protein/metabolism ; Rats, Wistar ; Aluminum Compounds ; }, abstract = {This study evaluated the neuroprotective potential of a combination therapy using liraglutide (LIRA), an antidiabetic agent, and rivastigmine (RIVA), a standard treatment for Alzheimer's disease (AD), in a rat model of aluminum chloride (AlCl3)-induced AD. Male rats were divided into five groups: control, AD (AlCl3,75 mg/kg for 60 days), RIVA-treated (1 mg/kg daily for 6 weeks), LIRA-treated (300 µg/kg daily for 6 weeks), and combination-treated (LIRA + RIVA). Cognitive function was assessed behaviorally, and hippocampal biomarkers related to AD-such as microtubule-associated protein Tau (MAPt), Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1), Sequestosome 1 (SQSTM1/p62), and acetylcholinesterase (AChE) activity-were evaluated. Histopathological changes, immunohistochemistry, and transmission electron microscopy were also assessed. The levels of MAPt, BACE1, SQSTM1/p62, and AChE in the LIRA + RIVA group were 11.32 ± 0.467 ng/mL, 1069 ± 80.1 pg/mL, 408.7 ± 19.41 pg/mL, and 0.805 ± 0.342 µmol of acetylthiocholine iodide hydrolyzed/min/g of tissue, respectively. These levels were significant (p < 0.01) when compared with the AlCl3 group. Histological findings supported these biochemical data, indicating enhanced neuroprotection. LIRA may have a potential neuroprotective effect due to the rise in AChE, BACE1, (SQSTM1/p62) amyloid beta (Aβ), and caspase-3 levels induced by AlCl3. Co-administration of LIRA and RIVA provided superior neuroprotective effects compared with RIVA alone, suggesting a promising therapeutic strategy for preserving cognitive function in AD.}, } @article {pmid40999308, year = {2025}, author = {Van Doeselaer, L and Colman, K and Crosiers, D and Dijkstra, F}, title = {Effect of patient education interventions on non-motor symptoms and disease outcomes in parkinson's disease: a systematic review.}, journal = {Acta neurologica Belgica}, volume = {125}, number = {5}, pages = {1195-1208}, pmid = {40999308}, issn = {2240-2993}, mesh = {Humans ; *Parkinson Disease/psychology/therapy/complications ; *Patient Education as Topic/methods ; Quality of Life/psychology ; Treatment Outcome ; }, abstract = {Parkinson's disease is the second most common neurodegenerative disease, characterized by both motor symptoms (MS) and non-motor symptoms (NMS). While MS have traditionally been the primary focus of treatment and research, NMS significantly contribute to disease burden. However, knowledge regarding NMS in Parkinson's patients seems particularly lacking. Educational interventions have previously shown a positive effect on health outcomes in chronic illnesses such as Alzheimer's disease and diabetes, warranting investigation into their impact on NMS in Parkinson's disease. We conducted a systematic review to evaluate whether education interventions on non-motor symptoms (NMS) in Parkinson's disease (PD) patients contribute to better disease outcomes. Education interventions showed significant effects on various patient-reported and physician-reported outcomes, including quality of life, motor symptoms, depression, fatigue, adherence to treatment, acceptance of diagnosis, satisfaction with care, psychosocial adjustment, and independence in activities of daily living. Some effects were temporary, implying the need for booster sessions in future education interventions. There was limited focus on the direct impact of education interventions on NMS other than depression and anxiety. No studies directly compared different education interventions, preventing conclusions on which type of intervention leads to the best outcome. In conclusion, education interventions on NMS in PD have significant effects on disease outcomes. Future research should determine the optimal timing for booster sessions and further investigate their impact on NMS beyond depression and anxiety. Direct comparisons between different education interventions are needed to identify the most effective approach.}, } @article {pmid40998043, year = {2025}, author = {Cheng, W and Ma, Y and Gao, F and Shi, Z and Zuo, D and Di, C and Jin, X and Chen, W and Ye, F and Li, Q}, title = {Effects of cranial X-ray irradiation in Presymptomatic 3 × Tg-AD mice.}, journal = {Experimental neurology}, volume = {395}, number = {}, pages = {115482}, doi = {10.1016/j.expneurol.2025.115482}, pmid = {40998043}, issn = {1090-2430}, abstract = {BACKGROUND: Recently, several animal studies have demonstrated the therapeutic potential of low-dose radiation therapy (LDRT) for Alzheimer's disease (AD), especially in decreasing amyloid-beta (Aβ) plaques. However, clinical concerns regarding the duration of efficacy and long-term safety of this treatment remain understudied. Additionally, LDRT has been shown to alleviate various neurological disorders. We hypothesize that the therapeutic mechanisms of LDRT in AD may extend beyond targeting Aβ and tau alone. In this study, we administered whole-brain X-ray irradiation (10 Gy in 5 fractions) to presymptomatic AD mice to re-examine its mechanism of action, duration of efficacy, and long-term safety profile. RESULTS: Two months after irradiation, the autonomous activity of 3 × Tg-AD mice was significantly enhanced, with specific improvements in the spatial learning and memory in females. Western blotting revealed reduced tau phosphorylation at Ser262 site in the hippocampus of females. SnRNA-seq demonstrated restored neuronal network in females. However, these therapeutic effects appeared exhibited transient characteristics. By ten months post-irradiation, no significant behavioral and AD-related pathological changes were detected across groups, except for the elevated Aβ1-42 in the hippocampus of females. CONCLUSIONS: In conclusion, the effects of early X-ray intervention on 3 × Tg-AD mice were sex-specific and time-dependent. The short-term improvement observed in female mice may be attributed to attenuated tau hyperphosphorylation and restored neuronal networks. Longitudinal observation over ten consecutive months post-irradiation showed no evidence of severe adverse effects.}, } @article {pmid40997839, year = {2025}, author = {Fox, NC and Belder, C and Ballard, C and Kales, HC and Mummery, C and Caramelli, P and Ciccarelli, O and Frederiksen, KS and Gomez-Isla, T and Ismail, Z and Paquet, C and Petersen, RC and Perneczky, R and Robinson, L and Sayin, O and Frisoni, GB}, title = {Treatment for Alzheimer's disease.}, journal = {Lancet (London, England)}, volume = {406}, number = {10510}, pages = {1408-1423}, doi = {10.1016/S0140-6736(25)01329-7}, pmid = {40997839}, issn = {1474-547X}, mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy ; *Antibodies, Monoclonal/therapeutic use ; Quality of Life ; Amyloid beta-Peptides/antagonists & inhibitors/immunology ; Antibodies, Monoclonal, Humanized/therapeutic use ; }, abstract = {Over the last three decades, the evidence on how to best treat the cognitive and non-cognitive symptoms of patients with Alzheimer's disease has increased. Although these pharmacological and non-pharmacological strategies have significantly improved health outcomes for patients with Alzheimer's disease, many lack stringent evidence of efficacy. In this second paper of the Series, we provide practical and realistic advice on how to prioritise pharmacological and non-pharmacological strategies to ameliorate cognitive impairment and behavioural and psychological symptoms of dementia. In this clinical environment, dementia specialists are faced with the challenge of holistically integrating the much anticipated and, in some respects, controversial anti-β amyloid monoclonal antibodies. Here, we present the current approval scenario of monoclonal antibodies, our view on how they might further contribute to improve patients' quality of life, and how they could be seamlessly integrated with existing best care options.}, } @article {pmid40997226, year = {2025}, author = {Teipel, S and Akmatov, M and Michalowsky, B and Riedel-Heller, S and Junghanss, C and Holstiege, J and Bohlken, J}, title = {Inverse association of cancer with diagnoses of dementia in a large health claims case-control study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {98-106}, doi = {10.1177/13872877251374675}, pmid = {40997226}, issn = {1875-8908}, mesh = {Humans ; *Dementia/epidemiology/diagnosis ; Male ; Female ; Case-Control Studies ; Aged ; *Neoplasms/epidemiology/diagnosis ; Aged, 80 and over ; Prevalence ; Middle Aged ; Risk Factors ; }, abstract = {BackgroundPrevious studies reported an inverse association of cancer with dementia risk.ObjectiveTo study associations of cancer diagnoses with risk of a dementia diagnosis in a large case-control study.MethodsWe included patients with a dementia diagnosis and controls matched 1:2 for age, sex, region, and earliest year of outpatient treatment in a case-control study from health insurance claims of outpatient consultations. Exposure included seventeen cancer categories. We compared the annual prevalence trajectories of cancer categories between dementia cases and controls over a period of 10 years before the index date. We report unadjusted odds ratios (ORs) and ORs adjusted for established dementia risk factors.ResultsWe included 1,686,759 patients with incident dementia and 3,373,518 matched controls. We identified four types of associations: Cancers with equal or lower prevalence in controls at year -10 and higher prevalence in controls after year 6 to 4 before the index date; with higher prevalence in controls at all time points; with a lower prevalence in controls up to three years before the index date and higher prevalence after that; and with equal prevalence in cases and controls until year -9 and a steep increase in controls after that. When using adjusted ORs the overall pattern of an inverse association of cancer with dementia was maintained.ConclusionsOur data suggest that a mixture of causes contributes to the inverse association of cancer and dementia diagnoses, including selective survival, underdiagnosis of dementia after cancer and of cancer in dementia, but also shared biological factors.}, } @article {pmid40997028, year = {2025}, author = {Ahmad, S and Siddiqua, A and Abbas, E and Wasim, M and Zia, SR and Khan, A and Siddiqi, HS and Arain, FM and Tabassum, S and Khaliq, S and Samad, N}, title = {Gender-Specific Neuroprotective Effects of Carum copticum and Thymol: Restoring Cholinergic Function and Cognition in an Aluminum-Induced Rat Model of Alzheimer's Disease.}, journal = {Chemistry & biodiversity}, volume = {22}, number = {12}, pages = {e01374}, doi = {10.1002/cbdv.202501374}, pmid = {40997028}, issn = {1612-1880}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; Male ; *Neuroprotective Agents/pharmacology/chemistry/isolation & purification/therapeutic use ; *Thymol/pharmacology/chemistry/isolation & purification/therapeutic use ; Rats ; Disease Models, Animal ; Female ; Acetylcholinesterase/metabolism ; Aluminum Chloride ; *Cognition/drug effects ; Molecular Docking Simulation ; Acetylcholine/metabolism ; Rats, Wistar ; Aluminum ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder causing memory loss. While treatments like donepezil and memantine offer limited symptom relief, natural compounds like Carum copticum Benth (Ajwain) and its active ingredient thymol show promising neuroprotective effects. This study examines the effects of C. copticum Benth and thymol, alone/combination, or with standard drugs, in an AD-like rat model induced by aluminum chloride and d-galactose. A total of 72 rats were divided into two groups of 36 each based on sex (male and female) and were then randomly assigned to six subgroups (n = 6 per group); healthy control, AD model, donepezil, memantine, C. copticum Benth, and C. copticum Benth + thymol. Behavioral tests assessed anxiety and memory. Biochemical analyses of the prefrontal cortex and hippocampus evaluated acetylcholine (ACh), acetylcholinesterase (AChE), and M1 receptor expression. Thymol's interaction with targets was studied via molecular docking. AD rats showed cognitive impairment, increased anxiety, reduced ACh, and elevated AchE. Treatment with C. copticum Benth and thymol significantly improved behavior and cholinergic function, comparable to standard drugs, and modulated M1 receptor expression. C. copticum Benth and thymol demonstrate therapeutic potential in AD, warranting further investigation as adjunct or alternative treatments.}, } @article {pmid40995095, year = {2025}, author = {J, A and Khan, S and H, AB and Albarrak, AM and Ali, A}, title = {An MRI based histogram oriented gradient and deep learning approach for accurate classification of mild cognitive impairment and Alzheimer's disease.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1529761}, pmid = {40995095}, issn = {2296-858X}, abstract = {Alzheimer's disease (AD) is a common form of dementia that affects the central nervous system, causing progressive cognitive decline, particularly in memory. Early, non-invasive diagnosis is critical for improving patient care and treatment outcomes. This study proposes a robust feature extraction approach combined with three classifiers to achieve optimal classification of AD stages. T1-weighted brain MRI scans were used as input data. Features were extracted using Harris Corner interest points and the Histogram of Oriented Gradients (HOG) method. Classification was performed using Support Vector Machine (SVM), K-Nearest Neighbor (KNN), and a Deep Neural Network (DNN)-based pipeline. The proposed system classified three AD stages-Control Normal (CN), Mild Cognitive Impairment (MCI), and AD-with high accuracy: KNN (88%), SVM (91.5%), and DNN (95.6%). The DNN approach outperformed other classifiers and was further compared with state-of-the-art deep learning models, demonstrating competitive performance. These results highlight the potential of the proposed framework for early, accurate AD diagnosis using non-invasive imaging.}, } @article {pmid40994826, year = {2025}, author = {Gong, L and Li, H and Li, M and He, Y and Liu, D and Zhou, W and Zhang, B and Xi, C}, title = {APOE genotype modulates the impact of sleep duration on locus coeruleus functional connectivity in pre-clinical Alzheimer's disease.}, journal = {Brain communications}, volume = {7}, number = {5}, pages = {fcaf341}, pmid = {40994826}, issn = {2632-1297}, abstract = {Sleep duration and Apolipoprotein E genotype are critical factors influencing Alzheimer's disease progression. This study investigates the interaction between sleep duration and Apolipoprotein E genotype on the functional connectivity of the locus coeruleus in clinically unimpaired older adults with elevated amyloid beta, a population at risk for pre-clinical Alzheimer's disease. The study included 692 clinically unimpaired older adults with elevated amyloid beta participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Study (A4). Resting-state functional MRI data were analysed to construct locus coeruleus-based functional connectivity networks, and a 2 × 2 analysis of covariance was conducted to examine the main and interactive effects of sleep duration (normal versus short sleep) and Apolipoprotein E genotype (ɛ4- versus ɛ4+) on locus coeruleus-functional connectivity. Structural equation modelling was used to explore whether locus coeruleus-functional connectivity mediated the relationship between age and cognitive performance. Significant main effects of sleep duration and Apolipoprotein E genotype on locus coeruleus-functional connectivity were observed in the right temporal pole, middle cingulate cortex, and superior temporal gyrus. An interactive effect of sleep and Apolipoprotein E genotype was noted, influencing left locus coeruleus-functional connectivity in regions in the precentral gyrus, and right locus coeruleus-functional connectivity network in the middle temporal gyrus and lateral orbitofrontal cortex. Mediation analysis revealed that locus coeruleus-functional connectivity in the middle cingulate cortex and lateral orbitofrontal cortex partially mediated age associated cognitive decline. These findings suggest that locus coeruleus-functional connectivity networks, influenced by sleep duration and Apolipoprotein E genotype, play a crucial role in cognitive aging, particularly in memory function. Understanding these interactions may inform early intervention strategies to preserve cognitive health in older adults at risk for Alzheimer's disease.}, } @article {pmid40993924, year = {2025}, author = {Gavade, S and Dubey, S and Tiwari, P}, title = {Benzimidazole Derivatives in Alzheimer's Therapy: Exploring Multi-Target Pathways.}, journal = {Current protein & peptide science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892037387954250901202157}, pmid = {40993924}, issn = {1875-5550}, abstract = {Alzheimer's disease (AD) is a leading cause of dementia worldwide and continues to be one of the most frequently diagnosed neurodegenerative disorders in adults aged 65 and older. While much progress has been made in exploring AD pathophysiology, there remains no current cure, and symptomatic treatment is the current standard at best. As life expectancy continues to rise, the global prevalence of AD is increasing, making it evident that new therapeutic strategies are sorely needed. The etiology of AD is complex and heterogeneous, with cholinergic dysfunction, taurelated dysfunction, amyloid cascade dysfunction, oxidative dysfunction, and neuroinflammation all contributing to the unique pathology. As a result, researchers are focused on safe and effective drug candidates capable of addressing all of these interrelated mechanisms. One group of such multidrug candidates is benzimidazole derivatives, which target numerous molecular targets, such as, but not limited to, cyclin-dependent kinase 5 (CDK5), tau protein, acetylcholinesterase (AChE), betasecretase 1 (BACE1), serotonin receptor 5-HT4, cannabinoid receptor CB2R, and the gammaaminobutyric acid receptor A (GABA-A). This study reveals the multitargeting promise of benzimidazole- based compounds that regulate not just symptomatic pathways but also pathways that are responsible for modifying AD disease activity. Ongoing studies in this area may lead to the discovery of new drugs that can not only manage the symptoms but also change the trajectory of this serious disease and provide hope to millions of AD patients.}, } @article {pmid40993834, year = {2025}, author = {Zhang, J and Song, A and Xiang, Y and Liu, J and Li, B and Li, X}, title = {Association Between Different Types of Lipids and Alzheimer's Disease, Parkinson's Disease, and Epilepsy: A Mendelian Randomization and Bioinformatics Analysis.}, journal = {Annals of human genetics}, volume = {}, number = {}, pages = {}, doi = {10.1111/ahg.70025}, pmid = {40993834}, issn = {1469-1809}, support = {82204079//National Nature Science Foundation of China/ ; }, abstract = {BACKGROUND: With the increasing prevalence of neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy (EP) worldwide, there is a growing burden on medical and healthcare resources. Therefore, it is crucial to identify the etiology of these diseases and implement targeted preventive, diagnostic, and treatment measures to address the existing shortage of medical resources. Lipids are integral components of biological membranes. They not only function in energy storage and maintaining cell structure but also play a pivotal role in intercellular communication and signal transmission. Hence, lipids may hold significant implications in the pathogenesis and progression of the aforementioned disorders. METHODS: Utilizing two-sample Mendelian randomization (MR) in this investigation, the IEU OpenGWAS database was analyzed to explore the potential causal association between 159 lipids and the mentioned conditions, with sensitivity analysis being performed. Differentially expressed genes (DEGs) were obtained through data analysis of these three diseases in the GEO database, followed by enrichment analysis and protein-protein interaction (PPI) network analysis. RESULTS: The findings indicated a potential causal association between the onset and progression of these disorders and 20 lipids categorized into six groups, which include sterol esters (SEs), ceramides (Cer), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and triacylglycerol (TAG). Furthermore, these lipids were found to regulate biological processes and pathways associated with endocytosis, synaptic vesicular circulation, signal release, MAPK signaling pathway, PI3 kinase (PI3K)-AKT signaling pathway, dopaminergic synapses, and malaria infection. It is worth noting that based on the comprehensive scores of protein interactions in the STRING database, as well as their connectivity and association strength with other proteins in the network, heat shock factor binding protein 1 (HSPB1), which is closely related to lipids and has a relatively close relationship with diseases, was identified as a key protein for AD. Similarly, RAB3A was identified as a key protein for PD. CD160 serves as the key protein of EP. CONCLUSION: This study, by combining MR with bioinformatics analysis, discovered the potential lipid-based biological processes, pathways, and biomarkers of AD, PD, and EP, respectively, suggesting new therapeutic targets for us, deepening our understanding of the mechanisms of neurological diseases, and providing support for future clinical interventions.}, } @article {pmid40993787, year = {2025}, author = {Lin, Y and Weng, R and Pan, H and Hou, Y and Sun, Y and Wen, J}, title = {Synbiotics in Alzheimer's disease: mechanisms, clinical evidence, and therapeutic prospects.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {1009}, pmid = {40993787}, issn = {1479-5876}, support = {82405349//National Natural Science Foundation of China (Youth) Program/ ; }, mesh = {*Synbiotics ; Humans ; *Alzheimer Disease/microbiology/therapy ; *Cognition ; *Brain-Gut Axis ; *Gastrointestinal Microbiome ; Animals ; Clinical Studies as Topic ; }, abstract = {BACKGROUND: Growing evidence implicates gut microbiota (GM) dysbiosis in Alzheimer's disease (AD) pathogenesis via the gut-brain axis. Dysbiosis contributes to neuroinflammation, amyloid-β deposition, tau hyperphosphorylation, blood-brain barrier disruption, and cognitive decline. Synbiotics (combinations of probiotics and prebiotics) offer a promising strategy to modulate GM, potentially ameliorating these AD hallmarks through multiple mechanisms including enhanced production of neuroprotective short-chain fatty acids (SCFAs), reduced inflammation, improved gut barrier integrity, and immunomodulation. OBJECTIVE: This review critically evaluates the current evidence on the therapeutic potential of synbiotics for AD. It aims to synthesize findings from preclinical and clinical studies regarding the efficacy of synbiotics in improving cognitive function and AD pathology, elucidate the underlying biological mechanisms including GM modulation, SCFA production, immune regulation, and gut-brain signaling, and identify key challenges and future research directions for translating GM-targeted interventions into effective AD therapies. CONCLUSION: Synbiotics demonstrate significant potential, particularly in early AD, by improving cognitive domains, reducing neuroinflammation and AD biomarkers, and modulating beneficial microbial metabolites. However, challenges include confounding factors, unresolved questions about causality, inconsistent results in advanced disease, and insufficient large-scale human trials. Future success hinges on rigorous longitudinal randomized controlled trials integrating multi-omics approaches, advanced in vitro models, and personalized strategies considering baseline microbiota and host genetics. While not a standalone cure, synbiotics represent a valuable component within multi-target therapeutic approaches aimed at modulating the gut-brain axis to slow AD progression.}, } @article {pmid40993746, year = {2025}, author = {Zhao, D and Wang, J and Zhu, Y and Zhang, H and Ni, C and Zhao, Z and Dai, J and He, R and Liu, G and Gan, C and Zhang, S and Tong, Z}, title = {Targeting the glymphatic system: Aβ accumulation and phototherapy strategies across different stages of Alzheimer's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {49}, pmid = {40993746}, issn = {2047-9158}, support = {62394314//Major Program of the National Natural Science Foundation of China/ ; 82071214//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; *Glymphatic System/metabolism/radiation effects ; *Amyloid beta-Peptides/metabolism ; Animals ; *Phototherapy/methods ; Brain/metabolism ; }, abstract = {The glymphatic system serves as the brain's clearance system. It deteriorates with age and is a significant contributor to the onset and progression of Alzheimer's disease (AD). Modulating cerebrospinal fluid (CSF)-based clearance and targeting key components of the glymphatic system, such as aquaporin-4, can enhance amyloid-beta (Aβ) clearance. Light therapy is emerging as a potential AD treatment approach, which involves the use of visible and near-infrared light at specific wavelengths (630/680/808/850/1070 nm), photosensitive proteins, and sensory stimulation at particular frequencies (e.g., 40 Hz). This phototherapy strategy can broadly influence the intracerebral fluid dynamics, including cerebral blood flow, CSF, and interstitial fluid (ISF), as well as structures related to the glymphatic system, such as vascular endothelial cells, glial cells, and neurons. Additionally, it may directly or indirectly inhibit Aβ accumulation by modulating endogenous small molecules, thereby improving cognitive function. Our previous research demonstrated that 630-nm red light can inhibit Aβ cross-linking by clearing endogenous formaldehyde and promoting ISF drainage. Notably, Aβ accumulation exhibits distinct characteristics at different phases of AD, accompanied by varying features of glymphatic system impairment. In the early stages, deep brain regions are significantly affected, whereas in the late stages, accumulation primarily occurs in the paracentral, precentral, and postcentral cortices. Owing to the limited penetration depth of light, this may pose a challenge to the clinical efficacy of phototherapy. Therefore, different stages of AD may require tailored phototherapeutic strategies. Meanwhile, it is important to acknowledge the ongoing controversies associated with lymphovenous anastomosis, a procedure that targets the glymphatic system. Therefore, this article reviews the characteristics of glymphatic system impairment across various AD stages and the mechanisms by which effective phototherapies modulate the glymphatic system. Potential phototherapeutic strategies corresponding to different stages of Aβ accumulation are also proposed.}, } @article {pmid40992617, year = {2025}, author = {Dahlén, AD and Roshanbin, S and Bucher, NM and Sehlin, D and Syvänen, S}, title = {Evaluating the impact of age and treatment on neuroinflammation-related proteins in mouse models of proteinopathies.}, journal = {Experimental neurology}, volume = {395}, number = {}, pages = {115475}, doi = {10.1016/j.expneurol.2025.115475}, pmid = {40992617}, issn = {1090-2430}, abstract = {Neuroinflammation plays a key role in Alzheimer's disease (AD), but the actions of microglial mediators may vary across stages of amyloid-beta (Aβ) pathology. While drugs targeting brain immune responses are advancing to clinical trials, biomarkers to monitor their effects are lacking. This study investigated proteins expressed by activated microglia in three mouse models of Aβ pathology and α-synuclein, both during disease progression and after treatment, to evaluate their potential as in vivo biomarkers. Immunofluorescent staining was performed on cortical sections from App[NL-G-F], tg-ArcSwe, and wild-type (WT) mice. TREM2, Axl, galectin-3, Aβ, and cytokines were measured by immunoassays in brain homogenates from WT, App[NL-G-F], tg-ArcSwe, and tg-UppSwe mice across four age groups and from mice subjected to three treatment strategies targeting Aβ (beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor NB-360 and antibody RmAb158) or α-synuclein (antibody RmAb38E2). TREM2 and Axl colocalized with Iba1 and Aβ in App[NL-G-F] and tg-ArcSwe mice, with age-dependent increases observed in both models but not in tg-UppSwe. The lectin galectin-3 increased with age across all genotypes, including WT. Aβ correlated with elevated TREM2, Axl, and Galectin-3. Two months of BACE1-inhibition reduced TREM2, Axl, and galectin-3 in tg-ArcSwe mice and TREM2 and Axl in App[NL-G-F] mice. In summary, microglial TREM2, Axl, and galectin-3 are promising biomarkers for tracking AD-related neuroinflammation. Microglial interactions with Aβ likely influence the outcomes of Aβ-targeting therapies, and characterizing their dynamic states will inform the development of diagnostic tools and treatments relying on microglial activation to alleviate pathologies associated with neurodegenerative diseases.}, } @article {pmid40992534, year = {2025}, author = {Bello, ST and Rafe, MR and Huang, F}, title = {New frontier for epilepsy treatment through targeting cellular senescence.}, journal = {Progress in neuro-psychopharmacology & biological psychiatry}, volume = {142}, number = {}, pages = {111506}, doi = {10.1016/j.pnpbp.2025.111506}, pmid = {40992534}, issn = {1878-4216}, mesh = {Humans ; *Epilepsy/drug therapy/metabolism/pathology ; *Cellular Senescence/physiology/drug effects ; Animals ; *Senescence-Associated Secretory Phenotype/physiology/drug effects ; *Anticonvulsants/therapeutic use/pharmacology ; *Senotherapeutics/pharmacology/therapeutic use ; }, abstract = {Epilepsy is a life-threatening brain disorder that affects about 1-2 % of the world's population. Various mechanisms facilitating epilepsy development and seizure propagation have been identified. Nevertheless, an improved understanding of the cellular mechanisms that underlie epilepsy development is necessary for designing better therapeutic strategies for epilepsy treatment. Cellular senescence, a cellular mechanism wherein cell growth is permanently halted and causes cells to exit the proliferative pool, has been associated with neurological disorders such as multiple sclerosis, Alzheimer's disease, Parkinson's disease, and epilepsy. How the various mechanisms that drive a cell towards senescence and the phenotypes that characterize senescent cells are associated with the development and progression of epilepsy might be necessary in improving our understanding of epilepsy. Therefore, this review discusses the mechanisms and pathways associated with cellular senescence and how senescence-associated secretory phenotype (SASP) promotes inflammation and tissue dysfunction. We then explained how different types of cells, including brain cells, become senescent, the inter-relationship between cellular senescence and epilepsy, and potential biomarkers common to epilepsy and cellular senescence. Finally, we reviewed the use of senolytics and senomorphics for epilepsy treatment. Further research can, therefore, be directed towards a thorough understanding of cellular senescence in epilepsy development, and this can open new frontiers for epilepsy treatment.}, } @article {pmid40991989, year = {2025}, author = {Kim, Y and Cho, M and Jeon, CJ and Goh, G and Kim, M}, title = {Neuroinflammatory suppression with protocatechuic acid attenuates Alzheimer's disease phenotypes in 5 ×FAD transgenic mice.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {192}, number = {}, pages = {118598}, doi = {10.1016/j.biopha.2025.118598}, pmid = {40991989}, issn = {1950-6007}, mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/metabolism/pathology ; *Hydroxybenzoates/pharmacology/therapeutic use ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Presenilin-1/genetics/metabolism ; Hippocampus/drug effects/metabolism/pathology ; Humans ; Amyloid beta-Protein Precursor/genetics/metabolism ; Microglia/drug effects/metabolism/pathology ; Phenotype ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Anti-Inflammatory Agents/pharmacology ; Male ; Amyloid beta-Peptides/metabolism ; Gastrointestinal Microbiome/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a complex pathobiology that includes neuroinflammation, the accumulation of extracellular amyloid-beta (Aβ) plaque, and intracellular neurofibrillary tangles comprising tau. Increasing evidence suggests that the aberrant activation of glial cells, including microglia and astrocytes, is a significant early characteristic that accelerates neuroinflammatory processes in the development of AD. Protocatechuic acid (PCA), a natural phenolic compound, has been investigated for its anti-inflammatory properties in various pathological conditions. Here, we demonstrated that administration of PCA significantly ameliorated neuroinflammation as well as cognitive deficits in the 5 ×FAD mouse model of AD, which overexpresses human amyloid precursor protein (APP) and presenilin-1 (PSEN1) genes carrying five familial Alzheimer's disease (FAD) mutations, leading to accelerated Aβ deposition. We further confirmed that PCA treatment significantly reduced microglial activation and downregulated the production of pro-inflammatory cytokines, astrogliosis, and tau hyperphosphorylation, thereby preserved the integrity of hippocampal neurons. Our RNA sequencing analysis revealed that PCA treatment restored the transcriptomic profile of hippocampal tissues in 5 ×FAD mice, particularly by downregulating genes associated with innate immune and inflammatory responses. Moreover, PCA alleviated gut dysbiosis and enhanced the integrity of the intestinal barrier. The findings suggest that PCA may serve as a promising therapeutic agent for early intervention in AD to mitigate its progression.}, } @article {pmid40991081, year = {2025}, author = {Belyaev, GP and Petrov, KA and Semenov, VE and Zueva, IV}, title = {Changes in Dendritic Spine Density and Morphology during Therapy with Acetylcholinesterase Inhibitors in a Mouse Model of Alzheimer's Disease.}, journal = {Bulletin of experimental biology and medicine}, volume = {179}, number = {3}, pages = {378-382}, pmid = {40991081}, issn = {1573-8221}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/genetics ; *Dendritic Spines/drug effects/pathology ; Mice, Transgenic ; *Cholinesterase Inhibitors/pharmacology/therapeutic use ; Mice ; Donepezil ; Disease Models, Animal ; *Uracil/analogs & derivatives/pharmacology/therapeutic use ; Entorhinal Cortex/drug effects/pathology/metabolism ; Presenilin-1/genetics/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Piperidines/pharmacology ; Male ; Humans ; Acetylcholinesterase/metabolism ; }, abstract = {We performed a comparative study of the effect of a new acetylcholinesterase inhibitor 1,3-bis[5-(o-nitrobenzylethylamino)pentyl]-6-methyluracil (C-35) and a commercial drug donepezil on the density and morphology of dendritic spines in the entorhinal cortex of transgenic APP/PS1 mice with a model of Alzheimer's disease. Administration of donepezil to transgenic mice did not significantly change spine density or morphology. In contrast, treatment with C-35 increased dendritic spine density by 56 and 34% in comparison with donepezil and the control group (untreated transgenic mice), respectively. This effect of C-35 was associated with an increase in the number of thin spines and a decrease number of stubby spines.}, } @article {pmid40990612, year = {2025}, author = {Naserramezani, Z and Palizvan, MR and Ganji, A and Ghazavi, A and Mosayebi, G}, title = {Synergistic neuroprotection of chitosan-cannabidiol nanoparticles in a rat model of Alzheimer's disease: Amelioration of cognitive deficits and neuroinflammation.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {790-804}, doi = {10.1177/13872877251379420}, pmid = {40990612}, issn = {1875-8908}, mesh = {Animals ; *Cannabidiol/administration & dosage/pharmacology ; *Alzheimer Disease/drug therapy/chemically induced/pathology ; Rats, Wistar ; Male ; Rats ; *Nanoparticles/administration & dosage ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Neuroinflammatory Diseases/drug therapy ; *Cognitive Dysfunction/drug therapy ; *Chitosan/administration & dosage/pharmacology ; Oxidative Stress/drug effects ; Streptozocin/toxicity ; Hippocampus/drug effects/pathology ; Maze Learning/drug effects ; }, abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, neuroinflammation, and oxidative stress. Current treatments are largely symptomatic, necessitating novel neuroprotective strategies.ObjectiveThis study aimed to investigate the anti-inflammatory and antioxidant effects of chitosan-cannabidiol (CS-CBD) nanoparticles in a streptozotocin (STZ)-induced rat model of AD.MethodsSixty male Wistar rats were randomly divided into five groups: control, AD model (STZ-induced), chitosan-treated, cannabidiol-treated, and CS-CBD-treated. AD was induced by intracerebroventricular injection of STZ (3 mg/kg). Treatments were administered intranasally for 21 days. Cognitive performance was assessed using the Morris water maze. After treatment, oxidative stress markers (NO, FRAP), liver enzymes (ALT, AST), and the expression of inflammatory and neuroprotective genes (IL1β, IL6, IL10, iNOS, PPARγ, BDNF) were evaluated by real-time PCR. Histological analysis of the hippocampus was also performed. Data were analyzed using one-way ANOVA and Tukey's post hoc test (p < 0.05).ResultsThe AD group showed significant impairments in memory and learning (p < 0.0001), increased oxidative stress, and upregulation of pro-inflammatory genes (IL1β, iNOS), with decreased neuroprotective markers (BDNF, PPARγ). CS-CBD treatment significantly improved cognitive function (p < 0.001), restored oxidative balance, reduced IL1β and iNOS expression, and elevated BDNF and PPARγ expression (p < 0.05). Histological analysis confirmed reduced neuronal degeneration and increased neuronal density in the CS-CBD group.ConclusionsCS-CBD nanoparticles exerted potent neuroprotective, antioxidant, and anti-inflammatory effects in an STZ-induced rat model of AD. These findings support the potential of CS-CBD nanoparticles as a promising adjunctive therapy for AD, warranting further investigation.}, } @article {pmid40990282, year = {2025}, author = {Barnwal, N and Dubey, S and Tiwari, P}, title = {Targeting Metabolic Dysregulation in Alzheimer's Disease: A Potential Therapeutic Strategy.}, journal = {Current drug metabolism}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113892002408089250912080734}, pmid = {40990282}, issn = {1875-5453}, abstract = {Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-beta plaques and tau tangles. Emerging evidence implicates metabolic dysfunction as a critical contributor to the pathogenesis and pro-gression of AD. Impaired glucose metabolism, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are frequently observed in AD brains, suggesting that metabolic dysfunction may exacerbate neurodegeneration and cognitive deficits. This review explores the therapeutic potential of targeting met-abolic pathways to mitigate AD pathology. Key metabolic disruptions, including insulin resistance, re-duced cerebral glucose utilization, and mitochondrial inefficiency, are closely linked to neuronal energy deficits and synaptic dysfunction. Therapeutic approaches, such as insulin sensitizers, ketogenic diets, and mitochondrial-targeted antioxidants, have shown promise in preclinical and early clinical studies. Addi-tionally, strategies to modulate lipid metabolism, such as enhancing cholesterol efflux via APOE or re-ducing neurotoxic ceramides, offer potential avenues for intervention. The review also highlights the roles of neuroinflammation and oxidative stress as mediators of metabolic dysfunction in AD, underscoring the need for multifaceted approaches that target both metabolic and inflammatory pathways. The emerging field of precision medicine offers opportunities to tailor interventions based on individual metabolic pro-files, potentially enhancing treatment efficacy. Despite the growing recognition of metabolic dysfunction in AD, translating these insights into effective therapies remains challenging due to the disease's com-plexity and heterogeneity. Future research must focus on elucidating the interplay between metabolic pathways and AD pathology, identifying reliable biomarkers, and designing targeted interventions. By addressing the metabolic underpinnings of AD, this review underscores the potential of metabolic repro-gramming as a novel and integrative therapeutic strategy to slow or prevent disease progression and im-prove patient outcomes.}, } @article {pmid40990274, year = {2025}, author = {Maiese, K}, title = {Cannabis and Cannabidiol: Pioneering Treatment for the Nervous System with Alzheimer's Disease and Peripheral Organ Involvement with Nonalcoholic Fatty Liver Disease (NAFLD).}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026446790250918074353}, pmid = {40990274}, issn = {1875-5739}, } @article {pmid40990233, year = {2025}, author = {Shami, R and El Majzoub, R and Ismail, A and Kotaich, J and Kassem, M and Safadieh, G and Fayyad-Kazan, M and Chahine, B}, title = {Effects of triptolide herb on the progression of Alzheimer's disease preclinical models: a systematic review.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/17582024.2025.2562776}, pmid = {40990233}, issn = {1758-2032}, abstract = {AIM: This study aims to systematically evaluate and synthesize preclinical evidence on the neuroprotective effects of Triptolide (Tri) in Alzheimer's disease (AD) models, focusing on its impact on amyloid-beta accumulation, synaptic dysfunction, neuroinflammation, oxidative stress, autophagy, and apoptosis. INTRODUCTION: AD is the most common cause of dementia, yet current treatments largely target symptoms rather than underlying pathology. Tri, a bioactive compound from Tripterygium wilfordii, has shown promise due to its anti-inflammatory, antioxidant, and neuroprotective properties. METHODS: A systematic search of PubMed, Embase, and Web of Science was conducted up to 16 March 2024. English-language in vivo and in vitro studies on Tri's effects in AD models were included. Methodological quality was assessed using SYRCLE and SciRAP tools. The review is registered in PROSPERO (CRD42024521822). RESULTS: Out of 403 studies, 15 met the inclusion criteria (6 in vivo, 8 in vitro, 1 both). Tri reduced Aβ burden, enhanced memory and synaptic integrity, suppressed neuroinflammation and oxidative stress, and modulated autophagy and apoptosis. CONCLUSION: Tri demonstrates significant multi-target neuroprotective effects in AD preclinical models. Further high-quality studies are warranted to optimize dosing, delivery, and safety for clinical translation.}, } @article {pmid40990131, year = {2025}, author = {Devanarayan, V and Donohue, MC and Sperling, RA and Johnson, KA and Ye, Y and Charil, A and Doherty, T and Tian, L and Raman, R and Aisen, PS and Kramer, LD and Irizarry, MC and Dhadda, S}, title = {Multimodal prognostic modeling of individual cognitive trajectories to enhance trial efficiency in preclinical Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70702}, pmid = {40990131}, issn = {1552-5279}, support = {/AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; //Eli Lilly and Company/ ; /ALZ/Alzheimer's Association/United States ; //Accelerating Medicines Partnership/ ; //GHR Foundation/ ; //Eisai Inc./ ; }, mesh = {Aged ; Female ; Humans ; Male ; *Alzheimer Disease/drug therapy/diagnostic imaging/diagnosis/genetics ; Antibodies, Monoclonal, Humanized/therapeutic use ; Brain/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging/diagnosis ; Longitudinal Studies ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Prognosis ; tau Proteins/blood ; }, abstract = {INTRODUCTION: Cognitive decline in asymptomatic preclinical Alzheimer's disease (AD) is slow and variable, limiting detection of treatment effects. This study developed models to forecast trajectories and improve trial efficiency. METHODS: Models were trained on longitudinal Preclinical Alzheimer's Cognitive Composite (PACC) data up to 240 weeks from the Phase III A4 study of solanezumab. Baseline inputs included demographics, apolipoprotein E (APOE) ε4, clinical scores, amyloid positron emission tomography (PET), plasma pTau217, magnetic resonance imaging (MRI), and tau PET (sub-study). Stochastic gradient boosting was used, with evaluation via cross-validation and trial simulations. RESULTS: The best model without tau PET used pTau217, clinical, and MRI data (R[2] = 0.32; area under the receiver operating characteristic curve (AUROC) for classifying a 0.5-point PACC decline = 78.6%). Replacing MRI with tau PET improved performance (R[2] = 0.42; AUROC = 83.1%). Predicted trajectories as a prognostic covariate reduced sample sizes by 35% and increased power from 80% to 94.7%. DISCUSSION: Prognostic models can predict decline in preclinical AD and improve trial efficiency. GOV IDENTIFIERS: NCT02008357 (Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss (A4)) HIGHLIGHTS: Models forecast 4.5-year cognitive decline in amyloid-positive preclinical Alzheimer's disease (AD). Plasma pTau217 and tau positron emission tomography (PET) standardized uptake value ratios (SUVRs) in early-accumulating regions are key predictors. Tau PET improves prediction beyond plasma, magnetic resonance imaging (MRI), and clinical measures. Forecasted decline as a prognostic covariate improves power and cuts sample size in trial simulations. Alternative models underperform yet retain practical utility when tau PET or pTau217 is unavailable.}, } @article {pmid40989580, year = {2025}, author = {Jiang, H and He, D and Hu, Y}, title = {Cognitive deterioration in patients undergoing hemodialysis: how variations in age influence the development of new mechanisms and treatment approaches?.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1645702}, pmid = {40989580}, issn = {1663-4365}, abstract = {The mechanisms of age-related differences and innovative intervention strategies for cognitive dysfunction in hemodialysis patients are crucial for enhancing patient outcomes. This research thoroughly examined the varying pathological aspects of cognitive decline across different age groups. Children and adolescents experience heightened permeability of the blood-brain barrier during critical developmental phases, along with the disruptive effects of uremic toxins on neurotransmitters and synaptic plasticity, which result in diminished white matter integrity and abnormal functioning of the default mode network. Additionally, genomic variations, such as harmful CNVs, coexist with the central nervous system's high plasticity and susceptibility. In contrast, elderly patients face cognitive impairment due to the combined effects of vascular diseases (like small vessel disease and impaired cerebral blood flow regulation) and Alzheimer's-like pathology, exacerbated by dialysis-related hypotension, oxidative stress, and inflammation, which further contribute to reduced cerebral blood flow and neurodegeneration. Consequently, a life cycle-based layered intervention strategy is suggested: children should focus on safeguarding their neural development through collaborative gene-environment interventions and neural stem cell transplants, while elderly patients require standardized treatment for vascular diseases and comorbidities, including Alzheimer's disease. Evidence indicates that incremental dialysis, low temperature dialysis, and high-dose hemodiafiltration can significantly reduce inflammation and oxidative stress markers, slow cognitive decline across all ages, and offer new insights for targeted nephrology management due to their universal effects. Future multi-center cohort studies are necessary to confirm the long-term advantages of age-specific interventions and to support the development of personalized precision treatment systems.}, } @article {pmid40988261, year = {2025}, author = {Gao, Y and Wang, X and Su, X and Liu, W and Zhang, Q}, title = {Acupuncture for hiccups: Case reports and literature review.}, journal = {Medicine}, volume = {104}, number = {38}, pages = {e44036}, pmid = {40988261}, issn = {1536-5964}, support = {ZKYB2410//the Hospital-level Project of Zhejiang Rehabilitation Medical Center/ ; (2022)NO:239//The National Program For Talents In Traditional Chinese Medicine/ ; }, mesh = {Aged ; Aged, 80 and over ; Humans ; Male ; *Acupuncture Therapy/methods ; *Hiccup/therapy ; }, abstract = {RATIONALE: Persistent hiccups following a stroke are a common complication that can adversely affect the patient's condition and rehabilitation. Certain refractory cases fail to respond adequately to pharmacological treatment. We report 2 cases of successful treatment of persistent hiccups with acupuncture and a medical electromagnetic device (trade name, TDP, an abbreviation of the Chinese phrase "Te-ding Dian-ci-bo Pu"). PATIENT CONCERNS: The first patient was a 94-year-old male who had experienced continuous hiccups for 7 days. His comorbidities included Alzheimer disease, cardiac arrhythmia following pacemaker implantation, chronic kidney disease, glaucoma, and recent COVID-19 infection complicated by pneumonia. The second patient was a 70-year-old male who had experienced hiccups for 10 days. He had a history of cerebellar and brainstem infarction, hypertension, and hypopharyngeal carcinoma. DIAGNOSES: Both patients were diagnosed with persistent hiccups. INTERVENTIONS: Both patients received combined treatment with acupuncture and TDP. OUTCOMES: Following treatment, hiccups were alleviated to different degrees, and no recurrence was observed at follow-up. LESSONS: Neuroexcitatory imbalance and thoracoabdominal pressure asymmetry are considered underlying causes of persistent hiccups. Acupuncture combined with TDP may modulate periumbilical arteriovenous networks and abdominal pressure, thereby relieving hiccups. This case series suggests a novel, easily implemented, well-tolerated therapeutic option for the management of persistent hiccups.}, } @article {pmid40987722, year = {2025}, author = {Sauerteig-Rolston, MR and Fowler, NR and Sachs, GA and Boustani, M and Slaven, J and Monahan, PO and Burke, ES and Higbie, A and Torke, AM}, title = {Pragmatic trial of a virtual dementia collaborative care management program: protocol for the Aging Brain Care Virtual (ABCV) program.}, journal = {BMJ open}, volume = {15}, number = {9}, pages = {e108800}, pmid = {40987722}, issn = {2044-6055}, support = {U54 AG063546/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Dementia/therapy ; Pragmatic Clinical Trials as Topic ; Aged ; Telemedicine ; Female ; }, abstract = {INTRODUCTION: Providing care management, treatment and support to patients with Alzheimer's Disease and Related Dementias (ADRD) is a difficult task for health systems. Over the past 20 years, interventions designed to improve outcomes for patients living in the community with dementia and their care partners have moved progressively, but separately, from large scale trials and pragmatic models of collaborative care. Given the projected increase in the number of people living with dementia coupled with the realignment of payment for services to be value-based and provided in the community, system-level approaches are needed to address the complex needs of patients with a dementia diagnosis and their care partners. We designed a statewide, pragmatic trial to evaluate virtual delivery of an evidence-based dementia collaborative care program on patient healthcare utilization and medication use. METHODS AND ANALYSIS: The Aging Brain Care Virtual (ABCV) program is a 12-month embedded, cluster randomized, usual care controlled trial designed to test the effectiveness of a virtual dementia collaborative care program in 24 Indiana University Health primary care clinics (12 intervention, 12 control) across the state of Indiana, enrolling 860 persons living with dementia (430 intervention, 430 control) and their care partners. ABCV relies on a tailored approach in which dyad needs are identified during virtual visits and addressed with standardized protocols previously tested in a randomized controlled trial delivered in person. The ABCV trial will measure emergency department utilization (primary outcome) and appropriate medication use (secondary outcome) at 12 months using electronic medical record data. Additionally, this study will use semi-structured interviews with care partners and clinicians to explore the implementation context, process and outcomes of the ABCV program. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Indiana University Institutional Review Board (20249). Research findings will be published in peer-reviewed journals and presented at scientific conferences. TRIAL REGISTRATION NUMBER: NCT06245499.}, } @article {pmid40987707, year = {2025}, author = {Yuan, J and Dong, X and Gao, Y and Nao, J}, title = {Pleiotropic regulatory mechanisms and targeted therapeutic prospects of Galectin-3 in aging-related diseases.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {22}, number = {6}, pages = {e00744}, pmid = {40987707}, issn = {1878-7479}, mesh = {Humans ; *Aging/metabolism/drug effects ; *Galectin 3/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; Diabetes Mellitus, Type 2/metabolism/drug therapy ; Alzheimer Disease/metabolism/drug therapy ; }, abstract = {Aging is a major risk factor for numerous chronic diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), atherosclerosis (AS), type 2 diabetes mellitus (T2DM), osteoarthritis (OA) and age-related macular degeneration (AMD). Galectin-3 (Gal-3), a unique β-galactoside-binding lectin, has emerged as a critical mediator in the pathogenesis of AD and other age-related disorders by modulating key mechanisms such as inflammation, oxidative stress, and apoptosis. While emphasizing neurological disorders (AD, PD), this review also examines Gal-3's role in systemic age-related conditions (T2DM, AS, OA, AMD) that frequently co-occur with or influence neurodegeneration. This review summarizes current knowledge on the expression patterns, molecular mechanisms, and therapeutic potential of Gal-3 in aging-related diseases. Elevated Gal-3 levels have been detected in the brain tissue and cerebrospinal fluid of AD patients, where it contributes to multiple pathological processes, including microglia-driven neuroinflammation, Aβ plaque deposition, tau hyperphosphorylation, oxidative damage, and neuronal apoptosis. Furthermore, Gal-3 upregulation is observed across various age-related diseases and correlates with disease progression, underscoring its potential as a diagnostic biomarker and therapeutic target. Preclinical studies demonstrate that Gal-3-targeted interventions-including small-molecule inhibitors (e.g., TD-139), natural compounds (e.g., modified citrus pectin), and other pharmacological agents-exert neuroprotective, anti-inflammatory, antioxidant, and anti-apoptotic effects by binding to Gal-3 and modulating its activity in animal models, offering promising avenues for multi-disease treatment. However, the dual roles and complex regulatory networks of Gal-3 present challenges for clinical translation, requiring context-specific therapeutic approaches tailored to distinct disease mechanisms. Future research should focus on elucidating tissue-specific mechanisms and optimizing combination therapies to enable precise targeting of aging-related pathologies.}, } @article {pmid40987594, year = {2025}, author = {Mandal, S and Shaw, S and Pandit, SK and Garai, P and Jana, NR}, title = {Ampholytic Carbon Dots Enable Imaging and Modulation of Amyloid Fibrillation with Reduced Neurotoxicity.}, journal = {Nano letters}, volume = {25}, number = {40}, pages = {14573-14581}, doi = {10.1021/acs.nanolett.5c03426}, pmid = {40987594}, issn = {1530-6992}, mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; *Carbon/chemistry ; Humans ; Reactive Oxygen Species/metabolism ; *Alzheimer Disease/metabolism/diagnostic imaging ; *Quantum Dots/chemistry ; *Amyloid/chemistry ; Lysosomes/metabolism ; Animals ; Optical Imaging ; }, abstract = {Neurodegenerative diseases like Alzheimer's are driven by protein aggregation, notably amyloid-β (Aβ) fibrillation and associated cytotoxicity. Here, we report the design of ampholytic carbon dots (ACDs) with red/green emission that bind/control amyloid fibrillation. These ACDs bind with amyloid structures via electrostatic and van der Waals interactions and effectively inhibit fibril formation as well as promote disintegration of mature fibrils. The fluorescence property of ACDs enable high-resolution fluorescence imaging of amyloid structures at intra/extracellular space. ACD-amyloid conjugates showed lysosomal entrapment with lower amyloid-induced cytotoxicity via the lowering of reactive oxygen species generation. Together, these results highlight the dual functionality of ACDs as imaging and antiamyloidogenic agents, offering a promising nanoplatform for the diagnosis and treatment of amyloid-associated neurodegenerative disorders.}, } @article {pmid40987553, year = {2025}, author = {Huang, X and Fang, Y and Song, J and Hao, Y and Cai, Y and Wei, P and Zhang, N}, title = {Rescuing lysosomal/autophagic defects via nanoapproach: implications for lysosomal/autophagic defect-related diseases.}, journal = {Journal of Zhejiang University. Science. B}, volume = {26}, number = {9}, pages = {813-842}, pmid = {40987553}, issn = {1862-1783}, support = {tsqn202103112//the Taishan Scholars Program of Shandong Province/ ; ZR2021QB202//the Shandong Provincial Natural Science Foundation/ ; 2021KJ052//the Development Plan of Youth Innovation Team in Colleges and Universities of Shandong Province/ ; CSTB2023TIAD-LDX0015//the Shandong-Chongqing Science and Technology Cooperation Project for Technological Innovation and Application Development/ ; }, mesh = {Humans ; *Lysosomes/physiology ; *Autophagy/physiology ; *Nanomedicine/methods ; Neurodegenerative Diseases/therapy ; Animals ; Nanostructures ; *Lysosomal Storage Diseases/therapy ; }, abstract = {The dysfunction of the lysosome and autophagy-lysosome system serves as a driving force for neurodegenerative diseases, metabolic disorders, inflammatory conditions, and other related diseases, closely influencing their onset and progression. Therefore, restoring the function of the lysosome or autophagy-lysosome system has become an increasingly crucial therapeutic strategy in disease management. In this review, we will introduce the lysosomal biogenesis, structure, and function, as well as the biological process of the autophagy-lysosome system. Various diseases closely associated with lysosomal/autophagic dysfunction are also reviewed, emphasizing the significance of targeting the function of the lysosome or autophagy-lysosome system in disease treatment. Finally, we focus on engineered nanomaterials that have the capabilities to restore the function of the lysosome or autophagy-lysosome system, and summarize different strategies and methods for achieving this goal. This review aims to elucidate the latest progress in the field of nanomedicine for lysosomal/autophagic defect-related diseases and inspire the development of innovative and clinically valuable nanomedicines.}, } @article {pmid40987204, year = {2025}, author = {Shahlaei, M and Afkhami, H and Ahmadieh-Yazdi, A and Mirmazloumi, SH and Sahraei, SS and Akbari, M and Yang, P and Manoochehri, H and Tanzadehpanah, H and Mahaki, H and Sundararaman, A and Mohan, S and Sheykhhasan, M and Al-Musawi, S and Dama, P}, title = {Exosomes in Alzheimer's disease: From pathogenesis to therapeutics-A comprehensive review of diagnostic and drug delivery applications.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {192}, number = {}, pages = {118548}, doi = {10.1016/j.biopha.2025.118548}, pmid = {40987204}, issn = {1950-6007}, mesh = {*Alzheimer Disease/drug therapy/diagnosis/metabolism/pathology ; *Exosomes/metabolism ; Humans ; *Drug Delivery Systems/methods ; Animals ; Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/metabolism ; Neuroprotective Agents/administration & dosage ; }, abstract = {Alzheimer's disease (AD) is still a major unmet medical challenge, with limited treatment options and a critical need for early diagnostics. Exosomes, nanoscale extracellular vesicles with a lipid bilayer, are pivotal players in intercellular communication and promising tools for AD management. Their unique ability to cross the bloodbrain barrier, low immunogenicity, and ability for cargo delivery make them ideal candidates for targeted drug delivery. This review comprehensively examines the biology of exosomes-including their structure, biogenesis, release, and uptake-and evaluates advanced methods for their isolation, purification, and characterization. We highlight their dual role in AD pathogenesis, where they can propagate pathological proteins such as amyloid-β and tau, and in therapeutic applications, where engineered exosomes deliver neuroprotective agents. Furthermore, exosomal biomarkers in biofluids show significant potential for noninvasive early diagnosis. Recent advances in loading strategies and surface engineering have been discussed, alongside challenges in scalability and safety. This synthesis bridges current knowledge with future directions, emphasizing the translational potential of exosomes in AD therapeutics and diagnostics.}, } @article {pmid40987016, year = {2025}, author = {Schuh, KM and Conrad, LM and Tronson, NC}, title = {Hormonal contraceptives modulate resilience to psychiatric and neurodegenerative disease.}, journal = {Hormones and behavior}, volume = {176}, number = {}, pages = {105823}, doi = {10.1016/j.yhbeh.2025.105823}, pmid = {40987016}, issn = {1095-6867}, mesh = {Humans ; Female ; *Resilience, Psychological/drug effects ; *Neurodegenerative Diseases/prevention & control/psychology ; Animals ; Depression ; Alzheimer Disease/prevention & control ; Stress, Psychological ; *Mental Disorders/prevention & control ; *Contraceptives, Oral, Hormonal/pharmacology ; }, abstract = {Hormonal contraceptives (HCs) are one of the most widely used classes of drug worldwide and are a critical part of women's health. Beyond their primary use for birth control, HCs exert many health benefits, including treatment of menstrual-related symptoms and reduced risk of certain types of cancers. Here, we focus on the role of HCs in promoting resilience to depression and Alzheimer's disease. Although risks for depression with HC use have been widely stated, HCs only increase risk for up to 10 % of users, and conversely improve mood and protect against depression for many others. Emerging evidence also suggests that HC use protects against age-related cognitive decline and Alzheimer's disease, even decades after HC use. We propose that these effects are due to modulatory effects of HCs on stress-related signaling and neuroimmune function. In this paper, we discuss how HCs interact with stress responsivity, neuroimmune signaling, and other individual differences to promote resilience or susceptibility to psychiatric and neurological disorders.}, } @article {pmid40986221, year = {2025}, author = {Yılmaz, ŞG and Almallohy, AM and Deveci, HA and Korkmaz, M and Balcı, SO}, title = {Thymoquinone regulates RSL3-induced ferroptosis in the alzheimer mouse hippocampus.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {942}, pmid = {40986221}, issn = {1573-4978}, support = {SBF.YLT.22.01//Gaziantep University/ ; }, mesh = {Animals ; *Ferroptosis/drug effects ; *Hippocampus/drug effects/metabolism/pathology ; Mice ; *Alzheimer Disease/metabolism/drug therapy ; Female ; *Benzoquinones/pharmacology ; Mice, Inbred C57BL ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Oxidative Stress/drug effects ; Lipid Peroxidation/drug effects ; Maze Learning/drug effects ; Iron/metabolism ; Glutathione/metabolism ; }, abstract = {INTRODUCTION: Ferroptosis, a type of iron-dependent regulated cell death driven by lipid peroxidation, has emerged as a critical contributing factor to hippocampal neurodegeneration in Alzheimer's disease (AD). Dysregulated iron homeostasis exacerbates oxidative injury, impairing cognitive function. This study provides experimental evidence that thymoquinone (TQ) exerts neuroprotective effects in an AD-related ferroptosis model by modulating iron, lipid, and glutathione metabolism. METHODS: Thirty female C57BL/6 mice (8-10 weeks, 18-22 g) were randomly allocated into five groups: 1- Control, 2- artificial cerebrospinal fluid (aCSF; 20 ng/L), 3- RAS-selective lethal 3 (RSL3) (100 ng/10 µL in aCSF), 4- RSL3 + TQ (50 mg/kg in 1.0% w/v acacia gum), and 5- TQ alone (50 mg/kg in 1.0% w/v acacia gum). A bilateral hole was drilled according to the Bregma coordinates (0.5 mm back, 1 mm left-right, 2,5 mm deep) and a 10 µl Hamilton syringe was inserted perpendicularly from the skull to the brain. RSL3 (100 ng/10 µl) was infused with 4 µl (Intracerebral-IC). Cognitive and anxiety-like behaviors were assessed using the Morris Water Maze (MWM) and the Open Field Test (OFT). Hippocampal oxidative markers, total antioxidant status (TAS), and total oxidant status (TOS), were determined by spectrophotometric quantification. GPx4, XCT, and Fpn mRNA levels were measured by qRT-PCR. Protein expression and distribution were assessed by Western blotting and immunohistochemistry. Iron accumulation was visualized using Perl's Prussian blue staining method. RESULTS: RSL3-induced ferroptosis impaired spatial learning and increased anxiety-like behavior, accompanied by elevated hippocampal iron accumulation, oxidative stress, and downregulation of GPx4, XCT, and Fpn. TQ treatment significantly restored TAS levels, reduced TOS, suppressed iron deposition, and reversed ferroptosis-associated molecular changes, upregulating GPx4 and Fpn while attenuating XCT downregulation (P < 0.05). Ferroptosis-induced behavioral deficits were significantly improved by TQ. CONCLUSION: These findings identify TQ as a potent modulator of ferroptosis, acting through coordinated regulation of iron export, lipid peroxidation, and glutathione-dependent antioxidant defenses. TQ targeting convergent ferroptosis pathways is a promising therapeutic candidate to alleviate hippocampal neurodegeneration and cognitive decline in AD.}, } @article {pmid40986212, year = {2025}, author = {Syed, A and Elgorban, AM and Bahkali, AH and Wang, S and Wong, LS and Dhara, B and Uti, DE and Alum, EU and Atangwho, IJ}, title = {Therapeutic Potential of products derived from Pluchea lanceolata for Alzheimer's Disease Treatment.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {4}, pages = {122}, pmid = {40986212}, issn = {1559-1166}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Kelch-Like ECH-Associated Protein 1/metabolism/chemistry ; Molecular Docking Simulation ; NF-E2-Related Factor 2/metabolism/chemistry ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; Molecular Dynamics Simulation ; *Triterpenes/chemistry/pharmacology/therapeutic use ; }, abstract = {AD is a neurodegenerative disorder and is associated with the presence of amyloid-β plaques and neurofibrillary tangles leading to net loss of neurons, which demonstrates an urgent unmet need to develop new human health therapies based on the fundamental mechanisms of oxidative stress and neuroinflammation. This work is a computational assessment of the potential use of neolupenol, a triterpenoid produced in Pluchea lanceolata, as a pharmacologically active compound that exerted its beneficial effect through the modulation of the Keap1-Nrf2 axis, one of the central regulators of the antioxidant response. Using an integrated approach that combined network pharmacology, molecular docking, and molecular dynamics (MD) simulations, we identified neolupenol as a high-affinity Keap1-binding molecule capable of activating the Nrf2-mediated neuroprotective pathway. Virtual screening of 25 phytochemicals from Pluchea lanceolata (retrieved from the PubChem database) with customized filters revealed neolupenol as the top candidate, showing strong binding affinity (- 8.22 kcal/mol; Ki = 1.45 µM) toward the Keap1 Kelch domain (PDB ID: 2FLU). The docked complex demonstrated hydrogen bonds with VAL463 (2.17 Å), THR560, and ILE559, along with hydrophobic interactions involving CYS513, ALA366, and VAL514, which collectively stabilized the ligand at the Neh2-binding interface. Network pharmacology yielded 30 of such common targets of AD-neolupenol (e.g., GSK3B, CASP3, TNF, and BACE1), enriched in pathways such as amyloid processing, tau phosphorylation, oxidative stress response, and lipid metabolism (FDR-adjusted p < 0.0001). Complex stability was verified by MD simulations (100 ns): RMSD of the backbone 2.34-3.84 = 2.34 Å, unchanged radius of gyration (17.8-18.0 Å), and stable inter-hydrogen bonding. Residues VAL561, PHE577, and SER602 were found to have an interaction occupancy of > 70%, providing a basis of dynamic stability. The triterpenoid cavity appeared in neolupenol contributing to pleasant PK, the ability to herald the blood-brain barrier, and suboptimal toxicity. These results position neolupenol as a potent, multi-target neuroprotective agent that disrupts Keap1-Nrf2 interaction, promoting Nrf2 nuclear translocation and antioxidant gene activation. Future work warrants in vivo validation of its efficacy in mitigating AD pathology and clinical translation.}, } @article {pmid40986147, year = {2025}, author = {Sun, J and Zheng, Z}, title = {The active ingredient of Ginkgo biloba extract (quercetin) improved H2O2-induced microglia injury by activating NQO1-PI3K/Akt/mTOR signaling.}, journal = {In vitro cellular & developmental biology. Animal}, volume = {61}, number = {9}, pages = {1171-1184}, pmid = {40986147}, issn = {1543-706X}, mesh = {*Quercetin/pharmacology/chemistry ; TOR Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; *Plant Extracts/pharmacology/chemistry ; *Microglia/drug effects/pathology/metabolism ; *Signal Transduction/drug effects ; Animals ; *NAD(P)H Dehydrogenase (Quinone)/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Ginkgo biloba/chemistry ; Hydrogen Peroxide/toxicity ; Mice ; Cell Line ; Cellular Senescence/drug effects ; Oxidative Stress/drug effects ; Molecular Docking Simulation ; Humans ; Ginkgo Extract ; }, abstract = {Activated microglia are considered to be closely related to brain senescence and the pathogenesis of neurodegenerative diseases. Ginkgo biloba extract (GBE) is widely used to treat cognitive impairment and Alzheimer's disease (AD). This study aims to investigate the active ingredients of GBE and the underlying molecular mechanisms. The active ingredients of GBE in AD treatment were first analyzed by network pharmacology, culminating in the identification of the key ingredient, quercetin, and its targeted protein, NQO1. GO function enriched the oxidative stress pathway, while KEGG enriched the PI3K/Akt/mTOR pathway. Quercetin binding to NQO1 was verified by molecular docking and DARTS analysis. Cytotoxicity assay revealed no significant toxicity of GBE (0-1 mg/mL) and quercetin (0-0.4 μM) over 48 h. Subsequently, we constructed the microglial injury model by H2O2-induced HMC3 and BV2 cell lines. GBE and quercetin suppressed the senescence characteristics in H2O2-induced microglia. Further investigation revealed that the expression of NQO1 was downregulated in the injury model, and treatment with GBE and quercetin facilitated the protein expression of NQO1. In addition, silencing NQO1 reduced the promoting effect of quercetin on microglia viability and phosphorylation levels of PI3K, Akt, and mTOR. At the same time, it significantly increased the levels of p53, p21, p16 and β-galactosidase (SA-β-gal). Collectively, GBE mitigated H2O2-induced microglial injury, which activated the PI3K/Akt/mTOR pathway through the quercetin/NQO1 axis. These findings highlight quercetin/NQO1 signaling as a possible therapeutic target for senescence-related neurodegeneration.}, } @article {pmid40985039, year = {2025}, author = {Cahan, JG and Bonakdarpour, B}, title = {Primary Progressive Aphasia Treatment: Current Treatment Options in Neurology Article Topic: Management of Primary Progressive Aphasia.}, journal = {Current treatment options in neurology}, volume = {27}, number = {1}, pages = {39}, pmid = {40985039}, issn = {1092-8480}, abstract = {Primary progressive aphasia(PPA) is a rare neurodegenerative condition and variant presentation of Alzheimer's disease or Frontotemporal Dementia. It is characterized by progressive decline isolated to language functions. PPA provides a model for understanding the anatomy of language, where each cortical language center corresponds to distinct PPA subtypes. Understanding this anatomy and its corresponding PPA subtypes helps clinicians choose testing, interpret imaging, and tailor treatment. These subtypes are termed agrammatic/nonfluent, semantic, and logopenic PPA. Each subtype is probabilistically associated with three proteinopathies: the amyloid and tau of Alzheimer's disease and frontotemporal lobar degeneration due to Tau or TDP-43. We will discuss when biomarker testing is indicated and the nuances of choosing among the increasing array of biomarker tests to improve diagnostic certainty. While medical treatment is limited, there are increasing pharmacologic options for treating Alzheimer's disease. Non-pharmacologic strategies can also be tailored to the patient's specific subtype and caregivers' needs.}, } @article {pmid40984910, year = {2025}, author = {Bains, J and Ogunjobi, O}, title = {A Case Report Exploring Early-Onset Alzheimer's Disease With No Known Family History.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e90576}, pmid = {40984910}, issn = {2168-8184}, abstract = {This case report conveys a rare presentation of early-onset Alzheimer's disease (EOAD) in a 58-year-old female with no family history of dementia. The patient demonstrates progressive cognitive decline with features of memory loss and associated severe language impairment, subsequently leading to a delay in the definite diagnosis. A systematic literature review using PubMed and Google Scholar was undertaken to explore the features of EOAD and how it differs from late-onset Alzheimer's disease (AD), focusing on risk factors, clinical presentation, investigation, and management. Although this patient was not known to have a family history of AD, evidence suggestive of EOAD could be observed within a series of neuroimaging and diagnostic tests such as magnetic resonance imaging scans, cerebrospinal fluid analysis, and blood tests. Management of EOAD involves a combination of pharmacological and non-pharmacological interventions using a biopsychosocial approach. Overall, the case highlights challenges in recognition of EOAD in its early stages of presentation for patients with no family predisposition, whilst emphasizing the importance of early detection and management to help improve patient outcomes. It also focuses attention on the significant impact a condition such as EOAD can have on the family members involved. Further research would be required to potentially redefine diagnostic criteria and treatment strategies for conditions of such rarity.}, } @article {pmid40984655, year = {2025}, author = {Bloemer, J and Pinky, PD and Suppiramaniam, V and Reed, MN}, title = {Adiponectin Receptor Agonist Ameliorates Synaptic Dysfunction in 3xTg Alzheimer's Disease Mouse Model by Activation of AMPK.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {9}, pages = {e70616}, pmid = {40984655}, issn = {1755-5949}, support = {//American Foundation of Pharmaceutical Education/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/pathology/physiopathology ; *Receptors, Adiponectin/agonists/metabolism ; Mice, Transgenic ; Disease Models, Animal ; *AMP-Activated Protein Kinases/metabolism ; Hippocampus/drug effects/physiopathology ; Mice ; Long-Term Potentiation/drug effects ; *Synapses/drug effects ; Male ; Amyloid beta-Protein Precursor/genetics ; Synaptic Transmission/drug effects ; tau Proteins/genetics ; Mice, Inbred C57BL ; Presenilin-1/genetics ; Piperidines ; }, abstract = {AIM: The hormone adiponectin impacts various facets of brain function, including neurogenesis, energy homeostasis, and synaptic processes. The use of adiponectin or adiponectin receptor agonists may protect against Alzheimer's disease (AD) and reduce AD pathology. Here, we investigated the ability of the adiponectin receptor agonist, AdipoRon, to restore synaptic function in an AD mouse model and the underlying mechanism. METHODS: Acute hippocampal slices from 3xTg-AD mice and age-matched controls were used to evaluate the ability of AdipoRon to rescue synaptic deficits in an AD model. Slices were incubated in AdipoRon or other pharmacological agents, followed by electrophysiological field recordings to evaluate synaptic function and plasticity. Signaling pathway alterations were evaluated by Western blot, with a focus on AMP-activated protein kinase (AMPK) signaling. RESULTS: Incubation of hippocampal slices with AdipoRon ameliorated long-term potentiation (LTP) and basal synaptic transmission deficits in 3xTg-AD mice. AdipoRon was unable to restore these parameters in the presence of the AMPK inhibitor, Compound C. AdipoRon altered presynaptic parameters by a mechanism that did not appear to be solely dependent on AMPK. AdipoRon slice incubation was associated with activation of AMPK, inhibition of GSK3β, and altered glutamatergic receptor subunit phosphorylation based on Western blot analysis. CONCLUSION: Activation of adiponectin receptors restores synaptic function in an AD model in part through AMPK signaling. These results warrant further investigation into adiponectin receptor agonists as a novel approach for AD prevention or treatment.}, } @article {pmid40983196, year = {2025}, author = {Yan, F and Niu, J and Zhang, Y and Sun, Y and Wang, J and Liang, G and Cui, J and Ge, Y and Yang, F and Feng, L}, title = {Rational design of MAO-B-activated fluorescent probe for activity evaluation and its biomedical applications.}, journal = {Free radical biology & medicine}, volume = {241}, number = {}, pages = {236-242}, doi = {10.1016/j.freeradbiomed.2025.09.034}, pmid = {40983196}, issn = {1873-4596}, mesh = {*Monoamine Oxidase/metabolism/chemistry ; *Fluorescent Dyes/chemistry/chemical synthesis ; *Monoamine Oxidase Inhibitors/pharmacology/chemistry ; Humans ; Hydrogen Peroxide ; Animals ; Oxidative Stress/drug effects ; *Oxazines/chemistry/chemical synthesis/pharmacology ; }, abstract = {Monoamine oxidase mainly includes two isoforms, monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B), of which MAO-B is a crucial metabolic enzyme, acts on dopamine and β-phenylethylamine and can be selectively inhibited by pargyline. MAO-B has emerged as a significant drug target for a variety of nervous system diseases. In the present work, a highly selective and sensitive fluorescent probe named 3-aminopropyl (3-oxo-3H-phenoxazin-7-yl) carbamate (AHPC) was designed and developed. AHPC showed good stability and cell membrane permeability in biological systems, and could detect endogenous MAO-B activity in real time, and accurately evaluate the changes of MAO-B under H2O2-induced oxidative stress. In addition, AHPC was able to detect the distribution of MAO-B in different organs. As MAO-B is an important drug target, we developed a high-throughput, visual screening system for MAO-B inhibitors based on AHPC. Glycyrrhizae radix et rhizome was screened from 272 kinds of Chinese medicine and displayed strong inhibitory effect toward MAO-B. After further separation of Glycyrrhizae radix et rhizome, it was found that Licoisoflavone B was the main active ingredient to inhibit MAO-B activity in different enzyme sources, and was expected to be a lead compound for the treatment of MAO-B-related diseases. In conclusion, with the advantages of fluorescent probe technology, we not only developed a handy molecular tool for real-time detection of MAO-B distribution and function in complex biosystems, but also established a high-throughput visualization method for screening MAO-B inhibitors from traditional Chinese medicine, which are promising for the treatment of many MAO-B-related diseases.}, } @article {pmid40982764, year = {2026}, author = {Cao, Q and Liu, Z and Kang, H and Wang, L}, title = {Mechanisms and parameters of photobiomodulation for neurological and neuropsychiatric disorders: whether and how to apply?.}, journal = {Reviews in the neurosciences}, volume = {37}, number = {1}, pages = {77-91}, pmid = {40982764}, issn = {2191-0200}, mesh = {Humans ; *Low-Level Light Therapy/methods ; *Mental Disorders/therapy ; *Nervous System Diseases/therapy/radiotherapy ; Animals ; *Brain/radiation effects ; Brain Injuries, Traumatic ; }, abstract = {Neurological and neuropsychiatric disorders are among the leading causes of mortality and disability worldwide, with current treatment modalities including traditional therapies, psychological and supportive interventions, and emerging therapeutic approaches. Photobiomodulation (PBM), a neuromodulatory technique using lasers and light-emitting diodes (LEDs), has emerged as a promising intervention for enhancing brain function by stimulating neural activity, thereby protecting brain tissue and restoring function. Despite its widespread application, the precise mechanisms underlying the selection of critical parameters and their associated therapeutic effects remain incompletely understood. This systematic review synthesizes data from multiples studies over the past decade, investigating the effects of PBM on neurological and neuropsychiatric disorders, including traumatic brain injury (TBI), spinal cord injury (SCI), Alzheimer's disease (AD), Parkinson's disease (PD), generalized anxiety disorder (GAD), major depressive disorder (MDD), and healthy subjects. Emerging evidence suggests that the therapeutic mechanisms of PBM may involve enhanced energy metabolism, increased cerebral blood flow (CBF), modulation of oxidative stress, anti-inflammatory effects, neuroprotection and regeneration, enhanced synaptic plasticity, and regulation of resting-state brain networks. Regarding parameter selection, wavelength has emerged as a critical factor influencing penetration depth and the specific chromophore responsible for photon absorption and therapeutic efficacy. This review focuses on the characteristics of diverse wavelengths, as well as the roles of multiple chromophores and associated signaling pathways. Different irradiation modalities, including both non-invasive and invasive approaches, are examined, alongside optimal treatment windows for power and fluence. Additionally, less frequently addressed aspects, such as spot area and power density patterns, are considered.}, } @article {pmid40982213, year = {2025}, author = {Onuh, VC}, title = {Advancing Alzheimer's disease treatment: A literature review on senolytic intervention.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {42-52}, doi = {10.1177/13872877251376540}, pmid = {40982213}, issn = {1875-8908}, mesh = {*Alzheimer Disease/drug therapy/pathology ; Humans ; *Senotherapeutics/therapeutic use/pharmacology ; Animals ; *Cellular Senescence/drug effects/physiology ; Aging/drug effects ; Quercetin/therapeutic use/pharmacology ; Dasatinib/therapeutic use/pharmacology ; }, abstract = {Alzheimer's disease (AD) is a leading cause of dementia, currently affecting over 50 million people globally. Despite decades of research, therapeutic development has continued to face high failure rates due to an incomplete understanding of the underlying disease mechanisms. Current drugs like rivastigmine focus on managing cognitive symptoms since there is no known cure to halt the disease's progression. However, recent research has suggested that advanced biological age, particularly the accumulation of senescent cells, is the most significant risk factor for AD pathology, and targeting these aging mechanisms may prove more effective in altering the disease progression. Senescent cells accumulate with age, contributing to inflammatory states and neurodegenerative diseases such as AD. Senolytic drugs, such as dasatinib and quercetin (D + Q), have shown promise in animal models by clearing senescent cells, delaying aging-related decline, and improving AD-related outcomes. This literature review aims to provide a comprehensive overview of the therapeutic potential of senolytic interventions for AD by examining the mechanisms of cellular senescence based on evidence of its accumulation in the human brain, critically analyzing the preclinical and clinical trials involving senolytic compounds, and discussing the implications and limitations of this approach. The findings from recent studies indicate that senolytics may pave the way for effective AD treatments, though further clinical validation is needed.}, } @article {pmid40981102, year = {2025}, author = {Juranek, JK and Kordas, B and Podlasz, P and Bossowska, A and Banach, M}, title = {Current Evidence on the Involvement of RAGE-Diaph1 Signaling in the Pathology and Treatment of Neurodegenerative Diseases-An Overview.}, journal = {Pathophysiology : the official journal of the International Society for Pathophysiology}, volume = {32}, number = {3}, pages = {}, pmid = {40981102}, issn = {1873-149X}, abstract = {Neurodegenerative diseases are a group of disorders characterized by the progressive deterioration of the structure and function of central nervous system neurons and include, among others, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's (PD), Alzheimer's (AD), and Huntington's (HD) diseases. And while all these diseases seem to have different genetic and environmental components, growing evidence shows that they share common underlying pathological features such as increased neuroinflammation and excessive oxidative stress. RAGE, the receptor for advanced glycation end-products, is a signal transduction receptor, and its activation triggers an increase in proinflammatory molecules, oxidative stressors, and cytokines. Diaph1, protein diaphanous homolog 1, is an actin modulator and an intracellular ligand of RAGE. Studies demonstrated that RAGE and Diaph1 act together, and their downstream signaling pathways play a role in neurodegeneration. Here, based on current evidence and our own research, we provide an overview of the RAGE-Diaph1 signaling and discuss the therapeutic potential of targeted therapy aimed at RAGE-Diaph1 signaling inhibition in the prevention and treatment of neurodegenerative diseases.}, } @article {pmid40980544, year = {2025}, author = {Goodson, MM and Gwizdala, KL and Manrique, IR and Rao, A and Beyl, R and Martin, CK and Firmin, S and Salceanu, V and Newton, RL and Carmichael, OT}, title = {Acute Effect of Intranasal Insulin on Food Intake Among Middle-Aged African American Adults: The FIINAAL Study.}, journal = {Journal of the Endocrine Society}, volume = {9}, number = {10}, pages = {bvaf138}, pmid = {40980544}, issn = {2472-1972}, support = {P30 DK072476/DK/NIDDK NIH HHS/United States ; U54 GM104940/GM/NIGMS NIH HHS/United States ; }, abstract = {CONTEXT: Intranasal insulin has emerged as a promising potential treatment for cognitive decline. However, African American adults are under-represented in this research area, and unintentional weight loss is a possible detrimental side effect. OBJECTIVE: We assessed effects of acute intranasal insulin exposure on food intake and appetite-related constructs among middle-aged, obese, cognitively normal African American adults. We hypothesized that intranasal insulin would result in fewer calories consumed, greater feelings of fullness, and less hunger compared to placebo. METHOD: A total of 39 participants received intranasal doses of Novolin-R (40 IU) and a saline placebo on separate days in a double-blind, counterbalanced, crossover design, with 3-day, eucaloric, nutritionally balanced diets preceding each dose. Doses were preceded by a 4-hour fast and followed by a test lunch. Visual analog scales (VAS) were used to assess appetite immediately before and after each dose, and after each lunch. Mixed effects linear model t tests were used to compare questionnaires and lunch intake between insulin and placebo. RESULTS: There were no significant differences in food intake between conditions. However, feelings of fullness were significantly greater immediately after insulin compared to placebo. In addition, the desire to consume sweet foods decreased significantly more after insulin than after placebo. CONCLUSION: Acute intranasal insulin was associated with a reduced desire for sweet foods and with increased feelings of fullness, but not reduced food intake, among middle-aged African American adults. Eating behavior and appetite changes should be explored further as possible side effects of intranasal insulin treatment for cognitive decline in diverse populations.}, } @article {pmid40979532, year = {2025}, author = {Bishara, MA and Chum, PP and Miot, FEL and Hooda, A and Hartman, RE and Behringer, EJ}, title = {Molecular pathogenesis of Alzheimer's disease onset in a mouse model: effects of cannabidiol treatment.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1667585}, pmid = {40979532}, issn = {1662-4548}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a common neurodegenerative condition involving a complex blend of disturbances in synaptic development and maintenance, neurovascular cross-talk, ionic and nutrient transport, and mitochondrial metabolism. The precise molecular profile of AD onset with insight for major pathological contributors remains unclear with corresponding impedances in therapeutic development. The current study sought two objectives, as (i) to resolve the molecular pathogenesis from cognitive impairment to the onset of AD-like neuropathology and (ii) whether the novel agent cannabidiol (CBD), noted for its neuroprotective effects, influences the molecular transition associated with AD onset. METHODS: Dietary CBD was administered daily (80-100 mg/kg/day) in male 3xTg-AD mice and wild-type B6129SF2/J animals from 4.5 to 6.5 mo of age with inclusion of vehicle controls. RNA sequencing encompassed longitudinal and cross-sectional blood and brain samples, respectively. Metabolomics and behavioral analyses examined brain regions (cortex, hippocampus) and associated integrated neurocircuitry. RESULTS AND DISCUSSION: There were >1,000 differentially expressed markers of AD onset, whereby >75% were either eliminated or reversed in the direction of expression in response to CBD. Signaling pathways encompassed synaptic development and plasticity (e.g., Foxp2), neurovascular interactions (Smad9, Angptl6), receptors and ion channels (Gria4, Chrna2, Rgs7/Rgs7bp), mitochondrial genes (Ndufa7, Cox7a2), immunity (Ncr1), oxidation-reduction (Esr1), lipid synthesis (Fasn, ApoE), and carbohydrate metabolism (Mafa, Mlxipl). As potentially addressable with CBD treatment, AD onset represents molecular integration of neurovascular interactions, channelopathies, metabolic disturbances, and aberrations in developmental genes with involvement of major pathological contributors such as inflammation, oxidative signaling, dyslipidemia, and insulin resistance.}, } @article {pmid40979047, year = {2025}, author = {Yashaeva, L and Montoya, M and Joshi, J and Stephens, A and McNulty, O and Kaur, G}, title = {Advancing Care in Alzheimer's Disease: Current Treatments and Their Impact on Quality of Life.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e90527}, pmid = {40979047}, issn = {2168-8184}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. It is currently the most common cause of dementia globally and carries a significant disease burden, given the rising aging population worldwide. Although AD is debilitating for the patient, the complex nature of the disease is also a source of tremendous mental distress for caregivers. Finding, understanding, and evaluating the best treatments can be challenging and overwhelming when coping with a life-changing diagnosis of AD. Although there is currently no definite cure for AD, all the discussed treatments aim to improve a patient's quality of life and attenuate the time spent in disability. This study compiles and discusses the risks, benefits, and efficacy of all currently available treatments for AD, including treatments that target the control of cognitive and non-cognitive symptoms. Additionally, the manuscript discusses investigational therapeutics, including small molecules and immunotherapies in phase 2 or 3 clinical trials, and assesses non-pharmacological interventions that may alleviate disease burden.}, } @article {pmid40978711, year = {2025}, author = {Liu, C and Meng, Y and Liu, R and Wang, Z and Zhao, H}, title = {Pathological Mechanisms and Molecular Imaging Advances in Alzheimer's Disease.}, journal = {Clinical interventions in aging}, volume = {20}, number = {}, pages = {1583-1603}, pmid = {40978711}, issn = {1178-1998}, mesh = {*Alzheimer Disease/diagnostic imaging/pathology ; Humans ; *Molecular Imaging/methods ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Gastrointestinal Microbiome ; Early Diagnosis ; Extracellular Vesicles ; Multimodal Imaging ; }, abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders globally, where early diagnosis plays a pivotal role in delaying disease progression and improving patient outcomes. In recent years, the rapid, multidisciplinary advances in molecular imaging and emerging technologies have significantly advanced our understanding of AD pathogenesis, early diagnosis, and intervention strategies. Imaging tools such as positron emission tomography (PET) and magnetic resonance imaging (MRI), alongside emerging technologies like retinal imaging, nanosensors, and quantum dots (QDs), are continuously enhancing AD diagnostic pathways. Studies on the gut microbiome and extracellular vesicles (EVs) offer novel insights into AD pathogenesis. Furthermore, AI-driven multimodal data fusion techniques hold great promise for improving diagnostic accuracy. Future research will increasingly focus on multi-target synergistic intervention strategies, standardization of multimodal imaging, and the integration of AI with molecular diagnostics and treatment to enable early detection and personalized precision therapy for AD.}, } @article {pmid40978281, year = {2025}, author = {Porayette, P and Kaltcheva, MM and Perry, G and Butler, T and Vadakkadath Meethal, S and Atwood, CS}, title = {Progesterone induction of tau phosphorylation during the differentiation of human embryonic stem cells into neuroectodermal rosettes.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251370643}, pmid = {40978281}, issn = {2542-4823}, abstract = {BACKGROUND: Tau phosphorylation is associated with neuronal division and differentiation in the fetal brain, in neuroblastoma cells, in the hibernating brains of ground squirrels and black bears, and in post-mitotic neurons in the Alzheimer's disease (AD) brain. The disassembly of the rigid microtubule structure of neurons for neuronal division and neurite remodeling requires the removal of the microtubule stabilizing protein tau via its phosphorylation. OBJECTIVE: To determine if tau phosphorylation is required during neural embryogenesis. METHODS: Using an in vitro human model of early embryonic development, human embryonic stem cells (hESC) were differentiated into embryoid bodies (EBs; akin to an early blastocyst) and then into neuroectodermal rosettes (akin to a rudimentary neural tube containing neuroectodermal precursor cells) upon treatment with progesterone. The neuroectodermal rosettes were then treated with and without LiCl (Cdk5 inhibitor) or roscovitine (GSK-3β inhibitor) and assayed for the expression of tau, P-tau, nestin (an early marker of neurogenesis), Cdk5 and GSK-3β. RESULTS: Tau was not expressed in hESC, but tau expression and its phosphorylation increase upon progesterone-induced differentiation of hESC into neuroectodermal rosettes. Both Cdk5 and GSK-3β, enzymes associated with tau phosphorylation, were expressed in hESCs, EBs, and neuroectodermal rosettes. The GSK-3β inhibitor LiCl, but not the Cdk-5 inhibitor roscovitine, prevented tau phosphorylation and nestin expression and the formation of neuroectodermal precursor cells. CONCLUSIONS: These preliminary results suggest that progesterone induces tau expression and its phosphorylation during the differentiation of neuroectodermal rosettes from hESC and suggest that tau and its phosphorylation is obligatory for neuronal precursor cell mitosis. The parallels between neural embryogenesis and neurodegeneration are discussed in the context of tau phosphorylation and the aberrant re-entry of neurons into the cell cycle in AD.}, } @article {pmid40977903, year = {2025}, author = {Verlaan, T and Bouland, GA and Mahfouz, A and Reinders, MJT}, title = {scAGG: Sample-level embedding and classification of Alzheimer's disease from single-nucleus data.}, journal = {Computational and structural biotechnology journal}, volume = {27}, number = {}, pages = {3753-3761}, pmid = {40977903}, issn = {2001-0370}, abstract = {Identifying key cell types and genes in Alzheimer's Disease (AD) is crucial for understanding its pathogenesis and discovering therapeutic targets. Single-cell RNA sequencing technology (scRNAseq) has provided unprecedented opportunities to study the molecular mechanisms that underlie AD at the cellular level. In this study, we address the problem of sample-level classification of AD using scRNAseq data, where we predict the disease status of entire samples from the gene expression profiles of their cells, which are not necessarily all affected by the disease. We introduce scAGG (single-cell AGGregation), a sample-level classification model that uses a sample-level pooling mechanism to aggregate single-cell embeddings, and show that it can accurately classify AD individuals and healthy controls. We then investigate the latent space learnt by the model and find that the model learns an ordering of the cells corresponding to disease severity. Genes associated with this ordering are enriched in AD-linked pathways, including cytokine signalling, apoptosis, and metal ion response. We also evaluate two attention-based models that perform on par with scAGG, but entropy analysis of their attention scores reveals limited interpretability value. As scRNAseq is increasingly applied to large cohorts and cell-level disease association annotations do not exist, our approach provides a way to classify phenotypes from single-cell measurements. The yielded cell- and sample-level severity scores may enable identification of AD-associated cell subtypes, paving the way for targeted drug development and personalized treatment strategies in AD. Code is available at: https://github.com/timoverlaan/scAGG.}, } @article {pmid40976462, year = {2025}, author = {Shi, M and Chu, F and Zhu, J}, title = {Stem cells therapy in neurodegenerative and neuroimmune diseases: Current status of treatments and future prospects.}, journal = {Pharmacological research}, volume = {221}, number = {}, pages = {107960}, doi = {10.1016/j.phrs.2025.107960}, pmid = {40976462}, issn = {1096-1186}, mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods ; }, abstract = {Neurodegenerative and neuroimmune diseases, such as multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) share a common pathologic hallmark i.e. loss of neurons in the central nervous system (CNS), despite diverse pathological manifestations. These diseases present major challenges to global health due to incurable or extremely difficult to treat, imposing a heavy burden on society and families. Stem cell therapy, as a novel promising approach for treating various neurological diseases, harnesses the regenerative potential of stem cells to repair damaged neural tissues and circuits, and has become the only hope for patients to recover their health or delay the deterioration of disease symptoms. In recent years, researchers have successfully generated neurons from multiple types of stem cells, and good curative effects have been achieved in their animal models and in clinical trials. This comprehensive review elaborates on the relevant content of stem cell biology, focuses on conducting an in-depth analysis of the current application status of various stem cells in major neurodegenerative and neuroimmune diseases including MS, AD, PD and ALS, kindling the hope for the development of stem cell-based cell therapies in neurological diseases.}, } @article {pmid40976434, year = {2025}, author = {Melcop, J and Ong, JY and Ciaghi, S and Keramopoulou, M and Schatz, A and Winter, Y and Szele, FG and Stumpenhorst, K}, title = {Correlation of adult neurogenesis and cognitive performance in touchscreen tasks - assessing the novel small molecule OXS-N1 in mice.}, journal = {Neuroscience}, volume = {589}, number = {}, pages = {322-334}, doi = {10.1016/j.neuroscience.2025.09.024}, pmid = {40976434}, issn = {1873-7544}, mesh = {Animals ; *Neurogenesis/drug effects/physiology ; Mice, Inbred C57BL ; *Cognition/drug effects/physiology ; Mice, Transgenic ; Male ; *Alzheimer Disease/physiopathology/drug therapy/pathology ; Mice ; Hippocampus/drug effects ; Dentate Gyrus/drug effects ; Disease Models, Animal ; Reversal Learning/drug effects ; Neurons/drug effects/physiology ; }, abstract = {Adult hippocampal neurogenesis in the dentate gyrus is well-defined in rodents, and its role in cognitive functions as well as its potential as a therapeutic target for neurodegenerative diseases such as Alzheimer's disease remain a topic of great scientific interest. In this study, we evaluated the effects of a novel small molecule, OXS-N1, on neurogenesis and behavior in C57Bl/6 wild-type and 5xFAD Alzheimer's disease model mice, which were tested independently at different ages. Modern, home-cage based set-ups were implemented for automated, voluntary animal behavioral testing. OXS-N1 failed to enhance hippocampal cognitive functions in either cohort as assessed by two hippocampus-dependent touchscreen tasks. Contrary to previous short-term assessments, OXS-N1 also had no significant treatment effect on adult hippocampal neurogenesis in both wild-type and 5xFAD mice. We further analyzed correlations between individual mouse neurogenesis levels and behavioral performance independent of treatment. The density of adult-born neurons in the dentate gyrus showed no significant correlation with spatial pattern separation or reversal learning ability in the Location Discrimination task and did not affect associative memory acquisition in the Paired-Associates Learning task in either wild-type or 5xFAD mice. Our results provide further critical evidence on the complex role of adult neurogenesis for hippocampal cognition in health and disease.}, } @article {pmid40976394, year = {2025}, author = {Aumer, B and Rosa Porto, R and Coles, M and Ulmer, N and Watt, G and Kielstein, H and Karl, T}, title = {Combination treatment with medium dose THC and CBD had no therapeutic effect in a transgenic mouse model for Alzheimer's disease but affected other domains including anxiety-related behaviours and object recognition memory.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {257}, number = {}, pages = {174101}, doi = {10.1016/j.pbb.2025.174101}, pmid = {40976394}, issn = {1873-5177}, mesh = {Animals ; *Dronabinol/administration & dosage/pharmacology/therapeutic use ; *Cannabidiol/administration & dosage/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/psychology ; Mice, Transgenic ; Female ; Mice ; *Anxiety/drug therapy ; Disease Models, Animal ; *Recognition, Psychology/drug effects ; Behavior, Animal/drug effects ; Maze Learning/drug effects ; Drug Therapy, Combination ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that effects memory and behaviour. The phytocannabinoid cannabidiol (CBD) has been found to reverse impairments of recognition as well as spatial memory deficits of AD transgenic mice but had only limited effects on disease-relevant brain pathologies. Recent evidence suggests that combining CBD with other cannabinoids including delta-9-tetrahydrocannabinol (THC) may lead to improved therapeutic outcomes. Thus, this study evaluated the chronic effects of combined treatment with 3 mg/kg THC and 20 mg/kg CBD on 14.5-month-old APPSwe/PS1ΔE9 (APP/PS1) transgenic females and control littermates. Mice were treated with THCxCBD or vehicle (VEH) daily via intraperitoneal injections for 3 weeks before behavioural testing commenced. AD-relevant behavioural domains were analysed utilising Elevated Plus Maze (EPM), open field (OF), novel object recognition test (NORT), social interaction (SI), Y-maze (YM), and prepulse inhibition test (PPI). APP/PS1 females showed an anxiety-like phenotype and object recognition deficits that remained unchanged by cannabinoid treatment. Interestingly, some effects of THCxCBD appeared genotype-dependent with cannabinoid treatment causing an anxiogenic EPM response in APP/PS1 mice but having an anxiolytic-like effect in WT females. Moreover, THCxCBD administration disrupted the novel object preference of control females. Noteworthy, THCxCBD significantly decreased different fat depots and bodyweight of all mice across genotype. No other differences between genotypes or treatment groups were detected. In conclusion, the particular cannabinoid combination strategy utilised had no prominent therapeutic-like effect in 14.5-month-old APP/PS1 females.}, } @article {pmid40975511, year = {2025}, author = {Alshehri, ZS}, title = {Integrating artificial intelligence with small molecule therapeutics and precision medicine for neurochemical understanding of Alzheimer's diseases.}, journal = {Neuroscience}, volume = {586}, number = {}, pages = {44-57}, doi = {10.1016/j.neuroscience.2025.08.055}, pmid = {40975511}, issn = {1873-7544}, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/therapy/diagnostic imaging ; *Artificial Intelligence ; *Precision Medicine/methods ; Animals ; Biomarkers/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative condition and continues to pose significant clinical and research challenges due to its complex causes and limited treatment success. Conventional therapies have primarily focused on amyloid-beta (Aβ) and tau proteins, but these efforts have yet to produce optimal results. This review explores emerging interdisciplinary strategies that integrate artificial intelligence (AI), small molecule drugs, and precision treatments to tackle AD's intricacies. AI has significantly enhanced early detection, neuroimaging, and biomarker discovery using machine learning and deep learning. These state-of-art methods helps to analyze biomarker profiles and imaging data, thereby enabling tailored diagnostic and therapeutic strategies for individual patients. At the same time, computational methods have expedited the development of small molecules targeting Aβ buildup, tau pathology, and inflammation. Emerging treatments, including monoclonal antibodies, RNA-based therapies, and nanotechnology, provide promising alternatives to conventional approaches. The integration of AI with multi-omics and structure-guided drug design supports the creation of precise, individualized treatments. However, challenges in ethics, regulation, and clinical application persist. This review emphasizes the collaborative potential of AI, pharmacology, and biomedical engineering in revolutionizing AD treatment, highlighting the need for cross-disciplinary efforts to confront this urgent neurological condition.}, } @article {pmid40975319, year = {2026}, author = {Sukumaran, ES and S, AN}, title = {Why 7-ketocholesterol matters now: A rapid review of its pathogenic and therapeutic relevance.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {255}, number = {}, pages = {106865}, doi = {10.1016/j.jsbmb.2025.106865}, pmid = {40975319}, issn = {1879-1220}, mesh = {*Ketocholesterols/metabolism ; Humans ; Animals ; Oxidative Stress ; Inflammation/metabolism ; Antioxidants/therapeutic use ; Neurodegenerative Diseases/metabolism ; Biomarkers/metabolism ; Aging/metabolism ; }, abstract = {7-Ketocholesterol (7-KC), a major oxysterol formed through cholesterol autoxidation, is increasingly recognized as a pathogenic mediator in ageing and chronic disease. Detected in atherosclerotic plaques, Alzheimer's cortex, aged retina, and lysosomal storage disorders, 7-KC actively drives oxidative stress, chronic inflammation, organelle dysfunction, and oxiapoptophagy. These mechanisms underpin its role in cardiovascular, neurodegenerative, and metabolic pathologies. Recent advances highlight nutritional antioxidants, pharmacological agents, microbial bioremediation, and nanotechnology as promising therapeutic avenues. Recognizing 7-KC as both a biomarker and therapeutic target offers opportunities for innovation in diagnostics and treatment of age-related and inflammatory disorders.}, } @article {pmid40974909, year = {2025}, author = {Fazeli, B and Botzenhardt, S and Bachhuber, F and Klassen, P and Klose, V and Dorst, J and Wiesenfarth, M and Uzelac, Z and Jesse, S and Brenner, D and Anderl-Straub, S and Ludolph, AC and Otto, M and Weishaupt, J and Tumani, H and Halbgebauer, S}, title = {Comparative analysis of cerebrospinal fluid neurofilament medium, light and heavy chain in neurodegenerative diseases using an in-house assay for the detection of neurofilament medium chain.}, journal = {EBioMedicine}, volume = {120}, number = {}, pages = {105930}, pmid = {40974909}, issn = {2352-3964}, mesh = {Humans ; *Neurofilament Proteins/cerebrospinal fluid ; Male ; Female ; Biomarkers/cerebrospinal fluid ; *Neurodegenerative Diseases/cerebrospinal fluid/diagnosis ; Aged ; Middle Aged ; Amyotrophic Lateral Sclerosis/cerebrospinal fluid/diagnosis ; ROC Curve ; Aged, 80 and over ; Frontotemporal Dementia/cerebrospinal fluid/diagnosis ; }, abstract = {BACKGROUND: Neurofilaments are key axonal proteins, with neurofilament light (NfL) and heavy (NfH) chain recognised as promising biomarkers for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). However, neurofilament medium chain (NfM) remained previously underexplored due to a lack of quantitative assays. In this study, we developed a sensitive immunoassay to measure NfM in cerebrospinal fluid (CSF) and analysed its levels in ALS, Alzheimer's disease (AD), frontotemporal dementia (FTD), and Lewy body dementia (LBD). Correlations among neurofilaments and their diagnostic performance were also evaluated. METHODS: In this study CSF levels of three neurofilament proteins were measured in 305 participants, including patients with ALS (n = 91), AD (n = 59), FTD (n = 38), LBD (n = 18), non-neurodegenerative controls (CTRL, n = 51), and 48 individuals initially evaluated for ALS but ultimately diagnosed with other conditions (CTRL.DD). NfM levels were quantified using a homemade sandwich ELISA, while NfL and NfH were measured using commercialised Ella cartridges. FINDINGS: All three neurofilaments were significantly elevated in ALS compared to CTRL and CTRL.DD groups (p < 0.0001 for both), with NfM and NfL also increased in FTD (p < 0.0001 for both) and AD (NfM, p < 0.0001; NfL, p = 0.0001) compared to CTRL. NfH demonstrated the greatest distinction between ALS and FTD (p < 0.0001). Strong correlations were observed among neurofilament subunits, particularly between NfM and NfL (r = 0.93, 95% CI: 0.91-0.94, p < 0.0001). All neurofilaments effectively distinguished ALS from CTRL and CTRL.DD, with AUC values ranging from 0.92 to 0.99. NfM and NfL showed high accuracy in differentiating AD (NfM, AUC: 0.91; NfL, AUC: 0.89) and FTD (NfM, AUC: 0.91; NfL, AUC: 0.92) from CTRL, while NfH best separated ALS from FTD (AUC: 0.96). INTERPRETATION: This study provides a quantitative comparison of NfM with NfL and NfH in a neurodegenerative cohort, highlighting its potential diagnostic value. Further research with larger cohorts, longitudinal studies, and investigations into neurofilament distribution in different compartments is needed to clarify the distinct roles of NfM, NfL, and NfH in the diagnosis and treatment of neurological diseases. FUNDING: The present study was supported by the Else Kroener-Fresenius Foundation (2024-EKEA.126) and Chemische Fabrik Karl Bucher GmbH.}, } @article {pmid40974820, year = {2026}, author = {Zhu, XD and Huang, LP and Zhu, N and Yang, XY and Yan, FX and Liu, M and Zhang, P and Wu, QY and Zhou, J and Wu, Y}, title = {A UPLC-Q/TOF-MS-based plasma and hippocampal metabolomics analysis was conducted to investigate the impact of Erjing Pills on Alzheimer's Disease rats.}, journal = {Journal of pharmaceutical and biomedical analysis}, volume = {267}, number = {}, pages = {117147}, doi = {10.1016/j.jpba.2025.117147}, pmid = {40974820}, issn = {1873-264X}, mesh = {Animals ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Hippocampus/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism/blood ; Rats ; Metabolomics/methods ; Male ; Rats, Sprague-Dawley ; Chromatography, High Pressure Liquid/methods ; Maze Learning/drug effects ; Disease Models, Animal ; Mass Spectrometry/methods ; }, abstract = {Alzheimer's Disease (AD), the most common form of dementia, places a significant burden on individuals and society. In line with the doctrines of Chinese medical practice, kidney deficiency and insufficient marrow cannot nourish the brain, leading to insufficient blood, cerebral dysfunction, and ultimately dementia. Erjing Pills contain wolfberry and Polygonati Rhizoma, which tonify the kidneys and improve the essence. Although pharmacological studies have demonstrated that Erjing Pills can be used to prevent and treat AD, the detailed action mechanism is yet to be determined. To comprehensively reveal the mechanism of action of Erjing Pills in the prevention and treatment of AD, three pharmacodynamic evaluations, the water maze test, both hematoxylin-eosin and immunohistochemical techniques were utilized to assess the effects of Erjing Pills on AD rats. Furthermore, plasma and hippocampus metabolomics were conducted by various statistical analyses combined with UPLC-Q/TOF-MS were employed for a comprehensive and accurate analysis of the in vivo anti-AD effects of Erjing Pills. Erjing Pills enhanced learning and memory capacity decreased hippocampal Aβ deposition expression, and enhanced hippocampal morphology in AD rats. After Erjing Pills treatment, 38 plasma metabolites and 15 hippocampal metabolites of AD rats were regressed to levels similar to those of controls. Moreover, pathways impacted by Erjing Pills on AD included arachidonic acid metabolism, retinol metabolism, glycerophospholipid metabolism, and caffeine metabolism. Additionally, adrenaline, leukotriene B4, retinol, and paraxanthine clearly distinguished the Erjing Pills group from the AD group. These findings significantly enhance our comprehension of the metabolic pathways implicated in AD and shed light on the therapeutic mechanisms of Erjing Pills in alleviating symptoms in rats with AD.}, } @article {pmid40974595, year = {2025}, author = {Li, RX and Shang, X and Shen, PQ and Zhu, YF and Gao, EQ and Yue, Q}, title = {Ultrasensitive Electrochemical Detection of Amyloid-β Peptide Using a Homochiral Metal-Organic Framework Binding to the l-Diphenylalanine Targeting Site.}, journal = {ACS sensors}, volume = {10}, number = {10}, pages = {7260-7269}, doi = {10.1021/acssensors.4c03425}, pmid = {40974595}, issn = {2379-3694}, mesh = {*Amyloid beta-Peptides/analysis/cerebrospinal fluid/chemistry ; *Metal-Organic Frameworks/chemistry ; *Electrochemical Techniques/methods ; *Phenylalanine/analogs & derivatives/chemistry ; Limit of Detection ; *Peptide Fragments/analysis ; Humans ; Animals ; Binding Sites ; Zinc/chemistry ; Dipeptides ; }, abstract = {The high sensitivity and accuracy of amyloid-β peptide (Aβ) detection could provide strong support for early diagnosis, monitoring of disease progression, and effective treatment of Alzheimer's disease (AD). Improving the specificity and affinity of sensing materials for Aβ is key to detecting Aβ. Herein, an electrochemical sensor based on an unmodified homochiral MOF, Zn-BPIleBp, was developed for the first time for the detection of Aβ1-40, with an ultralow detection limit of 1.7 pM (7.36 pg/mL). The Zn-BPIleBp sensor also displays high-efficiency enantioselectivity and ultrasensitivity in identifying diphenylalanine (PhePhe) corresponding to the core recognition motif of Aβ1-40, with a high peak current ratio (IL/ID) of 2.78, large potential difference (EL - ED) of 140 mV, and ultralow detection limit of 34 fM for l-PhePhe. The sensor has been successfully applied for the ultrasensitive quantification of l-PhePhe and Aβ1-40 in racemic mixtures, artificial cerebrospinal fluid (aCSF) and fetal bovine serum (FBS). According to structural and spectral analysis, the high sensitivity and affinity of homochiral MOF toward Aβ1-40, without the involvement of any biomolecular modifications such as antibodies or aptamers, stem from the structural, hydrophobic, and chiral matching between the framework and Aβ1-40. This sensor proffers a fast, highly stable, reproducible, ultrasensitive, and accurate detection method for Aβ1-40, demonstrating great potential in the clinical application of AD. This work also opens up new perspectives for designing sensing platforms using MOFs as sensing materials and expanding their functionality and applications to the fields of biological and medical analysis.}, } @article {pmid40974571, year = {2025}, author = {Naveed, M and Kim, MH}, title = {Nanoparticle-mediated magnetic hyperthermia in the treatment of neurological disorders.}, journal = {Nanomedicine (London, England)}, volume = {20}, number = {22}, pages = {2791-2803}, pmid = {40974571}, issn = {1748-6963}, support = {R01 AG076699/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Hyperthermia, Induced/methods ; *Magnetite Nanoparticles/chemistry/therapeutic use ; Animals ; *Nervous System Diseases/therapy ; Alzheimer Disease/therapy ; Glioblastoma/therapy ; Magnetic Fields ; }, abstract = {Neurological disorders including gliomas and neurodegenerative diseases are characterized by dysregulation of the central nerve system (CNS). Despite recent advances in disease-modifying treatments, pharmacological approaches for neurological disorders still face limitations due to the complexity of these diseases and the challenges in targeting the underlying mechanisms. Magnetic hyperthermia, an approach that utilizes magnetic nanoparticles (MNPs) to generate localized heat in target cells and tissues by responding to an alternating magnetic field (AMF), has been developed as a non-pharmacological treatment approach for targeting tumor cells or pathogens, primarily through thermal inactivation. Recently, beyond its traditional application in thermal therapies, magnetic hyperthermia has been increasingly explored for neurological diseases. Importantly, recent studies demonstrate the ability of magnetic hyperthermia in eliciting various biological effects by means of triggering heat shock protein (HSP) signaling, enhancing immune responses, and activating heat-sensitive ion channels in neurons. This review highlights the current understanding of magnetic hyperthermia in stimulating molecular and cellular effects on brain tissue and further discusses its potential in the treatment of neurological disorders including Glioblastoma Multiforme (GBM), Alzheimer's Disease (AD), Parkinson's Disease (PD). The studies discussed in this review were selected by using the search tool on PubMed with the suggested key words.}, } @article {pmid40974521, year = {2025}, author = {Jiang, HN and Zhang, B and Zhang, J and Zhou, YY}, title = {Dihuang Yinzi Regulates cAMP/PKA/CREB-BDNF to Improve Synaptic Plasticity in APP/PS1 Mice: A Study Based on Brain Metabolomics.}, journal = {Chinese journal of integrative medicine}, volume = {31}, number = {11}, pages = {991-1000}, pmid = {40974521}, issn = {1993-0402}, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; Male ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Brain/metabolism/drug effects ; *Metabolomics ; Mice, Inbred C57BL ; *Neuronal Plasticity/drug effects ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Cyclic AMP-Dependent Protein Kinases/metabolism ; *Cyclic AMP/metabolism ; Reactive Oxygen Species/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; Mice, Transgenic ; Mice ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects ; Alzheimer Disease/drug therapy ; Superoxide Dismutase/metabolism ; }, abstract = {OBJECTIVE: To explore the mechanism of Dihuang Yinzi (DHYZ) in the treatment of Alzheimer's disease (AD) by integrating metabolomics and experimental verification. METHODS: Forty-eight male APP/PS1 mice were divided into model, high- (DHYZ-H), medium- (DHYZ-M), and low-dose DHYZ (DHYZ-L) groups (12 mice per group) according to a random number table. Mice in DHYZ groups were gavaged with DHYZ 6.34, 12.68, and 25.35 g/(kg·d), respectively. Twelve C57BL/6 mice were gavaged with distilled water as the blank group. Metabolomics was used to analyze differential metabolites in the brains of mice. Morris water maze test was used to detect the memory abilities of mice. The hematoxylin-eosin staining and transmission electron microscopy were used to observe the general morphology and ultrastructure of neurons. The enzyme-linked immunosorbent assay was used to detect the levels of superoxide dismutase (SOD), reactive oxygen species (ROS), and amyloid β -protein 1-42 (A β1-42). The real-time quantitative polymerase chain reaction was used to detect the mRNA expressions of density-regulated protein 1 (DRP1), fission 1 (FIS1), mitofusin-1 (MFN1), and optic atrophy protein 1 (OPA1). Western blot was used to detect the protein expressions of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response binding protein (CREB), brain-derived neurotrophic factor (BDNF), synapsin 1 (SYN1), synaptophysin (SYP), and postsynaptic density protein 95 (PSD95). RESULTS: A total of 82 differential metabolites were identified in the brains of APP/PS1 mice, among which 7 differential metabolites could be regulated by DHYZ. After DHYZ intervention, the memory abilities of mice significantly increased (P<0.05 or P<0.01), the number of synapses and neurons in the hippocampus increased, and the mitochondrial morphology and structure were relatively intact. The DHYZ groups exhibited a significant reduction in hippocampal ROS and A β1-42 levels, along with a significant elevation in SOD level (P<0.05 or P<0.01). The mRNA expressions of DRP1 and FIS1 were reduced, while the mRNA expressions of MFN1 and OPA1 were increased after DHYZ treatment (P<0.05 or P<0.01). The cAMP/PKA/CREB-BDNF pathway was activated, and the expressions of SYN1, SYP and PSD95 proteins were significantly increased in the DHYZ-H group (P<0.05 or P<0.01). CONCLUSIONS: DHYZ could improve mitochondrial dynamics and synaptic plasticity in APP/PS1 mice, inhibit oxidative stress, and thereby enhancing learning and memory abilities in APP/PS1 mice. Its mechanism might be related to activation of the cAMP/PKA/CREB-BDNF signaling pathway.}, } @article {pmid40973891, year = {2025}, author = {Xie, R and Liu, Z and Zheng, J and Tan, Q and Wu, H and Liang, Y}, title = {Bioavailability enhancement and neuropharmacological effects of Dauricine under intranasal administration to improve cognitive impairment via PI3K/AKT/mTOR pathway.}, journal = {Drug delivery and translational research}, volume = {}, number = {}, pages = {}, pmid = {40973891}, issn = {2190-3948}, support = {2025A1515010474//Basic and Applied Basic Research Foundation of Guangdong Province/ ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder strongly associated with aging, and Dauricine (DAU) has demonstrated significant neuropharmacological properties for AD treatment. However, its bioavailability is significantly limited when administered orally, leaving the mechanisms underlying its effects on AD largely unexplored. In this study, a DAU-loaded thermosensitive gel was formulated for delivery via the nasal-nerve route, and its potential to enhance the bioavailability of DAU in rat plasma and cerebrospinal fluid (CSF) was assessed through a pharmacokinetic study. The anti-Alzheimer's disease (AD) mechanism of DAU was investigated using network pharmacology approaches, molecular docking, and dynamics simulations, complemented by in vivo experimental validation. DAU can be effectively incorporated into a thermosensitive gel and administered to the brain within 30 min via intranasal delivery. Following nasal administration, the pharmacokinetic parameters of DAU in cerebrospinal fluid and plasma were significantly elevated compared to oral administration ([**]P < 0.01), indicating a substantial improvement in bioavailability at equivalent doses. Behavioral studies demonstrated that DAU (dose of 1 mg/kg and 2 mg/kg in gel) enhanced cognitive function in intracerebroventricular-streptozotocin (ICV-STZ) rats and decelerated aging processes by reversing oxidative stress and mitigating neuronal apoptosis. Additionally, DAU contributed to lowering blood glucose levels, increasing insulin-like growth factor 1 (IGF-1) content, and reducing insulin resistance. Network pharmacological analysis, molecular docking, molecular dynamics simulations, and in vivo experiments collectively suggested that DAU exerted significant therapeutic effects on Alzheimer's disease by inhibiting the PI3K/AKT/mTOR pathway. Our study demonstrates a significant enhancement in the bioavailability of DAU in the brain via nasal-nerve delivery route and also this research is the first to report that DAU ameliorates cognitive impairment in ICV-STZ rats through the PI3K/AKT/mTOR pathway. Our findings contribute to the scientific understanding of DAU's potential in Alzheimer's disease treatment and offer a novel experimental foundation for the development of anti-Alzheimer's drugs.}, } @article {pmid40972689, year = {2025}, author = {Zhang, H and Huang, Y and Wang, W}, title = {Aβ oligomers promote lipid droplet accumulation and inflammatory responses in astrocytes but not neurons.}, journal = {Brain research bulletin}, volume = {231}, number = {}, pages = {111556}, doi = {10.1016/j.brainresbull.2025.111556}, pmid = {40972689}, issn = {1873-2747}, mesh = {*Astrocytes/metabolism/drug effects ; Animals ; *Neurons/metabolism/drug effects ; *Lipid Droplets/metabolism ; *Amyloid beta-Peptides/metabolism/pharmacology ; Oxidative Stress/physiology/drug effects ; Cells, Cultured ; Inflammation/metabolism ; Lipid Metabolism/physiology/drug effects ; Mice ; Alzheimer Disease/metabolism ; }, abstract = {Lipid droplets (LDs) are dynamic organelles central to cellular lipid homeostasis. Emerging evidence implicates LDs in Alzheimer's disease (AD) pathogenesis, though their cell-type-specific roles remain poorly defined. Here, we investigated the effects of amyloid-beta oligomers (AβOs) on LDs accumulation, oxidative stress, and inflammatory activation in primary astrocytes and neurons. We found that AβOs selectively triggered robust LDs formation in astrocytes, accompanied by significant increases in triglyceride (TG) and cholesterol (TC) content, and upregulation of the LD-associated protein perilipin 2 (PLIN2). Furthermore, AβOs induced pronounced oxidative stress, evidenced by elevated Malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), and promoted inflammatory activation via increased secretion of tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) in astrocytes. By contrast, neurons showed no significant changes in lipid metabolism, oxidative stress, or inflammatory responses under identical treatment conditions. Our results underscore the central role of astrocytes in AβO-induced metabolic and inflammatory dysregulation, revealing a cell-type-specific vulnerability with potential implications for AD pathogenesis. These in vitro findings provide a mechanistic basis for lipid-focused therapeutic strategies, pending further in vivo validation.}, } @article {pmid40972402, year = {2025}, author = {Chavoshinezhad, S and Beirami, E and Izadpanah, E}, title = {Neutrophils and NETosis in Alzheimer's disease: Unraveling pathogenic mechanisms and novel therapeutic targets.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {192}, number = {}, pages = {118568}, doi = {10.1016/j.biopha.2025.118568}, pmid = {40972402}, issn = {1950-6007}, mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology/metabolism/immunology ; *Neutrophils/metabolism/drug effects/pathology ; Animals ; *Extracellular Traps/metabolism/drug effects ; Blood-Brain Barrier/metabolism/pathology ; Brain/metabolism/pathology/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system that causes cognitive decline, memory loss, and neuropsychiatric symptoms. The condition is characterized by the buildup of β-amyloid plaques (Aβ), neurofibrillary tangles (NFTs), and persistent neuroinflammation. Despite ongoing research, current therapeutic strategies remain palliative and fail to halt or reverse disease progression, underscoring the need for novel treatment approaches. Recent evidence highlights neutrophils, the most abundant blood cells, as key contributors to AD pathology. These cells cross the blood-brain barrier (BBB) via specific molecular pathways and accumulate in brain regions such as the cortex and hippocampus, particularly near Aβ plaques and NFTs. Once in the brain, neutrophils release reactive oxygen species (ROS), generate neutrophil extracellular traps (NETs) via NETosis, and secrete proinflammatory cytokines and granule components. This cascade contributes to BBB disruption, increased Aβ deposition, glial activation, chronic inflammation, neurodegeneration, and cognitive impairment in AD. This review highlights the molecular mechanisms underlying both lytic and non-lytic NET formation (NETosis), explores peripheral neutrophil alterations and their migration pathways across the BBB, and discusses the role of intracerebral neutrophils, NETs, and NETosis in AD pathophysiology. Finally, we explore emerging therapeutic strategies targeting NETs, neutrophils, and NETosis as potential disease-modifying approaches in AD.}, } @article {pmid40972159, year = {2025}, author = {Laabs, M and Mulac, D and Langer, K}, title = {Targeting the blood-brain barrier with lipoprotein-mimicking nanoparticles loaded with flurbiprofenaxetil and coated with apolipoprotein E3.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {214}, number = {}, pages = {107272}, doi = {10.1016/j.ejps.2025.107272}, pmid = {40972159}, issn = {1879-0720}, mesh = {*Flurbiprofen/administration & dosage/chemistry/analogs & derivatives ; *Blood-Brain Barrier/metabolism/drug effects ; Animals ; *Nanoparticles/chemistry/administration & dosage ; Swine ; *Apolipoprotein E3/chemistry/administration & dosage ; Endothelial Cells/metabolism ; Drug Carriers/chemistry ; Drug Liberation ; *Lipoproteins/chemistry ; Drug Delivery Systems ; }, abstract = {In previous studies, it has been demonstrated that lipoprotein-mimicking nanoparticles with a solid lipid core of cholesteryl oleate, a lecithin coating and adsorptively bound apolipoprotein E3 (ApoE) may serve as a potential vehicle for drug delivery to the central nervous system. In this study, the impact of drug characteristics, particularly lipophilicity, was evaluated to achieve a stable incorporation of model drugs into these lipid-based nanoparticles (LNPs). This study explored the lipophilicity of flurbiprofen, a potential drug in the treatment of Alzheimer's disease (AD), and its prodrug flurbiprofenaxetil across varying pH levels. Our findings highlight how flurbiprofen's lipophilicity was influenced by its protonation state, affecting its incorporation into LNPs and consequently its release behaviour under physiological conditions, while flurbiprofenaxetil showed minimal variations due to its chemical structure. We also investigated the interaction between lipoprotein mimicking nanoparticles and primary porcine brain capillary endothelial cells to improve drug delivery across the blood-brain barrier (BBB). Permeation studies indicated that modification with ApoE enhanced the bidirectional permeability of LNPs across the BBB through receptor-mediated transcytosis. Furthermore, we demonstrated and identified the uptake mechanism involving the low density lipoprotein receptor-related protein 1 (LRP1), allowing these LNPs to be recognized by the same receptors as endogenous lipoproteins. Overall, these findings highlight the potential of ApoE modified LNPs as a promising strategy for targeted drug delivery to the brain.}, } @article {pmid40971327, year = {2025}, author = {Gitlin-Leigh, G and Wilson, J and Howard, R and Howard, R and Costello, H}, title = {Effects of monoclonal antibody therapies on depression in Parkinson's disease and Alzheimer's disease: Systematic review and meta-analysis.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {500-508}, doi = {10.1177/13872877251378156}, pmid = {40971327}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology/complications ; *Parkinson Disease/psychology/drug therapy/complications ; *Antibodies, Monoclonal/therapeutic use ; *Depression/drug therapy/etiology ; Randomized Controlled Trials as Topic ; }, abstract = {BackgroundDepression in Alzheimer's disease (AD) and Parkinson's disease (PD) is common, disabling and difficult to treat. Pathological protein deposition in PD and AD has been associated with late-life depression, and inflammatory and vascular changes have been proposed as key mechanisms underlying depression in neurodegenerative disorders. Monoclonal antibody therapies (mAbs) effectively clear pathological protein aggregates in PD and AD but are associated with cerebral inflammation and microvascular damage.ObjectiveWe conducted a systematic review and meta-analysis to determine whether mAb treatment influences the risk or severity of depression in AD and PD.MethodsCochrane, Ovid MEDLINE/PubMed, PsycINFO and Embase databases were searched for articles published from inception to 8 April 2025. Randomized controlled trials of mAbs for PD or AD reporting a validated measure of depressive symptoms, or depression incidence were included and meta-analyzed.ResultsWe identified 13 studies including 8603 participants (treatment arm: n = 4690, placebo arm: n = 3913). All studies reported depression incidence as an adverse event, but none assessed changes in depressive symptom severity using standardized mood scales. Meta-analysis revealed no significant difference in the incidence of depression with mAb therapy (log risk ratio: -0.24, 95% CI (-0.52, 0.04), p = 0.09).ConclusionsWe observed no significant association between mAb therapy and risk of depression in PD or AD. However, the absence of validated symptom assessments in these trials represents a critical gap in outcome reporting. Future trials should incorporate standardized depressive symptom measures as outcomes to evaluate the potential neuropsychiatric risks of these therapies.}, } @article {pmid40971324, year = {2025}, author = {Su, X and Chen, H and Cao, J and Zhang, Y and Kang, Y and Wang, L and Yin, J and Jing, Y}, title = {The effect of deprivation of whisker stimulation on cognition and synaptic plasticity in male and female Alzheimer's disease mice.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {2}, pages = {719-732}, doi = {10.1177/13872877251379079}, pmid = {40971324}, issn = {1875-8908}, mesh = {Animals ; *Vibrissae/physiology ; *Alzheimer Disease/psychology/pathology/physiopathology ; *Neuronal Plasticity/physiology ; Male ; Female ; Mice ; *Sensory Deprivation/physiology ; Disease Models, Animal ; Mice, Transgenic ; *Cognition/physiology ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; }, abstract = {BackgroundAmyloid-β (Aβ) and Aβ plaques can disrupt synaptic plasticity, leading to abnormalities in sensory function and cognition in Alzheimer's disease (AD). The whisker sensorimotor system is crucial for tactile perception, providing rodents with spatial and textural features information about their surroundings. Sensory inputs from whiskers have a clear topological localization in the barrel cortex.ObjectivePrevious studies have suggested that sensory stimulation can effectively ameliorate the pathology of AD mice and improve cognitive performance. However, it remains unknown whether tactile stimulation via whiskers can activate cortical sensory areas, protect synaptic structure and function.MethodsHere, we established a whisker deprivation (WD) model in the 5×FAD mouse.ResultsWe found that WD aggravated the deposition of Aβ1-42, 6E10 and fibrotic Aβ in the cortex, hippocampus and thalamus. Simultaneously, changes in dendritic morphology were consistent with the decreased pCreb levels in the hippocampal dentate gyrus region. WD also reduced axonal projections from layer L4/L5a to L2/3 in the barrel cortex, as well as projections from the entorhinal cortex to the DG, which may disrupt the integration of information in cortical functional columns and weaken the efficiency of information transmission. Additionally, we observed sex differences in effects of WD on AD pathology in 5×FAD mice, with female mice being more sensitive to WD treatment. Ultimately, WD impaired working memory, spatial memory and social behavior in 5×FAD mice.ConclusionsOur study suggested that WD exacerbated the progression of AD pathology in 5×FAD mice, which implicated with Aβ aggravation and synaptic dysfunction.}, } @article {pmid40971120, year = {2025}, author = {Kumar, RMR and Rajan, L and Chidambaram, SB}, title = {Exosomes as Emerging Therapeutic Platforms in Neurological and Psychiatric Disorders.}, journal = {Pharmaceutical medicine}, volume = {39}, number = {6}, pages = {427-443}, pmid = {40971120}, issn = {1179-1993}, support = {D.O. NO.BT/HRD/35/02/2006//Department of Biotechnology, Ministry of Science and Technology, India/ ; }, mesh = {Humans ; *Exosomes/metabolism ; *Mental Disorders/therapy/metabolism/diagnosis/drug therapy ; *Nervous System Diseases/therapy/metabolism/diagnosis/drug therapy ; Animals ; Biomarkers/metabolism ; }, abstract = {Exosomes, small extracellular vesicles (sEVs) that range in Size from 30 to 150 nm in diameter, have emerged as crucial mediators of intercellular communication within the central nervous system (CNS). They play significant roles in the pathogenesis and progression of various neurological and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, ischemic stroke, depression, bipolar disorder, and autism spectrum disorder. Exosomes carry a diverse cargo of proteins, nucleic acids, lipids, and other bioactive molecules that can influence neuronal function and synaptic plasticity. In disease states, exosomes derived from stressed neurons or glial cells can propagate neuroinflammation, synaptic dysfunction, and cognitive decline. They may also mediate the spread of abnormal proteins or microRNAs, disrupting neuronal connectivity and neurotransmitter signaling and contributing to the development of proteinopathies and neurotoxicity. Owing to their presence in bodily fluids such as blood plasma, cerebrospinal fluid, and saliva, exosomes hold promise as biomarkers for these disorders. Moreover, their regulatory roles present new opportunities for developing novel diagnostic biomarkers and therapeutic interventions. This review provides an overview of the multifaceted roles of exosomes in neurological and psychiatric disorders. We delve into their contributions to disease pathogenesis, their potential as diagnostic biomarkers, and the innovative therapeutic strategies leveraging exosome-based delivery systems. By exploring the current state of research, we aim to highlight the translational potential of exosomes in revolutionizing the diagnosis and treatment of these disorders.}, } @article {pmid40969901, year = {2025}, author = {Zhang, J and Du, X and Li, X and Lv, X and Wang, X}, title = {Hypoxia, Psychedelics, and Terminal Lucidity: A Perspective on Neuroplasticity and Neuropsychiatric Disorders.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {9}, pages = {2848-2854}, pmid = {40969901}, issn = {2575-9108}, abstract = {Hypoxia and psychedelics, despite their distinct origins, both induce altered states of consciousness and promote neuroplasticity, suggesting a shared underlying mechanism relevant to neuropsychiatric treatment and neurological recovery. Terminal lucidity, the transient resurgence of cognitive function in late-stage dementia, highlights the brain's latent capacity for rapid reorganization, a phenomenon that may be driven by transient hypoxia. Similarly, acute intermittent hypoxia and pharmacological agents like HypoxyStat, which modulate oxygen availability, have emerged as potential strategies for enhancing neural adaptability. This perspective explores the hypothesis that controlled reductions in oxygen availability(?)whether through psychedelics, near-death experiences, meditation, holotropic breathwork, or hypoxia therapies(?)trigger calcium signaling pathways that promote synaptogenesis and the formation of new neural circuits. Rather than restoring damaged connections, this process may enable functional rerouting, thereby supporting cognitive resilience and behavioral compensation in conditions such as stroke, Alzheimer's disease, and psychiatric disorders. By integrating insights from psychedelic research, hypoxia-based therapies, and neuroplasticity studies, we propose a unifying framework that leverages altered oxygen homeostasis as a novel therapeutic strategy for neuropsychiatric and neurodegenerative diseases.}, } @article {pmid40969869, year = {2025}, author = {Tanguturi, P and Mitchell, S and Moukha-Chafiq, O and Zhang, S and Tillotson, J and Ananthan, S and Augelli-Szafran, CE and Streicher, JM}, title = {Development of Delta Opioid Receptor Antagonists Which Prevent Alzheimer's Disease-Like Pathology in the 5X-Familial Alzheimer's Disease [5XFAD] Mouse Model.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {9}, pages = {3346-3370}, pmid = {40969869}, issn = {2575-9108}, abstract = {Alzheimer's Disease is a growing health concern, with no available disease-modifying treatments. A previous report suggested that a Delta Opioid Receptor (DOR) antagonist could prevent Alzheimer's-like pathology; however, no DOR antagonists are clinically approved. We thus expanded on our previous structure-activity relationship work on morphinan scaffold DOR antagonists to generate and evaluate new DOR antagonist ligands. We identified a lead compound 12 (SRI-22136) with sub-nM DOR potency, high selectivity, and high inhibition of β-secretase activity. We further evaluated 12 in CD-1 mice, finding full antagonist efficacy at 1 mg/kg by the intraperitoneal route. We then tested the ability of 12 to prevent Alzheimer's-like pathology in a 5XFAD transgenic mouse model, with daily treatment from 2 to 5 months of age. This treatment completely prevented Alzheimer's-like pathology, including memory deficits, β-secretase activity, Aβ1-42 accumulation, and brain inflammatory markers. Together these results suggest 12 as a potential new lead compound to prevent Alzheimer's Disease.}, } @article {pmid40969222, year = {2025}, author = {Liu, Y and Zhu, L and Pei, Z and Zhou, Z and Su, X and Ren, H and Fan, S and Lan, X and Lian, C and Shi, X and Guo, Y}, title = {Integrating repetitive transcranial magnetic stimulation and Mediterranean diet for cognitive and anxiety improvement in early Alzheimer's disease: A case report and literature review.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251377988}, pmid = {40969222}, issn = {2542-4823}, abstract = {A 52-year-old male with early-stage Alzheimer's disease and long-standing anxiety received 30 repetitive transcranial magnetic stimulation sessions over 8 months and 20-month Mediterranean diet intervention. Neuropsychological assessments [Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Clinical Dementia Rating, Hamilton Anxiety Rating Scale (HAMA), Hamilton Depression Rating Scale (HAMD), Pittsburgh Sleep Quality Index) and resting-state electroencephalogram (rsEEG) were conducted at baseline, during treatment, and at 6-month follow-up. After treatment, MoCA and MMSE scores improved by 6 and 5 points; HAMA and HAMD scores declined by 7 and 3 points. rsEEG showed progressive increases in individual alpha peak frequency (8.69 to 10.22 Hz), enhancement of alpha power, and reduction in theta power. Cerebrospinal fluid amyloid-β42 levels also normalized. The patient reported marked mental well-being.}, } @article {pmid40969221, year = {2025}, author = {Shaukat, A and Riaz, R and Khaliq, N and Shams, Z and Akilimali, A}, title = {Brexpiprazole: Pioneering medication for managing agitation in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251379881}, pmid = {40969221}, issn = {2542-4823}, abstract = {Alzheimer's disease poses intricate challenges, affecting cognition and behavior, notably marked by agitation. The FDA's approval of brexpiprazole, an atypical antipsychotic, stands as a milestone, representing the first treatment for Alzheimer's-related agitation. brexpiprazole's modulation of serotonin-dopamine activity has proven effective in clinical trials, reducing agitation as measured by CMAI scores. Gradual dosage escalation is recommended, with potential side effects including nasopharyngitis, urinary tract infections, dizziness, somnolence, headache, and insomnia. Also useful for schizophrenia and treatment-resistant depression, providing ongoing treatment and potential well-being enhancement by managing agitation and other symptoms.}, } @article {pmid40968664, year = {2025}, author = {Shao, X and Sun, J and Wang, X and Yin, XS and Chen, Z and Xu, Y and Wang, T and Yuan, B and Qiu, W and Liu, F and Chen, Y and Ma, C}, title = {Intraventricular Creatine Treatment Attenuates Alzheimer's Disease-Related Neuropathological Changes and Memory Impairment via Inhibiting STAT1 Phosphorylation.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {19}, pages = {3790-3800}, pmid = {40968664}, issn = {1948-7193}, mesh = {Animals ; *STAT1 Transcription Factor/metabolism/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Phosphorylation/drug effects ; *Creatine/administration & dosage/pharmacology ; *Memory Disorders/drug therapy/metabolism/pathology ; Mice ; Male ; Humans ; Female ; Aged ; Mice, Transgenic ; Hippocampus/metabolism/drug effects ; Injections, Intraventricular ; Disease Models, Animal ; Mice, Inbred C57BL ; Brain/drug effects/metabolism/pathology ; Microglia/drug effects/metabolism ; }, abstract = {The importance of neuroinflammation in Alzheimer's disease (AD) has attracted increasing attention, and the functions of the STAT1 signaling pathway have also generated widespread interest. However, the role of STAT1 in AD-related neuroinflammation and memory impairment is unclear. Therefore, this study was undertaken to elucidate the roles of the STAT1 signaling pathway in the brain tissue of AD patients and mouse of an AD model. Our results revealed that STAT1 phosphorylation was largely colocalized with the neuronal marker NeuN. Compared with that in control (non-AD) brain tissues, STAT1 phosphorylation was significantly upregulated in the brain cortex and hippocampus of both AD patients and FAD mice. Intraventricular injection of creatine (STAT1 signaling inhibitor) significantly reduced the level of neuronal STAT1 phosphorylation in the brain cortex and markedly alleviated cognitive impairment in FAD mice. Furthermore, intraventricular creatine treatment also reduced the number of Aβ plaques and the level of IBA1 expression in IBA1-positive microglia in FAD mice. These findings indicate that STAT1 phosphorylation may play an important role in AD-related neuroinflammation and memory impairment. The alleviation effects of intraventricular creatine in FAD mice may suggest that STAT1 is a potential therapeutic target for the treatment of AD in humans.}, } @article {pmid40968433, year = {2025}, author = {Goyal, A and Kumari, A and Verma, A and Bhatiya, S and Yadav, HN}, title = {Cannabinoid Receptor 1: The Neural Gatekeeper of Health and Disease.}, journal = {Current neurovascular research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672026403497250910124233}, pmid = {40968433}, issn = {1875-5739}, abstract = {INTRODUCTION: An essential component of the endocannabinoid system, cannabinoid receptor type 1 (CB1) is primarily expressed in the central nervous system, where it regulates several neurophysiological activities. Neurotransmitter release, synaptic plasticity, mood modulation, and cognitive processes are all influenced by CB1 receptors. The CB1 receptor is closely linked to a wide range of brain-related disorders, and regulating its activity may be a way to treat several brain-related diseases. METHODS: Literature search across Google Scholar, Scopus, PubMed, and Web of Science, covering publications from 1985 to 2025, aimed to gather extensive information on the pharmacological role of the CB1 receptor in various brain illnesses. Using keywords such as "CB1," "Brain," "Epilepsy," "Alzheimer's," "Parkinson's disease," "Neuroprotection," and "Neurodegeneration," this review consolidates existing knowledge and identifies potential avenues for future research. RESULTS: This study incorporates pre-clinical evidence and highlights the involvement of the CB1 receptor in etiologies, symptoms, and treatments related to distinct brain-related disorders. DISCUSSIONS: Potential treatment strategies that target the endocannabinoid system and the intricate relationship between CB1 receptor activity and its consequences in several brain disorders, including Parkinson's disease, Huntington's disease, Alzheimer's disease, depression, anxiety, etc., have been discussed. Additionally, the difficulties and disputes related to CB1 receptor modulation, including the contradictory actions of CB1 receptor agonists and antagonists, are also addressed. CONCLUSION: The CB1 receptor is a promising therapeutic target for brain disorders due to its key role in regulating various physiological functions in the CNS, suggesting potential for the treatment of several brain disorders.}, } @article {pmid40968081, year = {2025}, author = {Karki, A and Nawani, A and Sharma, S and Poddar, D and Singh, A}, title = {Early Alzheimer Biomarker Recognition Transition Metal Dichalcogenides as Electrochemical Biosensors for Detecting Alzheimer's Biomarkers.}, journal = {Critical reviews in analytical chemistry}, volume = {}, number = {}, pages = {1-24}, doi = {10.1080/10408347.2025.2558051}, pmid = {40968081}, issn = {1547-6510}, abstract = {Alzheimer's disease (AD) is a neurological ailment characterized by the degeneration of neurons in specific areas of the brain, resulting in memory loss, cognitive decline, and eventually dementia. AD is both lethal and currently incurable since the demise of brain cells cannot be reversed or stopped; however, ongoing advancements and research offer hope, aiming to uncover effective clinical and therapeutic strategies that could slow down the progression and improve patient outcomes. Surveys indicate that the treatment of AD is significantly expensive, with the global annual cost of treating AD amounting to US$1 trillion. Therefore, the early identification of this condition is of the utmost importance, as it can assist in slowing down the advancement of Alzheimer's and enable proper diagnosis. Biosensors are analytical instruments utilized for the early identification of AD and are in great demand due to their exceptional selectivity, sensitivity, and affordability. Biosensors integrated with transition-metal dichalcogenides (TMDCs) enhance the efficiency of a biosensor by significantly amplifying biosensing signals. This study examines AD and its underlying biochemical mechanisms, explicitly focusing on several hypotheses linked to AD, the biomarkers involved, and the use of TMDC-based biosensors for early detection of the illness with greater precision.}, } @article {pmid40968015, year = {2025}, author = {Vijayashankar, A and Keir, G and Sagnelli, M and Petrover, D and Djekidel, M and Glaser, J and Caravella, C and Clouston, SAP and Rini, J and Franceschi, AM}, title = {Added Value of Amyloid PET Quantification with the Centiloid Scale in Clinical Practice.}, journal = {AJNR. American journal of neuroradiology}, volume = {46}, number = {10}, pages = {2144-2153}, pmid = {40968015}, issn = {1936-959X}, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; Reproducibility of Results ; *Positron Emission Tomography Computed Tomography/methods ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Amyloid/metabolism ; Aged, 80 and over ; Sensitivity and Specificity ; *Positron-Emission Tomography/methods ; Observer Variation ; *Image Interpretation, Computer-Assisted/methods ; }, abstract = {BACKGROUND AND PURPOSE: The objectives for amyloid brain PET/CT and PET/MRI fusion images are to determine the agreement between visual interpretations of amyloid PET and to compare the results of visual interpretation with quantitative analysis as measured by the Centiloid (CL) scale. MATERIALS AND METHODS: One hundred sixty-seven clinical amyloid brain PET/CT scans were reviewed by 3 readers blinded to the original reports. Readers interpreted the amyloid PET scans as negative (0), positive (1), or indeterminate (2) for amyloid deposition. For quantitative analysis, 2 additional readers analyzed amyloid PET images using MIMNeuro to generate CL scores and regional standardized uptake ratios. Reader agreement was determined for visual and quantitative assessment. Using positive scan cutoffs of CL ≥ 40, we determined visual assessment-versus-quantitative assessment for scans consistently interpreted as positive by all 3 readers and for each reader. RESULTS: Fifty-three scans (31.74%) were rated amyloid-positive by all readers, while 62 scans (37.13%) were rated as amyloid-negative by all readers. The remaining 52 scans had inconsistent ratings with an agreement rate of 69.46%. Most (99/167; 59.28%) scans had CL scores above the CL-positive cutoff (CL ≥ 40), and 47/167 (28.14%) were CL-negative scans (CL <10). The lowest CL score to achieve visual positivity among all 3 readers was 57, while the lowest CL score to receive at least 1 indeterminate score was 11. The readers had a high degree of interreader reliability when rating scans as either positive (κ = 0.62) or negative (κ = 0.66) but were inconsistent when rating scans as indeterminate (κ = 0.17). Optimal cut-points were CL <3.6 for consistent negative and CL ≥28.8 for consistent visual positivity. CONCLUSIONS: Given the emergence of antiamyloid monoclonal therapies for early-stage Alzheimer disease, reliable detection of amyloidosis is critical for patient care. This study suggests that visual reads of amyloid PET may be insensitive when amyloidosis is milder but are spread across multiple regions (CL ranging from 40 to 59). Quantification of amyloid PET using the CL scale may help guide treatment of patients with mild amyloidosis who are under consideration for antiamyloid disease-modifying therapeutics.}, } @article {pmid40967916, year = {2025}, author = {Oh, KN and Bae, D and Oh, DR and Hong, JA and Kim, Y and Kim, E and Son, SA and Lee, KY and Kim, S}, title = {TLR4/NF-κB-Mediated Anti-Inflammatory and Cognitive Protective Actions of Curcuma longa and Ar-turmerone in Alzheimer's Disease Models.}, journal = {Journal of microbiology and biotechnology}, volume = {35}, number = {}, pages = {e2506044}, pmid = {40967916}, issn = {1738-8872}, mesh = {Animals ; *Alzheimer Disease/drug therapy ; *Curcuma/chemistry ; *Toll-Like Receptor 4/metabolism/genetics ; *NF-kappa B/metabolism ; Amyloid beta-Peptides/toxicity ; *Anti-Inflammatory Agents/pharmacology ; Disease Models, Animal ; Rats ; *Neuroprotective Agents/pharmacology ; *Plant Extracts/pharmacology ; Hippocampus/drug effects/cytology ; Mice ; Signal Transduction/drug effects ; Male ; Neurons/drug effects ; *Sesquiterpenes/pharmacology ; Monocyclic Sesquiterpenes ; Cells, Cultured ; Rats, Sprague-Dawley ; Cognition/drug effects ; Curcumin/pharmacology ; Peptide Fragments ; Ketones ; }, abstract = {In our previous study, we systematically compared various extraction methods and identified the 80% ethanolic extract of Curcuma longa L. (CL-80) as the most effective in protecting neurons from stress-induced damage in both in vitro and in vivo models. Although curcumin, a major constituent of C. longa, has demonstrated neuroprotective effects, the role of ar-turmerone, a bioactive sesquiterpenoid also derived from C. longa, remains underexplored in Alzheimer's disease (AD) models. In this study, we evaluated the anti-inflammatory and cognitive-protective effects of CL-80 and ar-turmerone in both in vitro and in vivo models of amyloid-β (Aβ)-induced neurotoxicity. Primary cultured rat hippocampal neurons exposed to Aβ25-35 showed significantly increased expression of TNF-α, IFN-β, and iNOS, all of which were dose-dependently attenuated by CL-80 or ar-turmerone. Furthermore, both compounds suppressed Aβ-induced activation of the TLR4/NF-κB signaling axis at mRNA and protein levels. In an Aβ1-42-injected mouse model, oral administration of CL-80 or ar-turmerone significantly improved learning and memory performance in the Morris water maze and passive avoidance tests. Biochemical analyses of hippocampal tissues revealed reduced TLR4 expression and NF-κB activation, decreased acetylcholinesterase (AChE) activity, and restoration of acetylcholine (ACh) levels following treatment. Collectively, these findings suggest that both CL-80 and ar-turmerone exert neuroprotective effects by inhibiting TLR4/NF-κB-mediated neuroinflammation and preserving cholinergic function in an AD animal model. This study offers novel insight into the therapeutic potential of C. longa constituents for the treatment of AD.}, } @article {pmid40967471, year = {2025}, author = {Iqbal, A and Iqbal, K and Shah, YA and Ullah, F and Khan, J and Yaqoob, S}, title = {Multi-filter stacking in inception V3 for enhanced Alzheimer's severity classification.}, journal = {Neuroscience}, volume = {586}, number = {}, pages = {21-31}, doi = {10.1016/j.neuroscience.2025.08.049}, pmid = {40967471}, issn = {1873-7544}, mesh = {*Alzheimer Disease/classification/diagnostic imaging/pathology ; Humans ; Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/pathology ; Aged ; *Deep Learning ; Neural Networks, Computer ; Male ; Severity of Illness Index ; Female ; Support Vector Machine ; Aged, 80 and over ; }, abstract = {Alzheimer's disease, a progressive neurodegenerative disorder, is characterized by a decline in brain volume and neuronal loss, with early symptoms often presenting as short-term memory impairment. Automated classification of Alzheimer's disease remains a significant challenge due to inter-patient variability in brain morphology, aging effects, and overlapping anatomical features across different stages. While traditional machine learning techniques, such as Support Vector Machines (SVMs) and various Deep Neural Network (DNN) models, have been explored, the need for more accurate and efficient classification techniques persists. In this study, we propose a novel approach that integrates Multi-Filter Stacking with the Inception V3 architecture, referred to as CASFI (Classifying Alzheimer's Severity using Filter Integration). This method leverages diverse convolutional filter sizes to capture multiscale spatial features, enhancing the model's ability to detect subtle structural variations associated with different Alzheimer's disease stages. Applied to MRI data, CASFI achieved an accuracy of 97.27%, outperforming baseline deep learning models and traditional classifiers in both accuracy and robustness. This approach supports early diagnosis and informed clinical decision-making, providing a valuable tool to assist healthcare professionals in managing and planning treatment for Alzheimer's patients.}, } @article {pmid40967324, year = {2025}, author = {de Andrade, PRA and Motta, RC and Fonseca-Santos, B}, title = {Unlocking ferulic acid for neurological diseases and tailoring of nanoformulations to advance its brain delivery.}, journal = {International journal of pharmaceutics}, volume = {684}, number = {}, pages = {126173}, doi = {10.1016/j.ijpharm.2025.126173}, pmid = {40967324}, issn = {1873-3476}, mesh = {Humans ; *Coumaric Acids/administration & dosage/chemistry/pharmacokinetics ; Animals ; Brain/metabolism/drug effects ; Drug Delivery Systems ; *Nervous System Diseases/drug therapy ; *Nanoparticle Drug Delivery System ; Neurodegenerative Diseases/drug therapy ; Drug Compounding ; }, abstract = {Mental disorders represent a significant global health challenge, with a high prevalence and substantial impact on individual well-being. Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and various mood disorders, contribute significantly to the burden of neurological conditions worldwide. Identifying novel drug targets and exploring natural product-based molecules have become essential priorities in advancing treatment strategies for these complex diseases. Nanoencapsulation technology has emerged as a valuable tool to increase the stability, solubility, and bioavailability of natural products, thus improving their efficacy in treating neurological disorders. By encapsulating natural compounds such as ferulic acid (FA) in nanoscale delivery systems, researchers have aimed to overcome challenges related to poor solubility and bioavailability, ultimately enhancing therapeutic outcomes. In this review, we examine recent advancements focused on the therapeutic potential of FA in AD, PD, MS, brain cancer, depression (DP), anxiety (AX), and epilepsy (EP). Furthermore, we explored the use of nanoscale delivery systems to optimise the delivery of FA for improved treatment efficacy. We aim to inspire discoveries and innovative approaches to address neurological diseases by highlighting current progress and future directions in this field with FA.}, } @article {pmid40967100, year = {2025}, author = {Alsiraey, N and Dewald, HD}, title = {Restoring nitric oxide/Peroxynitrite equilibrium in impaired human neural progenitor cells: Nanomedical approaches and their potential impact on neurodegenerative disease treatment.}, journal = {Journal of inorganic biochemistry}, volume = {274}, number = {}, pages = {113073}, doi = {10.1016/j.jinorgbio.2025.113073}, pmid = {40967100}, issn = {1873-3344}, abstract = {Nitric oxide (NO), an essential inorganic signaling molecule, involved in many physiological processes and has promising therapeutic potential Its oxidation product, peroxynitrite (ONOO[¯]), is cytotoxic, and elevated ONOO[¯] levels induce nitroxidative stress, a factor implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Through pharmacological modulation of NO and ONOO[¯] levels in human neural progenitor cell (hNPCs), this study explores the potential pharmaceutical interventions targeting the NO and the neuronal nitric oxide synthase (nNOS) pathway, (NO/nNOS), to prevent or reduce AD progression by restoring the [NO]/[ONOO[¯]] balance. To achieve this, metalloporphyrin nanosensors have been effectively employed for real-time, in-situ measurement of NO and ONOO[¯] concentrations (200-300 nm diameter) were applied and precisely positioned 4-5 ± 1 μm from hNPCs membranes, enabling precise investigation of the [NO]/[ONOO[¯]] ratio. The [NO]/[ONOO[¯]] ratio emerged as a critical biomarker for the evaluation of nNOS coupling/uncoupling to the hNPC functioning/dysfunction. In healthy cells, this ratio was around 0.25 ± 0.005, While dysfunctional hNPCs treated to amyloid beta 42 (Aβ42)-a hallmark of AD-caused a dramatic 94 % drop, signaling severe cellular dysfunction. Based on these findings, potential pharmacological interventions have been proposed to prevent or reduce AD progression by restoring the [NO]/[ONOO[¯]] balance. Notably, a co-treatment of sepiapterin (SEP), a cofactor precursor for NO synthesis, with VAS 2870 (an NADPH oxidase inhibitor) partially restored the ratio to 0.1, indicating improved nNOS function.}, } @article {pmid40966774, year = {2025}, author = {Mahajan, G and Pandya, K and Tripathi, A and Kumar, D}, title = {Integrating molecular imaging with near-infrared theranostics to improve early detection and therapy of Alzheimer's disease.}, journal = {Bioorganic chemistry}, volume = {165}, number = {}, pages = {108949}, doi = {10.1016/j.bioorg.2025.108949}, pmid = {40966774}, issn = {1090-2120}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/drug therapy/diagnosis/therapy ; *Molecular Imaging/methods ; *Theranostic Nanomedicine ; *Fluorescent Dyes/chemistry/therapeutic use ; Early Diagnosis ; Animals ; Molecular Structure ; Infrared Rays ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) remains a significant unmet clinical need due to its asymptomatic prodromal phase and multifaceted pathophysiology, which comprises amyloid-β (Aβ) plaques characterized by neurofibrillary tangles (NFTs) of hyperphosphorylated tau. Conventional diagnostic methods, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), detect AD only after extensive neuronal loss. Recent progress in chemical biology has enabled the creation of multifunctional small-molecule theranostic probes that integrate diagnostic imaging with therapeutic intervention. This review emphasizes the design and molecular engineering of new probes in particular, near-infrared (NIR) dyes, aryl quinolines, cyanine-based fluorophores, and curcumin derivatives, which are highly specific for Aβ and tau aggregates, penetrate the blood-brain barrier (BBB) effectively, and are amenable to multimodal imaging including near-infrared imaging (NIR) fluorescence, MRI, PET. These probes commonly contain donor-acceptor motifs and exhibit environment-sensitive fluorescence, allowing for the real-time imaging of pathological protein aggregation. Furthermore, we consider dual-mode probes, such as PiB-C and BTTA, which combine metal chelation therapy with imaging, providing a targeted approach to disaggregate Aβ plaques concurrently visualizing therapeutic effectiveness. Through the combination of synthetic chemistry, molecular imaging, and neurotherapeutics, this transdisciplinary approach outlines a promising new paradigm for early AD detection and treatment. The development of these small-molecule theranostics presents new opportunities for personalized medicine in treating neurodegenerative diseases.}, } @article {pmid40966159, year = {2025}, author = {Ehrhardt, AC and Rogatzki, MJ}, title = {Yoga, Meditation, and Mindfulness for Treatment of Traumatic Brain Injury: A Scoping Review.}, journal = {Journal of integrative and complementary medicine}, volume = {}, number = {}, pages = {}, doi = {10.1177/27683605251379812}, pmid = {40966159}, issn = {2768-3613}, abstract = {Objective: The objective of this scoping review was to analyze research using yoga, meditation, and mindfulness (YMM) as a treatment for traumatic brain injury (TBI). Introduction: The rationale for this review was to provide an understanding of the methodology and outcome measures used in studies that include YMM as TBI treatment. There are currently no reviews that investigate how all three of these modalities are used in TBI treatment. This review is meant to draw attention to how this research is done and potentially improve future research study design. Inclusion Criteria: Criteria for studies included in this review were developed according to the participants, concept, and context framework. Specifically, participants must have experienced a TBI, the TBI had to be treated with yoga, mindfulness, meditation, or some combination of the three, subjects could not exclusively have had acquired brain injury such as stroke or Alzheimer's disease, and the study must have been published in the English language. Methods: PubMed, Google Scholar, Scopus, Web of Science, Cumulative Index to Nursing and Allied Health Literature, PsyArXiv, ProQuest, and LoveYourBrain were searched for articles that met our criteria. A total of 72 articles were extracted to address 15 variables. Results: The majority of studies used either a pre-post or exploratory study design with no more than 29 female Caucasian subjects in the age range of 45-54 years. Most subjects participated in the study one month since their mild to severe TBI. In order to treat TBI symptoms, most studies used mindfulness, with the treatment done in person. Sessions of treatment typically occurred on a weekly basis for 10-30 min over 7-8 weeks. Outcome measures used to determine efficacy of treatment were primarily quality of life, followed by cognitive function and depression. Most studies were conducted in the United States after 2010 in the journal Brain Injury with no type of funding. Conclusions: Studies using YMM for treatment of TBI are typically done on a single type of population with a wide range of outcome variables and no control group. Future research may aim to include a control group and a variety of outcome measures consistent with those used in previous studies for result comparisons.}, } @article {pmid40964464, year = {2025}, author = {Ibrahim, R and Kambal, A and Abdelmajeed, MA}, title = {Glucagon-Like Peptide-1 Receptor Agonists in Neurodegenerative Diseases: A Comprehensive Review.}, journal = {Cureus}, volume = {17}, number = {9}, pages = {e92441}, pmid = {40964464}, issn = {2168-8184}, abstract = {There is a steadily increasing global burden of neurodegenerative diseases (NDs) such as dementia, including Alzheimer's disease (AD), and movement disorders like Parkinson's disease (PD), which emphasizes the importance of disease-modifying therapy (as opposed to symptomatic therapy). This review considers a new disease-modifying strategy through the so-called glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in these NDs, and the mechanistic rationale and evidence base. The review considers a multi-targeting strategy, translational issues, and a future research agenda. Translational challenges for these agents are also discussed, particularly the need to understand how the timing of treatment may influence outcomes. The review also considers unwanted side effects like unintended weight loss, which may compromise "at-risk" patient groups. In conclusion, GLP-1 RAs are an intriguing multitarget treatment option for people with NDs, and future research should focus on optimizing treatment for clinical trials, evolved agonists that can penetrate the central nervous system (CNS), and combination therapies.}, } @article {pmid40964378, year = {2025}, author = {Robinson-Cooper, L and Davidson, S and Koutoubi, R and Zhang, K and Park, H and Barker-Haliski, M}, title = {Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964378}, issn = {2692-8205}, support = {R01 AG067788/AG/NIA NIH HHS/United States ; }, abstract = {Presenilin 2 (PSEN2) gene variants increase the risk of early-onset Alzheimer's disease (AD). AD patients with PSEN2 variants have increased risk of unprovoked seizures versus age-matched healthy controls, yet few studies have interrogated PSEN2 contributions to seizures, and fewer have done so with aging. PSEN2 variant mice also do not exhibit amyloid-β (Aβ) accumulation, allowing for the assessment of Aβ-independent contributions to seizure risk in AD. Critically, PSEN proteolytic capacity may regulate hippocampal kainate-type glutamate receptors (KARs), with PSEN deletion reducing KAR availability and synaptic transmission in vitro (Barthet et al 2022). Kainic acid (KA) is a naturally occurring KAR agonist that acutely evokes severe seizures in mice. We thus hypothesized that PSEN2 knockout (KO) mice would have reduced latency to acutely evoked seizures and status epilepticus (SE), increased convulsive SE burden, worsened 7-day survival, and altered hippocampal KAR expression vs age-matched wild-type (WT) mice. Using a repeated low-dose systemic KA administration paradigm, we quantified the latency to acute seizures and convulsive SE, then quantified neuropathology in 3-4-month-old and 12-15-month-old male and female PSEN2 KO versus WT mice. GluK2 and GluK5 KAR subunit expression was colocalized in astrocytes and neurons by immunohistochemistry 7 days after KA-SE or sham-SE to define the interaction between PSEN2 loss and acute seizures on hippocampal KARs. Regardless of sex, young PSEN2 KO mice were more susceptible to KA-induced acute seizures than WTs. Young PSEN2 KO mice of both sexes also entered SE sooner than age-matched WT mice. In aged mice, there was no significant difference in latency to first seizure or SE onset between genotypes in either sex. However, regardless of genotype, aged females entered SE sooner than young females and experienced greater mortality. This was not observed in males. Among young animals, there was no difference in KAR expression between genotypes and regardless of treatment group. In both genotypes, hippocampal CA3 astrocytes expressed GluK5 following KA-SE, however, astrocytic GluK2 expression only occurred in WT mice. GluK5 expression was significantly reduced in untreated aged PSEN2 KO mice versus untreated WT mice, while total GluK2 expression did not differ between genotypes or seizure groups. Following KA-SE, astrocytic GluK5 expression was only present in WT animals in CA3, while both genotypes presented with astrocytic GluK5 expression. This study highlights that KARs are an understudied contributor to seizures in aging and AD that warrant further investigation.}, } @article {pmid40964168, year = {2025}, author = {Chai, Y and Shokri-Kojori, E and Saykin, AJ and Yu, M}, title = {Anxious-depressive symptoms and sleep disturbances across the Alzheimer disease spectrum.}, journal = {Nature. Mental health}, volume = {3}, number = {6}, pages = {594-612}, pmid = {40964168}, issn = {2731-6076}, support = {R01 AG019771/AG/NIA NIH HHS/United States ; U01 AG072177/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; }, abstract = {Patients with Alzheimer disease (AD) often experience neuropsychiatric symptoms, particularly anxious-depressive symptoms and sleep disturbances. These symptoms are associated with various factors related to AD, including amyloid-β and tau pathology, neurodegeneration, and cognitive decline, at different stages of the disease. However, it remains unclear whether anxious-depressive symptoms and sleep disturbances are merely symptoms or contribute as risk factors in the development and progression of AD. Consequently, there is a pressing need for a timely and informed discussion regarding these disturbances in AD. Here we discuss the most recent developments in understanding the etiology of anxious-depressive symptoms and sleep disturbances in AD, with a focus on how these symptoms interact with AD biomarkers to influence cognitive decline. Furthermore, we propose models of connections between anxious-depressive symptoms and/or sleep disturbances, AD biomarkers and cognition, aiming to inspire potential treatment plans for addressing these symptoms and exploring their impact on AD pathology and cognitive decline.}, } @article {pmid40964139, year = {2025}, author = {Kovacik, A and Vandergriff, K and Jarrett, B and Clevenger, C}, title = {An Update of the Treatment Landscape for Alzheimer's Disease: From Symptomatic Treatments to the Emergence of Amyloid-Targeting Therapies.}, journal = {Sage open aging}, volume = {11}, number = {}, pages = {30495334251376614}, pmid = {40964139}, issn = {3049-5334}, abstract = {Several approved Alzheimer's disease (AD) treatments help manage its associated cognitive symptoms (e.g., donepezil and memantine) or non-cognitive symptoms. However, disease-modifying AD therapies have recently emerged. These treatments aim to slow disease progression by targeting the pathology associated with progressive neurodegeneration. Specifically, two amyloid-targeting therapies (ATTs) are currently approved and available for use in the United States: the monoclonal antibodies donanemab (Kisunla™) and lecanemab (Leqembi[®]). Both treatments can slow disease progression and cognitive and functional decline in patients with mild cognitive impairment/mild dementia due to AD, but they are associated with class-based safety concerns, notably amyloid-related imaging abnormalities (ARIA). Because advanced practice providers (APPs) such as physician assistants and advanced practice nurses are key to AD patient care, they should be familiar with the biological continuum of AD and with ATTs and understand how to monitor and manage patients receiving these treatments. Therefore, this review aims to educate APPs about these new therapies. Specifically, it summarizes the approved indications and dosing for donanemab and lecanemab, as well as key clinical evidence of efficacy and safety. It also outlines practical considerations around the monitoring and management of patients treated with ATTs, including recommendations about treatment duration, adverse reaction management, and patient counseling.}, } @article {pmid40964091, year = {2025}, author = {Adhikary, K and Ganguly, K and Sarkar, R and Abubakar, M and Banerjee, P and Karak, P}, title = {Phytonutrients and their neuroprotective role in brain disorders.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1607330}, pmid = {40964091}, issn = {2296-889X}, abstract = {In the twenty-first century, cognitive impairment is a significant health problem. Function is substantially impaired by a number of neuropsychiatric and neurodegenerative diseases, such as Parkinsonism, schizophrenia, major depressive disorder, Alzheimer's disease and other types of cognitive impairment, cerebrovascular disabilities, seizure-related disorders, and brain traumas. Over time, a number of chemical messengers and signaling molecules have been identified as potential targets for treatment, and tests have been performed against these targets using both conventional and novel chemicals. Phytochemicals derived from medicinal plants are essential for preserving the chemical balance of the central nervous system because they change the activity of major inhibitory receptors that receive neurotransmitters. Many herbs have been used in conventional medicine to treat cognitive problems. Although the presence of receptors that are responsible or transporters for compounds called polyphenols and other phytochemicals in brain regions remains to be determined, multiple target substances seem to be a promising class of treatment options for treating disorders with multifactorial origins. Additional studies suggest that flavonoids possess significant anti-inflammatory properties in the brain, making them a promising therapeutic option for conditions such as ischemic or hemorrhagic stroke, as well as chronic neuroinflammatory disorders like Parkinson's and Alzheimer's disease. This review highlights how phytochemicals contribute to the protection against brain disorders and explores the underlying mechanisms involved in their action. It also emphasizes the core biological processes, providing deeper insight into the therapeutic potential of phytochemicals in the treatment of neurological conditions.}, } @article {pmid40963977, year = {2025}, author = {Wang, S and Luo, G and Zhao, Q and Zhang, S and Li, Z and Lu, J and Wang, F and Sun, D and Xu, H}, title = {Exploration of the potential role of plasma lipoprotein molecules in late-onset Alzheimer's disease among the Chinese population.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251378973}, pmid = {40963977}, issn = {2542-4823}, abstract = {BACKGROUND: Evidence suggests that lipoprotein metabolism play a crucial role in Alzheimer's disease (AD). However, their involvement in late-onset AD (LOAD) remains unclear. OBJECTIVE: This study aimed to uncover potential associations between lipoprotein metabolism and clinical LOAD diagnosis, cognitive function, and treatment. METHODS: We performed a lipidomic analysis of plasma samples from 46 individuals with LOAD and 16 healthy controls to investigate the potential association between lipoprotein profiles, LOAD diagnosis and cognitive function. Then, we conducted a protein-protein interaction analysis to explore the potential therapeutic role of lipoprotein molecules in LOAD. RESULTS: Our findings revealed that ApoA2 and HDL ApoA2 may be negatively associated with LOAD risk (odds ratio [OR] = 0.798, 95% confidence interval [CI] = 0.654-0.973, p = 0.026; OR = 0.785, 95% CI = 0.634-0.972, p = 0.026, respectively), while LDL-3 triglycerides showed a potential positive association (OR = 6.051, 95% CI = 1.789-20.470, p = 0.004). Additionally, HDL-4 ApoA1 may be positively correlated with cognitive function in LOAD (p = 0.047, r² = 0.087). Moreover, our findings suggest that ApoA2 may interact with targets of approved AD drugs. CONCLUSIONS: This study identifies potential key lipoprotein alterations associated with LOAD diagnosis and cognitive function, emphasizing the role of lipidomic insights in understanding and treating LOAD.}, } @article {pmid40963907, year = {2025}, author = {Yoon, BH and Kim, J and Sengupta, S and Park, CJ and Ko, M and Kang, JH and Ko, YT and Kim, Y and Lim, SM and Bae, Y and Choi, M and Jang, Y and Kwon, HJ and Son, HJ and Kim, HJ and Sim, T and Chang, KA and Lee, MS}, title = {Targeted autophagic clearance of Tau protects against Alzheimer's disease through amelioration of Tau-mediated lysosomal stress.}, journal = {Theranostics}, volume = {15}, number = {17}, pages = {9240-9260}, pmid = {40963907}, issn = {1838-7640}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Lysosomes/metabolism/drug effects ; *tau Proteins/metabolism/genetics ; *Autophagy/drug effects ; Mice ; Humans ; Disease Models, Animal ; Induced Pluripotent Stem Cells/metabolism ; Neurons/metabolism/drug effects ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; }, abstract = {Background: Lysosomal dysfunction could be an underlying cause of Alzheimer's disease, with Tau oligomer being an important inducer or amplifier of lysosomal stress associated with the disease. Tau oligomer is a well-known substrate of autophagy, and selective degradation of Tau with Tau-specific autophagy degrader might be feasible. Methods: Tau-specific autophagic degraders were synthesized by combining leucomethylene blue, linkers and a lysosomal degradation tag (Autac). Tau clearance and changes of Tau-mediated lysosomal stress by these degraders were studied in vitro. In vivo effects of a Tau-specific degrader were investigated employing a combined Tau/Aβ mutant mouse model characterized by an accelerated onset of neurological deficits. Human relevance was investigated using induced pluripotent stem cell (iPSC)-derived neuronal cells from an Alzheimer's disease patient. Results: Among Tau-specific Autac degraders, TauAutac-3 (TA-3) efficiently degraded Tau oligomer and monomer, an effect inhibited by bafilomycin A1, suggesting lysosomal Tau degradation. TA-3 treatment induced LC3, K63, OPTN or NDP52 puncta, which was partially colocalized with Tau oligomer. Signs of lysosomal stress, such as galectin-3 puncta, pHluorin fluorescence, altered lysosomal pH and CHMP2B recruitment, induced by Tau expression were reversed by TA-3. Autophagy impairment by Tau expression in vitro, likely due to lysosomal stress, was also reversed by TA-3. In vivo, TA-3 administration markedly reduced the accumulation of both Tau and Aβ in 6xTg mice, which was associated with amelioration of Tau-mediated lysosomal stress and autophagy impairment. Neuroinflammation characterized by increased numbers of GFAP[+] glial cells and Iba1[+] microglial cells, was also reduced following TA-3 administration. TA-3 remarkably improved neurologic deficits in 6xTg mice, such as impaired memory and reduced exploratory behavior. TA-3 reduced Tau and phospho-Tau accumulation in iPSC-derived neuronal cells from an Alzheimer's disease patient. Conclusion: These results suggest that Tau-specific autophagic (Autac) degraders could serve as novel therapeutic agents for Alzheimer's disease through reduction of Tau-mediated lysosomal stress.}, } @article {pmid40963573, year = {2025}, author = {Kaur, A and Alshammari, FS and Rehman, AU and Bharany, S}, title = {Intelligent Alzheimer's diagnosis and disability assessment: robust medical imaging analysis using ensemble learning with ResNet-50 and EfficientNet-B3.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1619228}, pmid = {40963573}, issn = {2296-858X}, abstract = {Neurodegenerative disorder Alzheimer's disease (AD) has progressive characteristics and leads to severe cognitive impairment that reduces life quality. Disease management along with effective intervention depends on the detailed diagnosis conducted early. The proposed framework builds an ensemble system from ResNet-50 and EfficientNet-B3 to conduct automated AD diagnostics by processing high-resolution Magnetic Resonance Imaging (MRI) images. The proposed model uses ResNet-50 to extract features coupled with EfficientNet-B3 as its robust classifier which achieves high accuracy alongside generalization performance. A large, high-quality dataset comprising 33,984 MRI images was used, ensuring diverse representation of different disease stages: the study included participants with four dementia stages organized as Mild, Moderate, Non-demented, and Very Mild Demented. The research applied several comprehensive data preprocessing methods combining normalization steps with rescaling algorithms alongside noise elimination techniques to achieve enhanced performance. Performance tests on the model required examination of accuracy along with precision and recall metrics and F1-score and ROC curve area measurements. The ensemble model delivered remarkable overall accuracy reaching 99.32% while surpassing separate deep learning architectures. The confusion matrix evaluation results showed superb classification results for Mild and Moderate stages along with non-dementia cases while maintaining minimal Wrong choices in Very Mild Demented cases. Experimental findings demonstrate the strength of deep learning algorithms to detect AD disease stages accurately. The robust and accurate performance of the proposed model indicates it has potential for use in medical environments to support radiologists in their work of early-stage AD screening and treatment development. Additional research in diverse clinical environments will strive to optimize and validate the model so it can meet real-world diagnostic requirements for medical use.}, } @article {pmid40963032, year = {2025}, author = {Hammonds, SK and Eftestøl, T and Kurz, KD and Fernandez-Quilez, A and , }, title = {Decision Strategies in AI-Based Ensemble Models in Opportunistic Alzheimer's Detection from Structural MRI.}, journal = {Journal of imaging informatics in medicine}, volume = {}, number = {}, pages = {}, pmid = {40963032}, issn = {2948-2933}, support = {F-12514//Helse Vest/ ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition and the most common form of dementia. Recent developments in AD treatment call for robust diagnostic tools to facilitate medical decision-making. Despite progress for early diagnostic tests, there remains uncertainty about clinical use. Structural magnetic resonance imaging (MRI), as a readily available imaging tool in the current AD diagnostic pathway, in combination with artificial intelligence, offers opportunities of added value beyond symptomatic evaluation. However, MRI studies in AD tend to suffer from small datasets and consequently limited generalizability. Although ensemble models take advantage of the strengths of several models to improve performance and generalizability, there is little knowledge of how the different ensemble models compare performance-wise and the relationship between detection performance and model calibration. The latter is especially relevant for clinical translatability. In our study, we applied three ensemble decision strategies with three different deep learning architectures for multi-class AD detection with structural MRI. For two of the three architectures, the weighted average was the best decision strategy in terms of balanced accuracy and calibration error. In contrast to the base models, the results of the ensemble models showed that the best detection performance corresponded to the lowest calibration error, independent of the architecture. For each architecture, the best ensemble model reduced the estimated calibration error compared to the base model average from (1) 0.174±0.01 to 0.164±0.04, (2) 0.182±0.02 to 0.141±0.04, and (3) 0.269±0.08 to 0.240±0.04 and increased the balanced accuracy from (1) 0.527±0.05 to 0.608±0.06, (2) 0.417±0.03 to 0.456±0.04, and (3) 0.348±0.02 to 0.371±0.03.}, } @article {pmid40962722, year = {2025}, author = {Wu, M and Hao, X and Li, T and Tian, JJ and Gao, XM and Li, ZG}, title = {[Effect of "Tongdu Qishen" acupuncture on pyroptosis in hippocampus and cortex of SAMP8 mice].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {50}, number = {9}, pages = {995-1004}, doi = {10.13702/j.1000-0607.20240754}, pmid = {40962722}, issn = {1000-0607}, mesh = {Animals ; *Pyroptosis ; Male ; Mice ; *Hippocampus/metabolism/cytology ; *Acupuncture Therapy ; Humans ; Acupuncture Points ; *Cerebral Cortex/metabolism/cytology ; Interleukin-1beta/genetics/metabolism ; Caspase 1/genetics/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism ; *Alzheimer Disease/therapy/genetics/physiopathology ; }, abstract = {OBJECTIVES: To explore the underlying mechanism of "Tongdu Qishen" acupuncture (dredging the Govern Vessel and normalizing mental activities) in treating SAMP8 mice from the perspective of pyroptosis. METHODS: Six-month-old male SAMP8 mice were randomly divided into model and "Tongdu Qishen" acupuncture (EA) groups, with 12 mice in each group. SAMR1 mice of the same age (n=12) were used as the normal group. In the EA group, EA (2 Hz/50 Hz, 20 min) was applied to "Baihui" (GV20) and "Yintang" (GV24[+]), and pricking bleeding was applied to "Shuigou" (GV26). The treatment was performed once a day, for a total of 28 days. Morris water maze test was used to evaluate the learning and memory ability of mice, and HE staining was used to observe the morphology of cells in the hippocampus and cortex. Nissl staining was used to observe the number of neurons in the hippocampus and cortex. Immunohistochemistry was used to observe the expressions of Aβ1-40, interleukin (IL)-1β and IL-18 in the hippocampus and cortex. The co-staining of TUNEL and Caspase-1 was detected by immunofluorescence. Western blot and real-time quantitative PCR were used to observe the protein and mRNA expression levels of Nod-like receptor 3 (NLRP3), Caspase-1 and Gasdermin D (GSDMD) in the hippocampus and cortex, respectively. RESULTS: Behavioral results showed that compared with the normal group, the escape latency was prolonged (P<0.001), the dwell time in the original platform quadrant and the times of crossing the original platform were considerably decreased (P<0.001) in the model group. In comparison with the model group, the escape latency was shortened (P<0.05, P<0.001, P<0.01), and the dwell time in the original platform quadrant was significantly increased (P<0.01) in the EA group. Following modeling, the number of neurons was decreased (P<0.001), the positive expression of Aβ1-40, IL-1β and IL-18 in the hippocampus and cortex, the co-expression of TUNEL and Caspase-1, and the protein and mRNA expression levels of NLRP3, Caspase-1, GSDMD were all increased (P<0.001) in the model group relevant to the normal group. After EA intervention, modeling induced increase and decrease of indexes mentioned above were completely reversed (P<0.01, P<0.05, P<0.001). CONCLUSIONS: "Tongdu Qishen" acupuncture may improve the cognitive function of SAMP8 mice by regulating the NLRP3/Caspase-1/GSDMD pathway, relieving the release of inflammatory factors and reducing the content of Aβ1-40.}, } @article {pmid40962125, year = {2026}, author = {Lian, W and Yuan, X and Zhou, F and Tong, Z and Cheng, Y and Zhang, W and He, J and Xu, J}, title = {Cornuside ameliorates LPS induced cognitive dysfunction and microglial NLRP3 inflammasome activation by enhancing Sirt1-mediated autophagy.}, journal = {Journal of ethnopharmacology}, volume = {355}, number = {Pt A}, pages = {120615}, doi = {10.1016/j.jep.2025.120615}, pmid = {40962125}, issn = {1872-7573}, mesh = {Animals ; *Sirtuin 1/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Autophagy/drug effects ; Mice ; *Microglia/drug effects/metabolism ; Inflammasomes/metabolism/drug effects ; Lipopolysaccharides/toxicity ; *Cognitive Dysfunction/drug therapy/chemically induced ; *Cornus/chemistry ; Male ; Mice, Inbred C57BL ; Cell Line ; Disease Models, Animal ; *Anti-Inflammatory Agents/pharmacology ; }, abstract = {Corni fructus are the fruits of Cornus officinalis Sieb. et Zucc. and is widely used in traditional Chinese Medicine for the treatment of dementia. Cornuside, derived from Corni fructus, has been shown to be effective in improving cognition of AD mouse. AIM: In the present study, we investigated the effect of cornuside on cognitive dysfunction and microglial NLRP3 inflammasome activation, as well as explored the underlying mechanism with respect to Sirt1 and autophagy. METHODS: AD mice were established and then treated with cornuside (3, 10, and 30 mg/kg) for 2 weeks. A series of behavioral tests were performed to assess cognition, including the Morris water maze, Y maze, nest building, step-down and step-through tests. Nissl staining was used to evaluate neuronal structural damage. LPS-stimulated BV2 cells were used for in vitro experiments. The anti-inflammatory effects of cornuside on cytokines and NLRP3 inflammasome activation were assessed using ELISA, RT-PCR, immunohistochemistry, western blotting, and immunofluorescence assays. To further elucidate the relationship between Sirt1, autophagy, and NLRP3 inflammasome activation, EX527 and 3-MA were used to inhibit Sirt1 and block autophagy flux in vitro, respectively. RESULTS: Cornuside significantly improved various behavioral performance and inhibited NLRP3 inflammasome activation in LPS-induced mice, as evidenced by decreased levels of NLRP3, ASC, pro-caspase1, caspase1, pro-IL-1β, IL-1β, GSDMD, GSDMD-NT and IL-18. Similar inhibitory effects of cornuside on NLRP3 inflammasome activation was also detected in LPS stimulated BV2 cells. The involvement of Sirt1 and autophagy were further explored in-vivo and in-vitro, revealing that cornuside increased the expression of Sirt1 and enhanced autophagy, with decreased SQSTM1/p62 and increased LC3BII. However, the inhibitory effect of cornuside on NLRP3 inflammasome activation was abrogated by 3-MA, and the effects of cornuside on promoting autophagy and inhibiting NLRP3 inflammasome activation was abolished by EX527. CONCLUSION: Cornuside exerts therapeutic effects on LPS induced AD mice by inhibiting microglial activation and NLRP3 inflammasome overactivation. And Sirt1 mediated autophagy activation is a vital mechanism by which cornuside degrades NLRP3 inflammasome, thereby alleviating neuroinflammation and improving cognitive function.}, } @article {pmid40959937, year = {2025}, author = {Navakkode, S and Kennedy, BK}, title = {Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer's Disease.}, journal = {Aging cell}, volume = {24}, number = {11}, pages = {e70235}, pmid = {40959937}, issn = {1474-9726}, support = {//NUS Medicine/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/physiopathology/genetics ; Disease Models, Animal ; Mice ; *Neuronal Plasticity/drug effects ; *Ketoglutaric Acids/pharmacology/therapeutic use ; Male ; Female ; Mice, Transgenic ; *Amyloid beta-Protein Precursor/metabolism/genetics ; Long-Term Potentiation/drug effects ; Synapses/drug effects/metabolism ; *Presenilin-1/metabolism/genetics ; Humans ; }, abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders, characterized by a progressive decline in cognitive function. Increasing evidence indicates that alpha-ketoglutarate (AKG), a key metabolite in the tricarboxylic acid (TCA) cycle, can extend lifespan and healthspan across various animal models, raising interest in its potential neuroprotective effects in age-related disorders such as AD. Our previous research found that dietary supplementation with calcium alpha-ketoglutarate (CaAKG), a calcium derivative of AKG, enhances both lifespan and healthspan in mice. However, little is known about the neuroprotective role of AKG/CaAKG in AD. Here, we show that CaAKG could rescue synaptic deficits that are associated with AD. Treatment with AKG or CaAKG ameliorates long-term potentiation (LTP) at hippocampal CA1 synapses in APP/PS1 mice, with a more profound effect in female AD mice than in males. The effects of CaAKG were mediated through an NMDA receptor-independent mechanism involving L-type calcium channels (LTCC) and calcium-permeable AMPA receptors (CP-AMPARs). Analysis of protein expression showed that AD hippocampal slices treated with CaAKG exhibited increased LC3-II levels, indicating enhanced autophagy. Similarly, rapamycin, an mTOR inhibitor, also rescued LTP deficits in AD mice, suggesting that the observed increase in autophagy may contribute to neuroprotection. Interestingly, rapamycin showed differential effects, as it rescued LTP in AD mice but blocked LTP in WT mice. We also observed that CaAKG facilitated synaptic tagging and capture (STC), a widely studied cellular model for associative memory, indicating its potential to facilitate associative memory. Overall, our findings suggest that CaAKG has neuroprotective effects in APP/PS1 mice. We propose CaAKG as a promising therapeutic target not only for aging but also for AD and potentially other age-associated neurodegenerative diseases, highlighting geroprotective strategies as viable alternatives for the prevention and treatment of AD.}, } @article {pmid40959879, year = {2025}, author = {Miller, ZA and Ossenkoppele, R and Graff-Radford, NR and Allen, IE and Shwe, W and Rosenberg, L and Olguin, DJ and Erkkinen, MG and Butler, PM and Spina, S and Yokoyama, JS and Desikan, RS and Scheltens, P and van der Flier, W and Pijnenburg, Y and Wolters, E and Rademakers, R and Geschwind, DH and Kramer, JH and Rosen, HJ and Rankin, KP and Grinberg, LT and Seeley, WW and Sturm, V and Perry, DC and Miller, BL and Rabinovici, GD and Gorno-Tempini, ML}, title = {Neurodevelopment and neural environment inform Alzheimer's disease age at onset and phenotype.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70668}, pmid = {40959879}, issn = {1552-5279}, support = {AG019724/NH/NIH HHS/United States ; AG062422/NH/NIH HHS/United States ; //Hellman Research Scientist Award/ ; AG062588/NH/NIH HHS/United States ; AG045611/NH/NIH HHS/United States ; DC015544/NH/NIH HHS/United States ; //Jon and Gale Love fund/ ; AG053435/NH/NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; AG048291/NH/NIH HHS/United States ; //Arking Foundation for Frontotemporal Dementia/ ; NS050915/NH/NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/epidemiology ; Age of Onset ; Female ; Phenotype ; Male ; Aged ; Risk Factors ; Middle Aged ; Cohort Studies ; Aged, 80 and over ; }, abstract = {INTRODUCTION: Risk factors associated with sporadic non-amnestic and early-onset Alzheimer's disease (AD) remain underexamined. METHODS: We investigated a large, clinically heterogeneous, AD cohort for frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus) alongside novel factors (non-right-handedness, learning disability, seizures, autoimmune disease). RESULTS: Early-onset AD possessed lower frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus, all p < 0.001) and higher frequencies of novel factors (non-right-handedness, learning disability, active seizure, all p < 0.001; remote seizure, p = 0.002; and autoimmune disease, p = 0.007). An age at onset < 70 maximally distinguished novel from typical factors. Principal component analysis loaded novel factors into two components, non-right-handedness and learning disability versus seizure and autoimmune disease, which combined, resulted in an exponential decrease in age at onset from one factor alone. DISCUSSION: Identifying novel factors enriched in early-onset and non-amnestic AD introduces new theories of AD susceptibility and phenotypic heterogeneity, with significant implications for disease prediction and treatment. HIGHLIGHTS: We identified a suite of novel factors overrepresented in early-onset and non-amnestic AD. These factors can be broadly conceptualized as neurodevelopmental (non-right-handedness and learning disability) and neural environmental (seizure and autoimmunity). The combination of these factors produced exponential decreases in AD age at onset, compared to each alone, supporting a new theoretical framework for understanding AD risk with implications for disease prediction, prevention, and therapeutic intervention.}, } @article {pmid40959450, year = {2025}, author = {Shi, G and Ni, L and Kong, X and Ren, R and Shi, X and Xu, Y and Qu, Z and Zhou, H and Zhang, X}, title = {Unveiling the therapeutic potential of caudatin: Structural optimization, pharmacological mechanisms, and therapeutic implications.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1640365}, pmid = {40959450}, issn = {1663-9812}, abstract = {Caudatin is a C21 steroidal glycoside isolated from many species of the genus Cynanchum, has been utilized by traditional medicine to treat cancer and inflammation which is increasingly being considered a drug candidate because of the pharmacological activity it displays. This review provides a discussion of caudatin's structure-activity relationship (SAR), pharmacology, and therapeutic uses along with a synthesis of future challenges. Caudatin is a potent anti-cancer therapeutic that has been shown to modulate several important signaling pathways, which include but are not limited to: Wnt/β-catenin, NF-κB, and PI3K/AKT pathway, induce apoptosis through ROS mediated mitochondrial dysfunction, reduce metastatic spread through inhibition of epithelial-mesenchymal transition (EMT), and have an anti-inflammatory effect through inhibition of JNK/AP-1/NF-κB signaling. Caudatin has also displayed neuroprotection in models of Alzheimer's disease by activating TFEB and the autophagosome-lysosomal pathway mechanism of action, while also modulating PPARα. Furthermore, pharmacokinetic studies indicate that caudatin is rapidly absorbed and is able to selectively tail hepatic tissue while having little to no toxicity or significant adverse events in pre- clinical animal studies. Structure-activity studies suggest that modifications on the C-3 hydroxyl position, primarily with nitrogen heterocycles and/or sugars greatly enhance the bioactivity and solubility. With caudatin being such a great scaffold for medicinal chemistry, there is great opportunity to take advantage of caudatin as a building block to generate novel therapies which bridge traditional medicine with modern drug discovery. The future is aimed primarily at a combination strategy of synthetic derivatives, translational studies, and formulations. In further exploring caudatin as a treatment for cancer and neurodegenerative diseases, and inflammation.}, } @article {pmid40959086, year = {2025}, author = {Chen, R and Tang, X and Wang, Y and Wang, B and Mao, F}, title = {Protein palmitoylation: an emerging regulator of inflammatory signaling and diseases.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1652741}, pmid = {40959086}, issn = {1664-3224}, mesh = {Humans ; *Lipoylation ; *Signal Transduction ; *Inflammation/metabolism/immunology ; Animals ; *Protein Processing, Post-Translational ; Thiolester Hydrolases ; }, abstract = {Protein palmitoylation is a reversible lipid modification in which palmitoyl esters are covalently attached to cysteine residues of proteins. It controls various cellular physiological processes and alters protein stability, conformation, localization, membrane binding, and interaction with other effector proteins. Palmitoylation is catalyzed by a group of zinc finger DHHC-containing proteins (ZDHHCs), while the acyl-protein thioesterase family mediates depalmitoylation. Emerging evidence suggests that palmitoylation is critical for inflammatory signaling pathways, where palmitoylation is particularly important in the membrane localization of inflammation-associated proteins. Notably, dysregulation of palmitoylation has been associated with a variety of inflammatory diseases. Here, we provide an overview of the regulatory mechanisms of palmitoylation, explore the emerging role of palmitoylation in inflammatory signaling pathways, and examine the link between dysregulated palmitoylation and the pathogenesis of inflammatory diseases, including inflammatory bowel disease, autoimmune diseases, metabolic dysfunction-associated steatohepatitis, sepsis, Alzheimer's disease, Parkinson's disease, and diabetes. Finally, we discuss some of the challenges and opportunities facing the field. Targeting palmitoylation or its associated enzymes serves as a novel therapeutic approach for the treatment of inflammatory diseases.}, } @article {pmid40958782, year = {2025}, author = {Sun, LC and Li, WS and Chen, W and Zhao, DQ and Zhang, X and Li, CX and Ren, Z}, title = {Frontiers and Emerging Trends in Edaravone Research: A Bibliometric Analysis of Molecular Basis and Clinical Studies Using CiteSpace and VOSviewer.}, journal = {Journal of multidisciplinary healthcare}, volume = {18}, number = {}, pages = {5743-5758}, pmid = {40958782}, issn = {1178-2390}, abstract = {PURPOSE: Edaravone is a potent free-radical scavenger and antioxidant that has been widely investigated for its therapeutic potential in neurodegenerative diseases and oxidative stress-related conditions. Although previous studies have explored its molecular structure, pharmacological effects, and clinical applications, a comprehensive bibliometric analysis of its research trends and future directions remains lacking. METHODS: This study employed bibliometric methods to analyze edaravone-related publications from 2000 to 2024, using the Web of Science Core Collection database. The analysis examined publication trends; contributions by countries, institutions, and authors; and keyword clustering. Data visualization tools, such as CiteSpace and VOSviewer, were utilized to identify research clusters and emerging trends in edaravone research. RESULTS: The findings revealed a significant increase in edaravone-related publications, with China, Japan, and the United States as the leading contributors. Notable researchers, including Abe K and Yoshino H, have made substantial contributions to this field. Four major research clusters were identified: free radical scavenging, cerebral infarction, amyotrophic lateral sclerosis, and oxidative stress. Emerging trends suggest a growing interest in edaravone dexbornel for acute ischemic stroke treatment, as well as its potential applications in blood-brain barrier interactions and Alzheimer's disease. CONCLUSION: This bibliometric analysis highlights the growing interest in edaravone and its potential clinical application, particularly in neuroprotection. While this study provides valuable insights into current research trends, future studies should incorporate a broader range of sources and languages to obtain a more comprehensive understanding of the impact and scope of edaravone.}, } @article {pmid40957902, year = {2025}, author = {Ekins, TG and Rybicki-Kler, C and Deng, T and Brooks, IAW and Jedrasiak-Cape, I and Donoho, E and Ahmed, OJ}, title = {Psychedelic neuroplasticity of cortical neurons lacking 5-HT2A receptors.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {40957902}, issn = {1476-5578}, support = {R34 NS127101/NS/NINDS NIH HHS/United States ; R34NS127101//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; T32DC000011//U.S. Department of Health & Human Services | NIH | National Institute on Deafness and Other Communication Disorders (NIDCD)/ ; P50NS123067//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01 MH129282/MH/NIMH NIH HHS/United States ; R01MH129282//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; T32 DC000011/DC/NIDCD NIH HHS/United States ; P50 NS123067/NS/NINDS NIH HHS/United States ; T32 NS076401/NS/NINDS NIH HHS/United States ; T32 DA007268/DA/NIDA NIH HHS/United States ; AARG-NTF-21-846572//Alzheimer's Association/ ; T32DA007268//U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/ ; }, abstract = {Classical psychedelic drugs show promise as a treatment for major depressive disorder and related psychiatric disorders. This therapeutic efficacy stems from long-lasting psychedelic-induced neuroplasticity onto prefrontal cortical neurons and is thought to require the postsynaptic expression of serotonin 2A receptors (5-HT2AR). However, other cortical regions such as the granular retrosplenial cortex (RSG) - important for memory, spatial orientation, fear extinction, and imagining oneself in the future, but impaired in Alzheimer's disease - lack 5-HT2AR and are thus considered unlikely to benefit from psychedelic therapy. Here, we show that RSG pyramidal cells lacking postsynaptic 5-HT2A receptors still undergo long-lasting psychedelic-induced synaptic enhancement. A newly engineered CRISPR-Cas-based conditional knockout mouse line reveals that this form of psychedelic-induced retrosplenial plasticity requires presynaptic 5-HT2A receptors expressed on anterior thalamic axonal inputs to RSG. These results highlight a broader psychedelic therapeutic utility than currently appreciated, suggesting potential for augmenting RSG circuit function in Alzheimer's disease, post-traumatic stress disorder, and other neuropsychiatric conditions, despite the lack of postsynaptic 5-HT2A receptors.}, } @article {pmid40956653, year = {2025}, author = {Shaker, A and Ljunggren, G and Vossen, LE and Religa, D and Raaschou, P}, title = {Impact of socio-economic and patient-centered characteristics on access to Alzheimer's disease medication in primary care: A population-based study in the Stockholm county, Sweden.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {180-192}, doi = {10.1177/13872877251375900}, pmid = {40956653}, issn = {1875-8908}, mesh = {Humans ; Sweden/epidemiology ; Male ; Female ; *Alzheimer Disease/drug therapy/epidemiology ; *Primary Health Care ; Aged ; Retrospective Studies ; Aged, 80 and over ; *Memantine/therapeutic use ; *Health Services Accessibility/statistics & numerical data ; Socioeconomic Factors ; *Cholinesterase Inhibitors/therapeutic use ; Cohort Studies ; Middle Aged ; Patient-Centered Care ; }, abstract = {BackgroundDespite treatment guidelines for Alzheimer's disease (AD), access to AD medications varies significantly within the same health care setting.ObjectivePredictors influencing access to AD medication were assessed in a retrospective cohort study comprising most individuals diagnosed with AD in Stockholm 2013-2021.Methods14,884 individuals were included, with an incident AD diagnosis between 2013-2021 in Stockholm, Sweden. The primary outcome was the dispensation of AD-specific drugs (cholinesterase inhibitors or memantine) within 90 days before to 180 days after AD diagnosis. We used a generalized linear mixed-effects model (GLMM). Variables included patient-centered characteristics such as age and comorbidities, and characteristics of the primary care centers (PCC) where the individuals were listed, including Care Need Index (CNI).ResultsOverall, 77% of diagnosed patients were dispensed AD medications. Individuals listed at PCCs with high CNI score, indicative of lower socio-economic resources of the area, were less likely to receive a dispensation of any AD medication compared with low CNI score (76.2% versus 84.8%; OR 0.65, 95% CI 0.50-0.86). The association between CNI score and likelihood of receiving AD medication was attenuated in subgroup analysis of individuals living in nursing homes. Also associated with lower likelihood of receiving AD medications were age ≥85 years (OR 0.25, 95% CI 0.21-0.28), nursing home residency (OR 0.37, 95% CI 0.34-0.41), and comorbidity (OR 0.63, 95% CI 0.57-0.70).ConclusionsSocio-economic factors strongly influenced the likelihood of receiving AD medication, in addition to more established factors such as age and comorbidities. Interventions are needed to eliminate barriers to equal drug treatment in AD, particularly those related to socio-economic disadvantages.}, } @article {pmid40956407, year = {2025}, author = {Guo, S and Wei, F and Chang, Y and Wu, S and Lou, Z and Ma, Y and Huang, Q and He, K and Fu, C and Cao, X and Liang, S and Cheng, W and Yin, Y}, title = {Early astrocyte-targeted intervention guided by [18]F-SMBT-1 imaging attenuates disease progression in 3xTg-AD mice.}, journal = {European journal of nuclear medicine and molecular imaging}, volume = {}, number = {}, pages = {}, pmid = {40956407}, issn = {1619-7089}, support = {82472014//National Natural Science Foundation of China/ ; 81974270//National Natural Science Foundation of China/ ; 24ZR1450000//Natural Science Foundation of Shanghai Municipality/ ; 23ZR1441200//Natural Science Foundation of Shanghai Municipality/ ; }, abstract = {PURPOSE: Astrocyte reactivity is a key pathological feature and potential therapeutic target of Alzheimer's disease (AD), however, the optimal timing of its modulation remains unexplored. This study aims to combine [18]F-SMBT-1 based molecular imaging with astrocyte-targeted intervention in 3xTg-AD mice to address this challenge. METHODS: PET imaging with [18]F-SMBT-1 was conducted in 3xTg-AD mice at 4, 6, 10, and 12 months of age, with age-matched wild-type (WT) mice as controls. The standardized uptake value ratio was calculated using cerebellum as the reference region by PMOD software. Immunofluorescence (IF) analysis was used to assess astrocyte reactivity ex vivo. Astrocyte-targeted intervention via Nrf2 overexpression was performed in 4-month-old 3xTg-AD mice using adeno-associated virus vectors. Following intervention, PET imaging with [18]F-SMBT-1 was performed to assess astrocyte reactivity, open field test and Morris water maze test were performed to evaluate cognitive function, and IF analysis was used to assess pathological feature of AD. RESULTS: In 3xTg-AD mice of different ages, higher uptake of [18]F-SMBT-1 was observed in the cortex and hippocampus compared to age-matched WT controls. IF analysis further confirmed the presence of reactive astrocytes activation in 3xTg-AD mice. Both in vivo [18]F-SMBT-1 imaging and ex vivo IF analysis identified early-onset astrocyte activation in 3xTg-AD mice. Based on these observations, we implemented early astrocyte-targeted intervention via Nrf2 overexpression at 4 months of age in 3xTg-AD mice. Subsequent in vivo [18]F-SMBT-1 PET imaging demonstrated a significant reduction in astrocyte reactivity following this intervention. Our findings also demonstrated that early astrocyte-targeted intervention might delay AD pathological progression in 3xTg-AD mice, as supported by attenuated anxiety-like behavior and ameliorated neuropathological features. CONCLUSION: [18]F-SMBT-1 PET imaging served as a diagnostic biomarker for monitoring astrocyte reactivity to guide therapeutic timing decisions, and as a therapeutic response indicator for evaluating treatment efficacy. Early astrocyte-targeted intervention demonstrated significant therapeutic potential. These findings highlighted the translational potential of molecular imaging-guided strategies and astrocyte-targeted therapies in AD.}, } @article {pmid40956219, year = {2025}, author = {Landhuis, E and Christiansen, J and Studios, NM}, title = {A Multipronged Assault: A new understanding of Alzheimer's is leading to a variety of new treatment approaches.}, journal = {Scientific American}, volume = {333}, number = {3}, pages = {89}, doi = {10.1038/scientificamerican102025-5T8bP0cW0x69LnvyUGc4td}, pmid = {40956219}, issn = {0036-8733}, } @article {pmid40955908, year = {2025}, author = {Atewogboye, O and Taylor, JP and Harrison, JR}, title = {Pharmacological strategies for managing dementia with Lewy bodies: an expert review of symptom-targeted care.}, journal = {Expert review of clinical pharmacology}, volume = {18}, number = {9}, pages = {645-653}, doi = {10.1080/17512433.2025.2562151}, pmid = {40955908}, issn = {1751-2441}, mesh = {Humans ; *Lewy Body Disease/drug therapy/physiopathology ; Antipsychotic Agents/adverse effects/administration & dosage/pharmacology ; Polypharmacy ; Cognitive Dysfunction/etiology/drug therapy ; Sleep Wake Disorders/etiology/drug therapy ; Animals ; }, abstract = {INTRODUCTION: Dementia with Lewy Bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease, characterized by a complex combination of cognitive, neuropsychiatric, motor, autonomic, and sleep-related symptoms. Symptom fluctuation, polypharmacy risks, and high sensitivity to commonly used drugs present unique challenges for management. AREAS COVERED: This review provides a comprehensive overview of the symptomatic management of DLB, organized by clinical domains. It critically evaluates current pharmacological and non-pharmacological treatment strategies for cognitive impairment, hallucinations, parkinsonism, autonomic dysfunction, and sleep disturbances. Evidence is drawn from clinical trials, meta-analyses, and extrapolated findings from related disorders such as Alzheimer's disease and Parkinson's disease. EXPERT OPINION: Effective DLB management requires an individualized, symptom-prioritized approach that carefully balances therapeutic benefit with potential adverse effects, particularly given the high risk of antipsychotic sensitivity and treatment-induced worsening of symptoms. Despite recent progress, evidence remains sparse for many symptom domains. Greater investment in DLB-specific clinical trials and development of targeted therapies is urgently needed to improve patient outcomes.}, } @article {pmid40955711, year = {2025}, author = {Tan, A and Wang, Z and Aumont, E and Li, A and Qin, X and Yang, X and Feng, W and Yang, J and Li, X and Xiao, J and Zhou, B and Xing, Y and Yi, Y and Li, J}, title = {Determinants of Treatment Willingness and Willingness-to-Pay for Lecanemab in China: A Network Analysis.}, journal = {Alzheimer disease and associated disorders}, volume = {39}, number = {4}, pages = {223-230}, doi = {10.1097/WAD.0000000000000689}, pmid = {40955711}, issn = {1546-4156}, mesh = {Humans ; China ; Male ; Female ; Surveys and Questionnaires ; Aged ; *Alzheimer Disease/drug therapy/economics/psychology ; *Caregivers/psychology ; Middle Aged ; *Patient Acceptance of Health Care ; }, abstract = {BACKGROUND: Lecanemab is the first disease-modifying therapy for Alzheimer disease (AD) approved in China. However, the factors affecting patient and caregiver willingness to adopt this novel treatment have not been assessed yet. OBJECTIVE: To investigate the factors influencing both treatment willingness and willingness-to-pay for lecanemab among Chinese AD patients and their caregivers. METHODS: We surveyed 195 AD patients and their caregivers using structured questionnaires assessing key factors influencing treatment willingness, including efficacy (W efficacy), adverse effects (W adverse), inconvenience (W inconvenience), cost (W cost), overall willingness to treat (W treat), and amount willing to pay (W amount). Additional variables included income, cognitive and functional assessments, caregiver burden (ZBI), health status (HS), education levels (patient/caregiver: edu, edu.c), psychiatric symptoms (PSY), and satisfaction with conventional treatments (effect). Network analysis mapped variable inter-relationships. RESULTS: W treat showed a strong direct association with W cost (0.99). W efficacy and W inconvenience indirectly influenced W treat through W cost (W efficacy -W inconvenience : 1.5, W inconvenience -W cost : 1.12, W cost -W treat : 0.99). Income (0.48) and effect (0.51) directly impacted W treat . Edu, edu.c, CDR, PSY, ZBI, and HS were indirectly correlated with W treat . W amount was directly associated with W treat (0.31), W cost (0.68), and W adverse (0.16). W efficacy and W inconvenience indirectly influenced W amount through W cost (W efficacy - W inconvenience : 1.5, W inconvenience -W cost : 1.12, W cost -W amount : 0.68). Network stability tests (CS >0.50) confirmed robustness. CONCLUSION: This study demonstrates that reducing payment barriers has a greater impact on real-world adoption of innovative therapies than clinical efficacy alone. Addressing financial constraints also enhances patients' willingness to pay. These findings provide evidence-based insights for developing patient-centered clinical decision pathways.}, } @article {pmid40955309, year = {2025}, author = {Wang, L and Feng, L and Ning, B and Wang, Z and Dai, C and Li, M}, title = {Natural Products from Chinese Medicine Targeting NF-κB Signaling: Emerging Therapeutic Avenues for Neurodegenerative Diseases.}, journal = {Drug design, development and therapy}, volume = {19}, number = {}, pages = {8135-8159}, pmid = {40955309}, issn = {1177-8881}, mesh = {Humans ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Biological Products/pharmacology/chemistry ; *Medicine, Chinese Traditional ; Signal Transduction/drug effects ; Animals ; *Drugs, Chinese Herbal/pharmacology/chemistry ; }, abstract = {This review summarizes recent advances in leveraging natural products from Chinese medicine to modulate the nuclear factor kappa B (NF-κB) signaling pathway for the prevention and treatment of neurodegenerative diseases (NDDs), focusing specifically on Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). NF-κB proteins regulate cellular biological activity by binding to promoter regions in the nucleus and transcribing various protein-coding genes. Emerging evidence indicates that NF-κB plays a pivotal role in driving key hallmarks of NDD progression, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and dysregulation of the cell cycle. Natural products from Chinese medicine exert modulatory effects on NF-κB signaling through diverse pharmacological mechanisms, ultimately improving cognitive and motor impairments in preclinical NDDs models. The pleiotropic nature of natural products derived from traditional Chinese medicine (TCM)-which operate through subunit-specific modulation of NF-κB-underscores their potential as next-generation therapeutics. Investigating the intricate regulation of NF-κB by natural products from Chinese medicine will not only enrich our understanding of the pathogenesis of NDDs but also establish a theoretical foundation for the development of new therapeutic drugs for NDDs, providing innovative strategies for prevention and treatment.}, } @article {pmid40954136, year = {2025}, author = {Martínez-García, J and Fernández, B and Artime, E and Álvarez, L and González-Iglesias, H and Clases, D and Pereiro, R}, title = {ICP-MS for Multiplexed Protein Determination in Extracellular Vesicles from APP/PS1 Mice Blood Serum-Application to a Zn Supplementation Pilot Study.}, journal = {Analytical chemistry}, volume = {97}, number = {38}, pages = {20928-20936}, pmid = {40954136}, issn = {1520-6882}, mesh = {Animals ; *Extracellular Vesicles/metabolism/chemistry ; Pilot Projects ; Mice, Transgenic ; Mice ; *Zinc/administration & dosage/pharmacology ; Mass Spectrometry/methods ; Male ; *Alzheimer Disease/blood ; Female ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Biomarkers/blood ; Dietary Supplements ; }, abstract = {Neurodegenerative diseases represent a significant challenge due to their complex etiology, late diagnosis, and lack of effective treatments. Extracellular vesicles (EVs) have emerged as promising carriers of disease biomarkers, especially proteins, but their low abundance in biological fluids complicates their detection. Here, we present a novel strategy for the multiplexed quantitative determination of EV-associated proteins in blood serum from APP/PS1 transgenic mice, a model of Alzheimer's disease. The method combines inductively coupled plasma-time-of-flight mass spectrometry (ICP-ToFMS) with competitive immunoassays using metal nanocluster-labeled (AuNCs, PtNCs, IrNCs) antibodies targeting Alpha-Actinin 1 (ACTN), Galectin-3-binding protein (LG3BP), and Moesin (MSN). EVs were isolated using an optimized ultracentrifugation protocol to reduce the level of serum protein contamination. Proteomic screening identified target proteins with a known relevance to neurodegeneration, and the developed assay achieved detection limits in the low femtomolar range. The approach was applied to a pilot study on Zn supplementation in 16-month-old APP/PS1 mice, revealing sex-dependent and genotype-specific differences in protein expression but sex-independent patterns in regulatory mechanisms (especially for MSN and LG3BP). Among the studied markers, MSN levels showed statistically significant differences with Zn treatment in male homozygous mice. This work demonstrates the potential of ICP-MS for sensitive and multiplexed biomarker quantification in EVs, supporting its use in neurodegenerative research and supplementation studies.}, } @article {pmid40953123, year = {2025}, author = {Haaland, B and Dickson, SP and Santana, AF and Tanzi, RE and Dubois, B and Peters, O and Grimmer, T and Christensen, J and Mallinckrodt, C and Schneeberger, A and Hendrix, SB}, title = {Efficacy of AD04, an aluminum-based vaccine adjuvant, in patients with early Alzheimer's disease: Post hoc analysis of AFF006 (NCT01117818), a proof-of-concept, phase 2 randomized controlled trial.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {234-242}, doi = {10.1177/13872877251375985}, pmid = {40953123}, issn = {1875-8908}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Adjuvants, Immunologic/therapeutic use ; *Adjuvants, Vaccine/therapeutic use ; *Aluminum Hydroxide/therapeutic use ; *Alzheimer Disease/drug therapy ; *Alzheimer Vaccines/therapeutic use ; Amyloid beta-Peptides/immunology ; Double-Blind Method ; Proof of Concept Study ; Treatment Outcome ; }, abstract = {BackgroundThe AFF006 trial (NCT01117818) provided unexpected evidence of benefits of the vaccine adjuvant AD04 (aluminum oxyhydroxide) in patients with early Alzheimer's disease (AD), compared with AD02, a vaccine consisting of a peptide that mimics the N-terminal region of human amyloid-β (Aβ) conjugated with keyhole limpet hemocyanin.ObjectiveThe objective of this post hoc analysis was to assess whether this unexpected benefit of AD04 was an artifact of multiple testing (i.e., type I error inflation) or a robust result.MethodsIn this post hoc assessment, we used permutation testing to estimate type I error inflation due to the evaluation of multiple outcomes in AFF006. Efficacy was assessed using a patient-level global statistical test combining composite endpoints of cognition, function, and global AD. In addition, we examined the observed treatment benefits of AD04 in the context of effects observed in trials of aducanumab, donanemab, and lecanemab, monoclonal anti-Aβ antibodies that received regulatory approval for AD.ResultsThe global statistical test suggested a treatment benefit of AD04 versus ineffective AD02 arms, even after accounting for multiplicity (primary methodology p-value, 0.03; permutation test p-value, 0.02). The observed effect estimates for AD04 compared favorably with approved monoclonal antibodies.ConclusionsPost-hoc analyses are hypothesis generating rather than confirmatory. Adjusting for multiplicity using permutation testing can determine whether post-hoc effects are worth pursuing, or unlikely to be confirmed. These analyses have motivated a follow-up prospective randomized controlled trial, ADVANCE (EudraCT 2022-003532-73), in which optimized AD04 dosing will be compared to placebo in early AD.}, } @article {pmid40953121, year = {2025}, author = {Gao, M and Chen, J and Zhang, B and Li, J and Lang, J and Zhao, X and Zhang, Q}, title = {Melatonin alleviates cognitive impairment via modulating NLRP3/Caspase 1 pathway in db/db mice.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {157-169}, doi = {10.1177/13872877251375479}, pmid = {40953121}, issn = {1875-8908}, mesh = {Animals ; *Melatonin/pharmacology/therapeutic use ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism/etiology ; Mice ; Signal Transduction/drug effects ; *Caspase 1/metabolism ; Hippocampus/drug effects/metabolism ; Male ; Apoptosis/drug effects ; Diabetes Mellitus, Experimental/metabolism ; Neurons/drug effects/metabolism ; Mice, Inbred C57BL ; }, abstract = {BackgroundActivation of NLRP3 inflammasome has been implicated in cognitive impairment. Melatonin, known for its anti-inflammatory properties and traditional use in regulating circadian rhythms, is the focus of this study. This study intended to investigate the role of melatonin in diabetic cognitive impairment model.ObjectiveThe present study aimed to investigate the underlying mechanism of melatonin in alleviating diabetic cognitive impairment by suppressing NLRP3/Caspase 1 signaling pathway.MethodsCognitive function was assessed using Morris water maze test and Novel Object Recognition test. Apoptosis rate of hippocampal neurons was evaluated by TUNEL staining. Western blot was used to evaluate NLRP3/Caspase 1 pathway expression. Double immunofluorescence labelling of GFAP, Iba-1 or NeuN with NLRP3 respectively showed the localization of NLRP3 in hippocampus of db/db mice. In vitro, HT-22 cells treated with high glucose as cellular model were transfected with pc-DNA3.1-mNLRP3 or co-cultured with NLRP3 inhibitor MCC950 to elucidate NLRP3/Caspase 1 pathway in neuronal apoptosis regulation.ResultsMelatonin treatment improved cognitive function and morphologic abnormalities of hippocampal neurons. The double immunofluorescence labelling revealed melatonin inhibited NLRP3 inflammasome activation in hippocampal neurons rather than microglia or astrocytes. TUNEL staining and western blot showed melatonin markedly reversed the upregulation of NLRP3/Caspase 1 signaling pathway against neuronal apoptosis.ConclusionsMelatonin attenuates diabetic cognitive impairment in db/db mice with down-regulation of NLRP3/Caspase 1 signaling pathway. In vivo and vitro studies supported that NLRP3 activation in hippocampal neurons was associated with diabetic cognitive impairment progression.}, } @article {pmid40953107, year = {2025}, author = {Li, H and Wu, Y and Huang, T and Sun, Y and Lu, Z and Li, M and Wo, H and Shao, F and Tang, S and Zhao, Y and Dai, J and Yi, H and The Alzheimer's Disease Neuroimaging Initiative, }, title = {Development of a risk prediction model for Alzheimer's disease based on the UK Biobank prospective study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {142-156}, doi = {10.1177/13872877251375473}, pmid = {40953107}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/genetics/epidemiology/diagnosis ; United Kingdom/epidemiology ; Male ; Female ; *Biological Specimen Banks ; Risk Factors ; Prospective Studies ; Aged ; Proportional Hazards Models ; Middle Aged ; Risk Assessment ; Polymorphism, Single Nucleotide ; Multifactorial Inheritance ; Genetic Predisposition to Disease ; UK Biobank ; }, abstract = {BackgroundEarly prevention and intervention for Alzheimer's disease (AD) are critical due to the absence of effective therapeutic treatment. However, a widely accepted risk prediction model for AD has yet to be established.ObjectiveTo develop a novel risk prediction model for AD by leveraging recent advances in identifying risk factors, focusing on multi-omics data.MethodsGenetic data from the UK Biobank were employed to calculate the polygenic risk score (PRS) using the clumping and thresholding (C + T) method. Univariate Cox regression and Elastic Net Cox models were utilized to identify significant predictors in the training cohort. Subsequently, a multivariate Cox regression model was developed to construct the prediction model, which was visualized using a nomogram. The performance of the model was evaluated through calibration curves, receiver operating characteristic (ROC) curves, and the Hosmer-Lemeshow test.ResultsTen risk factors, including age, education, family history of dementia, diabetes, depression, hypertension, anemia, coronary heart disease (CAD), falls and PRS, were identified as significant predictors through Cox regression and Elastic Net Cox model. The model demonstrated strong predictive performance, with area under the curves (AUCs) of 0.864 [95% CI: (0.814, 0.911)], 0.860 [95% CI: (0.842, 0.876)], and 0.842 [95% CI: (0.819, 0.863)] at 5, 10, and 14 years, respectively, in the validation cohort.ConclusionsIncorporating colocalized single nucleotide polymorphisms (SNPs) into the PRS derived using the C + T method significantly enhances predictive accuracy. This study highlights the importance of integrating multimodal patient data, including colocalized genetic information, to refine AD risk prediction.}, } @article {pmid40952625, year = {2025}, author = {Kocanci, FG and Sarban, HE and Yildiz, F}, title = {Evaluating the Neuroprotective and Acetylcholinesterase Inhibitory Properties of Four Calcineurin Inhibitor Drugs: Tacrolimus, Pimecrolimus, Cyclosporin A, and Voclosporin.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {16592-16616}, pmid = {40952625}, issn = {1559-1182}, support = {32126//President of the Turkish Health Institutes (TUSEB)/ ; }, mesh = {*Tacrolimus/pharmacology/analogs & derivatives ; *Neuroprotective Agents/pharmacology ; *Calcineurin Inhibitors/pharmacology ; Humans ; *Cholinesterase Inhibitors/pharmacology ; *Acetylcholinesterase/metabolism ; Molecular Docking Simulation ; *Cyclosporine/pharmacology ; Cell Line, Tumor ; Hydrogen Peroxide ; Cell Survival/drug effects ; Molecular Dynamics Simulation ; }, abstract = {Neurodegenerative diseases (ND), marked by progressive neuronal degeneration, often involve dysregulation of acetylcholinesterase (AChE), a key enzyme in cholinergic neurotransmission. AChE inhibition is a well-established therapeutic strategy for Alzheimer's disease (AD), the most prevalent ND, as it aims to restore impaired cholinergic function. However, the effects of calcineurin inhibitors (CNIs), primarily used as immunosuppressants, on AChE activity remain largely unexplored. Recent evidence suggests CNIs possess neuroprotective properties, highlighting their potential for ND treatment. This study evaluated the binding affinities of FDA-approved CNIs-Tacrolimus (Tac), Pimecrolimus (Pim), Cyclosporine A (Csa), and Voclosporin (Voc)-to AChE via molecular docking and molecular dynamic simulation. AChE inhibition was assessed in vitro using the Ellman method and in H2O2-induced degenerative neuron-like SH-SY5Y cells via ELISA and qRT-PCR. Neuroprotection was examined through MTT assays and neurite analysis. Additionally, the antiapoptotic effect was examined by ELISA analysis measuring caspase-3. Docking studies confirmed strong AChE binding for all CNIs, with Voc exhibiting the highest affinity. Voc demonstrated superior in vitro AChE inhibition, surpassing galantamine at low concentrations. Cellular assays showed that CNIs, particularly Voc, significantly inhibited AChE expression at the gene level. Moreover, Voc markedly restored cell viability and reduced neuronal degeneration in H2O2-treated cells. These findings suggest CNIs, especially Voc, as promising candidates for ND treatment, targeting AChE overactivity and oxidative stress.}, } @article {pmid40952411, year = {2025}, author = {Kanda, A and Rani, A and Mazumder, A}, title = {Exploring precision medicine by utilizing individual genetic information for the management of Alzheimer's disease.}, journal = {Pharmacogenomics}, volume = {26}, number = {10-12}, pages = {455-474}, pmid = {40952411}, issn = {1744-8042}, mesh = {Humans ; *Alzheimer Disease/genetics/therapy/drug therapy ; *Precision Medicine/methods ; Apolipoproteins E/genetics ; Biomarkers ; Methylenetetrahydrofolate Reductase (NADPH2)/genetics ; Genetic Predisposition to Disease ; }, abstract = {Alzheimer's Disease (AD) represents a formidable challenge in neurology, characterized by progressive neurodegeneration and cognitive decline. Traditional therapeutic approaches have failed to deliver significant outcomes, underscoring the need for innovative paradigms such as precision medicine. The review explores integrating genomic, biomarker-driven, and individualized therapeutic strategies to tackle AD. It examines the role of key genetic factors, including APOE and MTHFR polymorphisms, in influencing disease susceptibility and treatment responses. Advances in biomarker technologies, such as blood-based and imaging biomarkers, are highlighted for their potential in early diagnosis and patient stratification. Additionally, the review underscores the importance of tailoring interventions across different stages of AD, incorporating lifestyle modifications and emerging tools like artificial intelligence & recent patented technologies. Precision medicine offers a transformative pathway, aiming to deliver personalized, effective care that addresses the complex and multifactorial nature of AD. The paradigm shift promises improved clinical outcomes and enhanced patient quality of life.}, } @article {pmid40952136, year = {2025}, author = {Frykman, H}, title = {Analytical considerations and clinical utility of plasma phosphorylated Tau217.}, journal = {Critical reviews in clinical laboratory sciences}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/10408363.2025.2551648}, pmid = {40952136}, issn = {1549-781X}, abstract = {Blood-based biomarkers are an easily available and practical tool for Alzheimer's disease (AD) screening and diagnosis. Plasma phosphorylated Tau217 (p-tau217) is the front-runner candidate for AD diagnosis due to its strong correlation with core AD pathology determined either by cerebrospinal fluid biomarker (CSF) and positron emission tomography (PET) or postmortem examination. While plasma p-tau217 is firmly associated with AD pathology, it is crucial to evaluate its performance in distinguishing AD from mixed pathologies, as brain autopsies have shown the coexisting of AD pathology with other related types of dementia. Moreover, the measurement of AD biomarkers will be a crucial element in defining eligibility for disease-modifying treatment in clinical practice. Moreover, plasma p-tau217 is a highly efficacious biomarker in the early detection of Aβ pathology, making it a feasible test for AD screening in clinical practice. Several assays, including the ALZpath p-tau217 assay and the Fujirebio plasma p-tau217 assay, have been made commercially available for research use. A few studies analytically and clinically have validated these immunoassays as laboratory diagnostic tests for AD diagnosis and differentiating from non-AD neurodegenerative disorders in clinical practice.}, } @article {pmid40951935, year = {2025}, author = {Wei, Y and Li, H}, title = {The Efficacy and Safety of Amyloid Beta-Directed Monoclonal Antibodies for Alzheimer's Disease: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials.}, journal = {Human psychopharmacology}, volume = {40}, number = {5}, pages = {e70017}, doi = {10.1002/hup.70017}, pmid = {40951935}, issn = {1099-1077}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Randomized Controlled Trials as Topic ; *Antibodies, Monoclonal/adverse effects/pharmacology/administration & dosage/therapeutic use ; Clinical Trials, Phase III as Topic ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of mortality worldwide. One of the newer treatments for AD is amyloid beta (Aβ) directed monoclonal antibodies (mAbs). This systematic review and meta-analysis aimed to assess the efficacy and safety of this class of drugs. METHODS: A comprehensive literature search was conducted across Scopus, Web of Science, PubMed, and the Cochrane Library until January 30, 2025, focusing on phase III randomized controlled trials (RCTs) evaluating anti-Aβ mAbs. RESULTS: Twelve RCTs with 24 arms were included. Anti-Aβ mAbs significantly reduced the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score (mean difference (MD): -0.16, 95% confidence interval (CI) (-0.29, -0.04)), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score (MD: -0.87, 95% CI (-1.13, -0.60)), and amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR) (MD: -0.11, 95% CI (-0.19, -0.02)). They also significantly increased the Mini-Mental State Examination (MMSE) score (MD: 0.31, 95% CI (0.15, 0.46)) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score (MD: 1.21, 95% CI (0.89, 1.53)). However, they were associated with a significant increase in complications, including amyloid-related imaging abnormalities-edema/effusion (ARIA-E) (odds ratio (OR): 10.20, 95% CI (7.17, 14.50)), ARIA-hemosiderosis or microhemorrhage (ARIA-H) (OR: 1.75, 95% CI (1.22, 2.50)), and any adverse events (OR: 1.22, 95% CI (1.08, 1.38), I[2]: 48.59%)). The subgroup analysis showed that treatment administered in the early/preclinical stages of AD resulted in a greater reduction in CDR-SB and ADAS-Cog scores, as well as in amyloid burden. CONCLUSIONS: Anti-Aβ mAbs offer modest clinical benefits, and pose some serious complications, necessitating a cautious approach to their prescription.}, } @article {pmid40951730, year = {2025}, author = {Besin, V and Humardani, FM and Yudiarto, FL and Ong, PA and Putra, SED and Ningrum, RA}, title = {Amyloid-Related Imaging Abnormality (ARIA) Beyond the APOE-ε4 Allele.}, journal = {Chronic diseases and translational medicine}, volume = {11}, number = {3}, pages = {186-196}, pmid = {40951730}, issn = {2589-0514}, abstract = {Monoclonal antibodies (mAbs) have made significant progress in the treatment of Alzheimer's disease (AD). However, mAbs are associated with adverse effects, including Amyloid-Related Imaging Abnormality (ARIA), which manifests as edema or effusion (ARIA-E) and hemorrhage (ARIA-H). The mechanisms behind these effects are not yet fully understood. Moreover, spontaneous ARIA has been insufficiently explored, and mAb therapies, particularly lecanemab, have mainly focused on patients with the APOE-ε4 allele carrier. This review aims to address this gap by examining the mechanisms of spontaneous ARIA, ARIA induced by mAbs, and the influence of genetic variants on ARIA development. The autoantibody-Aβ-mediated immune response targets excessive Aβ deposits, increasing immune activity through microglial reactivity. The heightened immune response, driven by Aβ accumulation in blood vessels, promotes angiopathy and inflammation, potentially contributing to spontaneous ARIA. The APOE-ε4 allele carrier is more strongly associated with ARIA-E because it redistributes Aβ deposition from the brain to blood vessels, influencing microglial reactivity. The redistribution enhances vascular integrity and reduces the risk of ARIA-H. However, it also increases the likelihood of ARIA-E due to Aβ accumulation in the vasculature, triggering inflammation. In contrast, the development of ARIA-H is linked to increased TREM2 expression and microglial reactivity, leading to impaired vascular integrity and disrupted matrix remodeling, which worsens the condition. Additionally, the adverse effects of mAbs may extend beyond the APOE-ε4 allele, possibly impacting other genetic variants involved in microglial reactivity, Aβ redistribution, and vascular integrity.}, } @article {pmid40951709, year = {2025}, author = {Cui, CX and Shao, XN and Li, YY and Qiao, L and Lin, JT and Guan, LH}, title = {Therapeutic potential of mesenchymal stem cells in neurodegenerative diseases.}, journal = {World journal of stem cells}, volume = {17}, number = {8}, pages = {107717}, pmid = {40951709}, issn = {1948-0210}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, are characterized by the progressive loss of neuronal function and structure, leading to severe morbidity and mortality. Current therapeutic approaches are ineffective at stopping or reversing disease progression. Stem cell therapy has emerged as a promising candidate in research and treatment. Mesenchymal stem cells (MSCs) are considered ideal candidates for regenerative medicine because of their high proliferation rate and multi-differentiation potential. MSCs can differentiate into neurons and glial cells, modulate immune responses, and reduce inflammation, and their exosomes can promote neural repair and regulate neuronal function; thus, MSCs offer unique advantages for treating neurodegenerative diseases. However, challenges remain in optimizing cell delivery methods, ensuring the long-term survival and integration of transplanted cells, and fully understanding their therapeutic effects. This article primarily outlines the functions of MSCs in neurodegenerative diseases, with the intention that further research will fully harness their potential and translate these findings into clinical applications, offering new hope for patients suffering from neurodegenerative diseases.}, } @article {pmid40951706, year = {2025}, author = {Shan, XQ and He, MH and Gao, WL and Li, YJ and Liu, SZ and Liu, Y and Wang, CL and Zhao, L and Xu, SX}, title = {Mesenchymal stem cell-derived exosomes: Shaping the next era of Alzheimer's disease treatment.}, journal = {World journal of stem cells}, volume = {17}, number = {8}, pages = {109006}, pmid = {40951706}, issn = {1948-0210}, abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disease for which effective disease-modifying therapies are lacking. Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as a promising therapeutic approach due to their unique biological functions and favorable biocompatibility. This review systematically explores the mechanism of action of MSC-Exos in AD therapy, including the removal of β-amyloid via the delivery of degradative enzymes, modulation of neuroinflammation, and promotion of neural regeneration. Meanwhile, this paper summarizes recent advances in preclinical and clinical studies, and analyzes the challenges in production standardization, safety assessment, and long-term efficacy validation of exosome therapies. Finally, several innovative strategies are proposed to enhance the therapeutic potential of MSC-Exos, including exosome functionalization and targeting optimization, gene editing techniques. This aims to promote the translation of exosomes from basic research to clinical application.}, } @article {pmid40951469, year = {2025}, author = {Widaja, E and Pawitan, JA and Ramli, Y}, title = {Therapeutic potential of hUC-MSC secretome preconditioned with IFN-γ and/or TNF-α: An in vitro study on Alzheimer's neuronal cell models.}, journal = {Narra J}, volume = {5}, number = {2}, pages = {e2281}, pmid = {40951469}, issn = {2807-2618}, mesh = {Humans ; *Interferon-gamma/pharmacology ; *Alzheimer Disease/therapy ; *Mesenchymal Stem Cells/metabolism ; *Tumor Necrosis Factor-alpha/pharmacology ; *Neurons/drug effects ; *Secretome/metabolism ; Umbilical Cord/cytology ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disease that is characterized by toxic Amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). Treatment options include the use of human umbilical cord mesenchymal stem cell (hUC-MSC)-based therapy. Its secretome contains healing substances such as neprilysin (CD10), which breaks down Aβ42; anti-inflammatory cytokines, which lower inflammation; and growth factors, which promote neuronal regeneration. The aim of this study was to produce hUC-MSC secretomes preconditioned with tumor necrosis factor-alpha (TNF-α) and/or interferon-gamma (IFN-γ) to enhance the secretion of these healing substances. hUC-MSCs were sub-cultured in T-25 flasks at a seeding density of 5×103 cells/cm[2] in 10 mL xeno-free medium. hUC-MSCs were preconditioned with TNF-α only, IFN-γ only, and a combination of TNF-α and IFN-γ. This study used 10 ng/mL TNF-α and 20 ng/mL IFN- γ. The secretome was harvested after 48 hours of preconditioning and then filtered through a 0.22 µm filter. In vitro tests were conducted to assess the effects of the secretome on neuronal survival using the neuroblastoma SH-SY5Y cell line. These cells were differentiated with retinoic acid (RA) and then exposed to Aβ42 to mimic Alzheimer's disease neurons. Secretome therapy was applied at concentrations of 5%, 10%, and 20% to evaluate neuroprotective effects. Four types of secretome were tested: unpreconditioned, TNF-α preconditioned, IFN-γ preconditioned, and a combination of TNF-α and IFN-γ. High levels of CD10 (neprilysin) expression were observed in hUC-MSCs treated with IFN-γ and TNF-α, although they did not release sufficient soluble neprilysin (sNEP). Viability results indicated that secretomes preconditioned with IFN-γ at 10% and 20% concentrations provided the highest increase in cell viability after 72 hours post-therapy. The combination of TNF-α and IFN-γ preconditioned secretome exhibited synergistic effects, particularly at 5% and 10% doses at 24- and 72-hours post- therapy. In conclusion, preconditioned hUC-MSC secretome represents a promising therapeutic approach for Alzheimer's disease, as it enhances neuronal cell viability and promotes neuronal regeneration. However, further studies are required to optimize sNEP release and maximize therapeutic efficacy in in vivo models.}, } @article {pmid40950425, year = {2025}, author = {Brown, CA and Cousins, KAQ and Korecka, M and McGrew, E and Chen-Plotkin, A and Detre, JA and McMillan, CT and Lee, EB and Das, SR and Mechanic-Hamilton, D and Yushkevich, PA and Nasrallah, IM and Shaw, LM and , and Wolk, DA}, title = {Temporal Modeling of Amyloid and Tau Trajectories in Alzheimer's Disease using PET and Plasma Biomarkers.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40950425}, support = {P01 AG084497/AG/NIA NIH HHS/United States ; RF1 AG069474/AG/NIA NIH HHS/United States ; R25 NS065745/NS/NINDS NIH HHS/United States ; R01 AG072796/AG/NIA NIH HHS/United States ; R01 AG055005/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG056014/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {OBJECTIVE: To compare PET and plasma-based temporal modeling of amyloid and tau biomarkers in Alzheimer's disease. METHODS: Longitudinal amyloid PET, [18]F-flortaucipir tau-PET, and Fujirebio Lumipulse plasma p-tau217 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and University of Pennsylvania Alzheimer's Disease Research Center (Penn ADRC) were used to generate biomarker trajectory models using Sampled Iterative Local Approximation (SILA). SILA models using plasma p-tau217 were compared to amyloid and tau PET-based models to estimate tau onset age (ETOA) and estimate amyloid onset age (EAOA), and factors influencing ETOA and time from ETOA to dementia were evaluated for PET and plasma-based models. RESULTS: Plasma-based models generated similar results to PET for EAOA and ETOA, with stronger model agreement for ETOA than EAOA. Accuracy of estimated onset age compared to actual onset age was high within modality with slightly greater error when comparing across modalities (i.e. plasma to PET). For both plasma and PET models, earlier ETOA was associated with younger EAOA, female sex, and ≥1 ApoE ε4 allele. Earlier dementia onset after ETOA was associated with later ETOA for both plasma and PET models, while male sex was associated with shorter tau to dementia gap in plasma models. INTERPRETATION: Temporal modeling of plasma biomarkers provides comparable information to PET-based models, particularly for tau onset age. Plasma-based temporal modeling can serve as a widely accessible tool for clinical assessment of biological disease duration that places the patient on the disease timeline, which may allow for improved discussion of prognosis and treatment decisions.}, } @article {pmid40950166, year = {2025}, author = {Wang, Y and Anchipolovsky, S and Bhuiyan, P and Sato, L and Liang, G and Chuang, DM and Wei, H}, title = {Lithium Chloride Inhibits Iron Dysregulation and Ferroptosis in Induced Pluripotent Stem Cells with ApoE4/E4 from a sporadic Alzheimer's disease patient.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40950166}, issn = {2692-8205}, support = {R01 AG061447/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD), particularly its sporadic form (SAD, 95% AD patients), is strongly associated with the apolipoprotein E4 ApoE4 genotype and characterized by oxidative stress, iron dysregulation, and increased susceptibility to ferroptosis. Lithium, a well-established neuroprotective agent, has shown potential to mitigate several pathological mechanisms in AD, including ferroptosis. This study investigates the therapeutic potential of lithium chloride in human induced pluripotent stem cells (iPSCs) derived from a SAD patient with ApoE4/E4 genotype, and compared effects with those of isogenic gene-edited ApoE3/E3 control. Lithium treatment significantly improved cell viability in ApoE4/E4 iPSCs. It also reversed key ferroptosis phenotypes, including elevated cytosolic Fe[[2+]], increased expression of divalent metal transporter 1, reduced level of glutathione peroxidase 4, enhanced lipid peroxidation, and excessive ROS production. Moreover, lithium normalized mitochondrial respiration and reduced proton leak, indicating preservation of mitochondrial function and protection against mitochondrial damage and cell death. Lithium also reduced the expression of type 1 InsP3 receptor (InsP3R-1) protein, a Ca[[2+]] channel located on the endoplasmic reticulum (ER) membrane. Together, these findings highlight lithium's inhibition of ferroptosis through modulation of iron metabolism, antioxidant defenses, and inhibition of disrupted Ca[2+] signaling. Given its demonstrated efficacy in reversing ApoE4-driven cellular vulnerabilities, lithium salt warrants further investigation for the treatment of AD.}, } @article {pmid40950069, year = {2025}, author = {Simpson, D and Morrone, CD and Wear, D and Khani, A and Liu, F and Gutierrez, J and Yu, WH}, title = {Brain large artery dilatation increases the risk for Alzheimer's disease pathology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.08.29.672901}, pmid = {40950069}, issn = {2692-8205}, abstract = {Alzheimer's disease (AD) and related dementia cases are increasing globally, emphasizing the urgent need to clarify disease mechanisms for translational application in diagnoses and treatment. Vascular alterations represent a major pathological feature of AD, and beyond the well-established roles of small vessel disease and large artery atherosclerosis, our group has previously demonstrated that brain large artery dilatation is associated with elevated risk of dementia and Alzheimer pathology. The most severe manifestation of this non-atherosclerotic arterial phenotype is dolichoectasia, an enlargement of large blood vessels (Gutierrez et al., 2019; Melgarejo et al., 2024). Despite consistent epidemiological evidence across populations, the mechanistic link between arterial dilatation and AD remains poorly understood. To address this gap, we induced dolichoectasia in App [NL-G-F] mice, a model of amyloid pathology, by injecting elastase into the cisterna magna. After three months, brains were examined using biochemical and immunohistochemical methods. Elastase-treated mice exhibited a significant increase in amyloid plaques in the hippocampus (p = 0.021) and cortex (p = 0.029) compared with vehicle-treated controls. Neuronal loss was evident in the CA1 region of the hippocampus (p = 0.036), with a trend towards neurodegeneration in CA3 (p = 0.055). We also observed elevated p62 in the hippocampus and cortex (p = 0.009 and p = 0.001 , respectively), suggesting impaired protein or autophagic-lysosomal clearance. Although no overt increase in neuroinflammation or astrogliosis was detected at this time point, matrix metalloproteinase-9 (MMP-9) levels were trending towards elevated levels (p = 0.058). Combined, these findings indicate successful elastase-induced brain arterial dilatation accelerates AD-related pathology in App [NL-G-F] mice, providing mechanistic evidence that large artery dilatation may contribute directly to Alzheimer's disease progression.}, } @article {pmid40949788, year = {2025}, author = {Alzenaidi, F and Aldoweesh, O and Alghofaili, S and Fadel, A and Ali Awad Lasloom, R and Alharbi, D and Almalki, F and Ahmad Alkhairi, A and Alharbi, M and Ahmed Alhamdan, N and Azzam, AY}, title = {Selective serotonin reuptake inhibitors and glucose metabolism in Alzheimer's disease and related dementias: A systematic review and meta-analysis of brain metabolic and adverse event data.}, journal = {Metabolism open}, volume = {27}, number = {}, pages = {100389}, pmid = {40949788}, issn = {2589-9368}, abstract = {INTRODUCTION: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression in Alzheimer's disease (AD), however their effects on glucose metabolism remain poorly understood. We conducted a systematic review and meta-analysis to evaluate SSRI effects on brain glucose metabolism and metabolic adverse events in AD patients. METHODS: Following PRISMA 2020 guidelines, we searched multiple databases up to July 11, 2025 for studies investigating SSRI effects on glucose-related outcomes in AD patients. Despite significant heterogeneity in study designs and populations, we performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. We performed meta-analyses for adverse events and coordinate-based meta-analysis for neuroimaging data. Advanced Bayesian hierarchical modeling and Markov simulations projected long-term metabolic outcomes. RESULTS: Twelve studies with total included 7143 participants met our inclusion criteria, including nine randomized controlled trials and three observational studies. Brain FDG-PET revealed SSRI use restored dorsal raphe nucleus hypometabolism (standardized mean difference 0.87, 95 % CI: 0.52-1.22, P-value = 0.001). Meta-analysis demonstrated increased gastrointestinal adverse events (risk ratio 2.15, 95 % CI: 1.68-2.76, P-value<0.001, with moderate between-study heterogeneity), with sertraline showing highest rates. Citalopram 30 mg provided significant weight loss protection (risk ratio 0.13, 95 % CI: 0.02-0.98, P-value = 0.02), though this exceeds the recommended 20 mg maximum dose for elderly patients due to cardiac safety considerations. Long-term diabetes incidence showed no increased risk (hazard ratio 0.75, 95 % CI: 0.50-1.12, P-value = 0.15). Bayesian modeling revealed 85 % probability of beneficial brain metabolic effects and 89 % probability of citalopram superiority for weight protection. CONCLUSIONS: SSRIs restore brain glucose metabolism in AD patients while causing manageable peripheral metabolic effects. Citalopram appears the best for weight-sensitive patients, while sertraline requires gastrointestinal monitoring. These findings support SSRI safety for metabolic outcomes in AD treatment, however longer-term studies with controlled metabolic outcomes are needed to confirm our findings. The observed citalopram weight protection benefit was documented at 30 mg daily, which exceeds recommended dosing limits for elderly patients due to cardiac safety concerns.}, } @article {pmid40949676, year = {2025}, author = {Cai, H and Hu, J and Zhao, C and Lin, J}, title = {Wearable devices in neurological disorders: a narrative review of status quo and perspectives.}, journal = {Annals of translational medicine}, volume = {13}, number = {4}, pages = {46}, pmid = {40949676}, issn = {2305-5839}, abstract = {BACKGROUND AND OBJECTIVE: Neurological disorders are a group of diseases involving motor, sensory, cognitive, and autonomic functions, among which stroke, Alzheimer's disease (AD), and Parkinson's disease (PD) are prevalent. Their management, especially in conditions with chronic courses or long-term sequelae, remains a substantial unmet need. With the growing comprehension of neuroscience, the development of digital technology, and the rising demand for quality of life, wearable devices offer a promising solution for disease management. The review aimed to evaluate the application and prospect of wearable devices in neurological disorders. METHODS: We conducted the review by searching papers on the application of wearable devices and wearable technology in neurology and neurological disorders using multiple databases. We summarized the present development status of wearable devices, and outlined the potential value and future direction for further research. KEY CONTENT AND FINDINGS: Existing wearable devices for neurological diseases can be applied to diagnosis and follow-up, as an electronic biomarker detector capturing subtle and objective changes in motor, sensory, and cognitive function. The devices can also be utilized for treatment and rehabilitation, mainly through exoskeletons and brain-computer interface. The application of wearable devices in neurology currently faces several critical limitations, including technical bottlenecks in the detection of fine motor and sensory functions, a lack of industry standards, and a limited sample size. CONCLUSIONS: This review demonstrates the potential of wearable technology in people with neurological disorders, enabling disease management and clinical trials outside clinical settings in the future. Nevertheless, further research is required to develop lighter, more user-friendly devices with various functions. It is believed that with increasing demand and technical support, wearable devices would have a promising range of applications.}, } @article {pmid40949612, year = {2025}, author = {Gao, L and Wang, J and Bi, Y}, title = {Nanotechnology for Neurodegenerative Diseases: Recent Progress in Brain-Targeted Delivery, Stimuli-Responsive Platforms, and Organelle-Specific Therapeutics.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {11015-11044}, pmid = {40949612}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Blood-Brain Barrier/metabolism ; Brain/metabolism/drug effects ; *Drug Delivery Systems/methods ; Nanomedicine/methods ; Nanoparticles/chemistry ; Organelles/drug effects/metabolism ; Liposomes/chemistry ; *Nanoparticle Drug Delivery System/chemistry ; Drug Carriers/chemistry ; }, abstract = {Neurodegenerative diseases-including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis-are characterized by progressive neuronal loss and complex pathological mechanisms such as protein aggregation, mitochondrial dysfunction, and neuroinflammation. Conventional therapies offer limited efficacy due to the blood-brain barrier (BBB) and lack of targeted delivery. Nanotechnology has emerged as a transformative strategy for precise brain-targeted treatment. This review summarizes recent advances in nanoparticle-based drug delivery systems, including polymeric nanoparticles, liposomes, inorganic nanomaterials, and biomimetic carriers, highlighting their design features, BBB-penetration mechanisms, and disease-specific applications. Emphasis is placed on stimuli-responsive nanocarriers that react to pH, reactive oxygen species, or enzyme activity, enabling site-specific drug release. Additionally, organelle-targeting strategies-particularly those directed at mitochondria and lysosomes-are explored for their role in subcellular precision therapy. The integration of diagnostic and therapeutic modalities in theranostic nanoplatforms is also discussed. By consolidating preclinical progress and emerging technologies, this review offers insights into the future of nanomedicine in treating neurodegenerative diseases and lays the groundwork for clinical translation.}, } @article {pmid40949219, year = {2025}, author = {Van, DTT and Hoang, TLH and Tran, TVT and Le, TH and Le, LS and Nguyen, QM and Nguyen, THH and Bich, TTN and Nguyen, THC and Phan, CU and Nguyen, CC}, title = {Structural Characterizations and In Vitro Bioactivities of a d‑Fructose-Rich Polysaccharide from Gymnopetalum cochinchinense as a Potential Candidate for Alleviating Alzheimer's Disease.}, journal = {ACS omega}, volume = {10}, number = {35}, pages = {40342-40353}, pmid = {40949219}, issn = {2470-1343}, abstract = {The presented investigation attempts to unveil the structural characteristics, bioactivities, and potential application of Gymnopetalum cochinchinense-derived d-fructose-rich heteropolysaccharide (denoted as PS-HB5) for the treatment of Alzheimer's disease (AD). Structural analyses of the PS-HB5 evaluated by FT-IR, GC-MS, and NMR techniques reveal a novel repeating unit composed of d-glucose and d-fructose linked through (1 → 6)-glucosyl, (2 → 6)-fructosyl, and (2 → 4)-fructosyl bonds, and possesses a molecular weight of 1.217 × 10[5] Da. The PS-HB5 exhibits strong antioxidant activity, as evidenced by its DPPH and ABTS radical scavenging rates of 84.12% and 74.14%, associated with the IC50 values of 0.80 and 3.06 mg.mL[-1], respectively. In addition, the PS-HB5 shows an inhibition rate of 78.37% (IC50 = 221.96 μg.mL[-1]) toward nitric oxide (NO) production in LPS-stimulated macrophages. Cytotoxicity assays indicate selective inhibition of the PS-HB5 against HepG2 and KB cancer cell lines (IC50 = 449.95 and 408.34 μg/mL), with minimal impact on MCF-7 and SK-LU-1. Interestingly, PS-HB5 demonstrates an outstanding AChE inhibitory effect, achieving 41.01% inhibition at 500 μg.mL[-1], placing it among the most active AChE-inhibitory polysaccharides. These findings unveil the PS-HB5 potential as a candidate for the treatment of Alzheimer's Disease.}, } @article {pmid40949132, year = {2025}, author = {Han, X and Meng, X and Wu, Y and Xia, W and Xue, S and Liu, X and Lyu, C and Li, Z and Yan, X and Won Jung, H and Zhang, S}, title = {Systems pharmacology identifies ajugol-mediated NF-κB/caspase-3 inhibition and isoacteoside-driven p62/mTOR-mediated autophagy as key mechanisms of Rehmanniae Radix and its processed form in Alzheimer's treatment.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1644847}, pmid = {40949132}, issn = {1663-9812}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the deposition of senile plaques, neurofibrillary tangles, and neuronal dysfunction, resulting in severe cognitive and memory decline. The root of the Scrophulariaceae plant Rehmannia glutinosa (Gaertn.) DC. (Rehmanniae radix; RR) and its product Rehmanniae radix praeparata (RRP) possess high nutritional and medicinal value. Both show therapeutic potential for AD in traditional medical settings. However, the differences in their bioactive components and the mechanisms of action underlying their anti-AD effects remain unclear. METHODS: In this study, APP/PS1 mice were used as the animal model of AD. Ultra-high-performance liquid chromatography coupled with Q-Exactive tandem mass spectrometry (MS/MS) (UPLC-QE-MS/MS), network pharmacology, proteomics, molecular docking, and 16S rRNA sequencing were used to investigate the differences in the medicinal components of RR and RRP and their mechanisms of action in the treatment of AD. The mechanisms of action of two identified critical components, ajugol and isoacteoside, were further verified in the D-galactose/AlCl3-induced Institute of Cancer Research (ICR) mouse model of AD-with cognitive function evaluated using the Morris water maze and open-field tests-and the amyloid-beta (Aβ)-induced BV2 cell model of inflammation. RESULTS: Ajugol and isoacteoside were identified as the key anti-AD bioactive compounds in RR and RRP, respectively, through UPLC-QE-MS/MS. Integrated network pharmacology, proteomics, and 16S rRNA sequencing implicated neuroinflammation, apoptosis, and autophagy as critical pathways for their anti-AD effects. Subsequently, in vivo and in vitro experiments demonstrated that ajugol exerted its effects mainly by modulating the TLR/NF-κB/NLRP3 and BCL-2/BAX/cytochrome C/caspase-3 pathways, while isoacteoside primarily acted via the LC3-Ⅱ/P62/p-mTOR/mTOR pathway. Ajugol and isoacteoside mitigated cognitive impairment in AD models, decreased Aβ plaque accumulation in hippocampal tissues, and attenuated inflammatory injury-induced cytotoxicity in BV2 microglia, thereby suppressing AD progression. CONCLUSION: In this work, we systematically elucidated the differential mechanisms underlying the anti-AD effects of ajugol and isoacteoside. We found that ajugol primarily acts via the TLR/NF-κB/NLRP3 and BCL-2/BAX/cytochrome C/caspase-3 pathways, while isoacteoside acts via the LC3-II/P62/p-mTOR/mTOR pathway. These findings establish a foundation for developing RRP-based complementary medicines and functional foods.}, } @article {pmid40948811, year = {2025}, author = {Imiruaye, OE and Perez, IG and Carson, BC and Crouzet, C and Garcia, J and Han, D and Bhattacharya, S}, title = {Spatiotemporal differential regulation of extrasynaptic GluN2B receptor subunits and PSA-NCAM in brain aging and Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1649625}, pmid = {40948811}, issn = {1662-4548}, abstract = {INTRODUCTION: Extrasynaptic GluN2B N-methyl-D-aspartate receptors (ES-GluN2B) are localized outside synapses and promote excitotoxic signaling, apoptosis, and long-term depression (LTD) in Alzheimer's disease (AD). Polysialylated neural cell adhesion molecule (PSA-NCAM) physiologically inhibits ES-GluN2B activity, and its downregulation is associated with impaired synaptic plasticity. However, the spatiotemporal changes of ES-GluN2B and PSA-NCAM during brain aging versus AD remain poorly understood. METHODS: We investigated GluN2A, GluN2B, ES-GluN2B, and PSA-NCAM expression across brain regions in young and old Tg2576 AD and wild-type (WT) mice. Additional experiments included PSD-95 pulldown assays, analysis of GluN2B phosphorylation at Ser1480, CRISPRa-driven ST8Sia4 upregulation in IMR-32 neuroblastoma cells, and Aβ treatment to assess effects on PSA-NCAM biosynthetic enzymes. RESULTS: Normal aging was associated with decreased GluN2B, increased GluN2A, stable ES-GluN2B, and elevated PSA-NCAM levels. In contrast, AD aging showed elevated ES-GluN2B and reduced PSA-NCAM, particularly in the hippocampus and cortex, with no change in total NCAM expression. PSD-95 pulldown revealed increased extrasynaptic GluN2B in aged AD brains. AD aging was associated with elevated phosphorylation of GluN2B at Ser1480 by casein kinase 2 (CK2), promoting GluN2B redistribution to extrasynaptic sites. CRISPRa-driven ST8Sia4 upregulation increased PSA-NCAM and reduced pGluN2B expression supporting a direct regulatory role for PSA-NCAM in GluN2B trafficking. Additionally, Aβ suppressed PSA-NCAM biosynthetic enzymes ST8Sia4 and UDP-E linking Aβ to impaired polysialylation. DISCUSSION: These findings highlight distinct regulatory patterns of ES-GluN2B and PSA-NCAM in AD versus normal aging and support a model in which impaired PSA-NCAM buffering facilitates pathological ES-GluN2B signaling and plasticity loss in AD progression.}, } @article {pmid40948809, year = {2025}, author = {Kynigopoulos, D and Fella, E and Shahabian, L and Christodoulou, CC and Papacharalampous, R and Diskos, K and Vagiaki, LE and Sidiropoulou, K and Pipis, M and Kleopa, KA and Panayiotou, E}, title = {Systemic lipid and glucose modulation differentially affects cognitive function and neuroinflammation in a mouse model of Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1636624}, pmid = {40948809}, issn = {1662-4548}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and cognitive decline. Increasing evidence implicates systemic metabolic dysregulation in AD pathogenesis, yet it remains unclear whether modulation of peripheral lipid and glucose metabolism can alter disease progression. METHODS: We investigated the effects of two FDA-approved metabolic agents-Alirocumab, a PCSK9 inhibitor that lowers LDL cholesterol, and Gliclazide, a sulfonylurea that enhances insulin secretion-in male 5xFAD mice, a transgenic model of AD. Animals received chronic treatment for five months. Behavioral testing, hippocampal electrophysiology, ELISA, lipidomics, and adipokine profiling were performed to assess cognitive, synaptic, and molecular outcomes. RESULTS: Alirocumab significantly improved spatial working memory, restored hippocampal long-term potentiation, and normalized synaptophysin expression. Gliclazide reduced neuroinflammation and partially preserved glial and neuronal markers. Both treatments decreased amyloid burden and modulated adipokine levels, with Alirocumab elevating leptin and omentin in brain and serum. Lipidomic profiling of visceral adipose tissue revealed distinct lipid remodeling and highlighted candidate pathways linking systemic metabolism to central nervous system outcomes. DISCUSSION: These findings demonstrate that systemic modulation of lipid and glucose metabolism can influence neurodegenerative and synaptic processes in AD. The results support metabolic interventions as a potential strategy to modify AD progression through peripheral-central metabolic crosstalk.}, } @article {pmid40948808, year = {2025}, author = {Cansiz, B and Ilhan, HO and Aydin, N and Serbes, G}, title = {Olfactory EEG based Alzheimer disease classification through transformer based feature fusion with tunable Q-factor wavelet coefficient mapping.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1638922}, pmid = {40948808}, issn = {1662-4548}, abstract = {INTRODUCTION: Alzheimer's disease has been considered one of the most dangerous neurodegenerative health problems. This disease, which is characterized by memory loss, leads to conditions that adversely affect daily life. Early diagnosis is crucial for effective treatment and is achieved through various imaging technologies. However, these methods are quite costly and their results depend on the expertise of the specialist physician. Therefore, deep learning techniques have recently been utilized as decision support tools for Alzheimer's disease. METHODS: In this research, the detection of Alzheimer's disease was investigated using a deep learning model applied to electroencephalography signals, taking advantage of olfactory memory. The dataset comprises three categories: healthy individuals, those with amnestic mild cognitive impairment, and Alzheimer's disease patients. The proposed model integrates three distinct feature types through a transformer-based fusion approach for classification. These feature vectors are derived from the Common Spatial Pattern, Covariance matrix-Tangent Space and a Tunable Q-Factor wavelet coefficient mapping. RESULTS: The results demonstrated that subject-based classification of rose aroma attained a 93.14% accuracy using EEG-recorded olfactory memory responses. CONCLUSION: This output has demonstrated superiority over EEG-based results reported in the literature.}, } @article {pmid40948654, year = {2025}, author = {Cui, S and Zhao, Y and Wang, X and Huang, Y and Ye, J and Deng, Z and Li, Y and Qin, H and Wang, L and Li, Y and Wang, K and Zheng, G and Qin, Q}, title = {Evaluating the clinical evidence of TCM in Alzheimer's disease: an evidence map perspective.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1571361}, pmid = {40948654}, issn = {1664-2295}, abstract = {OBJECTIVE: This systematic review aimed to synthesize current clinical evidence from randomized controlled trial (RCT) and meta-analyses on the efficacy and safety of TCM in the treatment of Alzheimer's Disease (AD). METHODS: Systematic searches across eight biomedical databases (PubMed, Embase, Web of Science, Cochrane Library, CNKI, Wanfang, VIP, SinoMed) through October 26, 2024 yielded an evidence matrix, which was analyzed through integrated narrative-graphic synthesis. RESULTS: Our analysis encompassed 187 studies (141 RCTs and 46 systematic reviews/meta-analyses), demonstrating cyclical publication growth with recent contraction. Study characteristics included sample sizes of 50-100 participants and intervention durations of 4-24 weeks. Interventions included acupuncture, herbal decoctions, and proprietary medicines. Outcomes focused on clinical efficacy, scale scores, TCM syndrome scores, and safety. While TCM demonstrated therapeutic potential, prescription heterogeneity and diagnostic ambiguity constrained specificity. Methodological quality was generally low, with few high-quality systematic reviews or meta-analyses. CONCLUSION: While TCM shows therapeutic potential in Alzheimer's disease, methodological limitations persist. Subsequent research requires enhanced trial designs with standardized outcome metrics and rigorous bias control protocols.}, } @article {pmid40947745, year = {2025}, author = {Ogunsuyi, OB and Oluokun, OO and Ademiluyi, AO and Oboh, G and Akeeb, RA and Umar, HI and Olagoke, OC}, title = {Synergistic effects of curcumin-donepezil therapy in a Drosophila Alzheimer's disease model.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/17582024.2025.2558428}, pmid = {40947745}, issn = {1758-2032}, abstract = {BACKGROUND: Despite emerging therapeutic options, Alzheimer´s disease (AD) management remains suboptimal due to multimodal pathogenesis. We investigated curcumin-donepezil combination therapy, as curcumin demonstrates antioxidant, anti-inflammatory, and anti-amyloidogenic properties that may complement donepezil's cholinesterase inhibition. RESEARCH DESIGN AND METHODS: We employed the elav-Gal4/UAS-hAPP-BACE-1 Drosophila melanogaster model alongside molecular docking simulation and ADMET prediction to evaluate curcumin-donepezil combination versus monotherapy. Fruit flies received the treatment regimen, and were tested for survival, memory performance, and biochemical markers, including BACE-1 activity and oxidative stress parameters. RESULTS: Combination therapy significantly improved survival rates and memory performance compared to individual treatment. The combination effectively modulated multiple AD-related pathways, demonstrating reduced BACE-1 activity and decreased oxidative stress markers. Molecular docking confirmed favorable drug interactions, and ADMET profiles supported therapeutic viability. CONCLUSIONS: Curcumin-donepezil combination therapy shows promise as a multi-target approach for AD management. However, translation to clinical applications requires validation in higher-order models and human trials.}, } @article {pmid40947724, year = {2025}, author = {Aljabali, AAA and Alkaraki, A and Obeid, MA}, title = {MAPT Haplotype Variation and Alzheimer's Disease Risk: A Narrative Review with Focus on the Jordanian Population.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X371971250818110608}, pmid = {40947724}, issn = {1875-6190}, abstract = {INTRODUCTION: Genetic variations in the microtubule-associated protein tau (MAPT) gene play a central role in Alzheimer's disease (AD) pathogenesis. Two major MAPT haplotypes, H1 and H2, show differential associations with tau expression and AD risk. However, data from Middle Eastern populations remain limited, restricting our understanding of population-specific disease susceptibility patterns and therapeutic responses. METHODS: We conducted a comprehensive literature review using PubMed, Scopus, and Web of Science databases. Search terms included "MAPT haplotype," "Alzheimer's disease," "H1 H2," "tau pathology," and "pharmacogenetics." We analyzed peer-reviewed articles published between 2000 and 2024, focusing on studies reporting haplotype frequencies, MAPT expression levels, APOE interactions, and clinical outcomes. This review synthesizes published data without generating new experimental results. RESULTS: The H1 haplotype consistently associates with increased MAPT expression, tau accumulation, and elevated AD risk, particularly in APOE ε4 noncarriers. Conversely, the H2 haplotype appears protective, correlating with reduced tau burden and slower cognitive decline. Notably, recent reports reveal significant overrepresentation of the H2 haplotype in the Jordanian population compared to European and East Asian cohorts, where H2 frequency is substantially lower or absent. This distinct genetic architecture suggests altered regional AD risk profiles. DISCUSSIONS: The elevated H2 frequency in Jordan represents a unique population-specific genetic signature that may influence regional AD susceptibility patterns. These findings challenge current risk models predominantly based on European populations and suggest the need for populationtailored approaches in neurodegenerative disease research. The naturally H2-enriched Jordanian cohort provides an exceptional opportunity to investigate protective mechanisms against tau pathology. CONCLUSION: MAPT haplotype distributions show significant population variation with important implications for AD risk assessment and therapeutic targeting. The high H2 frequency in Jordan warrants integration into personalized medicine frameworks and population-specific disease models, potentially informing more effective regional prevention and treatment strategies.}, } @article {pmid40947692, year = {2025}, author = {Manubolu, K and Peeriga, R}, title = {Revolutionizing Neurodegenerative Disease Management: The Synergy of AI and Pharmacy.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098375978250820220024}, pmid = {40947692}, issn = {1874-6128}, abstract = {Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS), represent major healthcare challenges worldwide. Despite advances in diagnosis and treatment, these conditions remain incurable, and there is a need for more effective management strategies. The integration of artificial intelligence (AI) in healthcare has emerged as a promising solution, offering new approaches to diagnosis, personalized treatment, and patient care. This paper explores the potential of AI to revolutionize the management of neurodegenerative diseases, with a focus on its synergistic role in pharmacy. By leveraging AI in drug discovery, personalized treatment plans, and clinical decision-making, AI can enhance therapeutic outcomes and improve patient quality of life. The study reviews the current landscape of AI applications in neurodegenerative disease management, with a focus on pharmacy-related interventions. The review includes AI-driven approaches in genomics, biomarkers, drug repurposing, and clinical trials. It also examines AI's role in optimizing pharmaceutical care, improving medication adherence, and tailoring treatments based on individual genetic profiles. AI has demonstrated its capability to analyze vast datasets, from genetic information to clinical records, to identify novel drug targets and predict patient responses to specific therapies. The use of AI in precision medicine has enabled more accurate diagnosis and has facilitated the development of personalized treatments for neurodegenerative diseases. Additionally, AI tools are enhancing medication management by providing personalized therapy adjustments and improving adherence. AI offers transformative potential for the future of neurodegenerative disease management. Its integration into pharmacy practice promises more effective, individualized treatments, accelerating drug discovery, and optimizing patient care. As AI technologies continue to advance, their role in managing complex neurological disorders will become increasingly vital.}, } @article {pmid40947660, year = {2025}, author = {Noguchi, Y and Masuda, R and Yoshimura, T}, title = {Sequence Symmetry Analysis of the Interrelationships Between Ramelteon and Parkinson's Disease.}, journal = {Journal of pineal research}, volume = {77}, number = {5}, pages = {e70080}, doi = {10.1111/jpi.70080}, pmid = {40947660}, issn = {1600-079X}, support = {//This study was supported by JSPS KAKENHI, 22K12890./ ; }, mesh = {*Parkinson Disease/epidemiology/drug therapy ; Humans ; *Indenes/adverse effects/therapeutic use ; Female ; Male ; Aged ; Middle Aged ; }, abstract = {Parkinson's disease is the second most frequent neurodegenerative disease after Alzheimer's disease, and the most common neurodegenerative disease that causes movement dysfunction. Without innovations in prevention and treatment, the incidence and prevalence of Parkinson's disease is projected to increase by > 30% by 2030, making the development of new treatments an urgent priority. We previously investigated the association between melatonin receptor agonists and Parkinson's disease using the US Food and Drug Administration's Adverse Event Reporting System (FAERS). The results showed that ramelteon may reduce the incidence of Parkinson's disease. However, since the US FAERS relies on spontaneous reports, which are susceptible to reporting bias, further validation using real-world data is required. This study investigated the association between ramelteon use and risk of developing Parkinson's disease using the DeSC database, a Japanese claims database reported to be representative of the general Japanese population. The association was evaluated using sequence symmetry analysis, with the adjusted sequence ratio (ASR) serving as the evaluation index. Our DeSC database analysis showed a negative association between ramelteon use and Parkinson's disease (ASR: 0.959, 95% confidence interval: 0.955-0.964). Our results support previous reports suggesting that ramelteon may help suppress the onset of Parkinson's disease. However, even though this study used real-world data, these results should be interpreted with caution, as a sequence symmetry analysis cannot be adjusted for covariates. Therefore, additional pharmacoepidemiological studies are needed to further verify the potential risk of Parkinson's disease associated with ramelteon use.}, } @article {pmid40947402, year = {2025}, author = {Ghosh, D and Xu, X and Luo, S and , }, title = {Power and Sample Size Calculation for Multivariate Longitudinal Trials Using the Longitudinal Rank Sum Test.}, journal = {Statistics in medicine}, volume = {44}, number = {20-22}, pages = {e70261}, pmid = {40947402}, issn = {1097-0258}, support = {P30 AG072958/AG/NIA NIH HHS/United States ; R01 AG064803/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; R01AG064803/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Longitudinal Studies ; Sample Size ; Alzheimer Disease/therapy/drug therapy ; Parkinson Disease/therapy/drug therapy ; Multivariate Analysis ; *Clinical Trials as Topic/methods/statistics & numerical data ; Computer Simulation ; Models, Statistical ; Treatment Outcome ; Statistics, Nonparametric ; }, abstract = {Neurodegenerative diseases such as Alzheimer's and Parkinson's often exhibit complex, multivariate longitudinal outcomes that require advanced statistical methods to comprehensively evaluate treatment efficacy. The Longitudinal Rank Sum Test (LRST) offers a nonparametric framework to assess global treatment effects across multiple longitudinal endpoints without requiring multiplicity corrections. This study develops a robust methodology for power and sample size estimation specific to the LRST, integrating theoretical derivations, asymptotic properties, and practical estimation techniques under large sample conditions. Validation through numerical simulations demonstrates the accuracy of the proposed methods, while real-world applications to clinical trials in Alzheimer's disease (AD) and Parkinson's disease (PD) highlight their practical significance. This framework facilitates the design of efficient, well-powered trials, advancing the evaluation of treatments for complex diseases with multivariate longitudinal outcomes.}, } @article {pmid40946953, year = {2025}, author = {Sun, C and Cai, X and Jiang, X and Wen, F and Wan, L}, title = {Neuroprotective alpha-linolenic acid derived from black pepper targets PGK1 and activates the Nrf2 pathway in PC12 cells and mice.}, journal = {European journal of pharmacology}, volume = {1006}, number = {}, pages = {178154}, doi = {10.1016/j.ejphar.2025.178154}, pmid = {40946953}, issn = {1879-0712}, mesh = {Animals ; PC12 Cells ; *NF-E2-Related Factor 2/metabolism ; *alpha-Linolenic Acid/pharmacology/therapeutic use/isolation & purification ; Rats ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Male ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Hydrogen Peroxide/pharmacology ; Mice, Inbred C57BL ; Apoptosis/drug effects ; }, abstract = {BACKGROUND: Oxidative stress is a significant contributor to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Nuclear factor E2-related factor 2 (Nrf2), a pivotal regulator of antioxidant responses, is an emerging therapeutic target for these conditions. Our study assessed the neuroprotective effects of monomeric compounds derived from black pepper against hydrogen peroxide (H2O2)-induced damage in neuron-like PC12 cells. Alpha-linolenic acid (ALA) demonstrated superior protective effects. PURPOSE: The aim of this study was to investigate the mechanism underlying the neuroprotective activity of ALA derived from black pepper. METHODS: H2O2 induces oxidative stress in vitro, and MPTP induces Parkinson's syndrome in vivo. Proliferation and apoptosis assays, fluorescent dye staining, Western blotting, real-time PCR, immunofluorescence, luciferase reporter assays, behavioural experiments, and immunohistochemistry were performed to investigate the effects of ALA and the underlying mechanism in vitro and in vivo. RESULTS: Our findings indicate that the ROS-scavenging and cytoprotective properties of ALA are likely mediated through Nrf2 activation and the upregulation of phase II antioxidant enzymes, including HO-1 and NQO1. Drug affinity responsive target stability (DARTS) assays revealed that ALA interacts with the PGK1 protein, potentially inhibiting its activity to promote Nrf2 activation. In vivo, the oral administration of ALA (60 and 120 mg/kg) significantly mitigated the behavioural deficits associated with Parkinson's disease, preserved dopaminergic neurons in an MPTP-induced mouse model of PD, and relieved nerve inflammation. CONCLUSION: Our data suggest that ALA may be a candidate neuroprotective agent for the treatment of neurodegenerative diseases, offering novel insights and potential therapeutic targets for future interventions.}, } @article {pmid40945030, year = {2025}, author = {Tang, P and Zhao, D and Lin, H and Li, X and Shi, C and Li, P and Chen, H}, title = {Potential modulation of microglial ferroptosis by Linggui Zhugan decoction in Alzheimer's disease through IL-17 and TNF pathways.}, journal = {International immunopharmacology}, volume = {165}, number = {}, pages = {115489}, doi = {10.1016/j.intimp.2025.115489}, pmid = {40945030}, issn = {1878-1705}, mesh = {*Ferroptosis/drug effects ; Animals ; *Alzheimer Disease/drug therapy/immunology/metabolism ; *Microglia/drug effects/metabolism ; Signal Transduction/drug effects ; Mice ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Tumor Necrosis Factor-alpha/metabolism ; *Interleukin-17/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Mice, Inbred C57BL ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Peptide Fragments ; }, abstract = {Alzheimer's Disease (AD) is a neurodegenerative condition marked by cognitive decline and memory loss, with ferroptosis, an iron-dependent form of regulated cell death, emerging as a contributing factor. This study explored the potential modulatory effects of key components of the traditional Chinese medicine (TCM) formula Linggui Zhugan Decoction (LZD) on microglial ferroptosis in AD, focusing on IL-17 and TNF signaling pathways. Using single-cell RNA sequencing, we observed alterations in microglial populations and ferroptosis-related gene expression in AD mice. Network pharmacology and in vitro experiments indicated that LZD components might influence ferroptosis-related pathways, coinciding with reduced IL-17 and TNF levels in Aβ1-42-treated microglia. In vivo, LZD administration was associated with improved behavioral outcomes and modulation of ferroptosis markers. Although our findings suggest a correlation between LZD treatment and attenuation of ferroptosis-associated pathology, further mechanistic validation is necessary to establish causal links. This study provides preliminary evidence supporting the therapeutic potential of TCM in AD via inflammatory pathway modulation.}, } @article {pmid40944899, year = {2025}, author = {Sharma, DK}, title = {Nanotechnology-driven approaches for the early detection and targeted treatment of Alzheimer's disease.}, journal = {Journal of drug targeting}, volume = {}, number = {}, pages = {1-18}, doi = {10.1080/1061186X.2025.2561788}, pmid = {40944899}, issn = {1029-2330}, abstract = {A neurodegenerative condition called Alzheimer's disease (AD) is brought on by the buildup of beta-amyloid plaques in the brain. As of right now, AD has no known cure. The only thing the medications on the market can do is slow their development. Nonetheless, nanotechnology has demonstrated its superiority in its application in medicine. It has great promise for AD therapy, mostly in diagnosing the ailment and offering a different treatment method. Penetrating and bypassing the blood-brain barrier (BBB) increases the effectiveness of drug delivery. The most recent advancements in AD diagnosis using nanotechnology based on nanoparticles with optical sensing, electrochemical sensing, and imaging approaches are summarised in this study. When treating AD, nanocarriers help deliver the targeted medication. Since one of the newest and most active treatments for AD is nanomedicines, the main goal of this review is to comprehend the sophisticated application of nanocarriers for targeted drug delivery in AD treatment.}, } @article {pmid40943807, year = {2025}, author = {Rajič Bumber, J and Rački, V and Mežnarić, S and Pelčić, G and Mršić-Pelčić, J}, title = {Clinical Significance of APOE4 Genotyping: Potential for Personalized Therapy and Early Diagnosis of Alzheimer's Disease.}, journal = {Journal of clinical medicine}, volume = {14}, number = {17}, pages = {}, pmid = {40943807}, issn = {2077-0383}, support = {uniri-iskusni-biomed-23-82//University of Rijeka/ ; }, abstract = {Apolipoprotein E (APOE) remains the most robust and widely replicated genetic risk factor for late-onset Alzheimer's disease (AD) susceptibility, with the ε4 allele (APOE4) demonstrating profound associations with accelerated symptom manifestation, enhanced disease trajectory, and modified therapeutic responsiveness. This comprehensive review synthesizes contemporary evidence regarding the clinical utility of APOE4 genotyping, emphasizing its integration into personalized therapeutic frameworks and early diagnostic paradigms. The APOE4 variant exerts pathogenic influence through impaired amyloid-β clearance, enhanced tau pathology, and compromised neuronal repair mechanisms that alter disease phenotype. We systematically examine available genotyping methodologies, encompassing polymerase chain reaction (PCR) and next-generation sequencing (NGS) platforms, and evaluate their practical implementation within clinical environments. Recent investigations demonstrate that APOE4 status profoundly influences therapeutic efficacy, particularly with anti-amyloid interventions such as lecanemab, where carriers exhibit enhanced treatment response alongside increased adverse event susceptibility. Emerging gene therapeutic approaches show promise in mitigating APOE4-associated risks through targeted molecular interventions. The integration of APOE4 genotyping with fluid biomarkers and neuroimaging techniques enables refined patient stratification and enhanced diagnostic precision, facilitating earlier intervention windows that optimize therapeutic outcomes before irreversible neuronal damage occurs. This review underscores APOE4 testing as a transformative component of precision medicine in AD management, emphasizing its contribution to diagnostic refinement, clinical decision support, and targeted therapeutic interventions.}, } @article {pmid40943686, year = {2025}, author = {Bishara, H and Cohen, H and Hadar, D and Specktor, P}, title = {Ethnic Differences in Dementia Diagnosis and Treatment in Israel.}, journal = {Journal of clinical medicine}, volume = {14}, number = {17}, pages = {}, pmid = {40943686}, issn = {2077-0383}, abstract = {Background/Objectives: Lifestyle and socioeconomic disparities influence dementia prevalence and treatment across ethnic groups worldwide. Our study aimed to examine differences in the diagnosis, work-up, and treatment of mild cognitive impairment (MCI) as well as various types of dementia provided to Arab and Jewish participants in Israel. Methods: Data were collected retrospectively and anonymously between 1 January 2010 and 12 September 2021, by Clalit Health Services' research department. Ethnicity was determined based on residence, including only cities with a 99% majority of either Jewish or Arab participants, according to the Central Bureau of Statistics (CBS). Subjects over the age of 60 with an MCI or dementia diagnosis were analyzed. Results: Of 212,091 diagnosed individuals, 14,742 were of a definite ethnicity as defined. The mean age at diagnosis was significantly younger for Arab participants (75.78 ± 10.28) compared to Jewish participants (80.14 ± 9.45) (p < 0.001). The gender distribution was similar (42.5% male). The most common diagnosis was Alzheimer's disease (AD), affecting 2495 (29.8%) of Jewish participants and 2387 (38%) of Arab participants (p < 0.001). Vascular dementia (VD) was also more prevalent in Arab participants, 12.6%, vs. 6.42% in Jewish participants (p < 0.001). MCI was more common in Jewish participants, 26.2%, compared to 10.3% in Arab participants (p < 0.001). Conclusions: Arab participants were diagnosed with dementia at a younger age and showed higher rates of AD and VD diagnosis compared to Jewish participants, but were significantly less likely to be diagnosed with MCI. Efforts to understand and address these underlying causes are warranted to promote health equity.}, } @article {pmid40943548, year = {2025}, author = {Yudaev, P and Aleksandrova, Y and Neganova, M}, title = {Recent Insights into the Creation of Histone Deacetylase Inhibitors for the Treatment of Human Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943548}, issn = {1422-0067}, support = {25-73-20033//Russian Science Foundation/ ; }, mesh = {Humans ; *Histone Deacetylase Inhibitors/therapeutic use/chemistry/pharmacology ; Histone Deacetylases/metabolism ; Neoplasms/drug therapy ; Cardiovascular Diseases/drug therapy ; Animals ; Autoimmune Diseases/drug therapy ; Nervous System Diseases/drug therapy ; Hydroxamic Acids/therapeutic use/chemistry/pharmacology ; }, abstract = {This review examines publications over the past two years devoted to histone deacetylase inhibitors for the treatment of cancer, diseases of the nervous, cardiovascular, digestive, and respiratory systems, and autoimmune diseases. The review covers various classes of histone deacetylase inhibitors depending on the zinc-binding group, in particular hydroxamic acids, benzamides, hydrazides, carboxylic acids, and cyclic peptides. The review pays special attention to the mechanisms of development of pathologies involving various isoforms of histone deacetylases. The review shows that, for the treatment of cancer, nervous, cardiovascular, respiratory systems, and autoimmune diseases, the most promising compounds are hydroxamic acids, and for the treatment of diseases of the digestive system, they are hydrazides and cyclic peptides. Variation in the linker and cap group of hydroxamic acids will allow the creation of an inhibitor selective for a specific histone deacetylase isoform. The review may be useful for molecular biologists, medical workers, and pharmacologists involved in the design of new drugs.}, } @article {pmid40943460, year = {2025}, author = {Del Rio, EA and Valenzano, MC and DiGuilio, KM and Rybakovsky, E and Kjelstrom, S and Montone, G and Mercogliano, G and Newman, G and Wong, P and Albert, N and Burris, V and Szymanski, K and Rodriguez, A and Hollis, E and Kossenkov, A and Mullin, JM}, title = {Orally Administered Zinc Gluconate Induces Tight Junctional Remodeling and Reduces Passive Transmucosal Permeability Across Human Intestine in a Patient-Based Study.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943460}, issn = {1422-0067}, support = {2023-02//Sharpe-Strumia Research Foundation of the Bryn Mawr Hospital/ ; }, mesh = {Humans ; *Gluconates/administration & dosage/pharmacology ; *Tight Junctions/drug effects/metabolism ; *Intestinal Mucosa/metabolism/drug effects ; Administration, Oral ; Male ; Female ; Adult ; Permeability/drug effects ; Middle Aged ; Tight Junction Proteins/metabolism ; Gastrointestinal Microbiome/drug effects ; Zinc ; }, abstract = {This study focuses on the issue of whether orally administered zinc (gluconate) (26 mg BID) can induce the remodeling of gastrointestinal barrier function and reduce passive leak across the human intestinal mucosal barrier in situ. Increased transmucosal leak has been implicated in diseases as diverse and seemingly unconnected as Inflammatory Bowel Disease (IBD), Celiac Disease, Autism Spectrum Disorders and Alzheimer's Dementia. Our current investigation represents the first patient-based study to examine the effect of zinc on gastrointestinal epithelial tight junctions and gastrointestinal barrier leak in otherwise healthy test subjects. Using independent test subject groups for each endpoint, three separate molecular analyses indicated that zinc treatment can achieve a positive outcome: (1) RNA-seq analyses of intestinal biopsies showed salutary patterns of gene transcription changes dealing with not only transcripts of junctional proteins but also transcripts mitigating the proinflammatory state, as well as dedifferentiation (both modulators of tight junction permeability); (2) Western immunoblot analyses of intestinal tissue indicated that tight junctional protein expression was being modified by the administered zinc, most notably Claudin-2 and Tricellulin; (3) zinc treatment induced a reduction in serum levels of a functional marker of passive intestinal leak, namely the GI microbiome metabolite D-Lactate. The data collectively suggest that orally administered zinc can induce remodeling of the intestinal epithelial barrier, resulting in the reduction in GI barrier leak. The overall safety and economy of supplement levels of zinc suggest that this micronutrient could be efficacious as an adjuvant therapy to reduce the condition known as leaky gut, and possibly therefore be protective regarding diseases postulated to involve leaky gut.}, } @article {pmid40943200, year = {2025}, author = {Zhao, D and Ma, L and Brownlie, J and Tonissen, K and Pan, Y and Feng, Y}, title = {Neuroprotective Potential of Major Alkaloids from Nelumbo nucifera (Lotus): Mechanisms and Therapeutic Implications.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943200}, issn = {1422-0067}, mesh = {Humans ; *Nelumbo/chemistry ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; *Alkaloids/pharmacology/chemistry/therapeutic use ; Animals ; Benzylisoquinolines/pharmacology/chemistry ; Neurodegenerative Diseases/drug therapy/metabolism ; }, abstract = {Nelumbo nucifera (lotus) has long been used in traditional medicine across Asia, and its bioactive alkaloids have recently garnered attention for their neuroprotective properties. This review summarizes the current research on the mechanisms by which lotus-derived alkaloids, particularly neferine, nuciferine, liensinine, and isoliensinine, protect neural tissues. These compounds exhibit a wide range of pharmacological activities, including antioxidant and anti-inflammatory effects, regulation of calcium signaling and ion channels, promotion of neurogenesis, and modulation of key neurotransmitter systems, such as dopaminergic, cholinergic, and GABAergic pathways. Notably, they attenuate tau hyperphosphorylation, reduce oxidative stress-induced neuronal apoptosis, and enhance neurotrophic signaling via BDNF-related pathways. While antioxidant and anti-inflammatory actions are the most extensively studied, emerging evidence also highlights their roles in autophagy modulation and mitochondrial protection. Together, these findings suggest that lotus alkaloids are promising candidates for the prevention and treatment of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Further investigation is warranted to explore the synergistic mechanisms and potential clinical applications of these compounds.}, } @article {pmid40943177, year = {2025}, author = {Bowirrat, A and Pinhasov, A and Bowirrat, A and Badgaiyan, R}, title = {Navigation Between Alzheimer's Disease (AD) and Its Various Pathophysiological Trajectories: The Pathogenic Link to Neuroimmunology-Genetics and Neuroinflammation.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943177}, issn = {1422-0067}, mesh = {*Alzheimer Disease/genetics/pathology/metabolism/physiopathology/immunology/etiology ; Humans ; *Neuroinflammatory Diseases/pathology/genetics ; Blood-Brain Barrier/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Brain/pathology/metabolism ; Animals ; Inflammation ; }, abstract = {One hundred and eighteen years have passed since Alzheimer's disease (AD) was first diagnosed by Alois Alzheimer as a multifactorial and complex neurodegenerative disorder with psychiatric components. It is inaugurated by a cascade of events initiating from amnesic-type memory impairment leading to the gradual loss of cognitive and executive capacities. Pathologically, there is overwhelming evidence that clumps of misfolded amyloid-β (Aβ) and hyperphosphorylated tau protein aggregate in the brain. These pathological processes lead to neuronal loss, brain atrophy, and gliosis culminating in neurodegeneration and fueling AD. Thus, at a basic level, abnormality in the brain's protein function is observed, causing disruption in the brain network and loss of neural connectivity. Nevertheless, AD is an aging disorder caused by a combination of age-related changes and genetic and environmental factors that affect the brain over time. Its mysterious pathology seems not to be limited to senile plaques (Aβ) and neurofibrillary tangles (tau), but to a plethora of substantial and biological processes, which have also emerged in its pathogenesis, such as a breakdown of the blood-brain barrier (BBB), patients carrying the gene variant APOE4, and the immuno-senescence of the immune system. Furthermore, type 2 diabetes (T2DM) and metabolic syndrome (MS) have also been observed to be early markers that may provoke pathogenic pathways that lead to or aggravate AD progression and pathology. There are numerous substantial AD features that require more understanding, such as chronic neuroinflammation, decreased glucose utilization and energy metabolism, as well as brain insulin resistance (IR). Herein, we aim to broaden our understanding and to connect the dots of the multiple comorbidities and their cumulative synergistic effects on BBB dysfunction and AD pathology. We shed light on the path-physiological modifications in the cerebral vasculature that may contribute to AD pathology and cognitive decline prior to clinically detectable changes in amyloid-beta (Aβ) and tau pathology, diagnostic biomarkers of AD, neuroimmune involvement, and the role of APOE4 allele and AD-IR pathogenic link-the shared genetics and metabolomic biomarkers between AD and IR disorders. Investment in future research brings us closer to knowing the pathogenesis of AD and paves the way to building prevention and treatment strategies.}, } @article {pmid40943145, year = {2025}, author = {Öztan, G and İşsever, H and İşsever, T}, title = {The Role of miRNAs in the Differential Diagnosis of Alzheimer's Disease and Major Depression: A Bioinformatics-Based Approach.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943145}, issn = {1422-0067}, mesh = {Humans ; *MicroRNAs/genetics/metabolism ; *Alzheimer Disease/diagnosis/genetics/metabolism ; *Depressive Disorder, Major/diagnosis/genetics/metabolism ; *Computational Biology/methods ; Diagnosis, Differential ; Biomarkers/metabolism ; Gene Expression Profiling ; Gene Regulatory Networks ; Transcriptome ; Gene Expression Regulation ; Signal Transduction ; }, abstract = {Alzheimer's disease (AD) and major depressive disorder (MDD) are prevalent central nervous system (CNS) disorders that share overlapping symptoms but differ in underlying molecular mechanisms. Distinguishing these mechanisms is essential for developing targeted diagnostic and therapeutic strategies. In this study, we integrated multi-tissue transcriptomic datasets from brain and peripheral samples to identify differentially expressed microRNAs (miRNAs) in AD and MDD. Functional enrichment analyses (KEGG, GO) revealed that dysregulated miRNAs in AD were associated with MAPK, PI3K-Akt, Ras, and PD-1/PD-L1 signaling, pathways linked to synaptic plasticity, neuroinflammation, and immune regulation. In contrast, MDD-associated miRNAs showed enrichment in Hippo signaling and ubiquitin-mediated proteolysis, implicating altered neurogenesis and protein homeostasis. Network analysis highlighted key disease- and tissue-specific miRNAs, notably hsa-miR-1202 and hsa-miR-24-3p, with potential roles in neuronal survival and molecular network regulation. These findings suggest that miRNAs may serve as non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring in both disorders. While therapeutic targeting of miRNAs offers promise, challenges such as blood-brain barrier penetration and tissue-specific delivery remain. This integrative approach provides a translational framework for advancing miRNA-based strategies in CNS disease research.}, } @article {pmid40943059, year = {2025}, author = {Nojima, H and Yamamoto, M and Kamada, J and Hamanaka, T and Aoyagi, K}, title = {Fully Automated Measurement of GFAP in CSF Using the LUMIPULSE[®] System: Implications for Alzheimer's Disease Diagnosis and Staging.}, journal = {International journal of molecular sciences}, volume = {26}, number = {17}, pages = {}, pmid = {40943059}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; *Glial Fibrillary Acidic Protein/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Male ; Aged ; Female ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; tau Proteins/cerebrospinal fluid ; Cognitive Dysfunction/cerebrospinal fluid/diagnosis ; Aged, 80 and over ; Peptide Fragments/cerebrospinal fluid ; ROC Curve ; Immunoenzyme Techniques/methods ; }, abstract = {Glial fibrillary acidic protein (GFAP) has been shown to be a reliable biomarker for detecting neurological disorders. Recently, we developed the Lumipulse G GFAP plasma assay, which is a commercially available tool. Compared to existing assays, the LUMIPLSE G platform offers the high-throughput, rapid, and fully automated quantification of biomarkers, enabling more standardized and accessible clinical study. In this study, we evaluated this assay using cerebrospinal fluid (CSF) samples. Assessing GFAP in CSF may provide more direct insights into central nervous system pathology than plasma and could improve the characterization of Alzheimer's disease (AD) stages and support treatment monitoring. The LUMIPULSE G system is a chemiluminescent enzyme immunoassay (CLEIA) platform equipped with full automation, utilizing specialized cartridges to process samples within 30 min. The assay, which employs a pair of proprietary monoclonal antibodies targeting GFAP, was evaluated for clinical performance using 30 CSF samples from patients diagnosed with AD, patients with mild cognitive impairment (MCI), and cognitively unimpaired (CU) individuals, with 10 samples from each group. In addition, levels of β-amyloid 1-40 (Aβ40), β-amyloid 1-42 (Aβ42), and pTau181 were simultaneously measured. The Lumipulse G GFAP assay significantly differentiated (p < 0.05) between the amyloid accumulation and non-amyloid accumulation groups, as classified based on the CSF Aβ test. Furthermore, GFAP showed a moderate correlation with pTau181 (r = 0.588), as determined based on Spearman's rank correlation coefficient. Moreover, receiver operating characteristic (ROC) analysis was performed to determine the performance of GFAP in distinguishing amyloid-positive and amyloid-negative subjects, with an area under the curve (AUC) of 0.72 (0.50-0.93). When stratified by CSF pTau181 positivity, GFAP demonstrated an improved diagnostic accuracy, achieving an AUC of 0.86 (95% CI: 0.68-1.00). This study demonstrates that the Lumipulse G GFAP assay, when applied to CSF samples, has the potential to differentiate AD from non-AD cases, particularly suggesting its utility in detecting tau-related pathology. While GFAP has previously been established as a biomarker for AD, our findings highlight that combining GFAP with other biomarkers such as Aβ40, Aβ42, and pTau181 may enhance the understanding of AD pathogenesis, disease staging, and possibly treatment responses. These findings suggest that GFAP may serve as a complementary biomarker reflecting astroglial reactivity associated with tau positivity, alongside established biomarkers such as Aβ40, Aβ42, and pTau181. However, since GFAP levels may also be elevated in other neurological disorders beyond AD, further investigation into these conditions is required.}, } @article {pmid40942908, year = {2025}, author = {Mbue, ND and Tabei, F and Williams, K and Olanrewaju, K}, title = {Innovative Sensor-Based Approaches for Assessing Neurodegenerative Diseases: A Brief State-of-the-Art Review.}, journal = {Sensors (Basel, Switzerland)}, volume = {25}, number = {17}, pages = {}, pmid = {40942908}, issn = {1424-8220}, support = {2024 TARC Pitch//2024 Texas A&M Engineering Experiment Station Annual Research Conference (TARC)./ ; }, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis ; *Biosensing Techniques/methods ; Artificial Intelligence ; Nanotechnology ; Alzheimer Disease/diagnosis ; Parkinson Disease/diagnosis ; }, abstract = {Sensor-based approaches are transforming the diagnosis and treatment of neurodegenerative diseases by offering more sensitive, non-invasive tools and are capable of real-time monitoring. Integrating advanced materials, nanotechnology, and artificial intelligence presents promise for earlier detection, enhanced disease management, and improved patient outcomes. From a clinical perspective, these technologies facilitate the shift toward precision medicine by enabling early intervention strategies, real-time treatment monitoring, and more refined patient stratification in practice and research contexts. This review provides an overview of recent advancements in sensor-based technologies aimed at enhancing the diagnosis and monitoring of neurodegenerative diseases (NDDs) such as Alzheimer's and Parkinson's, among others. Sensor-based technologies are adjunct tools and integral components of a next-generation framework for diagnosing, monitoring, and understanding neurodegenerative disorders.}, } @article {pmid40942040, year = {2025}, author = {Charissopoulos, E and Pontiki, E}, title = {Targeting Metal Imbalance and Oxidative Stress in Alzheimer's Disease with Novel Multifunctional Compounds.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {17}, pages = {}, pmid = {40942040}, issn = {1420-3049}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; *Oxidative Stress/drug effects ; *Metals/metabolism ; Animals ; *Antioxidants/pharmacology/therapeutic use/chemistry ; *Chelating Agents/therapeutic use/pharmacology/chemistry ; Brain/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is considered to be one of the most common types of dementia, threatening the health of elderly individuals. Enhancing the brain's cholinergic activity is currently the primary therapeutic strategy for treating AD patients. Acetylcholine and butyrylcholine are key targets in this approach, as they function as neuromodulators within the cerebrum-particularly in its various cholinergic regions responsible for essential functions like memory, thought, inspiration, and excitement. Oxidative stress and free radicals are considered to play a crucial role in the pathogenesis of AD and may be key factors in its etiology. Additionally, oxidants and oxidative stress-induced products can upregulate amyloid precursor protein (APP) expression, promoting Aβ aggregation. Another major factor in the pathogenesis of AD is the imbalance of metal homeostasis in the brain. Notably, the mammalian brain contains significantly higher concentrations of Cu, Zn, and Fe ions compared to other tissues. The present review focuses on novel bifunctional metal chelators with potential antioxidant activity for the treatment of AD.}, } @article {pmid40942007, year = {2025}, author = {Li, H and Shen, X and Zhang, B and Zhu, Z}, title = {Biologics as Therapeutical Agents Under Perspective Clinical Studies for Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {17}, pages = {}, pmid = {40942007}, issn = {1420-3049}, mesh = {Humans ; *Alzheimer Disease/drug therapy/therapy/metabolism ; *Biological Products/therapeutic use/pharmacology ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Clinical Trials as Topic ; Genetic Therapy/methods ; tau Proteins/metabolism ; Oligonucleotides, Antisense/therapeutic use ; Animals ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, synaptic loss, and multifaceted pathology involving amyloid-β (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, and impaired proteostasis. In recent years, biologic therapies, such as monoclonal antibodies, vaccines, antisense oligonucleotides (ASOs), and gene therapies, have gained prominence as promising disease-modifying strategies. In this review, we provide a comprehensive synthesis of current biologic approaches under clinical evaluation for AD. Drawing on data curated from ClinicalTrials.gov (as of 2025), we systematically summarise the molecular targets, therapeutic modalities, mechanisms of action, trial phases, and sponsors of over 60 biologic agents. These include Aβ-directed antibodies targeting distinct conformers such as protofibrils, pyroglutamate-modified species, and soluble oligomers; tau-targeted immunotherapies and RNA-based interventions; and emerging platforms focused on neuroimmune modulation, peptide hormones, and microbiota-based strategies. Gene and RNA therapeutics, particularly ASOs and small interfering RNAs (siRNAs) delivered intrathecally or via lipid nanoparticles, are also reviewed for their potential to modulate intracellular targets with high specificity. We also analyse the historical landscape of biologic candidates that failed to reach approval, discussing key reasons for trial discontinuation, including lack of clinical efficacy, safety concerns (e.g., amyloid-related imaging abnormalities), or inadequate biomarker responses. These cases offer crucial insights for refining future drug design. Looking ahead, we highlight major challenges and evolving perspectives in AD biologic therapy: expanding therapeutic targets beyond Aβ and tau, overcoming delivery barriers to the brain, designing prevention-oriented and genetically stratified trials, and navigating regulatory and ethical considerations. Together, these efforts signal a paradigm shift in AD drug development, from symptomatic treatment to mechanism-based precision biologics. By integrating real-time clinical trial data with mechanistic insight, this review aims to inform both translational research and therapeutic innovation in AD.}, } @article {pmid40941958, year = {2025}, author = {Rodríguez-Escobar, ML and Martínez-Francés, V and Ríos, S and Feresin, GE and Borges, WS and Bastida, J and Torras-Claveria, L and Tallini, LR}, title = {Alkaloid Profile of Fifteen Different Species of Narcissus L. (Amaryllidoideae) Collected in Spain.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {17}, pages = {}, pmid = {40941958}, issn = {2223-7747}, abstract = {Molecular diversity is a key component of overall biodiversity, playing a vital role in evolution. It results from the adaptation of organisms to various habitats, which impacts their survival. The Amaryllidoideae subfamily is a significant group of monocotyledonous plants known for producing an exclusive and still-expanding group of molecules with diverse biological activities. Galanthamine (Gal), the most renowned metabolite from Amaryllidoideae subfamily, has been marketed for the palliative treatment of Alzheimer's disease since 2001 due to its ability to inhibit the acetylcholinesterase enzyme. Due to the high cost and low yield of its synthesis, pharmaceutical companies extract this drug from Amaryllidoideae plants, such as Narcissus pseudonarcissus cv. Carlton in Europe and Lycoris radiata in China. The aim of this study was to describe the alkaloid profile of fifteen different species of Narcissus L. (commonly known as daffodils) collected in Spain using gas chromatography coupled with mass spectrometry. Fifty-one alkaloids were identified and quantified within these species through our private library of Amaryllidaceae alkaloids (AA) built over the last four decades, while thirty structures remained not identified in thirteen of these species. The highest concentration of these nitrogenate metabolites was quantified in N. confusus, 541 μg Gal·100 mg[-1] DW, which also exhibited a notably high concentration of Gal, 301 μg Gal·100 mg[-1] DW, which represents about 55% of the alkaloids identified in this species. The species N. bujei was also found to contain a significant quantity of this compound, amounting to 103.2 μg Gal·100 mg[-1] DW. The plant N. assoanus harbored a total of seven unidentified compounds, indicating that this species could be a potentially important source of novel alkaloids. In conclusion, this study facilitates a direct comparison of alkaloid profiles for fifteen Narcissus plant species. This serves as a valuable tool for identifying possible new sources of galanthamine, as well as other novel medicinal alkaloids. Finally, this work presents the first alkaloid profile of the species N. minor and N. nevadensis.}, } @article {pmid40941620, year = {2025}, author = {Altıntop, ÇG}, title = {Enhancing Diagnostic Accuracy of Neurological Disorders Through Feature-Driven Multi-Class Classification with Machine Learning.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {15}, number = {17}, pages = {}, pmid = {40941620}, issn = {2075-4418}, abstract = {Background/Objectives: Neurological disorders (ND) are a global health challenge, affecting millions and greatly reducing quality of life. Disorders such as Alzheimer's disease, mild cognitive impairment (MCI), schizophrenia, and depression often share overlapping symptoms, complicating diagnosis and treatment. Early detection is crucial for timely intervention; however, traditional diagnostic methods rely on subjective assessments and costly imaging, which are not universally accessible. Addressing these challenges, this study investigates the classification of multiple ND using electroencephalography (EEG) signals. Methods: Various feature extraction methods were employed, and the Least Absolute Shrinkage and Selection Operator (Lasso) algorithm was utilized for effective feature selection. Two-class (disease-disease and healthy control-disease), three-class (healthy control and two ND, as well as three ND), and four-class (healthy control and three ND) classifications were conducted using different machine learning algorithms with the selected features. An EEG dataset comprising 40 Alzheimer's patients, 43 healthy controls, 42 schizophrenia patients, 28 MCI patients, and 28 depression patients served as the experimental benchmark. Results: The Linear Discriminant Analysis (LDA) classifier achieved the highest accuracy, distinguishing between healthy controls and Alzheimer's with 100% accuracy and demonstrating strong performance in other comparisons. Multi-class classification reached 84.67% accuracy for distinguishing depression, MCI, and schizophrenia, while four-class classification achieved 57.89%, highlighting the complexity of differentiating among multiple ND. The frequent selection of frontal lobe channels across ND indicates their critical role in classification. Conclusions: This study contributes to the literature by emphasizing disease-to-disease classification over the traditional control-versus-patient framework, highlighting the potential for more effective diagnostic tools in clinical settings.}, } @article {pmid40941175, year = {2025}, author = {Jeong, H and Choi, H and Park, YS}, title = {Neuroprotective Potential of Broccoli Sprout Extract in Scopolamine-Induced Memory-Impaired Mice.}, journal = {Foods (Basel, Switzerland)}, volume = {14}, number = {17}, pages = {}, pmid = {40941175}, issn = {2304-8158}, support = {P0025365//Ministry of Trade, Industry and Energy/ ; }, abstract = {Alzheimer's disease is characterized by progressive cognitive decline associated with oxidative stress, neuroinflammation, and impaired neurotrophic signaling. Sulforaphane, a bioactive compound found in broccoli, has demonstrated neuroprotective effects by activating NRF2 and inhibiting NF-κB. However, the efficacy of whole-food-derived sulforaphane remains unclear. This study evaluated the neuroprotective potential of broccoli sprout extract using a scopolamine-induced mouse model of memory impairment. Mice were orally administered broccoli sprout extract once daily at doses of 100 mg/kg or 200 mg/kg for four weeks prior to behavioral and biochemical assessments. Treatment with broccoli sprout extract significantly improved scopolamine-induced deficits in long-term memory, as determined by the passive avoidance test. The spatial working memory remained unaffected. High doses of broccoli sprout extract restored hippocampal brain-derived neurotrophic factor levels and reduced cortical lipid peroxidation, suggesting antioxidant and neurotrophic benefits. Additionally, the low dose preserved striatal choline acetyltransferase expression and reduced systemic tumor necrosis factor-alpha and hippocampal cyclooxygenase-2 levels, indicating its anti-inflammatory and cholinergic protective effects. No significant changes in acetylcholinesterase activity or glutathione levels were observed. Overall, these results imply that broccoli sprout extract has multi-targeted neuroprotective effects, possibly involving redox and inflammatory regulation. Therefore, it may be a safe dietary strategy to support cognition in neurodegenerative conditions.}, } @article {pmid40940798, year = {2025}, author = {Li, L and Zheng, X and Ma, H and Zhu, M and Li, X and Sun, X and Feng, X}, title = {TREM2 in Neurodegenerative Diseases: Mechanisms and Therapeutic Potential.}, journal = {Cells}, volume = {14}, number = {17}, pages = {}, pmid = {40940798}, issn = {2073-4409}, mesh = {Humans ; *Receptors, Immunologic/metabolism ; *Membrane Glycoproteins/metabolism ; *Neurodegenerative Diseases/metabolism/therapy/pathology ; Animals ; Microglia/metabolism ; Phagocytosis ; }, abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), represent significant global health challenges, affecting millions and straining healthcare systems. These disorders involve progressive neuronal loss and cognitive decline, with incompletely elucidated underlying mechanisms. Chronic neuroinflammation is increasingly recognized as a critical contributor to disease progression. The brain's resident immune cells, microglia, are central to this inflammatory response. When overactivated, microglia and other immune cells, such as peripheral macrophages, can exacerbate inflammation and accelerate disease development. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily that demonstrates high expression on microglia in the central nervous system. TREM2 serves a vital role in regulating phagocytosis, synaptic pruning, and energy metabolism. This review examines the functions of TREM2 in neurodegenerative diseases and its potential as a therapeutic target, aiming to inform future treatment strategies.}, } @article {pmid40940766, year = {2025}, author = {Kochman, U and Sitka, H and Kuźniar, J and Czaja, M and Kozubek, P and Beszłej, JA and Leszek, J}, title = {Neuronal Death and Biomolecular Condensates: Are There Any New Treatment Options for Alzheimer's Disease?.}, journal = {Cells}, volume = {14}, number = {17}, pages = {}, pmid = {40940766}, issn = {2073-4409}, mesh = {Humans ; *Alzheimer Disease/pathology/drug therapy/metabolism/therapy ; *Neurons/pathology/metabolism/drug effects ; *Biomolecular Condensates/metabolism ; Animals ; tau Proteins/metabolism ; Cell Death ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is marked by the pathological aggregation of amyloid β (Aβ) and tau proteins. Emerging research reveals that these proteins undergo liquid-liquid phase separation (LLPS), forming biomolecular condensates that promote aggregation and neurotoxicity. These phase-separated structures reshape the intracellular environment, facilitating protein misfolding and spreading. This review highlights recent advances in understanding the role of condensates in AD pathogenesis and explores novel therapeutic strategies targeting condensate dynamics. Promising approaches include small molecules that disrupt LLPS, epigenetic drugs influencing nuclear condensates, and compounds like DDL 920 and RI AG03 that modulate tau phase separation and neuroinflammation, respectively. Additionally, anti-inflammatory agents, such as nucleotide reverse transcriptase inhibitors (NRTIs), offer potential for upstream intervention. Targeting biomolecular condensates presents a next-generation strategy for AD treatment. Future research should focus on in vivo profiling of condensate composition, biomarker development, and the development of patient-specific therapies to enable early, disease-modifying interventions.}, } @article {pmid40940699, year = {2025}, author = {Fazio-Eynullayeva, E and Mystkowski, P and Lv, L and Aly, A and Cotton, S and Grant, N and Johnson, W and Mattke, S}, title = {A Real-World Analysis of the Clinical Journey, Diagnosis, and Monitoring Patterns of Patients With Alzheimer Disease by Stage in the United States.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {40}, number = {}, pages = {15333175251375378}, pmid = {40940699}, issn = {1938-2731}, mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; Cross-Sectional Studies ; United States ; Female ; Male ; Aged ; Severity of Illness Index ; *Cognitive Dysfunction/diagnosis ; Middle Aged ; Disease Progression ; *Physicians, Primary Care/statistics & numerical data ; Aged, 80 and over ; }, abstract = {This study aimed to describe the clinical journey of patients with different stages of Alzheimer disease (AD). This was a cross-sectional survey of US primary care physicians (PCPs)/specialists and patients using the Adelphi Real World AD Disease Specific Programme™ (December 2022 - September 2023). Patients were stratified by disease severity and data are presented as the mean (SD) or frequencies/percentages. In the overall sample (N = 990), mean time from symptom onset to first evaluation was 31.4 (40.6) weeks and mean time from evaluation to diagnosis was 14.2 (29.0) weeks (mild cognitive impairment due to AD, 12.0 [22.7] weeks; mild AD dementia, 15.7 [31.6] weeks; moderate AD dementia, 14.0 [29.9] weeks; severe AD dementia, 5.1 [9.6] weeks). 74.5% of the overall sample was initially evaluated by their PCP and 13.8% by a neurologist. Patients with AD experience many barriers during the diagnostic journey; however, PCPs and neurologists play key roles in early diagnosis.}, } @article {pmid40940304, year = {2025}, author = {Francis, E and Paylor, S and Van, C and Mathews, B and Sobhanian, MJ and Mansour, DZ and Hennawi, G and Brandt, NJ}, title = {Review of anti-amyloid-beta (Aβ) monoclonal antibodies for the treatment of Alzheimer's disease.}, journal = {Expert review of clinical pharmacology}, volume = {18}, number = {12}, pages = {1063-1078}, doi = {10.1080/17512433.2025.2556122}, pmid = {40940304}, issn = {1751-2441}, mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology ; *Amyloid beta-Peptides/immunology ; *Antibodies, Monoclonal/adverse effects/pharmacology/administration & dosage ; Animals ; Disease Progression ; Risk Assessment ; Precision Medicine ; Apolipoprotein E4/genetics ; Drug Development ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) remains a major public health challenge, with growing prevalence and limited treatment options that modify disease progression. Recent advances have led to the development and approval of Anti-amyloid-β (Aβ) monoclonal antibodies, which represent a paradigm shift from symptomatic management to targeted disease modification. AREAS CCOVERED: Agents such as lecanemab and donanemab selectively bind aggregated forms of Aβ and have demonstrated modest but statistically significant slowing of cognitive and functional decline in early AD. However, these therapies are associated with amyloid-related imaging abnormalities (ARIA), particularly in individuals carrying the APOE ε4 allele, necessitating close monitoring and individualized risk assessment. Implementation challenges, including high treatment burden, cost, and real-world applicability, have limited broad clinical adoption. This review examines the mechanistic differences, clinical trial outcomes, and safety considerations of Aβ monoclonal antibodies, while also highlighting emerging therapies and the need for inclusive, precision-guided approaches. EXPERT OPINION: As research continues to evolve, balancing clinical benefits with safety and accessibility will be critical in defining the role of anti-amyloid-β therapies within the broader landscape of AD care.}, } @article {pmid40940223, year = {2025}, author = {Liu, C and Zhao, Y and Dao, JJ and Zhang, W and Liu, J and Ma, YK and Qiao, CM and Cui, C and Chen, SX and Shen, YQ and Zhao, WJ}, title = {Targeted ErbB4 receptor activation ameliorates neuronal deficits via DOCK3 signaling in a transgenic mouse AD model.}, journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics}, volume = {22}, number = {6}, pages = {e00739}, pmid = {40940223}, issn = {1878-7479}, mesh = {Animals ; *Receptor, ErbB-4/metabolism/agonists ; *Alzheimer Disease/metabolism/drug therapy/genetics/pathology ; Mice ; Mice, Transgenic ; Signal Transduction/drug effects/physiology ; *Neurons/metabolism/drug effects ; Disease Models, Animal ; Hippocampus/metabolism/drug effects ; Male ; Mice, Inbred C57BL ; Humans ; }, abstract = {Accumulating evidence has highlighted the critical involvement of ErbB4 receptor in the onset and progression of Alzheimer's disease (AD). Utilizing a small molecule ErbB4 receptor agonist (E4A) identified through virtual screening, it was observed that activation of ErbB4 receptor significantly ameliorated the cognitive behavioral deficits in APP/PS1 mice. Additionally, E4A treatment enhanced the expression of DOCK3 and SIRT3, leading to improvements in synaptic and mitochondrial dysfunction within the hippocampus of these mice. E4A also attenuated the activation of the TLR4-NF-κB-NLRP3 pathway, thereby reducing neuroinflammation and the formation of β-amyloid (Aβ) plaques. In vitro studies revealed that E4A partially mitigated the impact of hippocampal neuronal damage on microglial inflammation, which was partly compromised by the silencing of DOCK3. Collectively, our data suggest that targeted activation of ErbB4 receptor may treat AD via DOCK3 signaling by inhibiting neuronal damage and subsequent neuroinflammation, thereby offering a viable strategy for this neurodegenerative disease.}, } @article {pmid40939527, year = {2025}, author = {Pagan, FL and Torres-Yaghi, Y and Hebron, ML and Wilmarth, B and Liu, X and Ahn, J and Moussa, C}, title = {Safety, tolerability and potential biomarkers of vodobatinib in patients with dementia with Lewy bodies.}, journal = {Parkinsonism & related disorders}, volume = {140}, number = {}, pages = {108020}, doi = {10.1016/j.parkreldis.2025.108020}, pmid = {40939527}, issn = {1873-5126}, mesh = {Humans ; Female ; *Lewy Body Disease/drug therapy/cerebrospinal fluid ; Aged ; Male ; Double-Blind Method ; Aged, 80 and over ; Biomarkers/cerebrospinal fluid/blood ; Amyloid beta-Peptides/cerebrospinal fluid ; *Protein Kinase Inhibitors/adverse effects/administration & dosage/therapeutic use ; Peptide Fragments/cerebrospinal fluid ; }, abstract = {INTRODUCTION: Activation of the tyrosine kinase Abelson (Abl) was suggested in the pathogenesis of neurodegenerative diseases. We investigated the effects of a potent and highly specific Abl kinase inhibitor vodobatinib (K0706) in patients diagnosed with dementia with Lewy bodies (DLB). We determined safety, tolerability and potential biomarkers following oral administration of vodobatinib versus placebo in DLB patients. METHODS: Participants were randomized 1:1:1 into vodobatinib 192 mg, or 384 mg or matching placebo in a single-center, double-blind study. Study drug was taken orally once daily for 3 months followed by one-month wash-out. RESULTS: Twenty-nine individuals were enrolled, 3 were women (10.3 %), age 76.3 ± 6 years (mean ± SD). Vodobatinib was safe and well-tolerated and more adverse events were noted in the placebo (56) vs vodobatinib 192 mg (19) or 384 mg (6) groups. The number of falls were reduced in the vodobatinib 192 mg (6) and 384 mg (0) compared to placebo (28) groups. The only potential significant change in cerebrospinal fluid (CSF) biomarkers was Aβ42/Aβ40 in 192 mg vodobatinib (p = 0.0002) and 384 mg (0.0121) compared to placebo. There was no change in homovanillic acid, a biomarker of dopamine level, or other potential CSF and plasma biomarkers of DLB. Exploratory clinical outcomes were not different between baseline and 3 months in vodobatinib compared to placebo. CONCLUSIONS: Vodobatinib appears to be safe and tolerated, but larger trials and longer treatment periods are needed to determine its effects on biomarkers and clinical outcomes.}, } @article {pmid40939126, year = {2025}, author = {Boccalini, C and Mathoux, G and Hristovska, I and Ribaldi, F and Peretti, DE and Arnone, A and Scheffler, M and Frisoni, GB and Hansson, O and Vogel, JW and Garibotto, V}, title = {Visual Classification of Tau-PET Detects 4 Subtypes With Different Long-Term Outcomes.}, journal = {Neurology}, volume = {105}, number = {7}, pages = {e213950}, pmid = {40939126}, issn = {1526-632X}, mesh = {Humans ; Male ; Female ; *tau Proteins/metabolism ; Aged ; *Positron-Emission Tomography/methods ; *Alzheimer Disease/diagnostic imaging/classification/metabolism ; Prospective Studies ; Aged, 80 and over ; *Brain/diagnostic imaging/metabolism ; Middle Aged ; Carbolines ; }, abstract = {BACKGROUND AND OBJECTIVES: Tau accumulation pattern shows substantial variability in Alzheimer disease (AD), and 4 distinct spatiotemporal trajectories were distinguished using a data-driven approach called the Subtype and Stage Inference (SuStaIn). A visual method to validate and identify these subtypes is a requirement for their clinical translation. Our study aimed to provide a standardized topographic method for identifying tau patterns visually using tau-PET in a clinical setting. METHODS: Participants in this prospective study were included from the memory clinic of Geneva University Hospital. Inclusion criteria required participants to have undergone at least 1 [18]F-Flortaucipir tau-PET scan and a Mini-Mental State Examination (MMSE) within a 1-year time frame. All scans were classified into different tau subtypes (limbic [S1], medial temporal lobe-sparing [S2], posterior [S3], and lateral temporal [S4]) using both visual rating and SuStain algorithm. A subgroup underwent amyloid-PET and clinical follow-up. Cohen's κ tested the agreement between raters and between visual and automated subtypes. Chi-squared and Kruskal-Wallis tests assessed differences in clinical and biomarker features between subtypes, whereas differences in cognitive trajectories were tested using linear mixed-effects models, controlling for age, sex, and clinical and tau stages. RESULTS: A total of 245 tau-PET scans of individuals ranging from cognitively unimpaired to mild dementia (mean age: 68.25 years, 52% women) were included and classified into different tau pattern subtypes. A substantial agreement between raters was found in visually interpreting tau subtypes (κ > 0.65, p < 0.001) and a fair agreement between visual and automated subtypes (κ = 0.39, p < 0.001), with the automated approach more likely to classify a scan as tau negative and lower agreement between methods in more severe cases and AD clinical variants. Regarding the visual classification, individuals with S2 subtype were younger than S1 and S3, had lower MMSE and verbal fluency scores than S4 and S1, showed higher global tau burden than other subtypes, and a steeper cognitive decline. DISCUSSION: Visual classification reliably identified 4 tau patterns that differ in global tau load, clinical features, and long-term outcomes, suggesting its clinical usefulness for the detection of higher-risk AD variants. A clinically implementable classification of subtypes with faster decline is paramount for personalized diagnosis, accurate prognosis, and treatment.}, } @article {pmid40939031, year = {2025}, author = {Chun, H and Yoon, ML and Lee, HW and Lee, JY and Hong, SB and Ha, SS and Yoon, KJ}, title = {The Efficacy and Safety of Transcranial Photobiomodulation for Mild Cognitive Impairment Due to Alzheimer's Disease: A Randomized, Double-Blind, Sham-Controlled Study.}, journal = {Photobiomodulation, photomedicine, and laser surgery}, volume = {43}, number = {9}, pages = {411-416}, doi = {10.1177/15578550251369575}, pmid = {40939031}, issn = {2578-5478}, mesh = {Humans ; *Alzheimer Disease/complications ; *Cognitive Dysfunction/etiology/therapy ; *Low-Level Light Therapy/methods ; Male ; Aged ; Female ; Double-Blind Method ; Treatment Outcome ; Aged, 80 and over ; Middle Aged ; }, abstract = {Background: Transcranial photobiomodulation (tPBM) is a promising noninvasive neuromodulation modality with potential therapeutic benefits for neurodegenerative diseases. Infrared light delivered by a tPBM device penetrates the cortex, stimulating neuronal activity by increasing mitochondrial adenosine triphosphate production and enhancing regional cerebral blood flow. Objective: This study investigated the efficacy and safety of a self-administered, at-home, wearable tPBM device for improving cognitive function in individuals with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Methods: Individuals with MCI due to AD, diagnosed according to the National Institute on Aging and Alzheimer's Association criteria, with a Korean version of Mini-Mental State Examination-2 (K-MMSE2) score of 23-27 and a global Clinical Dementia Rating (CDR) score of 0.5-1.0 were enrolled. Subjects self-administered tPBM six times per week for 12 weeks. Assessments were conducted at weeks 7 and 13 using the Korean version of the Montreal Cognitive Assessment (K-MoCA), K-MMSE2, the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease, and the Geriatric Depression Scale. Results: A total of 26 participants were enrolled. The treatment group showed a statistically significant improvement in K-MoCA scores at week 13 (p < 0.05) compared with the sham group. Although K-MMSE2 scores improved in the treatment group, the difference was not statistically significant. No serious adverse events were reported. Conclusion: Findings suggest that tPBM is an effective and safe home-use intervention for individuals with MCI, with promising therapeutic and preventative roles in Alzheimer's dementia.}, } @article {pmid40938652, year = {2025}, author = {Tho Chu, TQ and Morimoto, K and Kowa, H}, title = {Cognitive performance and blood biomarkers: Insights into their relationship and predicting high Amyloid Probability Score in cognitively impaired older adults.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {4}, pages = {1661-1673}, doi = {10.1177/13872877251372958}, pmid = {40938652}, issn = {1875-8908}, mesh = {Humans ; Aged ; Male ; Female ; *Cognitive Dysfunction/blood/psychology/diagnosis ; Biomarkers/blood ; Aged, 80 and over ; Neuropsychological Tests ; Mental Status and Dementia Tests ; Middle Aged ; *Cognition/physiology ; Cohort Studies ; Japan ; *Amyloid beta-Peptides/blood ; Alzheimer Disease/blood ; }, abstract = {BackgroundUnderstanding associations between cognitive performance and blood biomarkers supports diagnosis and treatment of Alzheimer's disease (AD); however, this relationship remains unclear.ObjectiveExploring associations between the Amyloid Probability Score (APS; PrecivityAD® blood test) and cognitive performance, and between Mini-Mental State Examination (MMSE) and Cogstate Brief Battery (CBB) in cognitively impaired older adults.MethodsOlder adults aged ≥ 60 years with MMSE from 10 to 27, recruited from a cohort in Japan, were assessed with the CBB, and plasma biomarkers to calculate APS. We used Spearman correlation to explore relationships; receiver operating curves and cross-validation to identify the best model for predicting high APS.ResultsAmong 46 participants (mean age = 78.3 ± 5.9; mean MMSE = 20.3 ± 4.6), 39.1% did not complete at least one test in the CBB. Lower MMSE were observed in those who were non-completers. MMSE correlated with Detection (Psychomotor function), Identification (Attention), and their composite (r = 0.34-0.52; p < 0.05; 95%CI excluding null value). Higher APS was seen in those who did not complete the One Card Learning (OCL-visual learning and short-term memory). The best model for predicting High APS included OCL completion status, MMSE and Years of Education, achieving accuracy = 0.808 and kappa = 0.606 in participants with MMSE < 21.ConclusionsOur findings suggest a consideration of incompletion when using CBB in cognitively impaired older adults and a potential approach to differentiate High APS group among those with moderate to severe dementia based on visual learning and short-term memory, global cognition and education level.}, } @article {pmid40938517, year = {2025}, author = {Xie, F and Zhou, L and Yu, M}, title = {Dihuang Yinzi Ameliorates Cognitive Impairments and Inhibits Ferroptosis in APP/PS1 Mice.}, journal = {Biochemical genetics}, volume = {}, number = {}, pages = {}, pmid = {40938517}, issn = {1573-4927}, support = {2024CCCX259//Anhui Traditional Chinese Medicine Inheritance and Innovation Research Project/ ; 2021byzd058//Bengbu Medical University Key Project/ ; Chinese Medicine Education Letter (2022) No. 75//National Administration of Traditional Chinese Medicine National Famous Traditional Chinese Medicine Expert Inheritance Studio Construction Project/ ; Project No. 202204295107020034//Clinical Medical Research Translation Special Project of Anhui Provincial Science and Technology Department/ ; 81803984//National Natural Science Foundation of China/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss. Ferroptosis, a form of regulated cell death driven by iron overload and lipid peroxidation, has been implicated in AD pathology. DiHuangYinZi (DHYZ), a traditional Chinese herbal remedy, has been suggested to ameliorate cognitive impairments and reduce ferroptosis in AD models. This study aimed to investigate the effects of DHYZ on learning, memory, ferroptosis markers, and neuronal integrity in APP/PS1 transgenic mice. Six-month-old APP/PS1 transgenic mice were treated with DHYZ or donepezil for four weeks. Learning and memory functions were evaluated using the Morris Water Maze (MWM) and open field test. Neuronal integrity was assessed through Hematoxylin and Eosin (H&E) and Nissl staining. Ferroptosis markers, including superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), and the GSH/GSSG ratio, were measured in hippocampal tissues. Ferroptosis-related protein expressions, such as ferritin, DMT1, FPN1, Nrf2, and GPX4, were analyzed using Western blot. DHYZ treatment significantly improved learning and memory deficits in APP/PS1 mice, as evidenced by reduced escape latency and increased platform crossings in the MWM. DHYZ also reversed anxiety-like behavior in the open field test. Histological analysis showed that DHYZ treatment restored neuronal integrity, as indicated by better cellular arrangement and staining compared to untreated APP/PS1 mice. DHYZ inhibited ferroptosis by reducing iron overload, increasing SOD and GSH levels, and normalizing the GSH/GSSG ratio. Moreover, DHYZ modulated the expression of ferroptosis-related proteins, restoring FPN1 levels while reducing ferritin and DMT1 expressions. Nrf2 and GPX4 levels, which were reduced in APP/PS1 mice, were significantly increased after DHYZ treatment. DHYZ effectively improved cognitive deficits, inhibited ferroptosis, and restored neuronal integrity in APP/PS1 mice. These findings suggest that DHYZ may have therapeutic potential for AD by targeting ferroptosis and regulating iron metabolism.}, } @article {pmid40938483, year = {2025}, author = {Comert Onder, F and Ural, K and Onder, A and Ozpolat, B and Ay, M}, title = {Boron Containing Curcumin-Like Compound as an Acetylcholinesterase Inhibitor and Anticancer Agent: Synthesis, Biological Evaluation, and Computational Insights.}, journal = {Cell biochemistry and biophysics}, volume = {}, number = {}, pages = {}, pmid = {40938483}, issn = {1559-0283}, abstract = {Alzheimer's disease (AD) and cancer are significant global health challenges that highlight the need for the development of new therapeutics. Targeting biological mechanisms involved in both AD and cancer could be an effective treatment strategy for developing novel inhibitors. In this study, we investigated the effect of a newly synthesized boron containing curcumin-like compound as a potential acetylcholinesterase (AChE) inhibitor along with its cytotoxic effects on breast and colorectal cancer cell lines. Compound A exhibited a potent AChE inhibitory activity (IC50 = 22.89 ± 2.32 nM), demonstrating that it was more effective than the known inhibitors donepezil (IC50 = 28.32 ± 3.27 nM) and tacrine. Compound A showed a moderate cytotoxic activity on MCF-7 and BT20 cells with the IC50 values 40.70 ± 2.31 μM and 41.71 ± 4.51 μM, respectively. Throughout molecular dynamics (MD) simulations, the RMSD value of the protein was calculated as 1.56 ± 0.20 Å and 1.65 ± 0.19 Å for the complexes of compound A and curcumin, respectively. The interactions with specific amino acid residues such as Tyr124, Tyr337, and Trp86 for AChE, and Trp82, His438, and Tyr332 for BChE were obtained. Additionally, MM/GBSA calculations demonstrated that Compound A had the highest binding free energies (-88.89 ± 8.34 kcal/mol for AChE and -73.25 ± 8.83 kcal/mol for BChE) compared to curcumin (-67.87 ± 5.48 kcal/mol for AChE and -51.68 ± 5.28 kcal/mol for BChE) and tacrine (-56.67 ± 2.22 kcal/mol for BChE) were calculated. Overall, these findings suggest that Compound A is a promising agent with its potent AChE inhibitory activity and anticancer potential, making it a valuable candidate for further research in neurodegenerative diseases and cancer therapy.}, } @article {pmid40937962, year = {2025}, author = {Hillerstrom, H and Das, A and Janicki, MP and Rozas, NS and Santoro, SL}, title = {Specialists' perceptions of clinical instruments, practices, and staging of DS-AD: Results from an international survey.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70356}, pmid = {40937962}, issn = {1552-5279}, support = {//LuMind IDSC Foundation/ ; /DP/NCCDPHP CDC HHS/United States ; 1NU58DP006782-01-00//Healthy Brain Initiative/ ; //Eli Lilly and Company/ ; //Rainwater Charitable Foundation/ ; }, mesh = {Humans ; *Down Syndrome/complications/diagnosis ; *Alzheimer Disease/diagnosis ; Surveys and Questionnaires ; Cognitive Dysfunction/diagnosis ; Male ; Female ; Neuropsychological Tests ; }, abstract = {INTRODUCTION: Diagnosing and staging Down syndrome-associated Alzheimer's disease (DS-AD) is hindered by the lack of standardized criteria, complicating clinical decision making, trial participation, and access to advanced therapies. This study aimed to explore perceptions of these issues. METHOD: An international survey of 42 clinicians and researchers specializing in DS-AD gathered perspectives on instruments, symptomatic staging, clinical practices, and research priorities. RESULTS: Respondents noted that key domains of impairment in mild cognitive impairment in Down syndrome and DS-AD dementia included memory, executive functioning, personality, social behavior, attention, mood, and language. Among the 10 assessment tools evaluated, informant-based interviews were noted as critical for individuals with severe intellectual disability (ID), while direct assessments were noted as useful for those with mild to moderate ID. Common diagnostic confounders like hypothyroidism and sleep disorders were identified. DISCUSSION: Behavioral assessments provide a valuable function; however, future efforts should integrate behavioral assessments with biomarkers and develop standardized staging frameworks to improve diagnostic reliability, care planning, and treatment strategies for DS-AD. HIGHLIGHTS: Personality, social behavior, language, mood/affect, memory, executive functioning, and attention are recognized as key domains of impairment in both mild cognitive impairment in Down syndrome (MCI-DS) and Down syndrome-associated Alzheimer's disease (DS-AD). Ten prominent informant and direct assessment tools were noted as appropriate for individuals with DS and mild to moderate intellectual disability (ID) for identifying both MCI-DS and DS-AD; however, for individuals with severe/profound ID, there was less assurance of applicability. Harmonizing recommended tools in a standardized list was identified as a strategy to promote consistency across clinical and research contexts.}, } @article {pmid40937948, year = {2025}, author = {Zhao, J and Chen, J and Lu, J and Shi, Q and Wang, Q and Gao, Z and Zeng, L and Liu, Q}, title = {Nitration of Tyrosine Residue Y10 of Aβ1-42 Ameliorates Aβ1-42-Induced Neurotoxicity and Memory Impairment In Vitro and In Vivo.}, journal = {Journal of neurochemistry}, volume = {169}, number = {9}, pages = {e70218}, doi = {10.1111/jnc.70218}, pmid = {40937948}, issn = {1471-4159}, support = {22377027//National Natural Science Foundation of China/ ; 2022C03034//Key R&D Program Project of Zhejiang/ ; 2023SHIBS0003//Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions/ ; LTGD23C050001//Zhejiang Provincial Natural Science Foundation of China/ ; }, mesh = {*Amyloid beta-Peptides/toxicity/metabolism ; Animals ; *Peptide Fragments/toxicity/metabolism ; *Tyrosine/metabolism ; Mice ; Humans ; Male ; Cell Line, Tumor ; *Memory Disorders/chemically induced/metabolism ; Alzheimer Disease/metabolism ; Mice, Inbred C57BL ; Hippocampus/drug effects/metabolism ; }, abstract = {The abnormal generation and aggregation of Aβ has been considered the central pathogenic mechanism of Alzheimer's disease (AD). Soluble Aβ tends to aggregate into toxic oligomers, which initiate neuronal dysfunction. Therefore, attenuation of Aβ oligomer formation might be an effective therapeutic strategy for AD. It has been reported that Aβ can be nitrated at tyrosine 10. Our previous study found that nitration of Y10 in Aβ significantly inhibits its aggregation and reduces its toxicity. However, the effects of Aβ nitration on its neurotoxicity remain unclear. Here, we used SH-SY5Y cells and a mouse model of AD induced by intrahippocampal Aβ1-42 oligomer injection to investigate the effects of tyrosine nitration on the neurotoxicity of Aβ1-42. The results of dot blot, gel electrophoresis analysis, transmission electron microscopy, atomic force microscopy, and dynamic light scattering indicated that nitration of Y10 in Aβ1-42 inhibits its oligomerization. Aβ1-42 treatment perturbed the integrity of intracellular membranes, eventually leading to apoptosis of SH-SY5Y cells. In contrast, nitrated Aβ1-42 exhibited little neurotoxicity toward SH-SY5Y cells. Additionally, mice injected with Aβ1-42 oligomer developed cognitive impairment in behavioral tests. Aβ1-42 oligomer caused neurotoxicity in the hippocampus of the mice, possibly through triggering apoptosis and neuroinflammation and promoting aberrant amyloid processing. As expected, nitrated Aβ1-42 also had little effect on physiological and cognitive capacities. These results further confirm that nitration of Y10 in Aβ can significantly inhibit its neurotoxicity. Moreover, our findings contribute to the understanding of the role of Aβ in the development of AD.}, } @article {pmid40937337, year = {2025}, author = {Han, SH and Jeong, HB and Lee, SJ and Jeong, HT and Shin, HW and Park, CY and Ahn, SW and Park, KY and Kim, HR and Youn, YC}, title = {Therapeutic Potential of Porcine Brain-Derived Peptide Mixture (PBDP) in Alzheimer's Disease: An Exploratory Study on Quantitative Electroencephalography (qEEG) Changes.}, journal = {Neuropsychiatric disease and treatment}, volume = {21}, number = {}, pages = {1981-1992}, pmid = {40937337}, issn = {1176-6328}, abstract = {BACKGROUND: This exploratory study investigates the therapeutic potential of Porcine Brain-Derived Peptide Mixture (PBDP) in Alzheimer's Disease (AD) by examining changes in quantitative electroencephalography (qEEG) parameters following treatment. METHODS: We analyzed qEEG data from 27 AD patients treated with 2-weeks of PBDP treatment and compared them to a control group of 20 patients at 2-month follow-up, all of whom were previously on donepezil therapy. RESULTS: EEG modifications were noted within two weeks of PBDP administration, including improvements in EEG patterns such as reduced Theta/Beta (4.437 ± 3.979 to 3.859 ± 3.587, p = 0.442), Theta/Alpha ratio (1.815 ± 1.637 to 1.578 ± 1.304, p < 0.05), and Delta/Alpha ratio (2.365 ± 2.471 to 2.105 ± 2.402, p < 0.05) across various brain regions, suggesting enhanced cortical activity. Post-intervention, 55% of patients showed caregiver-reported improvements in mood and daily activities. CONCLUSION: PBDP could serve as a viable therapeutic approach for managing AD, and qEEG could serve as a monitoring biomarker for acute drug effects, warranting further investigation into its long-term benefits and mechanistic pathways.}, } @article {pmid40936998, year = {2025}, author = {Duehring, JA and Jacobs, DM and Thomas, ML and Dodge, HH and Feldman, HH and Edland, SD}, title = {Implications of practice effects for the design of Alzheimer clinical trials.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70154}, pmid = {40936998}, issn = {2352-8737}, abstract = {INTRODUCTION: Practice effects (PEs) are a well-known potential confound in natural history studies of longitudinal cognitive decline in aging and early-stage Alzheimer's disease. The implication of PEs on Alzheimer's disease clinical trials is less well understood, although we have previously speculated that a "run-in" period of repeated cognitive assessments prior to randomization may improve the efficiency of clinical trials [Jacobs et al. Alzheimer's & Dementia 2017;3(4):531-535]. We have also described how the performance of composite outcome measures depends on parameters that may be influenced by PEs. METHODS: To investigate this, we used the cognitive battery within the National Alzheimer's Coordinating Center (NACC) Uniform Data Set to characterize the potential impact of PEs on clinical trial design and outcome measures. The analysis restricted to N = 1094 amnestic mild cognitively impaired participants with 3 years of follow-up data. Linear mixed effects models estimate the magnitude of PEs observed in aMCI participants. Power calculations informed by the pattern of progression in the NACC sample were used to describe the net impact of PEs on trials with and without a run-in phase. Weighting parameters of optimal composite measures constructed from the NACC battery were also compared. RESULTS: PEs were large, often exceeding the magnitude of annual rate of change observed in later assessments. Annualized rate of change, and therefore target treatment effect sufficient to achieve a specified percentage reduction in rate of decline, was larger after run-in. Sample size projections for the run-in design were a fraction of those required for trials without run-in. Weighting parameters that optimize composite outcome performance were also different for the two designs, underscoring the importance of considering design in the construction of composite outcomes. DISCUSSION: Clinical trials randomizing after a run-in period measure treatment efficacy relative to decline unbiased by PEs, and require smaller sample size. HIGHLIGHTS: In the National Alzheimer's Coordinating Center (NACC), amnestic mild cognitive impairment (aMCI) cohort practice effects often exceed annualized rate of change.Run-in clinical trial designs can be used to extinguish practice effects.Rate of decline after run-in is faster and unbiased by practice effects.Run-in designs correctly target the most clinically relevant outcome signal.Practice effects also impact weighting of optimal composite measures.}, } @article {pmid40936458, year = {2025}, author = {Paul, I and Roy, A and Ray, S and Pyne, S and Saha, M and Ray, S}, title = {Exploring the novel protein drug target BAG33339.1 of Porphyromonas gingivalis: an integrative subtractive proteomics and structural dynamics study.}, journal = {Journal of biomolecular structure & dynamics}, volume = {}, number = {}, pages = {1-45}, doi = {10.1080/07391102.2025.2553155}, pmid = {40936458}, issn = {1538-0254}, abstract = {Porphyromonas gingivalis, a gram-negative, bacterium interacts favourably with host subgingival biofilms to cause adult tooth decay and loss. Consequently, the host is infested with an uncontrollable microbial community and a compromised immune system, ultimately leading to tissue damage and bone resorption. P. gingivalis has also been known to cause cardiovascular and metabolic diseases, Alzheimer's disease, depression, prostate and digestive system cancer, rheumatoid arthritis, and adverse pregnancy outcomes with high detection frequencies. Rising concerns in the recent past, highlight the inefficiency of antibiotics and antiseptics in the treatment of P. gingivalis-related infections. Hence, the current scenario impels the discovery of an alternative therapeutic avenue against P. gingivalis-infections. To elucidate the unidentified bacterial mechanisms of infection, we screened a non-homolog of the host and gut microbiome as a novel druggable target from 173 essential hypothetical proteins of P.gingivalis (BAG33339.1). BAG33339.1 was an inner membrane protein with a hydrophobic N-terminal transmembrane helix and a primarily reconfiguring C-terminal helical region (Y36 to E52) while the residues (downstream of Lys45) lay in the disordered region. Frustration index coupled with the mutation matrix showed the steadiness of the transmembrane helix and dynamicity of the C-terminal residues finally yielding a 'U'-shaped protein conformation. The tendency of the disordered C-terminal residues was to generate P. gingivalis variants. The overall conformational stability was determined by equilibrating RMSD, Rg and SASA values corroborated by increasing H-bonds and helix settling. Targeting the ligand binding pockets of BAG33339.1 would guide future endeavours to tackle P. gingivalis interaction with host systems.}, } @article {pmid40936007, year = {2025}, author = {Tskhakaia, I and Lema, D and Tsibadze, N and Lam, JR and Subramanian, A and Lau, A}, title = {Proton pump inhibitors in systemic sclerosis: should we exercise caution? Insights from a large-scale data analysis.}, journal = {Clinical rheumatology}, volume = {44}, number = {10}, pages = {4061-4070}, pmid = {40936007}, issn = {1434-9949}, mesh = {Humans ; *Proton Pump Inhibitors/adverse effects/therapeutic use ; *Scleroderma, Systemic/complications/drug therapy ; Female ; Male ; Retrospective Studies ; Middle Aged ; *Gastroesophageal Reflux/drug therapy/complications ; *Renal Insufficiency, Chronic/epidemiology/chemically induced ; Aged ; Osteoporosis/epidemiology/chemically induced ; Adult ; Alzheimer Disease/epidemiology ; }, abstract = {BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disorder often accompanied by gastroesophageal reflux disease (GERD), necessitating frequent use of proton pump inhibitors (PPIs). While PPIs mitigate GERD symptoms and protect against lung injury, concerns about their long-term safety, particularly regarding chronic kidney disease (CKD), osteoporosis, and Alzheimer's disease, are growing. This study aimed to assess whether the adverse effects of PPI are amplified in patients with scleroderma. METHODS: This was a retrospective observational analysis that utilized the TriNetX research network, including over 130 million patients globally. The study population comprised 6800 SSc patients on PPIs and 1,889,433 GERD patients on PPIs. Outcomes were evaluated pre- and post-propensity score matching for demographic and clinical factors. Risks of CKD (including stages 3, 4, 5, ESRD, hemodialysis dependence), osteoporosis, vascular dementia, and Alzheimer's disease were assessed. RESULTS: The SSc cohort exhibited higher risks of developing CKD (attributable risk [AR] 2.8%, p < 0.01) and osteoporosis (AR 9%, p < 0.01) after matching, compared to the GERD cohort. Notably, CKD stages 4 and 5 showed minimal differences between groups. SSc patients on PPI had lower risks of Alzheimer's disease (AR - 0.7%, p < 0.01). While the findings highlight an amplified risk of CKD and osteoporosis in SSc patients, the differences in advanced renal disease were modest. CONCLUSION: PPI therapy remains indispensable in SSc management. While potentially associated with a slight but significant increase in the risks of CKD and osteoporosis, these adverse effects do not negate the critical role of PPIs in mitigating GERD and its serious pulmonary complications. A strategy of targeted monitoring is recommended to maximize safety. Key Points • Identified Amplified Risks in SSc: This large-scale study reveals that SSc patients on PPIs face significantly higher risks of chronic kidney disease and osteoporosis compared to GERD patients on PPIs, suggesting SSc pathophysiology amplifies PPI-associated adverse effects. • Uncovered Neuroprotective Association: Contrary to general population trends, SSc patients on PPIs showed a reduced risk of Alzheimer's disease, potentially linked to immunosuppressant use, closer monitoring, or unique disease mechanisms-a finding warranting further investigation. • Provided Real-World Safety Evidence: Leveraging global data (> 130 million patients), this study offers robust real-world evidence on PPI safety in SSc, reinforcing PPIs' vital role in GERD/ILD management while advocating vigilant monitoring for CKD/osteoporosis. • Informed Risk-Benefit Clinical Strategy: The findings underscore the need to balance PPI benefits (reducing GERD/aspiration-related lung injury) against amplified renal/bone risks in SSc, guiding individualized treatment and monitoring protocols despite causal limitations of retrospective data.}, } @article {pmid40935607, year = {2025}, author = {Yoo, HB and Kang, SK and Shin, SA and Kim, D and Choi, H and Kim, YK and Yi, D and Byun, MS and Lee, DY and Lee, JS and , }, title = {Artificial Intelligence-Powered Quantification of Flortaucipir PET for Detecting Tau Pathology.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {66}, number = {11}, pages = {1827-1833}, pmid = {40935607}, issn = {1535-5667}, mesh = {Humans ; *Positron-Emission Tomography ; *tau Proteins/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Carbolines ; Male ; Female ; *Artificial Intelligence ; Aged ; Image Processing, Computer-Assisted/methods ; }, abstract = {We developed and evaluated an artificial intelligence (AI)-powered approach for easier quantification of tau PET uptake without requiring structural MR to aid earlier tracking of Alzheimer disease (AD). Methods: We implemented a deep neural network model that normalizes [18]F-AV1451 (tau) PET images to a standard template without requiring MR, using transfer learning from a model pretrained on amyloid PET. This model was integrated into an MR-free pipeline for tau PET quantification and validated on external dataset (Alzheimer Disease Neuroimaging Initiative). We examined correlations between model-derived tau uptake estimates and cognitive measures, including AD stage and episodic memory performance (n = 666). Longitudinal analyses were conducted to assess whether baseline tau deposition predicted future cognitive decline (n = 168). Results: The AI-powered pipeline achieved robust performance with intraclass correlation coefficients exceeding 0.97 for regional uptake estimation compared with MR-based ground truth. We also showed that the tau deposition in metatemporal regions was significantly correlated with Mini-Mental State Examination and Montreal Cognitive Assessment scores. Elevated tau PET uptake in the entorhinal cortex and inferior temporal gyrus predicted future cognitive decline. Conclusion: The proposed AI-powered pipeline enhances the clinical accessibility of tau PET by reducing scan costs and streamlining the uptake quantification, achieving high performance without requiring structural MR. We further demonstrated that the pipeline yields cognitively relevant outcome measures for early diagnosis and monitoring of AD progression to aid more personalized treatment strategies targeting AD biomarkers.}, } @article {pmid40935215, year = {2026}, author = {Huang, H and Lu, W and Huang, Y and Su, Y and Luo, R and Zeng, Y and Yuan, C and Jia, Z and Wang, X}, title = {Bazi Bushen improves cognitive dysfunction in 5×FAD mice by targeting amyloid pathology, neuroinflammation and cellular senescence.}, journal = {Journal of ethnopharmacology}, volume = {355}, number = {Pt A}, pages = {120586}, doi = {10.1016/j.jep.2025.120586}, pmid = {40935215}, issn = {1872-7573}, mesh = {Animals ; *Cellular Senescence/drug effects ; Mice ; Mice, Transgenic ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Cognitive Dysfunction/drug therapy/pathology/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Disease Models, Animal ; Aspartic Acid Endopeptidases/metabolism ; *Neuroinflammatory Diseases/drug therapy/pathology ; Male ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism/genetics ; Hippocampus/drug effects/metabolism/pathology ; Cognition/drug effects ; Maze Learning/drug effects ; Plaque, Amyloid/drug therapy/pathology ; }, abstract = {Bazi Bushen (BZBS), a Traditional Chinese Medicine (TCM) formula, is composed of fourteen herbal ingredients, including classic tonics such as Ginseng Radix et Rhizoma and Cistanches Herba. Traditionally used to combat fatigue and promote vitality in aging individuals, BZBS is rooted in TCM principles of kidney essence replenishment and brain function enhancement. Recent pharmacological studies have begun to validate its efficacy in age-related cognitive decline, but its effects and mechanisms in Alzheimer's disease (AD) remain unclear. AIM OF THE STUDY: This study aimed to evaluate the potential therapeutic effects of BZBS in 5 × FAD transgenic mice, a commonly used Alzheimer's disease model, and to shed light on its possible mechanisms of action. METHODS: Four- and six-month-old 5 × FAD mice were treated with BZBS to examine how it might influence cognitive performance. Behavioral assessments were carried out using Y-Maze and the Morris Water Maze. To investigate the biological changes and uncover the mechanisms involved, we used a range of techniques-Thioflavin S staining, immunofluorescence, Western blotting, and qPCR-to look at Aβ plaque accumulation, Amyloid Precursor Protein C-terminal Fragments (APP-CTF) and β-secretase 1 (BACE1) expression levels, markers of inflammation, and indicators of cellular aging in hippocampus and motor cortex. RESULTS: In the 4-month group, where treatment was started before severe pathology developed, BZBS improved learning and memory performance. It also reduced amyloid deposition in the cortex and hippocampus, and lowered the levels of APP-CTFs and BACE1. In addition, we observed decreased mRNA expression of IL-1α, IL-6, and NF-κB, along with reduced microglial activation in the hippocampus of BZBS-treated mice. Similarly BZBS downregulated key markers of cellular senescence, including p16, p21, and senescence-associated β galactosidase (SA-β-gal) activity. In the 6-month group, which already showed signs of amyloid pathology, BZBS still had beneficial effects-improving cognition, lowering Aβ load, and reducing microglial activity-suggesting that it may be effective even after disease onset. CONCLUSION: These findings demonstrate that BZBS exerts significant therapeutic effects in 5 × FAD mice, including improved cognitive improvement, reduced Aβ deposition, suppressed microglial activation, and attenuated hippocampal cellular senescence. Notably, BZBS was effective whether administered from the early stage of pathology (at four months of age) or after established amyloidosis (at six months of age), highlighting its dual potential as both a preventive and disease-modifying intervention for Alzheimer's disease (AD).}, } @article {pmid40935202, year = {2026}, author = {Yang, X and Hu, D and Zhao, S and Wan, J and Chen, L and Bao, Q and Zhang, Y and Wang, Q and Huang, Z}, title = {Neuroprotective effects of butyrolactone II from Aspergillus terreus via Nrf-2/SKN-1 pathway modulation in Caenorhabditis elegans.}, journal = {The Journal of nutritional biochemistry}, volume = {147}, number = {}, pages = {110107}, doi = {10.1016/j.jnutbio.2025.110107}, pmid = {40935202}, issn = {1873-4847}, mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism/genetics ; *Aspergillus/chemistry/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *NF-E2-Related Factor 2/metabolism/genetics ; *4-Butyrolactone/pharmacology/analogs & derivatives ; *Transcription Factors/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; *DNA-Binding Proteins/metabolism/genetics ; Signal Transduction/drug effects ; Longevity/drug effects ; }, abstract = {Fourteen compounds were isolated from the fermentation broth of Aspergillus terreus, all of which were isolated from A. terreus for the first time. Among them, butyrolactone II (A9) had excellent DPPH radical scavenging activity, with an EC50 value of 42.05 µM superior to positive control drug BHT. Further neuroprotective activity evaluation of in Caenorhabditis elegans CL2355 revealed that butyrolactone II could alleviate Aβ, causing chemotaxis disorder, prolonging lifespan of C. elegans, and reducing 5-HT sensitivity. Butyrolactone II treatment significantly elevated the chemotaxis index of genotyped nematode CL2355 by 15.06% (P<0.05), and reduced the sensitivity of nematodes to 5-HT, decreasing the paralysis rate by 9.8% (P<0.05). Moreover, it significantly increased median lifespan and maximum lifespan by 20% and 26% respectively. In the RNA transcriptome, Butyrolactone II caused upregulation of 277 differentially expressed genes and downregulation of 171 differentially expressed genes, inducing the entry of transcription factor SKN-1 into the nucleus and changes in its downstream genes. The annotation and enrichment of GO and KEGG pathways indicated that differentially expressed genes might be related to pathways such as metabolic detoxification, oxidative stress, and lysosomal autophagy. The qRT-PCR validation of gene expression was consistent with transcriptomics. Butyrolactone II could significantly increase the expression of mitochondrial fission factor (mff-2), downstream genes related to SKN-1 (dod-17, gst-38), heat shock protein genes (hsp-17, hsp-12.6), and oxidative stress related genes (cyp-14A5) in nematodes, while having no significant effect on the expression level of gst-33 gene. Taken conclusion, butyrolactone II exerts neuroprotective effects by modulating the Nrf-2/SKN-1 pathway and regulating metabolic pathways, underscoring its potential as a therapeutic strategy for Alzheimer's disease and other related neurodegenerative disorders.}, } @article {pmid40934766, year = {2025}, author = {Xin, X and Zong, T and Hu, Z and Jin, L and Zhou, W and Sun, J and Li, G}, title = {Discovery of natural compounds and their derivatives against neuroinflammation: Pharmacological mechanisms and structure-activity relationship.}, journal = {Bioorganic chemistry}, volume = {165}, number = {}, pages = {108934}, doi = {10.1016/j.bioorg.2025.108934}, pmid = {40934766}, issn = {1090-2120}, mesh = {Humans ; Structure-Activity Relationship ; *Biological Products/chemistry/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Animals ; *Neuroinflammatory Diseases/drug therapy ; Molecular Structure ; *Drug Discovery ; *Neuroprotective Agents/chemistry/pharmacology ; }, abstract = {Neuroinflammation refers to the inflammatory response within the central nervous system mediated by immune and glial cells, constitutes a pivotal mechanism in the pathological progression of neurodegenerative diseases. Alzheimer's disease (AD) serves as a paradigmatic example of neuroinflammation role in driving cytokine-mediated neuronal damage and perpetuating of disease progression. AD, which is characterized by memory decline and progressive cognitive impairment as its core clinical manifestations, currently has no effective treatment. Recent advances have underscored natural products as promising candidates for the development of safer and more effective anti-AD agents, particularly through the targeting of neuroinflammatory pathways that have emerged as central pathological mechanisms in the progression of AD. This review aims to elucidate the pathogenesis of neuroinflammation in AD and provides a comprehensive overview of anti-AD drugs currently in clinical research as well as those already available on the market. Additionally, this paper highlights natural compounds and their derivatives discovered over the past decade that exhibit anti-AD neuroinflammatory properties, analyzing the structure-activity relationships of selected compounds and their permeability across the blood-brain barrier. The goal is to offer valuable insights and references for drug developers.}, } @article {pmid40934542, year = {2025}, author = {Liu, T and Zhang, W and Bao, W and Wang, X and Zhang, F and Guo, J and Li, M}, title = {Aβ impairs bone vascular homeostasis in APP/PS1 mice via disrupting the mitochondrial fission-efferocytosis axis in macrophages.}, journal = {International immunopharmacology}, volume = {165}, number = {}, pages = {115526}, doi = {10.1016/j.intimp.2025.115526}, pmid = {40934542}, issn = {1878-1705}, mesh = {Animals ; *Mitochondrial Dynamics/drug effects ; *Macrophages/metabolism/physiology/drug effects ; Mice ; Homeostasis ; Mice, Transgenic ; Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/metabolism/immunology/pathology ; Phagocytosis ; c-Mer Tyrosine Kinase/metabolism ; *Bone and Bones/blood supply/pathology/metabolism ; Amyloid beta-Protein Precursor/genetics ; Endothelial Cells ; Humans ; ADAM17 Protein/metabolism ; Mice, Inbred C57BL ; Disease Models, Animal ; Presenilin-1/genetics ; Apoptosis ; Reactive Oxygen Species/metabolism ; Dynamins/metabolism ; Male ; Efferocytosis ; }, abstract = {Alzheimer's disease (AD) is associated with progressive bone loss, but the underlying mechanisms remain unclear. This study focused on how amyloid-β (Aβ) disrupted bone vascular homeostasis by impairing macrophage efferocytosis in APP/PS1 mice. We found that Aβ accumulation in bone tissue impaired MerTK-mediated macrophage efferocytosis and promoted excessive accumulation of apoptotic endothelial cells (ECs). Mechanistically, Aβ triggered excessive mitochondrial fission via GSK-3β-mediated DRP1 phosphorylation, resulting in elevated reactive oxygen species (ROS) and subsequent ADAM17 activation. ADAM17 cleaved MerTK, a critical efferocytosis receptor, impairing apoptotic cells (ACs) clearance. Pharmacological inhibition of GSK-3β (LiCl and TDZD-8) or mitochondrial fission (Mdivi-1) restored MerTK expression, improved efferocytosis, and reduced inflammatory cytokine release (such as TNF-α, IL-6), while enhancing vascular endothelial growth factors (VEGFs). In vivo, LiCl treatment ameliorated bone loss and vascular dysfunction in APP/PS1 mice. These findings revealed that Aβ disrupted the mitochondrial fission-efferocytosis axis in macrophages, contributing to AD-related bone pathology, and highlighted GSK-3β as a potential therapeutic target for preserving bone vascular homeostasis in AD.}, } @article {pmid40933919, year = {2025}, author = {Song, B and Yue, D and Yan, H and Feng, L and Li, M}, title = {Traditional Chinese Medicine Natural Products Targeting Shared Mechanisms of T2DM and AD: Potential Therapeutic Insights.}, journal = {Drug design, development and therapy}, volume = {19}, number = {}, pages = {7681-7705}, pmid = {40933919}, issn = {1177-8881}, mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Medicine, Chinese Traditional ; *Biological Products/pharmacology/therapeutic use/chemistry ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Animals ; Oxidative Stress/drug effects ; }, abstract = {As highly prevalent chronic diseases globally, AD (Alzheimer's disease) and T2DM (type 2 diabetes mellitus) not only severely affect the quality of life of patients but also impose a significant burden on their families. Numerous studies have gradually revealed that T2DM and AD are bidirectional risk factors, each capable of exacerbating the other. There is a notable correlation in their pathological mechanisms, primarily manifested in insulin resistance, OS (oxidative stress), and inflammatory responses. Currently, available drugs can only delay the progression of AD, such as Donepezil, Galantamine, and Carbamylcholine, making complete cures challenging to achieve. TCM (Traditional Chinese medicine) natural products exhibit characteristics such as multi-targeting, multi-pathway interactions, diverse biological activities, and relatively mild side effects, enabling synergistic intervention in both diseases. In recent years, TCM natural products have garnered increasing attention in research concentrated on the prevention and management of AD and T2DM. This article aims to comprehensively elucidate the collective pathogenic mechanism of AD and T2DM, and explore the progress of TCM natural products based on these mechanisms in the prevention and treatment of both diseases, thereby providing a theoretical foundation for the advancement of innovative treatment tactics.}, } @article {pmid40933857, year = {2025}, author = {Li, H and Zhu, J and Li, J and Wu, Y and Luo, C and Huang, Y and Wu, J and Liu, W and Wang, H and Mo, Z}, title = {Human brain organoids: an innovative model for neurological disorder research and therapy.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1658074}, pmid = {40933857}, issn = {1662-5102}, abstract = {The emergence of human brain organoids (hBOs) has transformed how we study brain development, disease mechanisms, and therapy discovery. These 3D in vitro neural models closely mimic the cellular diversity, spatial structure, and functional connectivity of the human brain, providing a groundbreaking platform that outperforms traditional 2D cultures and animal models in studying neurodevelopment and neurological disorders. To further explore the potential of hBOs technology, we review current literature focusing particularly on its applications for diagnosing and treating major neurological diseases such as Alzheimer's disease, Parkinson's disease, and other related neurological disorders. Using patient-derived induced pluripotent stem cells combined with cutting-edge gene-editing technologies, hBOs enable highly precise mechanistic studies and scalable drug screening. Moreover, we further discuss the advantages and current limitations of hBOs. Despite these challenges, hBOs remain a transformative platform for the development of targeted neurotherapeutics. Collectively, this review offers a solid foundation for advancing neuroscience research and fostering innovative treatment strategies for neurological disorders.}, } @article {pmid40933625, year = {2025}, author = {Hean, AC and Jones, J and Arena, M and Kavanagh, K}, title = {Memantine leading to physical aggression in the treatment of chronic catatonia secondary to schizophrenia: A case report.}, journal = {The mental health clinician}, volume = {15}, number = {4}, pages = {218-221}, pmid = {40933625}, issn = {2168-9709}, abstract = {INTRODUCTION: Memantine is a noncompetitive N-methyl-D-aspartate receptor antagonist approved by the FDA for moderate to severe Alzheimer's dementia. Memantine is also recommended as an off-label treatment in current catatonia clinical guidelines when benzodiazepines alone are inadequate. CASE: A 37-year-old male with a history of schizophrenia on psychiatric conservatorship, stimulant use disorder, and traumatic brain injury was stabilized on risperidone 4 mg twice daily, diphenhydramine 50 mg twice daily, divalproex delayed release 500 mg twice daily, and lorazepam 1 mg twice daily for catatonia. Lorazepam was titrated for unresolved chronic catatonic symptoms but was not tolerated beyond 5 mg total per day due to hemodynamic instability. Owing to barriers in initiating clozapine or electroconvulsive therapy, the patient was started on memantine to address residual catatonia symptoms. After the addition of memantine, the patient began to spontaneously speak in multiple languages and engage in discharge planning, but shortly after a dose increase to 15 mg daily also displayed increased aggressive behaviors. The aggression improved after decreasing the dose to 10 mg daily, and the patient was discharged. CONCLUSIONS: This case adds to the body of evidence for memantine in catatonia with underlying schizophrenia and, to our knowledge, is the first described case of memantine uncovering aggression during catatonia treatment.}, } @article {pmid40933191, year = {2025}, author = {Zhao, Y and Wang, X and Zhang, J and Zhao, Y and Li, Y and Shen, J and Yuan, Y and Li, J}, title = {Plasma FGF2 and YAP1 as novel biomarkers for MCI in the elderly: analysis via bioinformatics and clinical study.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1663276}, pmid = {40933191}, issn = {1662-4548}, abstract = {The contemporary consensus firmly emphasizes the urgent need to reorient research efforts toward the early detection of preclinical Alzheimer's disease (AD) or mild cognitive impairment (MCI). However, there is still a notable absence of novel biomarkers that are both efficient, minimally invasive, and cost-effective in real-world clinical settings. To address this gap, datasets GSE29378 and GSE12685 were selected to screen differentially expressed genes (DEGs), and hub genes were identified by different algorithms. A total of 350 DEGs were identified in bioinformatics data mining. Functional enrichment analysis showed that fibroblast growth factor 2(FGF2) and yes-associated protein 1(YAP1) protein levels were highly expressed in AD samples, indicating their potential regulatory roles in AD. Between October and November 2024, a total of 146 elderly individuals diagnosed with MCI and 54 healthy elderly subjects were successfully recruited. Enzyme linked immunosorbent assay (ELISA) was used to detect plasma hub gene protein concentration. The results showed that the expression levels of plasma FGF2 and YAP1 proteins in the MCI group were significantly higher compared to the control group. Logistic regression analysis indicated that high plasma FGF2 and YAP1 expression levels were independently associated with MCI in the elderly. The Area under the curve (AUC) of FGF2 model and YAP1 model were 0.907 and 0.972, respectively. Therefore, the high expression of plasma FGF2 and YAP1 proteins may be independent predictive risk factors for MCI in the elderly. Our findings may provide targets for the development of early minimally invasive, efficient, and convenient screening tools, and even for the treatment of AD in the future.}, } @article {pmid40933041, year = {2025}, author = {He, C and Chen, B and Yan, C and Zhou, X}, title = {Stem cell and CRISPR/Cas9 gene editing technology in Alzheimer's disease therapy: from basic research to clinical innovation.}, journal = {Frontiers in genome editing}, volume = {7}, number = {}, pages = {1612868}, pmid = {40933041}, issn = {2673-3439}, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by Aβ plaques, tau protein neuronal fiber tangles, and neuroinflammation, poses a significant global health problem, and current therapies focus on the symptoms rather than the cause. This paper gives a new multidimensional therapeutic form to AD treatment by exploring the integrated application of stem cell therapy and CRISPR/Cas9 gene editing technology. The study comprehensively dissected the roles of neural stem cells (NSCs), induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) in neural replacement, neuroinflammation modulation and neuroplasticity enhancement, and also explored the application of CRISPR/Cas9 in modifying the pathogenic variants of AD-related genes (APP, PSEN1 and PSEN2). The key findings suggest that gene-edited iPSCs can reduce abnormal Aβ and tau protein accumulation in AD models, improve cognitive function, and provide a platform for disease modeling and drug screening. Stem cell transplantation promotes neurogenesis and synaptic plasticity by secreting neurotrophic factors to improve the brain microenvironment. Despite the challenges of off-target effects, immune rejection, and long-term safety, the synergistic application of these two technologies offers a breakthrough solution for AD treatment. This paper highlights the translational potential of combining stem cells with gene editing technology, which is expected to drive clinical applications in the next 5-10 years. The integration of these advanced technologies not only addresses the limitations of current AD treatments, but also paves the way for a personalized medical approach that is expected to revolutionize the AD treatment landscape and bring new hope to patients worldwide.}, } @article {pmid40932994, year = {2025}, author = {Katel, S and Cicalo, J and Vasciaveo, V and Vecchio, LM and Carrion, J and Mahadeo, L and Huerta, PT and Choksi, JD and Aubert, I and Marambaud, P and Giliberto, L and d'Abramo, C}, title = {AAV-mediated peripheral scFv's administration to reduce cerebral tau in adult P301S transgenic mice: Mono-vs. combination therapy.}, journal = {Molecular therapy. Methods & clinical development}, volume = {33}, number = {3}, pages = {101563}, pmid = {40932994}, issn = {2329-0501}, support = {P01 AI073693/AI/NIAID NIH HHS/United States ; P01 AI102852/AI/NIAID NIH HHS/United States ; R01 AG061381/AG/NIA NIH HHS/United States ; }, abstract = {Tau is a primary target for immunotherapy in Alzheimer's disease (AD). Recent studies have shown the potential of anti-tau fragment antibodies in lowering pathological tau levels in vitro and in vivo. Here, we compared the effects of single-chain variable fragments (scFvs) derived from the well-characterized monoclonal antibodies PHF1 and MC1. We used adeno-associated virus 1 (AAV1) to deliver scFvs to skeletal muscle cells in 8-week-old P301S tau transgenic mice. We evaluated motor and behavioral functions at 16 and 23 weeks of age and measured misfolded, soluble, oligomeric, and insoluble brain tau species. Monotherapy with scFv-MC1 improved motor and behavioral functions more effectively than scFv-PHF1 or combination therapy. Brain glucose metabolism also benefited from scFv-MC1 treatment. Surprisingly, combining scFvs targeting early (MC1) and late (PHF1) tau modifications did not produce additive or synergistic effects. These results confirm that intramuscular AAV1-mediated scFv-MC1 gene therapy holds promise as a potential treatment for AD. Our findings also suggest that combining scFvs targeting different tau epitopes may not necessarily enhance efficacy if administered together in a prevention paradigm. Further research is needed to explore whether other antibodies' combinations and/or administration schedules could improve the efficacy of scFv-MC1 alone.}, } @article {pmid40931963, year = {2025}, author = {Nardi Cesarini, E and Falcicchio, G and Librizzi, L and Sciaccaluga, M and Assenza, G and Galimberti, CA and Giorgi, FS and DiFrancesco, JC and Costa, C and , }, title = {Etiological diagnosis of late-onset epilepsy: A key priority for Italian epileptologists - Insights from a LICE survey.}, journal = {Epilepsia open}, volume = {10}, number = {5}, pages = {1639-1647}, pmid = {40931963}, issn = {2470-9239}, mesh = {Humans ; Italy/epidemiology ; *Epilepsy/etiology/diagnosis/epidemiology ; Cross-Sectional Studies ; Electroencephalography ; Male ; Middle Aged ; Magnetic Resonance Imaging ; Female ; Surveys and Questionnaires ; *Neurologists ; Age of Onset ; Aged ; Adult ; }, abstract = {OBJECTIVE: The incidence of epilepsy rises markedly after age 50. While late-onset epilepsy (LOE) is often linked to structural brain abnormalities, non-structural factors, such as infections, autoimmune disorders, and neurodegenerative diseases, also contribute. Approximately 20% of LOE cases remain of unknown etiology (LOEU). This study evaluated the diagnostic and therapeutic strategies employed by Italian epileptologists in managing LOE and LOEU, with the ultimate goal of proposing a standardized diagnostic algorithm. METHODS: Data were collected through a cross-sectional online survey administered to neurologists who are formal members of the Italian Chapter of the International League Against Epilepsy (LICE). Descriptive statistics were used to summarize responses, and inferential statistics were applied to derive meaningful conclusions. RESULTS: Sixty-five epilepsy centers across 19 of the 20 Italian regions participated in the survey. EEG (100%; n = 65) and brain MRI (92.31%; n = 60) were routinely employed in the diagnostic evaluation of LOE. In over half of the centers (58.46%; n = 38), sleep-activated or sleep-influenced EEGs were also used. For LOEU cases, neuropsychological assessments were performed in 60% of centers. More than 30% of centers employed additional diagnostic tools, including lumbar puncture, FDG-PET, and serum antibody testing for neural autoantibodies. The most commonly prescribed anti-seizure medications (ASMs) for LOE were levetiracetam (86.15%; n = 56), lacosamide (81.54%; n = 53), and lamotrigine (61.54%; n = 40). SIGNIFICANCE: These findings suggested that Italian epileptologists frequently evaluate patients with LOE during routine outpatient visits. LOEU is increasingly recognized as a distinct subtype of LOE that may warrant a targeted diagnostic approach due to the potential involvement of autoimmune and neurodegenerative mechanisms. There is a pressing need for focused cross-sectional or prospective multicenter studies to refine the diagnostic strategies for LOE, particularly for LOEU, and to enhance the characterization of its clinical and etiological features. PLAIN LANGUAGE SUMMARY: After age 50, epilepsy rates rise, often linked to brain changes but sometimes with no clear cause (LOEU). We surveyed Italian epilepsy specialists and found that routine EEG and MRI are widely used, yet about 20% of cases require advanced tests to identify rare or autoimmune causes. Our findings will inform patient-focused diagnostic and treatment guidelines and underscore the need for standardized care pathways and further research in adult-onset epilepsy.}, } @article {pmid40931717, year = {2025}, author = {Rogers, EA and Diorio, TC and Beauclair, T and Martinez, J and Mufti, SJ and Kim, D and Krishnan, N and Rayz, V and Shi, R}, title = {Concussive injuries induce neuronal stress-dependent tau mislocalization to dendritic spines with acrolein and functional network alteration in TBI-on-a-chip.}, journal = {Lab on a chip}, volume = {25}, number = {20}, pages = {5203-5220}, pmid = {40931717}, issn = {1473-0189}, support = {UL1 TR002529/TR/NCATS NIH HHS/United States ; }, mesh = {Animals ; *Acrolein/metabolism ; *tau Proteins/metabolism ; Mice ; *Dendritic Spines/metabolism/pathology ; *Lab-On-A-Chip Devices ; *Brain Concussion/metabolism/pathology ; *Neurons/metabolism/pathology ; Oxidative Stress ; }, abstract = {Traumatic brain injuries (TBIs) are a risk factor for Alzheimer's disease (AD), and share several important pathological features including the development of neurofibrillary tangles (NFT) of tau protein. While this association is well established, the underlying pathogenesis is poorly defined and current treatment options remain limited, necessitating novel methods and approaches. In response we developed "TBI-on-a-chip", an in vitro trauma model utilizing murine cortical networks on microelectrode arrays (MEAs), capable of reproducing clinically relevant impact injuries while providing simultaneous morphological and electrophysiological readout. Here, we incorporate a digital twin of the TBI-on-a-chip model to resolve cell-scale mechanical deformation via shear stresses and demonstrate direct connections between impact forces with aberrations in tau and synaptic deficits, and correlate these changes with elevations of oxidative stress, a suspected key contributor to both trauma and neurodegeneration. This multi-disciplinary investigation combines computational modeling, electrophysiology, and imaging, to explore tau mislocalization and functional deficits as a function of force, in the context of a potential mechanism via acrolein. We hope that this novel, integrative approach will help improve our mechanistic understanding of trauma and neurodegeneration, solo and in concert, and ultimately assist in generating more effective treatment options.}, } @article {pmid40931680, year = {2025}, author = {Stone, WJ and Pair, FS and Ekkatine, R and Gannon, M and Scholz, K and Pattanayak, R and Syed, R and Yacoubian, TA}, title = {14-3-3 Proteins Negatively Regulate Microglial Activation via Inhibition of the NF-κB Pathway.}, journal = {Journal of neurochemistry}, volume = {169}, number = {9}, pages = {e70228}, pmid = {40931680}, issn = {1471-4159}, support = {R01NS112203/NH/NIH HHS/United States ; R01 NS112203/NS/NINDS NIH HHS/United States ; F31 ES034985/ES/NIEHS NIH HHS/United States ; F31ES034985/NH/NIH HHS/United States ; //Parkinson Association of Alabama/ ; }, mesh = {*Microglia/metabolism/drug effects ; *14-3-3 Proteins/metabolism/antagonists & inhibitors ; Animals ; Mice ; *NF-kappa B/metabolism/antagonists & inhibitors ; *Signal Transduction/physiology/drug effects ; Lipopolysaccharides/pharmacology ; Mice, Inbred C57BL ; Cells, Cultured ; }, abstract = {Microglia, the resident immune cells of the central nervous system (CNS), are involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Dementia with Lewy Bodies (DLB), and Parkinson's disease (PD). 14-3-3 proteins act as molecular hubs to regulate protein-protein interactions, which are involved in numerous cellular functions, including cellular signaling, protein folding, and apoptosis. We previously revealed decreased 14-3-3 levels in the brains of human subjects with neurodegenerative diseases. In this study, we examined the role of 14-3-3 proteins in the microglial proinflammatory response to lipopolysaccharide (LPS). We found that LPS treatment induced 14-3-3 protein levels within 6 hours. With the use of BV02 and dimeric fourteen-three-three peptide inhibitor (difopein), a small molecule and peptide inhibitor of 14-3-3 protein-protein interactions, respectively, we found a dramatic increase in microglial activation markers in both immortalized BV-2 microglial cells and in primary mouse microglia. Both 14-3-3 inhibitors also increased LPS-induced microglial phagocytosis, lysosomal proteolysis, and cytokine release in primary microglia. In contrast, chemotaxis toward the cellular damage stimulus, adenosine triphosphate (ATP), was diminished with 14-3-3 inhibition. Inhibition of 14-3-3's hastened LPS-induced activation of the nuclear factor-kB (NF-κB) signaling pathway, as measured by its nuclear translocation. 14-3-3's reduced activation of the NF-κB pathway by binding and inhibiting the release of IκB kinase beta (IKKβ). Disruption of 14-3-3's binding to IKKβ with BV02 or difopein increased the downstream phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα). Collectively, our findings suggest 14-3-3 proteins play a critical role in the regulation of inflammatory responses in microglia and may serve as potential targets for immunotherapy of CNS diseases.}, } @article {pmid40931359, year = {2025}, author = {Ramonet, D and Daerr, A and Hallbeck, M}, title = {Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer's disease mouse model.}, journal = {Acta neuropathologica communications}, volume = {13}, number = {1}, pages = {190}, pmid = {40931359}, issn = {2051-5960}, support = {2019-01016//Swedish Research Council/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics/drug therapy ; Mice ; *Endosomes/metabolism/drug effects/pathology ; Disease Models, Animal ; *Synapses/metabolism/drug effects/pathology ; Mice, Transgenic ; *Vesicular Transport Proteins/metabolism/genetics ; Protein Transport/drug effects/physiology ; Humans ; }, abstract = {Disruptions in synaptic transmission and plasticity are early hallmarks of Alzheimer's disease (AD). Endosomal trafficking, mediated by the retromer complex, is essential for intracellular protein sorting, including the regulation of amyloid precursor protein (APP) processing. The VPS35 subunit, a key cargo-recognition component of the retromer, has been implicated in neurodegenerative diseases, with mutations such as L625P linked to early-onset AD. Despite growing evidence for retromer dysfunction in AD, its role in synaptic pathology and neuroinflammation remains incompletely understood. Here, we investigate the acute molecular effects of retromer stabilization in the 5xFAD mouse model of AD using the pharmacological chaperones R55 and R33, previously identified to enhance VPS35 stability. Following intracranial stereotaxic injections, we performed transcriptomic profiling, quantitative histology, and immunohistochemistry to assess synaptic function, neuroinflammation, and endosomal trafficking. Our findings reveal that retromer stabilization reverses multiple AD-associated molecular changes. R55 treatment significantly reduced Aβ-related pathology, normalized synaptic gene expression, and restored long-term potentiation (LTP)-associated pathways, including Gria1 (AMPA receptors), Grip1, and semaphorin/plexin signaling. Additionally, retromer stabilization counteracted dysregulated calcium signaling by modulating Ryr2 and L-type calcium channel expression. Beyond synaptic effects, we observed broad transcriptional and structural changes in the endosomal system. Notably, R55 treatment decreased VPS13 family gene expression, implicated in membrane contact site regulation, while increasing RAB7 levels, suggesting enhanced late-endosomal recycling. VPS35-positive vesicles were redistributed away from the nucleus, indicating restored intracellular trafficking dynamics. In the neuroinflammatory domain, retromer stabilization modulated microglial activation, shifting towards a profile characterized by balanced pro-inflammatory (Il1, Nfkb2) and anti-inflammatory (Il4r, Il13ra1, Stat6) markers, consistent with disease-associated microglia (DAM) phenotypes. Together, these findings demonstrate that retromer dysfunction contributes to key AD pathologies, including synaptic dysfunction and neuroinflammation, and that pharmacological retromer stabilization can restore cellular homeostasis. Given that 5xFAD mice lack direct VPS35 mutations, our results suggest that retromer-targeting strategies may be applicable to both familial and sporadic AD, offering a promising therapeutic avenue for modifying disease progression.}, } @article {pmid40931113, year = {2025}, author = {Hu, M and Kang, X and Liu, Z and Wang, S and Liu, S and Li, C and Lu, D and Qin, Q and Liu, Y and Yi, H and Yuan, L and Liu, Q and Lu, Z and Cai, W}, title = {Senescent-like border-associated macrophages regulate cognitive aging via migrasome-mediated induction of paracrine senescence in microglia.}, journal = {Nature aging}, volume = {5}, number = {10}, pages = {2039-2054}, pmid = {40931113}, issn = {2662-8465}, support = {82271348//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, mesh = {Animals ; *Microglia/metabolism/physiology ; *Cellular Senescence/physiology ; Mice ; *Paracrine Communication/physiology ; *Macrophages/physiology/metabolism ; *Cognitive Aging/physiology ; Apoptosis ; Mice, Inbred C57BL ; *Aging ; Cell Movement ; Male ; Amyloid beta-Peptides/metabolism ; Brain/pathology ; Humans ; }, abstract = {Aging is a major risk factor for various neurological disorders, including Alzheimer's disease, and is associated with the accumulation of senescent cells, which can themselves propagate the senescence process through paracrine signaling. Migrasomes are organelles that form during cellular migration, detach from parent cells and mediate intercellular communication. Here we demonstrate that border-associated macrophages (BAMs) acquire senescence-associated properties during early brain aging, possibly due to prolonged exposure to amyloid beta. Senescent-like BAMs show elevated production of migrasomes, which convey senescence-associated signals including the apoptosis inhibitor of macrophage to neighboring cells. We show that microglia are prominent recipients of senescent-like BAM-derived migrasomes, and that through activation of CD16 in recipient cells, the apoptosis inhibitor of macrophage inhibits apoptosis and promotes senescence induction. Blocking migrasome induction in senescent-like BAMs through treatment with Tspan4-targeting siRNA-encapsulated liposomes ameliorates cognitive deficits in aged mice. Our findings suggest that migrasomes are potent vehicles of senescence-regulatory signals and represent a promising target for senomorphic therapy.}, } @article {pmid40930236, year = {2025}, author = {Zhang, F and Ding, K and Zhang, LM and Liu, DY and Dong, X and Wang, MN and Zhou, FL and Sun, YW and Zhang, WK and Yan, Y and He, J and Xu, JK}, title = {The role of the gut microbiota in neuropsychiatric disorders and therapy.}, journal = {Ageing research reviews}, volume = {112}, number = {}, pages = {102894}, doi = {10.1016/j.arr.2025.102894}, pmid = {40930236}, issn = {1872-9649}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Mental Disorders/therapy/microbiology ; Animals ; *Dysbiosis/microbiology ; Fecal Microbiota Transplantation ; Probiotics/therapeutic use ; Brain ; Brain-Gut Axis/physiology ; Prebiotics ; }, abstract = {The vast microbial community residing in the gut is known as the gut microbiota (GM). Alterations in the compositional equilibrium of the GM, a phenomenon termed GM dysbiosis, have been increasingly associated with the pathogenesis of various diseases, particularly neuropsychiatric disorders. The microbiota-gut-brain axis (MGBA) serves as a bidirectional communication system that connects the gut to the brain. Notably, several prevalent neuropsychiatric disorders, including depression, Alzheimer's disease (AD), and Parkinson's disease (PD), collectively affect over one billion individuals globally. Emerging scientific evidence has consistently demonstrated the presence of GM dysbiosis in various neuropsychiatric disorders, suggesting a potential etiological role of GM in these conditions through MGBA-mediated mechanisms. In this comprehensive review, we systematically discussed the GM and MGBA, and presented evidence from both animal and human studies that highlighted the significance of GM in the occurrence and development of neuropsychiatric disorders. Subsequently, we emphasized the potential impact of GM and its metabolites on neuropsychiatric disorders. Next, we summarized the drugs used to treat diseases by regulating the GM. Finally, we proposed strategies to ameliorate the malignant progression of neuropsychiatric disorders by manipulating the composition of the GM. These strategies encompass the application of probiotics, prebiotics and synbiotics, postbiotics, fecal microbiota transplantation (FMT), and dietary interventions. Collectively, targeted GM therapy has the potential to be an effective treatment for neuropsychiatric disorders.}, } @article {pmid40929163, year = {2025}, author = {Schwertner, K and Basílio, J and Hoffmann-Sommergruber, K and Ellinger, I and Geiselhart, S}, title = {Global transcriptional analysis of human FHs 74 Int intestinal epithelial cells after exposure to advanced glycation end products.}, journal = {PloS one}, volume = {20}, number = {9}, pages = {e0331325}, pmid = {40929163}, issn = {1932-6203}, mesh = {Humans ; *Glycation End Products, Advanced/pharmacology ; *Intestinal Mucosa/metabolism/cytology/drug effects ; *Epithelial Cells/metabolism/drug effects ; S100A12 Protein/pharmacology ; *Transcriptome/drug effects ; Gene Expression Profiling ; Cell Line ; Gene Expression Regulation/drug effects ; Cell Proliferation/drug effects ; }, abstract = {Advanced glycation end products (AGEs) and reactive intermediates, such as methylglyoxal, are formed during thermal processing of foods and have been implicated in the pathogenesis of a series of chronic inflammatory diseases. AGEs are thought to directly interact with the intestinal epithelium upon ingestion of thermally processed foods, but their effects on intestinal epithelial cells are poorly understood. This study investigated transcriptomic changes in human intestinal epithelial FHs 74 Int cells after exposure to AGE-modified human serum proteins (AGE-HS), S100A12, a known RAGE ligand, and unmodified human serum proteins (HS). In contrast to previous studies employing cancer cell lines, RNA sequencing of FHs 74 Int cells treated with AGE-HS did not reveal transcriptional changes associated with increased proliferation, increased expression of tight junction proteins or proinflammatory responses. Surprisingly, neither AGE-HS nor S100A12 treatments resulted in significant differential gene expression at standard analysis thresholds, while unmodified HS induced minor transcriptional changes. Gene set enrichment analysis revealed that AGE-HS treatment induced downregulation of gene sets linked to MYC, interferon responses, and oxidative phosphorylation, as well as pathways related to neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, paralleling some effects observed with S100A12. This is the first global transcriptomic analysis of FHs 74 Int cells and the first unbiased investigation of signaling pathway alterations in intestinal epithelial cells exposed to AGEs. In contrast to previous studies, this analysis did not reveal any significantly differentially expressed genes, thus challenging previous reports of robust AGE-induced inflammatory and proliferative effects and emphasizing the importance of an isolated experimental setting and rigorous endotoxin testing.}, } @article {pmid40928812, year = {2025}, author = {Taragano, F and Seinhart, D and Epstein, P and Sylvestre, V and Barañano, C and Otero Castro, V and Sánchez, V and Kilstein, A and González, R and Franco-Trecu, V and Costa-Urrutia, P}, title = {A real-world study on the safety and efficacy of therapeutic plasma exchange in patients with Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {108}, number = {1}, pages = {129-141}, pmid = {40928812}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; Male ; Aged ; *Plasma Exchange/methods/adverse effects ; Treatment Outcome ; Aged, 80 and over ; Middle Aged ; Neuropsychological Tests ; Mental Status and Dementia Tests ; Argentina ; }, abstract = {BackgroundTherapeutic plasma exchange (TPE) with albumin replacement has emerged as a potential treatment for Alzheimer's disease (AD). The AMBAR trial showed that TPE could slow cognitive and functional decline, along with changes in core and inflammatory biomarkers in cerebrospinal fluid.ObjectiveTo evaluate the safety and effectiveness of TPE in a real-world setting in Argentina.MethodsFrom 2022 to 2024, 32 patients with mild-to-moderate AD received TPE and were compared to a historical control group (2008-2018, n = 194) matched for inclusion criteria and cognitive assessments. The protocol included six weekly intensive sessions followed by at least 10 monthly maintenance sessions. Outcomes were measured using the Mini-Mental State Examination (MMSE), and tests of memory, language, executive function, and attention. Linear models were used for analysis.ResultsPatients had a mean age of 72.1 years; 42.4% were female. Baseline MMSE scores ranged from 15 to 26. A total of 514 procedures were performed; 81.5% were uneventful. Mild-to-moderate adverse events occurred in 18.5% of sessions, mainly related to venipuncture; no severe events were reported. Mean plasma exchange volumes were 88.2% and 49.8% of estimated plasma volume during the intensive and maintenance phases, respectively. TPE significantly slowed MMSE decline (45% less than controls, p < 0.001) and reduced memory deterioration (88% less in immediate recall, p < 0.001; 74% in delayed recall, p = 0.04). Other domains were also better preserved.ConclusionsTPE appears to be a safe and effective intervention for slowing cognitive decline in AD, supporting the AMBAR findings.}, } @article {pmid40928277, year = {2025}, author = {Fu, JX and Wang, WP and Wang, YD and Wang, PC}, title = {Beams of Hope: Shedding New Light on Alzheimer's Treatment with Low-Dose Radiation Therapy.}, journal = {Biomedical and environmental sciences : BES}, volume = {38}, number = {8}, pages = {1001-1002}, doi = {10.3967/bes2025.100}, pmid = {40928277}, issn = {2214-0190}, } @article {pmid40928009, year = {2025}, author = {Weden, MM and Frank, L and Dick, AW and Wang, Z and Peschin, S and Bovenkamp, DE and Rossi, SL and Sciullo, D and Hillerstrom, H and Fisher, RA}, title = {Investment in Alzheimer's disease research for the next generation of adults with Down syndrome will yield health benefits for future generations.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70348}, pmid = {40928009}, issn = {1552-5279}, support = {//LuMind IDSC Foundation/ ; //Alliance for Aging Research/ ; //BrightFocus® Foundation/ ; //National Down Syndrome Society/ ; }, mesh = {Humans ; *Down Syndrome/economics/complications/epidemiology/therapy ; *Alzheimer Disease/economics/therapy/epidemiology ; Life Expectancy ; Adult ; *Biomedical Research/economics ; Caregivers/economics ; }, abstract = {Recent innovations in Alzheimer's disease (AD) treatment highlight critical gaps in knowledge about how to support healthy aging of adults with Down syndrome (DS). RAND researchers updated demographic and epidemiological evidence about the DS population to assess the impact of increased investment in treatment innovations for DS-associated Alzheimer's disease (DS-AD). They estimated life expectancy at birth in 2020 to be 55 years, with ≈ 5 years of DS-AD. They found that the results of investment were dramatic. Between 2020 and 2070, adult years of life are expected to increase by 5 years without any increase in unhealthy years of life with DS-AD. Caregiving hours for individuals with DS-AD are expected to be reduced by 40%, which will generate large annual savings. The new evidence underscores the magnitude of the impact that investment in DS-AD treatments could have for individuals with DS, their families, and caregivers. HIGHLIGHTS: Evidence is sparse about treatment for Down syndrome (DS)-associated Alzheimer's disease (DS-AD) and healthy aging of DS adults. This population simulation model estimates DS-AD caregiving costs at ≈ $1 billion per year. DS-AD innovations could increase life expectancy by 5 years and reduce caregiving by 40% by 2070. This better forecasting can improve policy and service planning. DS-AD research investment could yield dramatic gains for individuals and families.}, } @article {pmid40927759, year = {2025}, author = {Aggarwal, A and Rajalekshmi, R and Aggarwal, A and Agrawal, DK}, title = {Plants, Pills, and the Brain: Exploring Phytochemicals and Neurological Medicines.}, journal = {International journal of plant, animal and environmental sciences}, volume = {15}, number = {3}, pages = {90-114}, pmid = {40927759}, issn = {2231-4490}, support = {R25 AI179582/AI/NIAID NIH HHS/United States ; }, abstract = {Neurological disorders, such as Alzheimer's disease, Parkinson's disease, epilepsy, spinal cord injuries, and traumatic brain injuries, represent substantial global health challenges due to their chronic and often progressive nature. While allopathic medicine offers a range of pharmacological interventions aimed at managing symptoms and mitigating disease progression, it is accompanied by limitations, including adverse side effects, the development of drug resistance, and incomplete efficacy. In parallel, phytochemicals-bioactive compounds derived from plants-are receiving increased attention for their potential neuroprotective, antioxidant, and anti-inflammatory properties. This review will explore the therapeutic landscape of neurological diseases by providing a comprehensive overview of prevalent conditions and the current allopathic treatments available. Furthermore, this review will investigate specific phytochemicals, including flavonoids, alkaloids, and terpenoids, that exhibit promise in modulating various disease pathways. Emphasis will be placed on the interactions between plant-derived compounds and prescription medications, highlighting both potential synergistic effects and possible adverse interactions. A thorough understanding of these interactions is essential for the development of integrative treatment approaches that enhance therapeutic efficacy while minimizing harm. By bridging traditional herbal medicine with contemporary pharmacotherapy, this review aims to promote a more holistic perspective on the management of neurological diseases, while also encouraging further research into safe and effective combinatory therapies.}, } @article {pmid40927393, year = {2025}, author = {Ning, G and Fan, X and Juan, D and Wenxue, Z and Sijia, W and Meinei, C and Xiaolong, D and Yiming, Q}, title = {The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1637671}, pmid = {40927393}, issn = {1663-4365}, abstract = {The intramembrane aspartic protease, γ-secretase, is a heterotetrameric protein complex composed of four integral membrane proteins: presenilin (PSEN), nicastrin (NCT), Anterior pharynx defective-1 (APH-1), and presenilin enhancer 2 (PEN-2). These components are sequentially assembled into a functional complex. γ-secretase is ubiquitously expressed in all cells and tissues and exhibits enzymatic activity akin to "molecular scissors" by cleaving various type I transmembrane proteins. The primary substrates of this complex include amyloid precursor protein (APP) and Notch. The role of APP in the pathogenesis of Alzheimer's disease (AD) has been extensively investigated. Although γ-secretase inhibitors (GSIs) have been evaluated for their therapeutic potential in AD, their clinical application is limited due to significant toxic side effects. Recently, γ-secretase modulators (GSMs) have emerged as promising alternatives, offering new opportunities for the treatment of AD, especially the inherent γ-secretase modulatory proteins (GSMPs) within cells. Research on GSMPs has ushered in a new era for mitigating the side effects of AD drugs. In this review, we systematically summarize recent advancements in the study of γ-secretase in relation to AD and provide an overview of GSMs and GSMPs, thereby offering potential insights for the development of therapeutic strategies for AD.}, } @article {pmid40927301, year = {2025}, author = {Heller, LI and Lowe, AS and Del Rosario Hernández, T and Gore, SV and Chatterjee, M and Creton, R}, title = {Target the Heart: A New Axis of Alzheimer's Disease Prevention.}, journal = {Journal of dementia and alzheimer's disease}, volume = {2}, number = {2}, pages = {}, pmid = {40927301}, issn = {3042-4518}, support = {R01 GM136906/GM/NIGMS NIH HHS/United States ; }, abstract = {BACKGROUND/OBJECTIVE: Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer's disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved compounds using Z-LaP Tracker revealed that some heart medications produce a similar behavioral profile, suggesting these drugs may exert calcineurin-inhibitor-like effects relevant to prevent-ing or ameliorating Alzheimer's disease. METHODS: Screening a large library of FDA-approved drugs using Z-LaP Tracker, a neural network model, revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. Fourteen of these drugs were heart medications, including angiotensin receptor blockers, beta blockers, al-pha-adrenergic receptor antagonists, and a statin. RESULTS: Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. Other studies have shown that many of these heart medica-tions drugs directly or indirectly inhibit the calcineurin-NFAT pathway, like cyclo-sporine A, providing a potential mechanism. CONCLUSIONS: Co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for preventing Alzheimer's disease occurrence and simultaneously treating cardiovascular dysfunction, while mitigating the side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer's disease in many patients, physicians may be able to create a treatment regimen that addresses both con-ditions. Our results suggest that a calcineurin inhibitor combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol is the most promising candidate for future exploration.}, } @article {pmid40926822, year = {2025}, author = {Guo, W and Dong, L and Lu, Q and Xie, M and Yang, Y and Zhang, Y and Lu, X and Yu, Q}, title = {Association Between Cannabis Use and Neuropsychiatric Disorders: A Two-sample Mendelian Randomization Study.}, journal = {Alpha psychiatry}, volume = {26}, number = {4}, pages = {46108}, pmid = {40926822}, issn = {2757-8038}, abstract = {BACKGROUND: The progressive legalization and widespread use of cannabis has led to its use as a treatment for certain neuropsychiatric disorders. Traditional epidemiological studies suggest that cannabis use has an effect on some neurocognitive aspects. However, it is unclear whether cannabis use is causally related to common neuropsychiatric disorders. The present study was conducted to illustrate the causal relationships of genetically predicted cannabis use with common neuropsychiatric disorders. METHODS: We used a two-sample Mendelian randomization method using genome-wide association study (GWAS) summary statistics obtained from publicly available databases on lifetime cannabis use and 10 neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), autism spectrum disorder (ASD), epilepsy, generalized epilepsy, focal epilepsy, migraine, migraine with aura, migraine without aura, schizophrenia (SCZ), anorexia nervosa (AN), attention-deficit/hyperactivity disorder (ADHD), and Parkinson's disease (PD) were studied with a two-sample Mendelian randomization method for GWAS summary statistics. The inverse variance weighted (IVW) method was used as the main analysis model. RESULTS: Our study suggests that lifetime cannabis use is associated with an increased risk of developing PD (odds ratio (OR) = 1.782; 95% CI 1.032-3.075; p = 0.038) and an increased risk of ADHD in female participants (OR = 1.650; 95% CI 1.051-2.590; p = 0.029). CONCLUSIONS: Cannabis intake may cause adverse effects relating to certain neuropsychiatric disorders. Therefore, special attention should be paid to the side effects of addictive drugs during clinical treatment to avoid harmful effects on the brain and neurocognition.}, } @article {pmid40926795, year = {2025}, author = {Zhang, Y and Silang, Q and Wang, Y and Wang, N and Gesang, L and Tang, L and Liu, L}, title = {Integrated Gut Microbiota, Metabolomics, and Network Pharmacology to Investigate the Anti-Alzheimer's Mechanism of Tripterygium Glycoside.}, journal = {Neuropsychiatric disease and treatment}, volume = {21}, number = {}, pages = {1911-1933}, pmid = {40926795}, issn = {1176-6328}, abstract = {BACKGROUND: Tripterygium glycoside (TG) has been reported to have the effect of ameliorating Alzheimer's disease (AD)-like symptoms in mice model. However, the underlying mechanism is largely unknown. This study aimed to investigate the potential mechanism of TG against AD by integrating metabolomics, 16s rRNA sequencing, network pharmacology, molecular docking, and molecular dynamics simulation. METHODS: Memory and cognitive functions were assessed in mice via the Morris water maze. The pathological changes were assessed using hematoxylin and Nissl's straining. Pathological changes in p-Tau and Aβ1-42 were assessed using immunohistochemistry, immunofluorescence, ELISA, and Western blotting. 16S rRNA sequencing and metabolomics were performed to analyze alterations in the structure of gut microbiota and hippocampus metabolites. Network pharmacology, molecular docking, and molecular dynamics simulation were performed to determine the putative molecular regulatory mechanism of TG in treating AD. RESULTS: TG significantly could inhibit neuron loss, improved cognitive and memory functions, and significantly reduce the expression of p-Tau and Aβ1-42. In addition, 16s rRNA analysis revealed that TG could reverse AD-induced gut microbiota dysbiosis in AD model mice by reducing the abundance of Alistipes. Furthermore, metabolomic analysis revealed that TG may reverse AD-induced metabolic disorders by regulating glycerophospholipid metabolism. And spearman analysis revealed that glycerophospholipids metabolism might closely related to Alistipes. Moreover, network pharmacology, molecular docking, and molecular dynamics simulation analyses indicated that TG might regulate lipid metabolism-related pathways via SRC for the treatment of AD. CONCLUSION: TG may serve as a potential therapeutic drug for preventing AD via the microbiota-gut-brain axis.}, } @article {pmid40926603, year = {2025}, author = {Porwal, S and Malviya, R and Sridhar, SB and Wadhwa, T and Shareef, J and Meenakshi, DU}, title = {Trends and Advancements in Smart Electrospun Food Fibers for the Management of Neurological Disorders.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273375873250829060106}, pmid = {40926603}, issn = {1996-3181}, abstract = {Neurological disorders are complex conditions characterized by impairment of the nervous system, affecting motor, cognitive, and sensory functions. Current treatments meet substantial obstacles, primarily due to the difficulty of transporting drugs across the blood-brain barrier and ineffective therapy for nerve regeneration. Emerging technologies, such as electrospinning, offer innovative solutions to overcome these challenges. The study explores the potential of electrospun food fibers in managing and treating neurological disorders, concentrating on their role in drug delivery and nerve tissue regeneration. Electrospinning allows for the generation of nanofibers from diverse natural and synthetic polymers that imitate the extracellular matrix and stimulate brain healing. These fibers may be loaded with therapeutic drugs, permitting controlled, localized drug release while limiting systemic toxicity. For instance, electrospun fibers loaded with neuroprotective drugs, such as donepezil and levodopa, have exhibited better drug stability, enhanced bioavailability, and prolonged therapeutic efficacy in treating syndromes such as Alzheimer's and Parkinson's diseases. Furthermore, the biodegradable and biocompatible nature of food-based polymers like chitosan, cellulose, and zein makes them great candidates for medicinal applications, minimizing the risk of inflammation and unfavorable immunological reactions. In conclusion, electrospun food fibers show tremendous promise in resolving the issues of drug delivery and nerve regeneration in neurological illnesses. Their capacity to boost therapeutic results via targeted and regulated drug release makes them a possible alternative to established treatment procedures, bringing renewed hope to patients suffering from neurodegenerative disorders.}, } @article {pmid40926398, year = {2025}, author = {Nie, RZ and Zhang, QL and Tan, XR and Hu, SS and Zhou, XT and Jiang, WK and Guo, BW and Cao, X and Yuan, DH and Long, Y and Hong, H and Tang, SS}, title = {Cholinergic G protein-coupled bile acid receptor 1 (TGR5/GPBA) in the medial septal orchestrates adult hippocampal neurogenesis and cognition in Alzheimer's disease mice.}, journal = {British journal of pharmacology}, volume = {182}, number = {21}, pages = {5409-5429}, doi = {10.1111/bph.70185}, pmid = {40926398}, issn = {1476-5381}, support = {82071202//National Natural Science Foundation of China/ ; 82173805//National Natural Science Foundation of China/ ; 82373860//National Natural Science Foundation of China/ ; 2024YFA1308200//National Key Research and Development Program of China/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Receptors, G-Protein-Coupled/metabolism/genetics ; *Neurogenesis ; *Hippocampus/metabolism ; Mice ; *Cognition/physiology ; Male ; Mice, Transgenic ; Disease Models, Animal ; Mice, Inbred C57BL ; Cholinergic Neurons/metabolism ; }, abstract = {BACKGROUND AND PURPOSE: The pathological role of the bile acid receptor TGR5/GPBA in Alzheimer's disease (AD) is not fully understood. We investigated the pharmacological effects and mechanisms of TGR5 in AD model mice. EXPERIMENTAL APPROACH: TGR5 expression was assessed in AD mice using immunofluorescence and immunoblotting. Bidirectional modulation of TGR5 expression was achieved via stereotaxic delivery of adeno-associated virus vectors, while localized pharmacological activation was conducted through intracerebral cannula implantation. Cognition was evaluated using the Morris water maze and novel object recognition test. Adult hippocampal neurogenesis was assessed via immunofluorescence. Neuronal activity was analysed using immunofluorescence, fibre photometry and chemogenetics-coupled fibre photometry. Acetylcholine dynamics were monitored using fibre photometry, both alone and in combination with chemogenetic manipulation. KEY RESULTS: TGR5 expression was selectively decreased in the medial septal (MS) cholinergic neurons during middle-late AD stages. Bidirectional genetic regulation of TGR5 in MS cholinergic neurons significantly affected cognition and adult hippocampal neurogenesis in mice. Pharmacological activation of TGR5 in the MS not only increased cholinergic neuronal activity and acetylcholine release, but also enhanced DG glutamatergic neuronal activity, acetylcholine levels and neurogenesis in AD mice. TGR5 modulated cognition and neurogenesis via the MS[cholinergic(ChAT)]→ DG[glutamatergic(Glu)] circuit. Furthermore, α7 nAChRs in the DG were involved in TGR5-mediated improvements in cognition and neurogenesis. CONCLUSION AND IMPLICATIONS: Our findings demonstrate that TGR5 in MS cholinergic neurons is critical during the middle-late stage of AD and provide valuable insights into the underlying neuronal circuit mechanisms. TGR5 (GPBA) represents a potential therapeutic target for AD treatment.}, } @article {pmid40925485, year = {2026}, author = {Prokop-Millar, S and Di Passa, AM and Yaya, H and McIntyre-Wood, C and Farzan, F and Terpstra, AR and Fein, A and Vandehei, E and MacKillop, E and MacKillop, J and Duarte, D}, title = {Predictive and mechanistic biomarkers of treatment response to Transcranial Magnetic Stimulation (TMS) in Psychiatric and Neurocognitive Disorders, identified via TMS-Electroencephalography (EEG) and Resting-State EEG: A systematic review.}, journal = {Journal of affective disorders}, volume = {393}, number = {Pt A}, pages = {120194}, doi = {10.1016/j.jad.2025.120194}, pmid = {40925485}, issn = {1573-2517}, mesh = {Humans ; *Transcranial Magnetic Stimulation/methods ; *Electroencephalography/methods ; Biomarkers ; *Mental Disorders/therapy/physiopathology ; Bipolar Disorder/therapy/physiopathology ; Schizophrenia/therapy/physiopathology ; *Neurocognitive Disorders/therapy/physiopathology ; Treatment Outcome ; Alzheimer Disease/therapy/physiopathology ; }, abstract = {Electroencephalography (EEG) is a comparatively inexpensive and non-invasive recording technique of neural activity, making it a valuable tool for biomarker discovery in transcranial magnetic stimulation (TMS). This systematic review aimed to examine mechanistic and predictive biomarkers, identified through TMS-EEG or resting-state EEG, of treatment response to TMS in psychiatric and neurocognitive disorders. Nineteen articles were obtained via Embase, APA PsycInfo, MEDLINE, and manual search; conditions included, unipolar depression (k = 13), Alzheimer's disease (k = 3), bipolar depression (k = 2), and schizophrenia (k = 2). Two mechanistic biomarkers were identified: one TMS-EEG marker, reductions in N100 post-dorsolateral prefrontal cortex (DLPFC) repetitive TMS or intermittent theta burst stimulation (iTBS) in unipolar depression (n = 120; k = 2), and one resting-state marker, reductions in theta connectivity post-DLPFC repetitive TMS in unipolar and bipolar depression (n = 89; k = 2). Whereas one predictive TMS-EEG biomarker was isolated: greater baseline N100 was predictive of unipolar depression improvement in DLPFC repetitive TMS and iTBS (n = 113; k = 2). Promising markers were briefly discussed for future research in Alzheimer's disease and schizophrenia. In conclusion, across the psychiatric and neurocognitive disorders considered in this study, TMS-EEG and resting-state mechanistic and predictive biomarkers of depression appear to hold the most promise. Further research is needed to validate the biomarkers identified in depression, to help guide treatment plans and advance precision medicine in psychiatry.}, } @article {pmid40925435, year = {2025}, author = {Liu, Y and Wang, Y and Liang, Y and Yang, S and Deng, Y and Zeng, S and Wang, Y and Shu, Z and Shuai, Y and Guo, H}, title = {Transcriptomics and metabolomics revealed the effects of Polygonatum Rhizoma polysaccharide on delaying C. elegans senescence and ameliorating Alzheimer's disease.}, journal = {International journal of biological macromolecules}, volume = {327}, number = {Pt 2}, pages = {147375}, doi = {10.1016/j.ijbiomac.2025.147375}, pmid = {40925435}, issn = {1879-0003}, mesh = {Animals ; *Caenorhabditis elegans/drug effects/genetics/metabolism ; *Polysaccharides/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Polygonatum/chemistry ; *Metabolomics/methods ; *Aging/drug effects/genetics ; *Rhizome/chemistry ; Oxidative Stress/drug effects ; *Transcriptome/drug effects ; Gene Expression Profiling ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; }, abstract = {We explored the role of Polygonatum Rhizoma polysaccharide (PRP) in delaying aging and improving Alzheimer's disease (AD) and revealed its potential molecular mechanism. Through chemical characterizations to clarify the physicochemical properties of PRP, it was found that PRP mainly consists of mannose, glucose, galactose, and arabinose, with molecular weights ranging from 7.4 × 10[4] to 9.1 × 10[4] Da; using Caenorhabditis elegans (C. elegans) models, its anti-AD activity was verified by combining approaches using pharmacodynamics, molecular biology, metabolomics, and transcriptomics sequencing. The results of this study showed that PRP significantly extended the lifespan of C. elegans, reduced the accumulations of lipofuscin and increased the ability of C. elegans to resist oxidative stress, and reduced the aggregation of Aβ protein in the AD model C. elegans, and improved neuromuscular dysfunction. Transcriptomic analysis revealed that PRP modulated the expression of genes involved in key processes, including anti-stress and senescence (daf-12, skn-1, gst-4, ctl-1, sod-3, age-1, gcs-1), autophagy (unc-51, bec-1, lgg-1), and mitochondrial function (clk-1, mev-1, isp-1). Metabolomic analysis revealed that PRP improved metabolic disorders in C. elegans by regulating phenylalanine/purine metabolism pathway. These results indicated that PRP exerted its effects through multiple pathways to delay C. elegans aging and improve AD symptoms, providing a strong theoretical basis for the development of AD treatment drugs based on traditional Chinese medicine.}, } @article {pmid40924554, year = {2025}, author = {Zhao, ZQ and Liang, L and Hu, LF and He, YT and Jing, LY and Liu, Y and Chen, BZ and Guo, XD}, title = {Correction to "Subcutaneous Implantable Microneedle System for the Treatment of Alzheimer's Disease by Delivering Donepezil".}, journal = {Biomacromolecules}, volume = {26}, number = {10}, pages = {7222-7223}, doi = {10.1021/acs.biomac.5c01588}, pmid = {40924554}, issn = {1526-4602}, } @article {pmid40923675, year = {2025}, author = {Evans, RC and Dar, NJ and Chen, L and Na, R and O'Connor, JC and Jiang, J and Zheng, S and Ran, Q}, title = {Inhibition of Hippo Signaling Through Ablation of Lats1 and Lats2 Protects Against Cognitive Decline in 5xFAD Mice via Increasing Neuronal Resilience Against Ferroptosis.}, journal = {Aging cell}, volume = {24}, number = {11}, pages = {e70218}, pmid = {40923675}, issn = {1474-9726}, support = {R01 AG086496/AG/NIA NIH HHS/United States ; S10 OD030311/OD/NIH HHS/United States ; I01 BX003507/BX/BLRD VA/United States ; R01 AG064078/AG/NIA NIH HHS/United States ; P30 CA054174/CA/NCI NIH HHS/United States ; R01AG064078/AG/NIA NIH HHS/United States ; R01AG086496/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Protein Serine-Threonine Kinases/metabolism/genetics ; Mice ; *Neurons/metabolism/pathology ; *Cognitive Dysfunction/metabolism/genetics/pathology ; Hippo Signaling Pathway ; *Tumor Suppressor Proteins/metabolism/genetics ; *Ferroptosis/genetics ; Signal Transduction ; Disease Models, Animal ; Mice, Transgenic ; Humans ; *Alzheimer Disease/genetics/metabolism ; }, abstract = {The Hippo signaling pathway is a key regulator of cell growth and cell survival, and hyperactivation of the Hippo pathway has been implicated in neurodegenerative diseases such as Huntington's disease. However, the role of Hippo signaling in Alzheimer's disease (AD) remains unclear. We observed that hyperactivation of Hippo signaling occurred in the AD model 5xFAD mice. To determine how inhibition of Hippo signaling might affect disease pathogenesis, we generated 5xFAD mice with conditional neuronal ablation of Lats1 and Lats2, the gatekeepers of Hippo signaling activity. Our results indicated that 5xFAD mice with ablation of Lats1 and Lats2 were protected against cognitive decline compared with control 5xFAD mice, and this protection was correlated with a marked reduction in neurodegeneration. Interestingly, primary culture neurons with ablation of Lats1 and Lats2 had significantly increased survival following treatment with chemical inducers of ferroptosis and exhibited reduced lipid peroxidation, the driving force of ferroptotic cell death. Moreover, 5xFAD mice with ablation of Lats1 and Lats2 showed reduced lipid peroxidation, and transcriptomic analysis revealed that 5xFAD mice with ablation of Lats1 and Lats2 had enriched metabolic pathways associated with ferroptosis. These results indicate that inhibition of Hippo signaling activity confers neural protection in 5xFAD mice by augmenting resilience against ferroptosis.}, } @article {pmid40923656, year = {2025}, author = {Li, Q and He, B and Xiong, Y}, title = {Calycosin attenuates neuronal ferroptosis in Alzheimer's disease mice by activating the Nrf2/HO-1 pathway.}, journal = {General physiology and biophysics}, volume = {44}, number = {5}, pages = {363-375}, doi = {10.4149/gpb_2025021}, pmid = {40923656}, issn = {0231-5882}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Ferroptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; Mice ; *Neurons/drug effects/metabolism/pathology ; *Isoflavones/pharmacology/administration & dosage ; *Heme Oxygenase-1/metabolism ; Signal Transduction/drug effects ; Male ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Membrane Proteins ; }, abstract = {In this study, we investigated the therapeutic potential of calycosin (from Astragalus) in Alzheimer's disease (AD), focusing on ferroptosis modulation. APP/PS1 mice received 40 mg/kg calycosin for 3 months. Cognitive function was assessed via Morris water maze test. Tau hyperphosphorylation and amyloid-β (Aβ) aggregation were analyzed using immunofluorescence and Western blotting. In vitro, Aβ1-42-treated HT22 neuronal cells were exposed to calycosin. Ferroptosis-related phenotypes were assessed in vivo and in vitro using Prussian blue staining, commercial kits, and Western blotting. The nuclear factor-erythroid factor 2-related factor 2 (Nrf2) signaling was examined by Western blotting. Calycosin treatment significantly improved cognitive deficits in APP/PS1 mice and inhibited Tau hyperphosphorylation and Aβ aggregation. Calycosin attenuated neurotoxicity and Tau hyperphosphorylation in Aβ1-42-treated HT22 cells. Moreover, calycosin inhibited ferroptosis in vivo and in vitro by decreasing iron aggregation and lipid peroxidation, downregulating transferrin receptor expression, and upregulating ferroportin, cystine/glutamate antiporter, and glutathione peroxidase 4 expression. Mechanistically, the anti-ferroptosis effects of calycosin were linked to the activation of the Nrf2-mediated pathway. These findings suggest that calycosin may exhibit neuroprotective effects against neuronal ferroptosis in AD, indicating its potential as a therapeutic candidate for further investigation in AD.}, } @article {pmid40922888, year = {2025}, author = {Kademani, A and Avraam, C and Montenegro, D and Paloh, A and Somannagari, N and Gupta, A and Lafi, AW and Algaba, AE and Islam, R and Fahima, C and Siddiqui, HF}, title = {Exploring the Emerging Role of Stem Cell Therapy in Neurodegenerative Diseases and Spinal Cord Injury: A Narrative Review.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e89629}, pmid = {40922888}, issn = {2168-8184}, abstract = {Neurodegenerative diseases and spinal cord injuries (SCI) pose a significant burden on the healthcare system globally. Diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease precipitate cognitive, motor, and behavioral deficits. Parallelly, spinal cord injuries produce sensory and motor deficits, which are burdensome psychologically, socially, and economically. Current management strategies focus only on symptomatic relief, with no definitive cure. Stem cells have been explored for regenerative therapy. This review focuses on developments, limitations, and future potential of stem cell therapy. Stem cells affect the central nervous system via neuroprotective mechanisms, immunomodulatory effects, and mitigation of oxidative stress. The clinical implications of stem cell therapy in treating neurodegenerative diseases and SCI are debatable due to varied outcomes. Challenges related to sample size, long-term follow-up, and assessment of adverse effects should be mitigated in future research. Researchers are currently exploring optimal stem cell types along with various transplantation strategies. Biomaterials integrated with stem cells are a novel approach for treating neurodegenerative diseases and spinal cord injuries. Certain genetic modifications have shown improved results. Screening patients to ascertain better responses to therapy has proven to be a challenge. Other complications include graft vs. host reaction and degeneration of transplanted neurons due to pathogenesis and tumorigenesis. However, the majority of the potential stem cell therapeutic avenues are in the preclinical stage and are being tested on animal models. Guidelines pertaining to ethical concerns and regulatory frameworks need to be established to unfold the full potential of stem cell therapy in the clinical setting. Recent advances also show an increased need to formulate patient-specific approaches to treatment, ranging from stem cell selection to the technique of transplantation. Ongoing clinical trials can address the current challenges and leverage emerging technologies, leading to definitive treatments for neurodegenerative diseases and spinal cord injuries.}, } @article {pmid40922863, year = {2025}, author = {Murali, A and Muddappa, SC and Rajan, RR and Joseph, A and Ravi, AB}, title = {Barriers to Geriatric Oral Health: A Multifaceted Public Health Issue.}, journal = {Cureus}, volume = {17}, number = {8}, pages = {e89604}, pmid = {40922863}, issn = {2168-8184}, abstract = {Oral health is important for the overall health of an individual, particularly older adults. However, a number of obstacles frequently prevent older people from receiving timely and appropriate dental care. These obstacles are intricate and multifaceted, involving systemic diseases, cognitive elements, and psychological, financial, and educational issues. Dementia and Alzheimer's disease are examples of cognitive impairments that can make it difficult for an elderly person to seek or cooperate with dental treatment. Additional psychological factors that decrease care-seeking behaviour include anxiety, fear of dental treatments, depression, and a general lack of motivation. Financial constraints are major deterrents, such as low income and no dental insurance. Furthermore, polypharmacy and multimorbidity not only make treatment planning more difficult, but they also deprive oral health of priority. The problem is made worse by systemic healthcare barriers like inadequate referral systems, a lack of geriatric-focused dentists, and poor integration between dental and medical services. Neglect is also exacerbated by older adults' and their caregivers' perceived lack of need for dental care. A comprehensive, multidisciplinary strategy is needed to address these issues, one that incorporates training dental professionals in geriatric care, better public health regulations, caregiver education, and the creation of easily accessible, reasonably priced services. Improving the general and oral health of the elderly requires an understanding of and commitment to removing these obstacles.}, } @article {pmid40922111, year = {2025}, author = {Vitali, F and Torrandell-Haro, G and Arias, JC and French, SR and Zahra, S and Brinton, RD and Weinkauf, C}, title = {Carotid endarterectomy mitigates Alzheimer's disease and non-Alzheimer's disease dementia risk linked to asymptomatic carotid stenosis.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70674}, pmid = {40922111}, issn = {1552-5279}, support = {R01AG070987/AG/NIA NIH HHS/United States ; R01AG057931/AG/NIA NIH HHS/United States ; P01AG026572/AG/NIA NIH HHS/United States ; //Arizona Alzheimer's Consortium/ ; CTR056056//Arizona Biomedical Research Commission/ ; //Richard and Jan Highberger Award/ ; //Health Sciences, University of Arizona/ ; /DDCF/Doris Duke Charitable Foundation/United States ; }, mesh = {Humans ; *Endarterectomy, Carotid/statistics & numerical data ; *Alzheimer Disease/epidemiology/prevention & control ; *Carotid Stenosis/surgery/complications/epidemiology ; Male ; Female ; Aged ; Retrospective Studies ; Propensity Score ; United States/epidemiology ; Stents ; *Dementia/epidemiology/prevention & control ; Risk Factors ; Incidence ; Middle Aged ; }, abstract = {INTRODUCTION: Asymptomatic extracranial carotid artery disease (aECAD) is associated with increased Alzheimer's disease (AD) and non-AD dementia risk. aECAD treatment includes carotid endarterectomy (CEA) and carotid artery stenting (CAS) for stroke prevention, but their impact on dementia incidence is poorly studied. METHODS: Propensity score matching was used in a retrospective cohort study of United States-based insurance claims (2010-2022) in 487,676 patients with aECAD to evaluate the effect of CEA and CAS on AD and non-AD dementia incidence. RESULTS: After matching, 37,317 patients underwent CEA or CAS. CEA was associated with a significantly lower AD risk (relative risk = 0.93; 95% confidence interval, 0.86-0.99; P < 0.05), whereas CAS was associated with a slight but non-significant increase. Similar trends were observed for non-AD dementia. DISCUSSION: CEA, but not CAS, may confer a protective effect against AD and non-AD dementia in patients with aECAD, a common cerebrovascular disease affecting up to 15% of adults over age 60. HIGHLIGHTS: Asymptomatic extracranial carotid artery disease (aECAD) is associated with increased Alzheimer's disease (AD) and non-AD dementia risk. Limited studies have evaluated the role of carotid endarterectomy (CEA) and (carotid artery stenting (CAS) on dementia outcomes. Using United States-based insurance claims data, 487,676 patients with aECAD were evaluated. After propensity score matching, CEA was significantly associated with reduced AD risk. CAS was not significantly associated with a change in AD risk.}, } @article {pmid40922100, year = {2025}, author = {Floud, S and Hermon, C and Whiteley, W and Fitzpatrick, KE and Reeves, GK}, title = {Hypertension in pregnancy and in midlife and the risk of dementia: prospective study of 1.3 million UK women.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70595}, pmid = {40922100}, issn = {1552-5279}, support = {A29186/CRUK_/Cancer Research UK/United Kingdom ; CAF/17/01//Chief Scientist's Office/ ; //Health Data Research UK/ ; //BHD Data Science Centre/ ; /ALZS_/Alzheimer's Society/United Kingdom ; CAF/17/01//Chief Scientist Office, Scottish Government Health and Social Care Directorate/ ; }, mesh = {United Kingdom/epidemiology ; *Hypertension/complications/epidemiology/psychology ; *Dementia/epidemiology/etiology ; *Hypertension, Pregnancy-Induced/epidemiology/psychology ; Risk Factors ; Humans ; Female ; Pregnancy ; Middle Aged ; Proportional Hazards Models ; Alzheimer Disease/epidemiology/etiology ; Dementia, Vascular/epidemiology/etiology ; Age Factors ; Prospective Studies ; Causality ; }, abstract = {INTRODUCTION: Midlife hypertension is associated with dementia risk, although uncertainties remain regarding its association with subtypes and regarding the effect of pregnancy-related hypertension on dementia risk. METHODS: In the Million Women Study, 1,363,457 women (mean age 57) were asked about current treatment for hypertension and hypertension in pregnancy and were followed for first hospital record with any mention of dementia. Cox regression yielded hazard ratios (HRs) adjusted for socioeconomic, lifestyle, and metabolic factors. RESULTS: With 84,729 dementia cases over 21 years, midlife hypertension was positively associated with dementia (HR 1.17, 95% confidence interval [CI] 1.15 to 1.19); higher for vascular dementia (VaD) (HR 1.50; 95% CI 1.45 to 1.56) than Alzheimer's disease (AD) (HR 1.01; 95% CI 0.98 to 1.04). Hypertension in pregnancy but not in midlife was only weakly associated with dementia (HR 1.04; 95% CI 1.01 to 1.06). DISCUSSION: Midlife hypertension is a strong risk factor for dementia, largely through VaD. Hypertension during pregnancy does not appear to materially affect dementia risk. HIGHLIGHTS: Midlife hypertension was associated with long-term all-cause dementia risk. Midlife hypertension was associated with VaD, not AD. Hypertension in pregnancy has little effect on dementia risk.}, } @article {pmid40922096, year = {2025}, author = {Ottoy, J and Owsicki, N and Bilgel, M and Binette, AP and Salvadó, G and Kang, MS and Cash, DM and Ewers, M and La Joie, R and Wisse, LEM and Goubran, M and Betthauser, T}, title = {Recent advances in neuroimaging of Alzheimer's disease and related dementias.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70648}, pmid = {40922096}, issn = {1552-5279}, support = {CIHR-PJT-190220//Canadian Institutes for Health Research/ ; CIHR-187890//Canadian Institutes for Health Research/ ; ALZ23-05//Alzheimer Society of Canada/ ; ALZ26-021//Alzheimer Society of Canada/ ; 24AARF-1242638/ALZ/Alzheimer's Association/United States ; 22AARF-972612/ALZ/Alzheimer's Association/United States ; SG-666374-UK/ALZ/Alzheimer's Association/United States ; AARG-22-926899/ALZ/Alzheimer's Association/United States ; AS-DRL-23-005//Alzheimer's Society Dementia Research Leaders Fellowship/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; 101061836//European Union's Horizon 2020 Research and Innovation Program/ ; //Strategic Research Area MultiPark/ ; A2024012F//BrightFocus Foundation/ ; A2024007F//BrightFocus Foundation/ ; R01AG080766//National Institutes of Health National Institute on Aging/ ; P30AG062715//National Institutes of Health National Institute on Aging/ ; R01AG027161//National Institutes of Health National Institute on Aging/ ; P30AG062422//National Institutes of Health National Institute on Aging/ ; 24AARF-1242638//Brain Canada/ ; AF-980942//Alzheimerfonden/ ; AF-994514//Alzheimerfonden/ ; AF-1012218//Alzheimerfonden/ ; BMBF//ERAPerMed/ ; 01KU2203//ERAPerMed/ ; //Alzheimer's Society Research Program/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology ; *Neuroimaging/methods/trends ; Biomarkers ; *Brain/diagnostic imaging/pathology ; *Dementia/diagnostic imaging ; Positron-Emission Tomography ; Disease Progression ; tau Proteins/metabolism ; }, abstract = {This review covers recent advances (2023-2024) in neuroimaging research into the pathophysiology, progression, and treatment of Alzheimer's disease (AD) and related dementias (ADRD). Despite the rapid emergence of blood-based biomarkers, neuroimaging continues to be a vital area of research in ADRD. Here, we discuss neuroimaging as a powerful tool to topographically visualize and quantify amyloid, tau, neurodegeneration, inflammation, and vascular disease in the brain. We examine the utility of neuroimaging for (1) tracking the spatiotemporal progression of pathology, (2) serving as the reference standard for validating novel fluid biomarkers, (3) characterizing disease heterogeneity, (4) exploring the role of brain networks in ADRD progression, and (5) evaluating biomarkers for better individualized estimates of treatment benefit. Finally, we discuss advances in radiotracer development and AD risk factors. By reviewing the most promising breakthroughs in the neuroimaging field, we hope to spark new ideas for future discoveries that will deepen our understanding of ADRD. HIGHLIGHTS: The diagnostic and staging criteria for Alzheimer's disease (AD) were updated in 2024. Despite robust harmonization methods for amyloid beta positron emission tomography (PET), parallel efforts for tau PET remain challenging. Larger anti-amyloid drug effects were seen at lower levels of amyloid and tau PET. Phosphorylated tau217 (p-tau217) is currently the most promising plasma biomarker to detect AD pathology. There are new tracer developments for alpha-synuclein, primary tauopathies, and inflammation.}, } @article {pmid40921933, year = {2025}, author = {Sehlin, D and Aguilar, X and Cortés-Canteli, M and Syvänen, S and Lopes van den Broek, S}, title = {Brain-penetrating peptide and antibody radioligands for proof-of-concept PET imaging of fibrin in Alzheimer's disease.}, journal = {EJNMMI radiopharmacy and chemistry}, volume = {10}, number = {1}, pages = {59}, pmid = {40921933}, issn = {2365-421X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a multifactorial disorder with vascular contributions, including a pro-coagulant state marked by fibrin deposition in the brain. Fibrin accumulation may exacerbate cerebral hypoperfusion and neuroinflammation, leading to neurodegeneration. Identifying patients with this pathology could enable targeted anticoagulant therapy. However, current imaging tools lack the specificity and sensitivity to detect fibrin in the brain non-invasively. This study aimed to develop and evaluate brain-penetrating peptide- and antibody-based PET radioligands targeting fibrin to enable individualized treatment strategies in AD. RESULTS: A fibrin-binding peptide (FBP) was conjugated to the antibody fragment scFv8D3, which targets the transferrin receptor (TfR), to facilitate transcytosis across the blood-brain barrier. FBP-scFv8D3 bound TfR and with modest affinity to fibrin. In vivo studies in Tg-ArcSwe mice, that exhibit fibrin along with brain amyloid-β pathology, and wild-type mice showed that [[125]I]FBP-scFv8D3 retained brain-penetrating properties but did not demonstrate significant fibrin-specific retention. In contrast, the monoclonal antibody 1101 and its bispecific, brain penetrant variant 1101-scFv8D3 exhibited higher fibrin selectivity and TfR binding. Both antibodies showed a trend towards higher brain retention in Tg-ArcSwe mice and [[125]I]1101-scFv8D3 showed a higher brain-to-blood ratio compared to [[124]I]1101. PET imaging with [[124]I]1101 and [[124]I]1101-scFv8D3 revealed low global brain uptake. However, ex vivo autoradiography and regional PET quantification (ROI-to-cerebellum ratios) indicated significant cortical and caudate retention of [[124]I]1101-scFv8D3 in Tg-ArcSwe mice, supporting region-specific target engagement. CONCLUSION: This proof-of-concept study demonstrates the feasibility of using bispecific antibody-based PET radioligands to target fibrin in the AD brain. While the FBP-scFv8D3 conjugate showed limited specificity, the bispecific antibody 1101-scFv8D3 exhibited higher brain penetration and fibrin selectivity. These findings support further development of antibody-based imaging tools toward the goal to stratify AD patients who may benefit from anticoagulant therapy.}, } @article {pmid40921720, year = {2025}, author = {Moreira, IP and Vieira-Coelho, MA and Guimarães, J}, title = {Dopamine System Dysfunction in Alzheimer's Disease.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {25}, number = {5}, pages = {e70097}, pmid = {40921720}, issn = {1479-8301}, mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology ; *Dopamine/metabolism ; Animals ; Disease Models, Animal ; Cognitive Dysfunction ; *Receptors, Dopamine/metabolism ; }, abstract = {The dopaminergic system may be at the base of some neurobehavioral symptoms, as apathy and depression, and extrapyramidal symptoms, often seen in Alzheimer's disease patients. It can also have an impact on cognitive decline, as extrapyramidal symptoms, classically linked with dopamine dysfunction, are associated with increased risk of cognitive impairment and Alzheimer's disease progression. We review the knowledge of the dopaminergic system, emphasizing changes in Alzheimer's disease. Both animal models, post-mortem and in vivo human studies, point to a dopaminergic system dysfunction in this disease. Dopamine dysfunction seems more associated with neuronal loss, modification of dopamine receptors and anomalies in terminal function, including irregularities in dopamine metabolism, than with neurofibrillary tangles or β-amyloid plaques depositions. This dysfunction has an impact on both cognitive and non-cognitive symptoms. A better understanding of the dopaminergic system may help in understanding the pathophysiology of Alzheimer's disease and assist in the diagnosis. Clinical trials aimed at modulating the dopaminergic system may be promising in the treatment of symptoms associated with Alzheimer's disease.}, } @article {pmid40920304, year = {2025}, author = {Bhujbal, SP and Hah, JM}, title = {Advances in JNK inhibitor development: therapeutic prospects in neurodegenerative diseases and fibrosis.}, journal = {Archives of pharmacal research}, volume = {48}, number = {9-10}, pages = {858-886}, pmid = {40920304}, issn = {1976-3786}, support = {NRF-RS-2020-NR049583//National Research Foundation of Korea/ ; NRF- RS-2024-00397929//National Research Foundation of Korea/ ; NRF-RS-2024-00333784//National Research Foundation of Korea/ ; }, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/enzymology/metabolism/pathology ; Animals ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use ; *Fibrosis/drug therapy ; *JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism ; *Drug Development ; }, abstract = {c-Jun N-terminal kinases (JNKs), a subfamily of mitogen-activated protein kinases (MAPKs), are key mediators of cellular responses to environmental stress, inflammation, and apoptotic signals. The three isoforms-JNK1, JNK2, and JNK3 exhibit both overlapping and isoform-specific functions. While JNK1 and JNK2 are broadly expressed across tissues and regulate immune signaling, cell proliferation, and apoptosis, JNK3 expression is largely restricted to the brain, heart, and testis, where it plays a crucial role in neuronal function and survival. Subtle structural variations among the isoforms, particularly within the ATP-binding pocket and activation loop, provide a basis for the developing isoform-selective inhibitors to improve therapeutic precision. JNK3 has been increasingly recognized for its involvement in the pathogenesis of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, through mechanisms involving neuroinflammation, oxidative stress, and neuronal apoptosis. Given the limited efficacy of current therapies, which remain largely symptomatic and do not modify disease progression, covalent inhibitors of JNK3 represent a compelling alternative due to their potential for high selectivity and sustained target engagement. In parallel, JNK signaling contributes to fibrosis, with JNK1 serving as the predominant isoform driving profibrotic pathways such as fibroblast activation and extracellular matrix (ECM) deposition. Current antifibrotic agents provide only partial benefit and lack specificity for downstream effectors like JNK1. PROteolysis TArgeting Chimeras (PROTACs), which induce selective protein degradation via the ubiquitin-proteasome system, represent a promising modality to overcome these limitations. Selective degradation of JNK1 could provide a novel therapeutic avenue for fibrotic diseases. This review highlights therapeutic efforts to date and discusses how emerging approaches-particularly covalent JNK3 inhibitors for neurodegeneration and PROTACs for JNK1 in fibrosis-may advance future treatment paradigms.}, } @article {pmid40920073, year = {2025}, author = {Peng, L and Xie, X and Chen, X and Chen, C}, title = {Electrochemical Biosensors Combined with Nanomaterial Signal Amplification for the Detection of Alzheimer's Disease Biomarkers in Blood.}, journal = {ACS sensors}, volume = {10}, number = {9}, pages = {6380-6405}, doi = {10.1021/acssensors.5c02453}, pmid = {40920073}, issn = {2379-3694}, mesh = {*Alzheimer Disease/blood/diagnosis ; *Biosensing Techniques/methods ; Humans ; Biomarkers/blood ; *Electrochemical Techniques/methods ; *Nanostructures/chemistry ; Amyloid beta-Peptides/blood ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by cognitive decline and behavioral impairments, typically manifesting in the elderly and presenile population. With the rapid global aging trend, early diagnosis and treatment of AD have become increasingly urgent research priorities. The primary pathological features of AD include excessive accumulation of β-amyloid (Aβ) plaques, the formation of neurofibrillary tangles, and neuronal loss. Conventional diagnostic techniques, such as positron emission tomography-computed tomography (PET-CT) and cerebrospinal fluid (CSF) analysis, are limited by their high cost and invasiveness. As a result, there is growing interest in developing blood-based biomarker assays for AD detection. Electrochemical biosensors offer notable advantages in this context, including high sensitivity, low cost, and minimally invasive sampling. However, due to the extremely low concentrations of AD-related biomarkers in blood, signal amplification is necessary. The incorporation of nanomaterials significantly enhances the sensitivity and performance of the electrochemical biosensors. This Perspective highlights the application of various nanomaterial-enhanced electrochemical biosensors in the early diagnosis and disease monitoring of AD, underscoring their potential in advancing AD prevention, diagnosis, and therapeutic strategies.}, } @article {pmid40919318, year = {2025}, author = {Harrison, D and Billinton, A and Bock, MG and Clarke, NP and Digby, Z and Gabel, CA and Lindsay, N and Reader, V and Scanlon, J and Smolak, P and Thornton, P and Wescott, H and Watt, AP}, title = {Profile of NT-0527, a brain penetrant NLRP3 Inflammasome inhibitor suitable as an in vivo tool compound for neuroinflammatory disorders.}, journal = {RSC medicinal chemistry}, volume = {}, number = {}, pages = {}, pmid = {40919318}, issn = {2632-8682}, abstract = {Inhibition of the NLRP3 inflammasome has emerged as a high potential treatment paradigm for the treatment of neuroinflammation, with demonstrated anti-neuroinflammatory effects in Parkinson's disease patients and a strong rationale in Alzheimer's disease and amyotrophic lateral sclerosis. To facilitate further progress in this field, brain penetrant NLRP3 inflammasome inhibitors as leads and tool compounds are required. We discovered a small molecule NLRP3 inflammasome inhibitor, NT-0527 (11), and extensively profiled this to reveal a highly potent, selective and brain penetrant compound. This was shown to be orally bioavailable, efficacious in an in vivo model of inflammation, and with good developability characteristics. However, NT-0527 exhibited CYP 2C19 time-dependent inhibition, which halted development, but this molecule could be employed as a valuable tool compound for the investigation of neuroinflammatory conditions where NLRP3 inflammasome activation is implicated.}, } @article {pmid40919134, year = {2025}, author = {Zheng, K and Huang, HZ and Liu, D and Brazhe, N and Chen, J and Zhu, LQ}, title = {Targeting the miR-96-5p/Cathepsin B Pathway to Alleviate Neuron-Derived Neuroinflammation in Alzheimer's Disease.}, journal = {MedComm}, volume = {6}, number = {9}, pages = {e70368}, pmid = {40919134}, issn = {2688-2663}, abstract = {Alzheimer's disease (AD) is one of the leading causes of dementia in the elderly, and no effective treatment is currently available. Cathepsin B (CTSB) is involved in key pathological processes of AD, but the underlying mechanisms and its relevance to AD diagnosis and treatment remain unclear. In the present study, we found that CTSB expression was abnormally elevated in the hippocampus of 3×Tg mice and was regulated by miR-96-5p. Abnormalities in the miR-96-5p/CTSB signaling pathway were detected in the serum of both mild cognitive impairment and AD patients, and the combination of serum miR-96-5p and CTSB demonstrated strong diagnostic efficacy for cognitive impairment (AUC = 0.7536). Abnormalities in the miR-96-5p/CTSB signaling pathway in AD may be associated with Aβ pathology, and neuronal CTSB can be released extracellularly to reactivate adjacent astrocytes. Ultimately, the reconstitution of the miR-96-5p/CTSB signaling pathway effectively rescued astrocyte reactivity and memory impairment in AD. Our findings suggest that the neuron-derived inflammatory mediator CTSB reactivates adjacent astrocytes and mediates memory impairment in early AD. The combination of serum miR-96-5p and CTSB represents potential serum biomarkers for cognitive impairment, and targeting the neuronal miR-96-5p/CTSB pathway may serve as a promising therapeutic strategy for AD.}, } @article {pmid40918977, year = {2025}, author = {Yang, H and Dong, C and Cai, Y and Zhao, M and Liu, J and Bian, S and Ding, X}, title = {Advances in the use of structural and diffusion magnetic resonance imaging for characterizing SCD and MCI due to Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1596459}, pmid = {40918977}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) has become a great concern for society in general and clinicians specifically because of its high morbidity, relative lack of awareness of its characteristics, and low diagnosis and treatment rates. Worldwide, there is a lack of effective treatments for slowing the progression of AD in clinical practice. Thus, the management of patients in the preclinical phase of AD (PPAD) has been identified to be highly important for addressing this concern. PPAD is considered a preclinical manifestation of the early stages of AD and includes subjective cognitive decline (SCD) and mild cognitive impairment (MCI). Developments in magnetic resonance imaging (MRI) technology have led to its demonstration of great potential in the early identification and progression monitoring of PPAD. Thus, in this review, we summarized the concepts, principles and applications of structural and diffusion MRI in the identification of PPAD to provide potential imaging markers that can be used by clinicians in clinical practice.}, } @article {pmid40918734, year = {2025}, author = {Sun, X and Lu, Y and Hu, J and Meng, S and Wang, X and Jiang, Q}, title = {Tooth loss impairs cognitive function in SAMP8 mice by aggravating pyroptosis of microglia via the cGAS/STING pathway.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1628520}, pmid = {40918734}, issn = {1663-4365}, abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a common neurodegenerative disease among the elderly population. It has been posited that the onset and progression of AD are influenced by a combination of various factors. Occlusal support loss due to tooth loss has been reported to be a risk factor triggering cognitive dysfunction. This study aimed to investigate the relationship between tooth loss and cognitive dysfunction and illustrate the role of pyroptosis in advancing Alzheimer's disease. METHODS: Male 5-month-old senescence-accelerated mouse strain P8 (SAMP8) mice were divided into two groups (n = 6): the S (sham-operated) and TL (tooth loss) groups. We assessed spatial memory ability using the Y-maze and Novel Object Recognition (NOR) tests. In addition, we performed pathological and molecular biological assessments of the hippocampus to evaluate pyroptosis-related indicators and changes in cGAS/STING. We further verified the correlation between the two in vitro. RESULTS: The pathological section staining revealed an upregulation of GSDMD, a target protein of pyroptosis, and abnormal activation of the cGAS/STING pathway, particularly in microglia, after tooth loss. In vitro, we demonstrated that the BV2 microglia knockdown STING group improved the inflammatory cascade response and down-regulated the pyroptotic features. DISCUSSION: These data suggest that the occlusal support loss due to tooth loss induces pyroptosis-related protein deposition, which may be intimately associated with the cGAS/STING signaling pathway. This provides new insights into the treatment and prevention of oral health and cognitive behavioural disorders in the elderly population.}, } @article {pmid40918343, year = {2025}, author = {Kaya, B and Çevik, UA and Çiftçi, B and Necip, A and Işik, M and Ay, EN and Yur, S and Özkay, Y and Beydemir, Ş and Kaplancıklı, ZA}, title = {Design, Synthesis, and Molecular Docking Studies of Novel Pyrazoline-Thiazoles as Cholinesterase Dual-Target Inhibitors for the Treatment of Alzheimer's Disease.}, journal = {ACS omega}, volume = {10}, number = {34}, pages = {38427-38439}, pmid = {40918343}, issn = {2470-1343}, abstract = {Ten novel pyrazoline-thiazole derivatives were synthesized and assessed for their potential as acetylcholinesterase and butyrylcholinesterase inhibitors. The structure of the target compounds was characterized by [1]H NMR and [13]C NMR, and purity was determined using HPLC. The in vitro enzyme inhibitory activity assays determined that compounds 3f (IC50 = 0.382 μM) and 3g (IC50 = 0.338 μM) showed good inhibitory activity of acetylcholinesterase (AChE). Compound 3f has a selective inhibitory effect on AChE, while compound 3g has a dual effect, being effective against both AChE and BChE (IC50 = 2.087 μM). The molecular docking results of compound 3g with high inhibitory activity for AChE experimentally showed that it has a strong inhibitory effect close to that of the reference inhibitor tacrine. The compound 3g was found to have the highest activity in its interaction with the BChE (4BDS) protein with a low docking score (-5.555 kcal/mol). Furthermore, the prediction of ADME properties of compounds 3f and 3g was determined through Swiss ADME.}, } @article {pmid40917662, year = {2025}, author = {Sun, Z and Li, Y and Qu, X and Wang, L and Zhu, S and Sun, X and Yang, L and Sun, X}, title = {Research trend of functional magnetic resonance imaging in diabetes mellitus research: a visualization and bibliometric analysis.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1539995}, pmid = {40917662}, issn = {1664-2295}, abstract = {BACKGROUND: Understanding the neurological complications associated with diabetes mellitus is essential for developing comprehensive treatment strategies. Functional magnetic resonance imaging (fMRI) is a powerful tool for investigating brain functional and structural changes associated with various conditions, including diabetes mellitus. OBJECTIVES: To analyze the application trends, research hotspots, and emerging frontiers of fMRI in diabetes mellitus research through a comprehensive bibliometric analysis. METHODS: A systematic literature search was conducted utilizing the Web of Science Core Collection (WoSCC) database. Bibliometric tools, including VOSviewer (version 1.6.20), CiteSpace (version 6.3.R1), and R (version 4.3.3), were employed for data analysis. RESULTS: A total of 706 articles about fMRI and diabetes mellitus were published from 1987 to 2024. The United States of America (USA) ranks first (n = 931), followed by China (n = 756) and Germany (n = 270) regarding total publications. Harvard University ranks first in terms of total publications. Among the top ten institutions regarding publications, the majority of articles originated from the USA. The journal Diabetes has the highest number of publications. The author SHAO YI ranks first in total publications, while FRITSCHE ANDREAS ranks first in total citations. The top five keywords identified are "dementia," "risk," "brain," "Alzheimer's disease," and "functional connectivity." Keyword burst analysis indicates that the recent research hotspots included "impairment," "dysfunction," and "diagnosis." CONCLUSION: Cognitive impairment and dysfunction related to diabetes mellitus, along with Alzheimer's disease and dementia, and their diagnosis were identified as focal areas of research. Future investigations should concentrate on predicting and early diagnosing cognitive function in patients with diabetes mellitus using fMRI. The findings of this study provide a valuable reference for researchers and clinicians seeking to explore the neurological dimensions of diabetes mellitus and develop targeted therapeutic approaches.}, } @article {pmid40917568, year = {2025}, author = {Yoon, DM and Plante, DT and Fleming, V and Handen, B and Lao, P and Peven, J and Christian, B and Okonkwo, O and Laymon, C and Ances, B and Hom, C and Helsel, B and Hartley, SL}, title = {Preliminary investigation of obstructive sleep apnea and Alzheimer's disease in down syndrome.}, journal = {Sleep advances : a journal of the Sleep Research Society}, volume = {6}, number = {3}, pages = {zpaf044}, pmid = {40917568}, issn = {2632-5012}, support = {R01 AG070028/AG/NIA NIH HHS/United States ; F31 AG085730/AG/NIA NIH HHS/United States ; U19 AG068054/AG/NIA NIH HHS/United States ; P50 HD105353/HD/NICHD NIH HHS/United States ; U01 AG051412/AG/NIA NIH HHS/United States ; K01 AG083130/AG/NIA NIH HHS/United States ; U01 AG051406/AG/NIA NIH HHS/United States ; }, abstract = {This study provided a preliminary examination of indices of obstructive sleep apsnea (OSA) and sleep disruptions in adults with Down syndrome (DS), and their associations with Alzheimer's disease (AD) pathology and symptomatology. A total of 93 adults with DS (aged 25-61 years) from the Alzheimer Biomarker Consortium-DS completed cognitive assessments, MRI and positron emission tomography (PET) scans (assessing amyloid-beta [Aβ] and tau), and a one-night home sleep study using the WatchPAT-300 device. Study partners also reported on depressive symptoms and diagnoses. Correlational analyses examined relationships between sleep variables, PET biomarkers, and AD symptomatology (cognitive functioning and depressive mood), controlling for sociodemographics. A total of 81 participants (87 per cent) completed valid WatchPAT data. Of these, 60 (74 per cent) screened positive for OSA, and an additional 11 had a prior OSA diagnosis and used CPAP during the test night. Nearly half (45 per cent) of those screening positive for OSA had no prior diagnosis, indicating under-detection. Among the 22 participants using OSA treatment, 50 per cent continued to show sleep-disordered breathing, suggesting suboptimal treatment effectiveness. Higher wake percentage and shorter total sleep time were associated with greater Aβ and tau burden. Cognitive performance was negatively associated with wake percentage, total sleep time, and oxygenation indices (minimum oxygen, desaturation, and time ≤ 88 per cent oxygen). Depressive symptoms were negatively related to total sleep time. These findings add preliminary evidence linking sleep disruption and OSA with AD-related pathology and symptomatology. Larger, longitudinal studies are needed to confirm these associations and evaluate whether improving sleep quality and treating OSA may help delay AD onset in this high-risk population.}, } @article {pmid40917296, year = {2025}, author = {Önder, S and Biberoğlu, K and Tacal, Ö}, title = {Thionine modulates tau phosphorylation in an Alzheimer's disease cell culture model.}, journal = {Turkish journal of biology = Turk biyoloji dergisi}, volume = {49}, number = {4}, pages = {400-408}, pmid = {40917296}, issn = {1303-6092}, abstract = {BACKGROUND/AIM: Tau protein, which is crucial for sustaining the cytoskeletal network by assisting microtubule construction, contributes significantly to the pathophysiology of Alzheimer's disease (AD). The hyperphosphorylation of tau causes it to detach from microtubules (MTs), leading to the formation of neurofibrillary tangles (NFTs) in neurons, which ultimately results in cell death. Thionine (TH), a cationic phenothiazine-structured compound, has been the topic of extensive research due to its interesting physicochemical properties. It is a common biological dye, especially useful in histology due to its strong affinity for biological membranes. Furthermore, TH serves as a photosensitizer in phototherapy. It has a phenothiazine pharmacophore, which makes it selective against microbial and tumor cells. Our prior studies demonstrated that TH inhibits human plasma butyrylcholinesterase (BChE) by acting as a nonlinear inhibitor and also affects amyloid precursor protein (APP) metabolism in PS70 cells. In the current research, we investigated whether TH modulates the phosphorylation of tau in N2a/APPSwe cells. MATERIALS AND METHODS: Using flow cytometry, we identified the dose range and treatment time of TH that did not affect the viability of N2a/APPSwe cells. The western blot method was used to investigate the effects of TH on total tau and four key tau phosphorylation sites. RESULTS: The results indicated that TH reduces tau phosphorylation at residues Ser202/Thr205, Ser396, Ser396/Ser404, and Thr181, which contribute to NFT formation. CONCLUSION: When all these findings are evaluated together, TH may have a therapeutic potential against AD.}, } @article {pmid40916557, year = {2025}, author = {Feng, X and Wang, H}, title = {Antibody Therapies for Alzheimer's Disease: A New Strategy for Targeted Therapy and Blood-Brain Barrier Delivery.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3450-3464}, doi = {10.1021/acschemneuro.5c00484}, pmid = {40916557}, issn = {1948-7193}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/diagnosis/therapy ; *Blood-Brain Barrier/metabolism/drug effects ; Animals ; *Antibodies/therapeutic use/administration & dosage ; *Drug Delivery Systems/methods ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment and neuronal loss, with pathological hallmarks including Aβ plaque deposition and tau tangles. At present, the early diagnosis and treatment of AD still face great challenges, such as limited diagnostic methods, difficulty in blood-brain barrier (BBB) penetration, complex disease mechanisms, and lack of highly effective targeted therapies. Antibody drugs have shown broad prospects in the field of AD due to their high specificity, engineering and multifunctional therapeutic potential, include targeted Aβ clearance, tau pathological regulation, imaging probes, and blood biomarkers. In the future, with the development of antibody engineering technologies (such as PROTAC-antibody conjugates and antibody-based gene therapies), the precision diagnosis and treatment of AD is expected to usher in new breakthroughs. This article systematically reviews the latest advances in the treatment and diagnosis of AD and discusses their potential for clinical translation.}, } @article {pmid40916410, year = {2025}, author = {Algazzawi, H and Abujamai, J and Alshanberi, AM and Satar, R and Ansari, SA}, title = {Role of GSK-3 Inhibition in Alzheimer's Disease Therapy.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050400781250904082943}, pmid = {40916410}, issn = {1875-5828}, abstract = {A serine/threonine kinase with a wide variety of substrates, Glycogen Synthase Kinase-3 (GSK-3) is widely expressed. GSK-3 is a key player in cell metabolism and signaling, modulating numerous cellular functions and playing significant roles in both healthy and diseased states. The two histopathological features of Alzheimer's disease, the intracellular neurofibrillary tangles composed of hyperphosphorylated tau, and the extracellular senile plaques composed of beta-amyloid, have been linked to GSK-3. It alters multiple tau protein locations found in neurofibrillary tangles. Additionally, GSK-3 can react to this peptide and regulate the production of beta-amyloid. The overexpression of GSK-3 in several transgenic models has been linked to tau hyperphosphorylation, neuronal death, and a reduction in cognitive function. It has been shown that lithium, a medication commonly used to treat affective disorders, inhibits GSK-3 at therapeutically relevant concentrations and stops tau phosphorylation. In this review, we provide an overview of the most recent research on the potential of GSK-3 inhibitors for treating Alzheimer's disease.}, } @article {pmid40916051, year = {2025}, author = {Le, HT and Lau, ECY and Lu, CY and Hilmer, SN and Jeon, YH and Low, LF and Nguyen, TA and Tan, ECK}, title = {Treatment modifiers and predictors of risperidone response in dementia: An individual participant data meta-analysis of six randomized controlled trials.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70665}, pmid = {40916051}, issn = {1552-5279}, mesh = {Humans ; *Risperidone/therapeutic use ; Randomized Controlled Trials as Topic ; *Dementia/drug therapy ; *Antipsychotic Agents/therapeutic use ; Aggression/drug effects ; Treatment Outcome ; Male ; Female ; Aged ; }, abstract = {INTRODUCTION: Risperidone is approved for behaviors and psychological symptoms of dementia (BPSD), despite modest efficacy and known risks. Identifying responsive symptoms, treatment modifiers, and predictors is crucial for personalized treatment. METHOD: A one-stage individual participant data meta-analysis of six randomized controlled trials (risperidone: n = 1009; placebo: N = 712) was conducted. Mixed-effects models assessed treatment effects, modifiers, and predictors, with BPSD measured via the Behavioral Pathology in Alzheimer's Disease scale. RESULTS: Risperidone showed modest 8 week benefits for aggression (standardized mean difference [SMD]: -0.22; p < 0.001), psychosis (SMD: -0.23; p = 0.001), and anxiety/phobias (SMD: -0.19; p = 0.014), but not for activity, affective, or sleep disturbances. Pharmacokinetic/pharmacodynamic-related factors (e.g., body mass index, endocrine disease, race/ethnicity) potentially modified treatment effects. Week 2 response predicted week 8 improvement (odds ratio: 4.46; p < 0.001). DISCUSSION: Risperidone provided symptom-specific benefits in reducing aggression, psychosis, and anxiety/phobias. Week 2 response predicted treatment outcomes, while certain patient characteristics may modify treatment response. Further research is needed to optimize the benefit-risk balance and individualize treatment. HIGHLIGHTS: Risperidone modestly reduces symptoms of psychosis, aggression, and anxiety/phobias. Risperidone shows no effect on activity, affective, or sleep disturbances. Patient factors (body mass index, endocrine disease, race/ethnicity) may affect response. Positive response by week 2 predicts significant improvement later.}, } @article {pmid40915373, year = {2026}, author = {Lei, HP and Yang, X and Hu, YT and Wu, LN and Wei, AH and Yu, L and Liu, TT and Ji, XH and Liu, J and Jin, H and Zhou, SY and Jin, F}, title = {Gastrodin alleviates mitochondrial energy metabolism dysfunction via activating β-catenin/c-Myc/MCT2 signaling in Alzheimer's disease models.}, journal = {Journal of ethnopharmacology}, volume = {354}, number = {}, pages = {120548}, doi = {10.1016/j.jep.2025.120548}, pmid = {40915373}, issn = {1872-7573}, mesh = {Animals ; *Glucosides/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism ; beta Catenin/metabolism ; Male ; Proto-Oncogene Proteins c-myc/metabolism ; Mice ; Signal Transduction/drug effects ; *Mitochondria/drug effects/metabolism ; Disease Models, Animal ; *Benzyl Alcohols/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology ; Energy Metabolism/drug effects ; Mice, Transgenic ; Cell Line ; Mice, Inbred C57BL ; }, abstract = {Gastrodia elata, also known as Chijian, belongs to the Orchidaceae family of plants. The "Compendium of Materia Medica" records that Gastrodia elata treats "confused speech, excessive fear, and loss of willpower". Gastrodin (GAS) is the main bioactive component of Gastrodia elata. Research has shown that GAS possesses protective effects on multiple animal models of Alzheimer's disease (AD). However, the exact molecular mechanism of GAS-mediated neuroprotection in AD pathology remains unclear. AIM OF THE STUDY: This study aims to determine whether GAS exerts neuroprotective effects on AD models through regulating β-catenin/c-Myc/MCT2 signaling axis. MATERIALS AND METHODS: Behavioral and histopathological tests, including Morris water maze test, Nissl staining, and NeuN immunofluorescence staining in 3 × Tg-AD male mice, were used to assess the pharmacological effect of GAS on AD. To investigate the neuroprotective mechanisms of GAS, we established an in vitro AD model using Aβ25-35-treated HT22 cells. The expressions of proteins and mRNA related to the β-catenin/c-Myc signaling axis were determined by western blotting and quantitative PCR. The change in energy metabolism was evaluated by measuring pyruvate, cellular ATP production, and mitochondrial membrane potential (MMP). The molecular mechanism of GAS-mediated neuroprotection was further explored using pharmacological and genetic interventions targeting β-catenin and c-Myc. Transcriptional regulation was interrogated through β-catenin chromatin immunoprecipitation (ChIP) coupled with JASPAR-based motif prediction, while ligand-receptor interactions were characterized by AutoDock-based molecular docking validated through drug affinity responsive target stability (DARTS) assay and cellular thermal shift assay (CETSA). RESULTS: In vivo experimental results revealed that GAS ameliorated cognitive impairment in 3 × Tg-AD mice, attenuated neuronal damage, and markedly inhibited the downregulation of active-β-catenin, c-Myc, and MCT2 in the hippocampal tissues. In Aβ25-35-challenged HT22 cells, the relevant protein levels of β-catenin/c-Myc signaling axis were reduced, with both mRNA and protein expressions of MCT2 declining, alongside reductions in pyruvate and ATP concentrations. GAS treatment reversed these pathological alterations, while this effect was antagonized by β-catenin and c-Myc inhibitors. Additionally, lentiviral-mediated β-catenin overexpression markedly increased MCT2 mRNA and protein expression in HT22 cells. The results of chromatin immunoprecipitation assay coupled with quantitative PCR and JASPAR-based motif prediction revealed that β-catenin bound to the MCT2 promoter region. Autodock Vina simulation demonstrated that GAS binds to β-catenin with a binding energy of less than -5 kcal/mol. Both DARTS and CETSA experiments showed that the binding of GAS to β-catenin protects the β-catenin protein from degradation. CONCLUSION: This study demonstrates that GAS plays a protective role in experimental AD models through enhancing MCT2 expression and improving mitochondrial energy metabolism function by activation of the β-catenin/c-Myc/MCT2 signaling axis.}, } @article {pmid40913913, year = {2025}, author = {Lee, H and Hossain, MK and Lee, HY and Kumar, V and Shin, SJ and Kim, BH and Park, HH and Son, JG and Moon, M and Kim, HR}, title = {Taurine suppresses Aβ aggregation and attenuates Alzheimer's disease pathologies in 5XFAD mice and patient-derived cerebral organoids.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {191}, number = {}, pages = {118527}, doi = {10.1016/j.biopha.2025.118527}, pmid = {40913913}, issn = {1950-6007}, mesh = {*Taurine/pharmacology ; Animals ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Humans ; Mice ; *Organoids/drug effects/metabolism/pathology ; tau Proteins/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Doublecortin Protein ; *Peptide Fragments/metabolism ; Phosphorylation/drug effects ; Hippocampus/drug effects/metabolism/pathology ; Neurogenesis/drug effects ; *Neuroprotective Agents/pharmacology ; Cell Line ; Male ; }, abstract = {Alzheimer's disease (AD) is marked by amyloid-beta (Aβ) plaque buildup, tau hyperphosphorylation, neuroinflammation, neuronal loss, and impaired adult hippocampal neurogenesis (AHN). Taurine has shown protective effects in various cellular and animal models of AD, though the molecular mechanisms of free taurine and its effects in patient-derived models remain underexplored. This study evaluates taurine's therapeutic potential using integrated in silico, in vitro, in vivo, and ex vivo approaches. In vitro aggregation assays revealed that taurine (10-100 μM) inhibited Aβ42 fibril formation, with transmission electron microscopy showing looser, amorphous fibrils, particularly at higher doses. Computational simulations further supported that taurine binds stably to Aβ peptide fragments and facilitates the dissociation of Aβ dimers. In HT22 cells, taurine protected against Aβ-induced cytotoxicity. In 5XFAD mice, oral administration of taurine (1000 mg/kg, 4 weeks) significantly reduced Aβ accumulation and hyperphosphorylation of tau at Ser202/Thr205 in the dorsal subiculum. Furthermore, taurine attenuated microgliosis, as evidenced by decreased Iba-1 immunoreactivity, protected against neurodegeneration demonstrated by preserving NeuN-positive neurons, and ameliorated deficit of AHN shown by increasing DCX-positive cells in the subgranular zone of the dentate gyrus. Importantly, in cerebral organoids derived from an AD patient carrying the APOE ε4/ε4 genotype, taurine treatment attenuated Aβ accumulation, decreased tau phosphorylation. These findings highlight taurine's multi-target therapeutic potential targeting amyloid aggregation, tau pathology, neuroinflammation and neurogenesis. Our data support taurine emerges as a promising therapeutic candidate for AD.}, } @article {pmid40913683, year = {2025}, author = {Smoller, C and Schiller, E and Yamashita, K and Silverglate, BD and Grossberg, GT}, title = {Current and Emerging Pharmacological Approaches to Agitation in Alzheimer's Disease: A Narrative Review of New and Repurposed Therapies.}, journal = {Drugs}, volume = {85}, number = {11}, pages = {1391-1411}, pmid = {40913683}, issn = {1179-1950}, mesh = {Humans ; *Alzheimer Disease/drug therapy/complications ; *Psychomotor Agitation/drug therapy/etiology ; Drug Repositioning ; *Antipsychotic Agents/therapeutic use ; Selective Serotonin Reuptake Inhibitors/therapeutic use ; Antidepressive Agents/therapeutic use ; Anticonvulsants/therapeutic use ; Hypnotics and Sedatives/therapeutic use ; }, abstract = {This narrative review explores current pharmacological treatments for agitation in Alzheimer's disease (AD). Agitation, a common and difficult-to-manage symptom in AD, often requires targeted intervention. While nonpharmacological methods, such as behavioral therapy and environmental modifications, are considered first line, they may not always be effective. In cases where these approaches fail, pharmacological treatment can become a necessary component of care. Historically, antipsychotics have been the mainstay of pharmacological treatment for agitation in AD; however, safety and efficacy concerns have prompted exploration into alternative treatments. The purpose of this narrative review is to synthesize current literature on pharmacological treatments for agitation in AD with a focus on new and repurposed drugs. It also examines agents that have failed to demonstrate clinical benefit, offering insights into the ongoing challenges of drug development in this area. This review synthesizes recent findings on various drug classes, including anticonvulsants, antipsychotics, selective serotonin reuptake inhibitors (SSRIs), atypical antidepressants, sedatives, anti-dementia drugs, dextromethorphan, and cannabinoids. Both brexpiprazole and risperidone have demonstrated efficacy and received approval from government agencies, including brexpiprazole in the USA and risperidone in parts of Europe. Despite these advances, concerns remain regarding their long-term use and safety profiles. As a result, multiple other therapies are currently being studied as possible alternative solutions. However, no other pharmacological agents are currently approved, underscoring the need for further research on safe and effective options for this vulnerable population.}, } @article {pmid40913351, year = {2025}, author = {Peng, D and Wei, P and Li, Z and Wei, R and Li, H and Li, S}, title = {The Role of P62/Nrf2/Keap1 Signaling Pathway in Lead-Induced Neurological Dysfunction.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {9}, pages = {e70566}, pmid = {40913351}, issn = {1755-5949}, support = {82160626//National Natural Science Foundation of China/ ; 81803281//National Natural Science Foundation of China/ ; }, mesh = {*Kelch-Like ECH-Associated Protein 1/metabolism ; *NF-E2-Related Factor 2/metabolism ; Animals ; *Signal Transduction/drug effects/physiology ; *Lead/toxicity ; *Sequestosome-1 Protein/metabolism ; Male ; Oxidative Stress/drug effects/physiology ; Mice ; Reactive Oxygen Species/metabolism ; Neurons/drug effects/metabolism ; Cells, Cultured ; Rats ; Autophagy/drug effects ; Mice, Inbred C57BL ; }, abstract = {BACKGROUND: Lead (Pb) exposure is recognized for its contribution to the development of neurodegenerative diseases. However, the precise mechanisms underlying Pb-induced neurological dysfunction remain elusive. This study aimed to investigate the role of oxidative stress and the autophagy-related P62/kelch like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in neuronal impairment caused by Pb. METHODS: By employing both in vivo and in vitro approaches, we explored the involvement of the P62/Nrf2/Keap1 pathway in Pb-induced neurotoxicity. RESULTS: Our findings demonstrated that Pb exposure triggers excessive production of reactive oxygen species (ROS), upregulates Keap1 protein expressions, promotes Nrf2 degradation, and inhibits expression of antioxidant proteins such as heme Oxygenase-1 (HO-1) and glutathione peroxidase (GPx), resulting in oxidative damage in neurons. Furthermore, we observed that the autophagy protein P62 disrupts the normal autophagy process by interacting with the Nrf2/Keap1 axis, leading to an accumulation of Tau, a protein associated with Alzheimer's disease (AD), ultimately resulting in neurodegeneration. However, treatment with the antioxidant N-acetylcysteine, Nrf2 activator Artemisitene, and autophagy activator Rapamycin attenuated these detrimental changes. CONCLUSION: The P62/Nrf2/Keap1 pathway mediates Pb-induced neuronal dysfunction and highlights its potential as a therapeutic target for mitigating the neurodegenerative effects associated with Pb exposure.}, } @article {pmid40912996, year = {2025}, author = {Greeley, D and Nash, M and Herskowitz, B and Kim, F and Rock, J and Prins, N and Kim, S and Xi, T and Busam, JA and Tete, B and Choung, JJ and Sha, SJ}, title = {A phase 2 randomized, placebo-controlled study on the efficacy and safety of AR1001, a phosphodiesterase-5 inhibitor, in patients with mild-to-moderate Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {9}, pages = {100337}, pmid = {40912996}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/drug therapy ; Aged ; Male ; Double-Blind Method ; Female ; Middle Aged ; *Phosphodiesterase 5 Inhibitors/therapeutic use/adverse effects/administration & dosage ; Aged, 80 and over ; Treatment Outcome ; tau Proteins/blood ; Amyloid beta-Peptides ; Cognition/drug effects ; Biomarkers/blood ; }, abstract = {BACKGROUND: AR1001 is a phosphodiesterase-5 inhibitor that produces improved cognitive performance and reduces amyloid-β and phosphorylated tau burdens in preclinical models of Alzheimer's disease (AD). OBJECTIVES: To evaluate the safety and efficacy of AR1001 in participants with mild-to-moderate Alzheimer's disease (AD). DESIGN: Randomized, double-blind, placebo-controlled phase 2 trial conducted at 21 sites in the United States. PARTICIPANTS: Adults aged 55-80 years with mild-to-moderate dementia as determined by National Institutes of Aging-Alzheimer's Association (NIA-AA) stage 4 or 5 and Mini-mental State Exam (MMSE) score 16-26. INTERVENTION: Once daily oral administration of placebo, 10 mg AR1001, or 30 mg AR1001 for 26 weeks followed by 26 weeks optional extension. MEASUREMENTS: Co-primary efficacy endpoints were changes from baseline at Week 26 in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog 13) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Secondary endpoints included measures of cognition, daily living, and depression. Levels of plasma biomarkers pTau-181, pTau-217, Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were also examined. RESULTS: A total of 210 participants were enrolled and 82% completed 26 weeks of treatment. AR1001 10 mg and 30 mg were well-tolerated with a similar safety profile compared to placebo. After 26 weeks, there were no differences in ADAS-Cog13, ADCS-CGIC, or in secondary efficacy endpoints between groups. Levels of plasma biomarkers pTau-181, pTau-217, and GFAP were improved in the 30 mg AR1001 group compared to placebo. CONCLUSION: AR1001 was safe and well tolerated. Although primary efficacy endpoints were not met after 26 weeks of treatment, participants receiving 30 mg AR1001 showed favorable changes in AD-related plasma biomarkers compared to placebo. TRIAL REGISTRATION: clinicaltrials.gov; NCT03625622.}, } @article {pmid40912535, year = {2025}, author = {Cheng, F and Gao, H and Yan, B and Chen, F and Lei, P}, title = {From disinfectant to neurodegeneration: Integrating machine learning and mendelian randomization reveals triclosan as a novel environmental risk factor for Alzheimer's disease.}, journal = {Environmental pollution (Barking, Essex : 1987)}, volume = {385}, number = {}, pages = {127068}, doi = {10.1016/j.envpol.2025.127068}, pmid = {40912535}, issn = {1873-6424}, mesh = {*Triclosan/toxicity/adverse effects ; *Alzheimer Disease/epidemiology/chemically induced ; *Machine Learning ; Humans ; Risk Factors ; Mendelian Randomization Analysis ; *Disinfectants/toxicity ; *Environmental Exposure/statistics & numerical data ; }, abstract = {This study systematically investigated the association between triclosan (TCS) exposure and Alzheimer's disease (AD) risk via integrated bioinformatics approaches. TCS-AD-related genes were identified using bioinformatics tools and public databases, followed by the screening of key genes through multi-model machine learning algorithms (LASSO, SVM-RFE, RF) to mitigate random errors in small sample sizes. DRD2 was confirmed as the most robust core gene by LASSO confidence interval analysis and SHAP evaluation, while APP and SLC6A3 were validated through cross-method intersection. Findings from functional enrichment analysis, Mendelian randomization, and molecular docking demonstrated that TCS may affect AD pathogenesis through these key genes. Moreover, a stable AD risk scoring model and predictive formula were developed via logistic regression analysis of T-A-Key Genes. This study constitutes an innovative and transformative research endeavor. Building upon the understanding of TCS-induced neurotoxicity, it extends to the clinical translational direction of predicting AD onset risk, thereby establishing a quantitative association model of "environmental exposure-core genes-disease risk. " It not only provides novel evidence for the potential role of TCS neurotoxicity as an environmental pathogenic factor in AD, emphasizing the necessity of prioritizing risk management of daily chemical exposure in AD prevention and treatment, but also offers a scientific foundation for the formulation of public health policies aimed at preventing long-term TCS exposure.}, } @article {pmid40912368, year = {2025}, author = {Wang, J and Qiao, Z and Cao, X and Li, H and Wang, Y and Jiao, Q and Chen, X and Du, X}, title = {G Protein-coupled receptors: key targets for maintaining the function of basal ganglia-thalamus-cortical circuits in Parkinson's disease.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 2}, pages = {117303}, doi = {10.1016/j.bcp.2025.117303}, pmid = {40912368}, issn = {1873-2968}, mesh = {*Parkinson Disease/metabolism/drug therapy/physiopathology ; Humans ; *Receptors, G-Protein-Coupled/metabolism/antagonists & inhibitors ; *Basal Ganglia/metabolism/drug effects ; Animals ; *Cerebral Cortex/metabolism/drug effects ; *Nerve Net/metabolism/drug effects ; *Drug Delivery Systems/methods ; }, abstract = {Parkinson's Disease (PD), the second most common neurodegenerative disease after Alzheimer's disease, is clinically characterized by resting tremor, rigidity and postural balance disorder. Its pathological essence is the progressive degenerative death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to a significant decrease in striatal dopamine (DA) levels. This results in the dysfunction of basal ganglia-thalamus-cortex (BGTC) circuit. This circuit is the core neural circuit of motor control, and its abnormality not only directly causes the motor symptoms of PD, but also participates in the cascade of disease progression through the disorder of neurotransmitter signals. At present, DA replacement therapy and DA receptors (DARs) agonists are still the main methods of clinical treatment, but single therapy cannot fully correct the imbalance of other neurotransmitter systems, which has significant limitations in long-term efficacy and symptom management. G protein-coupled receptors (GPCRs), as the largest family of membrane proteins, have become important targets for PD treatment due to their extensive participation in physiological regulatory networks and excellent drug development potential. These transmembrane signaling molecules play important roles in multiple key nodes in the pathological process of PD by precisely regulating the release of neurotransmitters, the maintenance of synaptic plasticity and the dynamic balance of neural circuits. Here, we review the transition of BGTC in the context of PD and then focus on the pathological cascade of GPCRs mediating PD in this loop. Finally, we update the clinical trials or approvals of GPCR drugs under investigation for the treatment of PD.}, } @article {pmid40912064, year = {2025}, author = {Ali, N and Al-Rejaie, SS and Babu, MA and Nayak, P and VenuPrasad, KD and Mohany, M and Singh, TG and Akhter, MS and Fareed, M and Tyagi, Y and Bansal, N and Puri, S}, title = {Exploring the bioactive constituents from spices targeting N-methyl-d-aspartate receptors: An in silico and in vitro approach to identify druggable leads against neurological disability.}, journal = {Bioorganic & medicinal chemistry}, volume = {130}, number = {}, pages = {118378}, doi = {10.1016/j.bmc.2025.118378}, pmid = {40912064}, issn = {1464-3391}, mesh = {*Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; Molecular Docking Simulation ; Humans ; *Spices/analysis ; *Curcumin/chemistry/pharmacology ; Structure-Activity Relationship ; Molecular Structure ; *Neuroprotective Agents/chemistry/pharmacology ; Dose-Response Relationship, Drug ; Quercetin/chemistry/pharmacology ; }, abstract = {N-methyl-d-aspartate (NMDA) receptors are validated druggable targets for the treatment of Alzheimer's and other associated neurological conditions, particularly in individuals with disabilities. Considering the excitotoxicity associated with NMDA receptors, which leads to neuronal damage, cognitive impairment, and limitations of current therapeutic regimens, better therapeutic candidates are required. One of the validated drug discovery approaches is computer-assisted drug discovery, supplemented by molecular docking, mechanics, and dynamics. To this end, we curated 134 bioactive constituents derived from spices. These were subjected to high-throughput virtual screening (HTVS) considering the pharmacophoric features of the NMDA receptor. Molecular docking, followed by molecular mechanics and dynamics, indicated that curcumin and quercetin could plausibly bind to the NMDA receptor in comparison to memantine. In vitro ELISA-based analysis revealed that curcumin may inhibit the NMDA receptor with an IC50 of 2.36 μM compared to memantine's 736.48 nM, employed as a positive control. However, targeting the neuronal receptor NMDA requires that the ligand efficiently cross the blood-brain barrier (BBB). To overcome this challenge, we performed a rational bioisosteric replacement strategy to potentially optimize the pharmacokinetic features of curcumin without affecting its NMDA binding. We generated 150 bioisosteres of curcumin, and through extensive computational analyses, the top 5 scoring molecules were further validated via a molecular dynamics approach. However advantageous, in the present work, curcumin or its proposed derivatives have not been corroborated by extensive biological investigation. It is a prototype study to identify the druggable leads from the spices that have the potency to interact and inhibit NMDA. Owing to this, the mechanism of action is not fully elucidated. Further, the work upon validation (biologically) may serve as a useful pharmacophore (tool molecule) using which NMDA may be downregulated. The designed derivatives thus open avenues to synthesize and biologically test them against NMDA inhibition, plausibly establishing their roles in Alzheimer's and related disabilities.}, } @article {pmid40911712, year = {2025}, author = {Wang, G and Li, Y and McDade, E and Xiong, C and Hartz, SM and Bateman, RJ and Morris, JC and Schneider, LS and , }, title = {Clinical progression on CDR-SB©: Progression-free time at each 0.5 unit level in dominantly inherited and sporadic Alzheimer's disease populations.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70643}, pmid = {40911712}, issn = {1552-5279}, support = {R01AG046179//National Institute on Aging of the National Institutes of Health/ ; R01AG068319//National Institute on Aging of the National Institutes of Health/ ; R01 AG068319/AG/NIA NIH HHS/United States ; SG-20-690363-DIAN//National Institute on Aging (NIA), the Alzheimer's Association/ ; U01 AG024904/AG/NIA NIH HHS/United States ; U01 AG059798/AG/NIA NIH HHS/United States ; U01 AG024904/NH/NIH HHS/United States ; R01 AG046179/AG/NIA NIH HHS/United States ; U01AG042791//National Institute on Aging of the National Institutes of Health/ ; 1U01AG059798//National Institute on Aging of the National Institutes of Health/ ; R01AG053267-S1//National Institute on Aging of the National Institutes of Health/ ; R01AG053267//National Institute on Aging of the National Institutes of Health/ ; U19 AG032438/AG/NIA NIH HHS/United States ; U01 AG052564/AG/NIA NIH HHS/United States ; P30AG066530//National Institute on Aging of the National Institutes of Health/ ; HI21C0066//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; P30 AG066530/AG/NIA NIH HHS/United States ; U01AG042791-S1//National Institute on Aging of the National Institutes of Health/ ; R01 AG053267/AG/NIA NIH HHS/United States ; U19AG032438//The Dominantly Inherited Alzheimer Network/ ; U01AG052564//National Institute on Aging of the National Institutes of Health/ ; W81XWH-12-2-0012//Department of Defense/ ; U01 AG042791/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/drug therapy/diagnosis ; *Disease Progression ; Female ; Male ; Aged ; *Mental Status and Dementia Tests ; Cohort Studies ; Middle Aged ; Neuropsychological Tests ; }, abstract = {INTRODUCTION: Clinical Dementia Rating Sum of Boxes (CDR-SB) is a reliable and clinically meaningful composite for assessing treatment effects in Alzheimer's disease (AD) clinical trials. Small CDR-SB differences at the end of a trial often lead to controversy in deriving clinically meaningful interpretations. METHODS: We estimated progression-free time (PFT) participants remained at each 0.5 unit CDR-SB increment in dominantly inherited AD (DIAD) and sporadic AD populations, evaluating its potential as an alternative measure of treatment effects. RESULTS: PFT is longer at CDR-SB ≤ 2.0 (1-2 years) and shorter at CDR-SB ≥ 5 (≤ 0.33) in the Alzheimer's Disease Neuroimaging Initiative cohort. The DIAD cohort showed similar but shorter times. Using PFT, continuous lecanemab treatment for 3 years is estimated to delay disease progression by 0.62 years in the sporadic population. DISCUSSION: PFT provides a benchmark for expressing clinical progression and treatment effects and can be applied particularly during open-label extensions and single-arm trials without placebo comparisons. HIGHLIGHTS: We estimated the progression-free time at each 0.5 unit Clinical Dementia Rating Sum of Boxes increment in dominantly inherited Alzheimer's disease (AD) and sporadic AD populations. We proposed using progression-free time to estimate treatment effects in open-label extension or single-arm studies. If further validated, progression-free time could serve as a benchmark for assessing clinical progression and treatment effects.}, } @article {pmid40911700, year = {2025}, author = {Maria, and Khan, A and Ajaj, R and Rauf, A and , and Shah, ZA and Ahmad, Z and Hemeg, HA and Rashid, U}, title = {Secondary metabolites isolated from Fernandoa adenophylla (Wall. ex G.Don) steenis as multitarget inhibitors of cholinesterases for the treatment of Alzheimer's Disease, followed by molecular docking studies.}, journal = {PloS one}, volume = {20}, number = {9}, pages = {e0331119}, pmid = {40911700}, issn = {1932-6203}, mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use/isolation & purification ; Molecular Docking Simulation ; *Alzheimer Disease/drug therapy/enzymology ; Butyrylcholinesterase/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; Humans ; *Plant Extracts/chemistry/pharmacology ; Secondary Metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder categorized by the progressive loss of cognitive function, with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as key therapeutic targets. In this study, we report the isolation, characterization, and evaluation of the cholinesterase inhibitory potential of phytochemicals from Fernandoa adenophylla (Wall. ex G. Don) Steenis, a plant known for its medicinal properties. Using in-vitro enzyme inhibition assays, we identified five bioactive compounds, including lapachol (1), α-lapachone (2), peshawaraquinone (3), dehydro-α-lapachone (4), and an indanone derivative (5), which demonstrated significant inhibition of AChE and BuChE. The compounds exhibited varied inhibitory potency, with peshawaraquinone (3) showing the most promising AChE (IC50 = 0.90 ± 0.04 µM) and BuChE (IC50 = 8.39 ± 0.14 µM) inhibition, followed by dehydro-α-lapachone (4), which exhibited an AChE IC50 value of 2.64 ± 0.08 µM. Further, the selectivity index (SI) for AChE over BuChE was highest for dehydro-α-lapachone (SI = 21.1), suggesting its potential as a selective inhibitor. Molecular docking studies provided insights into the binding interactions between these compounds and the enzyme active sites, highlighting key interactions that may contribute to their inhibitory activity. These findings suggest that phytochemicals from F. adenophylla possess significant cholinesterase inhibition potential and may serve as leads for the development of novel therapeutic agents for Alzheimer's disease.}, } @article {pmid40911470, year = {2025}, author = {Yamamoto, N and Yuzu, K and Morishima, K and Inoue, R and Sugiyama, M and Koyama, D and Chatani, E}, title = {Targeting Both Monomer and Oligomer with Fibrinogen Efficiently Suppresses Amyloid Fibril Formation and Cell Toxicity of Amyloid β 1-42.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3623-3630}, pmid = {40911470}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; *Fibrinogen/pharmacology/metabolism ; Humans ; *Peptide Fragments/metabolism/toxicity ; Animals ; *Amyloid/metabolism ; Cattle ; Microscopy, Atomic Force ; Alzheimer Disease/metabolism ; Cell Survival/drug effects ; }, abstract = {The development of drugs for Alzheimer's disease, which accounts for over half of all dementia cases, remains challenging. Amyloid β 1-42 (Aβ42) is widely recognized for its deposition in the brains of patients with Alzheimer's disease. Furthermore, Aβ42-induced cell toxicity likely plays a role in disease onset. Molecular species present in the early stages, such as monomers and oligomers, are appropriate therapeutic targets for suppressing amyloid fibril formation and cell toxicity. In this study, we investigated the effects of bovine fibrinogen (bFg) and human fibrinogen (hFg) since these molecules have been known to exhibit chaperone-like activities. Our findings indicate that bFg exerts a strong inhibitory effect on amyloid fibril formation. Dot blot assays, analytical ultracentrifugation (AUC), and atomic force microscopy (AFM) suggest that bFg interacts with both Aβ42 monomers and oligomers. In contrast, human fibrinogen (hFg), which interacts only with oligomers, exhibits a weaker inhibitory effect on amyloid fibril formation. Moreover, bFg significantly rescued cells from Aβ42-induced toxicity, whereas hFg provided only partial protection. These findings underscore the potential of molecules targeting early stage Aβ42 species as promising candidates for Alzheimer's disease treatment.}, } @article {pmid40911101, year = {2025}, author = {Qian, J and Ren, S and Ren, T and Shi, R and Qiao, L and Kang, J}, title = {Astrocyte Autophagy in Neurodegenerative Diseases: Current Progress in Mechanisms and Therapeutics.}, journal = {Neurochemical research}, volume = {50}, number = {5}, pages = {287}, pmid = {40911101}, issn = {1573-6903}, support = {202310472004//the College Students' Innovation and Entrepreneurship Training Program/ ; 82071326//the National Natural Science Foundation of China/ ; 232102310288//Key Technologies R&D Program of Henan Province/ ; 252300421395//Natural Science Foundation of Henan/ ; 505511, XYBSKYZZ202124, 506017//Doctoral Scientific Research Foundation of Xinxiang Medical University/ ; }, mesh = {Humans ; *Autophagy/physiology/drug effects ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy/therapy ; *Astrocytes/metabolism/pathology/drug effects ; Animals ; Oxidative Stress/physiology ; }, abstract = {Astrocytes, the most abundant and functionally diverse glial cell type in the brain, play a crucial role in maintaining cellular homeostasis and promoting neuronal survival. Autophagy is the process of transferring senescent, denatured, or damaged proteins and organelles from cells to lysosomes for degradation. However, recent research on autophagy in the central nervous system has focused on neurons. In this paper, we reviewed the latest findings on astrocyte autophagy and its mechanisms in regulating neurodegenerative disorders. It influences the pathological processes of Alzheimer's disease, Parkinson's disease, Huntington's disease, and other synucleinopathies (including dementia with Lewy bodies and Parkinson's disease dementia) by regulating oxidative stress and inflammatory responses, as well as aberrant protein aggregation and folding. Furthermore, we listed medications that can prevent or treat neurodegenerative disorders by modulating astrocyte autophagy pathways, providing new insights into preventive and therapeutic strategies for neurodegenerative diseases.}, } @article {pmid40910917, year = {2025}, author = {Xin, YX and Xiao, YL}, title = {[Research progress on the relationship between traumatic brain injury and neurogenic lower urinary tract dysfunction].}, journal = {Zhonghua nan ke xue = National journal of andrology}, volume = {31}, number = {7}, pages = {650-653}, pmid = {40910917}, issn = {1009-3591}, mesh = {Humans ; *Brain Injuries, Traumatic/complications ; *Urinary Bladder, Neurogenic/etiology ; Risk Factors ; }, abstract = {Urinary dysfunction caused by central nervous system or peripheral nerve disease represents a significant global medical and social problem. Neurologic abnormalities, including traumatic brain injury (TBI), stroke, Alzheimer's disease, and Parkinson's disease, have been identified as potential risk factors for neurogenic urinary tract dysfunction. The relationship between TBI and neurogenic lower urinary tract dysfunction (NLUTD) will be introduced in this article, with the mechanisms, clinical manifestations, diagnostic methods, and treatment strategies of NLUTD after TBI being evaluated as well, which provides a reference for the diagnosis and treatment.}, } @article {pmid40910390, year = {2025}, author = {Frederiksen, KS and Gramkow, MH and Hasselbalch, SG and Law, I and Waldemar, G}, title = {[Anti-amyloid antibodies for the treatment of early-stage Alzheimer's disease].}, journal = {Ugeskrift for laeger}, volume = {187}, number = {35}, pages = {}, doi = {10.61409/V03250217}, pmid = {40910390}, issn = {1603-6824}, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/immunology ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; }, abstract = {Alzheimer's disease is the most common neurodegenerative dementia disorder and is associated with several negative health outcomes. Current treatment consists of symptomatic treatment and supportive measures. However, advances have led to the development of antibodies towards beta-amyloid, which likely plays a pivotal role in the pathophysiology. Lecanemab and donanemab have shown efficacy in the early stages of Alzheimer's disease but are also associated with a risk of cerebral haemorrhages and oedema. The introduction of these antibodies will require adjustment of diagnostic and management pathways as discussed in this review.}, } @article {pmid40910338, year = {2025}, author = {Navarra, AN and Wang, LA and Al-Sahlani, H and Liu, AJ and Doraiswamy, PM}, title = {Severe Persistent Urinary Retention Following Treatment With Intravenous Lecanemab.}, journal = {Pharmacotherapy}, volume = {45}, number = {10}, pages = {702-705}, doi = {10.1002/phar.70060}, pmid = {40910338}, issn = {1875-9114}, mesh = {Humans ; *Urinary Retention/chemically induced ; Male ; Alzheimer Disease/drug therapy ; Aged ; Administration, Intravenous ; }, abstract = {Lecanemab is an amyloid-targeted antibody indicated for treating patients with amyloid-confirmed early Alzheimer's Disease in mild dementia or mild cognitive impairment stages. We report here a case of a subject with early stage of Alzheimer's Disease dementia, amyloid positive, who developed severe acute urinary retention following his first dose of intravenous lecanemab. His urinary retention resolved after a week but recurred following the second intravenous dose 2 weeks later. Lecanemab was discontinued, but the urinary retention has persisted for 8 months indicating possible permanent adverse impact on the bladder. The Naranjo causality probability score was 6. The incidence of urinary retention with intravenous lecanemab is not known but given that elderly patients with dementia may have multiple risks for bladder dysfunction, clinicians should remain vigilant. It is hoped that newer formulations, such as subcutaneous lecanemab, may prove safer in such patients.}, } @article {pmid40910212, year = {2025}, author = {Zhang, YY and Cheng, YY and Guan, W}, title = {Betaine, a Potential Therapeutic Alternative for the Treatment of Depression.}, journal = {Current drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113894501394957250818110931}, pmid = {40910212}, issn = {1873-5592}, abstract = {Depression is a debilitating psychiatric disorder characterized by loss of interest, anhedonia, and social isolation, which is projected to become the leading cause of disability worldwide by 2030. Despite the greater economic and social burden imposed by depression, the precise pathophysiology underlying the development of depression remains elusive. Betaine (N, N, N-trimethylglycine), an amino acid derivative, is widely distributed in various animals and plants and has been shown to have numerous beneficial effects, including antioxidant activities, anti-inflammatory functions, regulation of energy metabolism, and reduction of endoplasmic reticulum stress. It has been used to treat Alcohol-Associated Liver Disease (AALD), type 2 diabetes, cancer, obesity, and Alzheimer's Disease (AD). Interestingly, accumulating evidence has shown that betaine exerts a significant role in alleviating depressive-like behavior in patients and animals resulting from chronic stress. Although the antidepressant effects of betaine have not been compared with traditional antidepressants with insufficient verification, based on the neurobiological mechanisms of depression, it may be a potential alternative medicine for the treatment of depression. This is the first review aiming to provide a comprehensive overview of the remarkable effects of betaine in the pathophysiology of depression. These pieces of evidence are of great importance for deepening our understanding of the antidepressant mechanism of betaine, so as to develop betaine supplements for the supplementary treatment of depression.}, } @article {pmid40910023, year = {2025}, author = {Shahid, SB and Kaikaus, M and Kabir, MH and Yousuf, MA and Azad, AKM and Al-Moisheer, AS and Alotaibi, N and Alyami, SA and Bhuiyan, T and Moni, MA}, title = {Novel deep learning for multi-class classification of Alzheimer's in disability using MRI datasets.}, journal = {Frontiers in bioinformatics}, volume = {5}, number = {}, pages = {1567219}, pmid = {40910023}, issn = {2673-7647}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is one of the most common neurodegenerative disabilities that often leads to memory loss, confusion, difficulty in language and trouble with motor coordination. Although several machine learning (ML) and deep learning (DL) algorithms have been utilized to identify Alzheimer's disease (AD) from MRI scans, precise classification of AD categories remains challenging as neighbouring categories share common features. METHODS: This study proposes transfer learning-based methods for extracting features from MRI scans for multi-class classification of different AD categories. Four transfer learning-based feature extractors, namely, ResNet152V2, VGG16, InceptionV3, and MobileNet have been employed on two publicly available datasets (i.e., ADNI and OASIS) and a Merged dataset combining ADNI and OASIS, each having four categories: Moderate Demented (MoD), Mild Demented (MD), Very Mild Demented (VMD), and Non Demented (ND). RESULTS: Results suggest the Modified ResNet152V2 as the optimal feature extractor among the four transfer learning methods. Next, by utilizing the modified ResNet152V2 as a feature extractor, a Convolutional Neural Network based model, namely, the 'IncepRes', is proposed by fusing the Inception and ResNet architectures for multiclass classification of AD categories. The results indicate that our proposed model achieved a standard accuracy of 96.96%, 98.35% and 97.13% for ADNI, OASIS, and Merged datasets, respectively, outperforming other competing DL structures. DISCUSSION: We hope that our proposed framework may automate the precise classifications of various AD categories, and thereby can offer the prompt management and treatment of cognitive and functional impairments associated with AD.}, } @article {pmid40909873, year = {2025}, author = {Wang, X and Dong, B and Gan, Q and Li, J and Wu, P and Guan, Y and Wang, J}, title = {Unraveling the Vicious Cycle: Oxidative Stress and Neurotoxicity in Neurodegenerative Diseases.}, journal = {FASEB bioAdvances}, volume = {7}, number = {8}, pages = {e70041}, pmid = {40909873}, issn = {2573-9832}, abstract = {Oxidative stress is characterized by an imbalance between the production and elimination of free radicals, where the rate of free radical generation surpasses the rate of their removal. This imbalance can lead to tissue and organ damage, contributing to the pathogenesis of various diseases. The nervous system, due to its high oxygen consumption, is particularly susceptible to oxidative stress. Numerous neurotoxins can induce neurotoxicity through oxidative stress, thereby contributing to the onset of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Furthermore, neurotoxicity can exacerbate oxidative stress by disrupting mitochondrial metabolism and impairing the activity of antioxidant enzymes, thereby intensifying neurotoxic effects. This review examines the mechanisms underlying the interaction between oxidative stress and neurotoxicity and explores strategies to mitigate neurotoxicity by reducing oxidative stress, with the aim of informing future clinical approaches for the treatment of neurodegenerative diseases.}, } @article {pmid40908886, year = {2025}, author = {Singh, T and Yadav, R and Hazra, S}, title = {Atomically Dispersed Ru Catalyst Locked in Knitting Aryl Network Polymers: A Robust Heterogeneous Catalyst for Borrowing Hydrogenation in Aqueous Micelles.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {37}, pages = {52024-52036}, doi = {10.1021/acsami.5c09711}, pmid = {40908886}, issn = {1944-8252}, abstract = {Fabrication of water-stable and atomically dispersed ruthenium catalysts for sustainable borrowing hydrogenation (BH) reactions is a long-standing challenge. Herein, we developed an atomically dispersed Ru catalyst that has been successfully employed for BH reactions in aqueous micelles under mild conditions. The micellar cooperativity with the hydrophobic knitted aryl polymers (KAPs) led to the formation of microconfinements, which act as the confined space for catalysis in water. The catalyst was characterized by using various techniques such as transmission electron microscopy (TEM), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (AC-HAADF-STEM), X-ray photoelectron spectroscopy (XPS), and X-ray absorption spectroscopy (XAS). Confocal laser scanning microscopy (CLSM) and fluorescence lifetime imaging microscopy (FLIM) have been used to understand the role of micelles, reagents, and materials in the generation of confined space in water. The catalyst was found to be recyclable for five cycles without a significant loss of its catalytic activity. We have also demonstrated a 1 g scale reaction for the alkylation of acetophenone and synthesis of Donepezil, a marketed drug for the treatment of Alzheimer's disease, using our method.}, } @article {pmid40908772, year = {2025}, author = {Faysal, M and Zehravi, M and Sutradhar, B and Al Amin, M and Shanmugarajan, TS and Arjun, UVNV and Ethiraj, S and Durairaj, A and Dayalan, G and Ahamad, SK and Rab, SO and Raman, K and Emran, TB}, title = {The Microbiota-Gut-Brain Connection: A New Horizon in Neurological and Neuropsychiatric Disorders.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {9}, pages = {e70593}, pmid = {40908772}, issn = {1755-5949}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Mental Disorders/microbiology/metabolism/therapy ; *Nervous System Diseases/microbiology/metabolism/therapy ; *Brain/metabolism ; Animals ; Dysbiosis ; *Brain-Gut Axis/physiology ; Probiotics ; }, abstract = {INTRODUCTION: The microbiota-gut-brain axis (MGBA), a complex two-way connection between the gut microbiota and the brain, has become a key regulator of neurological and neuropsychiatric disorders. Neurological disorders and gut microbiota dysbiosis are linked to these diseases. Changes in gut microbiota can lead to neurotransmitter imbalances, oxidative stress, and neuroinflammation. Gut dysbiosis may contribute to the development of diseases such as depression, autism, schizophrenia, bipolar disorder, Parkinson's disease, Alzheimer's disease, dementia, multiple sclerosis, epilepsy, anxiety, and autism spectrum disorders through immunological regulation, neuroinflammation, and neurotransmitter metabolism changes. METHOD: This review systematically sourced articles related to microbiota gut brain axis, neurological disorders, neuropsychiatric disorders and clinical studies from major medical databases, including Scopus, PubMed, and Web of Science. RESULTS: This review explores the molecular processes underlying MGBA interactions, including vagus nerve signaling, systemic immunological responses, and metabolites produced by microorganisms. The discussion explores the potential of microbiome-targeted treatments like fecal microbiota transplantation, probiotics, and prebiotics as effective treatment methods. The comprehension of the MGBA can revolutionize neurology and psychiatry, introducing innovative diagnostic and therapeutic approaches. Multiple elements, including diet, metabolism, age, stress, and medications, shape the human gut microbiota, and intestinal imbalances can lead to CNS diseases. The MGBA interacts with gut bacteria, and gut dysbiosis is associated with neurological disorders. CONCLUSIONS: The review demonstrates the correlation between gut microbiota and neurologically associated diseases, highlighting its importance in neurogenesis, mental development, emotions, and behaviors. MGBA, mediated by microbial metabolites, affects brain function and neuroinflammation. Interventions like fetal microbiota transplantation, probiotics, and prebiotics can improve microbial balance, but more clinical research is needed.}, } @article {pmid40908698, year = {2025}, author = {Singh, A and Maheshwari, S and Ansari, VA and Verma, A and Ansari, TM and Akhtar, J and Ahsan, F and Vishwakarma, VK and Wasim, R}, title = {Dendrimers: Advancing Therapeutic Strategies for Dementia.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098343913250818112618}, pmid = {40908698}, issn = {1874-6128}, abstract = {Dementia, characterized by a progressive decline in cognitive function, poses a significant challenge to global healthcare systems, with current therapeutic approaches offering limited efficacy. The development of nanotechnology-based drug delivery systems has introduced promising avenues for enhancing the treatment of neurodegenerative disorders such as Alzheimer's disease. Dendrimers, with their highly branched, nanoscale structure, provide an innovative platform for targeted drug delivery to the brain. Dendrimers serve as nanoscale drug carriers that facilitate controlled drug release, enhance bioavailability, and improve penetration across the blood-brain barrier (BBB), leading to superior therapeutic efficacy in neurodegenerative disorders. In particular, dendrimers can encapsulate both hydrophilic and hydrophobic drugs, increasing their stability and minimizing systemic side effects. This review explores the unique properties of dendrimers, focusing on their potential as drug delivery vehicles in dementia treatment. We also highlight advancements in the design and application of dendrimer-based therapeutics, emphasizing their role in targeting key pathological mechanisms underlying dementia. Through these approaches, dendrimers represent a promising strategy for developing more effective and personalized treatment modalities for patients suffering from cognitive impairment and dementia.}, } @article {pmid40908696, year = {2025}, author = {Paul, S and Tiwari, P and Dubey, S}, title = {Precision Enzyme: Targeted Drug Discovery in Neurodegenerative Disorders.}, journal = {Protein and peptide letters}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298665391103250825102319}, pmid = {40908696}, issn = {1875-5305}, abstract = {INTRODUCTION: Neurodegenerative disorders such as Alzheimer's, Parkinson's, and ALS are characterized by progressive neuronal dysfunction with limited therapeutic options. Recent advances in molecular biology and drug development have highlighted the therapeutic promise of precision enzyme targeting, offering novel strategies for disease modulation and symptom management. METHODS: A comprehensive literature review spanning recent/current was conducted using PubMed, Scopus, and ScienceDirect. Studies focusing on enzyme-based targets, high-throughput screening, and molecular docking in neurodegeneration were included. Thematic synthesis was employed to categorize findings based on enzyme class, disease relevance, and therapeutic outcomes. RESULTS: Key enzyme families such as kinases, proteases, and oxidoreductases were identified as pivotal modulators in disease progression. Emerging enzyme-targeted compounds demonstrated enhanced bioavailability, blood-brain barrier permeability, and disease-specific efficacy. Novel screening platforms and computational modeling enabled the precise selection of inhibitors, significantly improving the therapeutic index and reducing off-target effects. DISCUSSION: Targeting enzymes implicated in neuroinflammation, oxidative stress, and protein misfolding has shown disease-modifying potential. Integrating precision drug discovery tools, such as AI-assisted modeling and enzyme kinetics, supports rational drug design. However, translational challenges persist due to variability in enzyme expression and disease heterogeneity. CONCLUSION: Future research should focus on refining enzyme inhibitors and integrating biomarkers to facilitate personalized treatment strategies for neurodegenerative disorders. As the understanding of enzymatic roles in neurodegeneration deepens, precision enzyme-targeted drug discovery holds significant promise in transforming neurotherapeutic approaches.}, } @article {pmid40908524, year = {2025}, author = {Oba, GMJ and Sahu, R and Shah, K and Paliwal, D and Kumar Sah, A and Thakur, A}, title = {Current Developments in the Pharmacological Activities and Synthesis of Carbazole Derivatives.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575407122250822095143}, pmid = {40908524}, issn = {1875-5607}, abstract = {The growing prevalence of multidrug resistance and its detrimental effects pose a significant threat to public health, which is one reason for the current interest in the introduction of novel agents. To combat this adverse effect and drug resistance, numerous drugs have been developed over time, and their safety is still being evaluated; derivatives or medications based on the carbazole moiety are one of the key contributors. Therefore, this review explores carbazole-based derivatives as possible drugs to treat Alzheimer's, diabetes, inflammation, cancer, and many more, along with their synthetic schemes, SARs, and activity. Some of the carbazole-based drugs available in the market and under clinical trials are also tabulated. By integrating this insight, describe how these compounds are being reinvented as targeted therapeutic agents. This comprehensive analysis is designed to guide researchers in developing next-generation drugs to address various challenges and leverage the unique pharmacological properties of carbazole-derived drugs.}, } @article {pmid40908201, year = {2025}, author = {Jung, JH and Kong, N and Lee, S and , }, title = {Pulse pressure as a predictor of Alzheimer's disease biomarkers and cognitive decline: The moderating role of APOE ε4.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {10}, pages = {100363}, pmid = {40908201}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/genetics/physiopathology/diagnosis/diagnostic imaging ; *Apolipoprotein E4/genetics ; Male ; *Cognitive Dysfunction/genetics/physiopathology/diagnosis ; Female ; Biomarkers/metabolism ; Aged ; Amyloid beta-Peptides/metabolism ; *Blood Pressure/physiology ; tau Proteins/metabolism ; Prospective Studies ; Positron-Emission Tomography ; Aged, 80 and over ; Longitudinal Studies ; }, abstract = {BACKGROUND: Elevated pulse pressure (PP), indicative of arterial stiffness, has been implicated in cognitive impairment and Alzheimer's disease (AD) pathology. However, its role in preclinical AD and interactions with genetic risk factors like apolipoprotein E ε4 (APOE4) remain unclear. OBJECTIVES: To investigate the association between baseline PP and AD biomarkers (amyloid-beta (Aβ) and tau) and cognitive decline, and to determine whether APOE4 carrier status moderates these relationships. DESIGN: Prospective cohort study and secondary analysis of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) randomized clinical trial SETTING: Multicenter observational cohort and randomized clinical trial conducted at 67 sites across the United States, Canada, Australia, and Japan. PARTICIPANTS: This study included 1690 cognitively unimpaired older adults from the A4 and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Participants underwent baseline PP assessment, Aβ and tau PET imaging, and cognitive testing with longitudinal follow-up over 240 weeks. MEASUREMENTS: Blood pressure was measured at baseline, with PP calculated as the difference between systolic and diastolic pressures. AD pathologies were assessed through Aβ PET imaging using 18F-Florbetapir, and regional tau deposition in inferior temporal and meta-temporal regions using 18F-Flortaucipir PET imaging. Cognitive performance was measured using the Preclinical Alzheimer Cognitive Composite (PACC). RESULTS: Higher baseline PP was significantly associated with increased Aβ (β = 0.078; p = 0.001), inferior temporal tau (β = 0.110; p = 0.032), and meta-temporal tau deposition (β = 0.116; p = 0.022). In longitudinal analyses, elevated PP predicted greater decline in PACC scores (β = -0.020; p < 0.001). APOE4 status moderated these associations, with significant effects of PP on tau deposition and cognitive decline observed exclusively among APOE4 carriers. Mediation analysis indicated that tau deposition significantly mediated the association between PP and cognitive decline (indirect effect β = -0.068; 95 % CI [-0.126, -0.011]). CONCLUSIONS: Elevated PP is associated with increased AD biomarker burden and accelerated cognitive decline in cognitively unimpaired older adults, particularly among APOE4 carriers. Our study suggests that arterial stiffness may contribute to AD pathogenesis and progression via tau pathology. These results highlight the potential of vascular health management as an early intervention target for AD prevention, especially in genetically at-risk populations.}, } @article {pmid40907816, year = {2025}, author = {Rai, S and Nair, A and Saleem, Z and Ray, SK and Kanwar, JR and Mukherjee, S}, title = {Advancing nanotheranostics for neuro-immunological disorders: current status and future prospects.}, journal = {Neuroscience}, volume = {585}, number = {}, pages = {233-248}, doi = {10.1016/j.neuroscience.2025.08.051}, pmid = {40907816}, issn = {1873-7544}, mesh = {Humans ; Animals ; *Theranostic Nanomedicine/methods/trends ; *Nervous System Diseases/drug therapy/immunology/therapy ; *Immune System Diseases/drug therapy/therapy ; *Neuroinflammatory Diseases/drug therapy ; }, abstract = {Neuroimmunological disorders involve complex interactions between the nervous and immune systems, leading to various severe neurological conditions such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. These disorders are characterized by immune-mediated damage or inflammation within nervous tissue, resulting in cognitive deficits, movement issues, sensory impairments, and other neurological problems. They can affect people of all ages, but incidence increases significantly with advancing age, making them a growing public health concern. As the global population ages, the prevalence of neuroimmunological diseases is expected to rise sharply. Projections indicate that by 2050, approximately 150 million individuals worldwide may suffer from dementia-related disorders alone, with an economic burden reaching around $10 trillion. Current therapies mainly focus on symptom management, aiming to slow disease progression and improve quality of life. Emerging therapeutic strategies show promise, particularly nanomedicine, which employs nanoscale materials to deliver drugs precisely to affected tissues. This targeted approach reduces side effects and increases treatment effectiveness. Additionally, natural products and plant-based compounds are gaining attention for their neuroprotective effects, as they can modulate pathways involved in neuronal survival, repair, and immune regulation. Future research aims to deepen understanding of the molecular and genetic mechanisms underlying these disorders through advanced experimental models and technologies. These insights will facilitate the development of innovative therapies targeting neuroinflammation and immune dysregulation, with the goal of preventing disease progression or even achieving cures. Continued progress in neuroimmunology offers hope for improved treatment outcomes, reduced disease burden, and transformative advances in neurological healthcare worldwide.}, } @article {pmid40907613, year = {2025}, author = {Li, K and Qiu, X and Yang, Q and Wang, Z}, title = {Histone modifications: Key players in Alzheimer's disease.}, journal = {Mechanisms of ageing and development}, volume = {228}, number = {}, pages = {112102}, doi = {10.1016/j.mad.2025.112102}, pmid = {40907613}, issn = {1872-6216}, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Histones/metabolism ; Animals ; tau Proteins/metabolism ; *Histone Code ; Amyloid beta-Peptides/metabolism ; Acetylation ; }, abstract = {Alzheimer's disease (AD) is one of the most prevalent diseases in the older population. AD causes progressive cognitive and behavioral impairment, but current treatments are unable to slow or prevent the progression of this disease. Thus, identification of novel biomarkers and therapeutic targets is urgently needed. We previously described the roles of histone acetylation, crotonylation, and lactylation in the accumulation of amyloid beta and hyperphosphorylation of Tau protein, which are the hallmarks of AD. In this review, we summarize and discuss the current knowledge of the role of histone modifications in AD, with a particular emphasis on its association with characterized pathological alterations, including amyloid plaques, Tau tangles, neuroinflammation, and synaptic dysfunction. This review provides novel insights into the central role of histone modifications in AD pathogenesis and evaluates histone-modifying enzymes as potential therapeutic targets for the treatment of AD.}, } @article {pmid40907541, year = {2025}, author = {Wu, N and Wu, Z and Wang, P and Zhang, C and Wu, C and Huo, X and Zhang, G}, title = {Three-dimensional magnetic field measurement of transcranial magnetic stimulation using a printed circuit board-based miniature orthogonal coil array.}, journal = {Biomedical physics & engineering express}, volume = {11}, number = {5}, pages = {}, doi = {10.1088/2057-1976/ae0340}, pmid = {40907541}, issn = {2057-1976}, mesh = {*Transcranial Magnetic Stimulation/instrumentation ; Equipment Design ; Humans ; *Magnetic Fields ; Miniaturization ; Printing, Three-Dimensional ; }, abstract = {Objective. Transcranial magnetic stimulation (TMS) is a promising neuromodulation therapy for treating diseases such as depression and Alzheimer's disease. However, its efficacy depends on precise magnetic field targeting. Current measurement methods face a trade-off between accuracy and complexity. Their intricate designs limit miniaturization, and they are typically confined to one-dimensional detection.Approach. This study proposes a miniaturized printed circuit board (PCB)-integrated coil array (11.10 mm × 9.10 mm × 1.60 mm) as a novel solution to replace complex probe systems for the synchronous measurement of three-dimensional magnetic field components (Bx,By,Bz) generated by a figure-8 coil.Results. Using this approach, we simulated and measured the magnetic field distribution produced by a self-made figure-8 coil, demonstrating consistency with relative errors below 5%, 10%, and 15% along the line of interest (LOI) in thex,y,zdirections, respectively. Variations in magnetic flux density from a commercial figure-8 coil were also measured at two specific spatial positions, showing consistent trends.Significance. The presented measurement probe enables feasible characterization of TMS-induced magnetic flux, with measured values aligning closely with simulated results. By integrating orthogonal coils into a compact PCB, it overcomes the traditional accuracy-complexity trade-off. Clinically, it assists in precise coil positioning during treatment, reducing off-target side effects via magnetic field validation. Technologically, its compact and cost-effective design accelerates testing of novel TMS coils, advancing the development of efficient neuromodulation devices.}, } @article {pmid40906916, year = {2025}, author = {Kakoty, V and Kang, JH and Lee, OH and Oh, DH and Ko, YT}, title = {Grueneberg Ganglion: An Unexplored Site for Intranasal Drug Delivery in Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3425-3437}, doi = {10.1021/acschemneuro.5c00376}, pmid = {40906916}, issn = {1948-7193}, mesh = {Animals ; Administration, Intranasal/methods ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Delivery Systems/methods ; Humans ; Mice ; Blood-Brain Barrier/metabolism/drug effects ; }, abstract = {Neurological disorders such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis pose significant challenges for treatment. Reasons for the difficulty in finding cures for these conditions include complications in early diagnosis, progressive and irreversible neuronal damage, and the presence of the blood-brain barrier (BBB), which hinders the delivery of drugs to the affected areas of the brain. Intranasal (INL) drug administration has increasingly gained popularity among researchers for targeting neurological conditions, because of its ability to bypass the BBB. However, chronic INL administration leads to nasal mucosa irritation. Additionally, rapid mucociliary clearance, a lack of targeted drug delivery, increased enzymatic degradation, and tight junctions that obstruct drug transport limit the clinical applicability of the INL route. To overcome these challenges, a unique region in the rodent nose, known as the Grueneberg Ganglion (GG), can be considered to be a novel site for INL drug administration. GG is a small structure housed under the snout cartilage of the nasal septum, approximately 1.5 mm from the nasal opening in mice. It is directly connected to the main olfactory bulb through axons. This Perspective aims to expand knowledge on why GG may be a viable option for INL delivery to combat neurological conditions. For better understanding, we have explained the INL administration in GG, using Alzheimer's Disease and INL insulin therapy as a role model for the current review.}, } @article {pmid40904621, year = {2025}, author = {Castilhos, RM and Formoso, CR and Borelli, WV and Teixeira, EC and Dousseau, GC and Chaves, MLF and Brucki, SMD}, title = {Anticholinergic burden and polypharmacy in patients referred from primary care to tertiary dementia centers in Brazil.}, journal = {Dementia & neuropsychologia}, volume = {19}, number = {}, pages = {e20240246}, pmid = {40904621}, issn = {1980-5764}, abstract = {UNLABELLED: Anticholinergic burden (ACB) and polypharmacy are poorly studied in the context of primary care in Brazil. OBJECTIVE: To evaluate the ACB and polypharmacy of individuals with suspected dementia referred from primary care to tertiary dementia outpatient clinics in Brazil. METHODS: We performed a cross-sectional study in two tertiary dementia clinics. We included individuals with suspected dementia referred from primary care. Sociodemographic variables, number of drugs, ACB score, disease duration, Mini Mental State Examination (MMSE) were collected in the first evaluation. Final diagnosis received was also collected. RESULTS: A total of 921 individuals were included, with a median (IQR) age of 72 [64-78] years, 57.8% (532) women, 4 [2-7] years of formal education and 15 [10-20] points in MMSE. Most patients had a final diagnosis of dementia (66%, 616) and Alzheimer's disease (21.4%, 197), psychiatric disorders (16%, 147) and multifactorial dementia (14.8%, 136) were the most common diagnoses. Most individuals (68.1%, 627) were using at least one medication with anticholinergic effect, and in 44.6% (411) there was polypharmacy. ACB total score correlated with MMSE (rho=-0.13) and with total number of medications (rho=0.52). In multivariate regression, ACB score ≥1 was associated with MMSE and polypharmacy. CONCLUSION: Most individuals referred from primary care in Brazil were using at least one medication with anticholinergic effect and this was correlated with cognitive severity. Educational measures for primary care physicians, focusing on the management of pharmacological treatment, are essential to reduce the anticholinergic load in this context.}, } @article {pmid40904419, year = {2025}, author = {Mullins, GR and Ardayfio, P and Gueorguieva, I and Anglin, G and Bailey, J and Chua, L and Zimmer, JA and Evans, CD and Nery, ESM and Wang, H and Khanna, R and Brooks, DA and Sims, JR}, title = {Donanemab immunogenicity in participants with early symptomatic Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70149}, pmid = {40904419}, issn = {2352-8737}, abstract = {INTRODUCTION: Donanemab is an immunoglobulin G1 antibody that targets an N-terminal truncated form of amyloid beta present in mature plaques. Treatment-emergent (TE) anti-drug antibodies (ADAs) were quantified in donanemab-treated participants from two pivotal clinical trials, and effects of TE ADAs on donanemab pharmacokinetics, efficacy, and safety were assessed. METHODS: Data were pooled from the phase 2 TRAILBLAZER-ALZ (NCT03367403) and phase 3 TRAILBLAZER-ALZ 2 trials (NCT04437511). Eligible participants were randomized 1:1 to donanemab (700 mg for the first three doses, 1400 mg thereafter) or placebo intravenously every 4 weeks up to 72 weeks. TE ADA-evaluable participants had a non-missing baseline ADA result and ≥ 1 non-missing post-baseline ADA result. TE ADA incidence and effect of titer on pharmacokinetics, amyloid plaque reduction, clinical efficacy (measured by change from baseline of integrated Alzheimer's Disease Rating Scale [iADRS] score and Clinical Dementia Rating Scale Sum of Boxes [CDR-SB]), and safety were assessed. RESULTS: Of 922 TE ADA-evaluable donanemab-treated participants, 56 (6.1%) had ADAs detected at baseline, and 812 (88.1%) were TE ADA positive. Donanemab clearance increased linearly with logarithm of ADA titer; however, titer did not affect maximum donanemab concentration. Amyloid plaque level was significantly reduced with donanemab versus placebo, irrespective of titer (P < 0.001 for all). No association was found between ADA presence or titer and donanemab efficacy by iADRS or CDR-SB. Eighty-four of 984 (8.5%) donanemab-treated participants and 4 of 999 (0.4%) placebo-treated participants reported infusion-related reactions (IRRs). All donanemab-treated participants reporting immediate IRRs developed ADAs at some point during the study; however, 90.5% of TE ADA-positive participants did not experience IRRs. DISCUSSION: Most participants were TE ADA positive. TE ADAs increased donanemab clearance but did not have clinically meaningful impact on plaque reduction or efficacy. While all participants reporting IRRs developed ADAs at some point during the study, the majority of participants with ADAs did not experience IRRs. HIGHLIGHTS: In pivotal trials, most donanemab-treated participants were treatment-emergent anti-drug antibody (TE ADA) positive.TE ADAs increased donanemab clearance but did not impact plaque reduction/efficacy.All participants reporting infusion-related reactions (IRRs) developed ADAs at some point during the study.However, the majority of participants with ADAs did not experience IRRs.}, } @article {pmid40904199, year = {2025}, author = {Isik, S and Osman, S and Yeman-Kiyak, B and Shamshir, SRM and Sanchez, NME}, title = {Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {9}, pages = {e70577}, pmid = {40904199}, issn = {1755-5949}, mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Neurodegenerative Diseases/therapy ; Animals ; *Stem Cell Transplantation/methods/trends ; *Clinical Trials as Topic/methods ; }, abstract = {AIM: This review provides a systematic evaluation of 94 stem cell clinical trials to treat neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. METHODS: Data were collected from using relevant search terms, focusing exclusively on stem cell therapy. Of the 8000+ participants in these trials, nearly 70% were enrolled in AD-related studies. Only three Phase 3 studies were conducted, and most trials were in the early phases (Phases 1 and 2). Mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, and embryonic stem cells are used the most to treat neurodegenerative diseases. This review also explores the emerging fields of preclinical and clinical investigations of stem cell-derived exosome-based therapies for neurodegenerative diseases. RESULTS: Exosomes can cross the blood-brain barrier to deliver therapeutic molecules directly to the brain, offering a less invasive alternative to stem cell transplantation. Mesenchymal stem cell-derived exosomes, in particular, have demonstrated significant potential in preclinical models by reducing neuroinflammation, oxidative stress, and promoting neuronal regeneration. Additionally, recent advances in exosome engineering, including surface modifications, therapeutic agent loading, and transgenic modifications, have improved targeting, stability, blood-brain barrier delivery, and neural cell interactions, enabling targeted and effective treatment. Exosome-based therapies are in the preliminary phases of clinical investigation, with only three clinical trials. CONCLUSION: Given the increasing interest in exosome therapy, clinical investigations are expected to increase. This growth will be driven by ongoing advancements in exosome technology, a deeper understanding of their therapeutic potential, and escalating demand for innovative treatment strategies for neurodegenerative diseases.}, } @article {pmid40904091, year = {2025}, author = {Hu, WQ and Gao, HY and Yang, L and Wang, YX and Cheng, HJ and Yang, SY and Zhang, MY and Sun, J}, title = {[Characterization of hippocampal components of Danzhi Xiaoyao Formula based on HPLC-Q-TOF-MS/MS and network pharmacology and assessment of its therapeutic potential for nervous system diseases].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {14}, pages = {4053-4062}, doi = {10.19540/j.cnki.cjcmm.20250426.201}, pmid = {40904091}, issn = {1001-5302}, mesh = {*Drugs, Chinese Herbal/chemistry/administration & dosage ; Animals ; Rats ; *Hippocampus/drug effects/chemistry/metabolism ; Network Pharmacology ; Chromatography, High Pressure Liquid ; Tandem Mass Spectrometry ; Rats, Sprague-Dawley ; Male ; *Nervous System Diseases/drug therapy/metabolism/genetics ; Humans ; Signal Transduction/drug effects ; }, abstract = {In this study, the pharmacodynamic components and potential pharmacological functions of Danzhi Xiaoyao Formula in treating nervous system diseases were investigated by hippocampal component characterization and network pharmacology. After rats were administrated with Danzhi Xiaoyao Formula by gavage, high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(HPLC-Q-TOF-MS/MS) was employed to explore the components in the hippocampus of rats. Fifty-seven components were identified in the hippocampus of rats by comparing the extract of Danzhi Xiaoyao Formula, herbal components in the hippocampus after administration, and blank samples. KEGG and GO analyses predicted 74 core targets including GSK3B, MAPK1, AKT, IL6. These targets were involved in PI3K/Akt, NF-κB, MAPK, JAK/STAT, Wnt, and other signaling pathways. The results indicated that Danzhi Xiaoyao Formula may ameliorate other nervous system diseases enriched in DO, such as neurodegenerative diseases, cerebrovascular diseases, and mental and emotional disorders by mediating target pathways, inhibiting inflammation, reducing neuronal damage, and alleviating hippocampal atrophy. The relevant activities exhibited by this formula in nervous system diseases such as Alzheimer's disease, Parkinson's disease, and diabetic neuropathy have extremely high development value and are worthy of further in-depth research. This study provides a theoretical basis and practical guidance for expanding the application of Danzhi Xiaoyao Formula in the treatment of nervous system diseases.}, } @article {pmid40904084, year = {2025}, author = {Pu, YZ and Chen, HF and Wang, XY and Su, C}, title = {[Caffeoylquinic acids from Erigeron breviscapus ameliorates cognitive impairment and mitochondrial dysfunction in AD by activating PINK1/Parkin-mediated mitophagy].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {14}, pages = {3969-3979}, doi = {10.19540/j.cnki.cjcmm.20250219.402}, pmid = {40904084}, issn = {1001-5302}, mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/metabolism/physiopathology/psychology ; *Mitophagy/drug effects ; *Mitochondria/drug effects/metabolism/genetics ; Caenorhabditis elegans/drug effects/genetics/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Cognitive Dysfunction/drug therapy/metabolism/genetics/physiopathology ; Rats ; *Protein Kinases/metabolism/genetics ; Humans ; Male ; Disease Models, Animal ; Caenorhabditis elegans Proteins/metabolism/genetics ; *Drugs, Chinese Herbal/administration & dosage ; }, abstract = {This study aimed to investigate the effects of caffeoylquinic acids from Erigeron breviscapus(EBCQA) on cognitive impairment and mitochondrial dysfunction in Alzheimer's disease(AD), and to explore its underlying mechanisms. The impacts of EBCQA on paralysis, β-amyloid(Aβ) oligomerization, and mRNA expression of mitophagy-related genes [PTEN-induced putative kinase 1(PINK1) homolog-encoding gene pink-1, Parkin homolog-encoding gene pdr-1, Bcl-2 interacting coiled-coil protein 1(Beclin 1) homolog-encoding gene bec-1, microtubule-associated protein 1 light chain 3(LC3) homolog-encoding gene lgg-1, autophagic adapter protein 62(p62) homolog-encoding gene sqst-1] were examined in the AD Caenorhabditis elegans CL4176 model, along with mitochondrial functions including adenosine triphosphate(ATP) content, enzyme activities of mitochondrial respiratory chain complexes Ⅰ,Ⅲ, and Ⅳ, and mitochondrial membrane potential. Additionally, the effects of EBCQA on the green fluorescent protein(GFP)/red fluorescent protein from Discosoma sp.(DsRed) ratio, the expression of phosphatidylethanolamine-modified and GFP-labeled LGG-1(PE-GFP::LGG-1)/GFP-labeled LGG-1(GFP::LGG-1), and GFP-labeled SQST-1(GFP::SQST-1) proteins were investigated in transgenic C. elegans strains. The effect of EBCQA on paralysis was further evaluated after RNA interference(RNAi)-mediated suppression of the pink-1 and pdr-1 genes in CL4176 strain. An AD rat model was established through intraperitoneal injection of D-galactose and intragastric administration of aluminum trichloride. The effects of β-nicotinamide mononucleotide(NMN) and EBCQA on learning and memory ability, neuronal morphology, mitophagy occurrence, mitophagy-related protein expression(PINK1, Parkin, Beclin 1, LC3-Ⅱ/LC3-Ⅰ, p62), and mitochondrial functions(ATP content; enzyme activities of mitochondrial respiratory chain complexes Ⅰ, Ⅲ, and Ⅳ; mitochondrial membrane potential) were investigated in this AD rat model. The results showed that EBCQA delayed paralysis onset in the CL4176 strain, reduced Aβ oligomer formation, and upregulated the mRNA expression levels of lgg-1, bec-1, pink-1, and pdr-1, while downregulating sqst-1 mRNA expression. EBCQA also enhanced ATP content, mitochondrial membrane potential, and the activities of mitochondrial respiratory chain complexes Ⅰ, Ⅲ, and Ⅳ. Furthermore, EBCQA improved the PE-GFP::LGG-1/GFP::LGG-1 ratio, reduced GFP::SQST-1 expression, and decreased the GFP/DsRed ratio. Notably, the ability of EBCQA to delay paralysis was significantly reduced following RNAi-mediated suppression of pink-1 and pdr-1 in CL4176 strain. In AD rats, the administration of NMN or EBCQA significantly improved learning and memory, restored neuronal morphology in the hippocampus, increased autophagosome numbers, and upregulated the expression of PINK1, Parkin, Beclin 1, and the LC3-Ⅱ/LC3-Ⅰ ratio, while reducing p62 expression. Additionally, the treatment with NMN or EBCQA both elevated ATP content, mitochondrial respiratory chain complex Ⅰ, Ⅲ, and Ⅳ activities, and mitochondrial membrane potential in the hippocampus. The above findings indicate that EBCQA improves cognitive impairment and mitochondrial dysfunction in AD, possibly through activation of PINK1/Parkin-mediated mitophagy.}, } @article {pmid40903965, year = {2025}, author = {Parikh, A and Cholavaram, A and Chitti Babu, AK and Deepankumar, K and Vijayan, M}, title = {Role of voltage-dependent anion channel 1 in neurodegeneration: Mechanisms, implications, and therapeutic potential.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00368}, pmid = {40903965}, issn = {1673-5374}, abstract = {Voltage-dependent anion channel 1 is an integral outer membrane protein of the mitochondria that governs apoptosis, enables metabolite exchange, and influences mitochondrial activity. In neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease, oxidative stress, neuroinflammation, and mitochondrial dysfunction are frequent features. Voltage-dependent anion channel 1 is a key regulator of these processes. This review described the structure, membrane topology, and physiological function of voltage-dependent anion channel 1 in neurons and glial cells. We emphasize how it affects mitophagy, oxidative damage, and changes in mitochondrial permeability. Special attention is focused on how voltage-dependent anion channel 1 interacts with pathogenic proteins that damage mitochondrial integrity and cause neurotoxicity, including mutant huntingtin, phosphorylated tau, α-synuclein, amyloid-beta, and TAR DNA-binding protein 43. Furthermore, the paper examines the function of voltage-dependent anion channel 1 in astrocytic dysfunction and microglial activation, highlighting its impact on neuroinflammation. In a nutshell, we assess treatment strategies that target voltage-dependent anion channel 1, such as VBIT-4, a selective inhibitor of voltage-dependent anion channel 1 oligomerization, and newer methods, including structure-based drug design and CRISPR/Cas9 regulation. Improved knowledge of the hinter voltage-dependent anion channel 1 of the molecular mechanism may allow for new therapeutic approaches in neurodegenerative diseases.}, } @article {pmid40903964, year = {2025}, author = {Wu, S and Guo, T and Zheng, X and Gu, C and Hu, Y and Gu, X and Zhou, X}, title = {Integrated machine learning-based RNA sequencing and single-cell analysis reveal RNA methylation regulation patterns in the immune microenvironment of Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-24-01650}, pmid = {40903964}, issn = {1673-5374}, abstract = {Alterations in RNA methylation may affect the initiation and development of Alzheimer's disease. However, the exact nature of the relationship between RNA methylation and Alzheimer's disease remains unclear. In this study, RNA methylation levels were analyzed by bulk transcriptomic and single-cell RNA sequencing. The expression levels of RNA methylation regulators were confirmed using molecular biology techniques. Co-expression network analysis was used to identify relevant long non-coding RNAs. Molecular subtypes related to RNA methylation were classified, and variations in clinical characteristics, biological behavior, and immune signatures between subtypes were assessed. Machine learning approaches were applied to identify methylation-associated long noncoding RNAs, which were used to construct a risk model and nomogram for Alzheimer's disease. Potential therapeutic agents for different risk groups were predicted, and in vitro experiments were conducted to identify key RNA methylation events. Single-cell analysis demonstrated enhanced RNA methylation in patients with Alzheimer's disease, particularly within T cells, B cells, and NK cells. Quantitative reverse transcription-polymerase chain reaction and western blot confirmed alterations in RNA methylation regulators in neurons treated with amyloid-β oligomers in vitro . This evidence supported the classification of patients with Alzheimer's disease into heterogeneous subtypes. Specifically, subtype 1 was identified as the immune-active subtype, while subtype 2 was characterized by a metabolic phenotype. Machine learning algorithms identified five significant methylation-associated long non-coding RNAs -LINC01007, MAP4K3-DT, MIR302CHG, VAC14-AS1, and TGFB2-OT1-that accurately predict clinical outcomes for patients with Alzheimer's disease. These patients were classified into low- and high-risk categories; the latter group displayed higher immune infiltration, upregulated immune regulatory gene expression, and elevated immune scores and responded better to treatment with arachidonic-trifluoroethane. These findings suggest that dysregulated RNA methylation alters the immune microenvironment in Alzheimer's disease and is closely associated with its progression. This phenomenon provides novel insights into potential therapeutic strategies for Alzheimer's disease that target RNA methylation.}, } @article {pmid40903963, year = {2025}, author = {Fan, F and Zhao, N and Guo, M}, title = {Lymphatic-venous anastomosis: Cracking the code of Alzheimer's disease treatment?.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00540}, pmid = {40903963}, issn = {1673-5374}, } @article {pmid40903956, year = {2025}, author = {Chen, Y and Yin, P and Chen, Q and Zhang, Y and Tang, Y and Jin, W and Yu, L}, title = {Neurodegenerative diseases and immune system: From pathogenic mechanism to therapy.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00274}, pmid = {40903956}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are a class of disorders with the gradual loss of the central nervous system and peripheral nervous system. Neurodegenerative diseases manifest primarily as cognitive and behavioral disorders that adversely affect the lives of millions of people worldwide. Therefore, it is necessary to elucidate the mechanism of neurodegenerative diseases further and find effective new therapies. In recent years, increasing evidence has shown that the immune system plays a significant role in the pathophysiology of neurodegenerative diseases and regulates this process. The central and peripheral immune systems exert different roles in the disease progression. The development of neurodegenerative diseases is influenced by interactions between them. This review focuses on how the immune system, including microglia mediated nucleotide-binding oligomerization domainlike receptor protein 3 inflammation activation and T cell-mediated neuroinflammation, interactions with neurodegenerative diseases by modulating protein aggregation and blood-brain barrier permeability. Besides, we gave particular attention to glial cell-centered multicellular interactions and the inflammatory signaling pathway. Insight into the immune system's functions and cellular interactions is essential for progressing disease research. In addition, the functions and mechanisms of these immune cells also suggest new ideas and targets for treatment. Therefore, this review summarizes some of the existing treatment strategies for amyloid-beta, tau, neuroinflammation, α-synuclein, associated microbiota, immune modulation, and neural injury repair. In addition, this review summarizes and compares animal models of different common neurodegenerative diseases and clinical research progress. In view of the current research status, new research directions and suggestions are proposed.}, } @article {pmid40903950, year = {2025}, author = {Liu, Y and Tang, T and Cai, H and Liu, Z}, title = {Bidirectional communication between the gut microbiota and the central nervous system.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00434}, pmid = {40903950}, issn = {1673-5374}, abstract = {In recent years, an increasing number of researchers have become interested in the bidirectional communication between the gut microbiota and the central nervous system. This communication occurs through the microbiota-gut-brain axis. As people age, the composition of the gut microbiota undergoes considerable changes, which are now known to play an important role in the development of many neurodegenerative diseases. This review aims to investigate the complex bidirectional signaling pathways between the gut and the brain. It summarizes the latest research findings on how the gut microbiota and its metabolites play critical roles in regulating inflammation, maintaining gut health, and influencing the development of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The review also analyzes the current clinical applications of gut microbiota-based treatments for neurological disorders, including fecal microbiota transplantation, probiotics, and prebiotics. Many studies show that the gut microbiota affects the brain in several ways. For example, it can produce substances such as short-chain fatty acids and activate inflammatory pathways. Studies involving animals and laboratory models have demonstrated that adjusting the gut microbiota can help improve behavior and reduce neurological problems. Recent metagenomic and metabolomics studies have shown that the microbiota plays a crucial role in maintaining the organism's health. Microorganisms primarily colonize the gut and are involved in host nutrient metabolism, maintaining the structural integrity of the intestine, preserving the intestinal mucosal barrier, and modulating the immune system. The gut microbiota communicates with the brain through a bidirectional microbiota-gut-brain axis. The composition of the gut flora changes considerably with age, and ecological dysregulation has been recognized as one of the twelve most recent hallmarks of aging. Recent studies have linked these changes to a variety of age-related neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, and Huntington's disease. Specifically, the gut microbiota influences the brain through the production of key metabolites such as short-chain fatty acids and the activation of inflammatory and other relevant signaling pathways. In preclinical studies, targeted modulation of the gut microbiota, through methods such as fecal microbiota transplantation, probiotics, and prebiotics, has demonstrated potential in improving host behavioral outcomes. Therefore, gut microbiotabased treatments offer new hope for the treatment of nervous system diseases. However, due to the complexity of the gut microbiota and the potential adverse reactions associated with these therapies, researchers need to carefully assess their safety and efficacy before widespread clinical application.}, } @article {pmid40903895, year = {2026}, author = {Higgins, A and Tewolde, S and Page, SD and Rubenstein, E}, title = {The Occurrence of Obstructive Sleep Apnea and Its Association With Alzheimer Dementia in Medicaid-Enrolled Adults With Down Syndrome, 2011-2019.}, journal = {American journal of medical genetics. Part A}, volume = {200}, number = {1}, pages = {129-136}, pmid = {40903895}, issn = {1552-4833}, support = {R01 AG073179/AG/NIA NIH HHS/United States ; R01AG073179/AG/NIA NIH HHS/United States ; R01AG073179/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Down Syndrome/complications/epidemiology ; *Sleep Apnea, Obstructive/epidemiology/complications ; *Alzheimer Disease/epidemiology/complications/etiology ; Male ; Female ; United States/epidemiology ; Adult ; Medicaid ; Middle Aged ; Prevalence ; Aged ; Risk Factors ; }, abstract = {Down syndrome is a condition caused by trisomy of chromosome 21 and is the most common genetic cause of intellectual disability. Due to distinct body and facial morphology, people with Down syndrome appear to be at increased risk for obstructive sleep apnea (OSA). Additionally, adults with Down syndrome are at increased risk for Alzheimer dementia at younger ages than the general population, and OSA has been identified as a risk factor for Alzheimer dementia in the general population. This study aims to explore the prevalence of diagnosed OSA, as well as the association between OSA and Alzheimer dementia, in adults with Down syndrome using Medicaid claims data from2011 to 2019. Of 118,539 adults with Down syndrome who met inclusion criteria, 23,785 had at least one OSA claim from2011 to 2019 (20.1%, 95% CI 19.8%-20.3%). After weighting for age, sex, dual enrollment, race, ethnicity, and region, adults with Down syndrome and OSA claims had 1.08 times the hazard of having a claim for Alzheimer dementia compared to those without OSA claims (95% CI 1.05-1.10). OSA is common in adults, and our findings have clinical implications for its evaluation and treatment in those with Down syndrome.}, } @article {pmid40903623, year = {2025}, author = {Anzai, Y and Minoshima, S}, title = {The role of brain MR and FDG-PET in the diagnosis of neurodegenerative disease.}, journal = {European radiology}, volume = {}, number = {}, pages = {}, pmid = {40903623}, issn = {1432-1084}, abstract = {Alzheimer disease (AD) is the most common dementing disorder, affecting 55 million people worldwide. Brain MRI plays an integral role in the diagnostic evaluation of patients with cognitive symptoms. When interpreting brain MRI for cognitive impairment, radiologists should assess the following four key features: (1) white matter ischemic burden, (2) structural changes to suggest normal pressure hydrocephalus, (3) locoregional pattern of brain atrophy, and (4) presence of microhemorrhage or superficial siderosis, particularly for determining eligibility for anti-amyloid monoclonal antibody (MAB) treatment when appropriate. The recent approval and clinical adoption of anti-amyloid MAB expanded the role of neuroradiologists in evaluating eligibility and monitoring ARIA (amyloid-related imaging abnormality) among patients receiving anti-amyloid MAB. This advancement underscores the importance of standardized imaging protocols and effective communication between neuroradiologists and cognitive neurologists. Depending on the severity of ARIA and patients' symptoms, treatment may need to be suspended or discontinued. This review article explores brain MRI and FDG-PET/CT imaging abnormalities in patients with major cognitive and movement disorders associated with dementia. It aims to assist radiologists in providing differential diagnoses within a clinical context. Finally, the article emphasizes the importance of recognizing co-pathologies, since patients may have more than one neurodegenerative disease rather than viewing these neurodegenerative diseases as being mutually exclusive. KEY POINTS: Question Traditional regional patterns of brain atrophy on MRI by neuroradiologists may not be effective given the recent advances in understanding of neurodegenerative disease and recognition of co-pathologies. Findings The locoregional atrophy and the patterns of metabolic abnormality help in the differential diagnosis of neurodegenerative disease. Remember that brain MRI determines eligibility for anti-amyloid immunotherapy. Clinical relevance Understanding clinical history is vital for interpreting brain MRI for patients with cognitive impairment or memory loss. Newly recognized entities such as limbic-predominant age-related TDP43 encephalopathy (LATE) can mimic Alzheimer disease among extremely elderly patients with amnestic symptoms with mesial temporal lobe atrophy.}, } @article {pmid40903613, year = {2025}, author = {Horn, A and Neumann, WJ}, title = {From adaptive deep brain stimulation to adaptive circuit targeting.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {10}, pages = {556-566}, pmid = {40903613}, issn = {1759-4766}, mesh = {Humans ; *Deep Brain Stimulation/methods ; Parkinson Disease/therapy ; *Brain/physiology/physiopathology ; }, abstract = {Deep brain stimulation (DBS) substantially improves motor symptoms and quality of life in people with movement disorders such as Parkinson disease and dystonia, and it is also being explored as a treatment option for other brain disorders, including treatment-resistant obsessive-compulsive disorder, Alzheimer disease and depression. Two major developments are currently driving progress in DBS research: first, the framework of adaptive DBS, which senses brain activity to infer the momentary state of the symptoms of a patient and reacts by adapting stimulation settings, and second, the concept of connectomic DBS, which identifies brain circuits that should optimally be stimulated to reduce specific symptoms. In this Perspective, we propose a unified framework that combines these two concepts. Our approach, termed adaptive circuit targeting, decodes symptom severity from brain signals and adaptively activates the most relevant symptom-response circuits. We discuss the state of the art in the adaptive and connectomic DBS fields and the research gaps that need to be addressed to unify these concepts.}, } @article {pmid40903459, year = {2025}, author = {Zhang, B and Zhang, S and Guo, Z and Hong, C and Zhang, F and Lin, H}, title = {Nesfatin-1 ameliorates blood-brain barrier dysfunction in Alzheimer's disease by targeting VEGF-R1 and reducing cellular senescence in brain vascular endothelial cells.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {341}, pmid = {40903459}, issn = {2158-3188}, mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects/physiopathology ; *Nucleobindins/metabolism ; *Cellular Senescence/drug effects ; *Alzheimer Disease/metabolism/physiopathology ; Mice ; *Endothelial Cells/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; Peptide Fragments ; Brain/metabolism ; Mice, Transgenic ; Male ; Disease Models, Animal ; Humans ; }, abstract = {Cellular senescence and associated endothelial permeability are crucial factors in the dysfunction of the blood-brain barrier (BBB) in neurodegenerative diseases, including Alzheimer's disease (AD). Nesfatin-1 (NF-1), a neuropeptide involved in regulating appetite and energy homeostasis, has not been extensively studied for its pathophysiological role in AD. In this study, we found that NF-1 treatment improved cellular senescence in brain vascular endothelial bEnd.3 cells by restoring the expression of hTERT and TERF2 against oligomerized Aβ1-42. Additionally, NF-1 reduced p53 and p21 protein levels in bEnd.3 cells exposed to oligomerized Aβ1-42. Notably, NF-1 reduced oligomerized Aβ1-42-induced endothelial monolayer permeability by maintaining transendothelial electric resistance (TEER) and the levels of tight junction proteins claudin 5 and ZO-1. Furthermore, NF-1 suppressed the expression of VEGF-R1 but not VEGF-R2 in bEnd.3 cells exposed to oligomerized Aβ1-42. Overexpression of VEGF-R1 negated the protective effects of NF-1 against oligomerized Aβ1-42-induced cellular senescence and increased endothelial monolayer permeability, indicating the involvement of VEGF-R1 in this process. Using a transgenic (Tg APPswe/PSEN1dE9) AD mouse model, we demonstrated that NF-1 administration lowered VEGF-R1 expression in the brain cortex of AD mice. Moreover, NF-1 mitigated BBB dysfunction and enhanced the expression of claudin 5 and ZO-1 in the brains of AD mice. Our results suggest that NF-1 may be a potential therapeutic strategy for treating AD.}, } @article {pmid40902672, year = {2025}, author = {Sharma, S and Bashir, B and Kolekar, KA and Acharya, A and Gupta, M and Jena, R and Vishwas, S and Kaur, J and Gupta, G and Kumbhar, PS and Patle, D and Chaitanya, M and Gulati, M and Singh, SK}, title = {Tailoring the biomarkers of Alzheimer's disease using a gut microbiome-centric approach: Preclinical, clinical, and regulatory perspectives.}, journal = {Ageing research reviews}, volume = {112}, number = {}, pages = {102888}, doi = {10.1016/j.arr.2025.102888}, pmid = {40902672}, issn = {1872-9649}, mesh = {Humans ; *Alzheimer Disease/therapy/metabolism/microbiology/diagnosis ; *Gastrointestinal Microbiome/physiology ; Biomarkers/metabolism ; Probiotics/therapeutic use ; Animals ; Fecal Microbiota Transplantation/methods ; Dysbiosis ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, poses significant therapeutic challenges due to its complex etiology and limited treatment options. Traditional pharmacotherapies targeting amyloid-β (Aβ) and cholinergic pathways offer modest benefits and are often associated with adverse effects. Emerging evidence implicates gut dysbiosis and the gut-brain axis in the pathogenesis and progression of AD. This review explores the multifactorial pathophysiology of AD and evaluates the therapeutic potential of gut-based interventions such as probiotics, prebiotics, synbiotics, metabiotics, postbiotics, and fecal microbiota transplantation (FMT) in mitigating disease pathology. Emphasis has also been given on role of miRNA released from FMT in management of AD. Preclinical and clinical studies demonstrate that these strategies can restore microbial homeostasis, reduce neuroinflammation, enhance gut barrier integrity, and improve cognitive outcomes. The regulatory aspects with use of probiotics based products and FMT is also highlighted. The modulation of neuroimmune, neuroendocrine, and neural pathways through microbiota-derived metabolites offers a promising avenue for AD management. Despite encouraging findings, further research is needed to address interindividual microbiome variability, delivery challenges, and the requirement for large-scale, randomized trials. Personalized gut-targeted approaches may open new horizons for the prevention and treatment of AD.}, } @article {pmid40901302, year = {2025}, author = {Stothart, G and Alderman, S and Hermann, O and Creavin, S and Coulthard, EJ}, title = {A passive and objective measure of recognition memory in mild cognitive impairment using Fastball memory assessment.}, journal = {Brain communications}, volume = {7}, number = {5}, pages = {fcaf279}, pmid = {40901302}, issn = {2632-1297}, abstract = {As viable pharmacotherapies and blood biomarkers emerge for dementia treatment and screening, there remains a great need for accurate, sensitive biomarkers of cognitive function. We have previously demonstrated that Fastball, a new Electroencephalography (EEG) method for the passive and objective measurement of recognition memory that requires no behavioural memory response or task comprehension, is sensitive to cognitive dysfunction in Alzheimer's disease. Here we present new evidence that Fastball is sensitive to amnestic dysfunction in an earlier stage of the dementia lifecourse, Mild Cognitive Impairment (MCI). 53 MCI patients and 54 healthy older adult (HOA) controls completed a 3-min Fastball task in which they passively viewed rapidly presented images while EEG captured their automatic ability to differentiate between images based on previous exposure. They also completed neuropsychological assessments of memory (Delayed Match to Sample-48), sustained attention (Psychomotor Vigilance Task), and general cognitive function (Addenbrookes Cognitive Exam-iii). Participants were re-tested after 1 year to establish the test-retest reliability of Fastball in HOAs, and the sensitivity of Fastball to cognitive decline in MCI patients, over a 1 year period. Amnestic MCI patients showed significantly reduced Fastball responses compared with non-amnestic MCI patients (P = 0.001, Cohen's d = 0.98) and HOA controls (P = 0.005, Cohen's d = 0.64). Regression analyses showed that Fastball EEG responses were selectively predictive of neuropsychological measures of recognition memory and not attention. Between baseline and year one follow-up Fastball showed moderate to good test-retest reliability in HOA controls, and the six MCI-dementia converters showed a trend for lower Fastball responses at baseline which will be confirmed with further longitudinal assessment. Fastball is further validated as a viable method for testing recognition memory in cognitively impaired populations. We have demonstrated that it is selectively predictive of memory dysfunction and not attention or other cognitive functions. It is passive, non-invasive, quick to administer and uses cheap, scalable EEG technology. Fastball is a viable functional biomarker that can help to advance cognitive assessment in MCI.}, } @article {pmid40899945, year = {2025}, author = {Saido, TC and Iwata, N}, title = {The tale of donanemab: God is in the details.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {4}, pages = {1364-1373}, pmid = {40899945}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; Animals ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; }, abstract = {Alzheimer's disease is a major cause of dementia, that affects approximately 7-8% of people aged 65 years and older (according to WHO & Alzheimer's Disease International) and thus is a major concern in public health world-wide. This review chronicles the foundational research and translational trajectory leading to the development of donanemab, a monoclonal antibody targeting pyroglutamyl amyloid-β (Aβ3pE-X) peptides, recently approved for the treatment of early Alzheimer's disease (AD). We trace a 30-year arc from the biochemical identification of Aβ species to the recognition of Aβ3pE-42 as a predominant pathological isoform in AD and Down syndrome brains-a fact still underrecognized among clinicians and researchers. We highlight key breakthroughs in antibody generation, Aβ peptide biochemistry, and resistance to enzymatic degradation. Mechanistic distinctions between donanemab (Kisunla[®]), and lecanemab (Leqembi[®]) are also explored, along with therapeutic implications for targeting specific Aβ species at preclinical stages of disease. The review emphasizes how persistent biochemical research, fueled by intellectual curiosity, serendipity, and rigorous experimentation, has culminated in clinical proof-of-concept for the amyloid hypothesis. In addition to its molecular specificity, donanemab's development underscores a critical shift toward precision medicine in Alzheimer's care. Its clinical validation, though limited in scope, reinforces the need for scalable and affordable interventions that can address the growing global burden of dementia. We expect these therapeutic antibodies to contribute to reducing the global burden by ceasing the disease progression in a preclinical stage now that new methods for fluid biomarkers are becoming available. As the global population ages, understanding and addressing AD has become a top priority in neuroscience and public health.}, } @article {pmid40899340, year = {2025}, author = {Zamanian, MY and Khachatryan, LG and Heidari, M and Darabi, R and Golmohammadi, M and Al-Aouadi, RFA and Akkol, EK}, title = {The Therapeutic Potential of Flavonols in Alzheimer's Disease: Inhibiting Amyloid-β, Oxidative Stress, and Neuroinflammation.}, journal = {BioFactors (Oxford, England)}, volume = {51}, number = {5}, pages = {e70047}, doi = {10.1002/biof.70047}, pmid = {40899340}, issn = {1872-8081}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology/genetics ; Oxidative Stress/drug effects ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors/genetics ; *Flavonols/pharmacology/therapeutic use ; Animals ; Kaempferols/pharmacology ; Flavonoids/pharmacology ; *Neuroprotective Agents/pharmacology ; Quercetin/pharmacology ; Mice ; Humans ; Male ; Mitochondria/drug effects ; *Neuroinflammatory Diseases/drug therapy ; Signal Transduction/drug effects ; Amyloid Precursor Protein Secretases/genetics/metabolism ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) aggregation, oxidative stress, and neuroinflammation, remains a significant global health challenge. This study investigates the therapeutic potential of flavonols-quercetin, kaempferol, myricetin, and fisetin-in targeting Aβ aggregation and mitigating AD pathology through diverse molecular mechanisms. Our findings reveal that flavonols effectively inhibit Aβ oligomerization and fibril formation, reduce oxidative stress via Nrf2/HO-1 pathway activation, and suppress neuroinflammation by modulating microglial polarization. Additionally, these compounds enhance mitochondrial function, promote autophagy-mediated clearance of Aβ aggregates, and regulate key enzymes such as β-secretase (BACE1) and α-secretases (ADAM10/17), favoring non-amyloidogenic pathways. Quercetin demonstrated neuroprotective effects by activating TrkB signaling, reducing tau phosphorylation, and enhancing synaptic plasticity. Kaempferol prevented Aβ-induced apoptosis via the ER/ERK/MAPK pathway and inhibited acetylcholinesterase activity, improving cognitive outcomes. Myricetin ameliorated mitochondrial dysfunction and oxidative damage through GSK3β/ERK2 signaling modulation and showed enhanced brain bioavailability when delivered via nanostructured lipid carriers. Fisetin reduced Aβ burden by upregulating neprilysin expression, suppressed neuroinflammation, and improved synaptic function by restoring synaptic protein levels. Overall, flavonols exhibit multi-targeted therapeutic potential against AD by addressing its complex pathogenesis. Their ability to cross the blood-brain barrier and low toxicity profiles position them as promising candidates for further clinical development. This study underscores the potential of flavonols as natural agents for AD treatment and highlights their role in advancing multi-mechanistic therapeutic strategies.}, } @article {pmid40898925, year = {2025}, author = {Park, HA and Amjad, E and Burnett, G and Ferdous, KA and Scott, M and Jansen, J and Bannerman, S and Scott, M and Correll, RN and Ciesla, L and Ellis, A}, title = {Oral supplementation of fucoxanthin regulates gene expression in the brain of middle-aged rats.}, journal = {The British journal of nutrition}, volume = {134}, number = {6}, pages = {451-461}, doi = {10.1017/S0007114525104996}, pmid = {40898925}, issn = {1475-2662}, mesh = {Animals ; *Xanthophylls/pharmacology/administration & dosage ; Male ; Rats, Sprague-Dawley ; Oxidative Stress/drug effects ; Rats ; *Brain/metabolism/drug effects ; *Dietary Supplements ; *Aging ; Antioxidants/pharmacology/administration & dosage ; *Gene Expression Regulation/drug effects ; Lipid Peroxidation/drug effects ; Administration, Oral ; Neurons/drug effects/metabolism ; }, abstract = {Age is the main risk factor for many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and frontotemporal dementia. Despite our limited understanding of cellular mechanisms of ageing-associated neuronal loss, an increasing number of studies demonstrate that oxidative stress and inflammation are key drivers. Epidemiological studies indicate that diet during middle adulthood can influence the risk of developing neurodegenerative diseases later in life, so it is important to investigate dietary interventions to combat oxidative stress and inflammation. In this study, we hypothesised that treatment with fucoxanthin, a marine carotenoid with strong antioxidant properties, prevents ageing-associated oxidative stress that is known to be related to natural brain ageing. Treatment with fucoxanthin protected rat primary hippocampal neurons against oxidative stress and ageing in vitro. In our in vivo study, middle-aged male Sprague-Dawley rats were gavaged with fucoxanthin (1 mg/kg, 5 d/week, n 6) or vehicle (n 6) for 4 weeks. After supplementation was completed, brain samples were harvested and subjected to quantitative and bioinformatic analyses. Fucoxanthin was detected and shown to decrease lipid peroxidation in the brains of the animals supplemented with fucoxanthin. Microarray analysis showed that treatment with fucoxanthin changed 5602 genes. Together, our results suggest that treatment with fucoxanthin prevents ageing-associated oxidative stress and is capable of regulating genes that potentially ameliorate age-related changes to the brain.}, } @article {pmid40898264, year = {2025}, author = {Drinkall, NJ and Siersma, V and Lathe, R and Waldemar, G and Janbek, J}, title = {Herpesviruses, antiviral treatment, and the risk of dementia - systematic review and meta-analysis.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {201}, pmid = {40898264}, issn = {1758-9193}, mesh = {Humans ; *Antiviral Agents/therapeutic use ; *Dementia/epidemiology/virology ; *Herpesviridae Infections/drug therapy/complications/epidemiology ; *Herpesviridae ; Risk Factors ; }, abstract = {INTRODUCTION: The aim of this systematic review and meta-analysis was to synthesize the evidence on the association between herpesviruses, antiviral treatment, and the risk of dementia. We also aimed to explore the impact of time between herpesviruses and dementia on the reported associations. METHODS: PubMed and Web of Science were searched along with reference lists of the included studies. We included studies that looked at clinical episodes or serology (IgG/IgM) of herpes simplex virus type 1/2 (HSV1/2) and/or varicella zoster virus (VZV), antiviral treatment and incident dementia (all-cause dementia, Alzheimer's disease, and vascular dementia). Study results were pooled with random effect meta-analyses. RESULTS: We included 32 studies. The pooled hazard ratio for all-cause dementia was 1.36 [95% CI: 1.01, 1.83] following a clinical episode of HSV1/2, and 1.12 [95% CI: 1.00, 1.25] following a clinical episode of VZV. The pooled estimate for all-cause dementia following antiviral treatment and VZV was 0.88 [95% CI: 0.81, 0.96]. CONCLUSIONS: The present review of the scientific literature generally shows little evidence of an association between herpesviruses and risk of dementia. However, the review shows evidence of an association between antiviral treatment and a decreased risk of dementia. Because of considerable heterogeneity, future investigations could advantageously target certain subgroups.}, } @article {pmid40896959, year = {2025}, author = {Yun, J and Moon, M and Yang, J and Yeom, HD and Lee, MH and Lee, G and Lee, JH}, title = {Molecular regulation and subtype-specific effects of naringenin and naringin on nicotinic acetylcholine receptors expressed in Xenopus oocytes.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {191}, number = {}, pages = {118494}, doi = {10.1016/j.biopha.2025.118494}, pmid = {40896959}, issn = {1950-6007}, mesh = {*Flavanones/pharmacology ; Animals ; *Receptors, Nicotinic/metabolism/genetics ; Xenopus laevis ; *Oocytes/metabolism/drug effects ; Molecular Docking Simulation ; Humans ; Mutagenesis, Site-Directed ; Female ; Dose-Response Relationship, Drug ; *Nicotinic Antagonists/pharmacology ; }, abstract = {Naringenin and naringin, bioactive flavonoids from citrus fruits, exhibit neuroprotective effects, showing promise for neurodegenerative diseases like Alzheimer's and Parkinson's. Additionally, they demonstrate significant anticancer potential, modulating key signaling pathways involved in tumor growth, apoptosis, and metastasis, thus expanding their therapeutic applications in cancer treatment. These compounds interact with nicotinic acetylcholine receptors (nAChRs), a class of ligand-gated ion channels critical for modulating neurotransmission within the central nervous system. In this study, naringenin and naringin were found to selectively inhibit specific subtypes of nAChRs in a concentration-dependent, reversible, and noncompetitive manner. These effects were examined using two-electrode voltage-clamp recordings in Xenopus laevis oocytes heterologously expressing various human nAChR subtypes, and further analyzed by site-directed mutagenesis and molecular docking simulations to identify key binding residues. Mutational analyses, supported by molecular docking, revealed that certain mutations in nAChRs eliminate naringin's inhibitory effect, highlighting a selective binding affinity. This inhibition was observed selectively in α3β2 and α3β4 nAChR subtypes, which are significant within the autonomic nervous system, while α7 and α4β2 nAChRs, often implicated in neurodegenerative processes, remained unaffected. These findings suggest that naringenin and naringin could be developed as targeted modulators of nAChRs, offering therapeutic potential.}, } @article {pmid40896796, year = {2025}, author = {Dirir, AM and Ali, A and Hachem, M}, title = {Recent Advancements in Lipid Nanoparticles-Based Phytoactives Delivery Systems for Neurodegenerative Diseases.}, journal = {International journal of nanomedicine}, volume = {20}, number = {}, pages = {10279-10300}, pmid = {40896796}, issn = {1178-2013}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; Blood-Brain Barrier/metabolism ; Animals ; *Phytochemicals/administration & dosage/pharmacokinetics/chemistry ; *Nanoparticles/chemistry ; *Neuroprotective Agents/administration & dosage/pharmacokinetics/chemistry ; *Lipids/chemistry ; Drug Carriers/chemistry ; *Drug Delivery Systems/methods ; }, abstract = {Neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, pose a significant and continuous burden on the healthcare system, urging the search for innovative therapeutical approaches targeting the central nervous system. Nowadays, no definitive treatment can effectively modulate the neuronal degeneration associated with such diseases. The current line of therapies is primarily symptomatic and suffers several drawbacks. Among these, phytochemicals are emerging for their potential in the management of neurodegenerative disorders. Indeed, plants produce secondary metabolites that provide defensive functions against abiotic and biotic stresses. These metabolites can target the neurons and represent a promising therapeutic intervention for neurological disorders. However, the polar nature of phytochemicals and their large size hinder their passage through the blood-brain barrier, a selective barrier separating blood and the brain. Emerging studies have shown that the therapeutic efficiency of phytochemicals has been enhanced following their encapsulation with engineered nanocarriers such as lipid nanoparticles. Recent research indicates that delivering phytochemicals through lipid nanoparticles improves their physiological stability, promotes their passage across the blood-brain barrier, and enhances their accumulation in brain tissue-resulting in more effective neuroprotective effects than their free, unencapsulated form. Hence, the aim of the present review is to highlight the application of lipid nanoparticles as carriers for phytoactives with neuroprotective properties, discuss the current challenges associated with such nanocarriers, and provide insights into potential future research work.}, } @article {pmid40896259, year = {2025}, author = {Xu, J and Jin, H and Li, X and Jiang, Z and Meng, F and Wang, W and Li, WY}, title = {ADAM17 Inhibition Protects Cognition in Intermittent Hypoxia: The Role of TREM2.}, journal = {Nature and science of sleep}, volume = {17}, number = {}, pages = {1915-1928}, pmid = {40896259}, issn = {1179-1608}, abstract = {PURPOSE: The triggering receptor expressed on myeloid cells 2 (TREM2) is a new therapeutic target in Alzheimer's disease. However, its role in obstructive sleep apnea (OSA)-related cognitive impairment is still unclear. This study aimed to investigate the effect and regulatory mechanism of TREM2 on cognitive impairment related to OSA. METHODS: Since intermittent hypoxia (IH) is the primary pathophysiologic characteristic of OSA, we conducted IH animal and BV2 cell model to investigate the mechanism. Trem2 knockdown and Trem2 overexpression cells were created by Lentivirus transfection. A disintegrin and metalloprotease 17 (ADAM17) is the primary enzyme for TREM2 shedding, we used TAPI-1 to inhibit its activity. Morris water maze, Nissl staining, real-time PCR, immunofluorescence, Western blotting, fluorometric assay kit, and enzyme-linked immunosorbent assay were used to explore the molecular mechanism. RESULTS: The TREM2 levels were decreased in BV2 cells exposed to IH for 24 hours. IH elevated the levels of IL-1β, TNF-α and CD86 in BV2 cells, as well as the levels of p-Tau in conditioned media-cultured HT-22 cells. Conversely, IH reduced the levels of IL-10 and CD206 in BV2 cells. However, these effects were exacerbated in BV2 cells with Trem2 knockdown, whereas they were mitigated in those with Trem2 overexpression. Additionally, the ADAM17 activity and soluble TREM2 (sTREM2) levels were increased in BV2 cells subjected to IH. Treatment with TAPI-1, suppressed ADAM17 activity and restored TREM2 expression both in vitro and in vivo. Inhibition of ADAM17 led to a reduction in the expression of CD86, IL-1β, TNF-α and p-Tau levels, while enhancing the expression of CD206, IL10 and cognitive functions. CONCLUSION: TREM2 played a protective role in IH-induced neuroinflammation and neuronal injury by promoting microglia M2 polarization. IH caused excessive activation of ADAM17 and resulted in augmented degradation of TREM2. Restoring TREM2 expression by inhibiting ADAM17 indicates a potentially promising therapeutic strategy for cognitive impairment in OSA.}, } @article {pmid40895811, year = {2025}, author = {Tysinger, B and Wei, Y and Heun-Johnson, H and Zissimopoulos, JM}, title = {Long-term value of lecanemab to individuals and families.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70151}, pmid = {40895811}, issn = {2352-8737}, abstract = {INTRODUCTION: An assessment of the value of lecanemab for patients living with Alzheimer's disease (AD) and their care partners provides them and their health-care providers important information for deciding treatment initiation. METHODS: We used data from a nationally representative sample of middle aged and older Americans combined with data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) on AD progression and data on lecanemab treatment effects from Clarity AD clinical trials. We use dynamic microsimulation modeling to quantify the long-term health and economic value of lecanemab for persons living with AD and their care partners. RESULTS: We quantified five measures of value: quality of life of the persons living with AD and their care partners, medical costs, caregiving costs, and earnings, and estimated that lecanemab had a value of $21,398 relative to no treatment after 4 years and $37,943 after 10 years. Extending the treatment to 48 months resulted in a value of $42,821 relative to no treatment after 4 years and $95,311 after 10 years. Forty-eight months of a similar next-generation therapy but with 50% efficacy in slowing cognitive and functional decline resulted in a value of $82,116 relative to no treatment after 4 years and $189,691 after 10 years. DISCUSSION: Over time, lecanemab treatment reduced medical costs, hours of care required from care partners, and improved quality of life. There is much value to be gained with next-generation treatments that have a larger impact on slowing decline. Considering a wider range of outcomes in future assessments will provide a more complete understanding of value to support decision making about treatment initiation and about reimbursement for payers. HIGHLIGHTS: There is significant value of lecanemab for persons with mild cognitive impairment or mild dementia.Over time, lecanemab reduces medical costs, caregiver hours, and improves the quality of life of persons living with Alzheimer's disease (AD) and their care partners.A next-generation treatment for AD with similar features to lecanemab but higher efficacy, more than doubles the value.Assessing therapy value supports decision making by patients and their health-care providers.}, } @article {pmid40895150, year = {2025}, author = {Chen, G and Su, Y and Chen, S and Lin, T and Lin, X}, title = {Polyphenols and Alzheimer's Disease: A Review on Molecular and Therapeutic Insights With In Silico Support.}, journal = {Food science & nutrition}, volume = {13}, number = {9}, pages = {e70496}, pmid = {40895150}, issn = {2048-7177}, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, characterized by amyloid-beta (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation resulted the cognitive memory loss. Despite extensive research, effective therapeutic treatment remains elusive. Polyphenols, naturally occurring bioactive compounds, have emerged as promising neuroprotective agents due to their potent antioxidant, anti-inflammatory, and amyloid-modulating properties. Research indicated that these bioactive compounds have potent antioxidant and anti-inflammatory properties, have garnered significant attention for their potential role in combating AD by targeting its key pathological mechanisms. Preclinical studies highlight the efficacy of various polyphenols, such as resveratrol, curcumin, and epigallocatechin gallate, in improving cognitive function and reducing neurodegeneration. Moreover, in silico approaches, displayed polyphenols mechanistic interactions with key AD targets to reduce pathogenesis. These computational models accelerate drug discovery by predicting binding affinities, optimizing structural modifications, and identifying novel polyphenol derivatives with enhanced therapeutic potential. This review explores the multifaceted role of polyphenols in AD mitigation, emphasizing their impact on oxidative stress and neuroinflammation while integrating in silico evidence to reinforce their therapeutic relevance. Convincingly, through the suppression of key mediators of AD, including oxidative stress, neuroinflammation, amyloid-beta and tau proteins, polyphenols exhibited outstanding therapeutic potential to treat AD.}, } @article {pmid40894925, year = {2025}, author = {He, G and Huang, J and Zeng, Z and Sun, H and Wu, C and Xu, Q and Hu, C and Jin, B and Tong, M and Wang, C}, title = {Stem cell therapy offers new hope for the treatment of Alzheimer's disease.}, journal = {Frontiers in cell and developmental biology}, volume = {13}, number = {}, pages = {1650885}, pmid = {40894925}, issn = {2296-634X}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory impairment and cognitive decline, for which no curative treatment is currently available. Existing therapeutic strategies, such as cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, can only provide limited symptomatic relief and fail to halt disease progression. In recent years, stem cell therapy has emerged as a promising approach for AD due to its multifaceted mechanisms of action. The therapeutic effects of stem cells in AD are mainly attributed to their ability to differentiate into functional neurons or glial cells, thereby replacing damaged cells and repairing neural networks. In addition, stem cells secrete neurotrophic and anti-inflammatory factors that contribute to the improvement of the brain microenvironment. Furthermore, they can regulate neuroinflammation, promote the clearance of β-amyloid (Aβ) deposits, and suppress neuroinflammation, thus potentially slowing disease progression. However, several challenges remain, including low cell survival rates, immune rejection, tumorigenic risks, and difficulties in crossing the blood-brain barrier. Looking ahead, the integration of advanced technologies such as organoid models, gene editing, artificial intelligence, and multi-omics approaches may drive substantial progress in the clinical translation of stem cell therapies for AD. Although still in its early stages, the future of this therapeutic strategy holds great promise.}, } @article {pmid40894255, year = {2025}, author = {Hu, N and Chen, L and Hu, G and Ma, R}, title = {Advancements in extracellular vesicle therapy for neurodegenerative diseases.}, journal = {Exploration of neuroprotective therapy}, volume = {5}, number = {}, pages = {}, pmid = {40894255}, issn = {2769-6510}, support = {R01 DA043138/DA/NIDA NIH HHS/United States ; R01 MH112848/MH/NIMH NIH HHS/United States ; R21 DA042704/DA/NIDA NIH HHS/United States ; R21 DA046831/DA/NIDA NIH HHS/United States ; }, abstract = {Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.}, } @article {pmid40894003, year = {2025}, author = {Kridawati, A and Indrawati, L and Hadisaputra, S and Adawiyah, AR}, title = {The preventive role of tempeh isoflavones on menopausal women's cognitive function: A multiple mechanism pathway.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251371284}, pmid = {40894003}, issn = {2542-4823}, abstract = {Cognitive dysfunction in the elderly is not only a disease but also could be considered a preclinical condition of Alzheimer's disease (AD), one of the most common types of dementia in the elderly. Therefore, treatment such as early detection and management of risk factors that could slow and prevent the onset of dementia is necessary for the elderly. Estrogen reduces the risk of AD in postmenopausal women. It has also been shown to reduce amyloid-β (Aβ) pathology in animal models of AD and suppress Aβ secretion from neuronal tissue. Estrogen receptors are involved in cognitive processes such as learning and memory, the formation of the hippocampus, the amygdala, and the cerebral cortex. Hormone replacement therapy (HRT) could improve cognition and thus delay the development of AD. Giving HRT after 9 years has been shown to increase the risk of breast cancer two-fold and cardiovascular disease. Phytoestrogens are hormones found in plants that can be an alternative to HRT. One of the foods that contains phytoestrogens and is widely consumed in Indonesia is tempeh. Isoflavone is a dominant phytoestrogen, structurally an estrogen-like substance, and functionally similar to 17β-estradiol. In this review article, we will discuss the role of tempeh isoflavones in a mechanism pathway on cognition.}, } @article {pmid40893997, year = {2025}, author = {Mokwenye, RC}, title = {A thematic analysis of Lay knowledge and beliefs about dementia among first-generation Black African immigrants from West Africa living in London: Informed by a grounded theory approach.}, journal = {Journal of public health research}, volume = {14}, number = {3}, pages = {22799036251368446}, pmid = {40893997}, issn = {2279-9028}, abstract = {BACKGROUND: Many Black Africans live in the UK. More than 850,000 people live with dementia in the UK, and more than 25,000 people with dementia are from Black and minority ethnic groups. The study explores themes of lay knowledge and beliefs about dementia. DESIGN AND METHODS: This study employs a qualitative research design and methods to explore lay knowledge and beliefs about dementia amongst Black African populations living in London. The research is philosophically underpinned by social constructionism and sociological and anthropological lay concepts of health and illness. The researcher interviewed 31 adult respondents, male and female, from the Black African community in London to generate rich data. Participants were first-generation immigrants from West Africa living in London and were mainly carers. Thematic data analysis informed by a grounded theory approach was used to analyse the data. RESULTS: The findings show that dementia is a complex biopsychosocial phenomenon. Four key themes with subthemes emerged and were developed: (i) Traditional views, (ii) Disease and illness, (iii) Help-seeking, and (iv) Caregiving and treatment. The group's understanding of dementia evolved from traditional views to a more medical perspective. This study added witchcraft to the dementia literature on BAME in the UK. CONCLUSIONS: The study concluded that the group does not lack knowledge of dementia. Their understanding and beliefs about dementia are evolving, and further efforts are needed to enhance awareness through education, training, and outreach to support individuals with dementia and their families within the Black African community.}, } @article {pmid40893935, year = {2025}, author = {Wu, H and Shi, J and Wang, X and Yang, M and Cai, J}, title = {A rare intronic c.2654+1G>A mutation in CSF1R-microglial encephalopathy: a case report.}, journal = {Frontiers in genetics}, volume = {16}, number = {}, pages = {1593964}, pmid = {40893935}, issn = {1664-8021}, abstract = {OBJECTIVE: We report a case of CSF1R-microglial encephalopathy associated with a rare intronic c.2654 + 1G>A mutation, featuring negative diffusion-weighted imaging (DWI) findings and a cerebrospinal fluid (CSF) biomarker profile indicative of Alzheimer's disease-related changes, and we explore the associations between genetic mutations, CSF biomarker alterations, and neuroimaging manifestations. METHODS: This study documents the demographic data, detailed medical history, and clinical manifestations of a patient with CSF1R-microglial encephalopathy. The medical histories of some family members were collected, and the proband underwent whole-exome sequencing (WES) for diagnostic confirmation. RESULTS: The patient, a 53-year-old woman, presented with early-onset cognitive decline, personality changes, and behavioral abnormalities. Neuropsychological testing revealed severe cognitive impairment, and the CSF biomarker profile suggested Alzheimer's disease-related changes. Cranial MRI showed bilateral, symmetric deep white matter changes, brain atrophy (including corpus callosum thinning), and low signal intensity on DWI. Family history revealed that 3 out of 19 individuals across four generations, including the proband, her aunt, and her sister, developed dementia and progressed to severe cognitive impairment rapidly. WES analysis revealed a heterozygous c.2654 + 1G>A variant in the CSF1R gene (NM_005211.3), confirming a diagnosis of CSF1R-microglial encephalopathy caused by a dominant autosomal mutation in exon 20 of the CSF1R gene. CONCLUSION: CSF1R-microglial encephalopathy is a progressive disorder with diverse early clinical presentations, making it prone to misdiagnosis and delayed treatment. This case suggests that, contrary to previous findings, negative DWI results should not exclude CSF1R-microglial encephalopathy. In addition, CSF biomarker profiles in patients with CSF1R-microglial encephalopathy may exhibit Alzheimer's disease-related changes. Early genetic testing is critical, and for genetically linked diseases, testing other family members can help ensure early diagnosis and intervention.}, } @article {pmid40893870, year = {2025}, author = {Kwak, MG and Mao, L and Zheng, Z and Su, Y and Lure, F and Li, J}, title = {A Cross-Modal Mutual Knowledge Distillation Framework for Alzheimer's Disease Diagnosis: Addressing Incomplete Modalities.}, journal = {IEEE transactions on automation science and engineering : a publication of the IEEE Robotics and Automation Society}, volume = {22}, number = {}, pages = {14218-14233}, pmid = {40893870}, issn = {1545-5955}, support = {P30 AG072980/AG/NIA NIH HHS/United States ; R01 AG069453/AG/NIA NIH HHS/United States ; R42 AG053149/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Early detection of Alzheimer's Disease (AD) is crucial for timely interventions and optimizing treatment outcomes. Integrating multimodal neuroimaging datasets can enhance the early detection of AD. However, models must address the challenge of incomplete modalities, a common issue in real-world scenarios, as not all patients have access to all modalities due to practical constraints such as cost and availability. We propose a deep learning framework employing Incomplete Cross-modal Mutual Knowledge Distillation (IC-MKD) to model different sub-cohorts of patients based on their available modalities. In IC-MKD, the multimodal model (e.g., MRI and PET) serves as a teacher, while the single-modality model (e.g., MRI only) is the student. Our IC-MKD framework features three components: a Modality-Disentangling Teacher (MDT) model designed through information disentanglement, a student model that learns from classification errors and MDT's knowledge, and the teacher model enhanced via distilling the student's single-modal feature extraction capabilities. Moreover, we show the effectiveness of the proposed method through theoretical analysis and validate its performance with simulation studies. In addition, our method is demonstrated through a case study with Alzheimer's Disease Neuroimaging Initiative (ADNI) datasets, underscoring the potential of artificial intelligence in addressing incomplete multimodal neuroimaging datasets and advancing early AD detection.}, } @article {pmid40893127, year = {2025}, author = {Lai, Z and Ke, L and Zhao, W}, title = {Naringenin as a neurotherapeutic agent in Alzheimer's disease: epigenetic signatures, gut microbiota alterations, and molecular neuroprotection.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1647967}, pmid = {40893127}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) remains a major neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) aggregation, tau pathology, oxidative stress, and chronic neuroinflammation. In recent years, the dietary flavonoid naringenin, abundant in citrus fruits, has gained attention as a multi-target neuroprotective agent with potential application in AD therapy. Preclinical studies demonstrate that naringenin exhibits robust antioxidant activity, notably through activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway, which reduces ROS and preserves mitochondrial integrity. Furthermore, naringenin upregulates AMPK-mediated autophagy, aiding in the clearance of toxic Aβ peptides and promoting neuronal survival. Inflammatory cascades are significantly downregulated following naringenin treatment. Additionally, naringenin modulates estrogen receptor and PI3K/Akt signaling, contributing to enhanced neuronal viability and reduced apoptosis. Notably, its ability to inhibit acetylcholinesterase suggests promise for restoring cholinergic neurotransmission. Despite these benefits, naringenin's poor solubility and limited oral bioavailability hinder clinical translation. To address these challenges, advanced nanocarrier-based delivery systems have been engineered to facilitate blood-brain barrier penetration and sustained brain targeting, markedly improving cognitive outcomes in animal models. Safety profiles in rodents indicate low toxicity at therapeutic doses, reinforcing its viability as a candidate compound. This review highlights the multifaceted mechanisms and delivery strategies of naringenin in AD, and underscores the need for well-designed clinical trials to confirm its efficacy and safety in humans.}, } @article {pmid40893125, year = {2025}, author = {Gu, Z and Ge, B and Wang, Y and Gong, Y and Qi, M}, title = {Artificial intelligence technologies for enhancing neurofunctionalities: a comprehensive review with applications in Alzheimer's disease research.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1609063}, pmid = {40893125}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition that impairs memory and cognition, presenting a growing global healthcare burden. Despite major research efforts, no cure exists, and treatments remain focused on symptom relief. This narrative review highlights recent advancements in artificial intelligence (AI), particularly machine learning (ML) and deep learning (DL), which enhance early diagnosis, predict disease progression, and support personalized treatment strategies. AI applications are reshaping healthcare by enabling early detection, predicting disease progression, and developing personalized treatment plans. In particular, AI's ability to analyze complex datasets, including genetic and imaging data, has shown promise in identifying early biomarkers of AD. Additionally, AI-driven cognitive training and rehabilitation programs are emerging as effective tools to improve cognitive function and slow down the progression of cognitive impairment. The paper also discusses the potential of AI in drug discovery and clinical trial optimization, offering new avenues for the development of AD treatments. The paper emphasizes the need for ongoing interdisciplinary collaboration and regulatory oversight to harness AI's full potential in transforming AD care and improving patient outcomes.}, } @article {pmid40893124, year = {2025}, author = {Kayano, M}, title = {Exploring efficient and effective mammalian models for Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1652754}, pmid = {40893124}, issn = {1663-4365}, abstract = {The aim of this study was to explore and discuss efficient and effective mammalian models for Alzheimer's disease (AD). In this study, efficient AD models are characterized by a small body size, a short lifespan, and rapid development of the main pathology including amyloid plaque formation. Effective AD models are expected to exhibit not only the main pathology, but also co-pathology associated with other neurodegenerative diseases (e.g., Lewy body dementia), systemic disturbances such as disrupted central-peripheral homeostasis, and sleep-circadian failures. This reflects recent findings indicating that AD is far more multifactorial than previously assumed. Although further investigation is required, non-human primates, particularly common marmosets (Callithrix jacchus), and dogs (Canis lupus familiaris) are candidates of promising and effective AD models. Tree shrews (Tupaia belangeri), guinea pigs (Cavia porcellus), and evolutionary related species including degus (Octodon degus) constitute an alternative group of AD models that remain underexplored but potentially efficient and effective. These mammalian models, together with hypothesis-driven mouse models and advances in data science technologies including omics and imaging analyses, may lead to breakthroughs in AD research, resulting in the development of effective prevention and treatment for AD.}, } @article {pmid40891144, year = {2025}, author = {Pascali, V and Tosoni, D and Altieri, S and Protti, N}, title = {Capture-enhanced neutron irradiation to treat Alzheimer's disease: Design of a small animal set-up for future in-vivo experiments.}, journal = {Medical physics}, volume = {52}, number = {9}, pages = {e18062}, pmid = {40891144}, issn = {2473-4209}, support = {964934//European Commission/ ; }, mesh = {*Alzheimer Disease/radiotherapy ; Animals ; Mice ; Monte Carlo Method ; *Boron Neutron Capture Therapy/instrumentation/methods ; *Neutrons/therapeutic use ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of β $\beta$ -Amyloid and τ $\tau$ proteins in the brain that causes dementia. To date, there is no cure capable of eradicating AD, so it is necessary to study a performing therapy. The NECTAR project aims to investigate an extension of the conventional Boron Neutron Capture Therapy principles as a possible treatment for AD at different scales (protein, cells, animal). PURPOSE: The present study focuses on a macroscopic scale and wants to propose an irradiation set-up for mice in the thermal column (TC) of the Triga Mark II reactor of Pavia University, in view of the forthcoming in vivo irradiation of healthy and transgenic AD mouse models. METHODS: Monte Carlo simulations were carried out with the MCNP6 code to test different irradiation positions and study the least toxic treatment possible by modeling neutron shielding to preserve healthy tissue. A shielding prototype was built and tested by means of neutron activation measurements. A geometrical mouse model was developed with the aim of computing the dose-rates induced in each radiosensitive organ and thus to estimate possible irradiation times for future in vivo experiments. RESULTS: The computational study showed that the safest irradiation condition involves placing the shielding 20 cm from the TC entrance and that the best performing shielding material is 6 Li $^{6} {\rm Li} $ enriched lithium carbonate. Furthermore, taking into account the tolerance doses of each organ, the maximum animal irradiation time in an AD context is 45 min. The proposed set-up could also be used for preclinical studies on brain tumors; in this context, the maximum estimated irradiation time is 11 min. CONCLUSION: The proposed work is pivotal in the study of a possible treatment for AD in a neutron irradiation context, paving the way for the next phase of the NECTAR project involving in vivo irradiation of AD mouse models and thus making it possible to assess its efficacy and its possible future extension to the human brain.}, } @article {pmid40891036, year = {2025}, author = {Wang, B and Wang, ZX and Lv, LM and Wang, X and Lu, JC and Zhao, YF and Jiang, R and Li, QF and Kong, Y and Yang, XW and Luo, J and Xiao, ZC and Li, AP and Yang, G and Ma, QH and Shao, L}, title = {Tenascin-R aggravates Aβ production in the perforant pathway by regulating Nav1.6 activity in APP/PS1 mice.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {9}, pages = {e70633}, pmid = {40891036}, issn = {1552-5279}, support = {82471464 to L.S.//National Natural Science Foundation of China/ ; 82301700 to B.W.//National Natural Science Foundation of China/ ; 82503370 to G.Y.//National Natural Science Foundation of China/ ; 2024-MS-157 to B.W.//Liaoning Province Natural Science Foundation/ ; ZR2023QH126 to X.W.//Shandong Provincial Natural Science Foundation/ ; LJ222510161002 to L.S.//Leading Talents Team Project of Liaoning Provincial Department of Education/ ; }, mesh = {Animals ; *NAV1.6 Voltage-Gated Sodium Channel/metabolism ; Mice ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Tenascin/metabolism/genetics ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Alzheimer Disease/metabolism/genetics ; Disease Models, Animal ; Hippocampus/metabolism ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) neuropathology exhibits early accumulation of amyloid beta (Aβ) plaques within the perforant pathway. This study explores how tenascin-R, a myelin-associated protein at nodes of Ranvier (NORs), modulates Aβ generation through Nav1.6 within this cortico-hippocampal circuit. METHODS: We integrated genetic, electrophysiological, and microdialysis techniques in APP/PS1 mice and constructed tenascin-R gene fragments and GEDC motif to identify potential therapeutic sequences for AD treatment. RESULTS: Stimulating the entorhinal cortex increased Aβ1-42 release along the perforant pathway through Nav-dependent mechanisms. Reducing tenascin-R decreased Aβ deposition and alleviated cognitive deficits. Overexpressing tenascin-R enhanced Nav1.6 currents and upregulated amyloid precursor protein and β-secretase. The GEDC motif within tenascin-R's epidermal growth factor-like domain controlled Nav1.6 activity. DISCUSSION: Our findings demonstrate that NORs signaling modulates Aβ processing independently of synaptic mechanisms. Tenascin-R regulates Aβ pathogenesis via Nav1.6 at NORs, underscoring myelin proteins and Nav1.6 as therapeutic targets. The GEDC motif represents a potential peptide-based compound for AD therapy. HIGHLIGHTS: Nodes of Ranvier-associated tenascin-R (Tn-R) regulate amyloid beta (Aβ) production in the perforant pathway of APP/PS1 mice. Tn-R enhances Nav1.6-mediated sodium currents, promoting amyloid precursor protein (APP) transcription and Aβ generation. Genetic downregulation of Tn-R mitigates Aβ deposition, restores synaptic integrity, and improves cognition. The conserved GEDC motif within Tn-R's epidermal growth factor-like domain is critical for modulating Nav1.6 activity and amyloidogenesis. The Tn-R/Nav1.6 axis represents a novel therapeutic target for Alzheimer's disease, with GEDC-derived peptides offering translational potential.}, } @article {pmid40890909, year = {2025}, author = {Maheta, P and Patel, C and Parmar, D and Beladiya, J and Patel, S and Sheth, D and Dholakia, S}, title = {Neuroprotective Effects of a 3-Amino Quinazoline Derivative via Keap1-Nrf2 Pathway Activation in an ICV-STZ-Induced Rat Model of Sporadic Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3611-3622}, doi = {10.1021/acschemneuro.5c00540}, pmid = {40890909}, issn = {1948-7193}, mesh = {Animals ; *NF-E2-Related Factor 2/metabolism/drug effects ; *Kelch-Like ECH-Associated Protein 1/metabolism/drug effects ; *Neuroprotective Agents/pharmacology ; *Alzheimer Disease/metabolism/drug therapy/chemically induced ; Rats ; Male ; Streptozocin ; Disease Models, Animal ; *Quinazolines/pharmacology ; Signal Transduction/drug effects ; Hippocampus/drug effects/metabolism ; Rats, Wistar ; }, abstract = {The Keap1-Nrf2 pathway has emerged as a promising target for Alzheimer's disease (AD). This study employed in silico modeling to identify Nrf2 activators through Keap1 inhibition. The most promising quinazoline derivative, LMDP10, was then evaluated in a rat model of sporadic AD induced by Intracerebroventricular (ICV) streptozotocin (STZ). ICV STZ-induced rats were treated with LMDP10 (5-50 mg/kg, orally). Behavioral changes were assessed using the Morris water maze (MWM) and novel object recognition (NOR) tests. Additionally, neurochemical marker (oxidant/antioxidant), proinflammatory cytokine (TNF-α) levels, Nrf2 levels, and histopathological alterations were analyzed in both the hippocampus and cortex. An oral toxicity study of LMDP10 was performed according to the OECD Guideline 425. LMDP10 treatment (50 mg/kg/day) significantly improved memory performance (increased percentage time spent in target quadrant in the MWM test and increased discrimination index in the NOR test; P < 0.001 for both). Notably, this dose also significantly increased Nrf2, SOD, and GSH levels while attenuating elevated MDA and TNF-α levels in both brain regions compared to those in vehicle-treated STZ rats. LMDP10 emerged as a potential therapeutic candidate for AD. LMDP10 improved memory function and increased Nrf2 signaling and antioxidant defenses while reducing neuroinflammation. These findings suggest that the neuroprotective effects of LMDP10 may involve Keap1-Nrf2 pathway activation, warranting further investigation of its therapeutic potential in AD.}, } @article {pmid40890872, year = {2025}, author = {Yuan, M and Nguyen, TTT and Gibb, AJ and Xian, YF and Xu, HX}, title = {Potential of phytochemicals in the treatment of Alzheimer disease by modulating lysosomal dysfunction: a systematic review.}, journal = {Chinese medicine}, volume = {20}, number = {1}, pages = {138}, pmid = {40890872}, issn = {1749-8546}, support = {82204723//National Natural Science Foundation of China/ ; }, abstract = {Alzheimer disease (AD) is a primary international health dilemma, especially in elderly populations, due to its progressive nature and its adverse cognitive impact. The dysfunction of lysosomes, which impairs protein degradation and leads to toxic accumulation in neurons, is a pivotal factor in AD. We explore phytochemicals that specifically target lysosomal dysfunction via the activation of autophagy, phagocytosis, and lysosome function, exhibiting anti-inflammatory and antioxidant properties. This study involves extracting and evaluating phytochemicals by exploring multiple databases, Google Scholar, PubMed, the Science Citation Index Expanded (SCIE), and the China National Knowledge Infrastructure (CNKI), integrating contemporary biochemical evidence with TCM principles-highlighting the interconnected roles of deficiency, stasis, and phlegm-to provide a comprehensive therapeutic framework. Key phytochemicals-magnolol, trehalose, and salidroside- demonstrate notable promise in enhancing lysosomal function, reducing amyloid beta accumulation, and improving cognitive outcomes. Addressing traditional theory and modern science, we underline the potential for future research by clarifying the mechanisms of compounds and their effectiveness, which may delay the disease process.}, } @article {pmid40889776, year = {2025}, author = {Cemali, SH and Poyraz, S and Belveren, S and Taş, S and Tamer, MA and Döndaş, NY and Döndaş, HA and Sansano, JM}, title = {Recent Insights in Multi-Target Drugs in Pharmacology and Medicinal Chemistry.}, journal = {ChemMedChem}, volume = {20}, number = {18}, pages = {e202500447}, pmid = {40889776}, issn = {1860-7187}, support = {TSA-2022-15050//Çukurova University/ ; TSA-2021-13814//Çukurova University/ ; FYL-2023-15939//Çukurova University/ ; TSA-2023-16116//Çukurova University/ ; TYL-2024-17047//Çukurova University/ ; }, mesh = {Humans ; Alzheimer Disease/drug therapy ; Antineoplastic Agents/pharmacology/chemistry/chemical synthesis ; *Chemistry, Pharmaceutical/trends ; *Drug Design ; Molecular Structure ; Neoplasms/drug therapy ; Parkinson Disease/drug therapy ; }, abstract = {Many of the drugs used in treatment today have been designed based on the "specificity paradigm". Resistance has developed against drugs designed using this approach, leading to a decrease in their effectiveness. In addition, it is well-documented in the literature that diseases with complex etiologies, such as Alzheimer's, Parkinson's, and cancer are influenced by multiple genetic and/or environmental factors. As a result, specificity paradigm is often insufficient for treating these diseases. Therefore, there is a need to develop drugs that interact with multiple targets simultaneously through different mechanisms. This review aims to provide an overview of the methods used in multitarget drug design, the reactions employed in the synthesis of these drugs, their applications, and recent research conducted in this field.}, } @article {pmid40889628, year = {2025}, author = {Çam Özünlü, SA and Uysal, F and Tatlı Doğan, H and Parlar, A and Çetinkaya, A and Arslan, SO}, title = {Thymoquinone ameliorates cognitive impairment and neuroinflammation in an amyloid-beta-induced rat model of Alzheimer's disease.}, journal = {Brain research}, volume = {1866}, number = {}, pages = {149918}, doi = {10.1016/j.brainres.2025.149918}, pmid = {40889628}, issn = {1872-6240}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Benzoquinones/pharmacology/therapeutic use ; Male ; Amyloid beta-Peptides/toxicity ; Rats ; Rats, Wistar ; *Cognitive Dysfunction/drug therapy/metabolism ; Disease Models, Animal ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Hippocampus/drug effects/metabolism ; Neuroprotective Agents/pharmacology ; Peptide Fragments ; Maze Learning/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment. Amyloid-beta (Aβ) peptide accumulation is one of the most important chatacteristics of AD that cause neuronal damage and neuroinflammation. Thymoquinone (TQ), a bioactive compound derived from Nigella sativa, has shown neuroprotective properties in previous studies. This study aimed to evaluate the ameliorative effects of TQ in an Aβ1-42-induced AD rat model. Male Wistar-Albino rats were divided into four groups: Control, AD, TQ-10 (10 mg/kg TQ), and TQ-30 (30 mg/kg TQ). TQ was administered orally for 7 days before and 10 days after Aβ1-42 injection into the hippocampus. Cognitive functions were assessed using the Passive Avoidance (PA) and Morris Water Maze (MWM) tests. After behavioral experiments, hippocampal cytokine (tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)) levels, as well as astrocyte and microglial activation, are evaluated. TQ treatment reversed memory impairements in the AD group. Hippocampal TNF-α and IL-1β levels were elevated in the AD and reduced in TQ-treated groups. Immunohistochemical analysis revealed that the increased reactivity of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1) in the AD group was significantly attenuated by TQ treatment. Both 10 mg/kg and 30 mg/kg doses of TQ administration improved cognitive performance, reduced neuroinflammation, and mitigated glial activation in an Aβ-induced AD rat model. These findings suggest that TQ may serve as a promising neuroprotective agent for AD. Further studies are required to elucidate its molecular mechanisms and therapeutic potential in clinical settings.}, } @article {pmid40889010, year = {2025}, author = {Gote, S and Dubey, S and Nargund, SL and Thapa, S}, title = {A systematic review of natural products targeting Nrf2-Keap1-ARE pathway and their influence on neurodegenerative disorders.}, journal = {Inflammopharmacology}, volume = {33}, number = {9}, pages = {5097-5111}, pmid = {40889010}, issn = {1568-5608}, mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Neurodegenerative Diseases/drug therapy/metabolism ; *Biological Products/pharmacology ; *Kelch-Like ECH-Associated Protein 1/metabolism ; Animals ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Neuroprotective Agents/pharmacology ; *Antioxidant Response Elements/drug effects/physiology ; }, abstract = {Neurodegenerative disease represents a significant public health concern, with conditions, such as Alzheimer's disease and Parkinson's disease, being among the most prevalent. The primary risk factor for these neurodegenerative diseases is the process of aging. Key factors, such as oxidative stress and mitochondrial dysfunction, play a crucial role in initiating neurodegeneration. The progressive deterioration and neuronal loss in both the central and peripheral nervous systems are hallmark features of neurodegenerative diseases. Plant-derived natural products and their bioactive components, such as curcumin, resveratrol, genistein, marine algae, quercetin, apigenin, and luteolin, have shown promise as therapeutic agents for treating neurodegenerative diseases. There are various medications approved for the management of neurodegenerative diseases; their usage is primarily limited to providing symptomatic relief. The utilization of natural products holds significant promise for the prevention and treatment of neurodegenerative diseases (ND). The review provides evidence that natural products and their bioactive compounds could be beneficial in the treatment of neurodegenerative disorders. This article delineates the Keap1-Nrf2-ARE pathway's role in ND progression, shedding light on the therapeutic efficacy of natural products and their bioactive constituents that have demonstrated neuroprotective properties.}, } @article {pmid40888949, year = {2025}, author = {Tang, L and Liu, F and Sun, X and Yang, J and Liu, Y and Pan, X and Hao, L and Lou, F and Su, J}, title = {The Janus face of CaMKII: from memory consolidation to neurotoxic switch in Alzheimer's disease.}, journal = {Archives of toxicology}, volume = {99}, number = {12}, pages = {4829-4868}, pmid = {40888949}, issn = {1432-0738}, support = {32271160//Natural Science Foundation of China/ ; 2021M693914//China Postdoctoral Science Foundation/ ; 2022JH2/20200069//Scientific Research Project of Liaoning Province/ ; xtcx2019-11//Medical Electrophysiological Key Lab Foundation of Sichuan Province/ ; KeyME-2019-07//Key Laboratory Foundation of Medical Electrophysiology of Ministry of Education/ ; }, mesh = {*Alzheimer Disease/physiopathology/pathology/enzymology/metabolism ; *Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Humans ; Animals ; Amyloid beta-Peptides/metabolism ; *Memory Consolidation/physiology ; Calcium Signaling ; Neuronal Plasticity ; Calcium/metabolism ; tau Proteins/metabolism ; Long-Term Potentiation ; }, abstract = {Alzheimer's disease (AD), a neurodegenerative "memory killer" demanding urgent global intervention, has long been shrouded in mystery regarding its core pathological mechanisms. Although the traditional amyloid-β (Aβ) hypothesis remains dominant, recent groundbreaking research has revealed that early activation of aberrant calcium (Ca[2][+]) signaling pathways serves as the "initiating trigger" of AD pathogenesis-preceding even the formation of classical Aβ plaques-a discovery that fundamentally overturns the existing cognitive framework. This study systematically deconstructs, for the first time, the cascading regulatory network of the Ca[2][+]/CaM-CaMKII signaling axis in AD pathology, elucidating its potential links with core AD mechanisms, including the Aβ hypothesis, tau hyperphosphorylation, Ca[2][+] dyshomeostasis, synaptic dysfunction, and neuronal loss. Furthermore, this pathway not only triggers neurotoxic cascades through spatiotemporally specific regulation of synaptic Ca[2][+] overload but also directly disrupts neuroplasticity-the physical basis of memory encoding-by reshaping the dynamic equilibrium between long-term potentiation (LTP) and long-term depression (LTD).Crucially, the research uncovers the dual role of CaMKII as a "molecular switch": while physiologically maintaining memory consolidation via Thr286 autophosphorylation, its pathological overactivation due to Ca[2][+] dyshomeostasis leads to a "memory solidification-toxicity cycle." These findings establish a theoretical foundation for developing innovative therapies based on precise calcium signaling modulation-including Ca[2][+] homeostasis intervention and CaMKII allosteric modulators-offering a potential breakthrough in overcoming the long-standing limitation of "symptom relief without targeting root causes" in AD treatment.}, } @article {pmid40888418, year = {2025}, author = {Tansir, G and Rastogi, S and Gounder, MM}, title = {Repurposing nirogacestat, a gamma secretase enzyme inhibitor in desmoid tumors.}, journal = {Future oncology (London, England)}, volume = {21}, number = {23}, pages = {2985-2993}, pmid = {40888418}, issn = {1744-8301}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Drug Repositioning ; *Amyloid Precursor Protein Secretases/antagonists & inhibitors ; *Desmoid Tumors/drug therapy/mortality/pathology ; *Enzyme Inhibitors/therapeutic use/pharmacology ; Tetrahydronaphthalenes ; Valine/analogs & derivatives ; }, abstract = {The gamma secretase (GS) enzyme controls cell-cell adhesion, neural stem cell proliferation, neo-angiogenesis, spinal maturation, and metabolism of amyloid precursor proteins (APP). Pathological production of abnormal amyloid-beta isoforms and senile plaques serves as the basis for pathogenesis of Alzheimer's disease (AD). GS enzyme inhibitors such as semagacestat and avagacestat were explored in AD but the studies were paused because of adverse events attributed to their influence on the Notch pathway.Crosstalk between Notch and Wnt signaling pathways created a potential role for GS inhibitors in the treatment of malignancies such as glioblastoma multiforme, pancreatic, and breast cancers. In a phase I study on nirogacestat among refractory solid malignancies, overall response rate (ORR) of 71.4% was observed in desmoid tumor (DT). The pivotal DeFi phase III trial established superiority of nirogacestat in terms of progression-free survival and ORR, reducing the likelihood of progression by 71%. Emphasis was placed on patient-reported outcomes (PRO) including the DT-specific tool, GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom Scale (GODDESS).Nirogacestat received Food and Drug Administration (FDA) approval in November 2023 and European Commission approval in August 2025 for adults with progressing desmoid tumors (DT) who require systemic treatment. Further studies are underway to investigate other GS inhibitors such as AL-102 in the management of DT.}, } @article {pmid40887393, year = {2025}, author = {Hsu, JL and Park, KH and Panegyres, PK and Huang, YH and Eom, YI and Prusty, V and Tan, LS and Shea, YF}, title = {Early Alzheimer's disease (mild cognitive impairment or mild dementia): Prevalence, diagnostics, treatment options, and guidelines in Asia, Australasia, and Pacific nations countries.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {9}, pages = {100362}, pmid = {40887393}, issn = {2426-0266}, mesh = {Humans ; *Cognitive Dysfunction/epidemiology/diagnosis/therapy ; *Alzheimer Disease/epidemiology/diagnosis/therapy ; Australasia/epidemiology ; Prevalence ; Asia/epidemiology ; Early Diagnosis ; Practice Guidelines as Topic ; }, abstract = {Early diagnosis of mild cognitive impairment (MCI) and Alzheimer's disease (AD) with mild dementia is becoming increasingly important to enable patients to receive appropriate treatment with available amyloid-targeting therapies. Reviews of AD prevalence and diagnostic and treatment patterns typically focus on global or western populations, but the situation in Asia, Australasia, and Pacific Nations (AAPN) countries is less clear. We performed a narrative review of literature for AD in several AAPN countries, focusing on patients with MCI or mild dementia who may benefit from early treatment. Published information regarding AD incidence and prevalence and current practice in AAPN countries is limited and the nature of available information differs between countries. However, AAPN countries include some of the most rapidly aging populations and show the associated increasing trend of all-cause dementia prevalence observed globally. Although lecanemab and donanemab are now approved for AD with MCI and mild dementia in several AAPN countries, the most appropriate diagnostic pathway for patients with MCI and early AD is not established. Even though the AAPN region includes countries with routine access to advanced technologies, concerns have already been raised about the ability of healthcare systems in Australia, New Zealand, and Korea to respond to approvals of new AD therapies, including the need to ensure availability of biomarker testing and dementia specialists to allow patients to receive the early diagnosis required to enable appropriate treatment. Guidelines and national policies also need updating to differentiate between dementia subtypes and include amyloid-targeting therapies for eligible patients with early AD.}, } @article {pmid40887244, year = {2025}, author = {Yamashita, C}, title = {[Development of Drug Delivery Systems Based on New Concepts].}, journal = {Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan}, volume = {145}, number = {9}, pages = {747-763}, doi = {10.1248/yakushi.25-00023}, pmid = {40887244}, issn = {1347-5231}, mesh = {*Drug Delivery Systems/trends ; Humans ; Alzheimer Disease/drug therapy ; Nanoparticles ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Administration, Inhalation ; Animals ; *Drug Development/trends ; Lipids ; Liposomes ; }, abstract = {This review is a partial summary of the author's 40 years of research and development at Otsuka Pharmaceutical Co., Ltd. and the Faculty of Pharmaceutical Sciences, Tokyo University of Science. The author has consistently addressed issues of clinical significance and developed drug delivery systems based on new concepts through a change in thinking, free from preconceptions and stereotypes. In this review, the following research and development projects that the author has been involved in are described: a new concept inhalation system applicable to proteins and created based on a patient's perspective; a radical treatment for chronic obstructive pulmonary disease using a nuclear transfer strategy combining lipid nanoparticles and nuclear transfer signals for alveolar regeneration; a glycosylated Nose-to-Brain system for the development of innovative therapeutic agents for Alzheimer's disease.}, } @article {pmid40887228, year = {2025}, author = {Kawaguchi, Y and Takei, K}, title = {[Aβ Receptor PirB and its regulation by LOTUS].}, journal = {Nihon yakurigaku zasshi. Folia pharmacologica Japonica}, volume = {160}, number = {5}, pages = {318-323}, doi = {10.1254/fpj.25018}, pmid = {40887228}, issn = {0015-5691}, mesh = {Humans ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Neuronal Plasticity ; *Receptors, Immunologic/metabolism/physiology ; }, abstract = {Over the years, research has accumulated a vast amount of knowledge about the pathogenesis of dementia, including Alzheimer's disease (AD). However, fundamental treatments for AD have not yet been established. In this article, we discuss an Aβ receptor, paired immunoglobulin like receptor B (PirB) and its endogenous regulator lateral olfactory tract usher substance (LOTUS), which are completely different novel drug target from existing drugs, and the possibility of endogenous inhibitors of PirB. PirB expressed in neurons is a negative regulator of neuronal plasticity, as loss or inhibition of PirB increases neuronal plasticity, leading to increased spine density and improved cognitive function. Furthermore, PirB is known to function as a receptor for Aβ, leading to reduced neuronal plasticity and cell death. These findingss suggest that PirB can be positioned as a novel drug target for the treatment of AD. The neuronal circuit-forming factor LOTUS, which binds to PirB and functions as an endogenous antagonist, has been shown to inhibit the neurotoxic effects of Aβ mediated by PirB. Namely, LOTUS is an endogenous molecule that inhibits Aβ receptor function of PirB and may have medicinal effects against Aβ pathology.}, } @article {pmid40886864, year = {2026}, author = {Su, Y and Shang, C and Cao, B and Ma, H and Wang, P and Song, J and Xie, Z and Zhang, Z}, title = {Ferulic acid derived from Huanshaodan improves cognitive deficits in Alzheimer's disease model through regulating APP proteolytic processing via downregulation of SIRT2 expression.}, journal = {Journal of ethnopharmacology}, volume = {354}, number = {}, pages = {120508}, doi = {10.1016/j.jep.2025.120508}, pmid = {40886864}, issn = {1872-7573}, mesh = {Animals ; *Coumaric Acids/pharmacology/therapeutic use/isolation & purification ; *Alzheimer Disease/drug therapy/metabolism ; *Sirtuin 2/genetics/metabolism ; Down-Regulation/drug effects ; Mice ; Disease Models, Animal ; *Drugs, Chinese Herbal/pharmacology/chemistry/therapeutic use ; *Amyloid beta-Protein Precursor/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Humans ; Proteolysis/drug effects ; Mice, Transgenic ; }, abstract = {Huanshaodan (HSD) is a Traditional Chinese Medicine Compound Prescription, traditionally used in the clinical treatment of Alzheimer's disease (AD) in China. Nevertheless, its bioactive constituents and mechanistic basis remain poorly understood. AIM OF THE STUDY: To identify the components derived from HSD that inhibit SIRT2 and investigate the underlying mechanisms in mitigating AD pathogenesis. MATERIALS AND METHODS: A luciferase reporter gene assay was employed to screen HSD for components that downregulate SIRT2 expression. The neuroprotective effects and the mechanisms of the screened component, ferulic acid (FA), was evaluated both in SAMP8 mice and HT22-APPswe cell using behavioral tests, H&E, immunohistochemistry, transmission electron microscopy, ELISA, MTT, Western blot, RT-qPCR, immunofluorescence and Co-immunoprecipitation, to assess its effect on SIRT2 expression, SIRT2-APP interaction, as well as the expression of proteins associated with APP proteolytic processing. SIRT2-overexpressing plasmids were transfected to assess FA's neuroprotection via SIRT2 modulation. RESULTS: As a component in HSD, FA inhibited SIRT2 promoter-driven transcription, ameliorated cognitive deficits, protected neuronal and synaptic structures, reduced Aβ deposition in SAMP8 mice and Aβ level in HT22-APPswe cells. FA suppressed SIRT2 expression, inhibited SIRT2-APP interaction, modulated the expression levels of proteins involved in APP proteolytic processing, namely ADAM10, sAPPα, BACE1, sAPPβ, and CTFα in vitro and in vivo. Notably, the regulatory effects of FA on APP proteolytic processing in HT22-APPswe cells were completely abolished upon SIRT2 overexpression. CONCLUSIONS: This study demonstrates that FA is an active component in HSD that mitigates AD pathology, potentially by modulating APP proteolytic processing through SIRT2 downregulation.}, } @article {pmid40886227, year = {2025}, author = {da Silva, AMP and Falcão, L and Ribeiro Gonçalves, O and Virgilio Ribeiro, F and Machado Magalhães, PL and Lee Han, M and Łajczak, P and Letícia de Bastos Maximiano, M and Cal, H and de Souza Franco, E and de Sousa Maia, MB}, title = {Brexpiprazole for the Treatment of Agitation in Older Adults with Alzheimer's Disease: A Systematic Review, Bayesian Meta-analysis, and Meta-regression.}, journal = {CNS drugs}, volume = {39}, number = {11}, pages = {1071-1082}, pmid = {40886227}, issn = {1179-1934}, mesh = {Humans ; *Alzheimer Disease/drug therapy/complications ; *Psychomotor Agitation/drug therapy/etiology ; *Thiophenes/therapeutic use/adverse effects/administration & dosage ; Randomized Controlled Trials as Topic ; Bayes Theorem ; Aged ; *Quinolones/therapeutic use/adverse effects/administration & dosage ; }, abstract = {BACKGROUND: Agitation is a common and distressing neuropsychiatric symptom in Alzheimer's disease (AD), affecting up to half of patients and contributing to faster cognitive decline and caregiver burden. Brexpiprazole, a serotonin-dopamine modulator, has been evaluated for this indication, but uncertainties remain regarding its efficacy, safety, and appropriate use in older adults. OBJECTIVE: We aimed to assess the efficacy and safety of brexpiprazole for the treatment of agitation in older adults with AD through a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020 guidelines and the Cochrane Handbook, we included RCTs comparing brexpiprazole (0.5-3 mg/day) with placebo in older adults with a clinical diagnosis of AD. Primary outcomes were agitation severity (measured using the Cohen-Mansfield Agitation Inventory [CMAI]), clinical impression (clinical global impression-severity scale [CGI-S]), neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]), and adverse events. Risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI) were pooled using a random-effects model. Random-effects meta-analyses were performed using frequentist and Bayesian models in R (version 4.3.0). RESULTS: A total of five RCTs (N = 1770) met the inclusion criteria. Brexpiprazole was associated with a modest reduction in agitation CMAI (MD - 5.79; 95% CI - 9.55 to - 2.04; prediction interval: - 14.07 to 2.49) and improved CGI-S scores (MD - 0.23; 95% CI - 0.32 to - 0.13; prediction interval: - 0.39 to - 0.06). No significant differences were found in NPI scores. Adverse events such as extrapyramidal symptoms and daytime somnolence occurred more frequently with brexpiprazole but with wide and nonsignificant intervals. Meta-regression did not identify dose or duration as effect modifiers. CONCLUSIONS: Brexpiprazole may offer modest short-term benefits for agitation in AD without cognitive worsening, but safety signals remain imprecise. However, prediction intervals indicate considerable uncertainty, and its use should be individualized and closely monitored. Future trials should prioritize long-term outcomes and patient-centered measures. CRD 42025646060.}, } @article {pmid40885501, year = {2026}, author = {Rahamouz-Haghighi, S and Akaberi, M and Emami, SA and Tayarani-Najaran, Z}, title = {Biochemical profiling and protective effects of Scutellaria litwinowii against AlCl3-Induced neurotoxicity in PC12 cells.}, journal = {Journal of ethnopharmacology}, volume = {354}, number = {}, pages = {120504}, doi = {10.1016/j.jep.2025.120504}, pmid = {40885501}, issn = {1872-7573}, mesh = {Animals ; PC12 Cells ; Aluminum Chloride ; Rats ; *Plant Extracts/pharmacology/isolation & purification ; *Neuroprotective Agents/pharmacology/isolation & purification ; *Scutellaria/chemistry ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Cell Survival/drug effects ; Reactive Oxygen Species/metabolism ; Antioxidants/pharmacology/isolation & purification ; *Aluminum Compounds/toxicity ; *Chlorides/toxicity ; *Cholinesterase Inhibitors/pharmacology/isolation & purification ; Acetylcholinesterase/metabolism ; Glutathione/metabolism ; }, abstract = {Scutellaria litwinowii Bornm. & Sint., native to Iran, belongs to the Lamiaceae family, Scutellaria species are widely used in traditional medicine for treating inflammation, infections, and Neurological diseases. AIM OF THE STUDY: This research aimed to assess the neuroprotective effects of S. litwinowii fractions, focusing on anti-acetylcholinesterase (anti-AChE), antioxidant, and anti-apoptotic activities. MATERIALS AND METHODS: Oxidative stress and apoptosis were created utilizing aluminum chloride (AlCl3) in PC12 cells. The neuroprotective effect was assessed using resazurin assays, while reactive oxygen species (ROS), AChE and glutathione (GSH) were assessed using DCF-DA and Ellman's Reagent, respectively. Apoptotic cells, and lactate dehydrogenase (LDH) release were also evaluated. Western blot analysis detected the expression of β-Catenin, Survivin, and phosphorylated SAPK JNK/SAPKJNK. A dichloromethane (DCM) root fraction underwent HPLC and LC-ESI-MS profiling to identify active anti-AChE compounds. RESULTS: 48 h treatment with 5 mM AlCl3 decreased cell viability by 27 %. Pretreatment with the DCM fraction at 6.25 and 12.5 μg/ml significantly improved viability, reduced ROS and LDH release, and prevented GSH depletion, comparable to the antioxidant N-acetylcysteine (p < 0.001). At a 12.5 μg/ml, the DCM fraction inhibited AChE activity by 63.61 %, while 12.5 μM baicalein showed 59.11 % inhibition. The DCM fraction and baicalein significantly reduced AlCl3-induced apoptosis (p < 0.001), increased of β-Catenin, Survivin expression and decreased p-JNK/JNK ratio (p < 0.001). In the active time window, baicalein and wogonin were detected. CONCLUSION: This research suggests that S. litwinowii and baicalein may serve as protective agents against oxidative stress and apoptosis-related cell damage.}, } @article {pmid40885031, year = {2026}, author = {Majie, A and Karmakar, V and Ghosh, A and Chakraborty, S and Apurva, and Layek, B and Gorain, B}, title = {Advanced intranasal peptide delivery systems for improved management of Alzheimer's disease.}, journal = {Biomaterials advances}, volume = {178}, number = {}, pages = {214474}, doi = {10.1016/j.bioadv.2025.214474}, pmid = {40885031}, issn = {2772-9508}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Administration, Intranasal ; *Peptides/administration & dosage/therapeutic use/chemistry ; Animals ; *Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism ; Nanoparticles/chemistry ; Brain/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline, memory loss, and impairment in daily functioning, making up nearly 60 % of all dementia cases. Current treatments primarily manage symptoms rather than address the disease itself, underscoring the need for more effective solutions. Therapeutic peptides have emerged as promising candidates, targeting critical pathological processes in AD. Additionally, intranasal delivery offers significant advantages, including non-invasiveness, enhanced stability, rapid absorption, and the ability to bypass the blood-brain barrier. This review explores the potential of intranasal peptide delivery for AD treatment, beginning with an overview of the disease's mechanisms and existing therapies. We discuss the challenges of targeting the brain, examine nose-to-brain delivery pathways, and highlight recent advancements in delivery techniques, including the role of nanoparticles in improving efficacy. Our goal is to encourage further research into these innovative delivery strategies that could improve patient compliance and treatment outcomes. While preclinical studies indicate substantial promise, advancing these findings into clinical applications remains crucial to overcoming drug delivery challenges and ensuring long-term safety.}, } @article {pmid40884977, year = {2026}, author = {Kong, X and Yu, Z and Sun, Q and Liu, Y and Yin, ZZ}, title = {An integrative and efficient microbiosensor for β-amyloid42 based on a molecularly imprinted layer coordinating built-in hemin on the acupuncture needle.}, journal = {Bioelectrochemistry (Amsterdam, Netherlands)}, volume = {167}, number = {}, pages = {109095}, doi = {10.1016/j.bioelechem.2025.109095}, pmid = {40884977}, issn = {1878-562X}, mesh = {*Amyloid beta-Peptides/analysis ; *Hemin/chemistry ; *Biosensing Techniques/methods/instrumentation ; *Molecular Imprinting ; *Peptide Fragments/analysis ; Humans ; *Needles ; *Electrochemical Techniques/methods ; Limit of Detection ; Polymers/chemistry ; Nanotubes, Carbon/chemistry ; }, abstract = {Monitoring beta-amyloid1-42 (Aβ42) is vital and challenging, which is a typical biomarker of Alzheimer's disease. Here, a novel electrochemical microbiosensor is developed to detect Aβ42 on an acupuncture needle. Hemin is well known for its characteristics, including its ability to self-assemble on single-walled carbon nanotube (SWCNT), the molecular interaction with Aβ42, and the intrinsic electroactive signal. These properties are exploited to anchor and respond to Aβ42 after integrating a molecularly imprinted surface polymer (SMIP). The SMIP layer of polydopamine/poly (ionic liquid) can be prepared by electropolymerization on an acupuncture needle microelectrode (ANME), which undergoes growth and formation of a polymeric structure around the anchored Aβ42. Interestingly, the imprinted cavities express a fluent signal of built-in hemin after eluting the templates, and show a highly selective and sensitive hindrance response for the recombined Aβ42. Under optimized conditions, the microbiosensor displays a linear range of 100 to 1 × 10[10] fM with a limit of detection of 0.05 fM. There are development and advances for the discipline of electroanalysis after comparing the technique and important indicators with the electrochemical biosensors reported of Aβ42. The microbiosensor also exhibited excellent selectivity, good stability, and reproducibility, which was effectively used to detect Aβ42 in real spiked samples. The improved behavior of the developed microbiosensor can be attributed to its superficial highly matched imprinted cavities, built-in hemin label, and electronic barrier without signal of the nonimprinted surface to outside molecules. This microbiosensor has a scientific and reference value for directly sensing non-electroactive biomarkers, functionalizing microelectrodes, and electron transport cavities. It would also be amazing if this new microbiosensor could combine with the unclear and magical property of acupuncture in the treatment of neurological disorders.}, } @article {pmid40883746, year = {2025}, author = {Holmes, BB and Weigel, TK and Chung, JM and Kaufman, SK and Apresa, BI and Byrnes, JR and Kumru, KS and Vaquer-Alicea, J and Gupta, A and Rose, IVL and Zhang, Y and Nana, AL and Alter, D and Grinberg, LT and Spina, S and Leung, KK and Miller, BL and Condello, C and Kampmann, M and Seeley, WW and Coutinho-Budd, JC and Wells, JA}, title = {β-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {96}, pmid = {40883746}, issn = {1750-1326}, support = {R35 GM122451/GM/NIGMS NIH HHS/United States ; P30AG062422/NH/NIH HHS/United States ; K24 AG053435/AG/NIA NIH HHS/United States ; ZEN-22-969903/ALZ/Alzheimer's Association/United States ; R01 NS121101/NS/NINDS NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; Shenandoah Community Foundation//Shenandoah Community Foundation/ ; P01 AG019724/AG/NIA NIH HHS/United States ; P01AG019724/NH/NIH HHS/United States ; U01AG057195/NH/NIH HHS/United States ; R01NS121101/NS/NINDS NIH HHS/United States ; RF1AG061874/NH/NIH HHS/United States ; BrightFocus Foundation//BrightFocus Foundation/ ; R35GM122451/GM/NIGMS NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; Brain Institute, University of Virginia//Brain Institute, University of Virginia/ ; U19 AG063911/AG/NIA NIH HHS/United States ; RF1 AG061874/AG/NIA NIH HHS/United States ; U19AG063911/NH/NIH HHS/United States ; K08 NS133290/NS/NINDS NIH HHS/United States ; K24AG053435/NH/NIH HHS/United States ; 1K08NS133290/NS/NINDS NIH HHS/United States ; }, abstract = {UNLABELLED: To define how Aβ pathology alters microglia function in Alzheimer’s disease, we profiled the microglia surfaceome following treatment with Aβ fibrils. Our findings reveal that Aβ-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). Glial GPC4 expression exacerbates motor deficits and reduces lifespan in a Drosophila amyloidosis model, implicating GPC4 in a toxic neurodegenerative program. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. In human Alzheimer’s disease brain, microglial GPC4 expression surrounding Aβ plaques correlates with neuritic tau pathology, supporting a pathological link between amyloid, GPC4, and tau. These studies define a mechanistic pathway by which Aβ primes microglia to promote tau pathology via HSPGs and APOE. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13024-025-00883-4.}, } @article {pmid40883512, year = {2025}, author = {Hanumanthappa, D and Kumar, BS and Shajan, SRO and Sadashivappa, NM and Walikar, SK and Hosur Dinesh, BG and Ganjipete, S and Kunjiappan, S and Theivendren, P and Chidamabaram, K and Ammunje, DN and Pavadai, P}, title = {Computational insights and experimental breakthroughs in identifying next-generation acetylcholinesterase inhibitors.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {31901}, pmid = {40883512}, issn = {2045-2322}, mesh = {Animals ; *Cholinesterase Inhibitors/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/pathology ; Rats ; Molecular Docking Simulation ; *Acetylcholinesterase/metabolism/chemistry ; Neuroprotective Agents/pharmacology/chemistry ; Male ; Nanoparticles/chemistry ; Brain/drug effects/pathology ; Disease Models, Animal ; Molecular Dynamics Simulation ; Humans ; }, abstract = {The study aimed to identify the potential acetylcholinesterase (AChE) inhibitors for effective Alzheimer's treatment from existing FDA-approved drugs through a drug repurposing technique via computational tools. Further, to evaluate the anti-Alzheimer's potency of the identified drug with the help of a suitable drug delivery system through in vivo pharmacological studies. The molecular docking and dynamics simulation studies indicated that letrozole has a significant binding affinity of -9.6 kcal/mol and a better interaction with AChE. The physicochemical properties of letrozole-encapsulated solid lipid nanoparticles (L-SLNs) were characterized and confirmed. Initially, acute toxicity tests of L-SLNs were performed according to OECD 423 guidelines. Biochemical studies revealed that L-SLNs significantly decreased brain Acetylcholine esterase activity induced by scopolamine, but L-SLNs significantly increased AChE activity compared to the Shaam control group. Histopathological evaluation of brain regions revealed significant insights into the neuroprotective potential of L-SLNs in an Alzheimer's disease (AD) rat model. Treatment with L-SLNs demonstrated dose-dependent neuroprotection across all studied brain regions. At a low dose of L-SLNs (2.5 mg/kg), neuronal and glial cells in the cortical and hippocampal regions showed improved regularity, although some disorganization persisted. At a mid-dose of L-SLNs (5 mg/kg), the histopathological architecture further normalized, with neurons and glial cells exhibiting regular arrangement and morphology akin to normal cells. The high dose of L-SLNs (10 mg/kg) provided the most significant protection, with neuronal and glial cells displaying near-normal arrangement and morphology in the cortical, hippocampal, and Substantia Nigra regions. This study highlights the importance of SLNs-based drug delivery systems in improving the efficacy of existing therapeutic agents in neurodegenerative conditions.}, } @article {pmid40859005, year = {2025}, author = {Toledano, RS and Akirav, I}, title = {Cannabidiol prevents cognitive and social deficits in a male rat model of Alzheimer's disease through CB1 activation and inflammation modulation.}, journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}, volume = {50}, number = {13}, pages = {1916-1927}, pmid = {40859005}, issn = {1740-634X}, support = {993/20//Israel Science Foundation (ISF)/ ; }, mesh = {Animals ; *Cannabidiol/pharmacology/therapeutic use ; Male ; *Alzheimer Disease/metabolism/chemically induced/drug therapy ; Rats ; *Receptor, Cannabinoid, CB1/metabolism ; Disease Models, Animal ; *Social Behavior ; Streptozocin ; Rats, Sprague-Dawley ; Hippocampus/drug effects/metabolism ; Neuroinflammatory Diseases ; *Cognitive Dysfunction/prevention & control/metabolism ; Receptor, Cannabinoid, CB2/metabolism ; Inflammation/metabolism ; }, abstract = {Cognitive decline is a hallmark of Alzheimer's disease (AD). Cannabidiol (CBD), a non-intoxicating phytocannabinoid with immunomodulatory properties, shows promise in alleviating AD symptoms. This study examined the effects of chronic CBD treatment in a male rat model of sporadic AD induced by intracerebroventricular streptozotocin (ICV-STZ) and explored its impact on neuroinflammatory genes and cannabinoid signaling. STZ rats showed impaired performance in object location and recognition tasks, along with reduced social behavior. STZ exposure also affected AD-related hippocampal markers, leading to increased levels of amyloid β-protein (Aβ) and tau phosphorylation (p-Tau) and elevated mRNA levels of triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E4 (APOEε4). Additionally, STZ increased hippocampal neuroinflammatory markers, including mRNA levels of Tumor Necrosis Factor α (TNF-α), nuclear factor kappa B subunit 1 (NF-κB1), and interleukin (IL)-1β. It also altered cannabinoid receptor expression, with cannabinoid receptor 1 (cnr1) and 2 (cnr2) genes upregulated in the dentate gyrus (DG), whereas in the CA1, cnr2 was upregulated and cnr1 downregulated. Chronic CBD treatment restored the STZ-induced behavioral deficits, reduced neuroinflammatory marker expression, and mitigated AD-associated changes. Importantly, the CB1 receptor antagonist AM251, but not CB2 antagonist AM630, blocked the beneficial effects of CBD on performance in object location and social tasks in STZ-treated rats, highlighting CB1 receptor activation as a key mechanism. These findings suggest that CBD holds promise as a therapeutic agent for inflammation-induced AD, with the potential to ameliorate cognitive deficits and prevent disease onset through mechanisms involving CB1 receptor activation and modulation of neuroinflammation.}, } @article {pmid40858778, year = {2025}, author = {Yan, J and Yang, X and Li, G and Ramirez, OA and Hagenston, AM and Chen, ZY and Bading, H}, title = {The NMDAR/TRPM4 death complex is a major promoter of disease progression in the 5xFAD mouse model of Alzheimer's disease.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {40858778}, issn = {1476-5578}, support = {FOR 2289//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; BA1007/20-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; Advanced Grant 233024//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; BMBF 180051//Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (Federal Ministry for Education, Science, Research and Technology)/ ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by cognitive decline and neuronal degeneration. The formation of amyloid β plaques and neurofibrillary tangles are key morphological features of AD pathology. However, the specific molecules responsible for the cell destruction triggered by amyloid β and tau proteinopathies in AD has not yet been identified. Here we use the 5xFAD mouse model of AD to investigate the role of a recently discovered death signaling complex which consists of the extrasynaptic N-methyl-D-aspartate receptor (NMDAR) and the transient receptor potential cation channel subfamily M member 4 (TRPM4). The NMDAR/TRPM4 death complex is responsible for toxic signaling of glutamate, which has been implicated in AD pathogenesis. We detected an increase in NMDAR/TRPM4 death complex formation in the brains of 5xFAD mice. This increase was blocked by the oral application of FP802, a small molecule TwinF interface inhibitor that can disrupt and thereby detoxify the NMDAR/TRPM4 death complex. FP802 treatment prevented the cognitive decline of 5xFAD mice assessed using a series of memory tasks. It also preserved the structural complexity of dendrites, prevented the loss of synapses, reduced amyloid β plaque formation, and protected against pathological alterations of mitochondria. These results identify the NMDAR/TRPM4 death complex as a major promoter of AD disease progression, amplifying potentially self-perpetuating pathological processes initiated by amyloid β. TwinF interface inhibitors offer a novel therapeutic avenue, serving as an alternative or complementary treatment to antibody-mediated clearing of amyloid β from AD brains.}, } @article {pmid40854422, year = {2025}, author = {Płoska, A and Radulska, A and Siekierzycka, A and Cieślik, P and Santocki, M and Dobrucki, IT and Kalinowski, L and Wierońska, JM}, title = {Allosteric modulation of M1 or M4 muscarinic receptors restores eNOS expression and L-arginine metabolism in dementia models and synergizes with NO releasers.}, journal = {Pharmacology, biochemistry, and behavior}, volume = {256}, number = {}, pages = {174085}, doi = {10.1016/j.pbb.2025.174085}, pmid = {40854422}, issn = {1873-5177}, mesh = {Animals ; Mice ; *Arginine/metabolism ; Male ; *Nitric Oxide Synthase Type III/metabolism/biosynthesis/genetics ; Allosteric Regulation/drug effects ; *Nitric Oxide/metabolism ; *Receptor, Muscarinic M1/metabolism/agonists ; *Receptor, Muscarinic M4/metabolism/agonists ; Disease Models, Animal ; *Dementia/metabolism/drug therapy ; Dizocilpine Maleate/pharmacology ; Scopolamine/pharmacology ; Drug Synergism ; Mice, Inbred C57BL ; Amidohydrolases/metabolism ; }, abstract = {BACKGROUND: Positive allosteric modulators (PAMs) of muscarinic receptors (M) have been shown to effectively prevent cognitive dysfunctions associated with dementias, but little is known about their impact on NO֗-dependent pathways, in particular eNOS expression, L-arginine metabolism and its derivatives (ADMA/SDMA/NMMA) production. METHODS: Biochemical studies were performed in frontal cortices, hippocampi and plasma samples from mice that were administered with MK-801 (schizophrenia-related dementa) or scopolamine (Alzheimer's disease model) for 14 days alone or together with muscarinic receptors modulators: VU0357017 (M1) and VU0152100 (M4). Western blot was used to measure eNOS, DDAH1 and PRMT5, while mass spectrometry was used to measure the levels of L-arginine derivatives. Behavioral studies aimed to investigate the procognitive effects of the combined administration of PAMs with NO[•] releasers, spermineNONOate or DETANONOate were performed in novel object recognition (NOR) test, in scopolamine- or MK-801- induced amnesia. RESULTS: Our results indicate that MK-801 or scopolamine disturb eNOS, DDAH1, PRMT5 expression, and L-arginine bioavailability. VU0357017 or VU0152100 prevented scopolamine or MK-801-induced eNOS dysfunction, but L-arginine derivatives synthesis was inhibited only in MK-801 model. Synergistic effect with NO֗ releasers was observed in NOR. CONCLUSIONS: eNOS expression and L-arginine bioavailability may contribute to antipsychotic action of VU0357017 or VU0152100. The antialzheimer's effect to a lesser extend involves normalization of L-arginine metabolism. The joint administration of the compounds with NO֗ releaser could be proposed as synergistic treatment for both schizophrenia and Alzheimer's disease.}, } @article {pmid40884807, year = {2025}, author = {Ding, MR and Xia, CY and Qu, YJ and Zhang, LM and Zhang, MX and Zhen, RR and Zhang, T and Chen, JF and Hu, B and An, HM}, title = {Identification of Flavonoid Compounds in Treating Alzheimer's Disease Based on Network Medicine Framework Strategy.}, journal = {The American journal of Chinese medicine}, volume = {53}, number = {7}, pages = {2167-2198}, doi = {10.1142/S0192415X25500806}, pmid = {40884807}, issn = {1793-6853}, mesh = {*Alzheimer Disease/drug therapy/genetics ; Animals ; Rats ; PC12 Cells ; *Flavonoids/pharmacology/therapeutic use/isolation & purification ; *Neuroprotective Agents/pharmacology ; Apoptosis/drug effects ; *Network Pharmacology ; Apigenin/pharmacology/therapeutic use ; Signal Transduction/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Microglia/drug effects ; Membrane Potential, Mitochondrial/drug effects ; Flavanones/pharmacology ; Quercetin/pharmacology/therapeutic use ; Luteolin/pharmacology/therapeutic use ; *Phytotherapy ; }, abstract = {Alzheimer's disease (AD) currently lacks effective therapeutics, but blood-brain-barrier-penetrating flavonoids show promising therapeutic potential. To address this critical need, we employed a novel network medicine framework to systematically identify flavonoid compounds for AD therapy by quantifying their network proximity to AD targets. Our systematic screening identified 48 potential anti-AD flavonoids, of which luteolin, quercetin, apigenin (API), and baicalein demonstrated significant neuroprotective effects in A[Formula: see text]25-35-induced rat pheochromocytoma (PC12) cell models. Of these, API emerged as the most promising candidate. A network pharmacological analysis revealed that API likely exerts its anti-AD effects through modulating apoptosis and inflammatory response, and AKT1 and NFKBIA were identified as key therapeutic targets. Experimental validation demonstrated that API treatment impeded the H2O2-induced decline in the mitochondrial membrane potential of PC12 cells, suppressed apoptosis, and mitigated neuronal damage. Furthermore, API downregulated the AKT/NF-[Formula: see text]B signal pathway, promoted microglial M2 polarization, and attenuated LPS-induced neuroinflammation in BV2 cells. API also alleviated the toxic effects of M1 microglia on neurons. This network-based screening strategy provides an innovative approach for developing new AD therapeutics.}, } @article {pmid40882479, year = {2025}, author = {Chen, T and Li, X}, title = {ResGSNet: Enhanced local attention with Global Scoring Mechanism for the early detection and treatment of Alzheimer's Disease.}, journal = {Computers in biology and medicine}, volume = {197}, number = {Pt A}, pages = {110951}, doi = {10.1016/j.compbiomed.2025.110951}, pmid = {40882479}, issn = {1879-0534}, mesh = {*Alzheimer Disease/diagnostic imaging/therapy ; Humans ; *Magnetic Resonance Imaging ; *Brain/diagnostic imaging ; Early Diagnosis ; Female ; Male ; Aged ; *Neural Networks, Computer ; }, abstract = {Recently, Transformer has been widely used in medical imaging analysis for its competitive potential when given enough data. However, Transformer conducts attention on a global scale by utilizing self-attention mechanisms across all input patches, thereby requiring substantial computational power and memory, especially when dealing with large 3D images such as MRI images. In this study, we proposed Residual Global Scoring Network (ResGSNet), a novel architecture combining ResNet with Global Scoring Module (GSM), achieving high computational efficiency while incorporating both local and global features. First, our proposed GSM utilized local attention to conduct information exchange within local brain regions, subsequently assigning global scores to each of these local regions, demonstrating the capability to encapsulate local and global information with reduced computational burden and superior performance compared to existing methods. Second, we utilized Grad-CAM＋＋ and the Attention Map to interpret model predictions, uncovering brain regions related to Alzheimer's Disease (AD) Detection. Third, our extensive experiments on the ADNI dataset show that our proposed ResGSNet achieved satisfactory performance with 95.1% accuracy in predicting AD, a 1.3% increase compared to state-of-the-art methods, and 93.4% accuracy for Mild Cognitive Impairment (MCI). Our model for detecting MCI can potentially serve as a screening tool for identifying individuals at high risk of developing AD and allow for early intervention. Furthermore, the Grad-CAM＋＋ and Attention Map not only identified brain regions commonly associated with AD and MCI but also revealed previously undiscovered regions, including putamen, cerebellum cortex, and caudate nucleus, holding promise for further research into the etiology of AD.}, } @article {pmid40877951, year = {2025}, author = {Jiao, HS and Ge, YJ and Huang, LY and Liu, Y and Wu, BS and Lian, PP and Hao, YN and Han, SS and Li, YT and Wu, KM and Wu, CY and Cheng, TL and Yuan, P and Yu, JT}, title = {MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer's disease model.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {94}, pmid = {40877951}, issn = {1750-1326}, support = {82071201//National Natural Science Foundation of China/ ; 32371036//National Natural Science Foundation of China/ ; 2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 2023SHZDZX02//Shanghai Municipal Science and Technology Major Project/ ; 2022JC01//Shanghai Municipal Health Commission Emerging Interdisciplinary Research Project/ ; 22TQ019//Shanghai Pilot Program for Basic Research - FuDan University 21TQ1400100/ ; LG-QS-202203-09//Lingang Laboratory/ ; }, mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; *Microglia/metabolism/pathology ; Humans ; Animals ; Mice ; Genome-Wide Association Study ; Disease Models, Animal ; *Inflammation/metabolism/genetics/pathology ; Male ; Female ; Mice, Transgenic ; Neuroprotection/physiology ; Membrane Proteins ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia. Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidences indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied. METHODS: We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis. RESULTS: We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures. CONCLUSIONS: Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.}, } @article {pmid40877781, year = {2025}, author = {Poulet, PE and Tran, M and Tezenas du Montcel, S and Dubois, B and Durrleman, S and Jedynak, B and , }, title = {Prediction-powered inference for clinical trials: application to linear covariate adjustment.}, journal = {BMC medical research methodology}, volume = {25}, number = {1}, pages = {204}, pmid = {40877781}, issn = {1471-2288}, mesh = {Humans ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; *Machine Learning ; Alzheimer Disease ; Sample Size ; Disease Progression ; Algorithms ; Prognosis ; Linear Models ; Models, Statistical ; }, abstract = {Prediction-powered inference (PPI) (Angelopoulos et al., Science 382(6671):669-674, 2023) and its subsequent development called PPI++ (Angelopoulos et al., 2023) provide a novel approach to standard statistical estimation, leveraging machine learning systems, to enhance unlabeled data with predictions. We use this paradigm in clinical trials. The predictions are provided by disease progression models, providing prognostic scores for all the participants as a function of baseline covariates. The proposed method would empower clinical trials by providing untreated digital twins of the treated patients while remaining statistically valid. The potential implications of this new estimator of the treatment effect in a two-arm randomized clinical trial (RCT) are manifold. First, it leads to an overall reduction of the sample size required to reach the same power as a standard RCT. Secondly, it advocates for an imbalance of controls and treated patients, requiring fewer controls to achieve the same power. Finally, this technique directly transfers any disease prediction model trained on large cohorts to practical and scientifically valid use. In this paper, we demonstrate the theoretical properties of this estimator and illustrate them through simulations. We show that it is asymptotically unbiased for the Average Treatment Effect and derive an explicit formula for its variance. We then compare this estimator to a regression-based linear covariate adjustment method. An application to an Alzheimer's disease clinical trial showcases the potential to reduce the sample size.}, } @article {pmid40877780, year = {2025}, author = {Brosch, JR and Summanwar, D and Fowler, NR and Hammers, DB and Perkins, AJ and Higbie, A and Swartzell, K and Willis, DR}, title = {An innovative health systems approach to support early detection of cognitive impairment in primary care - the brain health navigator.}, journal = {BMC primary care}, volume = {26}, number = {1}, pages = {271}, pmid = {40877780}, issn = {2731-4553}, mesh = {Humans ; *Cognitive Dysfunction/diagnosis ; *Primary Health Care/organization & administration ; Aged ; Male ; Female ; Early Diagnosis ; Aged, 80 and over ; Referral and Consultation ; *Dementia/diagnosis ; Feasibility Studies ; }, abstract = {BACKGROUND: Patients and providers experience barriers to early detection of mild cognitive impairment (MCI) and dementia. We developed a new primary care-based role, the Brain Health Navigator (BHN), who is trained to assess patients for cognitive impairment, identify addressable causes, suggest appropriate diagnostic testing, connect patients to resources, and assist patients in accessing disease-modifying treatments and dementia care management. This study describes the BHN role, the feasibility of implementing the BHN in Primary Care (PC) clinics, and the initial patients' outcomes for those who saw the BHN. METHODS: Patients ≥65 years were screened with a Digital Cognitive Assessment (DCA) in seven PC clinics from June 1, 2022, to May 31, 2023. Patients who scored likely cognitively impaired or borderline for impairment were eligible for referral to the BHN. Clinics and providers could determine if referrals were automatic or on a patient-by-patient basis. The BHN encounter included a comprehensive assessment of standardized tools and suggested laboratory and imaging studies to facilitate the diagnostic process and connect patients to resources, care and treatment, and research opportunities. RESULTS: 466 of 861 patients with likely impaired or borderline impaired DCA results were referred to the BHN.More patients with likely impaired scores (62.7%) were referred to the BHN compared to those with borderline scores (47.6%). Of the 466 referred patients, 28.9% with likely impaired scores and 23.5% with borderline scores completed a BHN visit. Patients who were seen by the BHN had a significantly higher likelihood of receiving a new diagnosis of MCI than patients who did not see the BHN and were more likely to have orders for diagnostic tests, such as vitamin B12 thyroid function and Magnetic Resonance Imaging of the head and neck. Referrals to both neurology and neuropsychology were significantly more common among patients who completed the BHN visit. CONCLUSIONS: A BHN enhances follow-up care and monitoring for patients with abnormal cognitive screening tests. A BHN visit increases the rate of evidence-based diagnostic evaluation for MCI and dementia in PC. TRIAL REGISTRATION: This study was designated as exempt by the Indiana University Institutional Review Board (#15281).}, } @article {pmid40872731, year = {2025}, author = {Vitturini, C and Cerquetella, M and Spaterna, A and Bazzano, M and Marchegiani, A}, title = {Diagnosis of Canine Cognitive Dysfunction Syndrome: A Narrative Review.}, journal = {Veterinary sciences}, volume = {12}, number = {8}, pages = {}, pmid = {40872731}, issn = {2306-7381}, abstract = {Many recent progresses in the overall quality of life have allowed for an increase in life expectancy, both in humans and in dogs. In addition, long-lived individuals may develop neurodegenerative disorders, and one of the most important in human medicine is Alzheimer's disease (AD). In veterinary medicine, the AD counterpart is Canine Cognitive Dysfunction Syndrome (CCDS), which, generally, affects elderly dogs from 8 years of age. These cognitive disorders are becoming frequently encountered conditions and, despite researchers' attention towards pathogenesis, treatment and diagnosis, more efforts are required to outline which clinical and laboratory evaluations must be carried out to reach a presumptive antemortem diagnosis of CCDS. The biggest need is the establishment of standardized protocols and guidelines for a correct clinical and diagnostic approach towards dogs with clinical signs referrable to CCDS. In this narrative review, we examined the up-to-date scientific literature on the topic, focusing our attention on sensitive and reliable markers for clinical antemortem CCDS diagnosis. Even if some parameters analyzed are interesting and promising, more investigations are needed to confirm the results obtained so far. This is crucial because a correct diagnosis is fundamental to determine the best treatment and, thus, to guarantee animals' health and welfare.}, } @article {pmid40872614, year = {2025}, author = {Marinescu, M and Zalaru, C}, title = {Benzimidazole-Pyrimidine Hybrids: Synthesis and Medicinal Properties.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {8}, pages = {}, pmid = {40872614}, issn = {1424-8247}, abstract = {Background: Heterocyclic compounds represent a key class of compounds in medicinal chemistry. Both benzimidazoles and pyrimidines are essential heterocycles in medicinal chemistry, with various therapeutic properties. Recent literature presents a series of hybrid heterocyclic compounds, as their medicinal properties are generally improved compared to those of single heterocyclic rings. Methods: A literature search was conducted across relevant scientific literature from peer-reviewed sources, using keywords, including "benzimidazole", "pyrimidine", "Biginelli", "benzimidazole-pyrimidine hybrids", "anticancer", "antiviral", "antimicrobial", and "anti-inflammatory". Results: In this review, benzimidazole-pyrimidine hybrids are reported as anticancer, antimicrobial, antiviral, anti-inflammatory, analgesic, antiulcer, antidepressant, anti-Alzheimer's, or antioxidant agents, with activities even better than those of existing drugs. The IC50 values for these anticancer hybrids are in the nanomolar range, which signifies potent anticancer agents. It can be mentioned here that the anticancer hybrid Abemaciclib, as a CDK4/6 inhibitor for the treatment of certain types of breast cancer, was approved in 2017. The antimicrobial activity of these hybrids proved especially potent against a broad variety of infections, with MIC values in the range of µM or even nM. Moreover, these hybrids exhibited good antiviral properties against SARS-CoV-2, HIV-1, and the hepatitis C virus. The hybrids also functioned as JAK3 inhibitors, COX-1 inhibitors, and MAO-A inhibitors. Conclusions: This review presents synthesis methods of benzimidazole-pyrimidine hybrids, their medicinal properties, and SAR studies reported in the last 20 years. For almost every therapeutic activity, SAR studies have revealed the essential presence of a substituent on the aromatic rings or between the two benzimidazole and pyrimidine nuclei.}, } @article {pmid40872509, year = {2025}, author = {Kruk-Słomka, M and Kuceł, D and Małysz, M and Machnikowska, A and Orzelska-Górka, J and Biała, G}, title = {New Approaches to the Treatment of Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {8}, pages = {}, pmid = {40872509}, issn = {1424-8247}, abstract = {Alzheimer's disease (AD) is one of the most common chronic neurodegenerative disorders worldwide. It is characterized by progressive memory loss and cognitive decline, leading to dementia. The pathogenesis of the disease is primarily attributed to two pathological protein structures: amyloid-beta (Aβ) plaques and tau protein neurofibrils. The current treatment strategies for AD are mainly symptomatic, highlighting the urgent need for the development of new, more effective therapies for the disease. The purpose of this paper is to provide a comprehensive and scientific review of the latest research regarding novel therapeutic options in the treatment of AD. In recent years, research has focused on more advanced and diversified strategies, including immunotherapy, gene therapy, tyrosine kinase inhibitors, therapies targeting mitochondrial function, and neurogenesis-related process modulation. One of the most promising treatment strategies for AD is immunotherapy. Intensive research is currently underway on both passive immunization, which involves the administration of monoclonal antibodies, and active immunization through vaccinations that stimulate the body to produce specific antibodies. Further research into novel therapeutic directions is essential, particularly concerning the role of the immune system in the pathogenesis of AD. Immunization appears to be a highly promising approach to developing effective methods for preventing AD or delaying the progression of this disease.}, } @article {pmid40871729, year = {2025}, author = {Vegh, C and Walach, G and Dube, K and Dobson, B and Talukdar, R and Wear, D and Jayawardena, H and Dufault, K and Culmone, L and Srikantha, S and Okaj, I and Huggard, R and Cohen, J and Pandey, S}, title = {Investigation into Efficacy and Mechanisms of Neuroprotection of Ashwagandha Root Extract and Water-Soluble Coenzyme Q10 in a Transgenic Mouse Model of Alzheimer's Disease.}, journal = {Nutrients}, volume = {17}, number = {16}, pages = {}, pmid = {40871729}, issn = {2072-6643}, mesh = {Animals ; *Ubiquinone/analogs & derivatives/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Mice, Transgenic ; *Plant Extracts/pharmacology ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; Mice ; Oxidative Stress/drug effects ; *Plant Roots/chemistry ; Male ; Autophagy/drug effects ; Cognition/drug effects ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Alzheimer's Disease (AD) is one of the most prevalent neurodegenerative disorders and the most common form of dementia. Although current treatments examine disease progression, many have side effects and primarily target symptomatic relief as opposed to halting further neurodegeneration. OBJECTIVE: The current study aims to determine the neuroprotective effects of water-soluble coenzyme Q10 (Ubisol-Q10) and an ethanolic Ashwagandha extract (E-ASH) on a transgenic mouse model of AD. METHODS: A variety of immunofluorescence staining of biomarkers was conducted to assess mechanisms commonly implicated in the disease. Additionally, spatial and non-spatial memory tests evaluated cognitive functions at two timepoints throughout the progression of the disease. RESULTS: A substantial reduction in microglial activation and amyloid-β (Aβ) plaques when treated with a combination of natural health products (NHPs), Ubisol-Q10 and E-ASH. Moreover, activation of autophagy was upregulated in both the Ubisol-Q10 and combination (Ubisol-Q10+E-ASH given as a combined "Tonic" solution) groups. Oxidative stress was decreased across treated groups, while astrocyte activation was elevated in both the E-ASH and Tonic group. The Tonic group expressed an elevation in the fluorescent intensity of neuronal nuclei (NeuN) and brain-derived neurotrophic factor (BDNF) levels. Interestingly, treatment with E-ASH and Ubisol-Q10 enhanced synaptic vesicle formation compared to controls. Pre-mortem memory tests revealed the treatments to be effective at preserving cognitive abilities. CONCLUSIONS: Based on these findings, the combination of E-ASH and Ubisol-Q10 may effectively mitigate the various mechanisms implicated in AD and ultimately prevent further disease progression.}, } @article {pmid40871707, year = {2025}, author = {Wang, M and Jin, B and Xu, J and Wang, C}, title = {Avenanthramide-C Mitigates High-Fat Diet-Accelerated Alzheimer's Pathologies via NOD1-Driven Neuroinflammation in 5×FAD Mice.}, journal = {Nutrients}, volume = {17}, number = {16}, pages = {}, pmid = {40871707}, issn = {2072-6643}, support = {LQ24H310001//Natural Science Foundation of Zhejiang Province/ ; 2022Z127//Municipal Key R&D Program of Ningbo/ ; 2024010317//Ningbo Top Medical and Health Research Program/ ; NRF-2021R1I1A1A01050493//Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education/ ; }, mesh = {Animals ; *Diet, High-Fat/adverse effects ; *Alzheimer Disease/drug therapy/etiology/metabolism/pathology ; Male ; Mice ; *ortho-Aminobenzoates/pharmacology ; Obesity/complications ; Disease Models, Animal ; *Nod1 Signaling Adaptor Protein/metabolism ; *Neuroinflammatory Diseases/drug therapy/etiology ; *Phenylenediamines/pharmacology ; Amyloid beta-Peptides/metabolism ; }, abstract = {Background: Obesity is clinically known to be associated with an increased risk and aggravated pathology of Alzheimer's disease (AD). A high-fat diet (HFD), the major contributor to obesity, induces neuroinflammation and central insulin resistance, both of which are linked to synaptic dysfunction. Our previous studies demonstrated that avenanthramide-C (Avn-C), a natural oat-derived phenolic compound, exerts anti-inflammatory effects and alleviates synaptic dysfunction in conventional AD models. The present study aimed to elucidate the underlying mechanisms of Avn-C in obesity-accelerated AD. Methods: Two-month-old male 5×FAD mice were fed an HFD to induce obesity and then treated with Avn-C. Cognitive performance, synaptic function, and structure were assessed via behavioral tests, electrophysiological recordings, and Golgi-Cox staining, respectively. Cytokine levels were quantified using ELISA and Western blotting. To explore the underlying mechanism, the NOD1 agonist C12-iE-DAP was administered to evaluate its effect on Avn-C-mediated neuroprotection. Results: Avn-C reduced Aβ deposition, enhanced the expression of synapse proteins, and restored synaptic plasticity, thereby improving both spatial and recognition memory in obese 5×FAD mice. Furthermore, Avn-C reduced neuroinflammation by inhibiting the NOD1/RIP2/NF-κB signaling pathway. Co-treatment with C12-iE-DAP abolished the beneficial effects of Avn-C on neuroinflammation, Aβ pathology, and cognitive function. Conclusions: These results suggest that Avn-C mitigates obesity-exacerbated AD-like pathological features by suppressing NOD1/RIP2/NF-κB-mediated neuroinflammation and could be a new potential therapeutic strategy for obesity-associated AD.}, } @article {pmid40871591, year = {2025}, author = {Jelčić, A and Talić, S and Odak, I and Pongrac, P and Štefok, D and Škorić, I}, title = {Photochemically Assisted Synthesis of Thienobenzotriazole-Based Dual Cholinesterase Inhibitors.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {16}, pages = {}, pmid = {40871591}, issn = {1420-3049}, mesh = {*Cholinesterase Inhibitors/chemical synthesis/pharmacology/chemistry ; Butyrylcholinesterase/metabolism/chemistry ; *Triazoles/chemistry/chemical synthesis/pharmacology ; Acetylcholinesterase/metabolism/chemistry ; Humans ; Structure-Activity Relationship ; Animals ; Molecular Structure ; Photochemical Processes ; Anti-Inflammatory Agents/pharmacology/chemical synthesis/chemistry ; }, abstract = {BACKGROUND: It has been shown previously that thienobenzo-1,2,3-triazoles exhibit very good selective inhibition toward butyrylcholinesterase (BChE), while the same derivatives converted into salts also display inhibitory activity against acetylcholinesterase (AChE), enzymes relevant to Alzheimer's disease therapy. They show even better BChE inhibition potential than neutral analogs. METHODS: This study presents the synthesis and biological evaluation of a novel series of charged thienobenzo-1,2,3-triazolinium salts (1-17) as inhibitors of AChE and BChE. The basic skeleton of the targeted compounds was synthesized via a photochemical method and subsequently converted into corresponding bromide salts. Their structures were confirmed using NMR and HRMS analyses. RESULTS: In vitro testing showed that all synthesized compounds exhibit moderate to strong BChE inhibition and, to a lesser extent, AChE inhibition. Compounds 8 and 11 emerged as the most potent AChE inhibitors (IC50 ~ 2.6-3.2 µM), while compounds 1, 2, and 8 demonstrated excellent and selective BChE inhibition (IC50 ~ 0.3-0.4 µM), outperforming the reference drug galantamine. Anti-inflammatory evaluation revealed limited activity, with compound 17 slightly reducing LPS-induced TNF-α production at the highest tested concentration. CONCLUSIONS: These findings highlight the role of the electric charge and substituent type in modulating biological activity and confirm the therapeutic potential of these molecules as dual cholinesterase inhibitors for further development in neurodegenerative disease treatment.}, } @article {pmid40871020, year = {2025}, author = {Renteros, MS and Barreto-Abanto, R and Huapaya, DC and Tovar-Cobos, M and Alvarado-Ramos, RD and Rivera-Lozada, O and Barboza, JJ}, title = {The Efficacy of Solanezumab in Patients with Alzheimer's Disease: A Systematic Review and Meta-Analysis of Clinical Trials.}, journal = {Pharmaceutics}, volume = {17}, number = {8}, pages = {}, pmid = {40871020}, issn = {1999-4923}, abstract = {Background/Objectives: Solanezumab is a humanized monoclonal antibody designed to bind soluble amyloid-beta (Aβ) and facilitate its clearance from the brain, aiming to slow the progression of Alzheimer's disease (AD). Methods: A systematic search was applied in four medical databases through October 2024 to identify phase 2 or 3 randomized controlled trials evaluating solanezumab in patients aged ≥50 years with mild AD or in preclinical stages. The primary outcomes were changes in cognitive and functional scales, including ADAS-cog14, MMSE, ADCS-ADL, and CDR-SB. Data were pooled using a random-effects model, and certainty of evidence was assessed using GRADE. Results: Seven trials involving 4181 participants were included. Solanezumab did not significantly reduce cognitive decline based on ADAS-cog14 (MD = -0.75; 95% CI: -2.65 to 1.15; very low certainty) or improve functional scores on ADCS-ADL (MD = 0.85; 95% CI: -1.86 to 3.56; very low certainty) and CDR-SB (MD = -0.15; 95% CI: -0.89 to 0.60; very low certainty). A modest but statistically significant improvement was observed in MMSE scores (MD = 0.59; 95% CI: 0.33 to 0.86; moderate certainty). Conclusions: While solanezumab may offer slight benefits in general cognitive performance, its overall impact on clinically meaningful outcomes remains limited. The results do not support its use as a disease-modifying therapy for Alzheimer's disease in either preclinical or symptomatic stages.}, } @article {pmid40870510, year = {2025}, author = {Bougea, A and Debasa-Mouce, M and Gulkarov, S and Castro-Mosquera, M and Reiss, AB and Ouro, A}, title = {From Better Diagnostics to Earlier Treatment: The Rapidly Evolving Alzheimer's Disease Landscape.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {8}, pages = {}, pmid = {40870510}, issn = {1648-9144}, support = {AWD00004772//The Alzheimer's Foundation of America Award/ ; //The Herb and Evelyn Abrams Family Amyloid Research Fund/ ; IN607A2022/07//Xunta de Galicia/ ; PI22/00938//Instituto de Salud Carlos III/ ; PI21/00727//Instituto de Salud Carlos III/ ; RD21/0006/0005//Instituto de Salud Carlos III/ ; CB22/05/00067//CIBERNED/ ; EAPA_791/2018_ NEUROATLANTIC project//INTERREG Atlantic Area/ ; 0624_2IQBIONEURO_6_E//INTER-REG V A España Portugal/ ; }, mesh = {*Alzheimer Disease/diagnosis/therapy/genetics ; Humans ; Biomarkers/analysis/blood ; Amyloid beta-Peptides/analysis ; tau Proteins/analysis ; Early Diagnosis ; Neuropsychological Tests ; Genome-Wide Association Study/methods ; }, abstract = {Background and Objectives: Over the past few years, there has been a significant shift in focus from developing better diagnostic tools to detecting Alzheimer's disease (AD) earlier and initiating treatment interventions. This review will explore four main objectives: (a) the role of biomarkers in enhancing the diagnostic accuracy of AD, highlighting the major strides that have been made in recent years; (b) the role of neuropsychological testing in identifying biomarkers of AD, including the relationship between cognitive performance and neuroimaging biomarkers; (c) the amyloid hypothesis and possible molecular mechanisms of AD; and (d) the innovative AD therapeutics and the challenges and limitations of AD research. Materials and Methods: We have searched PubMed and Scopus databases for peer-reviewed research articles published in English (preclinical and clinical studies as well as relevant reviews and meta-analyses) investigating the molecular mechanisms, biomarkers, and treatments of AD. Results: Genome-wide association studies (GWASs) discovered 37 loci associated with AD risk. Core 1 biomarkers (α-amyloid Aβ42, phosphorylated tau, and amyloid PET) detect early AD phases, identifying both symptomatic and asymptomatic individuals, while core 2 biomarkers inform the short-term progression risk in individuals without symptoms. The recurrent failures of Aβ-targeted clinical studies undermine the amyloid cascade hypothesis and the objectives of AD medication development. The molecular mechanisms of AD include the accumulation of amyloid plaques and tau protein, vascular dysfunction, neuroinflammation, oxidative stress, and lipid metabolism dysregulation. Significant advancements in drug delivery technologies, such as focused Low-Ultrasound Stem, T cells, exosomes, nanoparticles, transferin, nicotinic and acetylcholine receptors, and glutathione transporters, are aimed at overcoming the BBB to enhance treatment efficacy for AD. Aducanumab and Lecanemab are IgG1 monoclonal antibodies that retard the progression of AD. BACE inhibitors have been explored as a therapeutic strategy for AD. Gene therapies targeting APOE using the CRISPR/Cas9 genome-editing system are another therapeutic avenue. Conclusions: Classic neurodegenerative biomarkers have emerged as powerful tools for enhancing the diagnostic accuracy of AD. Despite the supporting evidence, the amyloid hypothesis has several unresolved issues. Novel monoclonal antibodies may halt the AD course. Advances in delivery systems across the BBB are promising for the efficacy of AD treatments.}, } @article {pmid40869897, year = {2025}, author = {Akbar, A and Haider, R and Agnello, L and Noor, B and Maqsood, N and Atif, F and Ali, W and Ciaccio, M and Tariq, H}, title = {CRISPR in Neurodegenerative Diseases Treatment: An Alternative Approach to Current Therapies.}, journal = {Genes}, volume = {16}, number = {8}, pages = {}, pmid = {40869897}, issn = {2073-4425}, mesh = {Humans ; *Neurodegenerative Diseases/therapy/genetics ; *CRISPR-Cas Systems/genetics ; *Gene Editing/methods ; *Genetic Therapy/methods ; Animals ; *Clustered Regularly Interspaced Short Palindromic Repeats ; RNA, Guide, CRISPR-Cas Systems/genetics ; }, abstract = {Neurodegenerative diseases (NDs) pose a major challenge to global healthcare systems owing to their devastating effects and limited treatment options. These disorders are characterized by progressive loss of neuronal structure and function, resulting in cognitive and motor impairments. Current therapies primarily focus on symptom management rather than on targeting the underlying causes. However, clustered regularly interspaced short palindromic repeat (CRISPR) technology offers a promising alternative by enabling precise genetic modifications that could halt or even reverse ND progression. CRISPR-Cas9, the most widely used CRISPR system, acts as a molecular scissor targeting specific DNA sequences for editing. By designing guide RNAs (gRNAs) to match sequences in genes associated with NDs, researchers can leverage CRISPR to knockout harmful genes, correct mutations, or insert protective genes. This review explores the potential of CRISPR-based therapies in comparison with traditional treatments for NDs. As research advances, CRISPR has the potential to revolutionize ND treatment by addressing its genetic underpinnings. Ongoing clinical trials and preclinical studies continue to expand our understanding and application of this powerful tool to fight debilitating conditions.}, } @article {pmid40869269, year = {2025}, author = {Zhang, YM and Yang, F and Li, Q and Zhang, JN}, title = {Role of Histone Lactylation in Neurological Disorders.}, journal = {International journal of molecular sciences}, volume = {26}, number = {16}, pages = {}, pmid = {40869269}, issn = {1422-0067}, support = {82371321 82271240 82301604//National Natural Science Foundation of China/ ; }, mesh = {Humans ; *Histones/metabolism ; *Nervous System Diseases/metabolism/genetics ; Animals ; Epigenesis, Genetic ; *Protein Processing, Post-Translational ; *Lactic Acid/metabolism ; }, abstract = {Lactate is not only the end product of glycolysis but also plays a key role in epigenetic regulation. Recently, lactate-derived histone lactylation has been identified as a novel epigenetic modification that can directly influence gene transcription. Histone lactylation has been associated with various pathological conditions and shows significant therapeutic potential. However, studies on histone lactylation in central nervous system diseases are still quite limited. In this review, we summarize the latest research progress on histone lactylation, detailing the specific mechanisms and sites of histone lactylation, including lactylation and delactylation. We also discuss the role of histone lactylation in Alzheimer's disease (glycolysis/H4K12la/PKM2 feedback loop), depression (neuronal excitation), neuroinflammation (anti-inflammatory/pro-inflammatory balance of microglia), aging, stroke (infarct volume), and glioblastoma (activation of oncogenes), pointing out the research directions for the future. This may provide new ideas for the diagnosis and treatment of neurological diseases.}, } @article {pmid40869160, year = {2025}, author = {Faustman, DL and Davis, M and Kuhtreiber, WM}, title = {TNFR2 Agonism: Basic Science and Promising Treatment for Multiple Sclerosis and Related Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {16}, pages = {}, pmid = {40869160}, issn = {1422-0067}, support = {001-20//Iacocca Foundation/ ; }, mesh = {Humans ; *Multiple Sclerosis/drug therapy/metabolism/immunology ; *Receptors, Tumor Necrosis Factor, Type II/agonists/metabolism ; Animals ; T-Lymphocytes, Regulatory/immunology/metabolism/drug effects ; }, abstract = {The three pathological hallmarks of multiple sclerosis (MS) are inflammation, demyelination, and progressive neurodegeneration. None of the approved disease-modifying therapies for MS counters all three pathologies, and, more specifically, none is approved for neuroprotection. Axonal loss is the most significant contributor to chronic and irreversible disability in MS. A tantalizing molecular target has emerged to uniquely counter all three MS pathologies: tumor necrosis factor receptor 2 (TNFR2). Agonism or activation of TNFR2 has been shown in MS models to induce immunosuppression, oligodendrocyte precursor differentiation, and neuroprotection. Further, in basic science studies stemming from the past 15 years, TNFR2 agonism is known to be a strong inducer of T-regulatory cells (Tregs). Treg cells, and especially those expressing TNFR2, are known to confer the strongest suppression per cell type. TNFR2 is even more attractive as a therapeutic target because of its restricted expression by only a handful of CNS and immune cell subsets, thereby minimizing the likelihood of systemic and other adverse effects. Recent antibody design work suggests many of the hurdles of Treg agonism may have been overcome. This review covers the current treatment landscape for MS, the basic science of TNFR2, the rationale for and evidence behind TNFR2 agonism to treat multiple sclerosis, the design of potent TNFR2 agonist antibodies, and the treatment applications for other neurological, autoimmune, or inflammatory diseases.}, } @article {pmid40869046, year = {2025}, author = {Koga-Batko, J and Antosz-Popiołek, K and Nowakowska, H and Błażejewska, M and Kowalik, EM and Beszłej, JA and Leszek, J}, title = {Nanoparticles as an Encouraging Therapeutic Approach to Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {16}, pages = {}, pmid = {40869046}, issn = {1422-0067}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Nanoparticles/chemistry/therapeutic use ; Animals ; Blood-Brain Barrier/metabolism/drug effects ; Neuroprotective Agents/therapeutic use/chemistry ; Drug Carriers/chemistry ; }, abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease of the central nervous system, responsible for 60-80% of dementia. Its pathogenesis is mainly based on the accumulation of beta-amyloid and tau proteins. Current pharmacological treatment includes acetylcholinesterase inhibitors, NMDA receptor antagonists, and monoclonal antibodies. However, their effect is limited by the blood-brain barrier (BBB). A new and promising way for different drugs to cross the BBB is the use of nanoparticles such as liposomes, micelles, solid lipid nanocarriers, polymeric nanoparticles, dendrimers, nanoemulsions, and inorganic nanoparticles as their carriers. Additionally, some nanoparticles present anti-inflammatory or neuroprotective effects. Some of them can also be used to treat cerebral amyloid angiopathy (CAA) by aiming at amyloid deposits in brain arterioles. All the properties of nanoparticles listed and discussed in the article allow us to hope that there will be more effective treatment in the future, which is extremely important as the number of patients with AD is still growing.}, } @article {pmid40868857, year = {2025}, author = {Tahiroglu, V and Karagecili, H and Aslan, K and Gulcin, İ}, title = {Polyphenolic Profiling and Evaluation of Antioxidant, Antidiabetic, Anti-Alzheimer, and Antiglaucoma Activities of Allium kharputense and Anchusa azurea var. azurea.}, journal = {Life (Basel, Switzerland)}, volume = {15}, number = {8}, pages = {}, pmid = {40868857}, issn = {2075-1729}, abstract = {The genera Allium (Liliaceae) and Anchusa (Boraginaceae) are flowering plant genera with a rich diversity, also including the Allium kharputense Freyn & Sint. and Anchusa azurea Mill. var. azurea species. The antioxidant, anti-Alzheimer's disease (AD), antidiabetic, and antiglaucoma effects of the Allium kharputense Freyn & Sint. and Anchusa azurea Mill. var. azurea species, which are commonly eaten foods in the Southeast of Türkiye in the treatment of several diseases, were studied. To interpret the antioxidant capacities of ethanol extract of two plant species, aerial parts were analyzed by ABTS and DPPH assays. The IC50 values of A. kharputense and A. azurea ethanol and water extracts for ABTS[•+] activities were recorded in the range of 30.93 to 33.94 µg/mL and 33.45 to 33.78 µg/mL, respectively. Also, DPPH[•] activities were measured at 30.78 to 36.87 µg/mL and 31.67 to 32.45 µg/mL, respectively. The best of the IC50 values was measured in the ethanol extract of A. kharputense as 30.78 µg/mL for DPPH scavenging activity. The total phenolic and flavonoid quantities in A. kharputense and A. azurea plants were measured. The highest phenolic and flavonoid contents of A. kharputense and A. azurea species were recorded in amounts of 445.52 and 327.35 mg GAE/g in ethanol extracts, respectively, and 332.88 and 234.03 mg QE/g in ethanol extracts, respectively. The effects of A. kharputense and A. azurea on diabetes, AD, and glaucoma were studied on the target enzymes of diseases. The most efficient IC50 values were recorded at 10.72 μg/mL against α-glycosidase, 35.01 μg/mL against AChE, 38.05 μg/mL against BChE, 9.21 μg/mL towards hCA I, and 81.02 μg/mL towards hCA II isoenzymes. The kinds and amounts of phenolic compounds in A. kharputense and A. azurea were determined using LC-MS/MS against 53 standards. A. kharputense and A. azurea plants have prospective use in enhancing glaucoma, diabetes, AD, Parkinson's disease, epilepsy, and cancerous disorders.}, } @article {pmid40868760, year = {2025}, author = {Georgieva, D and Bogdanova, I and Mihaylova, R and Alexandrova, M and Bozhilova, S and Christova, D and Kostova, B}, title = {Orodispersible Hydrogel Film Technology for Optimized Galantamine Delivery in the Treatment of Alzheimer's Disease.}, journal = {Gels (Basel, Switzerland)}, volume = {11}, number = {8}, pages = {}, pmid = {40868760}, issn = {2310-2861}, abstract = {Alzheimer's disease is the most widespread neurodegenerative disease in the world. Galantamine hydrobromide (GH) is one of the drugs used to treat mild to moderate dementia of the Alzheimer type. Due to the fact that the specificity of the disease requires maximally facilitated intake, orodispersible films present such an opportunity. In the present study orodispersible films based on poly(2-ethyl-2-oxazoline) as well as partially hydrolyzed poly(2-ethyl-2-oxazoline) were prepared and studied as delivery systems for GH. Two samples of partially hydrolyzed PEtOx were synthesized-one of relatively low degree of hydrolysis and another one of relatively high degree of hydrolysis, and studied by Nuclear Magnetic Resonance (NMR). Cytotoxicity assay was performed that validated the low hydrolyzed derivative as biocompatible polymer that maintained desirable physicochemical characteristics without compromising the safety, thereby it was selected for further research. The films were prepared by the solution casting method and characterized by different methods. FTIR was used to determine the potential interactions between the galantamine molecule and the film components. Based on the Thermogravimetric Analysis (TGA) conducted, it was concluded that all films were sufficiently thermally stable, as the component decomposition stage (after initial solvent removal) began above 180 °C. The polymer films were further characterized with the determination of Shore hardness and the results showed that the films containing glycerol as a plasticizer exhibited higher hardness compared to those with PEG as a plasticizer. The disintegration time of the films was determined visually using Petri dishes and it was found that the films disintegrated within the range of 0.52 to 1.58 min, fully meeting the pharmacopoeial requirements. GH release profiles in PBS at 37 °C were obtained, and it was found that by the second minute, 80-90% of the drug were released from the different films, and the release followed an anomalous diffusion mechanism (Case II).}, } @article {pmid40867632, year = {2025}, author = {Han, L and Wei, S and Wang, R and Liu, Y and Zhong, Y and Fu, J and Luo, H and Bao, M}, title = {Apelin-13-Mediated Upregulation of METTL3 Ameliorates Alzheimer's Disease via Inhibiting Neuroinflammation Through m6A-Dependent Regulation of lncRNA BDNF-AS.}, journal = {Biomolecules}, volume = {15}, number = {8}, pages = {}, pmid = {40867632}, issn = {2218-273X}, support = {82100040//National Natural Science Foundation of China/ ; 2024JJ5054//Natural Science Foundation of Hunan Province/ ; 2022JJ30640//Natural Science Foundation of Hunan Province/ ; 23A0666//Scientific Research Foundation of Hunan Provincial Education Department/ ; 2022CYY012//ESI Special Project of Changsha Medical University/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/drug therapy/pathology ; Rats ; *Brain-Derived Neurotrophic Factor/metabolism/genetics ; Male ; *Intercellular Signaling Peptides and Proteins/pharmacology ; Up-Regulation/drug effects ; *Methyltransferases/genetics/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; Amyloid beta-Peptides ; PC12 Cells ; Rats, Sprague-Dawley ; Hippocampus/metabolism/pathology/drug effects ; Disease Models, Animal ; Peptide Fragments ; *Neuroinflammatory Diseases/metabolism/genetics ; Signal Transduction ; }, abstract = {Apelin-13, a neuropeptide, has been recognized for its neuroprotective properties. Our previous study found apelin-13 improves cognitive function in Alzheimer's disease (AD) rats by inhibiting neuroinflammation through upregulation of BDNF/TrkB signaling pathway. However, the precise mechanism by which apelin-13 modulates BDNF remains unclear. Thus, this study aimed to unravel the specific regulatory mechanism by which apelin-13 regulates BDNF. Bilaterally intracerebroventricular injection with Aβ25-35 was used to establish an in vivo model of AD. For the generation of METTL3 KO rats, the Crispr/Cas9 method was applied. PC12 cells were treated with Aβ25-35 to establish an in vitro model of AD. The cognitive function of the rats was evaluated with the Morris water maze and the novel object recognition test. Hippocampal damage and neuron loss were detected through H&E and immunofluorescent staining. METTL3, BDNF, TrkB, and p-TrkB were examined by Western blotting. Inflammation-related cytokines, IBA1, GFAP, IL-1β, and TNF-α were detected by Western blotting, immunofluorescent staining, ELISA, and qRT-PCR. m6A modification level was evaluated through MeRIP. A flow cytometer was applied to evaluate cell apoptosis. Cell proliferation was examined using MTT. m6A methylation inhibitor DAA reverses the improvement effect of apelin-13 on cognitive function, hippocampal nerve damage, neuron loss, and neuroinflammation in Aβ25-35-treated rats. Further results showed that apelin-13 upregulated METTL3, BDNF-AS m6A methylation, inhibited BDNF-AS expression, and subsequently upregulated BDNF/TrkB signaling pathway and reduced neuroinflammation in in vivo and in vitro AD models in a dose-dependent manner. Knockdown of METTL3 abolished apelin-13's improvement effect in AD rats. Apelin-13-mediated upregulation of METTL3 enhances neuroinflammation inhibition and BDNF/TrkB signaling pathway via m6A-dependent downregulation of lncRNA BDNF-AS, thus ameliorating AD. Our study offers novel insights into the pathogenesis of AD and identifies potential drug targets for its treatment.}, } @article {pmid40867293, year = {2025}, author = {Arendash, GW}, title = {The Evidence That Brain Cancers Could Be Effectively Treated with In-Home Radiofrequency Waves.}, journal = {Cancers}, volume = {17}, number = {16}, pages = {}, pmid = {40867293}, issn = {2072-6694}, support = {9 R44 AG073096-02A1//National Institute of Health/ ; }, abstract = {There is currently no effective therapeutic capable of arresting or inducing regression of primary or metastatic brain cancers. This article presents both pre-clinical and clinical studies supportive that a new bioengineered technology could induce regression and/or elimination of primary and metastatic brain cancers through three disease-modifying mechanisms. Transcranial Radiofrequency Wave Treatment (TRFT) is non-thermal, non-invasive and self-administered in-home to safely provide radiofrequency waves to the entire human brain. Since TRFT has already been shown to stop and reverse the cognitive decline of Alzheimer's Disease in small studies, evidence is provided that three key mechanisms of TRFT action, alone or in synergy, could effectively treat brain cancers: (1) enhancement of brain meningeal lymph flow to increase immune trafficking between the brain cancer and cervical lymph nodes, resulting in a robust immune attack on the brain cancer; (2) rebalancing of the immune system's cytokines within the brain or brain cancer environment to decrease inflammation therein and thus make for an inhospitable environment for brain cancer growth; (3) direct anti-proliferation/antigrowth affects within the brain tumor microenvironment. Importantly, these mechanisms of TRFT action could be effective against both visualized brain tumors and those that are yet too small to be identified through brain imaging. The existing animal and human clinical evidence presented in this perspective article justifies TRFT to be clinically tested immediately against both primary and metastatic brain cancers as monotherapy or possibly in combination with immune checkpoint inhibitors.}, } @article {pmid40867182, year = {2025}, author = {Jensen-Kondering, U and Kuhn, V and Schacht, H and Neumann, A and Royl, G and Schramm, P}, title = {Cerebral Microbleeds with a Venous Connection on 3 Tesla Susceptibility-Weighted Imaging in Persons with Alzheimer's Disease and Healthy Aging Controls.}, journal = {Brain sciences}, volume = {15}, number = {8}, pages = {}, pmid = {40867182}, issn = {2076-3425}, abstract = {Introduction: It has been recently demonstrated that some cerebral microbleeds (CMBs) are connected to cerebral veins in patients with cerebral small vessel disease (CSVD) including cerebral amyloid angiopathy (CAA). We sought to demonstrate the presence of CMB at 3 Tesla using susceptibility-weighted imaging and speculated that it was more prevalent in persons with Alzheimer's disease (AD), another amyloid-related disease, than in healthy ageing controls. Material and Methods: We included persons from the publicly available OASIS3-database. Persons were included if they had a structural MRI including a susceptibility-weighted sequence (SWI) and relevant clinical data. Two raters assessed the presence and location of CMBs and CMBs with a venous connection (CMBven). Results: A total of 571 persons (AD, n = 140, healthy controls, n = 431) were included. In total, 367 CMBs were detected, encompassing 26/571 persons (4.5%) who had a total of 40/367 (10.9%) CMBs with a CMBven, though there was no difference between persons with AD and healthy controls (AD 6.6%, healthy controls 7.4%, p = 0.773). Persons with CMBven had a higher total CMB load, were more likely female, displayed an APOE ε2/2 genotype and had antithrombotic treatment more often. Logistic regression revealed a higher number of CMB (OR (95% CI) = 1.351 (1.161-1.688), p < 0.0014) and a lower MoCA score (OR (95% CI) = 0.862 (0.762-0.982), p = 0.018), indicating a statistically significant association with the presence of CMBven. Discussion: CMBven are not an uncommon finding in persons with AD and healthy ageing controls. Our results highlight the potential venous contribution to CSVD. Histopathological studies will be needed to assess these further.}, } @article {pmid40867162, year = {2025}, author = {Cont-Richter, C and Stute, N and Galli, A and Schulte, C and Wojtecki, L}, title = {Transcranial Pulse Stimulation in Alzheimer's: Long-Term Feasibility and a Multifocal Treatment Approach.}, journal = {Brain sciences}, volume = {15}, number = {8}, pages = {}, pmid = {40867162}, issn = {2076-3425}, abstract = {BACKGROUND/OBJECTIVES: Neuromodulation is under investigation as a possibly effective add-on therapy in Alzheimer's disease (AD). While transcranial pulse stimulation (TPS) has shown positive short-term effects, long-term effects have not yet been fully explored. This study aims to evaluate the long-term feasibility, safety, and potential cognitive benefits of TPS over one year in patients with Alzheimer's disease, focusing on domains such as memory, speech, orientation, visuo-construction, and depressive symptoms. METHODS: We analyzed preliminary data from the first ten out of thirty-five patients enrolled in a prospective TPS study who completed one year of follow-up and were included in a dedicated long-term database. The protocol consisted of six initial TPS sessions over two weeks, followed by monthly booster sessions delivering 6000 pulses each for twelve months. Patients underwent regular neuropsychological assessments using the Alzheimer Disease Assessment Scale (ADAS), Mini-Mental Status Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Beck Depression Inventory (BDI-II). All adverse events (AEs) were documented and monitored throughout the study. RESULTS: Adverse events occurred in less than 1% of stimulation sessions and mainly included mild focal pain or transient unpleasant sensations, as well as some systemic behavioral or vigilance changes, particularly in patients with underlying medical conditions, with some potentially related to the device's stimulation as adverse device reactions (ADRs). Cognitive test results showed significant improvement after the initial stimulation cycle (ADAS total improved significantly after the first stimulation cycle (M_pre = 28.44, M_post = 18.56; p = 0.001, d = 0.80, 95% CI (0.36, 1.25)), with stable scores across all domains over one year. Improvements were most notable in memory, speech, and mood. CONCLUSIONS: TPS appears to be a generally safe and feasible add-on treatment for AD, although careful patient selection and monitoring are advised. While a considerable number of participants were lost to follow-up for various reasons, adverse events and lack of treatment effect were unlikely primary causes. A multifocal stimulation approach (F-TOP2) is proposed to enhance effects across more cognitive domains.}, } @article {pmid40867144, year = {2025}, author = {Dong, Y and Shi, L and Ma, Y and Liu, T and Sun, Y and Jin, Q}, title = {Gender Differences in the Effects of Exercise Interventions on Alzheimer's Disease.}, journal = {Brain sciences}, volume = {15}, number = {8}, pages = {}, pmid = {40867144}, issn = {2076-3425}, support = {2016YFD0400603//The National Key Research and Development project in China/ ; Project No. KYCX25_3954//The Postgraduate Research & Practice Innovation Program of Jiangsu Province/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory loss, cognitive decline, and structural brain atrophy. Substantial sex differences have been observed in its incidence, clinical trajectory, and response to treatment. Women are disproportionately affected, exhibiting faster progression and more severe cognitive impairment. Exercise has emerged as a promising non-pharmacological intervention to mitigate AD-related decline, yet growing evidence reveals that its benefits vary by sex. This review synthesizes current findings from human and animal studies, focusing on how exercise impacts AD differently in males and females. In women, exercise is more strongly associated with improvements in cognitive function, neurotrophic support, and emotional regulation. In men, benefits tend to involve structural preservation and oxidative adaptations. Underlying mechanisms include differential hormonal profiles, inflammatory responses, and neuroplastic signaling pathways. These findings underscore the need to consider sex as a biological variable in AD research. Developing sex-specific exercise strategies may enhance therapeutic outcomes and support more individualized approaches in AD prevention and care.}, } @article {pmid40864805, year = {2025}, author = {Klein, BY and Gofrit, ON and Greenblatt, CL}, title = {BCG Impact on PD-1/PD-L1 Expression in Peripheral Immunocytes of Cancer Patients-A Potential Explanation for Its Activity in Preventing Alzheimer's Disease.}, journal = {Current issues in molecular biology}, volume = {47}, number = {8}, pages = {}, pmid = {40864805}, issn = {1467-3045}, abstract = {We found, retrospectively, that BCG therapy in non-muscle invasive bladder cancer (NMIBC) reduces the rate of Alzheimer's disease. Blockade of the ligand PD-L1 or its checkpoint receptor PD-1 has been shown to improve cognitive function and reduce brain pathology features in a mouse model of Alzheimer's disease (AD). Given that peripheral blood mononuclear cells (PBMCs) are involved in aging brain pathology and thus represent a potential AD therapeutic target, we analyzed the impact of BCG on the expression of PD-1, PD-L1, and inflammation modulators in PBMCs. Cryopreserved PBMCs pre- and post-BCG-treated six melanoma and six NMIBC patients were repurposed for immunoelectrophoretic analysis of PBMC-extracted proteins. PBMCs, post-BCG treatment in melanoma patients, were harvested only 4 months after the start of treatment (short BCG period), whereas the PBMCs of NMIBC patients were harvested 24 to 52 months after starting the BCG treatment. In melanoma PBMCs, BCG upregulated PD-L1 (p = 0.052) while downregulating PD-1 (insignificantly, p = 0.16). In contrast, in NMIBC patients, BCG downregulated PD-L1 (insignificantly, p = 0.67), while upregulating PD-1 (p = 0.0082). PD-L1 positive correlation with p-IkB (r = 0.7228) under BCG is inverted to that of PD-L1 against IkB (p = -0.9491). The difference between these opposite correlations is significant (p = 0.011), indicating that PD-L1 is upregulated early after BCG treatment, in association with p-IKB, which enables inflammation. This association subsided later, and for PD-1, did not occur at the short or long BCG periods. Experiments with a larger number of patients may substantiate the hypothesis that an increase in PD-1 by BCG relative to PD-L1 may protect against AD.}, } @article {pmid40864789, year = {2025}, author = {Szala-Rycaj, J and Zagaja, M and Szewczyk, A and Polak, J and Andres-Mach, M}, title = {Neuroprotective Potential of Phytocompounds in the Treatment of Dementia: The State of Knowledge from the Scopolamine-Induced Animal Model of Alzheimer's Disease.}, journal = {Current issues in molecular biology}, volume = {47}, number = {8}, pages = {}, pmid = {40864789}, issn = {1467-3045}, abstract = {Dementia is a broad category of neurodegenerative pathologies characterized by a progressive decline in two or more cognitive domains, including memory, language, executive and visuospatial functions, personality, and behavior, resulting in the loss of the ability to perform instrumental and/or basic daily activities. One of the most common types of dementia is Alzheimer's disease. Current approved treatments for Alzheimer's disease are mainly limited to alleviating cognitive, behavioral, and psychological deficits. To date, four drugs belonging to two families have been approved for the treatment of Alzheimer's disease: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and antiglutamatergic drugs (memantine). Drugs delay the progression of the disease, but they cause a number of side effects. Many scientific studies have focused on finding natural products with potential neuroprotective properties and no or minimal cytotoxicity that can support current drug therapy. The main objective of this review is to analyze and describe the neuroprotective potential of selected groups of natural substances (polyphenols, alkaloids, terpenoids) in one of the commonly performed in vivo studies, the scopolamine-induced animal model of Alzheimer's disease. The article is a review of literature reports from the last 5 years, and the information collected indicates that the neuroprotective activity of natural compounds may prove to be a potential alternative or add-on for Alzheimer's disease therapy.}, } @article {pmid40882298, year = {2025}, author = {Sobha, A and Krishnan, L and Shaik, S and Pai, A and Purushothaman, J and Alaganandam, K and Somappa, SB}, title = {Targeting Alzheimer's pathology: Tetralone- and thiochromanone-based benzyl pyridinium derivatives as promising multi-target-directed ligands.}, journal = {Bioorganic & medicinal chemistry}, volume = {130}, number = {}, pages = {118369}, doi = {10.1016/j.bmc.2025.118369}, pmid = {40882298}, issn = {1464-3391}, mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Ligands ; *Tetralones/chemistry/pharmacology ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; *Pyridinium Compounds/chemistry/pharmacology/chemical synthesis ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology/chemical synthesis ; Cell Line, Tumor ; Acetylcholinesterase/metabolism ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; Monoamine Oxidase/metabolism ; Structure-Activity Relationship ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Oxidative Stress/drug effects ; Molecular Structure ; }, abstract = {The lack of therapeutics that can fully halt the progression of Alzheimer's disease (AD) has prompted us to design and synthesize a series of tetralone/thiochromanone-based benzyl pyridinium salts (4a-4s) aimed at modulating multiple pathological targets associated with AD. Preliminary screening for cholinesterase and monoamine oxidase inhibition identified compounds 4e and 4g as the most potent inhibitors (AChE IC50: 2.17 ± 0.13 μM and 2.29 ± 0.15 μM; MAO-B IC50: 0.89 ± 0.07 μM and 0.92 ± 0.16 μM, respectively). Both compounds also demonstrated anti-neuroinflammatory activity by reducing pro-inflammatory cytokines (TNF-α and IL-6) and downregulating COX-2 and NF-κB signalling pathways. Additionally, 4e exhibited significant ROS scavenging ability by mitigating oxidative stress and conferred neuroprotection in SH-SY5Y cells by attenuating Aβ1-42-induced mitochondrial dysfunction and apoptosis. Collectively, these findings position compound 4e as a promising multi-target-directed ligand (MTDL) for the treatment of AD.}, } @article {pmid40882223, year = {2025}, author = {Jiang, X and Wu, L and Zhou, R and Quan, M and Xiang, X}, title = {Galanthamine promotes neuronal differentiation and neurite outgrowth of neural progenitor/stem cells by up-regulating IGF-2.}, journal = {Biochemistry and cell biology = Biochimie et biologie cellulaire}, volume = {103}, number = {}, pages = {1-9}, doi = {10.1139/bcb-2025-0058}, pmid = {40882223}, issn = {1208-6002}, mesh = {*Galantamine/pharmacology ; *Neural Stem Cells/drug effects/cytology/metabolism ; Animals ; *Cell Differentiation/drug effects ; *Up-Regulation/drug effects ; *Insulin-Like Growth Factor II/metabolism/genetics ; *Neuronal Outgrowth/drug effects ; Cells, Cultured ; *Neurons/cytology/drug effects/metabolism ; Signal Transduction/drug effects ; Mice ; *Neurites/drug effects/metabolism ; Neurogenesis/drug effects ; Rats ; }, abstract = {Galanthamine, an alkaloid derived from the Amaryllidaceae family, serves as an acetylcholinesterase inhibitor. Due to its central cholinergic properties, this compound is being actively studied as a potential treatment for Alzheimer's disease. However, the broader scope of its biological effects remains poorly understood. In this study, we explored the therapeutic potential of galanthamine in promoting neuronal differentiation and enhancing neurite outgrowth in neural stem and progenitor cells (NSPCs). Our detailed analysis demonstrated notable changes in neuronal morphology and complexity during maturation following galanthamine exposure. Notably, the compound significantly increased the proportion of neurons with multiple neurites, indicating its ability to stimulate neurite formation and foster the development of complex neuronal networks. Furthermore, galanthamine treatment led to a marked rise in the number of mature-appearing neurons, distinguished by elongated and intricate dendrites, highlighting its potential to enhance neural plasticity and repair mechanisms. Importantly, we also identified that galanthamine facilitates neuronal differentiation in NSPCs by up-regulating the insulin-like growth factor 2 signaling pathway. Collectively, these findings provide valuable insights into galanthamine's role in Alzheimer's disease and emphasize its promise as a therapeutic agent for this neurodegenerative disorder.}, } @article {pmid40881368, year = {2025}, author = {Zhao, J and Dong, X and Liu, B and Peng, Y and Yao, Z}, title = {Cognitive function enhancement in Alzheimer's disease through traditional Chinese medicine rehabilitation nursing: meta-analysis.}, journal = {Frontiers in psychiatry}, volume = {16}, number = {}, pages = {1631589}, pmid = {40881368}, issn = {1664-0640}, abstract = {Alzheimer's disease (AD) manifests as progressive cognitive deterioration with significant impact on patient independence and quality of life. While conventional treatments offer limited efficacy, Traditional Chinese Medicine (TCM) rehabilitation nursing presents a complementary approach deserving systematic evaluation. To synthesize existing evidence on the efficacy of TCM rehabilitation nursing for cognitive enhancement in AD through comprehensive meta-analysis. We conducted systematic searches across multiple electronic databases (PubMed, Embase, CNKI, Wanfang, and VIP) for controlled studies published from 2010 to present examining TCM rehabilitation nursing interventions for AD patients. Methodological quality was assessed using the Cochrane Risk of Bias 2.0 tool. Primary outcomes included Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), and treatment efficacy rates. Statistical synthesis employed RevMan 5.3 with random or fixed effects models based on heterogeneity assessment. Nine eligible studies encompassing 864 participants (432 intervention, 432 control) met inclusion criteria. Meta-analysis revealed significantly improved cognitive function in the TCM rehabilitation nursing group compared to conventional care, with MMSE scores showing substantial enhancement (mean difference = 4.63, 95% confidence interval: 3.74-5.53, P<0.00001). Treatment response analysis demonstrated higher rates of marked clinical improvement (risk ratio = 2.78, 95% CI: 1.65-4.70, P=0.0001) and substantially reduced treatment failure rates (85% reduction, P<0.00001). Though ADL scores showed positive trends, these did not reach statistical significance (P=0.07). TCM rehabilitation nursing demonstrates significant efficacy in enhancing cognitive function and treatment outcomes in AD patients. These findings support its integration into comprehensive care strategies, though additional research with standardized protocols is warranted for optimal implementation.}, } @article {pmid40881206, year = {2025}, author = {Parchwani, D and Singh, R and Patel, D}, title = {Biological and translational attributes of mitochondrial DNA copy number: Laboratory perspective to clinical relevance.}, journal = {World journal of methodology}, volume = {15}, number = {3}, pages = {102709}, pmid = {40881206}, issn = {2222-0682}, abstract = {The mitochondrial DNA copy number (mtDNAcn) plays a vital role in cellular energy metabolism and mitochondrial health. As mitochondria are responsible for adenosine triphosphate production through oxidative phosphorylation, maintaining an appropriate mtDNAcn level is vital for the overall cellular function. Alterations in mtDNAcn have been linked to various diseases, including neurodegenerative disorders, metabolic conditions, and cancers, making it an important biomarker for understanding the disease pathogenesis. The accurate estimation of mtDNAcn is essential for clinical applications. Quantitative polymerase chain reaction and next-generation sequencing are commonly employed techniques with distinct advantages and limitations. Clinically, mtDNAcn serves as a valuable indicator for early diagnosis, disease progression, and treatment response. For instance, in oncology, elevated mtDNAcn levels in blood samples are associated with tumor aggressiveness and can aid in monitoring treatment efficacy. In neurodegenerative diseases such as Alzheimer's and Parkinson's, altered mtDNAcn patterns provide insights into disease mechanisms and progression. Understanding and estimating mtDNAcn are critical for advancing diagnostic and therapeutic strategies in various medical fields. As research continues to uncover the implications of mtDNAcn alterations, its potential as a clinical biomarker is likely to expand, thereby enhancing our ability to diagnose and manage complex diseases.}, } @article {pmid40880849, year = {2025}, author = {Fu, L and Luo, T and Hao, Z and Pan, Y and Xin, W and Zhang, L and Lai, Z and Zhang, H and Liu, H and Wei, W}, title = {Exploring novel roles of lipid droplets and lipid metabolism in regulating inflammation and blood-brain barrier function in neurological diseases.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1603292}, pmid = {40880849}, issn = {1662-4548}, abstract = {The blood-brain barrier (BBB) is a critical structure that maintains the brain's homeostasis by regulating the transport of molecules and protecting it from harmful substances. However, in neurological diseases such as ischemic stroke, Alzheimer's disease, Parkinson's disease, and multiple sclerosis, the integrity and function of the BBB can be significantly compromised. In these conditions, BBB disruption leads to increased permeability, which facilitates neuroinflammation, exacerbates neuronal damage, and accelerates disease progression. Recent research has highlighted the potential of lipid-based carriers, including liposomes and lipid droplets (LDs), in modulating the BBB's integrity and function in various neurological diseases. Liposomes, with their ability to cross the BBB via mechanisms such as receptor-mediated transcytosis and carrier-mediated transport, are emerging as promising vehicles for the targeted delivery of therapeutic agents to the brain. These properties allow liposomes to effectively reduce infarct size and promote neuroprotection in ischemic stroke, as well as deliver drugs in the treatment of neurodegenerative diseases. Furthermore, LDs-dynamic regulators of lipid metabolism and cellular energy-play an essential role in maintaining cellular homeostasis, particularly during periods of stress when BBB function is compromised. These LDs help sustain cellular energy needs and modulate inflammatory responses, which are key factors in maintaining BBB integrity. Surface modifications of liposomes can further enhance their targeting efficiency, enabling them to selectively bind to specific brain cell types, including neurons, astrocytes, and microglia. This customization improves the precision of therapeutic delivery and supports the development of more tailored treatments. However, challenges such as immune responses, rapid clearance, and complement activation-related toxicity continue to hinder the broader application of liposomes and LDs in clinical settings. This review will focus on the roles of liposomes and LDs in regulating BBB integrity across a range of neurological diseases, discussing their potential for targeted drug delivery, neuroprotection, and the modulation of neuroinflammation. Additionally, we will explore the strategies being developed to address the limitations that currently restrict their clinical use.}, } @article {pmid40879893, year = {2025}, author = {Serio, MA and Dethloff, DR and Curry, GC and Beesley, ML and Shekoohi, S and Kaye, AD}, title = {Emerging Concepts in Diagnosis, Pathologic Features, and Treatment of Limbic-Predominant Amnestic Neurodegenerative Syndrome (LANS): A Narrative Review.}, journal = {Advances in therapy}, volume = {42}, number = {11}, pages = {5300-5312}, pmid = {40879893}, issn = {1865-8652}, mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/therapy/pathology/physiopathology ; *Alzheimer Disease/diagnosis/therapy/pathology/physiopathology ; *Amnesia/therapy/diagnosis/pathology ; *TDP-43 Proteinopathies/therapy/diagnosis/pathology/physiopathology ; }, abstract = {INTRODUCTION: Neurodegenerative disorders (NDs) are characterized by progressive loss of function and destruction of the central and peripheral nervous systems. These disorders result in devastating irreversible cognitive decline and affect millions of people worldwide. Alzheimer's disease (AD) is a common cause of dementia that increases in incidence with increasing age. Limbic-predominant amnestic neurodegenerative syndrome (LANS) is another common etiology of amnestic symptoms and often affects the "oldest-old" of the population. The two disorders share many similarities yet are clearly pathologically distinct. Establishing robust classifications to distinguish these two disorders is key to future management and care of an aging population. The present investigation explored the pathophysiology of neurodegenerative disorders (NDs), specifically Alzheimer's disease (AD), limbic-predominant amnestic neurodegenerative syndrome (LANS), and limbic-predominant age-related TDP-43 encephalopathy (LATE). METHODS: We performed a comprehensive narrative review of the literature, covering studies from database inception through November 2024. We searched PubMed/MEDLINE, Embase, Web of Science, Cochrane Library, and Google Scholar for relevant publications. We also reviewed reference lists of key articles. Two authors independently screened titles/abstracts for relevance and extracted data on study design, patient population, neuropathologic findings, imaging/biomarker methods, and clinical features. Discrepancies were resolved by discussion. This review synthesized findings on the need for LANS criteria and compared LANS to AD and LATE across clinical, imaging, pathologic, and biomarker domains. RESULTS: A comprehensive analysis of the key pathologic features and distinctions among selected neurodegenerative syndromes was carried out using peer-reviewed literature. CONCLUSIONS: Recently proposed clinical criteria for LANS are a milestone in the characterization and further treatment of neurodegenerative disease. Understanding the minute differences in pathophysiology among various NDs allows for pioneering more targeted disease-modifying treatments. This narrative review provides concise reflection between AD and other NDs involving LATE-NC changes.}, } @article {pmid40879814, year = {2025}, author = {Lei, J and Li, J and Wu, W and Xiong, R and Liu, Y and Tang, Y}, title = {Neuroprotective effects of Yangming-Kaixin-Yizhi formula in Alzheimer's disease: dual regulation of PI3K/Akt and p38 MAPK signaling via network pharmacology and experimental approaches.}, journal = {Metabolic brain disease}, volume = {40}, number = {7}, pages = {254}, pmid = {40879814}, issn = {1573-7365}, support = {2024ZYQN017//Joint Project of Chongqing Health Commission and Science and Technology Bureau/ ; 82405150//National Natural Science Foundation of China/ ; 2025ZNSFSC0740//Sichuan Provincial Science and Technology Support Program/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Mice ; *p38 Mitogen-Activated Protein Kinases/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; Network Pharmacology/methods ; Phosphatidylinositol 3-Kinases/metabolism ; Mice, Transgenic ; Male ; Signal Transduction/drug effects ; *MAP Kinase Signaling System/drug effects ; Molecular Docking Simulation ; Disease Models, Animal ; }, abstract = {As a neurodegenerative disease characterized by progressive cognitive decline, the pathogenesis of Alzheimer's disease (AD) is still poorly understood, and there is no effective cure currently available. Traditional Chinese medicine (TCM) prescription Yangming-Kaixin-Yizhi formula (YKY) has been clinically applied for the treatment of memory loss related disorders for more than 300 years with remarkable efficacy, but its pharmacological mechanism remains unclear. This study aimed to investigate the therapeutic effects of YKY on AD and its molecular mechanisms. We evaluated YKY's ameliorative effects on the AD phenotype in 3xTg-AD mice using the Morris water maze, histopathological staining, and immunofluorescence assays. The major chemical components of YKY were identified by UPLC-QTOF-MS/MS. Network pharmacology was employed to analyze the molecular mechanisms of YKY in treating AD, followed by validation of its regulatory effects on key pathways through immunofluorescence experiments and molecular docking. The results showed that YKY could significantly improve learning and memory ability, neuronal loss, β-amyloid deposition and glial cell activation in 3xTg-AD mice. 48 chemical components were identified from YKY, and network pharmacology analysis of them showed that YKY may improve AD by regulating apoptosis, PI3K/Akt and MAPK pathways. Immunofluorescence and molecular docking results also confirmed the regulatory effect of YKY on key targets of apoptosis, PI3K/Akt and p38 MAPK pathways. In conclusion, by integrating animal experiments and network pharmacology, the present study revealed the mechanism of YKY in inhibiting neuronal apoptosis by regulating PI3K/Akt and p38 MAPK pathways, which providing modern scientific evidence for the traditional clinical application of YKY.}, } @article {pmid40879672, year = {2025}, author = {Farajpour, N and Soraya, H}, title = {Neuroprotective effects of ivermectin on Alzheimer's model induced by streptozotocin in rats.}, journal = {Neurodegenerative disease management}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/17582024.2025.2554374}, pmid = {40879672}, issn = {1758-2032}, abstract = {BACKGROUND: Alzheimer's disease is a neurodegenerative condition characterized by memory deficits and cognitive decline. Ivermectin, an antiparasitic agent, has shown neuroprotective effects. The present study was conducted to determine the protective effects of ivermectin in a streptozocin-induced Alzheimer's model in rats. METHODS: Alzheimer's model was induced by bilateral intracerebroventricular injection of streptozocin (3 mg/kg BW, 2 doses). Ivermectin was administered intraperitoneally at a dose of 2 mg/kg. On day 19, after behavioral memory and learning tests, the samples were collected for histological and enzymatic studies. RESULTS: Ivermectin reduced the histopathological changes, including pyknotic and dead neurons and the accumulation of Aβ plaques. Ivermectin administration also reduced serum (p < 0.0001) and brain tissue (p < 0.01) acetylcholinesterase activity as well as improved learning (p < 0.05) and spatial memory (p < 0.0001). CONCLUSIONS: Ivermectin demonstrates protective effects in the STZ-induced Alzheimer's model by reducing pathological changes and Aβ plaques, acetylcholinesterase activity, as well as improving memory and learning.}, } @article {pmid40879647, year = {2025}, author = {Fabrik, I and Kupcik, R and Fabrikova, D and Chvojkova, M and Holubova, K and Hakenova, K and Horak, M and Soukup, J and Manethova, M and Rusina, R and Matej, R and Ryska, A and Soukup, O}, title = {Memantine Administration Enhances Glutamatergic and GABAergic Pathways in the Human Hippocampus of Alzheimer's Disease Patients.}, journal = {Proteomics}, volume = {25}, number = {15}, pages = {42-49}, pmid = {40879647}, issn = {1615-9861}, support = {24-10026S//Grantová Agentura České Republiky/ ; 00064190//Ministerstvo Zdravotnictví Ceské Republiky/ ; 00179906//Ministerstvo Zdravotnictví Ceské Republiky/ ; Cooperatio-Neurosciences//Univerzita Karlova v Praze/ ; CZ.02.01.01/00/22_008/0004562//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; LX22NPO5107//Ministerstvo Školství, Mládeže a Tělovýchovy/ ; }, mesh = {Humans ; *Memantine/pharmacology/administration & dosage/therapeutic use ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Hippocampus/metabolism/drug effects/pathology ; Male ; Female ; Aged ; *Glutamic Acid/metabolism ; Proteome/metabolism ; Proteomics/methods ; Aged, 80 and over ; Signal Transduction/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism/antagonists & inhibitors ; *Excitatory Amino Acid Antagonists/pharmacology ; Receptors, GABA/metabolism ; }, abstract = {One of the traditional treatments in Alzheimer's disease (AD) is administration of memantine, the NMDA receptor antagonist. However, the molecular mechanism of the complex memantine action and the impact on the hippocampal proteome in humans is unknown. In this study, hippocampal proteins extracted from formalin-fixed paraffin-embedded post mortem tissues obtained from healthy donors (n = 15), AD patients not treated with memantine (n = 11), and AD patients treated with memantine (n = 8) were investigated using tandem mass tag (TMT)-based quantitative proteomics. Memantine medication induced subtle but distinct changes in the hippocampal proteome in AD patients. Although it did not prevent the metabolic and physiologic decline associated with AD pathology, memantine administration upregulated several mitochondrially encoded proteins and mitigated the proteomic pattern of activated phagocytes. Furthermore, memantine specifically enhanced the expression of postsynaptic glutamatergic and GABAergic receptors and components of the respective pathways without affecting presynaptic proteome. This suggests that memantine treatment in AD patients not only alleviates excitotoxic stress by inhibiting NMDA receptor activity, but also triggers broader adaptations in the synaptic signaling and plasticity.}, } @article {pmid40879417, year = {2025}, author = {Zheng, J and Liu, G and Wang, Q and Liang, Y}, title = {Insights into CYP450 polymorphisms and their impact on drug metabolism in Alzheimer's disease therapy.}, journal = {Drug metabolism reviews}, volume = {57}, number = {4}, pages = {523-534}, doi = {10.1080/03602532.2025.2552786}, pmid = {40879417}, issn = {1097-9883}, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; *Cytochrome P-450 Enzyme System/genetics/metabolism ; Polymorphism, Genetic ; Pharmacogenetics ; Precision Medicine ; Animals ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder that poses significant therapeutic challenges. Currently available treatments offer symptomatic relief but often yield suboptimal outcomes due to inter-individual variability in drug metabolism. Cytochrome P450 (CYP450) enzymes, particularly those exhibiting genetic polymorphisms, play a central role in the hepatic metabolism of many AD medications. This review focuses on the influence of CYP450 polymorphisms-specifically in CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4-on the pharmacokinetics, efficacy, and safety of approved anti-AD drugs. We discuss how variability in CYP450 expression and activity affects drug response, and examine the implications for adverse drug reactions, therapeutic failure, and dosage optimization. In addition, we evaluate current evidence for CYP450-mediated interactions with traditional Chinese medicines, which are increasingly used in complementary AD therapy. The potential for CYP450 genotyping and phenotyping to guide personalized treatment strategies is critically assessed. We argue that integrating pharmacogenomics into clinical practice may enhance therapeutic precision, reduce adverse outcomes, and improve quality of life in patients with AD. This review provides updated insight into the clinical significance of CYP450 polymorphisms in AD therapy and outlines future directions for personalized medicine approaches.}, } @article {pmid40879416, year = {2025}, author = {Chen, J and Lin, B and Seow, E and Kim, S and Bajaj, PS and Mattke, S}, title = {Prediction of infusion capacity to deliver Alzheimer's disease treatments in the United States relative to expected demand.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {4}, pages = {1567-1574}, doi = {10.1177/13872877251372129}, pmid = {40879416}, issn = {1875-8908}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; United States/epidemiology ; Infusions, Intravenous ; *Health Services Needs and Demand/trends ; *Health Services Accessibility/trends/statistics & numerical data ; }, abstract = {BackgroundCapacity to deliver intravenous Alzheimer's disease (AD) treatments could constitute an obstacle to access in addition to AD specialist and PET scan capacity.ObjectiveWe aim to estimate the overall capacity for AD treatment infusions compared to expected demand in the United States.MethodsWe used published data and a survey of infusion sites to estimate the capacity to deliver AD treatments in physician offices, hospitals, standalone centers and at patients' homes from 2024 to 2033 relative to demand.ResultsCapacity for intravenous AD treatments is predicted to increase from 370,000 in 2024 to 5.2 million infusions in 2033. Nevertheless, a significant shortfall of over 13 million infusions remains in 2033, which would imply delayed access for 2.2 million patients.ConclusionsLimited infusion capacity could impede AD treatment access and result in avoidable disability progression. Expansion of capacity is needed in the short run until treatments with alternative routes of administration become available.}, } @article {pmid40877101, year = {2026}, author = {Lahmar, T and Thuau, F and Pinard, G and Boutoleau-Bretonniere, C and Perrot, P and Lancien, U}, title = {Brain lymphatic drainage pathways, deep cervical lymphatic surgery, and current insights: A systematic review.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {13}, number = {1}, pages = {100335}, doi = {10.1016/j.tjpad.2025.100335}, pmid = {40877101}, issn = {2426-0266}, mesh = {Humans ; *Lymphatic Vessels/surgery ; *Brain/metabolism ; *Glymphatic System/surgery ; *Lymphedema/surgery ; }, abstract = {The discovery of the glymphatic system and the later rediscovery of the meningeal lymphatic network have significantly changed our understanding of central nervous system (CNS) waste clearance. Aging is linked to a gradual decline in these clearance pathways, resulting in waste buildup. As a result, therapeutic strategies targeting cerebral lymphatic function have garnered growing interest, with lymphatic surgery emerging as a promising option. We conducted a review until July 2025, providing an overview of the potential of lymphatic surgical techniques to enhance CNS metabolic waste clearance pathways as a therapeutic approach for brain lymphatic system disorders. Currently available data are limited, nine publications addressing this approach. These studies explore an innovative technique involving lymphatico-venous anastomoses (LVA) targeting deep cervical lymphatic vessels to promote clearance for the treatment of Alzheimer's or Parkinson's diseases. Cerebral lymphatic drainage is critical for effective brain waste elimination such as amyloid-β, phosphorylated tau, and α-synuclein, which are linked to neurodegenerative diseases. Viewing these lymphatic dysfunctions as a form of "cerebral lymphedema," LVA, already used in treating peripheral lymphedema, shows potential as a therapeutic approach. Although clinical evidence is still limited, lymphatic supermicrosurgery presents promising therapeutic possibilities for neurodegenerative diseases and other conditions related to impaired CNS lymphatic outflow.}, } @article {pmid40874776, year = {2025}, author = {Chen, Y and Dong, C and Chen, J and Li, Q}, title = {Clinical observations on treating Alzheimer's disease with umbilical cord blood mononuclear cells.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {4}, pages = {1430-1436}, doi = {10.1177/13872877251366669}, pmid = {40874776}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Male ; Aged ; Female ; *Leukocytes, Mononuclear/transplantation ; Activities of Daily Living ; Treatment Outcome ; Neuropsychological Tests ; Middle Aged ; Aged, 80 and over ; Mental Status and Dementia Tests ; *Fetal Blood/cytology ; *Cord Blood Stem Cell Transplantation/methods ; }, abstract = {BackgroundThere are currently no relevant clinical research reports on the application of human umbilical cord blood mononuclear cells (hUCBMCs) treatment for Alzheimer's disease (AD) in humans.ObjectiveTo observe the clinical efficacy of intravenous transplantation of hUCBMCs in patients with AD.MethodsEleven AD patients with Clinical Dementia Rating (CDR) scores of 1 (mild) or 2 (moderate) were selected. Patients continued standard AD medication and received three intravenous infusions of UCBMCs, spaced seven days apart. Neurological and psychological assessments, including MMSE, ADAS-Cog, ADL, and PSQI scores, were conducted by neurologists at baseline and 1, 3, and 6 months post-treatment. The impact of UCBMCs on cognitive function, daily living activities, sleep disorders, and any adverse reactions were monitored. Repeated measures ANOVA and LSD-t post-hoc tests were used to analyze score changes.ResultsRepeated measures ANOVA revealed differences in MMSE, ADAS-Cog, ADL, and PSQI scores across the evaluated time points. Pairwise comparisons indicated substantial improvements, with MMSE scores increasing at 1, 3, and 6 months post-treatment, while ADAS-Cog scores decreased. ADL scores showed improvement at 1 and 3 months, and PSQI scores decreased consistently at all post-treatment intervals. Notably, MMSE and ADL scores peaked at 3 months before gradually declining, ADAS-Cog scores reached their lowest point at 3 months before increasing, and PSQI scores were lowest at 1 month, followed by a gradual rise.ConclusionsIntravenous infusion of UCBMCs can temporarily improve cognitive function, enhance daily living activities, and alleviate sleep disorders in AD patients, with a high safety profile.}, } @article {pmid40873665, year = {2025}, author = {Parks, AL and Thacker, A and Dohan, D and Gomez, LAR and Gale, SA and Johnson, KG and Ritchie, CS and Shah, SJ and Paladino, J}, title = {Characterizing clinician communication with patients about lecanemab: A qualitative study of clinicians across seven academic medical centers.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70150}, pmid = {40873665}, issn = {2352-8737}, support = {K76 AG083304/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Anti-amyloid monoclonal antibodies (mAbs) slow cognitive decline in Alzheimer's disease but may cause amyloid-related imaging abnormalities (ARIA), which can rarely be disabling or fatal. This qualitative study investigates how clinicians communicate the benefits and risks of mAbs to patients and caregivers. METHODS: Semi-structured interviews with clinicians who prescribe mAbs at seven academic medical centers. Hybrid inductive-deductive thematic analysis by interdisciplinary researchers. RESULTS: In 27 clinician interviews (women [n = 17], White individuals [n = 19], neurologists [n = 17]), three themes emerged. First, clinicians varied in techniques used and concepts emphasized, including using analogies, discussing statistics, and emphasizing versus de-emphasizing risks. Second, patient contextual factors (e.g., comorbidities), hopes, and fears shaped communication. Third, clinician communication varied by training, personal style, and ambivalence. While clinicians honor patients' choices to pursue treatment, many do not "recommend" it (but may recommend against it). DISCUSSION: Preliminary insights about how clinicians communicate tradeoffs can guide future shared decision-making interventions for mAbs. HIGHLIGHTS: This qualitative study among 27 clinicians across seven academic medical centers examined how clinicians communicate with people with Alzheimer's disease about risks and benefits of anti-amyloid therapy, which can influence treatment decisions.Clinicians varied in what techniques they employed and how they portrayed risks and benefits, and whether they incorporated patients' values.They cited comorbidities, eligibility criteria fit, and degree of social support or family involvement in decisions as factors used in framing discussions, while fewer used patients' goals to guide discussion.The professional training, individual practice style, and personal sense of ambivalence of clinicians shaped conversations.These findings can guide future interventions to improve communication and shared decision-making.}, } @article {pmid40873639, year = {2025}, author = {Huang, G and Liu, Y and Zhu, X and He, L and Chen, T}, title = {Exploring the Neuroprotective Role of Selenium: Implications and Perspectives for Central Nervous System Disorders.}, journal = {Exploration (Beijing, China)}, volume = {5}, number = {4}, pages = {e20240415}, pmid = {40873639}, issn = {2766-2098}, abstract = {Selenium (Se) is a crucial element in selenoproteins, key biomolecules for physiological function in vivo. As a selenium-rich organ, the central nervous system can express all 25 kinds of selenoproteins, which protect neurons by reducing oxidative stress and inflammatory response. However, decreased Se levels are prevalent in a variety of neurological disorders, which is not conducive to the treatment and prognosis of patients. Thus, the biological study of Se has emerged as a focal point in investigating the pivotal role of trace elements in neuroprotection. This paper presents a comprehensive review of the pathogenic mechanism of neurological diseases, the protective mechanism of Se, and the neurological protective function of selenoproteins. Additionally, the application of Se as a neuroprotective agent in neurological disorder therapy, including ischemic stroke, Alzheimer's, Parkinson's, and other neurological diseases, is summarized. The present review aims to offer novel insights and methodologies for the prevention and treatment of neurological disorders with trace Se, providing a scientific basis for the development of innovative Se-based neuroprotectants to promote their clinical application against neurological diseases.}, } @article {pmid40871270, year = {2025}, author = {Zhao, Z and Wu, X and Liu, W and Zheng, L and Tang, C}, title = {Effects of Treadmill Exercise on Gut Microbiota in Alzheimer's Disease Model Mice and Wild-Type Mice.}, journal = {Microorganisms}, volume = {13}, number = {8}, pages = {}, pmid = {40871270}, issn = {2076-2607}, support = {(no.S202410542224)//The Hunan Normal University Undergraduate Innovative Experiment Project and Entrepreneurship Program/ ; }, abstract = {There is a growing body of research showing that Alzheimer's disease (AD) is related to enteric dysbacteriosis. Exercise can be effective in alleviating AD, but the effects that exercise has on the gut microbiota in AD patients needs to be further studied. Through this study, we aimed to investigate the differences in the diversity of gut microorganisms between AD model mice and wild-type mice and the effect that treadmill exercise has on the composition of the gut microbiota in both types of mice. C57BL/6 wild-type mice were randomly divided into a sedentary control group (WTC) and an exercise group (WTE); APP/PS1 double transgenic mice were also randomly divided into a sedentary control group (ADC) and an exercise group (ADE). After the control group remained sedentary for 12 weeks and a 12-week treadmill exercise intervention was adopted for the exercise group, the rectal contents were collected so that they could undergo V3-V4 16S rDNA sequencing, and a comparative analysis of the microbial composition and diversity was also performed. The alpha diversity of the gut microbiota in AD mice was lower than that in wild-type mice, but exercise increased the gut microbial diversity in both types of mice. At the phylum level, the dominant microorganisms in all four groups of mice were Bacteroidetes and Firmicutes. There was an increase in the Bacteroidetes phylum in AD mice. Treadmill exercise reduced the abundance of Bacteroidetes in both groups of mice, whereas the abundance of Firmicutes increased. At the genus level, Muribaculaceae, the Lachnospiraceae_NK4A136_group, Alloprevotella, and Alistipes were in relatively high abundance. Muribaculaceae and Alloprevotella were in greater abundance in AD mice than in wild-type mice, but both decreased after treadmill exercise. Through performing linear discriminant analysis effect size (LEfSe), we found that the dominant strains in AD mice were Campilobacterota, Helicobacteraceae, Escherichia-Shigella, and other malignant bacteria, whereas exercise resulted in an increase in probiotics among the dominant strains in both types of mice. Although gut microbial diversity decreases and malignant bacteria increase in AD mice, treadmill exercise can increase gut microbial diversity and lead to the development of dominant strains of probiotics in both types of mice. These findings provide a basis for applying exercise as a treatment for AD.}, } @article {pmid40870360, year = {2025}, author = {Ozen Koca, R and Solak Gormus, ZI and Solak, H and Gultekin, B and Ozdemir, A and Eroglu Gunes, C and Kurar, E and Kutlu, S}, title = {Agomelatine Ameliorates Cognitive and Behavioral Deficits in Aβ-Induced Alzheimer's Disease-like Rat Model.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {61}, number = {8}, pages = {}, pmid = {40870360}, issn = {1648-9144}, support = {201218004//NEU Scientific Research Projects Coordinator/ ; }, mesh = {*Alzheimer Disease/complications/drug therapy/pathology/physiopathology ; Neuroprotective Agents/pharmacology/therapeutic use ; *Antidepressive Agents/pharmacology/therapeutic use ; Rats, Wistar ; Disease Models, Animal ; *Cognitive Dysfunction/drug therapy/etiology/physiopathology ; Behavior, Animal/drug effects/physiology ; Brain/drug effects/pathology/physiopathology ; *Learning/drug effects/physiology ; *Memory/drug effects/physiology ; Cognition/drug effects ; Amyloid beta-Peptides/administration & dosage/toxicity ; Male ; Animals ; Rats ; Acetamides ; Naphthalenes ; Peptide Fragments ; }, abstract = {Background and Objectives: Alzheimer's disease (AD) has become a serious health problem. Agomelatine (Ago) is a neuroprotective antidepressant. This study aimed to assess how Ago influences behavioral outcomes in AD-like rat model. Materials and Methods: Forty-eight Wistar albino rats were allocated into four groups: Control (C), Alzheimer's disease-like model (AD), Alzheimer's disease-like model treated with Ago (ADAgo), and Ago alone (Ago). Physiological saline was injected intrahippocampally in C and Ago animals, whereas Aβ peptide was delivered similarly in AD and ADAgo rats. On day 15, 0.9% NaCl was administered to the C and AD groups, and Agomelatine (1 mg/kg/day) was infused into ADAgo and Ago rats via osmotic pumps for 30 days. Behavioral functions were evaluated using Open Field (OF), Forced Swim (FST), and Morris Water Maze (MWM) tests. Brain tissues were examined histopathologically. Neuritin, Nestin, DCX, NeuN, BDNF, MASH1, MT1, and MT2 transcripts were quantified by real-time PCR. Statistical analyses were performed in R 4.3.1, with p < 0.05 deemed significant. Results: In the FST, swimming, climbing, immobility time, and mobility percentage differed significantly among groups (p < 0.05). In the MWM, AD rats exhibited impaired learning and memory that was ameliorated by Ago treatment (p < 0.05). DCX expression decreased in AD rats but was elevated by Ago (p < 0.05). Nestin levels differed significantly between control and AD animals; MT1 expression varied between control and AD cohorts; and MT2 transcript levels were significantly lower in AD, ADAgo, and Ago groups compared to C (all p < 0.05). Conclusions: Ago exhibits antidepressant-like activity in this experimental AD model and may enhance cognitive function via mechanisms beyond synaptic plasticity and neurogenesis.}, } @article {pmid40865469, year = {2025}, author = {Gurram, PC and Manandhar, S and Satarker, S and Nassar, A and Begum, F and Mudgal, J and Arora, D and Nampoothiri, M}, title = {Substance P mitigates lipopolysaccharide induced cognitive impairment in rats in a dose dependent manner.}, journal = {Neuropeptides}, volume = {113}, number = {}, pages = {102551}, doi = {10.1016/j.npep.2025.102551}, pmid = {40865469}, issn = {1532-2785}, mesh = {Animals ; Lipopolysaccharides ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Substance P/pharmacology/administration & dosage ; Male ; Rats ; Dose-Response Relationship, Drug ; Hippocampus/metabolism/drug effects ; Disease Models, Animal ; Acetylcholinesterase/metabolism ; Alzheimer Disease/metabolism/chemically induced ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/drug effects ; Rats, Sprague-Dawley ; Cyclic AMP Response Element-Binding Protein/metabolism ; Maze Learning/drug effects ; }, abstract = {Neuroinflammation contributes to cognitive decline in Alzheimer's disease (AD), and the neurokinin pathway has been implicated in the pathophysiology of AD. Although Substance P (SP), an endogenous ligand to the neurokinin 1 receptor (NK1R), is primarily known as a neurotransmitter, but emerging evidence indicates it has shown both pro and anti-inflammatory actions. However, the dose-dependent nature of the SP-NK1R axis's functional role remains to be fully elucidated. In this study, we examined the effects of SP in a rat model of AD induced by lipopolysaccharide (LPS). A dose of 150 μg/10 μl of LPS was administered through intracerebroventricular injection to induce cognitive impairment in the rats. Two doses of SP, 50 μg/kg and 500 μg/kg were administered intraperitoneally once a day for 21 days. Behavioral assessments included the Morris water maze test and novel object recognition test to investigate cognitive defects, and the open field test evaluated locomotion. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), amyloid-beta (Aβ), acetylcholinesterase (AChE), lipid peroxidation, and catalase were estimated in the frontal cortex and hippocampus. The cAMP-responsive element-binding (CREB) protein levels in the whole brain were estimated by western blot. The LPS treatment significantly impaired cognition, increased levels of cytokines, Aβ, oxidative stress, and AChE, while decreasing CREB levels. Notably, the lower dose of SP (50 μg/kg) restored cognitive performance and markers of AD. In contrast, the higher dose of SP (500 μg/kg) failed to reverse spatial memory impairment and neuroinflammation. Thus, our data propose the dose-dependent effect of SP on neuroinflammation-induced cognitive deficits in AD.}, } @article {pmid40865297, year = {2025}, author = {Araújo, R and Reis Carneiro, D and Nunes Rato, R and Massano, J}, title = {Time-saved and time-invested with anti-amyloid treatments in early Alzheimer's disease: practical considerations.}, journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia}, volume = {141}, number = {}, pages = {111584}, doi = {10.1016/j.jocn.2025.111584}, pmid = {40865297}, issn = {1532-2653}, mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; Female ; Male ; Aged ; Time Factors ; *Amyloid beta-Peptides/antagonists & inhibitors ; }, abstract = {Anti-amyloid treatments for early Alzheimer's disease very effectively remove amyloid deposits from the brain and have shown an approximately 30 % less worsening in cognitive functions compared to placebo. Some additional metrics, such as time-saved, i.e. the additional time people may live independently, have been suggested to better inform patients and the general public about the benefits and risks of these medications. Some authors report 4-6 months, and others 10-13 months, depending on the treatment period, time of follow-up, and the methodology used. Taking into consideration that these drugs' regimens are monthly or bi-weekly intravenous infusions requiring clinical supervision, and the necessary brain MRIs for follow-up, we argue that the time spent travelling by the patients and their family members should also be taken into consideration when proposing anti-amyloid treatments, and specifically, when discussing the amount of time saved. In this study, we report that nearly half of the possible eligible patients for anti-amyloid treatments experience a reduction in motivation after receiving the information about the number of times required to come to the hospital, especially those travelling long distances (average time: 60 min for one-way). We propose a rough estimate for the additional time patients and their family members are likely to spend in these arrangements and suggest these additional calculations should be part of the decision-making process.}, } @article {pmid40863632, year = {2025}, author = {Toulis, V and Marfany, G and Mirra, S}, title = {Marine Derived Strategies Against Neurodegeneration.}, journal = {Marine drugs}, volume = {23}, number = {8}, pages = {}, pmid = {40863632}, issn = {1660-3397}, support = {2021SGR-01093//Generalitat de Catalunya/ ; PID2022-140957OB-I00//MCIN/ AEI/10.13039/501100011033 / "ERDF A way of making Europe"/ ; }, mesh = {Humans ; Animals ; *Aquatic Organisms/chemistry ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification ; *Biological Products/pharmacology/therapeutic use/isolation & purification ; Alzheimer Disease/drug therapy ; Genetic Therapy/methods ; }, abstract = {Marine ecosystems are characterized by an immense biodiversity and represent a rich source of biological compounds with promising potential for the development of novel therapeutic drugs. This review describes the most promising marine-derived neuroprotective compounds with strong potential for the treatment of neurodegenerative disorders. We focus specifically on the retina and brain-two key components of the central nervous system-as primary targets for therapeutic interventions against neurodegeneration. Alzheimer's disease and retinal degeneration diseases are used here as a representative model of neurodegenerative disorders, where complex molecular processes such as protein misfolding, oxidative stress, and neuroinflammation drive disease progression. We also examine gene therapy approaches inspired by marine biology, with particular attention to their application in retinal diseases, aimed at preserving or restoring photoreceptor function and vision.}, } @article {pmid40863627, year = {2025}, author = {Debi, PR and Barua, H and Ahmmed, MK and Bhowmik, S}, title = {Therapeutic Potential of Sea Cucumber-Derived Bioactives in the Prevention and Management of Brain-Related Disorders: A Comprehensive Review.}, journal = {Marine drugs}, volume = {23}, number = {8}, pages = {}, pmid = {40863627}, issn = {1660-3397}, mesh = {Humans ; *Sea Cucumbers/chemistry ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/isolation & purification ; *Neurodegenerative Diseases/drug therapy ; *Brain Diseases/drug therapy/prevention & control ; *Biological Products/pharmacology/therapeutic use ; }, abstract = {The popularity of bioactive compounds extracted from sea cucumbers is growing due to their wide application in the pharmaceutical industry, particularly in the development of drugs for neurological disorders. Different types of compounds, such as saponins, phenolic compounds, cerebrosides, and glucocerebrosides, are being studied intensively for their efficacy in assessing the treatment of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and brain tumors, among others. Positive results have been observed in the upregulation in the content of p-CREB, p-PL3K, BDNF, SOD, and MDA. Furthermore, the neuroprotective mechanism of the compounds against Alzheimer's disease revealed that suppressing the phosphorylation of tau protein by the PI3K/Akt/GSK3β pathway leads to improved synaptic plasticity and reduced nerve fiber tangles. This comprehensive review explores recent findings on the therapeutic potential of sea cucumber bioactives in the treatment of brain-related disorders.}, } @article {pmid40863573, year = {2025}, author = {Farup, PG and Hestad, K and Engedal, K}, title = {Personalised Prevention of Falls in Persons with Dementia-A Registry-Based Study.}, journal = {Geriatrics (Basel, Switzerland)}, volume = {10}, number = {4}, pages = {}, pmid = {40863573}, issn = {2308-3417}, abstract = {BACKGROUND/OBJECTIVES: Multifactorial prevention of falls in persons with dementia has minimal or non-significant effects. Personalised prevention is recommended. We have previously shown that gait speed, basic activities of daily living (ADL), and depression (high Cornell scores) were independent predictors of falls in persons with mild and moderate cognitive impairment. This study explored person-specific risks of falls related to physical, mental, and cognitive functions and types of dementia: Alzheimer's disease (AD), vascular dementia (VD), mixed Alzheimer's disease/vascular dementia (MixADVD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). METHODS: The study used data from "The Norwegian Registry of Persons Assessed for Cognitive Symptoms" (NorCog). Differences between the dementia groups and predictors of falls, gait speed, ADL, and Cornell scores were analysed. RESULTS: Among study participants, 537/1321 (40.7%) reported a fall in the past year, with significant variations between dementia diagnoses. Fall incidence increased with age, comorbidity/polypharmacy, depression, and MAYO fluctuation score and with reduced physical activity, gait speed, and ADL. Persons with VD and MixADVD had high fall incidences and impaired gait speed and ADL. Training of physical fitness, endurance, muscular strength, coordination, and balance and optimising treatment of comorbidities and medication enhance gait speed. Improving ADL necessitates, in addition, relief of cognitive impairment and fluctuations. Relief of depression and fluctuations by psychological and pharmacological interventions is necessary to reduce the high fall risk in persons with DLB. CONCLUSIONS: The fall incidence and fall predictors varied significantly. Personalised interventions presuppose knowledge of each individual's fall risk factors.}, } @article {pmid40862941, year = {2025}, author = {Gao, F and Hou, Y and Wang, Y and Liu, L and Yi, X and Xia, N}, title = {Photothermal and Photodynamic Strategies for Diagnosis and Therapy of Alzheimer's Disease by Modulating Amyloid-β Aggregation.}, journal = {Biosensors}, volume = {15}, number = {8}, pages = {}, pmid = {40862941}, issn = {2079-6374}, support = {2023AYSYKYCXTD03//Program for Innovative Research Team of Science and Technology in Anyang Normal University/ ; }, mesh = {*Alzheimer Disease/therapy/diagnosis ; Humans ; *Amyloid beta-Peptides/metabolism ; *Photochemotherapy ; *Photothermal Therapy ; Photosensitizing Agents/therapeutic use ; Reactive Oxygen Species/metabolism ; Protein Aggregates ; }, abstract = {Amyloid-β (Aβ) aggregates are considered as the important factors of Alzheimer's disease (AD). Multifunctional materials have shown significant effects in the diagnosis and treatment of AD by modulating the aggregation of Aβ and production of reactive oxygen species (ROS). Compared to traditional surgical treatment and radiotherapy, phototherapy has the advantages, including short response time, significant efficacy, and minimal side effects in disease diagnosis and treatment. Recent studies have shown that local thermal energy or singlet oxygen generated by irradiating certain organic molecules or nanomaterials with specific laser wavelengths can effectively degrade Aβ aggregates and depress the generation of ROS, promoting progress in AD diagnosis and therapy. Herein, we outline the development of photothermal therapy (PTT) and photodynamic therapy (PDT) strategies for the diagnosis and therapy of AD by modulating Aβ aggregation. The materials mainly include organic photothermal agents or photosensitizers, polymer materials, metal nanoparticles, quantum dots, carbon-based nanomaterials, etc. In addition, compared to traditional fluorescent dyes, aggregation-induced emission (AIE) molecules have the advantages of good stability, low background signals, and strong resistance to photobleaching for bioimaging. Some AIE-based materials exhibit excellent photothermal and photodynamic effects, showing broad application prospects in the diagnosis and therapy of AD. We further summarize the advances in the detection of Aβ aggregates and phototherapy of AD using AIE-based materials.}, } @article {pmid40862772, year = {2025}, author = {de Munter, JPJM and Tsoy, A and Sitdikova, K and Wolters, EC and Chaprov, K and Yenkoyan, KB and Torosyan, H and Askarova, S and Anthony, DC and Strekalova, T}, title = {Therapeutic Effects of Neuro-Cells on Amyloid Pathology, BDNF Levels, and Insulin Signalling in APPswe/PSd1E9 Mice.}, journal = {Cells}, volume = {14}, number = {16}, pages = {}, pmid = {40862772}, issn = {2073-4409}, support = {(AP23485236//the Ministry of Higher Education and Science of the Re-public of Kazakhstan/ ; BR24992841//the Ministry of Higher Education and Science of the Re-public of Kazakhstan/ ; 21T-3A327 and 24YSMU-CON-I-3A//the Higher Education and Science Committee of the Republic of Armenia/ ; 101007642//European Union's H2020-MSCA-RISE-2020/ ; }, mesh = {Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; Mice, Transgenic ; Mice ; Signal Transduction ; *Alzheimer Disease/therapy/pathology/metabolism ; *Insulin/metabolism ; Disease Models, Animal ; *Plaque, Amyloid/pathology/metabolism ; *Neurons/metabolism ; Male ; Amyloid beta-Protein Precursor/metabolism ; }, abstract = {Stem cell therapies, including mesenchymal (MSCs) and haematopoietic stem cells (HSCs), have shown promise in neurodegenerative diseases. Here, we investigated the therapeutic effects of a defined combination of unmanipulated MSCs and CD34[+] HSCs, termed Neuro-Cells (NC), in a murine model of Alzheimer's disease (AD), the APPswe/PS1dE9 mouse. At 12 months of age, mice received intracisternal injections of NC (1.39 × 10[6] MSCs + 5 × 10[5] HSCs) or vehicle. After 45 days, behavioural testing, immunohistochemical analyses of amyloid plaque density (APD), and cortical gene expression profiling were conducted. NC-treated APP/PS1 mice exhibited preserved object recognition memory and reduced anxiety-like behaviours, contrasting with deficits observed in untreated transgenic controls. Histologically, NC treatment significantly reduced the density of small amyloid plaques (<50 μm[2]) in the hippocampus and thalamus, and total plaque burden in the thalamus. Gene expression analysis revealed that NC treatment normalised or reversed disease-associated changes in insulin receptor (IR) signalling and neurotrophic pathways. Specifically, NC increased expression of Bdnf, Irs2, and Pgc-1α, while attenuating aberrant upregulation of Insr, Igf1r, and markers of ageing and AD-related pathology (Sirt1, Gdf15, Arc, Egr1, Cldn5). These findings indicate that NC therapy mitigates behavioural and molecular hallmarks of AD, potentially via restoration of BDNF and insulin receptor-mediated signalling.}, } @article {pmid40859865, year = {2025}, author = {Mello-Hortega, JV and de Oliveira, CS and de Araujo, VS and Furtado-Alle, L and Tureck, LV and Souza, RLR}, title = {Cannabidiol and Alzheimer Disease: A Comprehensive Review and In Silico Insights Into Molecular Interactions.}, journal = {The European journal of neuroscience}, volume = {62}, number = {4}, pages = {e70229}, pmid = {40859865}, issn = {1460-9568}, support = {//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Cannabidiol/therapeutic use/pharmacology ; Humans ; Animals ; Oxidative Stress/drug effects ; Computer Simulation ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a set of multifactorial conditions that progressively impair memory processing and cognitive function. The study of this pathology is particularly challenging due to its complex etiology, which involves several pathological hallmarks, including amyloid plaque formation, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, and other contributing factors-all leading to neuronal loss. The primary therapeutic approach for AD involves the use of anticholinesterase agents; however, these treatments are associated with adverse effects, and their efficacy has been increasingly questioned. Against this backdrop, researchers have investigated cannabidiol (CBD) as a potential complementary treatment for AD. This study compiles and synthesizes current evidence regarding the therapeutic effects of CBD in the context of AD, examining its impact on the amyloid cascade, tau phosphorylation, neuroinflammation, oxidative stress, the cholinergic pathway, glucose and lipid metabolism, behavioral alterations, and physiological changes. In addition, an in silico analysis was conducted based on studies that identified differential gene expression in response to CBD. Through this analysis, we mapped the gene network and biological pathways involved in CBD's mechanism of action in AD, contributing to the identification of potential gene targets for further research and providing deeper insight into its therapeutic potential.}, } @article {pmid40857536, year = {2025}, author = {Xu, X and Ghosh, D and Luo, S}, title = {A novel longitudinal rank-sum test for multiple primary endpoints in clinical trials: Applications to neurodegenerative disorders.}, journal = {Statistics in biopharmaceutical research}, volume = {}, number = {}, pages = {}, pmid = {40857536}, issn = {1946-6315}, support = {P30 AG072958/AG/NIA NIH HHS/United States ; R01 AG064803/AG/NIA NIH HHS/United States ; }, abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD) present a significant global health challenge, characterized by cognitive decline, functional impairment, and other debilitating effects. Current AD clinical trials often assess multiple longitudinal primary endpoints to comprehensively evaluate treatment efficacy. Traditional methods, however, may fail to capture global treatment effects, require larger sample sizes due to multiplicity adjustments, and may not fully utilize the available longitudinal data. To address these limitations, we introduce the Longitudinal Rank Sum Test (LRST), a novel nonparametric rank-based omnibus test statistic. The LRST enables a comprehensive assessment of treatment efficacy across multiple endpoints and time points without the need for multiplicity adjustments, effectively controlling Type I error while enhancing statistical power. It offers flexibility for various data distributions encountered in AD research and maximizes the utilization of longitudinal data. Simulations across realistic clinical trial scenarios, including those with conflicting treatment effects, and real-data applications demonstrate the LRST's performance, underscoring its potential as a valuable tool in AD clinical trials.}, } @article {pmid40853684, year = {2025}, author = {Insel, PS and Mattsson-Carlgren, N and Langford, O and Caruso, VM and Leuzy, A and Young, CB and Boxer, A and Aisen, PS and Sperling, RA and Mormino, EC and Donohue, MC}, title = {Concurrent Changes in Plasma Phosphorylated Tau 217, Tau PET, and Cognition in Preclinical Alzheimer Disease.}, journal = {JAMA neurology}, volume = {82}, number = {10}, pages = {985-993}, pmid = {40853684}, issn = {2168-6157}, mesh = {Humans ; *tau Proteins/blood ; *Alzheimer Disease/diagnostic imaging/blood/psychology ; Aged ; Male ; Female ; Positron-Emission Tomography ; Aged, 80 and over ; Phosphorylation ; Longitudinal Studies ; *Cognition/physiology ; Amyloid beta-Peptides/metabolism ; Aniline Compounds ; Prodromal Symptoms ; Cognitive Dysfunction/diagnostic imaging ; Biomarkers/blood ; Ethylene Glycols ; }, abstract = {IMPORTANCE: Developing disease-modifying treatments is a priority for Alzheimer disease research. OBJECTIVE: To determine the potential of plasma phosphorylated tau 217 (p-tau217) and tau positron emission tomography (PET) to assess disease modification in treatment trials. This diagnostic/prognostic study used longitudinal data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study collected from April 2014 to June 2023. Recruited from 67 sites in the US, Canada, Australia, and Japan, participants included older individuals (age 65-85 years) who were cognitively unimpaired at screening and underwent an amyloid PET scan. Participants without elevated amyloid PET were included from a companion to the A4 study, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. EXPOSURE: 18F-florbetapir PET imaging. MAIN OUTCOMES AND MEASURES: 18F-florbetapir PET imaging was used to classify participants as having elevated amyloid β (Aβ+). Measures of tau included longitudinal plasma p-tau217 and 18F-flortaucipir PET. Cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). RESULTS: A total of 1169 individuals were included from A4 Study and 538 without elevated amyloid PET were included from the LEARN Study. Among these 1707 participants, the baseline mean (SD) age was 71.5 (4.7) years, 1024 (60%) were female, and 683 (40%) male; 1169 participants were Aβ+, and the mean (SD) Mini-Mental State Examination score was 28.8 (1.2). The tau PET substudy included 443 participants; plasma p-tau217 levels were available for 1643 participants. The largest effect size of longitudinal tau PET accumulation at 36 months in Aβ+ participants was in the inferior temporal gyrus. Baseline associations with longitudinal change in PACC score in Aβ+ participants were strongest in the entorhinal cortex (correlation [ρ] = -0.55; 95% CI, -0.63 to -0.45) and plasma p-tau217 levels (ρ = -0.47; 95% CI, -0.56 to -0.37). Tau PET changes in frontoparietal regions were strongly correlated with concurrent cognitive changes. Levels of plasma p-tau217 increased significantly in Aβ+ participants before showing significant deceleration (χ2 = 21.7; P < .001) and were not associated with concurrent cognitive change in the tau PET substudy (ρ = -0.03; 95% CI, -0.23 to 0.16) but were modestly associated with concurrent cognitive changes in the full plasma sample (n = 1119; ρ = -0.24; 95% CI, -0.34 to -0.14). CONCLUSIONS AND RELEVANCE: This study found that tau PET is valuable for both prognostic and real-time tracking of disease progression. Plasma p-tau217 predicts cognitive changes prior to overt cognitive impairment and can efficiently guide participant selection. Imaging-based tau measures may enhance detection of disease-modifying effects and refine therapeutic targets in future Alzheimer disease trials.}, } @article {pmid40851107, year = {2025}, author = {Wang, R and Maloney, B and Beck, JS and Counts, SE and Lahiri, DK}, title = {MicroRNA-153-3p targets repressor element 1-silencing transcription factor (REST) and neuronal differentiation: Implications for Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70399}, pmid = {40851107}, issn = {1552-5279}, support = {P01 AG014449/AG/NIA NIH HHS/United States ; 1R21 AG076202//NIA/NIH/ ; R56 AG051086/AG/NIA NIH HHS/United States ; P30CA082709/GF/NIH HHS/United States ; R21 AG056007/AG/NIA NIH HHS/United States ; R21 AG074539/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; NIA-P30 AG072931//Michigan Alzheimer's Disease Research Center/ ; 2R56 AG051086//NIA/NIH/ ; NIA-P30 AG072976//Indiana Alzheimer's Disease Research Center/ ; UL1TR002529/GF/NIH HHS/United States ; R56 AG072810/AG/NIA NIH HHS/United States ; }, mesh = {*Repressor Proteins/genetics ; Humans ; *Alzheimer Disease/genetics/pathology ; *MicroRNAs/genetics ; *3' Untranslated Regions ; Cell Differentiation ; Neurons/cytology ; Induced Pluripotent Stem Cells/cytology ; Cell Line ; Binding Sites ; Amyloid beta-Protein Precursor/genetics ; alpha-Synuclein/genetics ; Cognitive Dysfunction/genetics/pathology ; }, abstract = {INTRODUCTION: Small non-coding microRNAs (miRNAs) play essential roles in Alzheimer's disease (AD) pathogenesis. Repressor element 1-silencing transcription factor (REST) is involved in AD, though its regulation remains unclear. METHODS: We performed real-time quantitative polymerase chain reaction (qPCR) in autopsied brain tissues to determine miR-153-3p and AD associations. A reporter-based assay measured the activity of REST mRNA 3'-untranslated region (3'-UTR). Induced pluripotent stem cells (iPSC)-derived neurons and human cell lines were applied to determine miR-153-3p regulation of endogenous proteins. RESULTS: Elevation of miR-153-3p is associated with a reduced probability of AD, while elevated REST is associated with a greater probability of AD. The 3'-UTR functional assay pinpointed the miR-153-3p binding sites. miR-153-3p treatment reduced REST, amyloid precursor protein (APP), and α-synuclein (SNCA) 3'-UTR activities and protein levels. miR-153-3p treatment altered REST and neuronal differentiation in iPSC-derived neuronal stem cells. RNA-sequencing and proteomics revealed miR-153-3p-associated networks. DISCUSSION: miR-153-3p reduces REST, APP, and SNCA expression, pointing toward its therapeutic and biomarker potential in neurodegenerative diseases. HIGHLIGHTS: With the increased emphasis on comorbidities of Alzheimer's disease (AD) and other neurodegenerative diseases, we identified that miR-153-3p, as a master regulator, reduced a group of neurodegeneration related proteins: REST, amyloid precursor protein (APP) and α-synuclein (SNCA) levels. The elevation of miR-153-3p levels is associated with reduced probability of AD in posterior cingulate cortex (PCC), while REST, by contrast, is associated with a greater probability of AD. miR-153-3p treatment alters REST protein levels and neuronal differentiation in induced pluripotent stem cells (iPSC) derived neuronal cells. RNA sequencing proteomics and interactome analysis revealed the role of miR-153-3p in axonal guidance.}, } @article {pmid40864415, year = {2025}, author = {Wasim, R}, title = {Bioenergetic failure and oxidative stress: mitochondrial contributions to Alzheimer's disease.}, journal = {Inflammopharmacology}, volume = {33}, number = {9}, pages = {5273-5289}, pmid = {40864415}, issn = {1568-5608}, mesh = {Humans ; *Alzheimer Disease/metabolism/physiopathology/drug therapy/pathology ; *Oxidative Stress/physiology ; *Mitochondria/metabolism/pathology ; Animals ; *Energy Metabolism/physiology ; Reactive Oxygen Species/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {The pathophysiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, is greatly impacted by mitochondrial dysfunction. Recent research suggests that a number of interconnected processes, such as elevated oxidative stress, disturbed energy metabolism, compromised calcium homeostasis, and malformed mitochondrial dynamics, all lead to neuronal injury. The mitochondria in AD brains have structural defects and the function of important oxidative phosphorylation-related enzymes is lowered, which results in less ATP being produced. Further exacerbated by mitochondrial dysfunction is the build-up of amyloid-beta (Aβ) peptides and hyperphosphorylated tau proteins, which interact directly with mitochondrial membranes and proteins to cause mitochondrial fragmentation and hinder mitochondrial transport along neuronal axons. These occurrences cause an increase in reactive oxygen species (ROS) generation, which exacerbates oxidative damage and feeds a vicious cycle. In AD, mutations in mitochondrial DNA (mtDNA) and changes in mitochondrial biogenesis have also been documented, indicating a key involvement in the development of the illness. Preclinical models show promise for therapeutic approaches that attempt to maintain mitochondrial function, including antioxidants, drugs that target the mitochondria. It is crucial to comprehend the intricate relationship between mitochondrial dysfunction and other pathological aspects of AD to find new treatment targets and enhance patient outcomes. In addition to underlining its role in the development of AD, this review examines the complex interaction between mitochondrial dysfunction and AD pathogenesis, taking into account its potential as a biomarker and a target for intervention.}, } @article {pmid40864225, year = {2025}, author = {Terpstra, K and Gutiérrez, C and Gui, K and Mirica, LM}, title = {Donepezil and Memantine Derivatives for Dual-Function and Prodrug Applications in Alzheimer's Disease.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {18}, pages = {3591-3602}, pmid = {40864225}, issn = {1948-7193}, support = {RF1 AG083937/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Memantine/pharmacology/analogs & derivatives ; *Alzheimer Disease/drug therapy/metabolism ; *Donepezil/pharmacology ; *Prodrugs/pharmacology ; *Cholinesterase Inhibitors/pharmacology ; Mice ; Amyloid beta-Peptides/metabolism ; Molecular Docking Simulation ; Mice, Transgenic ; Brain/metabolism/drug effects ; Humans ; Plaque, Amyloid/metabolism ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; }, abstract = {The treatment of Alzheimer's disease by acetylcholinesterase (AChE) and N-methyl-d-aspartate receptor (NMDAR) inhibitors is limited by the narrow therapeutic window and adverse side effects of the drugs. This study aims to increase the efficacy and limit the side effects of donepezil, an AChE inhibitor, and memantine, an NMDAR inhibitor, through the addition of amyloid-β (Aβ)-targeting fragments to create dual-function compounds. The incorporation of the amyloid-targeting fragments successfully produced compounds with affinity for Aβ fibrils, and that can stain amyloid plaques in the brains of 5xFAD mice. The donepezil-based compounds showed significant changes in AChE inhibition compared to donepezil due to the incorporation of the Aβ-targeting fragment and as confirmed by molecular docking studies. The memantine-derived compound showed good brain uptake in 5xFAD mice but lacked compatibility with NMDAR inhibition based on in vitro assays and molecular docking. Importantly, the memantine-derived compound acts as a prodrug in vivo, releasing memantine within a pharmacologically relevant time frame. Overall, these findings suggest that dual-function compounds may be useful as drug delivery agents that can be metabolized to release an active drug in areas of the brain rich in amyloid plaques and thus could lead to improved treatments for Alzheimer's disease.}, } @article {pmid40862175, year = {2025}, author = {Azimi, SM and Elhaie, M and Abedi, I and Salehi, H}, title = {Assessing the Diagnostic Utility of FDG-PET and HPLC for Detecting Microglia Activation and Inflammation in Alzheimer's Disease.}, journal = {Advanced biomedical research}, volume = {14}, number = {}, pages = {59}, pmid = {40862175}, issn = {2277-9175}, abstract = {Early and accurate Alzheimer's disease (AD) diagnosis is essential due to its progressive nature and significant impact. This study reviews and analyses FDG-PET and HPLC techniques in detecting inflammation and microglia activation in AD, marking the first comparison of their diagnostic capabilities. Through a literature search of publications from January 2021 to December 2023 across Scopus, Science Direct, and PubMed databases, 31 relevant articles were selected for analysis. FDG-PET and HPLC data on sensitivity, specificity, and inflammation were examined, highlighting their roles in detecting amyloid plaques, microglial activation, and blood/CSF metabolite regulation. Although amyloid PET offers higher sensitivity, FDG-PET uniquely classifies cognitive stages in AD despite its limitations due to glucose metabolism variance. Whereas HPLC provides insight into metabolic profile changes, it is noted for being invasive and costly. The combined use of FDG-PET and HPLC promises a comprehensive AD diagnostic approach by offering unique, complementary insights into functional and molecular brain changes. However, further validation is needed to overcome technical challenges and confirm their effectiveness before widespread adoption. The advancement of these diagnostic tools, alongside ongoing research, could significantly improve early AD detection, monitoring, and treatment. This review provides a novel assessment and comparison of the diagnostic utility of FDG-PET and HPLC techniques for detecting neuroinflammation and microglia activation in Alzheimer's disease by analyzing relevant studies between 2021 and 2023, highlighting their complimentary strengths and limitations.}, } @article {pmid40860878, year = {2025}, author = {Hou, R and Song, W and Nan, Y and Gong, Y and Liu, J and Liu, J}, title = {Cistanche tubulosa glycosides ameliorate cognitive decline in APP/PS1 mice via modulation of gut microbiota and fatty acid metabolism: insights from multi-omics and experimental validation.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1662336}, pmid = {40860878}, issn = {1663-9812}, abstract = {OBJECTIVE: The dried succulent stem of C. tubulosa (Schenk) Wight has long been used as herbal medicine in China and other regions of Asia for its tonifying properties. This study aimed to elucidate the pharmacological mechanisms of the total glycosides from Cistanche tubulosa (GCT) in ameliorating cognitive decline, with a focus on gut microbiota remodeling and metabolic regulation. METHODS: Six-month-old APP/PS1 double-transgenic mice received oral GCT at three doses or donepezil for 60 days. Cognitive function was assessed by the Morris water maze. Aβ burden and inflammatory factors were evaluated by immunohistochemistry and ELISA. Gut microbiota was analyzed using 16S rRNA sequencing. Metabolomic profiles of mice serum and brain were profiled by a targeted metabolomics approach that enabled simultaneous quantitation of 306 metabolites. The effect of GCT on pure-cultured bacterial strain was assessed via growth curve analysis in vitro. RESULTS: GCT treatment significantly improved spatial memory and reduced the protein levels of Aβ and proinflammatory factors in APP/PS1 mice. Multi-omics analyses revealed that GCT rapidly enriched beneficial taxa like Akkermansia and suppresses Firmicutes since the seventh day of intervention, leading to increased neuroprotective short-chain fatty acids (e.g., β-hydroxybutyrate) and decreased pro-inflammatory long-chain fatty acids in both serum and brain. Crucially, in-vitro experiments demonstrated that GCT directly promoted the proliferation of Akkermansia muciniphila, a key probiotic implicated in AD amelioration. CONCLUSION: This work uncovers a novel "gut microbiota-fatty acid metabolism-neuroinflammation" axis as the primary mechanism underlying GCT's anti-AD effects. These findings highlight GCT's therapeutic potential and offer new mechanistic insights into how low-bioavailability phytochemicals exert systemic benefits via the gut-brain axis.}, } @article {pmid40860056, year = {2025}, author = {Kermaninia, S and Mohammadi-Khanaposhtani, M and Şenol, H and Khajeh Mohammadilar, FS and Dastyafteh, N and Moradkhani, F and Saeedi, S and Larijani, B and Dadgar, A and Aktaş, A and Sadeghian, N and Taslimi, P and Mahdavi, M}, title = {New 1E,1'E-hydrazine-bis(phenoxy-1,2,3-triazol-acetamide) derivatives as potent inhibitors against acetylcholinesterase, butyrylcholinesterase, and α-glucosidase.}, journal = {RSC advances}, volume = {15}, number = {36}, pages = {29960-29971}, pmid = {40860056}, issn = {2046-2069}, abstract = {In this study, novel 1E,1'E-hydrazine-bis(phenoxy-1,2,3-triazol-acetamide) derivatives 10a-n were synthesized, and because of their structural features, they were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase. AChE and BChE are two important targets in the treatment of Alzheimer's disease (AD), and α-glucosidase is a carbohydrate-hydrolyzing enzyme with therapeutic importance in diabetes. Furthermore, cell studies were performed on the title compounds against SH-SY5Y neuroblastoma cells as a cancer cell line and HEK293 cells as a normal cell line. In vitro enzymatic evaluations demonstrated that these new compounds were active against the studied enzymes in comparison to standard inhibitors. In this regard, all the synthesized compounds were more potent than the standard inhibitors tacrine and donepezil against BChE, and most of these compounds were more potent than tacrine against AChE. Moreover, most of the target synthesized compounds were more potent than the standard inhibitor acarbose against α-glucosidase. The most potent compound against AChE and BChE was the 2,4-dichloro derivative 10k, and the most potent compound against α-glucosidase was the 2-chloro derivative 10h. Moreover, in vitro cell studies demonstrated that compounds 10k and 10h with a selectivity index of >10 demonstrated more cytotoxic effects on the cancer cell line SH-SY5Y than on the normal cell line HEK293. A docking study showed that the latter compounds attached to the active sites of the target enzymes with binding energies more favorable than those of the selected standard inhibitors. Furthermore, docking studies demonstrated that compound 10k interacted with both the catalytic and peripheral anionic sites of AChE and BChE. This property led to the better efficacy of the compound in the treatment of AD.}, } @article {pmid40859959, year = {2025}, author = {Mao, S and Qiao, R and Wang, Q and Shen, L and Li, D and Huo, X and Wang, J and Liu, K and Chen, W and Zhu, T and Zhang, B and Leng, S and Bai, Y}, title = {Activity and Heterogeneity of Astrocytes in Neurological Diseases: Molecular Mechanisms and Therapeutic Targets.}, journal = {MedComm}, volume = {6}, number = {9}, pages = {e70329}, pmid = {40859959}, issn = {2688-2663}, abstract = {Astrocytes, the most prevalent glial cells in the central nervous system (CNS), play crucial roles in maintaining CNS homeostasis and responding to various pathological stimuli. They play key roles in neural development, neurotransmission, neuroinflammation, metabolic support, and tissue repair. Recent advancements in single-cell sequencing have revealed the remarkable heterogeneity of astrocytes, with distinct subpopulations differentially contributing to disease progression in neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, intracerebral hemorrhage, and multiple sclerosis. In addition, they play an important role in various behavioral neuropsychiatric disorders. This review highlights the dual roles of astrocytes in disease progression, driven by their diverse molecular profiles and functions. It outlines the key molecular mechanisms underlying astrocyte heterogeneity and their impact on neuroinflammation, neuronal support, and ionic balance regulation. Additionally, the review discusses potential therapeutic strategies targeting astrocytes to modulate these processes, aiming to improve treatment outcomes in neurological diseases. By elucidating the specific roles of astrocyte subsets in disease, this review seeks to advance the development of precision medicine for astrocyte-related neurological disorders.}, } @article {pmid40859930, year = {2025}, author = {Gao, JM and Li, WB and Chen, NN and Yi, Y and Wang, ZH and Chen, X and Zhao, YY and Yuan, ZL and Gao, J and Pan, YC and Guo, DS and Gong, QH}, title = {A Single-Molecule Pleuripotent Scaffold for Combinational Therapy of Alzheimer's Disease via Intranasal Administration.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {43}, pages = {e11611}, pmid = {40859930}, issn = {2198-3844}, support = {[2025]030//Central Government-Guided Local S&T Special Project of Guizhou Province/ ; GCC[2023]042//"'hundred"' level of high-level innovative talents in Guizhou Province/ ; //Fundamental Research Funds for the Central Universities/ ; 22371147//National Natural Science Foundation of China/ ; 22201141//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Administration, Intranasal/methods ; Animals ; Mice ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/administration & dosage/pharmacology ; Drug Delivery Systems/methods ; Humans ; Male ; }, abstract = {The intricate pathological mechanisms of Alzheimer's disease (AD), along with the restrictive nature of the blood-brain barrier (BBB) that further impedes the drug brain entry, underscore the pressing need for innovative combinational therapy to achieve effective treatment outcomes. Intranasal administration, capable of bypassing BBB by direct transport through olfactory and trigeminal nerves, provides a promising approach for treating neurological disorders. Herein, the guanidinium-modified calix[5]arene (GC5AY) is developed as a single-molecule pleuripotent scaffold, demonstrating small size, positive charge and desirable amphiphilicity, which facilitate its efficient traverse of nasal mucosal barrier. The multifunctionality of GC5AY, including inhibiting amyloid fibrosis, scavenging reactive oxygen species and drug delivery, enables it to serve as a sophisticated platform for constructing multi-target AD therapeutic agents. In light of this, by loading neuroprotective agent Trilobatin (TLB) into the cavity of GC5AY, intranasal administration of the TLB@GC5AY formulation is verified to effectively attenuate the cognitive impairment of AD mice, demonstrating multifaceted pathological improvements, while also possessing good biocompatibility. In response to the growing appeal for combinational therapy of AD, the approach proposed in this study has provided a readily generalizable strategy to fulfill this pursuit.}, } @article {pmid40858403, year = {2025}, author = {Gomaa, AA and Farghaly, HSM and Ahmed, AM and El-Mokhtar, MA and Hemida, FK}, title = {Corrigendum to "Advancing combination treatment with cilostazol and caffeine for Alzheimer's disease in high fat-high fructose-STZ induced model of amnesia'' [Europ. J. Pharmacol. 921 (2022), 174873].}, journal = {European journal of pharmacology}, volume = {1005}, number = {}, pages = {178074}, doi = {10.1016/j.ejphar.2025.178074}, pmid = {40858403}, issn = {1879-0712}, } @article {pmid40854983, year = {2025}, author = {Zhang, G and Pang, KK and Gao, Q and Chen, X and Huang, F and He, J}, title = {Cholecystokinin-expressing GABA neurons elicit long-term potentiation in the cortical inhibitory synapses and attenuate sound-shock associative memory.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {31220}, pmid = {40854983}, issn = {2045-2322}, support = {CityUHK 11101521//Hong Kong Research Grants Council/ ; CityUHK 11103922//Hong Kong Research Grants Council/ ; CityUHK 11104923//Hong Kong Research Grants Council/ ; CityUHK 11104524//Hong Kong Research Grants Council/ ; GHP_075_19GD//Innovation and Technology Fund of the Hong Kong SAR/ ; 09203656//Hong Kong Health Bureau, Health and Medical Research Fund/ ; 08194106//Hong Kong Health Bureau, Health and Medical Research Fund/ ; }, mesh = {Animals ; *Cholecystokinin/metabolism/genetics ; *Long-Term Potentiation/physiology ; *GABAergic Neurons/metabolism/physiology ; Mice ; *Synapses/metabolism/physiology ; *Memory/physiology ; Pyramidal Cells/metabolism/physiology ; *Auditory Cortex/physiology/metabolism ; Parvalbumins/metabolism ; Somatostatin/metabolism ; Interneurons/metabolism ; Male ; Mice, Transgenic ; }, abstract = {Neuronal interactions between inhibitory and excitatory neurons play a pivotal role in regulating the balance of excitation and inhibition in the central nervous system (CNS). Consequently, the efficacy of inhibitory/excitatory synapses profoundly affects neural network processing and overall neuronal functions. Here, we describe a novel form of long-term potentiation (LTP) induced at cortical inhibitory synapses and its behavioral consequences. We show that high-frequency laser stimulation (HFLS) of GABAergic neurons elicit inhibitory LTP (i-LTP) in pyramidal neurons of the auditory cortex (AC). The selective activation of cholecystokinin-expressing GABA (GABA[CCK]) neurons is essential for the formation of HFLS-induced i-LTP, rather than the classical parvalbumin (PV) neurons and somatostatin (SST) neurons. Intriguingly, i-LTP can be evoked in the AC by adding the exogenous neuropeptide CCK when PV neurons and SST neurons are selectively activated in PV-Cre and SST-Cre mice, respectively. Additionally, we discovered that low-frequency laser stimulation (LFLS) of PV neurons paired with HFLS of GABA[CCK] neurons potentiates the inhibitory effect of PV interneurons on pyramidal neurons, thereby generating heterosynaptic i-LTP in the AC. Notably, light activation of GABA[CCK] neurons in CCK-Cre mice significantly attenuates sound- shock associative memory, while stimulation of PV neurons does not affect this memory in PV-Cre mice. In conclusion, these results demonstrate a critical mechanism regulating the excitation-inhibition balance and modulating learning and memory in cortical circuits. This mechanism might serve as a potential target for the treatment of neurological disorders, including epilepsy and Alzheimer's disease.}, } @article {pmid40856257, year = {2025}, author = {Ghosh, A and Mukhopadhyay, TK and Datta, A}, title = {Two-dimensional materials can inhibit Aβ fibrillation in Alzheimer's disease.}, journal = {Physical chemistry chemical physics : PCCP}, volume = {27}, number = {36}, pages = {19134-19148}, doi = {10.1039/d5cp01461a}, pmid = {40856257}, issn = {1463-9084}, mesh = {*Amyloid beta-Peptides/chemistry/metabolism/antagonists & inhibitors ; *Alzheimer Disease/metabolism/drug therapy ; *Graphite/chemistry/pharmacology ; Boron Compounds/chemistry/pharmacology ; Humans ; *Nanostructures/chemistry ; Adsorption ; Protein Aggregates/drug effects ; }, abstract = {Alzheimer's disease (AD) is a major life-limiting neurodegenerative disorder caused by extracellular aggregation of amyloid β (Aβ) peptides. This forms amyloid plaques in the brain resulting in dementia and even causing death. In spite of great efforts towards developing therapies to cure AD, unfortunately, treatment is often ineffective. Herein, we investigate the possibility of state-of-the-art two-dimensional (2D) nanomaterials to treat AD by evaluating their potential to perturb and disrupt Aβ peptide aggregates. The adsorption mechanism for a pre-formed Aβ fibril is carefully studied on five 2D materials, namely graphene, hexagonal boron nitride (h-BN), h2D-C2N, g-C3N3, and g-C3N4. They are screened for their disrupting effects on the peptide aggregate. It is found that disruption of the Aβ fibril is directly related to the strength of its adsorption on the 2D material, which in turn, is dominated by the van der Waals interactions. h-BN shows a profound disruption of the Aβ fibril followed by graphene. The nitrogen-containing carbon-based 2D materials, h2D-C2N, g-C3N3, and g-C3N4, are found to be rather poor in this aspect. Structural disruption parameter ρd is proposed as an index to rank the potency of 2D materials to inhibit Aβ fibrillation. h-BN and graphene are shown to be highly potent towards disruption of misfolded protein aggregates like Aβ fibrils.}, } @article {pmid40856133, year = {2025}, author = {Korkmaz, E and Secerli, J and Erdoğan, H and Güdül Bacanlı, M}, title = {Cracking Amyloid Toxicity: Naringin Rescues Neuronal Cells in a Minimal Alzheimer's Model.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {21}, pages = {4224-4235}, doi = {10.1021/acschemneuro.5c00410}, pmid = {40856133}, issn = {1948-7193}, mesh = {*Flavanones/pharmacology ; Humans ; *Alzheimer Disease/metabolism/drug therapy ; *Neurons/drug effects/metabolism ; *Amyloid beta-Peptides/metabolism/toxicity ; Reactive Oxygen Species/metabolism ; Cell Line, Tumor ; DNA Damage/drug effects ; Apoptosis/drug effects ; *Neuroprotective Agents/pharmacology ; Cell Survival/drug effects ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, extracellular amyloid plaque accumulation, and neuronal dysfunction. The diphenylalanine (Phe-Phe) dipeptide, a core self-assembling motif of amyloid-β (Aβ) peptides, has recently gained attention as a simplified and cost-effective model for mimicking amyloid aggregation in vitro. In this study, we established a Phe-Phe-induced AD model in SH-SY5Y neuroblastoma cells to investigate the effects of naringin (NAR), a Citrus-derived flavanone glycoside known for its antioxidative and anti-inflammatory properties, on AD. Following Phe-Phe exposure, cells were treated with NAR at subcytotoxic concentrations. Multiple end points including cytotoxicity, reactive oxygen species (ROS) generation, DNA damage (Comet assay), AD-related biomarkers (acetylcholinesterase (AChE), amyloid beta (Aβ), amyloid precursor protein (APP), tau protein), cytokine levels, caspase activation, and apoptosis were evaluated. NAR treatment significantly attenuated Phe-Phe-induced ROS production, genotoxicity, and inflammatory responses, while reducing apoptotic cell death and restoring biomarker levels toward physiological norms. These findings demonstrate that NAR exerts multitargeted neuroprotective effects and suggest its therapeutic potential in AD. Additionally, the Phe-Phe model was validated as a reproducible and biologically relevant in vitro system for screening anti-amyloid agents.}, } @article {pmid40855593, year = {2025}, author = {Foreman, RM and Rodriguez, M}, title = {Understanding the correlative relationship between obesity and Alzheimer disease.}, journal = {The Nurse practitioner}, volume = {50}, number = {9}, pages = {40-45}, doi = {10.1097/01.NPR.0000000000000355}, pmid = {40855593}, issn = {1538-8662}, mesh = {Humans ; *Alzheimer Disease/nursing/physiopathology/epidemiology/etiology ; *Obesity/complications/physiopathology/nursing/epidemiology ; Risk Factors ; }, abstract = {Current literature suggests obesity can increase the risk of developing dementia, in addition to all-cause mortality. Although cardiovascular disease and metabolic disorders are well-known risks of obesity, the increased risk of Alzheimer disease is lesser known. This article explores the pathophysiologic processes behind obesity and dementia and offers recommendations for identification, treatment, and optimal health planning in primary care.}, } @article {pmid40854864, year = {2025}, author = {Chen, YZ and Wei, YT and Xiao, M and Xie, WT and Yan, XK}, title = {[The mechanism of PI3K/AKT pathway in Alzheimer's disease and the research progress of acupuncture intervention].}, journal = {Zhen ci yan jiu = Acupuncture research}, volume = {50}, number = {8}, pages = {965-973}, doi = {10.13702/j.1000-0607.20240371}, pmid = {40854864}, issn = {1000-0607}, mesh = {*Alzheimer Disease/therapy/genetics/metabolism/enzymology ; Humans ; *Proto-Oncogene Proteins c-akt/metabolism/genetics ; *Acupuncture Therapy ; *Signal Transduction ; *Phosphatidylinositol 3-Kinases/metabolism/genetics ; Animals ; Autophagy ; }, abstract = {Acupuncture has a definite effect on the treatment of Alzheimer's disease (AD), and its molecular mechanism has been studied more and more deeply. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway is mainly involved in the regulation of cell proliferation, apoptosis, autophagy and synaptic plasticity, and plays an important role in the occurrence and development of AD. In this paper, we reviewed the role of PI3K/AKT pathway in the pathogenesis of AD and the mechanism of acupuncture intervention, and concluded that the abnormal expression of PI3K/AKT signaling pathway can lead to imbalance of cellular oxidative defense system, impairment of mitochondrial structure and function synaptic destruction, abnormal autophagy and energy metabolism disorders, and acupuncture can improve oxidative stress damage, enhance synaptic plasticity, regulate autophagic activity and regulate energy metabolism by regulating PI3K/AKT signaling pathway to cure AD.}, } @article {pmid40854505, year = {2025}, author = {Tidke, B and Itekar, S and Khobragade, R and Vinchurney, M and Trivedi, R and Taksande, B and Umekar, M}, title = {Therapeutic implications of allopregnanolone in Alzheimer's related depression.}, journal = {Behavioural brain research}, volume = {495}, number = {}, pages = {115785}, doi = {10.1016/j.bbr.2025.115785}, pmid = {40854505}, issn = {1872-7549}, mesh = {*Pregnanolone/pharmacology/metabolism/therapeutic use ; Humans ; *Alzheimer Disease/drug therapy/metabolism/complications ; Animals ; *Depression/drug therapy/metabolism/etiology ; *Antidepressive Agents/pharmacology ; Neurosteroids ; }, abstract = {Alzheimer's disease (AD) and depression share common neuropathological mechanisms, with neuroinflammation, mitochondrial dysfunction, and impaired neurosteroid signalling contributing to both conditions. Allopregnanolone (ALLO), a potent neurosteroid, plays a crucial role in modulating mood, cognition, and neuroprotection via its interaction with GABA-A receptors and its ability to promote neurogenesis. Emerging evidence suggests that ALLO levels are significantly altered in AD, correlating with cognitive decline and neuropsychiatric symptoms, including depression. This review explores the pathological connection between AD and depression, highlighting the role of ALLO in mitigating disease progression and depressive symptoms. Preclinical studies demonstrate ALLO's ability to enhance synaptic plasticity, reduce β-amyloid toxicity, and alleviate depressive-like behaviours in AD models. Additionally, clinical trials investigating ALLO's therapeutic potential in AD and depression have shown promising results, though challenges remain in optimizing dosing, delivery, and patient selection. As a neurosteroid with both neuroprotective and antidepressant properties, ALLO represents a novel therapeutic approach that could bridge the gap between neurodegeneration and mood disorders. This review discusses the current understanding of ALLO's mechanistic role, its altered levels in AD and depression, and its potential as a disease-modifying therapy. Furthermore, we evaluate preclinical and clinical evidence supporting ALLO's efficacy, along with its limitations and future therapeutic prospects. By integrating neurosteroid-based strategies into AD treatment paradigms, ALLO may offer a promising avenue for addressing both cognitive decline and neuropsychiatric symptoms in AD-induced depression.}, } @article {pmid40854493, year = {2025}, author = {Huang, Y and Huo, X and Liu, H and Li, D and Yin, Z}, title = {Bile acids and polyphenols inhibit succinic anhydride-induced protein succinylation and amyloid aggregation: Mechanistic insights.}, journal = {Archives of biochemistry and biophysics}, volume = {773}, number = {}, pages = {110601}, doi = {10.1016/j.abb.2025.110601}, pmid = {40854493}, issn = {1096-0384}, mesh = {*Polyphenols/pharmacology/chemistry ; *Bile Acids and Salts/pharmacology/chemistry ; Molecular Docking Simulation ; *Protein Aggregates/drug effects ; *Succinic Anhydrides/chemistry ; *Amyloid/chemistry/metabolism ; Humans ; Protein Processing, Post-Translational/drug effects ; Glucosides/pharmacology ; }, abstract = {Lysine succinylation is a major post-translational modification affecting diverse proteins, and its excessive occurrence can lead to protein misfolding and aggregation-hallmarks of various proteinopathies, such as amyloid-β and Tau tangle formation in Alzheimer's disease and islet amyloid polypeptide aggregation in type 2 diabetes. Here, we investigated the inhibitory effects of bile acid metabolites (deoxycholic acid, glycocholic acid, and taurocholic acid sodium) and natural polyphenols (anthocyanin and salidroside) on succinylation and succinylation-induced amyloid aggregation. Succinylation levels were evaluated using the ninhydrin assay before and after treatment, and aggregation behavior and structural alterations were characterized by SDS-PAGE, inverted fluorescence microscopy, and intrinsic fluorescence spectroscopy. Additionally, fluorescence quenching and molecular docking were used to explore the underlying mechanisms. All five small molecules significantly reduced succinylation in a concentration-dependent manner (p < 0.05). Among bile acids, taurocholic acid sodium exhibited the strongest suppression of aggregation (40.99 %), followed by glycocholic acid (28.32 %) and deoxycholic acid (27.94 %). Anthocyanin showed greater inhibition (33.81 %) than salidroside (26.54 %) (all p < 0.05). The results suggest that these small molecules inhibit succinylation-induced aggregation potentially by interacting with proteins and altering their conformations, thereby preventing excessive succinylation at lysine residues. This study provides new insight into the interplay between bile acid metabolism and protein homeostasis and highlights the therapeutic potential of natural compounds in preventing protein aggregation-related diseases.}, } @article {pmid40854473, year = {2025}, author = {Ibrahim, KS and Colson, TL and Ferguson, SSG and Abd-Elrahman, KS}, title = {Positive allosteric modulation of M1 mAChRs with VU0486846 reverses cognitive deficits in male APPswe/PSEN1ΔE9 alzheimer's mice.}, journal = {Neuropharmacology}, volume = {280}, number = {}, pages = {110654}, doi = {10.1016/j.neuropharm.2025.110654}, pmid = {40854473}, issn = {1873-7064}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Male ; *Receptor, Muscarinic M1/metabolism/agonists/drug effects ; Mice ; Mice, Transgenic ; Presenilin-1/genetics ; *Cognitive Dysfunction/drug therapy/metabolism ; Female ; Disease Models, Animal ; Allosteric Regulation/drug effects ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is an age-associated neurodegenerative disease marked by progressive cognitive deterioration and beta-amyloid (Aβ) protein buildup, which currently lacks therapeutic interventions to decelerate its pathogenesis. The M1 muscarinic acetylcholine receptor (mAChR) is integral to synaptic plasticity and memory processes and has emerged as a critical target for ameliorating AD-associated cognitive deficits. Although M1 mAChR agonists have pro-cognitive potential, their clinical application is limited by significant cholinergic side effects. Our recent findings demonstrate that VU0486846, an M1 mAChR positive allosteric modulator (PAM) devoid of cholinergic toxicity, exhibits therapeutic benefits in a female APPswe/PSEN1ΔE9 (APP/PS1) Alzheimer's disease mouse model. This compound reversed memory deficits, alleviated anxiety-like behaviours, reduced Aβ pathology, and attenuated neuroinflammation in female mice. However, its therapeutic potential in male AD models remains to be fully characterized. In this study, we find that VU0486846 treatment restored cognitive function in male APP/PS1 mice, as evidenced by improved performance in the novel object recognition and Morris water maze tasks, and reduced anxiety-like behaviours in the open field test. VU0486846 ameliorates impaired autophagy signaling in the hippocampus, however, it does not alter hippocampal Aβ oligomer or plaque burden, despite decreasing BACE1 expression. These findings suggest that VU0486846 exerts behavioural and cognitive benefits via Aβ-independent mechanism(s). Collectively, this study highlights the therapeutic potential of VU0486846 in modulating AD pathophysiology, albeit via sex-specific signaling pathways.}, } @article {pmid40854437, year = {2025}, author = {Oh, JM and Shin, WH and Kim, B and Kim, E and Son, HJ and Kim, H}, title = {Farnesiferol B and Kamolonol Isolated from Ferula assa-foetida are Potent BACE1 Inhibitors with Neuroprotective Effects.}, journal = {Planta medica}, volume = {91}, number = {15}, pages = {933-942}, doi = {10.1055/a-2689-8035}, pmid = {40854437}, issn = {1439-0221}, support = {RS-2024-00347522//National Research Foundation of Korea (NRF) grant funded by Korean Government/ ; }, mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Animals ; *Neuroprotective Agents/pharmacology/isolation & purification/chemistry ; Molecular Docking Simulation ; Dogs ; *Ferula/chemistry ; Madin Darby Canine Kidney Cells ; *Aspartic Acid Endopeptidases/antagonists & inhibitors ; Humans ; Cell Line, Tumor ; Molecular Dynamics Simulation ; Amyloid beta-Peptides ; }, abstract = {Five compounds were isolated from Ferula assa-foetida and their beta-secretase 1 inhibitory activities were evaluated. Farnesiferol B and kamolonol showed potent beta-secretase 1 inhibitory activity with IC50 values of 8.11 and 1.00 µM and competitive inhibition patterns against beta-secretase 1 with Ki values of 6.51 and 0.41 µM, respectively. In silico pharmacokinetics showed that farnesiferol B was predicted to have high gastrointestinal absorption and blood-brain barrier permeability. In cell studies, farnesiferol B and kamolonol were nontoxic to normal Madin-Darby canine kidney and neuroblastoma cells, and both showed protective effects on neuroblastoma cells for Aβ42-induced neurotoxicity. In molecular docking simulations, we found that the efficacy of the compounds may be related to their interaction with the flap region and hydrogen bonding with ARG368. In addition, molecular dynamics simulation of kamolonol showed the ligand maintained its stability in interaction with the loop residues. These results show that farnesiferol B and kamolonol are potent beta-secretase 1 inhibitors with neuroprotective effects, suggesting that they are potential candidates for the treatment of neurodegenerative disorders, such as Alzheimer's disease.}, } @article {pmid40847318, year = {2025}, author = {Okafor, M and Faller, P and Vitale, N}, title = {Cell-specific copper dyshomeostasis mechanism in Alzheimer's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {42}, pmid = {40847318}, issn = {2047-9158}, support = {Idex PhD program//Université de Strasbourg/ ; ITI Neurostra program//Université de Strasbourg/ ; ITI Neurostra program//Université de Strasbourg/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology ; *Copper/metabolism ; Humans ; *Homeostasis/physiology ; Animals ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism/pathology ; Oxidative Stress/physiology ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive decline of cognitive functions, yet its underlying aetiology remains elusive. While amyloid-β (Aβ) and tau pathologies have been extensively studied, emerging evidence suggests that metal and especially copper dyshomeostasis may also play a crucial role in the pathogenesis of AD. This review explores the intricate relationship between copper and AD, shedding light on the multifaceted mechanisms through which copper dysregulation contributes to neurodegeneration. We delve into the impact of copper ions on Aβ aggregation, tau phosphorylation, and oxidative stress, providing a comprehensive overview of the molecular pathways involved. Furthermore, we discuss the interplay between different brain cell types and the impact Cu dysregulation may have on them. The therapeutic implications of targeting copper dysregulation for AD treatment are also addressed, emphasizing the potential of copper-modulating agents in ameliorating cognitive decline. In summary, this review discusses copper dyshomeostasis as a central player in the intricate tapestry of AD pathology, offering new insights and avenues for therapeutic interventions.}, } @article {pmid40853487, year = {2025}, author = {Wang, S and Xu, Z and Wang, S and Peng, Q and Zhu, S and Liu, C and Zhang, Y and Duan, R}, title = {Alamandine Rescues Cognitive Impairment and Ameliorates Alzheimer's Disease-Like Neuropathology in APP/PS1 Mice.}, journal = {Neurochemical research}, volume = {50}, number = {5}, pages = {277}, pmid = {40853487}, issn = {1573-6903}, support = {202201030//the International Joint Research and Development Project of Nanjing/ ; 82301609//the National Natural Science Foundation of China/ ; 2022M711666//China Postdoctoral Science Foundation/ ; BK20220196//Natural Science Foundation of Jiangsu Province/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism/pathology ; Oxidative Stress/drug effects ; Male ; Amyloid beta-Protein Precursor/genetics ; *Oligopeptides/therapeutic use/pharmacology ; Mice, Transgenic ; Endoplasmic Reticulum Stress/drug effects ; Maze Learning/drug effects ; Disease Models, Animal ; Mice, Inbred C57BL ; *Neuroprotective Agents/therapeutic use/pharmacology ; Presenilin-1/genetics ; Morris Water Maze Test/drug effects ; }, abstract = {Alzheimer's disease (AD) is on the rise worldwide, consequently driving a growing demand for effective prevention and treatment strategies. Alamandine is a member of the renin-angiotensin system family. Although alamandine exhibits protective effects in the pathophysiology of various disorders, its role in AD remains an unexplored area. This research aims to elucidate the benefits and mechanisms of alamandine in an in vivo model of AD. The mice received intracerebroventricular injections of vehicle or alamandine once daily for 4 weeks. The Morris water maze was conducted to assess spatial learning ability. Nissl staining was performed to evaluate neuronal injury. Important inflammation indictors were detected both by qRT-PCR and ELISA. Representative oxidative stress indicators and Fe[2+] levels were measured using corresponding assay kits. Western blot was employed to detect the expression levels of the related proteins. We found that alamandine mitigates cognitive function and spatial learning impairment in APP/PS1 mice. Alamandine shows positive therapeutic effects by ameliorating the phosphorylation of tau proteins and suppressing neuroinflammation. In addition, alamandine mitigates the oxidative stress, ferroptosis and endoplasmic reticulum stress (ERS) in the brain of APP/PS1 mice. Our research indicates that alamandine alleviates cognitive impairment in APP/PS1 mice and inhibits inflammation, oxidative stress, ferroptosis, and ERS. It may serve as a promising approach to alleviate symptoms and promote remission in AD.}, } @article {pmid40853403, year = {2025}, author = {Parmar, P and Chauhan, H and Modi, P and Israni, D}, title = {Pharmacological Evaluation and In-Silico Study of Sabinene as a Potential Anti-Alzheimer's Drug in AlCl3-Induced Rat Model via BACE-1 and GSK3β Modulation.}, journal = {Neurochemical research}, volume = {50}, number = {5}, pages = {278}, pmid = {40853403}, issn = {1573-6903}, mesh = {Animals ; Male ; *Glycogen Synthase Kinase 3 beta/metabolism ; Rats, Wistar ; *Amyloid Precursor Protein Secretases/metabolism ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; Aluminum Chloride ; *Aspartic Acid Endopeptidases/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Rats ; Molecular Docking Simulation ; Disease Models, Animal ; Aluminum Compounds ; Chlorides ; }, abstract = {Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disorder. β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and glycogen synthase kinase-3β (GSK3β) contribute to Aβ plaque development, tau hyperphosphorylation, neurofibrillary tangles, and neuronal dysfunction in AD pathogenesis. This study aimed to investigate the neuroprotective potential of sabinene in an Aluminum chloride (AlCl3)-induced model of AD in male Wistar rats. Thirty male Wistar rats were randomly divided into six groups (n = 6 per group). Group I (control) received normal saline for 30 days. Groups II-V were administered only AlCl3 (100 mg/kg, orally) for 20 consecutive days to induce AD-like pathology, which was confirmed through behavioral assessments. Following induction, Group II (AD control) received 1% Tween 80; Group III (standard treatment) was administered rivastigmine (2.5 mg/kg); while Groups IV-VI received sabinene at doses of 5, 10, and 20 mg/kg, respectively, for 10 days 1 h prior to AlCl3. Behavioral evaluations were conducted on days 0, 20, and 31. On the 31st day, animals were sacrificed for biochemical and molecular analyses. In silico molecular docking studies revealed that sabinene exhibited a higher binding affinity towards AD-related targets (BACE1, GSK-3β, TACE, and AChE) compared to rivastigmine. In vivo, sabinene treatment significantly mitigated oxidative stress, restored antioxidant enzyme activities, reduced pro-inflammatory cytokine levels, AChE, BACE1, and GSK3β expression, and ameliorated histopathological alterations in the rat brain. Thus, sabinene exerts potent neuroprotective and disease-modifying effects in AlCl3-induced AD via AchE, BACE-1, and GSK3β Modulation.}, } @article {pmid40850846, year = {2025}, author = {Mattke, S and Chen, J and Reiman, EM}, title = {A preliminary economic evaluation of a potential program for the primary prevention of Alzheimer's disease.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {12}, number = {9}, pages = {100334}, pmid = {40850846}, issn = {2426-0266}, mesh = {Humans ; *Alzheimer Disease/prevention & control/economics/genetics ; *Cost-Benefit Analysis ; Aged ; *Primary Prevention/economics/methods ; Middle Aged ; Male ; Female ; Plaque, Amyloid/prevention & control ; Apolipoprotein E4/genetics ; }, abstract = {INTRODUCTION: We evaluated the potential cost-effectiveness of a hypothetical primary prevention screening and treatment program to avert the biological and clinical onset of Alzheimer's disease (AD) in cognitively unimpaired older adults. METHODS: This hypothetical program would use an amyloid plaque-clearing antibody therapy monthly in the first six months and annually thereafter in cognitively unimpaired 55-79 year-old APOE4 carriers and 60-79 year-old non-carriers with a negative AD blood test (sensitivity and specificity of 0.9), averting the onset of moderately frequent neuritic amyloid plaques by 75 %. Lifetime hypothetical treatment outcomes were compared to natural history outcomes to estimate cost-effectiveness. RESULTS: The program would be cost-effective up to a per-dose price of $1173 in APOE4 carriers and $307 in non-carriers or a lifetime cost of $20,167 and $5146, respectively. DISCUSSION: Primary AD prevention could be cost-effective in older adults, especially in those at higher risk. Our findings and assumptions need to be confirmed with actual data.}, } @article {pmid40850200, year = {2025}, author = {Shen, D and Fan, S and Kong, W and Yuan, H and Wei, X and Zheng, K and Cao, S and Huang, L and Chu, L and Ge, L}, title = {Research progress on the interaction of artemisinin and its derivatives with TLR4 receptors in neuroinflammation.}, journal = {International immunopharmacology}, volume = {164}, number = {}, pages = {115402}, doi = {10.1016/j.intimp.2025.115402}, pmid = {40850200}, issn = {1878-1705}, mesh = {*Toll-Like Receptor 4/metabolism ; Humans ; *Artemisinins/therapeutic use/pharmacology/chemistry ; Animals ; *Neuroinflammatory Diseases/drug therapy/immunology ; Signal Transduction/drug effects ; }, abstract = {In recent years, TLR4, as a key member of the TLRs family, has attracted increasing attention for its role in neuroimmune diseases. As a critical immune surveillance molecule, TLR4 is considered a promising target for the modulation of neuroimmune disorders. A growing body of research has confirmed that artemisinin and its derivatives, as natural immunomodulators, participate in the regulation of TLR signaling pathways-particularly showing a close relationship with TLR4 among the TLR family.Recent studies have revealed a novel dual regulatory effect of artemisinin and its derivatives on the TLR4 signaling pathway. These compounds can not only selectively modulate TLR4-mediated inflammatory signaling cascades, such as the NF-κB pathway, effectively suppressing the excessive activation of microglia, but also inhibit TLR4 dimerization and endocytosis, thereby blocking downstream signal transduction and alleviating neuroinflammatory responses. This novel finding provides a molecular basis for targeting TLR4 in the treatment of neuroimmune diseases such as multiple sclerosis (MS) and Alzheimer's disease (AD).Moreover, as naturally derived TLR4 modulators, artemisinin and its derivatives show great potential as new lead compounds for targeted therapies in neuroimmune diseases, offering new avenues and strategies for treatment. Therefore, this review focuses on the molecular structural characteristics of artemisinin and its derivatives, and the TLR4-mediated signaling pathways. It explores their potential mechanisms of action in modulating neuroimmune disorders from multiple perspectives-including drug structural properties, molecular docking simulations, and target regulation. The objective is to identify safe and effective neuroimmune modulators from natural products and provide new research perspectives and strategies for the TLR4-targeted treatment of neuroimmune diseases.}, } @article {pmid40849807, year = {2025}, author = {Cong, C and Cong, H and Yao, Y and Bai, Y and Xu, L}, title = {Copper homeostasis and cuproptosis in Alzheimer's disease (Review).}, journal = {International journal of molecular medicine}, volume = {56}, number = {5}, pages = {}, pmid = {40849807}, issn = {1791-244X}, mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *Copper/metabolism ; *Homeostasis ; Animals ; Oxidative Stress ; Brain/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuroinflammation, synaptic dysfunction and neuronal loss. Research has revealed a connection between copper metabolism and the pathophysiology of AD, particularly through a newly identified form of copper‑dependent cell death referred to as cuproptosis. Cuproptosis is driven by the aggregation of lipoylated proteins and proteotoxic stress caused by excessive copper accumulation, leading to cellular demise, which is a key event in AD. While studies on copper levels in the brain in AD remain inconclusive, there is mounting evidence suggesting that an imbalance in copper homeostasis, particularly elevated labile copper levels, contributes to oxidative damage and neurodegeneration in patients with AD. The present review examines the role of cuproptosis in AD and discusses how targeting this pathway may provide novel therapeutic opportunities. By investigating the underlying mechanisms and potential clinical implications, the present review highlights that regulation of cuproptosis provides a promising approach for modulating disease progression and developing personalized treatment strategies for AD.}, } @article {pmid40849781, year = {2025}, author = {Kurochkina, N and Rudrabhatla, P}, title = {Role of Calmodulin in Neurodegeneration and Neuroprotection.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575403663250812115441}, pmid = {40849781}, issn = {1875-5607}, abstract = {Intracellular calcium (Ca2+) levels are critical in maintaining cellular activities and are tightly regulated. Neuronal degeneration and regeneration rely on calcium-binding proteins. Calmodulin (CaM) is a calcium sensor and the primary regulator of receptors and ion channels that maintain calcium homeostasis. The calmodulin binding domains are present in proteins that serve as risk factors and biomarkers associated with Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, and other neurodegenerative diseases, suggesting calmodulin ligands as emerging therapeutic targets for treatment. Inhibiting CaM to develop new therapies has drawbacks, as CaM is a ubiquitous molecule involved in many regulatory pathways. Recently, new strategies for disrupting CaM interactions with its targets have shown promising approaches to treatment. The structures of human CaM, its binding proteins, and inhibitors are well studied, with particular emphasis on the conservation of CaM amino acid sequences and the ability to bind protein fragments of high sequence variability, which exhibit common characteristics of amphipathic helices carrying basic amino acids. In this review, we discuss structural characteristics of CaM and its ligands in the context of transcriptional regulation. Specific binding of CaM to (1) basic region/helix-loop-helix/leucine zipper and (2) helix-turn-helix high mobility group box containing Sox families of transcription factors highlights common features of CaM binding sequences, which suggest their regulatory functions. We describe key proteins involved in neurodegeneration and transcription factors subject to calmodulin regulation that are candidates for the development of new approaches to treating neuronal diseases.}, } @article {pmid40849759, year = {2025}, author = {Maheshwari, S and Kumar, P and Dwivedi, V and Mishra, A and Singh, VK and Singh, A}, title = {Advances in Nanotechnology for Targeted Drug Delivery in Alzheimer's Disease.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098359258250727103551}, pmid = {40849759}, issn = {1874-6128}, abstract = {Alzheimer's Disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and hallmark pathological features, such as amyloid-beta plaques and tau protein tangles. Despite substantial research, current therapeutic strategies remain primarily symptomatic, with limited success in preventing or reversing disease progression. One major challenge is the Blood-Brain Barrier (BBB), which restricts the delivery of therapeutic agents to the brain. Nanotechnology provides innovative solutions to these challenges by enabling the development of targeted drug delivery systems tailored to AD's unique pathophysiology. Nanoparticles offer several advantages for AD therapy, including their small size, surface modifiability, and the ability to traverse the BBB. These carriers can enhance drug stability, prolong systemic circulation, and enable controlled drug release, reducing systemic toxicity while maximizing therapeutic efficacy. Among various approaches, nanoparticles functionalized with ligands targeting AD show promise in promoting the clearance of pathological aggregates, potentially slowing disease progression and alleviating neurotoxicity. Liposomes, polymeric nanoparticles, dendrimers, and exosomes are notable nanocarriers that have been successfully engineered to deliver a range of therapeutic agents, including anti-amyloid drugs, neuroprotective compounds, and gene therapies. Recent advancements also emphasize stimulus-responsive nanocarriers that release drugs in response to specific pathological cues, further enhancing treatment precision. This article delves into the most recent advancements in nanotechnology for AD therapy, and the potential of these innovative systems to overcome long-standing barriers in AD treatment and paving the way for more effective and targeted interventions.}, } @article {pmid40849753, year = {2025}, author = {Souza, FN and David, ES and Lima, HB and Silva, AG and Souto, RNP and Hage-Melim, LIS}, title = {Evidence of the Efficacy of Acetylcholinesterase Inhibitors in In Vivo Studies: A Systematic Review.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273388078250801044226}, pmid = {40849753}, issn = {1996-3181}, abstract = {INTRODUCTION: This systematic review aimed to provide an updated overview of studies using anticholinesterases with in vivo activity for the treatment of Alzheimer's disease. METHODS: A systematic review was conducted using searches in the following databases: PubMed, SciELO (Scientific Electronic Library Online), Web of Science, LILACS (Latin American and Caribbean Literature in Health Sciences), as well as gray literature, through the CAPES and Google Scholar databases of national and international journals. The research was registered on the International Prospective Register of Systematic Reviews (PROSPERO) platform under registration number: CRD42024482117 and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. RESULTS: A total of 1,191 articles were identified in the databases, of which 11 were selected to compose this systematic review, as they met the previously pre-defined selection criteria. The selected articles were published between 2019 and 2023. The substance most commonly used to induce Alzheimer's was scopolamine. As for administration routes, the most used was intraperitoneal. Some of the methods used to evaluate cognitive processes in rats and mice were- Elevated Plus Maze (EPM), Morris water maze (MWZ), Y maze, and passive avoidance tests. DISCUSSION: The reviewed studies demonstrated that the evaluated anticholinesterase agents exhibited anti-Alzheimer activity in animal models, with notable cognitive effects observed in behavioral tests. CONCLUSION: The data indicated that the analyzed anticholinesterase agents have therapeutic potential for Alzheimer's disease, justifying the continuation of preclinical research and future clinical investigations.}, } @article {pmid40848921, year = {2025}, author = {Ma, C and Campbell, K and Kovalenko, A and Li, J and Sandusky-Beltran, LA and Liang, H and Hunt, JB and Calahatian, J and Kallupurackal, M and Pandey, S and Vasisht, M and Watler, M and Quadri, Z and Michalski, C and Fahnestock, M and Papangelis, A and Pedersen, DS and Ulven, T and Nash, K and Selenica, MB and Morgan, D and Bickford, PC and Lee, DC}, title = {Nutrient sensing receptor GPRC6A regulates mTORC1 signaling and Tau biology.}, journal = {Neurobiology of disease}, volume = {216}, number = {}, pages = {107054}, doi = {10.1016/j.nbd.2025.107054}, pmid = {40848921}, issn = {1095-953X}, support = {R01 AG054559/AG/NIA NIH HHS/United States ; R21 AG055996/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Mechanistic Target of Rapamycin Complex 1/metabolism ; Humans ; *Receptors, G-Protein-Coupled/metabolism ; *tau Proteins/metabolism ; Signal Transduction/physiology ; Mice ; *Alzheimer Disease/metabolism/pathology ; *Tauopathies/metabolism ; Male ; Brain/metabolism ; Mice, Transgenic ; Arginine/metabolism ; Female ; Mice, Inbred C57BL ; }, abstract = {Tauopathies, including Alzheimer's disease (AD), comprise microtubule-associated protein tau aggregates that cause neuronal cell death and clinical cognitive decline. Reducing overall tau abundance remains a central strategy for therapeutics; however, no disease-modifying treatment exists to date. One principal pathway for balancing cellular proteostasis includes the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Recently, arginine emerged as one of the primary amino acids to activate mTORC1 through several intracellular arginine sensors and an extracellular arginine receptor, namely the G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A). Human AD brains were previously reported with elevated mTORC1 signaling; however, it is unclear whether arginine sensing and signaling to mTORC1 plays a role in tauopathies. Herein, we examined arginine sensing associated with mTORC1 signaling in the human AD and animal models of tauopathy. We found that human AD brains maintained elevated levels of arginine sensors with potential uncoupling of arginine sensing pathways. Furthermore, we observed increased GPRC6A and arginine in the brain, accompanied by increased mTORC1 signaling and decreased autophagy in a mouse model of tauopathy (Tau PS19). We also discovered that both supplementing arginine and overexpressing GPRC6A in cell culture models could independently activate mTORC1 and promote tau accumulation. In addition, we found that suppressing GPRC6A signaling by either genetic reduction or pharmacological antagonism reduced tau accumulation, phosphorylation, and oligomerization. Overall, these findings uncover the crucial role of arginine sensing pathways in deregulating mTORC1 signaling in tauopathies and identify GPRC6A as a promising target for future therapeutics in tauopathies and other proteinopathies. SIGNIFICANCE STATEMENT: Tauopathies, including Alzheimer's disease (AD), accumulate pathogenic tau protein inclusions that potentially contribute to the hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling and eventually cause neuronal cell death. Here, we presented novel findings that AD and animal models of tauopathy maintained increased expression of arginine sensors and uncoupling of arginine sensing associated with mTORC1 signaling. We investigated the role of a putative extracellular arginine and basic L-amino acid sensing G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A) in activating mTORC1 and accelerating pathogenic tau phenotypes in several cell models. Additionally, we showed that genetic repression or antagonism of GPRC6A signaling provides a novel therapeutic target for tauopathies and other proteinopathies.}, } @article {pmid40848864, year = {2025}, author = {Rao, J and Zheng, H and Lu, M and Chen, J and Wang, C and Cao, Y}, title = {Yanghuo Sanqi capsule against Alzheimer's disease by upregulating lipid metabolism: Network pharmacology and multi-omics analysis.}, journal = {Fitoterapia}, volume = {186}, number = {}, pages = {106837}, doi = {10.1016/j.fitote.2025.106837}, pmid = {40848864}, issn = {1873-6971}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; *Drugs, Chinese Herbal/pharmacology ; Caenorhabditis elegans/drug effects ; *Lipid Metabolism/drug effects ; Network Pharmacology ; Mice ; Molecular Docking Simulation ; Capsules ; Amyloid beta-Protein Precursor/metabolism ; Up-Regulation ; Amyloid beta-Peptides ; Multiomics ; }, abstract = {Yanghuo Sanqi capsule (YSC) consists of Yingyanghuo (Epimedium brevicornu Maxim., YYH) and Sanqi (Panax notoginseng (Burk.) F.H.Chen, SQ), which is used to treat cardiovascular diseases in Traditional Chinese Medicine (TCM). Additionally, the accumulated evidence suggests that it has the potential to treat Alzheimer's disease (AD). This study tries to elucidate the mechanisms of YSC against AD by combining network pharmacology of absorbed components with multi-omics of Caenorhabditis elegans (C. elegans). Firstly, network pharmacology was used to predict the target of the YSC in the treatment of AD. Then, Caenorhabditis elegans (C. elegans) CL4176 and CL2355 were used to study the effect of YSC on AD, and the mechanism was studied through multi-omics. Finally, potential therapeutic targets and bioactivity ingredients were identified through validation experiments, molecular docking, and molecular dynamics simulation. The network pharmacology of 15 mice blood components suggested that YSC may intervene in AD by regulating lipid metabolism and amyloid precursor protein (APP). In addition, YSC can alleviate Aβ-induced toxicity in both muscle and nerve in C. elegans. Transcriptomic and metabolomic analysis in C. elegans showed that YSC protected against AD by increasing lipid metabolism, which can maintain lipid homeostasis inside and outside the cell and down-regulating APP to alleviate Aβ-induced toxicity. Anhydroicaritin (AHI) is an important bioactive ingredient involved in regulating APP error clipping and lipid metabolism in YSC. This study reveals the mechanism of YSC anti-AD and provides experimental support for expanding its clinical use.}, } @article {pmid40848134, year = {2025}, author = {Mehra, A and Sachdeva, V and Khanna, J and Singh, G and Mahajan, M and Bhardwaj, J and Kaur, M and Bedi, N}, title = {Mirtazapine revisited: new therapeutic perspectives and formulation advances.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40848134}, issn = {1432-1912}, abstract = {Mirtazapine (MTZ) is a Food and Drug Administration-approved medication used primarily for the treatment of severe depression. It is a BCS class II drug having poor aqueous solubility (0.092 mg/mL), low oral bioavailability (50%), and high first-pass metabolism. This narrative review summarizes the ongoing research for the development of MTZ's novel formulations, keeping in view its physicochemical properties and its pharmacokinetic limitations. Owing to its novel pharmacodynamics, MTZ offers considerable potential for the management of various diseases, including schizophrenia, Alzheimer's disease, Parkinson's disease, epilepsy, post-traumatic stress disorder, diabetes, irritable bowel syndrome, and infertility, in addition to its widely established utility in depression. Nevertheless, the literature findings on the usage of MTZ in the aforementioned diseases remain contentious, which can be attributed to the inconsistencies in the research evidence and variable study outcomes. However, promising results of therapeutic effectiveness of MTZ against pruritus, cancer-induced nausea, emesis, and anorexia have been reported from preliminary investigations. Lastly, the present review provides a worthwhile overview of clinical trials and patents, which together put forward substantial evidence suggesting the potential repurposing of MTZ beyond from its use in depression, thereby accelerating advancements in drug delivery technologies.}, } @article {pmid40847656, year = {2025}, author = {Stroud, J and Cummings, JL and Chumki, SR and Such, P and Wang, D and Palma, AM and Zhang, Z and Brubaker, M and Grossberg, GT}, title = {Brexpiprazole for agitation in clinically relevant patient subgroups: a post hoc analysis of efficacy and safety in patients with agitation associated with dementia due to Alzheimer's disease.}, journal = {Current medical research and opinion}, volume = {41}, number = {8}, pages = {1523-1534}, doi = {10.1080/03007995.2025.2552278}, pmid = {40847656}, issn = {1473-4877}, mesh = {Humans ; *Alzheimer Disease/complications/drug therapy ; *Thiophenes/adverse effects/administration & dosage/therapeutic use ; Male ; *Psychomotor Agitation/drug therapy/etiology ; Female ; Aged ; Aged, 80 and over ; *Quinolones/adverse effects/administration & dosage/therapeutic use ; Middle Aged ; Double-Blind Method ; Treatment Outcome ; *Antipsychotic Agents/adverse effects/therapeutic use/administration & dosage ; }, abstract = {OBJECTIVE: To explore the efficacy and safety of brexpiprazole for the treatment of agitation symptoms in clinically relevant subgroups of patients with dementia due to Alzheimer's disease. METHODS: Data were pooled for brexpiprazole (2 or 3 mg/day) and placebo from two international, randomized, double-blind trials in adults with a clinical diagnosis of Alzheimer's dementia with mild-to-severe cognitive dysfunction and with agitation (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Change in agitation frequency over 12 weeks was measured using the Cohen-Mansfield Agitation Inventory (CMAI). Safety measures included treatment-emergent adverse events (TEAEs). In this post hoc analysis, thirteen clinically relevant subgroups were investigated based on care setting (institutionalized, non-institutionalized), severity of cognitive dysfunction (mild/moderate, severe), co-occurring behavioral symptoms (psychosis, depression, anxiety, irritability, sleep disturbance), and use of concomitant medications for dementia (acetylcholinesterase inhibitor, memantine) and psychiatric conditions (antidepressant, benzodiazepine). RESULTS: In the randomized sample (N = 621), mean age was 74 years (range 55-90 years), 344 (55.4%) participants were female, and 277 (44.6%) were male. Over 12 weeks, brexpiprazole showed numerically greater reduction in agitation frequency than placebo in 12 of 13 subgroups. The only exception was "concomitant benzodiazepines", which was a small subgroup (n = 71), but showed efficacy for brexpiprazole in secondary analyses. The largest differences in favor of brexpiprazole versus placebo were for the concomitant antidepressant, co-occurring sleep disorder, and co-occurring psychosis subgroups. The overall incidence of TEAEs was generally consistent across subgroups. CONCLUSION: In these exploratory analyses, brexpiprazole reduced symptoms of agitation across a wide range of patients with agitation associated with dementia due to Alzheimer's disease.}, } @article {pmid40846816, year = {2025}, author = {Akindele, RG and Adebayo, S and Yu, M and Kanda, PS}, title = {AlzhiNet: Traversing from 2D-CNN to 3D-CNN, Towards Early Detection and Diagnosis of Alzheimer's Disease.}, journal = {Interdisciplinary sciences, computational life sciences}, volume = {}, number = {}, pages = {}, pmid = {40846816}, issn = {1867-1462}, support = {E2021202179//Natural Science Foundation of Hebei Province/ ; 42075129//National Natural Science Foundation of China/ ; 21351803D//Hebei Provincial Key Research Projects/ ; SJMYF2022Y06//Hebei Provincial Key Research Projects/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with increasing prevalence among the ageing population, necessitating early and accurate diagnosis for effective disease management. In this study, we present a novel hybrid deep learning framework, AlzhiNet, that integrates both 2D convolutional neural networks (2D-CNNs) and 3D convolutional neural networks (3D-CNNs), along with a custom loss function and volumetric data augmentation, to enhance feature extraction and improve classification performance in AD diagnosis. According to extensive experiments, AlzhiNet outperforms standalone 2D and 3D models, highlighting the importance of combining these complementary representations of data. The depth and quality of 3D volumes derived from the augmented 2D slices also significantly influence the model's performance. The results indicate that carefully selecting weighting factors in hybrid predictions is imperative for achieving optimal results. Our framework has been validated on the magnetic resonance imaging (MRI) from Kaggle and MIRIAD datasets, obtaining accuracies of 98.9% and 99.99%, respectively, with an AUC of 100%. Furthermore, AlzhiNet was studied under a variety of perturbation scenarios on the Alzheimer's Kaggle dataset, including Gaussian noise, brightness, contrast, salt and pepper noise, color jitter, and occlusion. The results obtained show that AlzhiNet is more robust to perturbations than ResNet-18, making it an excellent choice for real-world applications. This approach represents a promising advancement in the early diagnosis and treatment planning for AD.}, } @article {pmid40846207, year = {2025}, author = {Sharma, T and Bashir, B and Sharma, P and Andotra, N and Singh, SK and Singh, TG and Vishwas, S}, title = {Quantum dots in neurotheranostics for the treatment of Alzheimer's disease.}, journal = {Ageing research reviews}, volume = {112}, number = {}, pages = {102876}, doi = {10.1016/j.arr.2025.102876}, pmid = {40846207}, issn = {1872-9649}, mesh = {*Alzheimer Disease/drug therapy/diagnosis/metabolism/therapy ; *Quantum Dots/therapeutic use ; Humans ; *Theranostic Nanomedicine/methods ; Animals ; Blood-Brain Barrier/metabolism ; Biomarkers/metabolism ; }, abstract = {Age-related neurodegeneration is one of the primary causes associated with the pathogenesis of Alzheimer's disease (AD). Currently, there are 5.8 million cases of AD worldwide. With the advancement in technology, the paradigm of treating the disease has shifted from one treatment or diagnosis to simultaneously diagnosing as well as treating the disease. Excellent efforts have been made by the scientists towards the development of nanotheranostics. Among them, quantum dots (QDs) have shown promising results due to their nanometer size, which enables them to cross the blood-brain barrier (BBB) and optical properties which help in imaging the environment/pathology inside the brain. Furthermore, their functionalization with the specific biomolecules or coupling with aptamers/proteins/peptides/antibodies offers site-specific detection of pathological biomarkers. The long-lasting, tunable, and strong fluorescence generated by them within the body helps in the selective detection of biomarkers at very low concentrations. This helps in the accurate and early diagnosis of AD. Their multiplexed sensing of multiple markers at a time due to the tunable property of their emission wavelengths, makes it a more specific and sensitive tool over microarray or other assays. Additionally, real-time tracking of drug delivery and parallel treatment of the disease at the targeted site make them a unique theranostic tool over other techniques. This review consolidates recent advances in QDs-based approaches, encompassing their physicochemical properties, blood-brain barrier (BBB) penetration strategies, synthesis, and functionalization techniques. The roles in targeted drug delivery, bioimaging, and biomarker detection, as well as their intrinsic therapeutic actions, including inhibition of amyloid beta formation and tau aggregation, antioxidative effects, and neuroprotection, have also been discussed. Multiple preclinical studies demonstrate the ability of QDs to enhance drug stability, improve BBB transport, enable high-sensitivity imaging of AD biomarkers, and modulate neuroinflammatory responses.}, } @article {pmid40845962, year = {2025}, author = {Zhou, Q and Zheng, N and Chen, Z and Xie, L and Yang, X and Sun, Q and Lin, J and Li, B and Li, L}, title = {The emerging role of disulfidptosis in Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1005}, number = {}, pages = {178085}, doi = {10.1016/j.ejphar.2025.178085}, pmid = {40845962}, issn = {1879-0712}, mesh = {*Alzheimer Disease/pathology/metabolism/drug therapy ; Humans ; Animals ; *Apoptosis/drug effects ; Oxidative Stress/drug effects ; *Disulfides/metabolism ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Disulfidptosis ; }, abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder primarily characterized by Aβ deposition and tau hyperphosphorylation. Clinically, AD manifests as progressive episodic-memory loss that ultimately erodes global cognition and the ability to perform activities of daily living. Despite decades of investigation, the molecular underpinnings of AD remain incompletely understood and no disease-modifying therapies are available. Recently, disulfidptosis, a novel form of programmed cell death (PCD) caused by disulfide stress with high expression of SLC7A11 (solute carrier family 7 member 11) under glucose starvation conditions, has emerged as a potential contributor to neurodegeneration. This review systematically summarizes the discovery, molecular features, and regulatory mechanisms of disulfidptosis, and critically evaluates its relevance to AD pathogenesis. We show that disulfidptosis can directly or indirectly modulate pivotal disease pathways, including Aβ accumulation, tau hyper-phosphorylation, and oxidative stress, through interconnected molecular cascades. Furthermore, we also delved into its potential application prospects in AD treatment, including inhibiting SLC7A11 activity, regulating NADPH (Nicotinamide Adenine Dinucleotide Phosphate) levels, targeting actin cytoskeleton dynamics, and antioxidant therapy. By integrating disulfidptosis into the AD landscape for the first time, this review offers a novel mechanistic perspective and identifies actionable therapeutic targets, thereby laying the groundwork for precision strategies against disulfidptosis-driven neurodegeneration.}, } @article {pmid40844953, year = {2025}, author = {Lalawat, RS and Kushwaha, N and Bajaj, V and Padhy, PK}, title = {NeuroFormer: A Deep Learning Framework for Alzheimer's Detection Using EEG Signals.}, journal = {IEEE journal of biomedical and health informatics}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/JBHI.2025.3601658}, pmid = {40844953}, issn = {2168-2208}, abstract = {Alzheimer's disease (AD), is a prevalent neurodegenerative disorder, characterized by cognitive decline. Alongside AD, and Frontotemporal dementia (FTD) poses significant challenges in clinical diagnosis due to overlapping symptoms and heterogeneous pathological mechanisms. This overlap often complicates timely and accurate diagnosis, which is crucial for effective intervention and treatment planning. To address this, a novel deep learning architecture, NeuroFormer is proposed for the classification of EEG signals captured through non-invasive neurophysiological measurement instruments into three categories: AD, FTD, and healthy controls (CN). The model integrates spectral processing, neural oscillatory dynamics, hierarchical capsule routing, adaptive normalization, and attention-based feature fusion to effectively extract discriminative spatiotemporal features from raw EEG signals. Advanced mechanisms such as dynamic spectral gating and graph convolutions capture both local and global brain activity patterns, while a multi-scale adaptive feature pyramid enhances feature representation. A lightweight classifier decodes the learned features, achieving a classification accuracy of 95.76%, significantly outperforming benchmark models across all key evaluation metrics. These findings demonstrate the strong potential of NeuroFormer as a measurement-driven diagnostic framework for early and accurate classification of dementia-related disorders using EEG instrumentation.}, } @article {pmid40844208, year = {2026}, author = {Sui, YV and Masurkar, AV and Shepherd, TM and Feng, Y and Wisniewski, T and Rusinek, H and Lazar, M}, title = {Associations Between Hippocampal Transverse Relaxation Time and Amyloid PET in Cognitively Normal Aging Adults.}, journal = {Journal of magnetic resonance imaging : JMRI}, volume = {63}, number = {1}, pages = {171-180}, pmid = {40844208}, issn = {1522-2586}, support = {P30 AG066512/AG/NIA NIH HHS/United States ; P41 EB017183/EB/NIBIB NIH HHS/United States ; P41 EB017183/EB/NIBIB NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Positron-Emission Tomography/methods ; *Hippocampus/diagnostic imaging ; Aged ; Middle Aged ; Aged, 80 and over ; *Magnetic Resonance Imaging ; *Amyloid beta-Peptides/metabolism ; *Aging ; Longitudinal Studies ; Retrospective Studies ; *Cognition/physiology ; Alzheimer Disease/diagnostic imaging ; }, abstract = {BACKGROUND: Identifying early neuropathological changes in Alzheimer's disease (AD) is important for improving treatment efficacy. Among quantitative MRI measures, transverse relaxation time (T2) has been shown to reflect tissue microstructure relevant in aging and neurodegeneration; however, findings regarding T2 changes in both normal aging and AD have been inconsistent. The association between T2 and amyloid-beta (Aβ) accumulation, a hallmark of AD pathology, is also unclear, particularly in cognitively normal individuals who may be in preclinical stages of the disease. PURPOSE: To investigate longitudinal hippocampal T2 changes in a cognitively normal cohort of older adults and their association with global Aβ accumulation. STUDY TYPE: Retrospective, longitudinal. SUBJECTS: 56 cognitively normal adults between 55 and 90 years of age (17 males and 39 females). FIELD STRENGTH/SEQUENCE: 3 Tesla; multi-echo spin echo sequence for T2 mapping; 18F-florbetaben positron emission tomography for Aβ measurement. ASSESSMENT: Bilateral hippocampal T2 and volume were extracted to relate to Aβ PET measurements. To understand variations in AD risk, participants were separated into Aβ-high and Aβ-low subgroups using a predetermined threshold. STATISTICAL TESTS: Linear mixed-effect models and general linear models were used. A p-value < 0.025 was considered significant to account for bilateral comparisons. RESULTS: Older age was associated with increased T2 in the bilateral hippocampus (left: β = 0.30, right: β = 0.25) and smaller hippocampal volume on the left (β = -0.12). In the Aβ-low subgroup, both longitudinal T2 increase rates (β = 0.65) in the left hippocampus and bilateral cross-sectional T2 (left: β = 0.64, right: β = 0.46) were positively correlated with Aβ PET, independent of hippocampal volume. DATA CONCLUSION: This study provided in vivo evidence linking hippocampal T2 to Aβ accumulation in cognitively normal aging individuals, suggesting that quantitative T2 may be sensitive to microstructural changes accompanying early Aβ pathology, such as neuroinflammation, demyelination, and reduced tissue integrity. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.}, } @article {pmid40844075, year = {2025}, author = {Zhang, Y and Zhang, Y and Liang, R and Zou, J and Pei, R and Chen, X}, title = {Targeted ROS Scavenging for Disease Therapies Using Nanomaterials.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {37}, number = {50}, pages = {e04435}, doi = {10.1002/adma.202504435}, pmid = {40844075}, issn = {1521-4095}, support = {NUHSRO/2020/133/Startup/08//National University of Singapore/ ; NUHSRO/2023/008/NUSMed/TCE/LOA//National University of Singapore/ ; NUHSRO/2021/034/TRP/09/Nanomedicine//National University of Singapore/ ; MOH-001388-00//National Medical Research Council/ ; MOH-001041//National Medical Research Council/ ; CG21APR1005//National Medical Research Council/ ; MOH-001127-01//National Medical Research Council/ ; MOH-001500-00//National Medical Research Council/ ; MOH-001609-00//National Medical Research Council/ ; MOE-000387-00//Singapore Ministry of Education/ ; NRF-000352-00//National Research Foundation/ ; 52203205//National Natural Science Foundation of China/ ; 22405291//National Natural Science Foundation of China/ ; BE2023731//Natural Science Foundation of Jiangsu Province/ ; }, mesh = {*Reactive Oxygen Species/metabolism ; Humans ; *Nanostructures/chemistry/therapeutic use ; Animals ; *Free Radical Scavengers/chemistry/therapeutic use ; Neoplasms/drug therapy/metabolism ; Alzheimer Disease/drug therapy/metabolism ; }, abstract = {Reactive oxygen species (ROS) are essential by-products of cellular metabolism and serve as key mediators in cell signaling and homeostasis. Excessive ROS production is associated with cellular damage and various diseases. Therefore, targeted ROS scavenging may enhance therapeutic efficacy and minimize side effects. With significant progress in nanotechnology, various nanomaterials with targeted ROS-scavenging properties have been developed to modulate ROS levels in biological microenvironments. In this review, the mechanisms underlying ROS generation and elimination in humans and in ROS-related diseases are first outlined. The latest advancements in ROS-scavenging nanomaterials, particularly their mechanisms and composition-based classifications, are then focused on. Strategies for improving the targeting ability of ROS-scavenging nanomaterials and their application in the therapeutics of ROS-induced diseases such as Alzheimer's disease, rheumatoid arthritis, acute kidney injury, diabetic wounds, and cancer are highlighted. Finally, the challenges faced by ROS-targeted nanotherapeutics are discussed, and possible alternatives to accelerate their clinical translation are proposed.}, } @article {pmid40843440, year = {2025}, author = {Phelps, J and Orr, A and Elvira, KS and Willerth, SM}, title = {Extracellular Vesicles for the Treatment of Alzheimer's Disease: A Systematic Review.}, journal = {Journal of extracellular biology}, volume = {4}, number = {8}, pages = {e70077}, pmid = {40843440}, issn = {2768-2811}, abstract = {The development of novel treatments that restore brain function and improve patient outcomes for Alzheimer's disease (AD) is necessary, given the complications and lack of improvement in recently approved amyloid beta (Aβ)-targeting drugs. Cell-derived extracellular vesicles (EVs) have been found to improve cognitive function through reduced inflammation, oxidative stress, and apoptosis, restoring neuronal and blood-brain barrier function, and inhibiting Aβ and phosphorylated tau build-up in the brain. Given the recent emergence of EVs into clinical trials, it is essential to provide the field with an update on proposed mechanisms of action, gaps in knowledge for further study, and recommendations for producing EVs with high therapeutic efficacy to ensure success in subsequent clinical trials. This systematic review summarizes original research to date that reports effects of mammalian cell-derived EVs for the treatment of AD. Evidence of therapeutic benefits and reported mechanisms of action are discussed. Further, methods for engineering EVs to increase their therapeutic efficacy and produce high-quality EVs relevant to the AD field are outlined. The quality of evidence is discussed in terms of reporting guidelines from the Minimal Information for Studies of Extracellular Vesicles (MISEV). The review further discusses current preclinical AD models and provides direction to improve the quality of AD models for testing novel therapeutics.}, } @article {pmid40843131, year = {2025}, author = {Xia, M and Liu, Q and Zhang, W and Ge, J and Mei, Z}, title = {Spatiotemporal Dynamics of Central Nervous System Diseases: Advancing Translational Neuropathology via Single-Cell and Spatial Multiomics.}, journal = {MedComm}, volume = {6}, number = {9}, pages = {e70328}, pmid = {40843131}, issn = {2688-2663}, abstract = {Central nervous system (CNS) diseases, a leading cause of global disability and mortality, encompass a wide range of brain disorders such as stroke, Alzheimer's disease, Parkinson's disease, and so on. These diseases are characterized by dynamic cellular heterogeneity and disrupted intercellular crosstalk, yet their molecular drivers remain incompletely resolved. Single-cell RNA sequencing (scRNA-seq) dissects transcriptional diversity at cellular resolution, while spatial transcriptomics (ST) maps niche-specific interactions within tissue architecture-complementary approaches that have revealed disease-associated subpopulations, neural-glial communication, and microenvironmental remodeling. However, standalone omics layers inadequately capture the genetic, epigenetic, and functional cascades underlying CNS pathologies. Here, we highlight the transformative potential of integrating scRNA-seq and ST with multiomic profiling to delineate spatially orchestrated molecular networks. Such multiomic convergence enables systematic deconstruction of molecular mechanisms and intercellular communication across disease progression. By correlating these signatures with clinical phenotypes, this strategy accelerates biomarker discovery, patient stratification, and therapeutic target identification. We further discuss challenges in data harmonization, subcellular spatial resolution, and computational scalability that must be addressed to realize personalized CNS medicine. This synthesis advocates for interdisciplinary frameworks to translate multiomic insights into mechanistically grounded diagnostics and therapies, ultimately bridging the gap between molecular discovery and precision clinical intervention.}, } @article {pmid40842924, year = {2025}, author = {Ella, FA and Ambamba, BDA and Njayou, FN and Moundipa, PF}, title = {Khaya grandifololia exerts multitarget neuroprotective potential against neurodegenerative disorders: In vitro and in silico studies.}, journal = {IBRO neuroscience reports}, volume = {19}, number = {}, pages = {400-408}, pmid = {40842924}, issn = {2667-2421}, abstract = {BACKGROUND: Treatment for complex multifactorial neurological disorders may benefit more from multifunctional chemicals. Dysregulation of monoaminergic pathways and neuroinflammation are typical confluence points in a range of neuropsychiatric and neurodegenerative illnesses. Polypharmacological medications that affect neuroinflammatory and monoaminergic pathways were investigated as potential targets for these diseases. The aim of this study was to investigate the in vitro and in silico multi-target neuroprotective activity of Khaya grandifololia. METHODS: Decoction and hydro-ethanolic extracts were prepared and screened for their ability to inhibit enzymes related to inflammation (15-lipoxygenase, LOX), neurodegeneration (monoamine oxidase, MAO), and protein glycation and fibrillation using enzymological fluorimetric assays and docking simulations. RESULTS: All extracts were able to strongly inhibit the activity of MAO as well as the glycation and fibrillation activities. Also, these extracts moderately inhibited 15-LOX activity. CONCLUSION: These results extend the knowledge on the potential use of Khaya grandifololia to combat multifactorial disorders, giving new approaches into therapeutic avenues for neurodegenerative disease such as Alzheimer's disease.}, } @article {pmid40842786, year = {2025}, author = {Jaramillo Ramos, JJ and Galindo Pupo, NM and Mena, D and Solis, RP and Bedoya Jaramillo, JE and Vega Solano, M}, title = {Cognitive Decline in Chronic Inflammatory Conditions: Exploring Links Between Systemic Inflammation and Neurodegeneration.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e88397}, pmid = {40842786}, issn = {2168-8184}, abstract = {Chronic inflammatory diseases (CIDs), such as rheumatoid arthritis (RA), obesity, type 2 diabetes mellitus (T2DM), systemic lupus erythematosus (SLE), fibromyalgia (FM), and chronic infection, are risk factors for neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This review synthesizes evidence from longitudinal cohort studies and clinical trials, highlighting the contrasting evidence to explain the complex association between systemic inflammation and neurodegeneration. These important mechanisms are disruption of the blood-brain barrier, microglial activation, cytokine-related neurotoxicity (e.g., IL-6, TNF-alpha), lysosomal maladaptation, and metabolic imbalance (e.g., insulin resistance, hyperglycemia). Disease-specific correlations present study outcomes that are paradoxical, including that RA has genetic protection against PD but an increased risk of AD, whereas obesity and T2D associations are the same across studies, persistent associations of these terms with worsened cognitive decline. The risk of dementia is worsened by autoimmune diseases, such as SLE and FM, involving neuroinflammation caused by autoantibodies and central sensitization in the latter, respectively. The new markers, such as glial fibrillary acidic protein (GFAP) (neuroinflammation) and neurofilament light (NfL) (axonal injury), have prospects in early detection, but there is a need for validation in future studies. Therapeutic approaches emphasize the need for immunomodulation (e.g., disease-modifying antirheumatic drugs {DMARDs} in RA), glycemic control in T2DM, and lifestyle interventions, with a lack of targeting the non-amyloid pathways. New studies should emphasize longitudinal studies, multiome-based methods, and clinical trials in an attempt to create precision treatment. Considering the inflammatory risk stratification in the prevention of neurodegeneration, this review sheds light on the possibility of early preventative action that may offset the progressive cognitive decline in especially vulnerable groups.}, } @article {pmid40842769, year = {2025}, author = {Faikoglu, G and Saygisever-Faikoglu, K and Ozbasak, H and Ugur, SA and Uskur, T and Akkan, AG and Kelicen-Ugur, P and Ozyazgan, S}, title = {Neuroprotective Effects of Phosphodiesterase Inhibitors on Sestrin-2 (SESN2) Expression and Autophagy in Alzheimer's Disease Model.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e88449}, pmid = {40842769}, issn = {2168-8184}, abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and the accumulation of amyloid-beta (Aβ) peptides. The neuroprotective protein sestrin-2 (SESN2) has been implicated in the cellular response to oxidative stress and autophagy, processes that are disrupted in AD. This study explores the effects of phosphodiesterase inhibitors (PDEIs) roflumilast (RF), rolipram (ROL), and tadalafil (TAD) on SESN2 expression and autophagy in Aβ25-35-treated hippocampal neuron (HT-22) cell cultures. METHODS: The HT-22 cells were exposed to 5 μM Aβ25-35 for 32 hours to induce AD-like pathology. Concurrently, cells were treated with PDEIs (ROL: 10 μM, TAD: 1.53 nM, RF: 5 μM). The SESN2, autophagy-related proteins (ATG5, beclin-1 (BECN1), LC3II), adenosine monophosphate-activated protein kinase (AMPK), and mTOR expression levels were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot techniques. RESULTS: The Aβ25-35 exposure significantly increased SESN2 expression and altered the levels of autophagy-related proteins, resulting in decreased active AMPK (phosphorylated (p)-AMPK) and increased active mTOR (phosphorylated (p)-mTOR). Treatment with PDEIs reduced the elevated SESN2 expression and modulated autophagy-related protein levels, enhancing ATG5, BECN1, and LC3II expression. The PDEIs also restored p-AMPK levels and reduced p-mTOR expression in Aβ25-35-treated cells. CONCLUSION: The PDEIs exhibit neuroprotective effects in an in vitro AD model by reducing SESN2 overexpression and modulating autophagy through the AMPK/mTOR pathway. These findings suggest that PDEIs could be potential therapeutic agents for AD, targeting SESN2 and autophagy pathways to mitigate neurodegenerative damage.}, } @article {pmid40842658, year = {2025}, author = {Mekulu, K and Aqlan, F and Yang, H}, title = {The mild cognitive impairment window for optimal Alzheimer's disease intervention.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251370768}, pmid = {40842658}, issn = {2542-4823}, abstract = {The FDA approval of disease-modifying Alzheimer's disease therapies marks a major shift in treatment but exposes a critical challenge: identifying patients during the mild cognitive impairment (MCI) stage when intervention is most effective. Despite early biological changes, most diagnoses occur after significant decline. Drawing from over 180 stakeholder interviews conducted through the NSF I-Corps program reveal major detection gaps across primary care, specialty access, and available tools. This commentary highlights the consequences of delayed diagnosis and proposes translational strategies to align early detection with therapeutic opportunity, positioning MCI as the critical window for Alzheimer's disease intervention.}, } @article {pmid40842657, year = {2025}, author = {Chen, S and Sun, Y and Yao, L and Peng, Q}, title = {Probable lecanemab-associated pontine hemorrhage following cardiovascular intervention: Clinical implications for lecanemab use.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251366998}, pmid = {40842657}, issn = {2542-4823}, abstract = {We report a 76-year-old patient with mild cognitive impairment and APOE ε3/ε3 genotype who developed a rare pontine hemorrhage following treatment with lecanemab, an anti-amyloid-β monoclonal antibody for Alzheimer's disease. She was initially on clopidogrel and rivaroxaban; rivaroxaban was discontinued prior to lecanemab initiation. After two infusions, lecanemab was paused due to angina. She then underwent coronary stenting and was placed on dual antiplatelet therapy (aspirin and clopidogrel). Pontine hemorrhage occurred after twenty days. This case highlights heightened bleeding risk when lecanemab is combined with intensified antithrombotic therapy, even without APOE ε4 or significant cerebral small vessel disease load.}, } @article {pmid40842647, year = {2025}, author = {Choi, BK and Jin, Y and Lee, H and Kim, SW and Park, S and Hong, I and Baek, MS}, title = {Effect of aspirin use on conversion risk from mild cognitive impairment to Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1603892}, pmid = {40842647}, issn = {1663-4365}, abstract = {BACKGROUND: The potential effect of the antiplatelet and anti-inflammatory properties of aspirin on Alzheimer's disease development, especially its role in the progression from mild cognitive impairment to Alzheimer's disease dementia, remains controversial. To evaluate the association between aspirin, use and the risk of conversion to Alzheimer's disease dementia among individuals diagnosed with mild cognitive impairment. METHODS: In this retrospective population-based cohort study, we used the Korean National Health Insurance Service database to collect data on patients with mild cognitive impairment enrolled between 2013 and 2016 and followed up until 2021. In total, 508,107 patients initially diagnosed with mild cognitive impairment (192,538 with aspirin prescriptions and 315,569 without aspirin prescriptions) were enrolled. Aspirin use was assessed by extracting information from the Korean National Health Insurance Service database using aspirin prescription codes. The primary outcome was newly diagnosed Alzheimer's disease dementia. Hazard ratios and 95% confidence intervals for Alzheimer's disease were analyzed according to aspirin use using Cox proportional hazards regression analysis. Secondary outcomes included ischemic and hemorrhagic stroke risk associated with aspirin use. RESULTS: The data of 508,107 individuals were analyzed (mean [standard deviation] age, 67.6 [10.7] years; 66.8% women and 33.2% men), and 39,318 developed Alzheimer's disease (22,572 controls and 16,746 using aspirin). The rate of conversion to Alzheimer's disease was lower in the aspirin user group, and the time to Alzheimer's disease dementia occurrence was longer than in the nonuser group. A decreased Alzheimer's disease dementia risk was found in patients using aspirin in Model 2 (adjusted hazard ratio, 0.939; 95% confidence interval, 0.920-0.959), with more pronounced effects in individuals aged ≥65 years (Model 2 adjusted hazard ratio, 0.934; 95% confidence interval, 0.914-0.955). For hemorrhagic stroke, the risk increased with aspirin use across all age groups, with the highest risk observed in younger patients (Model 2 adjusted hazard ratio, 5.082; 95% confidence interval, 4.838-5.338). CONCLUSION: Aspirin use was associated with reduced Alzheimer's disease risk in older patients with mild cognitive impairment. Notably, the bleeding risk associated with aspirin use should be considered, and personalized treatment should be provided.}, } @article {pmid40842491, year = {2025}, author = {Bonet Olivares, C and David, MCB and Estrada Obeso, M and Del Giovane, M and Reeves, S and Malhotra, PA}, title = {Cognitive effects of dopaminergic treatment in Alzheimer's disease: Systematic review and meta-analysis.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70142}, pmid = {40842491}, issn = {2352-8737}, abstract = {INTRODUCTION: Despite advances in disease-modifying drugs, better treatments for symptomatic Alzheimer's disease (AD) are needed, with dopaminergic neurotransmission representing a potential target. The objective of this systematic review and meta-analysis was to evaluate the efficacy of drugs with predominantly dopaminergic action in improving cognitive symptoms in AD. METHODS: The MEDLINE, Embase, and ClinicalTrials.gov databases were searched from 1980 to January 2023. We used random effect models to generate pooled effect estimates. RESULTS: We included 19 prospective randomized controlled AD trials (1408 total participants), of which 7 were of "good" quality, 8 "fair," and 4 "poor." All were included in the analysis. The overall pooled effect was small but showed a significant positive effect of dopaminergic drugs compared to placebo (standardized mean difference [SMD]: 0.33, 95% confidence interval [CI]: 0.08 to 0.59, P = 0.01; I [2] = 79%). Significance remained after removing outliers to account for heterogeneity. When exploring subgroups (divided by mechanism of action), 5 trials of dopamine reuptake inhibitors did not show a significant effect on cognition, whereas 12 monoamine oxidase B (MAO-B) inhibitor trials showed a moderately significant positive effect (SMD: 0.52, 95% CI: 0.13 to 0.90, P = 0.01; I [2] = 84%). DISCUSSION: We show evidence of the benefit of dopaminergic medications, specifically MAO-B inhibitors, on cognitive symptoms in AD. Several studies included here also used drugs with both noradrenergic and dopaminergic action, highlighting a potential dual stimulation that could lead to better clinical efficacy. Trials targeting well-defined patient populations, ideally supported by biomarker evidence of dopaminergic dysfunction, are needed to compare noradrenergic and dopaminergic agents-both separately and in combination-on cognitive function to maximize treatment effects. Particularly, further research should explore the impact of MAO-B drugs on specific aspects of cognitive function to better understand their mechanism given the upregulation of MAO-B expression in AD. HIGHLIGHTS: We conducted a meta-analysis investigating the efficacy of dopaminergic drugs in improving cognitive symptoms in Alzheimer's disease (AD).Our findings highlight the potential cognitive benefits of dopaminergic medications, particularly monoamine oxidase B inhibitors, in AD.Future trials are warranted and could focus on biomarker-defined patient groups to enhance effectiveness.}, } @article {pmid40842389, year = {2025}, author = {da Silva, AMP and Falcão, L and Virgilio Ribeiro, F and Ogasawara Donato, K and Machado Magalhães, PL and Nascimento, MDVS and Leite, M and Lee Han, M and Quiroga, DG and de Souza Franco, E and de Sousa Maia, MB}, title = {Efficacy and Safety of Escitalopram and Citalopram for Agitation in Alzheimer's Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {8919887251369893}, doi = {10.1177/08919887251369893}, pmid = {40842389}, issn = {1552-5708}, abstract = {BackgroundAgitation is a frequent and distressing neuropsychiatric symptom in patients with Alzheimer's disease (AD), often leading to increased caregiver burden, institutionalization, and healthcare costs. While antipsychotics are commonly prescribed, their use is limited by safety concerns. Selective serotonin reuptake inhibitors (SSRIs), such as citalopram and escitalopram, have emerged as alternative treatments with a more favorable safety profile. This study aimed to evaluate the efficacy and safety of these agents in the management of agitation in AD.MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing citalopram or escitalopram with placebo or other pharmacological treatments in older adults with AD and clinically defined agitation. Primary outcomes included changes in agitation severity, assessed by the Neuropsychiatric Inventory-Clinician Rating (NPI-C) and the Neurobehavioral Rating Scale (NBRS). Secondary outcomes included cognitive function (MMSE), anxiety symptoms, and adverse events. Standardized mean difference (SMD) and risk ratio (RR) were pooled using a random-effects model.ResultsFour RCTs comprising 502 patients were included. Pooled analysis showed no significant improvement in agitation severity (SMD -0.67; 95% CI -2.58, 1.25; I[2] = 98.3%) or cognitive outcomes (SMD 2.43; 95% CI -2.55, 7.41). Rates of serious adverse events (RR 0.85; 95% CI 0.50, 1.45) and treatment discontinuation (RR 1.05; 95% CI 0.80, 1.37) were similar between groups. However, SSRI use was associated with an increased risk of falls (RR 1.78; 95% CI 1.15, 2.75; I[2] = 0%).ConclusionEscitalopram and citalopram do not significantly reduce agitation in AD but are generally well tolerated. Increased fall risk warrants cautious clinical use.Registration PROSPERO protocol numberCRD420251055237.}, } @article {pmid40842219, year = {2025}, author = {Triplett, O and Varda, N and Decourt, B and Sabbagh, MN}, title = {Nonamyloid-beta active immunization for the treatment of Alzheimer's disease.}, journal = {Expert opinion on investigational drugs}, volume = {34}, number = {9}, pages = {685-693}, doi = {10.1080/13543784.2025.2551352}, pmid = {40842219}, issn = {1744-7658}, mesh = {*Alzheimer Disease/therapy/immunology/physiopathology ; Humans ; Animals ; tau Proteins/immunology/metabolism ; Amyloid beta-Peptides/immunology/metabolism ; Cognitive Dysfunction/therapy/immunology ; *Immunotherapy, Active/methods ; Immunity, Innate/immunology ; *Alzheimer Vaccines/administration & dosage/immunology ; Immunization/methods ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by the formation of senile plaques composed of amyloid-beta (Aβ) peptides and the intraneuronal accumulation of neurofibrillary tangles composed of abnormal, hyperphosphorylated tau proteins. These act in concert to drive cognitive decline, but it is widely held that tau spread correlates better with cognitive decline than does amyloid burden. Control of AD neuropathologies with active immunizations is studied as a potential therapeutic avenue because it could build innate immunity. Although most active immunization studies have focused on Aβ targets, tau and other targets continue to be explored. AREAS COVERED: This study aimed to identify and describe non-Aβ active immunization trials for AD treatment. A narrative review was conducted to analyze the current status of non-Aβ active immunization for AD using PubMed as the research database. EXPERT OPINION: The potential of active immunization beyond Aβ was explored as a therapeutic strategy for AD with a focus that targets tau and provides insights into its effectiveness, associated challenges, and limitations. Results from preclinical and clinical studies were examined, highlighting the progress and the hurdles that exist. Active immunization against non-Aβ targets, such as tau, for the treatment of AD remains a promising and expanding field.}, } @article {pmid40842206, year = {2025}, author = {Chen, PH and Bloom, S}, title = {Divergent Synthesis of ΔAA-Peptides Using a Bioorthogonal pro-Amino Acid and Aqueous Flavin Photocatalyst: Green Light Enhances Catalyst Performance and Product Selectivity.}, journal = {Angewandte Chemie (International ed. in English)}, volume = {64}, number = {39}, pages = {e202511832}, doi = {10.1002/anie.202511832}, pmid = {40842206}, issn = {1521-3773}, support = {/GM/NIGMS NIH HHS/United States ; R35GM147169/NH/NIH HHS/United States ; /GM/NIGMS NIH HHS/United States ; R35GM147169/NH/NIH HHS/United States ; }, mesh = {Catalysis ; *Amino Acids/chemistry ; *Light ; *Flavins/chemistry ; *Peptides/chemical synthesis/chemistry ; Photochemical Processes ; Water/chemistry ; Molecular Structure ; Green Light ; }, abstract = {Dehydroamino acids (ΔAAs) are vital building blocks in the design and optimization of peptide drugs. The exact olefin geometry, side chain chemotype, and ancillary β-carbon substituents play a significant role. Unfortunately, general approaches to install these motifs into peptides are lacking, complicated by the instability of unsaturated residues during traditional amide-bond coupling and failure of divergent protocols, such as oxidative Heck and Horner-Wadsworth-Emmons, to accommodate a complete range of substrate classes. Herein, we conceive and interrogate an original bioorthogonal reagent, β-sulfonyldehydroamino acid (ΔSulf), that can be site-specifically encoded into standard peptides through solid- or liquid-phase synthesis. When combined with an aqueous flavin photocatalyst, myriad boronic acids and 525 nm light-a more biologically benign portion of the flavin visible absorption spectra that has not previously been exploited for flavin photoredox catalysis,-this latent residue becomes one of several (Z)-ΔAA variants (aromatic, heteroaromatic, aliphatic) via stereoretentive radical conjugate addition and β-scission. The importance of green light is established through mechanistic studies showing that it tempers radical formation and discourages flavin-catalyzed isomerization, controlling product selectivity. We apply our original reagent and catalytic platform in a brief medicinal chemistry campaign to discover tetrapeptides that modulate Aβ42 aggregation for the treatment of Alzheimer's disease.}, } @article {pmid40841960, year = {2025}, author = {Wu, Q and Yan, J and Zhang, Y and Ming, X and Chen, S and Zou, Z and Feng, N and Xiao, J}, title = {Modulation of Aging Diseases via RAGE Targets: A Dietary Intervention Review.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {38}, pages = {e10242}, pmid = {40841960}, issn = {2198-3844}, support = {32472341//National Natural Science Foundation of China/ ; JCZRJQ202500133//Natural Science Foundation for Youth (Category A) of Hubei Province/ ; 2024AFD281//Natural Science Foundation of Hubei Province/ ; F2023006//Science and Technology Research Project of the Education Department of Hubei Province/ ; }, mesh = {Humans ; *Receptor for Advanced Glycation End Products/metabolism ; *Aging/metabolism ; Glycation End Products, Advanced/metabolism ; Signal Transduction ; Animals ; }, abstract = {With the acceleration of global population aging, effective strategies for the prevention and management of aging-related diseases have become increasingly urgent. The receptor for advanced glycation end products (RAGE), a pattern recognition receptor of the immunoglobulin superfamily, plays a central regulatory role in the pathogenesis of chronic conditions such as diabetes and Alzheimer's disease. By binding to a wide range of ligands (e.g., advanced glycation end products, amyloid beta), RAGE activates key inflammatory and stress-related signaling pathways, including NF-κB and MAPK, positioning it as a critical therapeutic target. This review systematically examines RAGE-ligand interactions and their downstream signaling cascades, and proposes targeted intervention strategies. Special emphasis is placed on the regulatory potential of dietary bioactive compounds, such as polyphenols, polysaccharides, and terpenoids, highlighting the distinct advantages of functional foods in anti-aging applications. In line with the World Health Organization's concept of "preventive aging," dietary-based approaches offer a long-term, safe, and integrative means of providing both nutritional support and disease prevention. This review provides a theoretical foundation for the development of RAGE-targeted dietary interventions and supports a paradigm shift from medical treatment to nutritional prevention in anti-aging strategies.}, } @article {pmid40838403, year = {2025}, author = {Rodríguez Sarmiento, RM}, title = {A Career Long Effort to Discover a Drug to Treat Neurodegenerative Diseases. My Adventures with γ-Secretase for the Treatment of Alzheimer's.}, journal = {Chimia}, volume = {79}, number = {7-8}, pages = {509-515}, doi = {10.2533/chimia.2025.509}, pmid = {40838403}, issn = {0009-4293}, mesh = {*Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy ; Humans ; *Drug Discovery ; *Neurodegenerative Diseases/drug therapy ; Amyloid beta-Peptides/metabolism ; }, abstract = {Neurodegenerative diseases encompass a range of chronic diseases marked by the progressive loss of structure or function of the nervous system, particularly within areas of the brain such as the neurons (or nerve cells). This degeneration leads to a decline in cognitive abilities, motor skills, and other neurological functions. The progression can be gradual, occurring over years or even decades, and often leads to significant disability and, ultimately, death. Alzheimer's disease (AD) is the most prevalent degenerative disease that affects cognition and that rises dramatically with age. It is a progressive, chronic disease that occurs when nerve cells in the brain die. Current treatments largely address symptoms without altering or reversing disease progression. However, recent advancements with amyloid-β (Aβ) antibodies validate Aβ as a therapeutic target for AD. This article details my long-term experience as a medicinal chemist and project leader working on γ-secretase, a key target in AD drug discovery. I will share initial insights from a multi-disciplinary effort to discover a disease modifying treatment for Alzheimer's disease.}, } @article {pmid40836982, year = {2024}, author = {Grados, M and Salehi, M and Lotfi, A and Dua, S and Xie, I}, title = {A selective review of inhibitors of protein kinase C gamma: a neuroplasticity-related common pathway for psychiatric illness.}, journal = {Frontiers in drug delivery}, volume = {4}, number = {}, pages = {1364037}, pmid = {40836982}, issn = {2674-0850}, abstract = {Psychotropics are currently developed and marketed with a limited understanding of their mechanism of action. The notion that protein kinase C (PKC) activity is highly relevant to learning and memory function stems from experiments in the 1980s, which associated protein kinase alpha (pka) and pkc to animal models of associative learning, opening an area of exploration for psychotropic development. The PKC family consists of several isoforms, including PKC alpha, beta1, beta1, gamma, delta and epsilon among others. In particular, PKC gamma (PRKCG) is highly brain-expressed and is singled out as a candidate for modulation in psychiatric illness. With hundreds of identified substrates, PRKCG affects multiple pathways relevant for regulation of neuronal health. In this review, converging lines of evidence are presented in the context of psychotropic drug action, which point to downregulation of PKC activity as a potential common mechanism across several psychiatric disorders. Using this mechanism through more targeted psychotropic action may then be used to develop agents that further ameliorate psychiatric symptom expression. Psychotropics including fluoxetine, tricyclics, lithium, valproate, ketamine and others are explored in relation to their effect of PKC, finding that across all drugs examined, a downregulation with chronic-but not acute-use constitutes their putative effect in ameliorating symptoms. This effect is compounded by findings that suggest that PKCs, and PRKCG in particular, promote neuroplastic effects by their downregulation. This effect is in contrast to PKC activators, which have been used in neurodegenerative disorders such as Alzheimer's disease. Cross-disorder mechanisms need to continue to be explored in neuropsychiatric illness and targeted treatments developed in turn to address treatment-resistant conditions.}, } @article {pmid40836645, year = {2025}, author = {Liu, T and Li, X}, title = {The Crosstalk Between Protective and Detrimental Interleukin (IL)-1 Family of Cytokines in Alzheimer's Disease.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {9}, pages = {e70460}, doi = {10.1002/jbt.70460}, pmid = {40836645}, issn = {1099-0461}, support = {//Project no. (2024 Foshan self-funded science and technology innovation project (2420001004404), Education and Department of Guangdong Province (2024GCZX011))./ ; }, mesh = {*Alzheimer Disease/metabolism/pathology/immunology ; Humans ; *Interleukin-1/metabolism/immunology ; Animals ; }, abstract = {Alzheimer's disease (AD) is a long-term, progressive, degenerative disorder. One of the most important pathological characteristics of AD is the deposition of β-amyliod (Aβ) peptide, which initiates a spectrum of cerebral neuroinflammation. Vascular changes also play an important role in the pathophysiology of the disease. Cytokines, secreted by immune cells, can facilitate cell-to-cell signaling and influence the functions of the central nervous system (CNS). These important mediators of the immune system, which are known to orchestrate various molecular and cellular mechanisms in both physiological and pathological situations, can be upregulated or downregulated, leading to a complex crosstalk with numerous receptors mediating pro-inflammatory and/or anti-inflammatory actions. In particular, the interleukin (IL)-1 family of cytokines has been implicated to significantly correlate with AD pathogenesis among other cytokines in the CNS. The IL-1 family of cytokines is essential in both the innate and adaptive immune responses. This pleiotropic family of cytokines includes IL-1α, IL-1β, IL-1 receptor antagonist (RA), IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36RA, IL-37, and IL-38. Recent studies have demonstrated that the upregulation of pro-inflammatory cytokines, such as IL-1α and IL-1β, or the downregulation of anti-inflammatory mediators, exerts multifaceted influences on both neurodegeneration and neuroprotection. The lack of effective treatment for AD necessitates the search for new drugs that target several processes in the disease's pathology. This review aims to give a comprehensive overview of the emerging roles of the IL-1 family of cytokines in AD pathology and to explain their perspectives on introducing novel strategies for effective therapeutic/neuropsychiatric management of AD in clinical settings by discussing both the pathogenic and protective roles of these cytokines.}, } @article {pmid40836165, year = {2026}, author = {Bayat, A and Mirmomeni, G and Aiken, S and Jafari, Z}, title = {Meta-Analyses of Auditory Evoked Potentials as Alzheimer Biomarkers.}, journal = {Ear and hearing}, volume = {47}, number = {1}, pages = {95-106}, doi = {10.1097/AUD.0000000000001718}, pmid = {40836165}, issn = {1538-4667}, mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology ; *Evoked Potentials, Auditory/physiology ; Biomarkers ; Early Diagnosis ; Electroencephalography ; }, abstract = {OBJECTIVES: Alterations in auditory evoked potential (AEP) parameters have been associated with sensory memory deficits and may serve as biomarkers for cognitive decline. This systematic review and meta-analysis aimed to evaluate the effectiveness of AEPs in the early detection of Alzheimer disease (AD). DESIGN: The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. A comprehensive search was performed across five electronic databases (EMBASE, Scopus, Cochrane Library, Web of Science, PubMed, and CINAHL) from their inception until August 2024, without restrictions on date or language. The methodological quality of evidence was assessed using the Crew Critical Appraisal Tool. Data were extracted on the latency and amplitude of five AEP components, including auditory P50 gating, mismatch negativity, and late-latency responses (N100, N200, P300), comparing patients with AD to age-matched control peers. RESULTS: Out of 437 publications, 54 articles were selected for review, with most rated as having high methodological quality. The analysis revealed a significantly larger P50 gating amplitude (p < 0.001) in patients with AD. Furthermore, patients with AD demonstrated significantly prolonged latencies and reduced amplitudes for N100, N200, and P300 components (p ≤ 0.001) compared with controls. Among all AEPs, P300 latency exhibited the largest effect size. Funnel plot analysis and Egger's regression test showed no evidence of publication bias. CONCLUSIONS: Our findings support the clinical utility of AEPs in early AD detection, with the P300 response identified as the most accurate electrophysiological measure for distinguishing patients with AD from the control group. These results highlight the value of incorporating AEPs into clinical assessment protocols to enhance early-stage AD diagnosis and monitoring, thereby facilitating timely interventions and the development of personalized treatment strategies.}, } @article {pmid40835596, year = {2025}, author = {Molokanova, E and Zhou, T and Vasupal, P and Cherkas, VP and Narute, P and Ferraz, MSA and Reiss, M and Almenar-Queralt, A and Chaldaiopoulou, G and de Souza, JS and Hemati, H and Downey, F and Olajide, OO and Thörn Perez, C and Puppo, F and Mesci, P and Pfaff, SL and Kireev, D and Muotri, AR and Savchenko, A}, title = {Non-genetic neuromodulation with graphene optoelectronic actuators for disease models, stem cell maturation, and biohybrid robotics.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7499}, pmid = {40835596}, issn = {2041-1723}, support = {R01 MH127077/MH/NIMH NIH HHS/United States ; R43 MH124563/MH/NIMH NIH HHS/United States ; R01 MH123828/MH/NIMH NIH HHS/United States ; 1R01ES033636//U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS)/ ; 1R43AG076088//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; 1R01MH128365//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; 1R43NS122666//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; MH123828//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01 NS123642/NS/NINDS NIH HHS/United States ; S10 OD026929/OD/NIH HHS/United States ; R01 ES033636/ES/NIEHS NIH HHS/United States ; R56 MH128365/MH/NIMH NIH HHS/United States ; R01NS123642//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R43 AG076088/AG/NIA NIH HHS/United States ; R43 NS122666/NS/NINDS NIH HHS/United States ; R01 NS105969/NS/NINDS NIH HHS/United States ; DISC2-13866//California Institute for Regenerative Medicine (CIRM)/ ; R44 DA050393/DA/NIDA NIH HHS/United States ; 5R44DA050393//U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA)/ ; 1R43MH124563//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; }, mesh = {*Graphite/chemistry ; *Robotics/methods/instrumentation ; Induced Pluripotent Stem Cells/cytology ; Humans ; Organoids/cytology ; Neurons/cytology ; Brain/cytology ; Alzheimer Disease/pathology/therapy ; Optogenetics/methods ; Cell Differentiation ; Animals ; }, abstract = {Light can serve as a tunable trigger for neurobioengineering technologies, enabling probing, control, and enhancement of brain function with unmatched spatiotemporal precision. Yet, these technologies often require genetic or structural alterations of neurons, disrupting their natural activity. Here, we introduce the Graphene-Mediated Optical Stimulation (GraMOS) platform, which leverages graphene's optoelectronic properties and its ability to efficiently convert light into electricity. Using GraMOS in longitudinal studies, we found that repeated optical stimulation enhances the maturation of hiPSC-derived neurons and brain organoids, underscoring GraMOS's potential for regenerative medicine and neurodevelopmental studies. To explore its potential for disease modeling, we applied short-term GraMOS to Alzheimer's stem cell models, uncovering disease-associated alterations in neuronal activity. Finally, we demonstrated a proof-of-concept for neuroengineering applications by directing robotic movements with GraMOS-triggered signals from graphene-interfaced brain organoids. By enabling precise, non-invasive neural control across timescales from milliseconds to months, GraMOS opens new avenues in neurodevelopment, disease treatment, and robotics.}, } @article {pmid40835473, year = {2025}, author = {Naeshiro, Y and Kitani-Morii, F and Kasai, T and Tanaka, E and Kobayashi, F and Ohara, T}, title = {Amyloid Clearance and Transient CSF Aβ40 Reduction in a Case of ARIA-E/H Following Lecanemab Treatment.}, journal = {Internal medicine (Tokyo, Japan)}, volume = {}, number = {}, pages = {}, doi = {10.2169/internalmedicine.6070-25}, pmid = {40835473}, issn = {1349-7235}, abstract = {We herein report a case of amyloid-related imaging abnormality (ARIA)-E/H following lecanemab treatment in a 70-year-old man with mild cognitive impairment due to Alzheimer's disease. Generalized seizures occurred after the third infusion and were accompanied by FLAIR hyperintensity, microbleeds, and a minor acute infarct. Amyloid PET revealed focal clearance of amyloid plaques in the ARIA-affected regions. CSF Aβ40 levels transiently decreased by ~30% during the ARIA episode, whereas Aβ42 remained stable, thereby increasing the Aβ42/40 ratio. These findings suggest that ARIA may facilitate focal amyloid clearance and that CSF Aβ40 reduction may serve as a potential biomarker for ARIA onset and resolution.}, } @article {pmid40833911, year = {2025}, author = {Wei, Y and Abrol, A and Lah, J and Levey, AI and Calhoun, VD}, title = {From Symptomatic to Pre-symptomatic: Adaptive Knowledge Distillation for Early Alzheimer's Detection Using Functional MRI.}, journal = {IEEE transactions on bio-medical engineering}, volume = {PP}, number = {}, pages = {}, doi = {10.1109/TBME.2025.3597261}, pmid = {40833911}, issn = {1558-2531}, abstract = {Alzheimer's disease (AD) progresses from asymptomatic changes to clinical symptoms, underscoring the critical need for early detection to facilitate timely treatment. Functional magnetic resonance imaging (fMRI) offers non-invasive biomarkers for detection, but current methods fail to reliably identify pre-symptomatic individuals due to two key challenges: (1) Subtle, anatomically distinct fMRI patterns in pre-symptomatic cases that resemble healthy controls more than symptomatic patients, and (2) Severe class imbalance in real-world data, where healthy controls vastly outnumber pre-symptomatic subjects. To address this, we reconceptualize AD diagnosis as a multi-stage distillation task, where insights from easier-to-detect symptomatic cases guide pre-symptomatic detection. We propose a novel margin-aware knowledge distillation (KD) framework with two innovations: (1) We leverage Unbalanced Optimal Transport (UOT) for Feature Distillation to flexibly adapt to anatomical differences in brain patterns caused by neurodegeneration and ensure effective distillation from later to earlier disease stages. (2) We propose Self-Distillation with Dynamic Margins to combat class imbalance by adaptively refining the classification boundary. We evaluate our proposed framework across four distinct base models and demonstrate its superiority over state-of-the-art KD methods. Additionally, we show the significance of various brain regions in identifying pre-symptomatic subjects, as well as how features are transferred during distillation. These contributions advance the development of more precise diagnostic tools and foster a deeper understanding of early disease manifestations, marking a significant stride towards more reliable and earlier AD diagnosis.}, } @article {pmid40833319, year = {2025}, author = {Agarwal, U and Verma, S and Gandhi, V and Patil, VM and Tonk, RK}, title = {Multitarget 8-methoxypsoralens against Alzheimer's disease: extraction, synthesis, in vitro and in silico studies.}, journal = {Future medicinal chemistry}, volume = {17}, number = {16}, pages = {1945-1957}, pmid = {40833319}, issn = {1756-8927}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism/chemistry ; Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; Butyrylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification/chemical synthesis ; *Methoxsalen/chemistry/pharmacology/isolation & purification/chemical synthesis ; Structure-Activity Relationship ; Molecular Structure ; Dose-Response Relationship, Drug ; }, abstract = {AIM: Alzheimer's disease poses a serious global health challenge, and there is an urgent need for novel therapeutic agents, as existing drugs have limited efficacy and notable adverse effects. Chromenones, known for their diverse biological activities, have emerged as promising drug candidates for AD treatment due to their capacity to target multiple enzymes. In this study, investigated the chromenone derivative 8-methoxypsoralen (8-MOP) as a potential multi-target inhibitor of key AD targets, highlighting the importance of the scaffold in target-based drug design. MATERIAL AND METHODS: 8-MOP, a phytochemical extracted and isolated from parsley leaves, was utilized to synthesize new derivatives, which were then screened against enzymes involved in AD progression (BACE1, AChE, BuChE) and targets involved in oxidative pathways (DPPH, NO). In support of the in vitro activity, in silico ADMET predictions and docking experiments were performed. RESULTS AND CONCLUSIONS: Among the synthesized compounds, 3d and 3e demonstrated significant inhibitory effects against the chosen targets, exhibiting IC50 values between 5.8 ± 0.13 μM and 13 ± 0.12 μM. Furthermore, the docking experiments showed important binding interactions of these compounds with BACE1, AChE, and BuChE. The study demonstrates the potential of 8-MOP derivatives for targeting AD drug targets.}, } @article {pmid40832968, year = {2025}, author = {Zhang, X and Chu, S and Huang, Y and Li, Z and Song, J and Wang, P and Su, Y and Zhang, Z and Xie, Z}, title = {Atractylenolide III Mitigates Alzheimer's Disease by Enhancing Autophagy via the YY1-TFEB Pathway.}, journal = {Phytotherapy research : PTR}, volume = {39}, number = {10}, pages = {4474-4490}, doi = {10.1002/ptr.70069}, pmid = {40832968}, issn = {1099-1573}, support = {2024ZY1027//Special Research Project of Henan Province on Traditional Chinese Medicine/ ; 82274612//National Natural Science Foundation of China/ ; 23HASTIT044//Program for Science & Technology Innovation Talents in Universities of Henan Province/ ; 231111312900//Key Research and Development Program of Henan Province/ ; 232301420085//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; 232301420093//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; 242301420019//Henan Provincial Science and Technology Research and Development Program Joint Fund/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Autophagy/drug effects ; Humans ; Mice ; *Sesquiterpenes/pharmacology ; *Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; *YY1 Transcription Factor/metabolism ; *Lactones/pharmacology ; Caenorhabditis elegans/drug effects ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects ; Cell Line, Tumor ; Mice, Transgenic ; Atractylodes/chemistry ; Disease Models, Animal ; Male ; }, abstract = {Autophagy dysregulation serves as a significant pathogenic factor in Alzheimer's disease (AD), with transcription factor EB (TFEB) acting as a pivotal transcription factor that governs the process of autophagy. Atractylenolide III (AT-III), a terpenoid compound found in medicinal Atractylodes macrocephala Koidz, is well-known for its role in antioxidant and anti-inflammatory activities. The purpose of this study is to explore the beneficial impact of AT-III on AD pathology and identify the mechanisms involved. C. elegans CL4176, SH-SY5Y APPSWE, and APP/PS1 mice were used to investigate the efficacy and possible mechanism of AT-III on the treatment of AD. AT-III reduced amyloid protein (Aβ) deposition in C. elegans CL4176 heads, prolonged the paralysis time, and reduced Aβ levels in SH-SY5Y APPSWE cells. AT-III improved the learning and memory ability of APP/PS1 mice and decreased the deposition of Aβ plaques. Transcriptomics and experimental validation showed that AT-III stimulated transcription and translation of autolysosome-associated genes. AT-III enhanced co-localization of LC3 and LAMP2 with Aβ in APP/PS1 mice. Meanwhile, AT-III increased TFEB transcriptional activity, mRNA, and protein levels in the nucleus. Furthermore, AT-III enhanced the expression of Yin Yang 1 (YY1) protein, an upstream regulator of TFEB, and led to the stimulation of autophagy and lysosome biogenesis both in vivo and in vitro. The observed effects were reversed upon silencing YY1. AT-III may regulate the YY1-TFEB pathway, thereby restoring autophagy flux disturbances and ameliorating AD-related pathological changes and cognitive decline. This study provides a promising lead compound for intervention in AD.}, } @article {pmid40832697, year = {2025}, author = {Kang, S and Kafetsouli, D and Ford, J and Wong, J and Bracoud, L and Suhy, J and Giannakopoulou, P and Udeh-Momoh, C and Russ, TC and Ritchie, C and Alexopoulou, Z and Salinas, C and Saad, ZS and Novak, G and Robinson, O and Middleton, LT}, title = {Prevalence and risk factors of cerebral microhemorrhages and superficial siderosis in cognitively unimpaired older adults: analysis from the CHARIOT-PRO SubStudy.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70594}, pmid = {40832697}, issn = {1552-5279}, support = {//Janssen Research & Development, LLC, a Johnson & Johnson company/ ; NIHR200180//NIHR ARC Dementia Fellowship/ ; MR/S03532X/1//UKRI Future Leaders Fellowship/ ; MR/Y02012X/1//UKRI Future Leaders Fellowship/ ; //Takeda/ ; //Merck/ ; //Gates Ventures/ ; }, mesh = {Humans ; Aged ; Female ; Male ; Risk Factors ; Cross-Sectional Studies ; Aged, 80 and over ; *Cerebral Hemorrhage/epidemiology/diagnostic imaging ; Prevalence ; Middle Aged ; Apolipoprotein E4/genetics ; *Siderosis/epidemiology ; Magnetic Resonance Imaging ; Amyloid beta-Peptides/metabolism ; Prospective Studies ; }, abstract = {INTRODUCTION: Cerebral microhemorrhages (CMHs) and superficial siderosis (SS) are relatively common side effects of anti-amyloid immunotherapies, termed amyloid-related imaging abnormalities (ARIA-H). They are also observed in treatment-naïve older adults. This study explored relationships with modifiable and non-modifiable risk factors. METHODS: This cross-sectional study included 1414 cognitively unimpaired, treatment-naïve individuals aged 60 to 85 years from the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy. Relationships between CMHs/SS and cardiovascular risk factors, amyloid beta (Aβ) load, apolipoprotein E (APOE) ε4 status, educational attainment, and white matter hyperintensities were investigated using regression analyses and structural equation modeling. RESULTS: CMHs were observed in 8.3% of participants and SS in 1.3%. Significant risk factors for CMHs included age and hypertension. Higher education attainment appeared to have a protective effect. Elevated amyloid is a risk factor, particularly when adjusting for APOE ε4 status in individuals aged 70 or younger. DISCUSSION: Increasing age and hypertension are significant risk factors of CMHs. Higher educational attainment may offer a protective effect. HIGHLIGHTS: Of the 1414 participants from the CHARIOT-PRO SubStudy (CPSS), CMHs were present in 118 (8.3%), and SS was present in 18 (1.3%). Age and hypertension were identified as significant risk factors for CMHs, and the latter had a stronger association with the presence of CMHs among female participants. Having a bachelor's degree or higher was found to be protective. Elevated brain amyloid burden, particularly when adjusted for APOE ε4 carrier status, was identified as a risk factor in individuals aged 70 years and below.}, } @article {pmid40832432, year = {2025}, author = {, and Boquet-Pujadas, A and Anagnostakis, F and Yang, Z and Tian, YE and Duggan, MR and Erus, G and Srinivasan, D and Joynes, CM and Bai, W and Patel, PJ and Walker, KA and Zalesky, A and Davatzikos, C and Wen, J}, title = {Multi-organ AI Endophenotypes Chart the Heterogeneity of Pan-disease in the Brain, Eye, and Heart.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40832432}, support = {RF1 AG054409/AG/NIA NIH HHS/United States ; RF1 AG092412/AG/NIA NIH HHS/United States ; }, abstract = {Disease heterogeneity and commonality pose significant challenges to precision medicine, as traditional approaches frequently focus on single disease entities and overlook shared mechanisms across conditions[1]. Inspired by pan-cancer[2] and multi-organ research[3], we introduce the concept of "pan-disease" to investigate the heterogeneity and shared etiology in brain, eye, and heart diseases. Leveraging individual-level data from 129,340 participants, as well as summary-level data from the MULTI consortium, we applied a weakly-supervised deep learning model (Surreal-GAN[4,5]) to multi-organ imaging, genetic, proteomic, and RNA-seq data, identifying 11 AI-derived biomarkers - called Multi-organ AI Endophenotypes (MAEs) - for the brain (Brain 1-6), eye (Eye 1-3), and heart (Heart 1-2), respectively. We found Brain 3 to be a risk factor for Alzheimer's disease (AD) progression and mortality, whereas Brain 5 was protective against AD progression. Crucially, in data from an anti-amyloid AD drug (solanezumab[6]), heterogeneity in cognitive decline trajectories was observed across treatment groups. At week 240, patients with lower brain 1-3 expression had slower cognitive decline, whereas patients with higher expression had faster cognitive decline. A multi-layer causal pathway pinpointed Brain 1 as a mediational endophenotype[7] linking the FLRT2 protein to migraine, exemplifying novel therapeutic targets and pathways. Additionally, genes associated with Eye 1 and Eye 3 were enriched in cancer drug-related gene sets with causal links to specific cancer types and proteins. Finally, Heart 1 and Heart 2 had the highest mortality risk and unique medication history profiles, with Heart 1 showing favorable responses to antihypertensive medications and Heart 2 to digoxin treatment. The 11 MAEs provide novel AI dimensional representations for precision medicine and highlight the potential of AI-driven patient stratification for disease risk monitoring, clinical trials, and drug discovery.}, } @article {pmid40832393, year = {2025}, author = {Cohen, BM and Koh, E and Levental, KR and Levental, I and Sonntag, KC}, title = {Specific Lipid Abnormalities Are Inherently Associated with Late-Onset Alzheimer's Disease.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.08.08.25333304}, pmid = {40832393}, abstract = {INTRODUCTION: Lipid abnormalities have been observed in brain, CSF, and blood in association with late-onset Alzheimer's disease (LOAD). It is unknown which abnormalities are precursors to LOAD and which are concomitants of illness or its treatment. Inherent abnormalities can be identified in induced pluripotent stem cell (iPSC)-derived neural lines. METHODS: iPSC lines of patients with LOAD or healthy individuals were differentiated to astrocytes. Lipidomics analyses were performed on whole cell and mitochondrial extracts. RESULTS: Large reductions in cholesterol esters (CE) and imbalances in fatty acids (FA) were observed in LOAD-associated cells or their mitochondria. There were only modest differences in other lipid classes, including membrane structural lipids. DISCUSSION: The findings identify abnormalities in CE and FA as likely precursors to LOAD. These differences implicate mechanisms contributing to disease pathogenesis. Further study may lead to early interventions to prevent or delay LOAD.}, } @article {pmid40832216, year = {2025}, author = {Bartlett, MJ and Erickson, RP and Frye, J and Doyle, KP and Pires, PW and Witte, MH}, title = {Manual lymph drainage massage of the head and neck improves cognition and reduces pathological biomarkers in the 5x-FAD mouse model of Alzheimers disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40832216}, issn = {2692-8205}, support = {R25 NS076437/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) affects 6.9 million people over the age of 65 in the US and is expected to double by 2060. While FDA approved immunotherapies slow cognitive decline in some individuals with AD, they do not improve cognition, are costly, and have significant side-effects. Therefore, new targets, approaches, and treatments for AD are a necessity. There are no FDA approved therapies for AD that target the brain's lymphatic system. It is well established that the toxic protein, amyloid-beta (Aβ), accumulates in the AD brain. Recent studies have shown that Aβ is cleared via interstitial fluid and cerebrospinal fluid through a pathway involving the glymphatic system-meningeal lymphatic vessels-leading to deep and superficial cervical lymphatic vessels and nodes. Therefore, any blockage along this route can cause inefficient drainage and result in pathological buildup of Aβ, which can lead to AD. Here, we propose a new approach to treating AD by manual lymph drainage (MLD), which is a light skin massage traditionally used to reduce fluid accumulation in lymphedema. This therapy has also been demonstrated to be safe in individuals with AD, but its effects on cognition and biomarkers of AD has never been investigated. In this study we demonstrate that repeated MLD of the head and neck, including the superficial cervical lymphatic vessels (scLVs), improves cognitive function in AD as measured in both the Y-maze and nest-building tests. We also show that this coincides with a reduction in plasma levels of neurofilament light chain (NfL), a non-specific biomarker for neuronal cell death and axonal damage. MLD was also shown to reduce Aβ in the hippocampus of these mice. Combined, this data provides compelling proof-of-principle evidence for the potential of MLD as a standalone or adjunct therapy in the treatment of AD.}, } @article {pmid40832110, year = {2025}, author = {Androni, X and Boyd, RJ and Rosenberg, PB and Mahairaki, V}, title = {Psychedelics meet human brain organoids: insights into proteomics and potential for Alzheimer's disease treatment.}, journal = {Frontiers in dementia}, volume = {4}, number = {}, pages = {1605051}, pmid = {40832110}, issn = {2813-3919}, abstract = {Alzheimer's disease (AD) is characterized by a long preclinical phase lasting more than a decade before the onset of its clinical phase of mild cognitive impairment (MCI) or dementia. Recent advances in psychedelic research underscore numerous neuroplastogenic and anti-inflammatory alterations induced by these compounds, making them promising therapeutic candidates for AD. In this mini review, we will briefly summarize the existing literature using human cerebral organoids to study the molecular and metabolic changes caused by various psychedelic compounds, focusing on their potential therapeutic applications for AD.}, } @article {pmid40831503, year = {2025}, author = {Lu, Y and Wang, X and Saibro-Girardi, C and Fitz, NF and Koldamova, R and Lefterov, I}, title = {Decoding the Effects of Bexarotene treatment on brain of AD-like model mice: Single-Cell Transcriptomics and Chromatin Accessibility Analysis.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40831503}, issn = {2693-5015}, support = {R01 AG066198/AG/NIA NIH HHS/United States ; RF1 AG075992/AG/NIA NIH HHS/United States ; R56 AG057565/AG/NIA NIH HHS/United States ; R01 AG057565/AG/NIA NIH HHS/United States ; R01 AG077636/AG/NIA NIH HHS/United States ; }, abstract = {BACKGOUND: Ligand-activated Retinoid X Receptors (RXRs) regulate gene networks essential for neural development, neuroinflammation, and metabolism. Understanding how RXR activation influences chromatin architecture and gene expression may reveal therapeutic strategies for neurodegenerative diseases. METHODS: We used Bexarotene-treated APP/PS1ΔE9 mice to study RXR-mediated regulatory mechanisms. To investigate epigenomic and transcriptional effects, we integrated single-nucleus ATAC-seq (snATAC-seq) with single-cell RNA-seq (scRNA-seq) and validated differentially accessible chromatin peaks using RXR ChIP-seq. Transcription factor (TF) footprinting analysis were performed to map regulatory networks activated by ligand-bound RXR. RESULTS: Our integrated analyses revealed a multilayered transcriptional cascade initiated by a single linear RXR signaling event. We identified RXR-centered regulatory circuits involving heterodimer activation, subsequent upregulation of multiple downstream TFs, and induction of metabolic pathways relevant to neural function. The results of a detailed analysis of TF regulatory networks in neuronal systems suggests that Bexarotene doesn't dismantle the fundamental regulatory scaffold in neurons but rather modulates RXR regulatory role through existing TF networks. CONCLUSIONS: This study demonstrates that combining scRNA-seq, snATAC-seq, and ChIP-seq enables a comprehensive analysis of RXR-mediated transcriptional regulation. RXR activation orchestrates complex gene networks that may help restore brain homeostasis in the context of amyloid pathology, neuroinflammation, and neuronal injury.}, } @article {pmid40831271, year = {2025}, author = {Takakuwa, M and Izuo, N and Chino, K and Yano, Y and Yokose, J and Shigetsura, Y and Nitta, A}, title = {Construction of Shati/Nat8l Plasmid Vectors, and Analysis of Mitochondrial Function Mediated by Shati/Nat8l Against Amyloid β Toxicity.}, journal = {Neuropsychopharmacology reports}, volume = {45}, number = {3}, pages = {e70041}, pmid = {40831271}, issn = {2574-173X}, support = {AdAMS JP22H04922//Japan Society for the Promotion of Science/ ; JP21H02632//Japan Society for the Promotion of Science/ ; JPMJSP2145//Japan Science and Technology SPRING/ ; //Tamura Science and Technology Foundation/ ; //Smoking Research Foundation/ ; //Kobayashi Foundation/ ; }, mesh = {*Amyloid beta-Peptides/toxicity ; Animals ; *Mitochondria/metabolism/drug effects ; Mice ; Plasmids/genetics ; Genetic Vectors ; Humans ; Cell Line, Tumor ; Membrane Potential, Mitochondrial/drug effects ; Peptide Fragments/toxicity ; }, abstract = {In Alzheimer's disease (AD), the accumulation of senile plaques composed of neurotoxic amyloid β (Aβ) is known to be one of the causes. Shati/Nat8l, a gene related to neuropsychiatric disorders, encodes an enzyme that biosynthesizes N-acetyl aspartate (NAA) from aspartate and acetyl CoA. Studies on AD patients and model mice show that NAA and Shati/Nat8l are associated with AD pathology. We previously demonstrated that hippocampal overexpression of Shati/Nat8l in 5xFAD mice, an AD model, improved cognitive suppress without altering the number or size of Aβ plaques. To investigate the cellular mechanisms underlying the neuroprotective effects of Shati/Nat8l on Aβ neurotoxicity, we constructed a vector containing the full-length Shati/Nat8l sequence and transfected it into Neuro-2a cells to produce a stably Shati/Nat8l-overexpressing cell line (N2A-Shati). N2A-Shati cells expressed threefold higher Shati/Nat8l mRNA levels compared with a control cell line (N2A-Control). Treatment with Aβ for 48 h reduced the viability of N2A-Shati and N2A-Control cells at concentrations ≧ 0.03 μM compared to their own vehicle. Exposure to 0.03 μM Aβ for 24 h did not induce any detectable changes in mitochondrial mass or mitochondrial membrane potential in either N2A-Control or N2A-Shati cells. However, N2A-Shati cells demonstrated reduced pyruvate dehydrogenase kinase 1 (Pdk1) mRNA expression and enhanced nuclear respiratory factor 1 (Nrf1) and mitochondrial transcription factor A (Tfam) mRNA expression levels. These results suggest that, although Shati/Nat8l does not significantly affect cell viability, mitochondrial mass, or membrane potential, it could modulate specific intracellular pathways.}, } @article {pmid40831183, year = {2025}, author = {Sampath, R and Baskar, M}, title = {Biomarker extraction-based Alzheimer's disease stage detection using optimized deep learning approach.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {682-698}, doi = {10.1177/13872877251360394}, pmid = {40831183}, issn = {1875-8908}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; Biomarkers ; Magnetic Resonance Imaging/methods ; Algorithms ; Male ; Aged ; Female ; Hippocampus/diagnostic imaging ; Early Diagnosis ; }, abstract = {BackgroundCognitive decline and memory loss in Alzheimer's disease (AD) progresses over time. Early diagnosis is crucial for initiating treatment that can slow progression and preserve daily functioning. However, challenges such as overfitting in prediction models, underutilized biomarker features, and noisy imaging data hinder the accuracy of current detection methods.ObjectiveThis study proposes a novel deep learning-based framework aimed at improving the identification of AD stages while addressing the limitations of existing diagnostic techniques.MethodsStructural MRI scans are employed as the primary diagnostic tool. To enhance image quality, contrast-limited adaptive histogram equalization and wavelet soft thresholding are applied for noise reduction. Biomarker segmentation focuses on ventricular and hippocampal abnormalities, optimized using a firefly algorithm. Dimensionality reduction is performed via Linear Discriminant Analysis to minimize overfitting. Finally, a Deep Belief Network optimized using the Cuckoo Search algorithm is employed for classification and feature learning.ResultsThe proposed framework demonstrates improved performance over existing methods, achieving a 0.66% increase in accuracy and a 0.0345% decrease in error rate for AD stage detection.ConclusionsThis deep learning strategy shows promise as an effective tool for early and accurate AD stage identification. Enhanced segmentation, dimensionality reduction, and classification contribute to its improved performance, offering a meaningful advancement in AD diagnostics.}, } @article {pmid40830489, year = {2025}, author = {de Weerd, L and Hummel, S and Müller, SA and Paris, I and Sandmann, T and Eichholtz, M and Gröger, R and Englert, AL and Wagner, S and Ha, C and Davis, SS and Warkins, V and Xia, D and Nuscher, B and Berghofer, A and Reich, M and Feiten, AF and Schlepckow, K and Willem, M and Lichtenthaler, SF and Lewcock, JW and Monroe, KM and Brendel, M and Haass, C}, title = {Early intervention anti-Aβ immunotherapy attenuates microglial activation without inducing exhaustion at residual plaques.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {92}, pmid = {40830489}, issn = {1750-1326}, mesh = {Animals ; *Microglia/metabolism/drug effects/immunology ; Mice ; *Plaque, Amyloid/pathology/metabolism/immunology ; *Amyloid beta-Peptides/immunology/metabolism/antagonists & inhibitors ; *Immunotherapy/methods ; *Alzheimer Disease/pathology/metabolism/immunology ; Mice, Transgenic ; Disease Models, Animal ; }, abstract = {Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer's disease. Efficient amyloid clearance has been proven in clinical trials testing anti-Aβ antibodies, by their impact on cognitive endpoints correlating with the extent of amyloid removal. However, treatment is associated with adverse side effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model with an intervention paradigm early during amyloidogenesis. Long-term treatment with anti-Aβ results in a robust and dose-dependent lowering of amyloid plaque pathology, with a higher efficiency for reducing diffuse over dense-core plaque deposition. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune-cell-related proteins. Bulk RNA-seq revealed a dose-dependent attenuation of disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around residual plaques remains high, regardless of treatment dose. In addition, microglia surrounding residual plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen-presenting and immune signalling proteins. These findings demonstrate that chronic early intervention by an anti-amyloid immunotherapy leads to a dose-dependent decrease in plaque formation, which is associated with lower brain-wide microglial DAM activation and neurodegeneration. Microglia at residual plaques still display a combined DAM and antigen-presenting phenotype that suggests a continued treatment response.}, } @article {pmid40829311, year = {2025}, author = {Park, S and Park, M and Lee, HJ}, title = {Ginkgolide A enhances cognition and reduces amyloid-β by activating autophagy in the murine 5xFAD Alzheimer's disease model.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {191}, number = {}, pages = {118472}, doi = {10.1016/j.biopha.2025.118472}, pmid = {40829311}, issn = {1950-6007}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/psychology ; *Ginkgolides/pharmacology/therapeutic use ; *Autophagy/drug effects ; Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; *Cognition/drug effects ; Disease Models, Animal ; *Lactones/pharmacology/therapeutic use ; Mice ; Plaque, Amyloid ; Endoplasmic Reticulum Stress/drug effects ; Signal Transduction/drug effects ; Male ; TOR Serine-Threonine Kinases/metabolism ; Neuronal Plasticity/drug effects ; Maze Learning/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Hippocampus/drug effects/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder closely associated with impaired autophagy. Ginkgolide A (GA), a principal bioactive constituent of Ginkgo biloba, has garnered attention for its antioxidant, anti-inflammatory, and autophagy-modulating properties. MAIN TEXT: To evaluate the therapeutic potential of GA, we administered oral GA (20 mg/kg/day) for four weeks to 5xFAD transgenic mice. GA treatment significantly reduced soluble and insoluble forms of amyloid-β (Aβ) in the cortex and hippocampus, and markedly decreased Aβ plaque deposition. Cognitive performance was improved, as evidenced by increased spontaneous alternation in the Y-maze test. GA enhanced synaptic plasticity, indicated by increased expression of the synaptic markers synaptophysin 11 (SP11) and postsynaptic density 95 (PSD95). At the molecular level, GA activated autophagy by modulating PI3K-Akt signaling, relieving endoplasmic reticulum (ER) stress, and enhancing energy stress responses, ultimately leading to mTOR pathway suppression. CONCLUSION: These findings demonstrate that GA is a promising multifunctional therapeutic candidate for AD. Its ability to regulate autophagy and related signaling pathways provides new insights into disease mitigation and cognitive improvement.}, } @article {pmid40829243, year = {2025}, author = {Liu, Z and Huang, X and Zhang, M and Quan, YS and Wang, YL and Liu, JY and Nie, WZ and Zhao, YQ and Guo, HY and Quan, ZS and Li, G and Shen, QK}, title = {Discovery of oleanolic acid derivatives that inhibit tau protein phosphorylation and neuroinflammation induced by Aβ25-35 in vitro and in vivo.}, journal = {Bioorganic chemistry}, volume = {164}, number = {}, pages = {108866}, doi = {10.1016/j.bioorg.2025.108866}, pmid = {40829243}, issn = {1090-2120}, mesh = {*Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Animals ; *Oleanolic Acid/pharmacology/chemistry/chemical synthesis/analogs & derivatives ; *tau Proteins/metabolism/antagonists & inhibitors ; Mice ; *Peptide Fragments/antagonists & inhibitors/metabolism ; Phosphorylation/drug effects ; Humans ; Structure-Activity Relationship ; Molecular Structure ; *Neuroprotective Agents/pharmacology/chemistry/chemical synthesis ; Alzheimer Disease/drug therapy/metabolism ; Dose-Response Relationship, Drug ; *Drug Discovery ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Male ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder. The primary pathological features of AD are the abnormal deposition of extracellular β-amyloid (Aβ) protein and hyperphosphorylated microtubule-associated protein tau. Excessive Aβ aggregation triggers neuroinflammation. Oleanolic acid (OA) has significant neuroprotective and anti-inflammatory effects. In this study, we designed and synthesized 35 OA derivatives for the treatment of AD, targeting Aβ and hyperphosphorylated tau. The results showed that compound B1, an OA derivative with a tetrazole, had the strongest activity against Aβ25-35-induced cytotoxicity (EC50 = 1.93 ± 0.76 μM), approximately 14.75-fold more potent than OA and could penetrate the BBB. Intracerebroventricular injection of Aβ25-35 to establish an AD-like mouse model, the histopathological results showed that B1 relieved nerve damage, and Morris water maze results showed that B1 improved learning and memory. Mechanistically, B1 reversed the hyperphosphorylation of tau, significantly inhibited the expression of certain immune-related cytotoxic factors, suppressed the MAPK and NF-κB signaling pathways, and significantly inhibited the expression of RAGE and the apoptosis factors Bax/Bcl-2, both in vitro and in vivo. In conclusion, B1 regulates neuroinflammatory mediators in response to Aβ and reverses the hyperphosphorylation of tau, and is a promising multifunctional compound for treating AD.}, } @article {pmid40827126, year = {2025}, author = {Price, BR and Walker, KA and Eissman, JM and Suryadevara, V and Sime, LN and Hohman, TJ and Gordon, MN}, title = {Sex differences and the role of estrogens in the immunological underpinnings of Alzheimer's disease.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70139}, pmid = {40827126}, issn = {2352-8737}, abstract = {UNLABELLED: Alzheimer's disease (AD) affects women more frequently and more severely than men, but the biological mechanisms underlying these sex differences remain poorly understood. This review integrates recent findings from neuroscience, immunology, endocrinology, and genetics to explore how sex steroid hormones, particularly estrogen, shape neuroimmune responses and influence AD risk. We highlight the pivotal roles of microglia and astrocytes, whose inflammatory and neuroprotective actions are modulated by hormonal fluctuations across the female lifespan, including pregnancy, menopause, and menopausal hormone replacement therapy. Key genetic risk factors, such as apolipoprotein E ε4, show sex-specific effects on glial activation, tau pathology, and cognitive decline. Furthermore, life-stage transitions, especially menopause, intersect with changes in brain metabolism, immune signaling, and epigenetic regulation, increasing susceptibility to neurodegeneration in women. We propose a framework for sex-aware, personalized approaches to AD prevention and treatment. By integrating hormone-immune interactions with genetic and glial biology, this review emphasizes the critical need for sex-specific models in AD research. HIGHLIGHTS: Women develop greater tauopathy, with more cognitive and clinical consequences in Alzheimer's disease (AD).Glial activation is adapted by estrogens to shape vulnerability or resilience to AD.Sex differences in innate and adaptive immunity could contribute to AD progression.Effects of menopausal hormone therapy on immunity in AD remain understudied.Future studies to explore sex differences in immune function during AD are needed.}, } @article {pmid40826719, year = {2025}, author = {Ma, W and Yuan, X and Liu, Y and Wang, Q and Zhang, Y and Dong, P and Zhou, C}, title = {Immune regulatory mechanisms of different exercise methods promoting Parkinson's rehabilitation: A narrative review.}, journal = {Medicine}, volume = {104}, number = {33}, pages = {e44035}, pmid = {40826719}, issn = {1536-5964}, support = {YDZX2022091//the central government guides local Sci-tech development funds/ ; ZR2021QH070//the Natural Scientific Foundation of Shandong Province, China/ ; }, mesh = {Humans ; *Parkinson Disease/rehabilitation/immunology ; *Exercise Therapy/methods ; }, abstract = {Parkinson disease (PD) is the second largest and most common neurodegenerative disease globally, following Alzheimer disease. Its pathological features include the deformation and loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, as well as the aggregation of α-synuclein in the form of Lewy bodies. This leads to motor symptoms such as resting tremors, muscle rigidity, bradykinesia, and postural instability, as well as non-motor symptoms including cognitive, emotional, and sleep disorders. Currently, PD is mainly treated by medication and surgery. Medication, though widely used, has limited efficacy and causes adverse reactions. With the intensification of global aging and the annual increase in the incidence of PD, the limitations of existing treatment approaches have become increasingly prominent, and there is an urgent need to explore safer and more effective treatment strategies. Numerous clinical studies have demonstrated that exercise rehabilitation training can not only effectively ameliorate the motor and non-motor symptoms of PD patients, but also promote the generation of neurotrophic factors, neurotransmitters, and hormones, and regulate the dopaminergic system. Therefore, an in-depth exploration of the mechanisms and effects of different exercise rehabilitation training methods in the treatment of PD holds great significance for refining the comprehensive treatment plan for PD and enhancing the quality of life of patients. This article will conduct a comprehensive review of the mechanisms and effects of various exercise rehabilitation training methods in treating PD.}, } @article {pmid40826256, year = {2025}, author = {Langness, VF and Simmons, DA and McHugh, TLM and Butler, RR and Zhou, J and Liu, H and Yang, T and Ellerby, LM and Longo, FM}, title = {Twenty years of therapeutic development in tauopathy mouse models: a scoping review.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70578}, pmid = {40826256}, issn = {1552-5279}, support = {PO1 AG066591/AG/NIA NIH HHS/United States ; T32 AG052374/AG/NIA NIH HHS/United States ; //Taube Philanthropies/ ; P01 AG066591/AG/NIA NIH HHS/United States ; //Jean Perkins Foundation/ ; }, mesh = {Animals ; Humans ; Mice ; *Disease Models, Animal ; Mice, Transgenic ; tau Proteins/genetics ; *Tauopathies/therapy/genetics/drug therapy ; }, abstract = {Tauopathies are neurodegenerative diseases characterized by pathological tau protein inclusions and dementia. Tauopathy mouse models with MAPT mutations replicate tau-related pathologies and are widely used for therapeutic research. This scoping review examines 409 treatment evaluations in MAPT mouse models. We identify trends in therapeutic strategies and frequently used mouse models, treatment routes, and endpoints. We also document treatment effects and when treatment is initiated relative to tau pathology emergence. Many treatments produced positive effects in multiple MAPT mouse models across many endpoints but showed limited success in clinical trials. Potential barriers to mouse-to-human translation include differences between mouse and human studies in the timing of treatment initiation relative to tau pathology onset, predominant testing of a limited number of endpoints, lack of translatable treatment response biomarkers, and the limited ability of individual mouse models to represent the diversity of tauopathies. Addressing these obstacles could improve mouse-to-human translation for tauopathy therapeutics. HIGHLIGHTS: Two decades of therapeutic research in tauopathy mouse models were reviewed. Treatments often began before or at tau pathology onset in tauopathy mouse models. Key endpoints (e.g., cognition and synaptic degeneration) were underassessed. Well-characterized preclinical treatments often had limited success in humans. Single-sex mouse studies and a lack of biomarkers hinder clinical translation.}, } @article {pmid40826098, year = {2025}, author = {Chia, SY and Li, M and Li, Z and Tu, H and Lee, JWL and Qiu, L and Ling, J and Reynolds, R and Albani, S and Tan, EK and Ng, ASL and Chen, J and Zeng, L}, title = {Single-nucleus transcriptomics reveals a distinct microglial state and increased MSR1-mediated phagocytosis as common features across dementia subtypes.}, journal = {Genome medicine}, volume = {17}, number = {1}, pages = {92}, pmid = {40826098}, issn = {1756-994X}, support = {LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; NMRC/OFLCG/002/2018//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; LCG002-SPARK II//National Medical Research Council Open Fund-Large Collaborative Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; CIRG19may0052//Clinician Scientist Individual Research Grant/ ; MOH-CIRG21nov-0001//Clinician Scientist Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; OFIRG23jul-0075//Open Fund-Individual Research Grant/ ; MOH-STaR19nov-0002//NMRC Awarded Projects Talent Development/ ; MOH-000988//Duke-NUS and SingHealth AMC core funding as well as Singapore Ministry of Health's NMRC under its Centre Grant Program/ ; A*STAR PEC21-H22P0M0003//A*STAR/ ; }, mesh = {*Microglia/metabolism ; Humans ; *Phagocytosis/genetics ; *Dementia/genetics/metabolism/pathology ; *Transcriptome ; Animals ; Mice ; Male ; *Scavenger Receptors, Class A/metabolism/genetics ; Aged ; Female ; Gene Expression Profiling ; Alzheimer Disease/genetics/metabolism ; Aged, 80 and over ; Single-Cell Analysis ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD) collectively represent the majority of dementia cases worldwide. While these subtypes share clinical, genetic, and pathological features, their transcriptomic similarities and differences remain poorly understood. METHODS: We applied single-nucleus RNA-sequencing (snRNA-seq) to prefrontal cortex samples from individuals with non-cognitive impairment control (NCI), and dementia subtypes (AD, DLB, and PDD) to investigate cell type-specific gene expression patterns and pathways underlying pathological similarities and differences across dementia subtypes. SnRNA-seq findings were validated through RNAscope, immunohistochemistry, and additional biochemical analyses in human tissues and cellular models. RESULTS: SnRNA-seq analysis revealed elevated microglial proportions across all dementia subtypes compared to NCI. Further analysis of cell type-specific transcriptomes identified overlapping differentially expressed genes (DEGs) between microglia and oligodendrocytes across all dementia subtypes. While AD showed molecular similarities to NCI, PDD and DLB were clustered more closely together, sharing a greater number of DEGs and related pathways, predominantly associated with microglia. Investigation of interactions between microglia and oligodendrocytes revealed a distinct microglial state in all dementia subtypes. MSR1, a gene encoding a scavenger receptor, was upregulated in microglia across all dementia subtypes, along with its associated gene HSPA1A in oligodendrocytes. RNAscope supported the potential interaction between microglia and oligodendrocytes, where these cells were in closer proximity to each other in human cortical tissues of PDD compared to NCI. MSR1 expression was significantly increased in cortical primary microglia from PD mice compared with non-transgenic (NTg) mice. Additionally, the expression of myelin-associated genes (MBP, MOBP, and PLP1) was significantly upregulated in PD microglia compared to NTg, supporting the presence of the distinct microglia. Furthermore, MSR1-positive microglia colocalised with MBP in cortical tissue of PDD patients, suggesting a functional role of MSR1 in myelin debris clearance. Overexpression of MSR1 in microglial cells enhanced their phagocytic activity toward myelin, and reciprocally, myelin treatment upregulated MSR1 protein levels, indicating enhanced MSR1-mediated myelin phagocytosis. CONCLUSIONS: Our findings provide novel insights into the cell type-specific role of microglial MSR1 in AD, DLB, and PDD, linking its increased phagocytic capacity to myelin defects as a common feature of neurodegenerative dementias.}, } @article {pmid40825623, year = {2025}, author = {Ma, W and Tang, B and Zhang, H and Qu, Y and Luan, J and Wang, K and Chen, W and Wang, X and Liu, X and Zhao, H and Li, H and Luo, M and Luo, Z and Shen, L and Chen, M}, title = {Small-molecule fluorescent probes for imaging intracellular amyloid toxicity induces ferroptosis via HClO fluctuation in Alzheimer's disease.}, journal = {Analytica chimica acta}, volume = {1371}, number = {}, pages = {344485}, doi = {10.1016/j.aca.2025.344485}, pmid = {40825623}, issn = {1873-4324}, mesh = {*Ferroptosis/drug effects ; *Alzheimer Disease/metabolism/diagnostic imaging ; Humans ; *Fluorescent Dyes/chemistry/chemical synthesis/pharmacology ; *Hypochlorous Acid/metabolism/analysis ; *Amyloid beta-Peptides/toxicity/metabolism ; Animals ; *Small Molecule Libraries/chemistry/pharmacology/chemical synthesis ; Optical Imaging ; Mice ; Blood-Brain Barrier/metabolism ; Molecular Structure ; Peptide Fragments/toxicity ; }, abstract = {BACKGROUND: Amyloid toxicity induces ferroptosis play a crucial role in the pathological dysfunction of brains affected by Alzheimer's disease (AD). Despite this, brain probing implements for looking into the relationship between ferroptosis and ROS in the brains of AD victims are currently scarce. Herein, a HClO activated ESIPT fluorescent probe HCC-Br was engineered to investigate the complicated correlations between HClO and AD, achieving in vivo diagnosing and evaluating of AD progression. RESULTS: With this probe, we could also utilize HCC-Br for the visualization and tracking of endogenous HClO production in live cells during Aβ42-induced ferroptosis. More crucially, our findings suggest that tannic acid (TA) shows promise as an effective neuroprotective agent to control MPO-mediated oxidative stress in this stimulated condition. The small molecular structure and suitable lipophilicity endowed HCC-Br with remarkable blood-brain barrier (BBB) permeability, making it enormously applicable to the in vivo detection of HClO variations in AD brains. SIGNIFICANCE AND NOVELTY: Overall, this study presents a versatile fluorescence tool that can help clarify the contributions of HClO production by MPO in the pathogenic mechanisms of AD. Furthermore, it holds tremendous prospects in exploring the function of HClO in ferroptosis-related pathogenesis and treatment of AD.}, } @article {pmid40825553, year = {2025}, author = {Sato, S and Iwata, A and Ishii, K and Kamiki, E and Nishimoto, T}, title = {[Donanemab, an Amyloid β-targeting Antibody for Early Symptomatic Alzheimer's Disease: Summary of Clinical Study Results].}, journal = {Brain and nerve = Shinkei kenkyu no shinpo}, volume = {77}, number = {8}, pages = {907-920}, doi = {10.11477/mf.188160960770080907}, pmid = {40825553}, issn = {1881-6096}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized ; }, abstract = {Alzheimer's disease is an age-related neurodegenerative disorder, and is considered to contribute to dementia in 60%-70% of individuals with dementia. In recent years, a series of amyloid β protein (Aβ)-targeting antibodies that act directly on Aβ aggregates in the brain, one of the factors which contributes to the onset of Alzheimer's disease, have been approved to suppress the clinical progression, and Alzheimer's disease treatment in Japan is changing. This review article focuses on one of these Aβ-targeting antibodies, donanemab, and summarizes its clinical study results. (Received November 1, 2024; Accepted May 7, 2025; Published August 1, 2025).}, } @article {pmid40825453, year = {2025}, author = {Cozza, M and Fimognari, FL and Castagna, A and Boccardi, V}, title = {Antidepressant use in dementia: Assessing effective strategies for a vulnerable population.}, journal = {Neuroscience and biobehavioral reviews}, volume = {177}, number = {}, pages = {106340}, doi = {10.1016/j.neubiorev.2025.106340}, pmid = {40825453}, issn = {1873-7528}, mesh = {Humans ; *Antidepressive Agents/therapeutic use ; *Dementia/drug therapy/complications/psychology ; *Depression/drug therapy ; Vulnerable Populations ; }, abstract = {Depression is closely associated with dementia and may serve as a risk factor, an early symptom, or a prodromal feature, particularly in Alzheimer's disease, the most common form of dementia. It can also emerge during disease progression, not only in Alzheimer's but in other dementias such as vascular dementia, Lewy body dementia, and frontotemporal dementia. Recognizing the timing and context of depressive symptoms is crucial for accurate diagnosis and management. While non-pharmacological interventions and psychosocial approaches are generally recommended as the first line of treatment, clinical practice often sees widespread use of antidepressants in this vulnerable population. However, such usage is not always supported by robust evidence, particularly given the heightened risk of side effects in older adults with cognitive decline. This narrative review seeks to critically examine the role of antidepressants in managing depression among patients with dementia. Rather than dismissing their use outright, we aim to provide a novel perspective on their application, emphasizing the importance of a thorough multidimensional geriatric assessment. The attempt is to help the clinicians in making more individualized, evidence-based decisions that balance the potential benefits and risks, ensuring that treatment is tailored to the unique needs of each patient.}, } @article {pmid40825161, year = {2025}, author = {Kapasi, A and James, BD and Yu, L and Sood, A and Arvanitakis, Z and Bennett, DA and Boyle, P and Schneider, JA}, title = {Mixed Pathologies and Cognitive Outcomes in Persons Considered for Anti-Amyloid Treatment Eligibility Assessment: A Community-Based Study.}, journal = {Neurology}, volume = {105}, number = {5}, pages = {e214004}, pmid = {40825161}, issn = {1526-632X}, mesh = {Humans ; Male ; Female ; Aged ; *Cognitive Dysfunction/pathology/drug therapy/psychology ; Aged, 80 and over ; *Alzheimer Disease/pathology/drug therapy ; *Amyloid beta-Peptides/metabolism ; Eligibility Determination ; *Brain/pathology ; Positron-Emission Tomography ; }, abstract = {BACKGROUND AND OBJECTIVES: Despite the capability of anti-amyloid monoclonal antibodies to lower β-amyloid (Aβ) brain levels, there is thus far limited clinical efficacy on cognitive outcomes. Among individuals with mild cognitive impairment (MCI) or mild-stage dementia, the cognitive impact of other brain pathologies may limit efficacy of anti-amyloid drugs. This study examined the burden and cognitive associations of mixed brain pathologies among autopsied persons who would have been considered as patients to undergo anti-amyloid treatment eligibility assessment. METHODS: Eligibility was defined based on a Mini-Mental State Examination score ≥20, a clinical diagnosis of MCI or mild-stage Alzheimer dementia, and a level of Aβ pathology at autopsy indicative of having a positive amyloid PET scan (Consortium to Establish a Registry for Alzheimer's Disease score ≥moderate). The number and types of copathologies were examined. Mixed-effects models were used to examine the association of Aβ, tangles, limbic predominant age-related transactive response DNA-binding protein 43 encephalopathy neuropathologic changes (LATE-NC), infarcts, Lewy bodies (LBs), and vessel diseases, with the rate of cognitive decline. RESULTS: Among 428 older autopsied persons (mean age at death = 91 years, 70% women) considered for anti-amyloid treatment eligibility assessment, 58% had MCI and 42% had mild-stage Alzheimer dementia. Although the majority (94%) had a pathologic diagnosis of Alzheimer disease neuropathologic changes (ADNC), only 26% had ADNC without LATE-NC, LB, or infarcts. The majority (68%) had ADNC with ≥1 copathology with ADNC + infarcts and ADNC + LATE-NC being equally common. In mixed-effects models, tangles and arteriolosclerosis were both associated with a faster rate of global cognitive decline. Separately, tangles and LATE-NC were associated with a faster decline in episodic memory, ADNC was associated with faster decline in semantic memory with Aβ being further associated with decline in working memory, and atherosclerosis was associated with a faster decline in perceptual speed. Infarcts and LBs were not associated with decline in global cognition or any cognitive domain. DISCUSSION: Mixed pathologies are common among community-dwelling older persons considered for anti-amyloid treatment eligibility assessment. Beyond Aβ, tangles, LATE-NC, and vessel pathologies drive cognitive decline in this group of individuals, especially episodic memory decline. These findings suggest that, even among those eligible for anti-amyloid therapies, substantial cognitive decline may occur because of the presence of coexisting pathologies.}, } @article {pmid40824894, year = {2025}, author = {Almarri, B}, title = {Deep learning-based Alzheimer's disease detection using magnetic resonance imaging and gene expression data.}, journal = {PloS one}, volume = {20}, number = {8}, pages = {e0330085}, pmid = {40824894}, issn = {1932-6203}, mesh = {*Alzheimer Disease/genetics/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; Gene Expression Profiling ; ROC Curve ; Male ; }, abstract = {Alzheimer's disease (AD) poses significant challenges to healthcare systems across the globe. Early and accurate AD diagnosis is crucial for effective management and treatment. Recent advances in neuroimaging and genomics provide an opportunity for developing multi-modality-based AD diagnosis models using artificial intelligence (AI) techniques. However, the data complexities cause challenges in developing interpretable AI-based AD identification models. In this study, the author built a comprehensive AD diagnostic model using magnetic resonance imaging (MRI) and gene expression data. MobileNet V3 and EfficientNet B7 model was employed to extract AD features from gene expression data. The author introduced a hybrid TWIN-Performer-based feature extraction model to derive features from MRI. The attention-based feature fusion was used to fuse the crucial features. An ensemble learning-based classification model integrating CatBoost, XGBoost, and extremely randomized tree (ERT) was developed to identify cognitively normal (CN) and AD features. The proposed model was validated on diverse datasets. It achieved a superior performance on MRI and gene expression datasets. The area under the receiver operating characteristic (AUROC) scores were consistently above 0.85, indicating excellent model performance. The use of Shapley Additive exPlanations (SHAP) values improved the model's interpretability, leading to earlier interventions and personalized treatment strategies.}, } @article {pmid40824589, year = {2025}, author = {Borioni, MS and Morano, A and De Matteis, AL and Mazzeo, A and Moro, P and Di Bonaventura, C and Irelli, EC}, title = {Neuroglial biomarkers in autoimmune encephalitis: advances in diagnosis, prognosis, and pathophysiological insights.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {10}, pages = {4925-4941}, pmid = {40824589}, issn = {1590-3478}, mesh = {Humans ; Biomarkers/cerebrospinal fluid/blood/metabolism ; Prognosis ; *Encephalitis/diagnosis/cerebrospinal fluid ; *Neuroglia/metabolism ; *Hashimoto Disease/diagnosis/cerebrospinal fluid ; Neurofilament Proteins/cerebrospinal fluid ; }, abstract = {Autoimmune encephalitis (AE) presents with a diverse spectrum of neuropsychiatric symptoms, often leading to diagnostic challenges and delays in treatment. Neuroglial biomarkers may improve AE diagnosis, disease monitoring, and prognostication. This review examines the diagnostic and prognostic value of fluid biomarkers in AE, focusing on markers of neuroaxonal damage, synaptic dysfunction, astroglial activation, and amyloid metabolism. A systematic search of PubMed, Cochrane, and Scopus databases (from inception until November 26, 2024) was performed. Of the 1,270 articles screened, 31 studies met the inclusion criteria. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was the most frequently investigated subtype (70% of studies). Neurofilament light chain (NfL) was the most widely analyzed biomarker, with elevated levels in both cerebrospinal fluid and serum, aiding in the differentiation of AE from primary psychiatric disorders and in the early identification of checkpoint inhibitor-related neurotoxicity. NfL and total tau (t-Tau) were consistently higher in paraneoplastic than non-paraneoplastic AE. Despite some variability across studies, amyloid-beta (Aβ) 42 and Aβ40, as well as phosphorylated tau (p-Tau), were altered in AE compared to controls, although generally to a lesser extent than in Alzheimer's disease. Higher baseline NfL and YKL-40 correlated with disease severity, and NfL reductions post-immunotherapy were linked to treatment response. Despite consistent heterogeneities in sampling timing, these findings highlight the potential of neuroglial biomarkers as diagnostic and prognostic tools in AE. Future studies should explore longitudinal biomarker dynamics and refine their clinical applications.}, } @article {pmid40823879, year = {2025}, author = {Lee, J and Sim, S and Jin, Y and Park, H and Byeon, EY and Kim, SJ and Yun, S and Lee, HE and Jeong, DU and Suh, JM and Lee, IH and Lee, HY and Choi, Y and Bae, YS}, title = {NADPH Oxidase Inhibition Promotes Brain Resilience by Attenuating Tauopathy and Neuroinflammation in Alzheimer's Disease.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {42}, pages = {e05495}, pmid = {40823879}, issn = {2198-3844}, support = {20165925//Starting Growth Technological R&D Program/ ; RS-2024-00398295//Korean National Reseach Foundation (NRF)/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; Mice ; *NADPH Oxidases/antagonists & inhibitors/metabolism ; *Tauopathies/drug therapy/metabolism ; *Brain/drug effects/metabolism ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Disease Models, Animal ; Reactive Oxygen Species/metabolism ; Mice, Transgenic ; Hippocampus/metabolism/drug effects ; Male ; Neurons/drug effects/metabolism ; }, abstract = {Alzheimer's disease (AD) associates closely associated with the activation of NADPH oxidase (Nox) isozymes. CRB-2131, a novel oxadiazole derivative, is identified as a potently suppresses Nox isozymes. It inhibits reactive oxygen species production (ROS) by hippocampal neuronal and microglial cells and reduces microglial activation. Prophylactic (starting at 3.5 months of age) and therapeutic (starting at 6 months of age) oral administration with CRB-2131 for 10 weeks in 5XFAD mice reduced hippocampal superoxide levels, lipid peroxidation, Tau phosphorylation, and neuroinflammation. Prophylactic and therapeutic CRB-2131 treatment of 5XFAD mice restored their impaired cognition as shown by the novel-object recognition, Y-maze, and Morris water-maze tests. CRB-2131 treatment increased mature neurons, reduced apoptotic mature neurons, and elevated immature neurons in the hippocampus. Positron-emission tomography/computed-tomography imaging confirmed that CRB-2131 stimulated neuronal regeneration. CRB-2131 suppresses brain oxidation, tauopathy, and neuroinflammation, thereby preventing mature neuron death and promoting neuron regeneration. Ultimately, this fosters a resilient brain and protects cognition.}, } @article {pmid40823789, year = {2025}, author = {Shwab, EK and Pathak, GA and Harvey, J and Belloy, ME and Fischer, CE and Lutz, MW and Scholz, SW and Cook, N and Reid, DM and Chen, J and Guan, DX and Oliveira, F and Sinclair, LI and Imo, U and Creese, B and Chiba-Falek, O and , }, title = {Leveraging multiomic approaches to elucidate mechanisms of heterogeneity in Alzheimer's disease: Neuropsychiatric symptoms, co-pathologies, and sex differences.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70549}, pmid = {40823789}, issn = {1552-5279}, support = {R01 AG057522/AG/NIA NIH HHS/United States ; RF1 AG077695/AG/NIA NIH HHS/United States ; R00AG078503//National Institutes of Health/National Institute on Aging/ ; R00AG075238//National Institutes of Health/National Institute on Aging/ ; R01AG067015//National Institutes of Health/National Institute on Aging/ ; RF1-NS113548-01A1//National Institute of Neurological Disorders & Stroke/ ; ZIANS003154//National Institute of Neurological Disorders & Stroke/ ; 2U10AA008401/AA/NIAAA NIH HHS/United States ; //Cure Alzheimer's Fund/ ; 2015/10109-5//The State of São Paulo Research Foundation/ ; AARG-24-1027303/ALZ/Alzheimer's Association/United States ; 22-AAIIA-953269/ALZ/Alzheimer's Association/United States ; AARF-22-967171/ALZ/Alzheimer's Association/United States ; }, mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *Sex Characteristics ; Comorbidity ; Female ; Male ; Sex Factors ; }, abstract = {The heterogeneity of Alzheimer's disease (AD) is multi-dimensional, encompassing clinical features such as neuropsychiatric symptoms (NPS), rate of progression, age of onset, comorbidities, and neuropathological features such as co-pathologies, and represents the diverse outcomes of manifold genetic and environmental risk determinants. These diverse features of AD also vary significantly between sexes and across ancestral backgrounds, but the specific variations and causal mechanisms are not well understood. Recent technological advances, particularly single-cell and spatial omics, have provided new tools to dissect the molecular underpinnings of AD heterogeneity and its multifactorial nature. This perspective review highlights molecular differences, general and sex-specific, that contribute to the heterogeneity of AD in aspects such as NPS, co-pathology prevalence, and general disease trajectories. We further examined the potential for multiomic approaches to direct future translational studies aimed at the development of precision medicine strategies for the treatment of AD in all its diverse forms. HIGHLIGHTS: Alzheimer's disease (AD) represents diverse subtypes characterized by comorbid clinical symptoms and co-pathologies. Integration of bulk, single-cell, spatial multiomics reveals factors underlying AD variation. Multiomics studies indicate shared and distinct mechanisms between major psychiatric disorders and AD. Multiomics data have transformative implications for sex- and population-specific AD therapies. New tailored precision medicine strategies are needed to address the full range of complexity in AD.}, } @article {pmid40823654, year = {2025}, author = {Dougnon, G and Matsui, H}, title = {Lipofuscin autofluorescence confounds intracellular amyloid β detection in the aged mouse brain.}, journal = {Aging brain}, volume = {8}, number = {}, pages = {100148}, pmid = {40823654}, issn = {2589-9589}, abstract = {Intracellular amyloid β (Aβ) accumulation is a contentious feature of Alzheimer's disease (AD), increasingly reported in young adults and aged animal models of AD. However, autofluorescent lipofuscin granules which consist of a mixture of highly oxidized lipids, misfolded proteins, and metals, accumulates with aging in neurons and microglia and renders difficult the interpretation of immunofluorescence-based studies. Here, we show that lipofuscin accumulation in aged wild-type (WT) mouse brains exhibits significant spectral overlap with commonly used antibodies for Aβ detection, leading to potential misinterpretation of intracellular Aβ signals. Through a combination of dye staining, immunohistochemistry (IHC), and confocal microscopy, we show that fluorescence signals resembling intracellular Aβ and commonly reported in aged animal models of AD, may reflect the presence of lipofuscin granules. Importantly, these signals persisted in control sections where primary Aβ antibodies were omitted, but disappeared following TrueBlack autofluorescence quencher. We also performed Aβ immunofluorescence staining using 5xFAD mice as model for AD, revealing that intracellular Aβ in these models can be diminished by TrueBlack treatment, thus confounding the interpretation of true intracellular Aβ signals. Our findings underscore the need for caution in interpreting intracellular Aβ signals in young adults and aged models of Aβ pathology inside neurons or microglia.}, } @article {pmid40822853, year = {2025}, author = {Tiunova, AA and Diffine, EA and Anokhin, KV}, title = {Memory reconsolidation impairment by amyloid beta (1-42) and its prevention by non-competitive antagonists of NMDA receptors.}, journal = {Frontiers in cellular neuroscience}, volume = {19}, number = {}, pages = {1629492}, pmid = {40822853}, issn = {1662-5102}, abstract = {In a healthy brain, the reactivation of memories under conditions of novelty leads to their labilization and subsequent reconsolidation. However, if plasticity of the nervous system is reduced reconsolidation mechanisms may be disrupted, leading to weakening and loss of existing memory. We hypothesize that such self-degradation of old memory due to its reactivation in the compromised brain may lead to progressive memory loss in Alzheimer's disease. Preventing memory lability when accessing it, may slow down such engram degradation. To test these hypotheses, we first examined whether beta-amyloid peptide Aβ1-42 can impair reconsolidation of memory in one-trial passive avoidance task in young chicks. Next, we examined the possibility to prevent such reminder-associated amnesia by administering a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 prior to memory reactivation. Finally, we compared the memory protecting effects of two non-competitive NMDA antagonists, MK-801 and memantine which is a clinically used medication for treatment of Alzheimer's disease. We found that administration of Aβ1-42 prior to memory reactivation in passive avoidance task in chicks impaired its subsequent reconsolidation. Concurrent systemic injection of MK-801 or memantine prevented this impairment. Our data thus support the hypothesis about the possible role of impaired reconsolidation in the progressive deterioration of old memories in neurodegenerative diseases, particularly in Alzheimer's disease. This hypothesis offers a new explanation for the protective effects of memantine and suggests the possibility of similar effects with other NMDA receptor antagonists.}, } @article {pmid40822397, year = {2025}, author = {Liu, X and Sun, C and Dai, Y and Duan, F and He, T and Zhen, M and Liang, E and Zhang, S and Xia, Y and Hu, N and Zhan, R and Deng, D and Liu, S}, title = {Study on the improvement of cognitive deficits in APP/PS1 mice by danggui shaoyao san and its disassembled prescriptions through modulation of the gut microbiota.}, journal = {Frontiers in microbiology}, volume = {16}, number = {}, pages = {1620784}, pmid = {40822397}, issn = {1664-302X}, abstract = {BACKGROUND: Alzheimer's disease (AD), a neurodegenerative disorders linked to gut microbiota dysbiosis, may benefit from Traditional Chinese Medicine (TCM) interventions. OBJECTIVES: Danggui Shaoyao San (DSS), a classic traditional Chinese Medicine (TCM) formula. This study investigated whether Danggui Shaoyao San and its disassembled prescriptions could improve cognitive deficits in APP/PS1 mice by modulating the structure of the gut microbiota, thereby providing a theoretical basis for AD treatment and the further development and application of Danggui Shaoyao San. METHODS: Forty APP/PS1 and eight C57BL/6 mice were divided into six groups: DSS (6.4 g/kg/d), QDW (4.6 g/kg/d), DW (1.8 g/kg/d), GV971 (positive control, 40 mg/kg/d), model (saline), and control (saline). After 60 days of treatment, the mice underwent behavioral testing in the open field, novel object recognition, and water maze. Gut microbiota composition, diversity, and function were then analyzed by 16S rRNA sequencing. RESULTS: The results of Behavioral experiment indicate that Danggui Shaoyao San and its disassembled prescriptions can ameliorate spatial memory deficits (Morris water maze), enhance recognition memory (novel object recognition), and reduce anxiety-like behaviors (open field test), with the DSS group demonstrating the most pronounced effects. In addition, through 16S sequencing analysis we predicted DSS and its disassembled prescriptions reduced harmful bacteria (Firmicutes, Akkermansia) while increasing beneficial bacteria (Bacteroidetes, Bifidobacterium, Lactobacillus). DSS restored microbial diversity closest to healthy controls, evidenced by elevated Chao1/Shannon indices and reduced Simpson index. Beta diversity revealed structural divergence between treatment and model groups. Functional predictions highlighted enriched pathways (D-glutamine metabolism, bile acid biosynthesis) and suppressed antibiotic biosynthesis. CONCLUSION: Danggui Shaoyao San and its disassembled prescriptions ameliorate AD-related cognitive impairment and gut dysbiosis, enhance microbial diversity, and modulate metabolic pathways, supporting their therapeutic potential via gut-brain axis regulation. This study elucidates the multi-target mechanisms of DSS in AD treatment, advancing TCM rationalization for neurodegenerative disorders.}, } @article {pmid40822322, year = {2025}, author = {Diniz, JRG and de Almondes, KM and Godeiro, C and Silva, RAE}, title = {Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy: report of two cases.}, journal = {Dementia & neuropsychologia}, volume = {19}, number = {}, pages = {e20240198}, pmid = {40822322}, issn = {1980-5764}, abstract = {UNLABELLED: The polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy-Nasu-Hakola disease-is a hereditary and progressive pathology, which is mainly associated with pre-senile dementia and changes in bone architecture. OBJECTIVE: To report two rare cases of sibling patients treated with early-onset dementia syndrome with genetic etiology, and to review the literature on the topic. METHODS: Review of medical records, interviews and recording of the diagnostic methods to which patients were subjected. From this, a report was prepared of two cases who began behavioral changes in the third decade of life, who developed, at different times, symptoms of similar cognitive impairment. Bibliographic research carried out in the United States National Library of Medicine (PubMed), Medical Literature Analysis and Retrieval System Online (MEDLINE), Latin American and Caribbean Health Sciences Literature (LILACS), UpToDate and Scientific Electronic Library Online (SciELO) databases for bibliographic review. RESULTS: Two clinical cases with genetic confirmation of Nasu-Hakola disease and a brief literature review were described. CONCLUSION: These cases illustrate a presentation of pre-senile dementia syndrome and reinforce the importance of adequate diagnosis for timely treatment, humanized multidisciplinary follow-up aiming to improve quality of life, as well as genetic and family counseling.}, } @article {pmid40822124, year = {2025}, author = {Wang, H and Qiu, M and Wang, C and Zhang, L and Fan, N and Chen, Z and Liu, Y and Li, T and Wang, Z and Zhu, Y and Zhang, Y and Tian, X and Wang, Y and Yang, M and Fan, D and Luo, Q and Jiang, K and Luo, H and Zhang, H}, title = {Light-Triggered Graphene/Black Phosphorus Heterostructure FET Platform for Ultrasensitive Detection of Alzheimer's Disease Biomarkers at the Zeptomole Level.}, journal = {Research (Washington, D.C.)}, volume = {8}, number = {}, pages = {0772}, pmid = {40822124}, issn = {2639-5274}, abstract = {Due to the low concentration of amyloid-beta (Aβ) in plasma and the high content of interfering factors, the conventional detection method for the quantification of Aβ still faces the problem of insufficient limit of detection (LOD). In this work, we propose a new light-triggered graphene-black phosphorus heterostructure (G-BP) field-effect transistor (FET) biosensing platform that achieves a marked reduction in the LOD. The LOD for Alzheimer's disease (AD) biomarker Aβ42 detection using the G-BP FET is as low as 235.1 zM (2.351 × 10[-19] M), which is the lowest value reported to date and is approximately 2 to 3 orders of magnitude lower than other reported biosensing platforms. The G-BP FET platform provides precise, real-time guidance for non-invasive early diagnosis, disease monitoring, and personalized treatment plans for AD. Moreover, this method has good scalability and potential applications in other areas, including early detection of cancer and other major chronic diseases.}, } @article {pmid40821309, year = {2025}, author = {Matsuura, K and Mayahara, T and Katayama, T and Arai, H}, title = {Recurrent Cholinergic Crisis Caused by Therapeutic-Dose Rivastigmine Patch in an Elderly Patient With Alzheimer's Disease: A Case Report.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e87868}, pmid = {40821309}, issn = {2168-8184}, abstract = {Cholinesterase inhibitors (ChEIs) are widely used for the treatment of dementia and other conditions, but may rarely cause cholinergic crisis, a potentially life-threatening complication. We report an elderly female patient with Alzheimer's disease who experienced three episodes of cholinergic crisis over 32 months while receiving a therapeutic dose of transdermal rivastigmine (18 mg/day). Each episode involved vomiting, diarrhea, diaphoresis, and neurological symptoms, with marked reductions in serum cholinesterase levels (53-63 U/L at presentation). During the first two episodes, alternative diagnoses such as acute gastroenteritis and possible pesticide exposure were initially suspected, and cholinergic crisis secondary to rivastigmine was not recognized. After the third episode, rivastigmine was permanently discontinued, resulting in the complete resolution of both acute and chronic mild gastrointestinal and autonomic symptoms. This case highlights the diagnostic challenges of cholinergic crisis in elderly patients receiving ChEIs and underscores the importance of considering this condition when unexplained gastrointestinal or autonomic symptoms occur even during standard therapeutic dosing.}, } @article {pmid40820453, year = {2025}, author = {Sharma, H and Chandra, P}, title = {Development of Ergosterol Nanoliposome-based Delivery System Pertaining Toxicity Evaluation and Therapeutic Potential for Alzheimer's Disease.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273388820250724174247}, pmid = {40820453}, issn = {1996-3181}, abstract = {INTRODUCTION: Alzheimer's disease (AD), a debilitating neurodegenerative disorder, presents a growing global health challenge due to limited therapeutic options. Ergosterol, known for its neuroprotective and antioxidant properties, suffers from poor bioavailability. This study aimed to develop ergosterol-loaded nanoliposomes (ER-NL-2) and evaluate their safety, antioxidant potential, and therapeutic efficacy in animal models of AD. METHODS: ER-NL-2 was formulated using the ultrasonic thin-film dispersion method and characterized via dynamic light scattering (DLS), zeta potential, and TEM. Acute oral toxicity was assessed in Wistar rats and Swiss mice (2000 mg/kg). Two AD models were employed: Streptozotocin (STZ)- induced in Swiss albino mice and AlCl₃-induced in Wistar albino rats. Behavioral studies included actophotometer and elevated plus maze tests. Antioxidant assays measured SOD, CAT, GSH, and LPO levels. Histopathological analysis of brain tissue was conducted. RESULTS: ER-NL-2 exhibited a mean droplet size of ~180 nm, PDI <0.3, and zeta potential of -27.9 mV. TEM confirmed spherical morphology. Toxicity studies showed no abnormalities. In both AD models, ER-NL-2 improved locomotor activity and reduced transfer latency. Biochemical analyses revealed elevated SOD, CAT, GSH and reduced LPO levels. Histopathology showed preserved neuronal integrity and reduced neurofibrillary tangles in treated groups. DISCUSSION: ER-NL-2 demonstrated neuroprotective efficacy through behavioral, biochemical, and histological endpoints, confirming its antioxidative mechanism and brain safety profile. It was comparable to standard therapy (donepezil). CONCLUSION: ER-NL-2 is a safe and promising nanocarrier for Alzheimer's treatment with significant neuroprotective and antioxidant properties. Further studies are warranted to explore its pharmacokinetics and clinical applicability.}, } @article {pmid40819956, year = {2025}, author = {Wang, J and Wang, ZY and Chen, SF and Wang, RZ and Chen, KL and Lu, JY and Xin, JW and Huang, YY and Wang, MY and Xie, F and Cheng, W and Yen, TC and Wischik, CM and Cui, M and Zuo, CT and Zhao, QH and Wang, YJ and Yu, JT}, title = {Role of [18]F-florzolotau PET in diagnostic and therapeutic decision-making for cognitive impairment.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70563}, pmid = {40819956}, issn = {1552-5279}, support = {2022ZD0211600//Science and Technology Innovation 2030 Major Projects/ ; 82371188//National Natural Science Foundation of China/ ; 2023YFC3605400//National Key Research and Development Program of China/ ; }, mesh = {Humans ; *Positron-Emission Tomography/methods ; Male ; Female ; *Cognitive Dysfunction/diagnostic imaging/therapy ; Aged ; Alzheimer Disease/diagnostic imaging ; Middle Aged ; *Carbolines ; Radiopharmaceuticals ; *Clinical Decision-Making ; *Tauopathies/diagnostic imaging ; Brain/diagnostic imaging ; Supranuclear Palsy, Progressive/diagnostic imaging ; Aged, 80 and over ; }, abstract = {INTRODUCTION: The novel positron emission tomography (PET) tracer, [18]F-florzolotau, enables in vivo visualization of tau pathology. METHODS: We evaluated the diagnostic performance of disease-specific spatial patterns of [18]F-florzolotau PET imaging by visual read for tauopathies and its added value in diagnostic and therapeutic decision-making in 1277 participants with cognitive complaints. RESULTS: The disease-specific spatial patterns of [18]F-florzolotau PET imaging demonstrated high diagnostic accuracy in differentiating various tauopathies, with 96.0% for Alzheimer's disease, 94.4% for frontotemporal lobe degeneration, 93.7% for progressive supranuclear palsy, and 97.5% for corticobasal degeneration. Added to a standard diagnostic workup, [18]F-florzolotau PET reading led to diagnostic revisions for 247 participants (19.3%), increased diagnostic confidence from 68.6% to 81.3%, and resulted in medication changes for 284 participants (22.2%). DISCUSSION: Our data advocate for the strategic implementation of [18]F-florzolotau PET in memory clinics, offering transformative potential for patient care and management. HIGHLIGHTS: [18]F-Florzolotau PET imaging presented disease-specific spatial patterns for different tauopathies. The disease-specific spatial patterns of [18]F-florzolotau positron emission tomography (PET) imaging exhibited high diagnostic accuracy in differentiating various tauopathies. Integration of [18]F-florzolotau PET imaging modality to a standard diagnostic workup significantly enhanced diagnostic confidence, enabled diagnostic revisions, and informed adjustments to treatment strategies.}, } @article {pmid40819191, year = {2025}, author = {Ismail, Z and Wilson, M and Khalifa, H and Belovich, D and Shaw, E and Pham, T and McMullen, S and Chen, Y and Sadman, N and Cai, J and Zulkernine, F and Barber, D}, title = {Diagnosis and Management of Alzheimer's Disease in Primary Care: A Real-World Study in Ontario, Canada.}, journal = {Journal of primary care & community health}, volume = {16}, number = {}, pages = {21501319251363156}, pmid = {40819191}, issn = {2150-1327}, mesh = {Humans ; *Alzheimer Disease/diagnosis/drug therapy/therapy ; Female ; *Primary Health Care ; Retrospective Studies ; Male ; Ontario ; Aged ; Aged, 80 and over ; *Practice Patterns, Physicians'/statistics & numerical data ; Cholinesterase Inhibitors/therapeutic use ; Middle Aged ; Electronic Health Records ; Antidepressive Agents/therapeutic use ; Antipsychotic Agents/therapeutic use ; }, abstract = {OBJECTIVE: To understand the real-world clinical practice patterns and variation in Alzheimer's disease (AD) diagnostic and screening tool utilization by primary care physicians (PCPs), including tools used for assessing dementia/AD severity and subsequent treatment patterns. METHODS: This retrospective observational study used de-identified primary care data from electronic medical records (EMR) data provided by the researchers from Queen's University, Ontario, Canada from August 2011 to August 2021. Individuals ≥50 years old with dementia or AD were identified using AD and dementia-related diagnostic codes, medications, and keywords searched using natural language processing (NLP) and Artificial Intelligence (AI) algorithms from EMR chart notes. Diagnostic and screening tools included scales, neuroimaging, and laboratory tests. Medications examined were cholinesterase inhibitors, memantine, antidepressants, and antipsychotics. RESULTS: The study cohort included 417 individuals with all-cause dementia (mean [standard deviation: SD] age: 78.86 [0.19] years), and 71 individuals with AD (mean [SD] age: 76.13 [1.07]). The most-used scale was the Montreal Cognitive Assessment (MoCA; dementia: 53.2%, AD: 84.5%). The mean [SD] frequency of MoCA administration doubled in the year following AD index date compared to the year prior (0.29 [0.82] to 0.67 [1.19] times per patient-year). Severity scores, often unspecified, suggested various stages of cognitive impairment. Among the medications examined, cholinesterase inhibitors were prescribed in 27.8% (n = 116) and 57.8% (n = 41) of people with dementia and AD, respectively. Antidepressants were the most frequently prescribed medication examined (dementia: 49.6%; AD: 71.8%). CONCLUSION: PCPs play an important role in the early detection and management of dementia/AD. As new biomarkers and therapies emerge for early AD, there is a need for connected health system data to guide PCPs through the early diagnostic process.}, } @article {pmid40818921, year = {2025}, author = {Moorthy, DK and Chinnasamy, P and Nagaraj, P}, title = {Optimization enabled ResNet features with transfer learning for Alzheimer's disease detection.}, journal = {Computational biology and chemistry}, volume = {119}, number = {}, pages = {108613}, doi = {10.1016/j.compbiolchem.2025.108613}, pmid = {40818921}, issn = {1476-928X}, mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; *Neural Networks, Computer ; Algorithms ; *Machine Learning ; }, abstract = {Millions of individuals worldwide suffer from Alzheimer's Disease (AD), a debilitating degenerative condition. Early detection of Alzheimer's disease is critical to ensure effective treatment and better patient outcomes. In the past few years, advanced medical imaging techniques, particularly MRI, have shown potential for diagnosing Alzheimer's disease. However, developing accurate and efficient techniques for Alzheimer's disease detection offcuts a demanding duty suitable to the complication of medical images and the limited availability of labelled data. The early detection of Alzheimer's disease is critical for effective treatment and management of this debilitating neurodegenerative condition. The research proposes a novel method for Alzheimer's disease detection using an optimization-enabled ResNet feature extraction technique with transfer learning that is proposed by combining LeNet and VGG networks. The pre-processing was done using image resizing and median filter and the featureextraction was conducted using the proposed Walrus Optimization Algorithm-Residual neural network (WOA-ResNet), where WOA is employed for training ResNet. The conducted experiments with the Alzheimer's dataset achieved a higher accuracy using the proposed LeNet-VGG method. The findings suggest that optimization-enabled ResNet feature extraction with LeNet-VGG networks can significantly improve the accuracy of Alzheimer's disease detection. The presented method achieved maximum accuracy value of 95.37 %, sensitivity value of 97.24 % and specificity value of 93.73 %.}, } @article {pmid40817880, year = {2025}, author = {da Silva, AWR and da Silva, LB and Rambo, DF and Biegelmeyer, R}, title = {Application of zebrafish (Danio rerio) as a model organism for central nervous system disorders screening of natural products.}, journal = {The Journal of pharmacy and pharmacology}, volume = {77}, number = {12}, pages = {1646-1662}, doi = {10.1093/jpp/rgaf067}, pmid = {40817880}, issn = {2042-7158}, support = {PIE0001/2024//Bahia State Research Support Foundation/ ; //National Council for Scientific and Technological Development/ ; //Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES)/ ; }, mesh = {Animals ; *Zebrafish ; *Biological Products/pharmacology/therapeutic use ; *Disease Models, Animal ; *Central Nervous System Diseases/drug therapy ; Humans ; Drug Evaluation, Preclinical/methods ; Neurodegenerative Diseases/drug therapy ; }, abstract = {OBJECTIVES: Natural products (NP) play a crucial role in the development of new compounds, due to their complex chemical structure and pharmacological diversity. Neurodegenerative diseases and other disorders in the central nervous system (CNS) have become a significant problem in the world due to the increase in life expectancy of the elderly population. This increases the risk of developing diseases, such as Parkinson's disease, Huntington's disease, Alzheimer's disease. Therefore, this exploratory review aims to show the applications of zebrafish for NP research and how they can be used in CNS's in vivo studies. METHODS: The present review covers the literature survey until 2023, including the descriptors for zebrafish, natural product and neurodegenerative diseases. The databases used were PubMed, Scopus, Cochrane and Lilacs. KEY FINDINGS: For the development of new medicines, an efficient animal model is required, and the zebrafish has stood out as a promising model due to its small size, low cost of maintenance, ease of handling, and transparency of embryos, which allows real-time observation of development and pathological processes. They possess conserved neurotransmission systems such as glutamatergic, cholinergic, dopaminergic, serotonergic, histaminergic, GABAergic, and purinergic pathways, making them especially relevant for modelling CNS disorders. From literature survey, flavonoids, alkaloids, and phenolic compounds were the most frequently studied, indicating that its influence the pathophysiological mechanisms associated with neurodegenerative diseases. CONCLUSIONS: This current review offers data for further research work with natural products aiming treatment for CNS disorders.}, } @article {pmid40817783, year = {2026}, author = {Torres, VO and Pizzo, ME and Chan, D and Dugas, JC and Huynh, D and Joy, D and Liang, EK and Sarrafha, L and Becerra, I and Chau, R and Chew, KS and Chow, J and Discenza, CB and Earr, TK and Furaso, L and Khoury, N and Lechtenberg, KJ and Leung, AW and Nguyen, HN and Ojo, ES and Roche, E and Simon, MJ and Solanoy, H and Tong, M and Tong, RK and Henne, K and Lewcock, JW and Watts, RJ and Calvert, ME and Thorne, RG and Zuchero, YJY}, title = {Transferrin receptor-mediated transport at the blood-brain barrier is elevated during early development and maintained across aging and in an Alzheimer's mouse model.}, journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}, volume = {46}, number = {1}, pages = {20-35}, pmid = {40817783}, issn = {1559-7016}, mesh = {Animals ; *Blood-Brain Barrier/metabolism ; *Receptors, Transferrin/metabolism ; *Alzheimer Disease/metabolism/pathology ; *Aging/metabolism ; Mice ; Disease Models, Animal ; Humans ; Mice, Transgenic ; Male ; Female ; Brain/metabolism ; Biological Transport ; }, abstract = {Transferrin receptor (TfR)-targeting of biologics has emerged as a promising strategy to improve drug delivery across the blood-brain barrier (BBB). However, most preclinical studies evaluating TfR-enabled drugs have been conducted in young adult animals. It remains unclear whether age and aging-related diseases impact TfR protein levels and/or BBB transport capacity. Here, we utilized a previously described TfR-targeting antibody transport vehicle (ATV[TfR]) to investigate how healthy aging and disease progression in the 5xFAD mouse model of Alzheimer's disease (AD) impact TfR protein and TfR-mediated brain delivery. ATV[TfR] transport capacity remained stable across 3- to 24-month-old healthy mice and 5xFAD progression did not impair ATV[TfR] brain transport up to 10.5 months, despite significant amyloid burden. Interestingly, neonates exhibited significantly elevated levels of vascular TfR protein and ATV[TfR] brain exposure compared to adult mice. Furthermore, vascular TfR in AD patient brains was similar to age-matched controls, suggesting conserved TfR transport is also likely in human AD. Overall, our data demonstrates broad functional utility for TfR-based brain delivery in both healthy aging and in an AD mouse model. Additionally, elevated TfR-mediated brain delivery during early mouse development highlights the potential of added efficacy in utilizing such platforms in disease treatment of infants and children.}, } @article {pmid40817729, year = {2025}, author = {Xia, S and He, C and Li, Y and Li, H and Wang, B and Xu, L and Zhao, X}, title = {Low-intensity transcranial ultrasound neuromodulation promotes neuronal regeneration: A new hope for noninvasive treatment of neurodegenerative diseases.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00113}, pmid = {40817729}, issn = {1673-5374}, abstract = {Neurodegenerative diseases, which are characterized by progressive neuronal loss and the lack of disease-modifying therapies, are becoming a major global health challenge. The existing neuromodulation techniques, such as deep brain stimulation and transcranial magnetic stimulation, show limitations such as invasiveness, restricted cortical targeting, and irreversible tissue effects. In this context, low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity. This review comprehensively assesses the therapeutic mechanisms, efficacy, and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases, with emphasis on its role in promoting neuronal regeneration, modulating neuroinflammation, and enhancing functional recovery. We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms, enhancing neural repair and regeneration, and alleviating symptoms associated with neurodegenerative diseases. Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors (e.g., brain-derived neurotrophic factor), promote autophagy to clear protein aggregates, modulate microglial activation, and temporarily open the blood-brain barrier to facilitate targeted drug delivery. Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-? plaques, improve motor and cognitive deficits, and promote remyelination in various disease models. Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer's disease and alleviate motor symptoms in Parkinson's disease, all while demonstrating a favorable safety profile. Past studies support the notion that by integrating safety, precision, and reversibility, low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease. However, more advancements are necessary for future clinical application of low-intensity transcranial ultrasound, including optimizing parameters such as frequency, intensity, and duty cycle; considering individual anatomical differences; and confirming long-term efficacy. We believe establishing standardized protocols, conducting larger trials, and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard. Future research should focus on translating preclinical findings into clinical practice, addressing technical challenges, and exploring combination therapies with pharmacological or gene interventions.}, } @article {pmid40817268, year = {2025}, author = {Ibrar, W and Khan, MA and Hamza, A and Rubab, S and Alqahtani, O and Alouane, MT and Teng, S and Nam, Y}, title = {A novel interpreted deep network for Alzheimer's disease prediction based on inverted self attention and vision transformer.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {29974}, pmid = {40817268}, issn = {2045-2322}, mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; *Deep Learning ; *Neural Networks, Computer ; Attention ; Aged ; }, abstract = {In the world, Alzheimer's disease (AD) is the utmost public reason for dementia. AD causes memory loss and disturbing mental function impairment in aging people. The loss of memory and disturbing mental function brings a significant load on patients as well as on society. So far, there is no actual treatment that can cure AD; however, early diagnosis can slow down this disease. Deep learning has shown substantial success in diagnosing AZ disease. However, challenges remain due to limited data, improper model selection, and extraction of irrelevant features. In this work, we proposed a fully automated framework based on the fusion of a vision transformer and a novel inverted residual bottleneck with self-attention (IRBwSA) for AD diagnosis. In the first step, data augmentation was performed to balance the selected dataset. After that, the vision model is designed and modified according to the dataset. Similarly, a new inverted bottleneck self-attention model is developed. The designed models are trained on the augmented dataset, and extracted features are fused using a novel search-based approach. Moreover, the designed models are interpreted using an explainable artificial intelligence technique named LIME. The fused features are finally classified using a shallow wide neural network and other classifiers. The experimental process was conducted on an augmented MRI dataset, and 96.1% accuracy and 96.05% precision rate were obtained. Comparison with a few recent techniques shows the proposed framework's better performance.}, } @article {pmid40816573, year = {2025}, author = {Škorić, I and Sviben, M and Mlakić, M and Čadež, T and Maček Hrvat, N and Kovarik, Z}, title = {Photochemistry-driven design of small molecule cholinesterase ligands.}, journal = {Chemico-biological interactions}, volume = {420}, number = {}, pages = {111703}, doi = {10.1016/j.cbi.2025.111703}, pmid = {40816573}, issn = {1872-7786}, mesh = {Ligands ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Humans ; Butyrylcholinesterase/metabolism/chemistry ; Acetylcholinesterase/metabolism/chemistry ; *Drug Design ; *Small Molecule Libraries/chemistry/pharmacology ; Animals ; *Cholinesterase Reactivators/chemistry/pharmacology ; Photochemical Processes ; }, abstract = {The development of small-molecule ligands targeting cholinesterases remains a central focus in neuropharmacology, particularly for the treatment of neurodegenerative disorders and organophosphate poisoning. This review highlights the rational design, synthesis, and biological profiling of diverse classes of heterocyclic compounds - including oxazoles, heterostilbenes, triazoles, and bicyclo[3.2.1]octane/octadiene derivatives - as reversible inhibitors and reactivators of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Novel amino-oxazolostilbenes and their photoproducts exhibited selective BChE inhibition, while naphtoxazole and triazole-containing scaffolds demonstrated promising dual-target or BChE-selective profiles. Several uncharged oximes, such as thienostilbene and heterostilbene oximes, showed potential for reactivating cyclosarin-inhibited BChE, supporting their further development as CNS-permeable antidotes. Additionally, resveratrol-based triazoles and carbamates revealed enhanced BChE inhibition, antioxidant activity, and favorable selectivity. Collectively, these findings underscore the therapeutic potential of structurally diverse cholinesterase ligands and provide a framework for the discovery of multifunctional agents for Alzheimer's disease and chemical threat countermeasures.}, } @article {pmid40816274, year = {2025}, author = {Zeng, PM and Sun, XY and Li, Y and Wu, WD and Huang, J and Cao, DD and Qian, PJ and Ju, XC and Luo, ZG}, title = {Thymosin beta 4 as an Alzheimer disease intervention target identified using human brain organoids.}, journal = {Stem cell reports}, volume = {20}, number = {9}, pages = {102601}, pmid = {40816274}, issn = {2213-6711}, mesh = {*Thymosin/metabolism/genetics/pharmacology ; *Organoids/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology/genetics/drug therapy ; Humans ; Animals ; Induced Pluripotent Stem Cells/metabolism/cytology ; *Brain/metabolism/pathology ; Mice ; Neurons/metabolism ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Neurogenesis ; Amyloid beta-Protein Precursor/genetics/metabolism ; }, abstract = {The developmental origin of Alzheimer disease (AD) has been proposed but is arguably debated. Here, we developed cerebral organoids from induced pluripotent stem cells (iPSCs) with mutations in amyloid precursor protein (APP) associated with familial AD (fAD) and analyzed the dynamic changes of cellular states. We found that mature neurons induced in fAD organoids markedly decreased compared to that of health control, accompanied with increased cell senescence and β-amyloid (Aβ) production. Interestingly, the expression level of the gene TMSB4X that encodes thymosin beta 4 (Tβ4) significantly decreased both in fAD organoids' neurons and AD patients' excitatory neurons. Remarkably, the neurodevelopmental deficits and Aβ formation in fAD organoids were rescued by treatment with Tβ4. The beneficial effects of Tβ4 were also revealed in 5xfAD model mice. Thus, this study has identified Tβ4 as a neuroprotective factor that may mitigate altered neurogenesis and AD pathology, highlighting a potential for disease intervention.}, } @article {pmid40815967, year = {2025}, author = {Scuteri, D and Adornetto, C and Greco, G and Nicotera, P and Bagetta, G and Corasaniti, MT}, title = {Pharmacoutilization data-driven artificial intelligence-assisted diagnosis algorithm to improve the pharmacological treatment of pain and agitation in patients suffering from severe dementia.}, journal = {Current opinion in pharmacology}, volume = {84}, number = {}, pages = {102563}, doi = {10.1016/j.coph.2025.102563}, pmid = {40815967}, issn = {1471-4973}, mesh = {Humans ; *Artificial Intelligence ; *Algorithms ; *Dementia/drug therapy/diagnosis ; Aged ; Aged, 80 and over ; *Pain/drug therapy/diagnosis ; *Psychomotor Agitation/drug therapy/diagnosis/etiology ; *Alzheimer Disease/diagnosis/drug therapy ; Retrospective Studies ; Male ; Antipsychotic Agents/therapeutic use ; Middle Aged ; Female ; }, abstract = {The number of diagnoses and drug prescriptions for dementia patients is poorly available. Delay in the diagnosis of Alzheimer's disease (AD), for which missed diagnoses amount to over half cases, and undertreatment of chronic and neuropathic pain mirroring excessive use of harmful antipsychotics and antidepressants is reported. Our study aimed at diagnosing AD through the most advanced artificial intelligence (AI) methodologies even in patients who escaped clinical observation. To this end, pharmacoepidemiology data collected as part of the first retrospective community study in a wide sample of 298,000 individuals, 84,235 aged over 60 years, were used to set up an AI algorithm for the rescue of missed diagnoses of AD. The core of the algorithm consisted in the management of time series represented by pharmacological therapies through a distance matrix and in the use of autoencoders. Patients without a diagnosis of AD based on pharmacotherapy were 114.920, while diagnosed patients were 1.150, mainly aged between 75 and 84 years, pointing at late start of treatment. Increased use of antidepressants, neuroleptics, and mood stabilizers is found in patients treated with acetylcholinesterase inhibitors (AChEIs) and memantine, while nonsteroidal anti-inflammatory drugs, paracetamol-codeine and opioids are mostly prescribed to patients not receiving AChEIs and memantine. The classification model demonstrated good global accuracy at the end of training, equal to 79.12%. Further studies and longitudinal monitoring of patients are needed to improve disease detection and management. The deep learning-based pharmacoutilization algorithm generated in the present study will aid the diagnosis of AD and the understanding of neuropsychiatric symptoms treatment.}, } @article {pmid40815522, year = {2025}, author = {Yun, H and Unruh, MA and Qian, Y and Zhang, Y and Jung, HY}, title = {Clinicians Who Practice Primarily in Nursing Homes and the Quality of Care for Residents With Alzheimer Disease and Related Dementias.}, journal = {JAMA health forum}, volume = {6}, number = {8}, pages = {e252465}, pmid = {40815522}, issn = {2689-0186}, mesh = {Humans ; Retrospective Studies ; Female ; Male ; *Nursing Homes/statistics & numerical data ; *Alzheimer Disease/therapy ; Aged ; United States ; *Quality of Health Care/statistics & numerical data ; Aged, 80 and over ; Medicare/statistics & numerical data ; *Dementia/therapy ; *Skilled Nursing Facilities/statistics & numerical data ; *Physicians/statistics & numerical data ; }, abstract = {IMPORTANCE: The number of physicians and advanced practitioners (APs) whose care is concentrated in nursing homes (often referred to as nursing home or skilled nursing facility specialists [SNFists]) has increased rapidly. Therefore, whether these clinicians provide better care is important. OBJECTIVE: To examine the association between SNFist care and outcomes of long-stay nursing home (NH) residents with Alzheimer disease and related dementias (ADRD). In this retrospective cohort study of 417 378 residents with ADRD in US NHs, claims for a 20% national sample of Medicare fee-for-service beneficiaries between 2013 and 2019 were analyzed. Adjusted estimates were based on a machine learning approach that incorporated a doubly robust procedure using a generalized estimating equation with inverse probability treatment weighting. Three secondary analyses were conducted: (1) stratified analyses for physicians and APs, (2) inclusion of physicians of any specialty and APs, and (3) use of proxy outcomes for in-place deaths. Data were analyzed from June 1, 2024, to May 3, 2025. INTERVENTION: Receipt of care from a SNFist; SNFists included generalist physicians and APs. MAIN OUTCOMES AND MEASURES: Hospitalizations and emergency department (ED) visits for ambulatory care-sensitive (ACS) conditions. Death without an ACS hospitalization and death without any hospitalization were used in secondary analyses. RESULTS: Of the total 417 378 residents, 242 540 received care from SNFists (mean [SD] age, 83.5 [8.7] years), and 174 838 never received care from SNFists (mean [SD] age, 84.8 [8.5] years). Compared with the residents who never received care from SNFists, the residents who received care from SNFists were more likely to be Black (12.6% vs 9.4%; P < .001), dually eligible (77.5% vs 73.1%; P < .001), and have more chronic conditions (eg, anemia, 60.9% vs 57.6%). Compared with non-SNFist clinicians, the SNFist clinicians were more likely to be female (physicians, 37.1% vs 23.3%; APs, 88.1% vs 85.1%), practice at more facilities (mean [SD] number of facilities, 9.4 [8.7] for SNFist physicians vs 6.4 [6.1] for non-SNFist physicians; 8.6 [8.1] for SNFist APs vs 7.1 [6.8] for non-SNFist APs), and less likely to practice in rural areas (physicians, 9.3% vs 25.4%; APs, 8.1% vs 20.2%). In adjusted analyses, receiving care from a SNFist vs non-SNFist was associated with 7% lower odds of an ACS hospitalization (odds ratio [OR], 0.93; 95% CI, 0.90-0.96) and 7% lower odds of an ACS ED visit (OR, 0.93; 95% CI, 0.90-0.96). In stratified analyses, receiving care from a SNFist physician vs a non-SNFist physician was associated with 13% lower odds (OR, 0.87; 95% CI, 0.83-0.90) of an ACS hospitalization and 7% lowers odds of an ACS ED visit (OR, 0.93, 95% CI, 0.88-0.97); comparisons of SNFist APs vs non-SNFist APs were not statistically significant. Estimates from the analysis including physicians of any specialty and APs were consistent with the primary results. SNFist care was associated with increased odds of in-place death. CONCLUSIONS AND RELEVANCE: Findings of this cohort study suggest that the use of SNFists by NHs may enhance the quality of care for residents with ADRD.}, } @article {pmid40814948, year = {2025}, author = {Bujalance-Fernández, J and Carro, E and Antequera, D and Jurado-Sánchez, B and Escarpa, A}, title = {ZIF-8 Microswimmers Self-Fast Dynamic Destruction in Microliter Volumes of Cerebrospinal Fluid Samples: Toward a Selective Assessment of Amyloidosis.}, journal = {Analytical chemistry}, volume = {97}, number = {33}, pages = {18282-18291}, pmid = {40814948}, issn = {1520-6882}, mesh = {*Amyloid beta-Peptides/cerebrospinal fluid ; Humans ; *Peptide Fragments/cerebrospinal fluid ; *Amyloidosis/cerebrospinal fluid/diagnosis ; *Zeolites/chemistry ; *Imidazoles/chemistry ; Alzheimer Disease/diagnosis/cerebrospinal fluid ; Fluorescent Dyes/chemistry ; Magnetite Nanoparticles/chemistry ; Quinine/chemistry ; Biomarkers/cerebrospinal fluid ; }, abstract = {Herein, we describe the synthesis of magnetic zeolitic imidazole framework (ZIF-8) microswimmers for detecting and quantifying the amyloid beta (Aβ1-42) peptide in cerebrospinal fluid (CSF) samples, which are used as a biomarker of amyloidosis for diagnosing Alzheimer's disease (AD). The microswimmers are prepared by external decoration of the ZIF-8 with magnetic Fe3O4 nanoparticles, followed by post internal encapsulation of quinine as fluorescent probe. The magnetic and surface properties of the microswimmers are fine-tuned to obtain tailored structures with an inner porous structure with the loaded fluorescent probe and outer magnetic engines. A macroporous structure was preferred over a microporous structure for quinine encapsulation, increasing the loading efficiency by about 50%, allowing also external decoration of the ferrite to impart the desired magnetic properties to the microswimmer. The principle for detection relies on the specific affinity of target sequence of amino acids in the Aβ1-42 peptide structure toward the Zn units in the ZIF-8, resulting in the self-destruction of the microswimmers and subsequent release of quinine in a concentration-dependent manner. The use of the bioreceptor-free magnetic assisted microswimmers allows for direct assessment of Aβ1-42 peptide in only 10 μL of CSF samples in just 10 min. Excellent analytical performance with a limit of detection of 40 pg/mL and a linear range ranging from 140 to 1200 pg/mL (r = 0.9990), covering the range in the clinical practice, is obtained. An excellent selectivity was also obtained toward the Aβ1-42 peptide which approaches an excellent assessment of amyloidosis in the human brain, as demonstrated by the good correlation obtained (r = 0.97) between the quantitative levels obtained in our microswimmers approach in comparison with the enzyme-linked immunosorbent assay method in diagnosed CSF samples from patients where Tau protein was also determined due to its coexistence with Aβ1-42 peptides. Since CSF biomarkers are currently the only clinically validated biofluid diagnostic test for AD, our approach will drastically reduce the volume required to determine Aβ levels, reducing the impact of the side effects of lumbar puncture in clinical practice. It became a novel bioreceptor-free approach to more easily, less invasively measure Aβ1-42 peptide in CSF, becoming a valuable tool for indirect amyloidosis prediction in brain tissues in the patient's lifetime, opening the possibility for early treatment of the AD.}, } @article {pmid40814010, year = {2025}, author = {Li, Z and Yang, J and Li, J and Zhao, S and Jiang, S and Liu, W and Li, X and Zhang, S and Du, H and Ni, J and Huang, Y and Qing, H and Ruan, S}, title = {Targeted delivery of BACE1 siRNA for synergistic treatment of Alzheimer's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {41}, pmid = {40814010}, issn = {2047-9158}, support = {82302387//Innovative Research Group Project of the National Natural Science Foundation of China/ ; L222128//Beijing Natural Science Foundation grant/ ; XSQD-202121010//Beijing Institute of Technology Research Fund Program for Young Scholars grant/ ; JCYJ20241202130511015//Fundamental Research Project funding from Shenzhen Science and Technology Innovation Committee/ ; JCYJ20230807142704008//Fundamental Research Project funding from Shenzhen Science and Technology Innovation Committee/ ; 2024KCXTD016//Alzheimer's Disease Pathogenesis and Drug Development Innovation Team, Innovation Team Project of Guangdong General Colleges and Universities (Natural Science)/ ; }, mesh = {*Amyloid Precursor Protein Secretases/genetics/metabolism ; *Alzheimer Disease/therapy/genetics/metabolism ; Animals ; *Aspartic Acid Endopeptidases/genetics/metabolism ; *RNA, Small Interfering/administration & dosage ; Mice ; Humans ; Blood-Brain Barrier/metabolism ; Mice, Transgenic ; Disease Models, Animal ; Mice, Inbred C57BL ; Microglia/metabolism ; Genetic Therapy/methods ; Brain/metabolism ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD. METHODS: We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1). RESULTS: PPR@siBACE1 crossed the blood-brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice. CONCLUSIONS: This study provides a reliable delivery platform for gene therapies for AD.}, } @article {pmid40812721, year = {2025}, author = {Barroso de Sousa, D and Zucato, MCR and Ribeiro, HM and Alexandre-Silva, V and Cominetti, MR}, title = {Interplay between depressive symptoms and Alzheimer's disease dementia: unraveling the potential roles of ADAM10 and Negr1.}, journal = {Neuroscience}, volume = {584}, number = {}, pages = {60-64}, doi = {10.1016/j.neuroscience.2025.08.012}, pmid = {40812721}, issn = {1873-7544}, mesh = {Humans ; *ADAM10 Protein/metabolism ; *Alzheimer Disease/metabolism ; *Amyloid Precursor Protein Secretases/metabolism ; *Depression/metabolism ; Animals ; Brain/metabolism ; Membrane Proteins ; }, abstract = {Late-onset depression (LOD) is closely linked to Alzheimer's disease (AD), marked by shared biological pathways and common risk factors. The neurobiological alterations associated with depression, particularly the dysregulation of amyloid-β (Aβ), play a critical role in the acceleration of disease progression. In individuals suffering from LOD, Aβ peptides - specifically Aβ40 and Aβ42 - exhibit distinct profiles in plasma, cerebrospinal fluid (CSF), and brain tissue, highlighting the substantial influence of AD pathology. Central to this relationship is A Disintegrin and Metalloprotease 10 (ADAM10), an essential α-secretase that exerts a protective effect by decreasing Aβ formation through the non-amyloidogenic processing of the amyloid precursor protein (APP). Furthermore, ADAM10 regulates the shedding of Neuronal Growth Regulator 1 (Negr1), a protein intricately linked to both LOD and AD, thereby enhancing synaptic plasticity and neuronal development - two critical processes in addressing these challenging disorders. Given the rapidly rising prevalence of both depression and dementia in aging populations, understanding these molecular interactions is more urgent than ever. Despite growing evidence, the interplay among LOD, AD, ADAM10, and Negr1 remains insufficiently explored, particularly in diverse populations. This review synthesizes recent advancements that illuminate the complex interactions among LOD, AD, and the regulatory function of ADAM10, particularly concerning one of its substrates, Negr1. By elucidating these fundamental interactions, the study paves the way for innovative treatment approaches aimed at both LOD and AD, advocating for a synergistic strategy to address these multifaceted conditions effectively, meeting a critical and time-sensitive challenge in global brain health.}, } @article {pmid40812585, year = {2025}, author = {Zhou, W and Yin, X and Huang, J and Fu, L and Yadav, H and Yao, W and Chu, D and Wu, F}, title = {Verapamil modulates astrocytic glycolytic dysfunction via TXNIP inhibition in the hippocampus of 3 × Tg-AD mice.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 2}, pages = {117233}, doi = {10.1016/j.bcp.2025.117233}, pmid = {40812585}, issn = {1873-2968}, mesh = {Female ; Animals ; Mice ; *Verapamil/pharmacology/therapeutic use ; *Calcium Channel Blockers/pharmacology/therapeutic use ; *Astrocytes/drug effects ; *Glycolysis/drug effects ; *Hippocampus/drug effects/metabolism ; Thioredoxins/antagonists & inhibitors ; *Cognitive Dysfunction/drug therapy ; Brain/drug effects/metabolism ; Carrier Proteins ; Glucose Transporter Type 1 ; }, abstract = {Alzheimer's disease (AD) is a gradually worsening neurodegenerative condition marked by the accumulation of amyloid-β plaques and a decline in cognitive abilities. Emerging research emphasizes astrocytic metabolic disturbances as contributors to AD development. This study investigates the therapeutic effects of Verapamil (VPM), a clinically approved calcium channel blocker, on astrocytic glycolysis in 3 × Tg-AD mice, focusing on the involvement of the thioredoxin-interacting protein (TXNIP)/glucose transporter 1 (GLUT1) pathway. VPM treatment significantly enhanced glycolytic activity in astrocytes, as evidenced by increased lactate production and improved metabolic function. Western blot and PCR analyses revealed a reduction in TXNIP levels and an upregulation of GLUT1 expression, particularly in the plasma membrane fraction, suggesting enhanced glucose uptake and glycolysis. Additionally, VPM treatment decreased soluble β-amyloid (Aβ) levels and alleviated cognitive impairments in the 3 × Tg-AD mice. These findings indicate that VPM restores glycolytic function in astrocytes through the TXNIP/GLUT1 pathway, offering a promising intervention targeting metabolic disruption and cognitive decline in AD. This study underscores the critical role of glycolysis in glial cells and highlights VPM's therapeutic potential in AD by targeting metabolic dysfunction.}, } @article {pmid40812500, year = {2025}, author = {Su, WS and Wu, MT and Cheng, IH and Yang, FY}, title = {Low-intensity pulsed ultrasound enhances microglial-mediated Aβ clearance and synaptic preservation in an APP transgenic mouse model of Alzheimer's disease.}, journal = {Experimental neurology}, volume = {394}, number = {}, pages = {115420}, doi = {10.1016/j.expneurol.2025.115420}, pmid = {40812500}, issn = {1090-2430}, mesh = {Animals ; *Alzheimer Disease/therapy/metabolism/genetics/pathology ; Mice, Transgenic ; *Microglia/metabolism/radiation effects ; Mice ; Amyloid beta-Protein Precursor/genetics/metabolism ; *Ultrasonic Waves ; Disease Models, Animal ; *Synapses/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; Humans ; Hippocampus/metabolism/pathology ; Male ; Maze Learning/physiology ; Plaque, Amyloid/pathology ; }, abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation and neurofibrillary tangles, leading to neuroinflammation, synaptic dysfunction, and cognitive decline. Despite extensive research, current therapies for AD show limited efficacy. Low-intensity pulsed ultrasound (LIPUS) has emerged as a promising non-invasive therapeutic approach due to its neuroprotective and immunomodulatory properties. This study investigates the effects of LIPUS on Aβ pathology, neuroinflammation, and cognitive deficits in a transgenic AD mouse model. Twelve-month-old J20 transgenic mice expressing human amyloid precursor protein (APP) were used to model middle-to-late-stage AD. LIPUS was administered for 30 days, targeting the bilateral hippocampus. Spatial memory was assessed via the Morris water maze (MWM). Aβ plaque burden and synaptic integrity were quantified using immunofluorescence and Thioflavin-S staining. Western blot analysis evaluated neurotrophic factors, inflammatory markers, and synaptic proteins (PSD95). LIPUS treatment significantly improved spatial learning and memory deficits in APP transgenic mice, as evidenced by reduced escape latency and increased platform crossings in the MWM test. LIPUS significantly reduced hippocampal amyloid plaque burden and promoted microglial recruitment to Aβ plaques. Importantly, LIPUS downregulated TNF-α expression without affecting IL-6 levels, suggesting enhanced Aβ clearance without inducing neuroinflammation. Furthermore, LIPUS increased synaptophysin expression in the CA3-mossy fiber and dentate gyrus (DG) regions, while PSD95 levels remained unchanged. Our findings demonstrate that LIPUS enhances microglial-mediated Aβ clearance, preserves synaptic integrity, and improves cognitive function in a transgenic AD model. As a non-invasive modality capable of targeting deep brain structures, LIPUS holds promise as a potential therapeutic strategy for AD.}, } @article {pmid40812427, year = {2025}, author = {Wu, J and Chai, K and Tu, Y and Fang, K and Shi, S and Hu, X and Liu, J and Yao, T}, title = {Multifunctional molecular agent for tau-targeted combinational therapy of Alzheimer's disease.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {9}, pages = {110583}, pmid = {40812427}, issn = {1083-351X}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; *tau Proteins/metabolism/chemistry/antagonists & inhibitors ; Humans ; Copper/metabolism/chemistry ; *Chelating Agents/pharmacology/chemistry/chemical synthesis ; Reactive Oxygen Species/metabolism ; }, abstract = {Tau aggregation inhibitors or neurotoxic-metal chelators have been extensively studied as potential treatment for Alzheimer's disease. However, it is a great challenge to improve their therapeutic effects while reducing neurotoxicity. Herein, we designed and synthesized two new compounds, (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis((3,4,5-trihydroxyphenyl)methanone) (4GA) and (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis((3,4,5-trihydroxyphenyl)methanone) (2GA). Each molecule is composed of a 1,4,7,10-tetraazacyclododecane (cyclen) core as the supramolecular chelator to copper ions, attached by 2 or 4GAllic acid polyphenol arms to capture tau peptide chain like a molecular hairpin. We interestingly found that 4GA and 2GA could inhibit self-aggregation through blocking the misfolding of tau peptide, suppress the promotion of Cu[2+] on tau aggregation by removing Cu[2+] from dyshomeostasis, and clear reactive oxygen species triggered by Cu[2+] using their reductive gallic acid groups. More significantly, the synthesized compounds exhibit remarkable efficiency on both in vitro and at cellular level. Our rational design of multifunctional therapeutic agent that simultaneously targets tau misfolding process, copper dyshomeostasis, and oxidative stress of reactive oxygen species, may hold considerable implications for the treatment of Alzheimer's disease.}, } @article {pmid40811673, year = {2025}, author = {Goodland, MN and Banerjee, S and Niehoff, ML and Young, BJ and Macarthur, H and Butler, AA and Morley, JE and Farr, SA}, title = {Cannabidiol improves learning and memory deficits and alleviates anxiety in 12-month-old SAMP8 mice.}, journal = {PloS one}, volume = {20}, number = {8}, pages = {e0296586}, pmid = {40811673}, issn = {1932-6203}, mesh = {Animals ; *Cannabidiol/pharmacology/therapeutic use/administration & dosage ; Mice ; *Anxiety/drug therapy ; *Memory Disorders/drug therapy ; Male ; Disease Models, Animal ; Maze Learning/drug effects ; Alzheimer Disease/drug therapy ; Memory/drug effects ; *Learning/drug effects ; }, abstract = {Cannabidiol (CBD) has gained a lot of interest in recent years for its purported medicinal properties. CBD has been investigated for the treatment of anxiety, depression, epilepsy, neuroinflammation, and pain. Recently there has been an interest in CBD as a possible treatment for age-related disorders such as Alzheimer's disease and related disorders (ADRD). Here we tested the hypothesis that chronic CBD administration would improve learning and memory in the SAMP8 mouse model of Alzheimer's disease. SAMP8 mice aged 11 months (at the start of the study) were administered vehicle or CBD (3 or 30 mg/Kg) daily via oral gavage for 2 months. Vehicle-treated young SAMP8 mice (age 3 months at the start of the study) served as unimpaired controls. After 30 days of treatment (4 and 12 months of age), learning and memory, activity, anxiety, strength and dexterity were assessed. High dose CBD treatment significantly improved learning and memory of the 12-month-old mice in the T maze. Novel object recognition memory was also improved by CBD in aged CBD treated mice. Aged CBD treated mice also displayed less anxiety in the elevated plus maze test compared to controls. However, activity and strength levels were similar between groups. Biochemical analysis revealed decreased markers of oxidative stress, providing a possible mechanism by which CBD treatment impacts learning, memory, and anxiety. These results highlight the potential use of CBD as a therapeutic for age related cognitive impairment and dementia.}, } @article {pmid40811499, year = {2025}, author = {Fernandez-Mendoza, J}, title = {Insomnia Phenotypes, Cardiovascular Risk and Their Link to Brain Health.}, journal = {Circulation research}, volume = {137}, number = {5}, pages = {727-745}, pmid = {40811499}, issn = {1524-4571}, support = {R01 HL136587/HL/NHLBI NIH HHS/United States ; R01 MH118308/MH/NIMH NIH HHS/United States ; R01 MH136472/MH/NIMH NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Sleep Initiation and Maintenance Disorders/epidemiology/physiopathology/therapy/diagnosis ; *Cardiovascular Diseases/epidemiology/physiopathology ; Phenotype ; *Brain/physiopathology ; Heart Disease Risk Factors ; Risk Factors ; Sleep ; }, abstract = {About 30% to 40% of the general population experiences insomnia symptoms of difficulty initiating or maintaining sleep, and another 10% to 15% of the general population experiences chronic insomnia disorder. The prevalence of insomnia is disproportionately higher in people with cardiometabolic risk factors, cardiovascular diseases, cerebrovascular diseases, and neurocognitive disorders, including vascular cognitive impairment. In fact, recent meta-analytic evidence from epidemiological studies has demonstrated that insomnia, especially when accompanied by objective short sleep duration, is a risk factor for incident hypertension, type 2 diabetes, heart failure, stroke, cognitive impairment, Alzheimer disease, and all-cause mortality. Insomnia should, thus, be part of the prevention and management of these adverse health outcomes. However, randomized clinical trials have not demonstrated whether treatment with cognitive-behavioral therapy for insomnia, the first-line guideline-recommended treatment, or hypnotics/sedatives improves heart- or brain-related outcomes. Studies have also failed to consider insomnia a heterogeneous disorder consisting of distinct phenotypes that result from the relative contribution of biological versus cognitive-behavioral perpetuating factors. Objective short sleep duration has emerged as a marker of physiological hyperarousal in insomnia (ie, dysregulation of the hypothalamic-pituitary axis, increased sympathetic nervous system activation, and increased inflammation), as a predictor of insomnia-related adverse heart and brain health outcomes and, potentially, poor response to cognitive-behavioral therapy for insomnia. This review summarizes the meta-analytic evidence on the association of insomnia with cardiometabolic risk factors, cardiovascular diseases, cerebrovascular diseases, and neurocognitive disorders, including current knowledge on the heterogeneity of the disorder. This review also summarizes the potential pathophysiologic mechanisms that lead to heart and brain morbidity, which vary across insomnia phenotypes based on objective sleep duration. This review suggests that basic and clinical sciences need to unveil the molecular, cellular, and behavioral mechanisms at play across insomnia phenotypes, as the public health and clinical implications of their association with adverse heart and brain health are demanding immediate attention.}, } @article {pmid40810748, year = {2025}, author = {Nabizadeh, A and Rafati, A and Karbalaei, N and Namavar, MR and Hosseinzadeh, S and Moatamed Jahromi, H and Rahimi, A and Naseh, M}, title = {Probiotic effects on cognitive performance, hippocampal oxidative stress, and structural damage induced by icv STZ in Alzheimer-like rat model.}, journal = {Brain structure & function}, volume = {230}, number = {7}, pages = {135}, pmid = {40810748}, issn = {1863-2661}, mesh = {Animals ; *Probiotics/pharmacology ; *Oxidative Stress/drug effects/physiology ; *Hippocampus/drug effects/pathology/metabolism ; Male ; Rats, Sprague-Dawley ; *Alzheimer Disease/chemically induced/pathology/metabolism/drug therapy ; Streptozocin/administration & dosage ; Rats ; Disease Models, Animal ; *Cognition/drug effects ; Lactobacillus acidophilus ; Maze Learning/drug effects ; Limosilactobacillus reuteri ; }, abstract = {Alzheimer's disease (AD) is a deteriorating neurodegenerative disorder defined by cognitive decline and neuronal damage, with oxidative stress and neuroinflammation as central pathological features. Emerging evidence suggests the gut-brain axis is a key modulator in neurodegeneration, highlighting probiotics' potential in mitigating AD progression. This study investigates the effects of Lactobacillus acidophilus ATCC4356, Lactobacillus reuteri DSM 17938, and their combination on cognitive performance, oxidative stress, and hippocampal structure in a streptozotocin (STZ)-induced AD-like rat model. Thirty-Five male Sprague-Dawley rats were randomly assigned to five groups: Sham, AD-like model (STZ), STZ + Ac, STZ + Re, and STZ + Comb. The AD-like model was induced via intracerebroventricular (icv) injection of STZ. Probiotics were administered by gavage for 35 days. Behavioral assessments, including the open field test and Morris water maze, were conducted to evaluate cognitive and anxiety-like behaviors. Hippocampal oxidative stress markers, including malondialdehyde (MDA), glutathione, superoxide dismutase, and catalase , were analyzed biochemically. Additionally, stereological techniques were used to assess hippocampal volume and cellular densities. Behavioral results demonstrated significant improvement in anxiety-like behavior and spatial memory in probiotic-treated groups compared to the STZ group. Biochemical analysis revealed reduced MDA levels and enhanced antioxidant markers following probiotic intervention. Histological and stereological analyses indicated increased neuronal density and reduced glial cell activation in hippocampal subregions (CA1, CA3, DG), though hippocampal volume loss remained unaltered. These findings underscore the neuroprotective potential of probiotics in alleviating AD-related neurodegeneration, possibly through antioxidative and anti-inflammatory mechanisms. Further pre-clinical studies are warranted to optimize probiotic regimens for AD prevention and treatment.}, } @article {pmid40810239, year = {2025}, author = {Jinglei, J and Tao, YU and Yulin, Q and Meng, W}, title = {Understanding the role of microglia in Alzheimer's disease: insights into mechanisms, acupuncture, and potential therapeutic targets.}, journal = {Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan}, volume = {45}, number = {4}, pages = {922-936}, pmid = {40810239}, issn = {2589-451X}, mesh = {Humans ; *Alzheimer Disease/therapy/immunology/genetics/metabolism ; *Microglia/immunology/metabolism ; *Acupuncture Therapy ; Animals ; Amyloid beta-Peptides/metabolism/genetics/immunology ; }, abstract = {Microglia (MG) are immune effector cells in the central nervous system (CNS) and play a pivotal role in the pathogenesis of various CNS diseases. Alzheimer's disease (AD) is defined as a severe chronic degenerative neurological disease in humans. The amyloid cascade hypothesis is a hypothesis on the pathogenesis of AD that suggests that abnormal extracellular aggregation of β-amyloid (Aβ) peptides is the main cause of the disease. Although this hypothesis has been found to be convincing, a growing body of evidence suggests that it does not fully explain the pathogenesis of AD. Neuroinflammation is a crucial element in the pathogenesis of AD, as evidenced by elevated levels of inflammatory markers and the identification of AD risk genes associated with innate immune function. This paper will first summarize the impact of microglia-mediated neuroinflammation on AD, exploring the phenotypic changes that follow microglia activation. Secondly, the interactions between microglia, Aβ, microtubule-associated protein, apolipoprotein E and neurons are thoroughly investigated, with particular focus on the interactive mechanisms. Furthermore, the recent progress and prospects of microglia as a diagnostic and therapeutic target for AD are analysed. A review of the literature on the mechanisms regulating MG for AD at home and abroad revealed that acupuncture modulation of microglia could help to delay the progression of AD. This was followed by an extensive discussion of the clinical possibilities and scientific validity of acupuncture treatment for AD, with the aim of providing new insights for acupuncture modulation of MG targeting for the treatment of AD.}, } @article {pmid40810165, year = {2025}, author = {Jeon, MT and Sung, B and Lee, JW and Hwang, DW and Lee, E and Kim, HK and Kim, DK and Kim, DG and Chang, Y}, title = {Therapeutic Potential of a Gadolinium Chelate Complex Conjugated with Vanillic Acid for Alzheimer's Disease.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {8}, pages = {2725-2735}, pmid = {40810165}, issn = {2575-9108}, abstract = {Magnetic resonance imaging (MRI) is a widely used diagnostic tool for neurodegenerative diseases, including Alzheimer's disease. A gadolinium chelate conjugated with vanillic acid (Gd-DO3A-Va) serves as a contrast agent that specifically targets activated microglia in the brains of Alzheimer's disease animal models, such as the 5XFAD mouse. In this study, we evaluated the therapeutic potential of Gd-DO3A-Va in this model. The 5XFAD mouse exhibits neuroinflammation, characterized by activation of the c-Jun N-terminal kinase signaling pathway, inflammasome activation, and increased amyloid-β (Aβ) production(?)all of which are pathological features of Alzheimer's disease. Treatment with Gd-DO3A-Va reduced inflammatory responses and Aβ deposits. Additionally, the peri-plaque dendritic loss observed in the brains of 5XFAD mice was attenuated following Gd-DO3A-Va treatment. Moreover, Gd-DO3A-Va treatment prevented memory loss, as indicated by the Y-maze test. Taken together, these findings suggest that Gd-DO3A-Va, an MR contrast agent that provides disease-specific signal enhancement in the brains of animal models of Alzheimer's disease, shows promising therapeutic potential for preventing disease progression by suppressing inflammation and inhibiting Aβ production. Therefore, Gd-DO3A-Va could serve as a theranostic agent for Alzheimer's disease.}, } @article {pmid40810164, year = {2025}, author = {Alo, B and Lamers, C}, title = {Crossing Barriers: Advancements in Macromolecular Therapeutics for Neurodegenerative Diseases and Strategies to Overcome the Blood-Brain Barrier.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {8}, pages = {2353-2383}, pmid = {40810164}, issn = {2575-9108}, abstract = {Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, present considerable challenges for our societies and health systems due to their progressive nature, the demographic shift toward older populations, and limited treatment options. Recent advances in macromolecular therapeutics, including antibodies, peptides, and proteins, offer novel therapeutic modalities for a broad range of diseases. Their high potency and specificity hold promise for disease-modifying therapies to combat neurodegenerative diseases. However, the blood-brain barrier poses a significant challenge for the effective delivery of these large molecules to the central nervous system. This review discusses the physiological role of the blood-brain barrier and its influence on restricting the exposure of macromolecules in the brain. Furthermore, emerging strategies for enhancing blood-brain barrier permeability to macromolecules are highlighted. This review summarizes modifications designed to utilize receptor-mediated uptake, adsorptive-mediated transcytosis, carrier-mediated transport, and nanoparticle-based delivery systems to overcome the blood-brain barrier. Additionally, we emphasize the importance of testing macromolecular therapeutics for their blood-brain barrier permeability and review the methods for such in vitro and in vivo testing. Finally, we shed light on therapeutics in preclinical and clinical development for neurodegenerative diseases and their challenges.}, } @article {pmid40810098, year = {2025}, author = {Cao, H and Zhong, J and Chen, L}, title = {Alterations of the oral microbiota in mild Alzheimer's disease and the appropriate application of chlorhexidine gluconate.}, journal = {JAR life}, volume = {14}, number = {}, pages = {100024}, pmid = {40810098}, issn = {2534-773X}, abstract = {OBJECTIVE: This study investigated the effect of 0.2 % chlorhexidine gluconate on oral microbiota dysbiosis in Alzheimer's disease (AD) and explored potential links between oral microbiota and cognition, offering new insights into its role in AD treatment. STUDY DESIGN: We assessed the impact of 0.2 % chlorhexidine gluconate on the oral microbiota of patients with AD. One hundred patients were divided into two groups based on oral health score (using a cut-off of 8). Subgingival plaque samples were analyzed using 16S rRNA sequencing; no significant differences in bacterial composition were observed between groups at baseline. RESULTS: Poor oral health correlated with higher oral health scores (P = 0.000), fewer teeth (P = 0.002), lower cognitive levels (P = 0.048), and a higher proportion of patients with diabetes (P = 0.032). After 24 weeks of treatment with 0.2 % chlorhexidine gluconate in a randomized controlled trial, subgingival plaques from 66 patients showed changes in Porphyromonas, Filifactor, Desulfobulbus, Anaeroglobus, Pyramidobacter, Mycoplasma, Dialister, Fretibacterium, and Tannerella (P < 0.05). Treponema and Porphyromonas gingivalis were identified as potential interventional targets. CONCLUSION: Chlorhexidine gluconate effectively alters oral flora, reducing harmful bacteria. Targeting specific microbiota disturbances may offer a promising strategy to delay AD onset or slow its progression. TRIAL REGISTRATION: This research was registered with the Chinese Clinical Trial Registry (ChiCTR; Reference: ChiCTR2000032876). Registered: 14th of May 2020; http://www.chictr.org.cn/showprojen.aspx?proj=53555.}, } @article {pmid40809903, year = {2025}, author = {Koch, G and Assogna, M and Gadola, Y and Alberici, A and Di Lorenzo, F and Bonnì, S and Borghi, I and Cerulli Irelli, E and Mencarelli, L and Maiella, M and Esposito, R and Casula, EP and Pezzopane, V and D'Acunto, A and Candeo, F and Ferraresi, M and Guerrera, G and Battistini, L and Premi, E and Bracca, V and Lucchini, S and Bertagna, F and Romano, P and Ludovici, A and Daniele, A and Motta, C and Ferrari, C and Martorana, A and Borroni, B}, title = {Safety and efficacy of rotigotine in patients with frontotemporal dementia: a phase 2, double-blind, randomized, placebo-controlled, multicenter trial.}, journal = {The Lancet regional health. Europe}, volume = {57}, number = {}, pages = {101409}, pmid = {40809903}, issn = {2666-7762}, abstract = {BACKGROUND: Frontotemporal dementia (FTD) is a common form of dementia with no approved pharmacological treatment. Clinical and experimental evidence suggest that dopaminergic transmission is impaired in FTD. Here we aimed at investigating the clinical impact of treatment with dopaminergic agonists in FTD. METHODS: This was a phase IIa 24-week randomized, double-blind, multicenter, placebo-controlled study, conducted in Italy from June 16th 2021 to April 30th 2023. Patients with a diagnosis of probable behavioral variant FTD (bvFTD) were randomly assigned in a 1:1:1 ratio to receive rotigotine transdermal patches at 4 mg/24 h, rotigotine transdermal patches at 6 mg/24 h, or placebo transdermal patches for 24 weeks. Randomization was centralized and performed using a double-blind covariate-adaptive scheme. The primary outcome was analyzed in the intention-to treat (ITT) population. The primary efficacy outcome measure was the change at 24-weeks from baseline in the Frontal Assessment Battery (FAB). The trial is completed and was registered on the clinicaltrial.gov website (NCT04937452). FINDINGS: A total of 128 patients were screened, of which 75 were randomized. 25 patients were randomized to receive Rotigotine 4 mg, 26 patients to Rotigotine 6 mg, and 24 patients to placebo. The mean age of patients was 66.5 ± 8 of which 31 (41%) were female. A total of 69 patients (92%) completed the study. The estimated mean change from baseline at 24 weeks in the FAB score in the ITT population was 0.18 (95% confidence interval [CI] -0.79 to 1.15) in the rotigotine 4 mg group, 0.89 (95% CI -0.09 to 1.88) in the rotigotine 6 mg group and 1.08 (95% CI 0.19-1.98) in the placebo group (rotigotine 4 mg vs placebo, -0.90; 95% CI -2.22 to 0.42; p = 0.18; rotigotine 6 mg vs placebo, -0.19; 95% CI -1.52 to 1.14; p = 0.77). No significant effect was found on secondary outcome measures. Adverse events were mild in all groups and more common in the rotigotine (4 mg: 4/25; 6 mg: 3/26) than in the placebo (1/24) group. INTERPRETATION: Rotigotine administration may not be a viable therapeutic option for enhancing frontal function, slowing disease progression, mitigating functional decline or ameliorating behavioral disturbances in bvFTD patients. The current findings provide data in a large sample of bvFTD that might be useful for the design of future clinical trials. FUNDING: This trial was funded by a joint grant from the Alzheimer Drug Discovery Foundation (ADDF) and the Association for Frontotemporal Degeneration (AFTD) grant to GK and BB (GFTD-201902-2017958).}, } @article {pmid40808707, year = {2025}, author = {Aydın, B and Aydın, AS and Çeçen, Ö and Yuca, H and Bona, GE and Demirci, B and Bona, M and Karakaya, S}, title = {From Herbal Tea to Science: Phytochemical and Biological Investigation of Ajuga chamaepitys subsp. chia (Lamiaceae) With Molecular Docking Analysis.}, journal = {Food science & nutrition}, volume = {13}, number = {8}, pages = {e70749}, pmid = {40808707}, issn = {2048-7177}, abstract = {The hypothesis that insulin resistance and impaired insulin-like growth factor signaling contribute to Alzheimer's disease (AD) has led to the designation of AD as "type 3 diabetes." Ajuga chamaepitys subsp. chia is traditionally used in Türkiye as an analgesic, tonic, and for the external treatment of hemorrhoids and wound healing. This study evaluates antioxidant, antidiabetic, and anticholinesterase activities of methanolic, aqueous extracts, and essential oils from the flowering aerial parts of A. chamaepitys subsp. chia, along with their phytochemical profiles (GC-MS/MS), morphological-anatomical characteristics, and molecular docking analysis. The essential oil yield was 0.002%, comprising 45 compounds (92.5%), with β-pinene (19.8%), α-pinene (12.8%), and germacrene D (10.0%) as major constituents, dominated by monoterpene (39.8%) and sesquiterpene hydrocarbons (23.5%). The methanolic extract exhibited moderate bioactivity, achieving 28.36% α-amylase inhibition at 5000 μg/mL and 21.85% acetylcholinesterase inhibition at 100 μg/mL, while also demonstrating notable antioxidant activity with 23.013% ABTS[•+] and 8.114% DPPH[•] scavenging. It showed the highest total phenolic (14.261 μg GAE/mg) and tannin content (34.444 μg TAE/mg) among the tested extracts. Morphologically, the plant features hairy stems and tripartite leaves with a cuticle, trichomes, and diacytic stomata, while anatomically, it presents collenchyma, starch-filled parenchyma, and a distinct cambium in the stem. Molecular docking studies revealed that germacrene D exhibited strong binding affinities to acetylcholinesterase, butyrylcholinesterase, α-amylase, and α-glucosidase, suggesting multitarget inhibition potential. These findings support the traditional use of A. chamaepitys subsp. chia and highlight its promise as a natural source for therapeutic agents targeting oxidative stress, diabetes, and neurodegenerative diseases.}, } @article {pmid40808471, year = {2025}, author = {Zhang, L and Cai, L and Lin, H and Wu, W and Zhu, Y and Cai, J and Hu, C and Lin, X and Sun, H and Wei, X}, title = {Two Birds With One Stone: The Protective Role of the Antidiabetic Drug Sodium-Glucose Cotransporter-2 Inhibitor in Neurodegenerative Diseases.}, journal = {The European journal of neuroscience}, volume = {62}, number = {3}, pages = {e70221}, doi = {10.1111/ejn.70221}, pmid = {40808471}, issn = {1460-9568}, support = {2021J01397//Natural Science Foundation of Fujian, China/ ; 2022GGA010//Fujian Provincial Health Technology Project/ ; 2023Y9347//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; 2023Y9298//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; 2023Y9343//Fujian Provincial Joint Funding Project of Scientific and Technological Innovation/ ; }, mesh = {Humans ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; *Neurodegenerative Diseases/genetics/drug therapy ; Polymorphism, Single Nucleotide ; Sodium-Glucose Transporter 2/genetics ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Hypoglycemic Agents/therapeutic use/pharmacology ; Mendelian Randomization Analysis ; Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Parkinson Disease/genetics ; Genome-Wide Association Study ; Protein Interaction Maps ; }, abstract = {The neuroprotective role of sodium-glucose cotransporter-2 inhibitor (SGLT2i) has attracted considerable interest. The purpose of this study was to investigate the role of SGLT2i in several common neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Utilizing drug-target Mendelian randomization (MR) and colocalization, we used single nucleotide polymorphisms (SNPs) proximal to the SLC5A2 gene to analyze the influence of SGLT2i on AD, PD, ALS, and MS. Sensitivity analyses were performed to assess heterogeneity and pleiotropy. Phenome-wide association study (PheWAS) was used to probe the relationship of SGLT2i with other characteristics. Protein-protein interaction (PPI) networks were used to explore how SLC5A2 affects other proteins, and enrichment analysis was used to explore possible biological processes. The MR analysis showed that SGLT2i was negatively associated with AD (OR = 0.77, p = 0.01), PD (OR = 0.52, p = 0.04), ALS (OR = 0.60, p = 0.01), and MS (OR = 0.33, p = 0.027), indicating that SGLT2i could reduce the risk of AD by 23%, PD by 48%, ALS by 40%, and MS by 67%. The colocalization supported this conclusion. The PheWAS showed that SGLT2i was associated with body mass index and systolic blood pressure. SGLT2i is biologically closely related to the development of NDs. This study suggested that SGLT2i was able to reduce the risk of NDs. SGLT2i may perform this process through many mechanisms. This study provides a new perspective on the treatment of NDs; clinical trials and relevant experiments are necessary to further validate the neuroprotective effects of SGLT2i.}, } @article {pmid40808466, year = {2025}, author = {Martinez, B and Peplow, PV}, title = {Amelioration of behavioral and neural deficits in animal models of neurodegenerative disease by nanoformulations of curcumin and quercetin.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00343}, pmid = {40808466}, issn = {1673-5374}, abstract = {Neurodegenerative diseases are increasing in prevalence due largely to aging populations worldwide and improved medical care for the elderly. Currently approved drugs can reduce some of the symptoms of neurodegenerative diseases but cannot cure them. Inflammation is involved in the development and progression of neurodegenerative diseases, and oxidative stress is implicated in neurodegeneration associated with cognitive decline and age-related cognitive impairment. Polyphenols such as curcumin, quercetin, and resveratrol possess potent anti-inflammatory and antioxidant properties. Nanoformulations of curcumin and quercetin can optimize their pharmacological effects in the treatment of neurodegenerative diseases. Nanocarriers play a crucial role in delivering drugs across the blood-brain barrier, thereby lowering the risk of peripheral side effects. Various nanoforms have been developed to induce bioavailability and solubility of curcumin and quercetin, including nanoparticles and nanoemulsions. The studies reviewed included 17 using curcumin nanoformulations and seven with quercetin nanoformulations and were tested in widely used animal models of Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Many of the curcumin and quercetin nanoformulations brought about improvements in learning and memory in behavioral tests of Alzheimer's disease models and were effective in reducing oxidative stress in the brain. Both nanocurcumin and nanoquercetin decreased the levels of inflammatory markers in the brain. Nanocurcumin formulations improved motor behavior, gait, and memory in Parkinson's disease models and increased dopaminergic neurons in the striatum and substantia nigra. Furthermore, nanocurcumin improved locomotor activity, memory, and learning, and the number of dendrites of medium spiny neurons in Huntington's disease models. Nanocurcumin formulations decreased oxidative stress and inflammation in a model of demyelination. Several important limitations were identified in the studies reviewed and these need to be considered in future studies. Also, clinical trials could be performed using the currently available nanoforms of curcumin and quercetin.}, } @article {pmid40808416, year = {2025}, author = {Figueiredo-Pereira, ME and Serrano, PA and Rockwell, P}, title = {Six promising drug repurposing candidates for Alzheimer's disease and their sex-specific mechanisms and efficacy.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00256}, pmid = {40808416}, issn = {1673-5374}, abstract = {Alzheimer's disease is a neurodegenerative disorder that leads to progressive memory loss, cognitive decline, and behavioral changes. Despite ongoing research, its exact causes and effective treatments remain elusive. Traditional approaches have focused on symptom management, but breakthroughs in bioinformatics and high-throughput drug screening are offering new pathways to potential therapies. This review highlights our recent efforts to identify novel drug candidates for Alzheimer's disease by leveraging computational methods and large-scale biological datasets. Our work introduces two key innovations in Alzheimer's disease research: addressing sex-specific differences and leveraging drug repurposing for accelerated treatment discovery. By combining sex-stratified preclinical data with machine learning and in vivo validation, we improve translational relevance and support precision medicine. Using the TgF344-AD rat model, which mimics human Alzheimer's disease spatial memory deficits and pathology, we explored the efficacy of various US Food and Drug Administration- approved and investigational drugs. These included ibudilast, timapiprant, RG2833, diazoxide/ dibenzoylmethane (combined), and BT-11, which targeted key Alzheimer's disease-related molecular pathways such as amyloid-beta plaques, Tau tangles, and neuroinflammation. These drugs, at various stages of development, offer hope for not only managing symptoms but also addressing the underlying mechanisms of Alzheimer's disease. This review underscores the need for a multifaceted approach to Alzheimer's disease treatment, combining symptom relief with disease modification.}, } @article {pmid40808358, year = {2025}, author = {Shelton, M and Kerns, KA and Shirali, S and Castora, FJ and Coleman, RA}, title = {Integrating mitochondrial gene expression data to model the effects of respirasome supercomplex formation on reactive oxygen species production in Alzheimer's disease models.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {734-742}, doi = {10.1177/13872877251362889}, pmid = {40808358}, issn = {1875-8908}, mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; Humans ; *Mitochondria/metabolism/genetics ; *Reactive Oxygen Species/metabolism ; Oxidative Stress/physiology ; Brain/metabolism ; *Genes, Mitochondrial ; Gene Expression ; }, abstract = {BackgroundIn the past decade, Alzheimer's disease (AD) researchers have found that the formation of amyloid aggregates occurs after dysregulation of respiratory chain activity.ObjectiveUsing our developing mathematical model to identify potential therapeutic targets for AD treatment.MethodsWe have constructed a mathematical model for AD that incorporates enzyme activities and kinetics, and protein and mRNA expression levels.ResultsOur analyses of gene expression in AD brains provide complimentary evidence that changes in mitochondrial energy production and biogenesis accompany AD pathogenesis. Using this data, we created a mitochondrial model of electron transport chain supercomplex assembly.ConclusionsBy carrying out sensitivity analyses of responses to oxidative stress and effects of gene expression on energy production, we demonstrate how oxidative stress and energy deficits change the initial antioxidant defense system and impact the progression of AD. We investigated the impact of gene expression changes in 9 genes as new therapeutic options via metabolic flux analysis of supercomplex assembly. Through careful analysis, we propose that UQCRC1 may be an effective therapy option for in vitro AD treatment testing.}, } @article {pmid40808348, year = {2025}, author = {Bhushan, B and Singh, NK and Singh, R}, title = {An Overview of Neuroprotective Effects of Erythropoietin Against Neurological Disorders: Beyond Erythropoiesis.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {9}, pages = {e70442}, doi = {10.1002/jbt.70442}, pmid = {40808348}, issn = {1099-0461}, support = {//The authors received no specific funding for this work./ ; }, mesh = {Humans ; *Erythropoietin/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Erythropoiesis/drug effects ; *Nervous System Diseases/drug therapy/metabolism/pathology ; }, abstract = {Brain related disorders are a set of medical ailments that cause motor incoordination, cognitive and memory problems due to neurodegeneration in the brain. Although current therapies alleviate symptoms, they fail to target the fundamental pathological processes driving the disorders. A hematopoietic growth factor, Erythropoietin, stimulates erythroid cell formation and is therapeutically applied for the treatment of anemia. Furthermore, Erythropoietin has shown improved neurological outcomes in preclinical models and is being investigated as a potential therapeutic agent for neurodegenerative disorders. Erythropoietin is potential target for the regulation of numerous cellular signal pathways to enhance the neuronal survival, promote neuronal differentiation via binding of Erythropoietin-to-Erythropoietin receptor to stimulate the protein Janus-tyrosine kinase 2 followed by regulation of protein kinase B, signal transducer and stimulators of transcription 5, protein tyrosine phosphatases, mitogen-activated protein kinases, nuclear factor kB and Wnt1. Numerous research studies have evaluated the therapeutic potential of Erythropoietin against several neurological disorders including Alzheimer's disease, Parkinson's disease, neuroinflammation and epilepsy and highlight that Erythropoietin exhibits significant neuroprotective effects by counteracting apoptosis, neuroinflammatory process, reactive oxygen species overburden and neuronal death, consequently, prevent the progression of such diseases. However, two major challenges in developing erythropoietin as a neuroprotective agent include optimizing its therapeutic window and addressing safety concerns, particularly its adverse interaction with tissue plasminogen activator, which has been shown to increase the risk of hemorrhagic complications in ischemic stroke patients. In present review, we discuss the neurotherapeutic applications of Erythropoietin against brain related disorders beyond erythropoiesis. In conclusion, it can be assumed that Erythropoietin could be an alternative therapeutic option for the management of neurological disorders.}, } @article {pmid40807333, year = {2025}, author = {Godela, A and Rogacz, D and Pawłowska, B and Biczak, R}, title = {Natural Neuroinflammatory Modulators: Therapeutic Potential of Fungi-Derived Compounds in Selected Neurodegenerative Diseases.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {15}, pages = {}, pmid = {40807333}, issn = {1420-3049}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy ; *Fungi/chemistry ; *Biological Products/therapeutic use/pharmacology/chemistry ; Animals ; }, abstract = {Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis remain incurable. Current therapeutic strategies primarily focus on slowing disease progression, alleviating symptoms, and improving patients' quality of life, including the management of comorbid conditions. Over the past few decades, the incidence of diagnosed neurodegenerative disorders has risen significantly. As the number of affected individuals continues to grow, so does the urgent need for effective treatments that can halt or mitigate the progression of these diseases. Among the most promising therapeutic resources are bioactive compounds derived from fungi. The high quality of proteins, polysaccharides, unsaturated fatty acids, triterpenoids, sterols, and secondary metabolites found in fungi have attracted growing interest from researchers across multiple disciplines. One intensively studied direction involves the use of naturally occurring fungi-derived nutraceuticals in the treatment of various diseases, including neurodegenerative conditions. This article provides an overview of recent findings on fungal compounds-such as phenolic compounds, carbohydrates, peptides and proteins, and lipids-that may have potential applications in the treatment of neurodegenerative diseases and the alleviation of their symptoms.}, } @article {pmid40807232, year = {2025}, author = {Chávez-Castillo, M and Gotera, MP and Duran, P and Díaz, MP and Nava, M and Cano, C and Díaz-Camargo, E and Cano, G and Cano, R and Rivera-Porras, D and Bermúdez, V}, title = {Neuroprotective Role of Omega-3 Fatty Acids: Fighting Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {15}, pages = {}, pmid = {40807232}, issn = {1420-3049}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; *Fatty Acids, Omega-3/therapeutic use/pharmacology ; Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; }, abstract = {Alzheimer's disease (AD) is one of the main causes of dementia, with an exponential increment in its incidence as years go by. However, since pathophysiological mechanisms are complex and multifactorial, therapeutic strategies remain inconclusive and only provide symptomatic relief to patients. In order to solve this problem, new strategies have been investigated over recent years for AD treatment. This field has been reborn due to epidemiological and preclinical findings that demonstrate the fact that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) can be promising therapeutic agents because of their anti-inflammatory, antioxidant, and neurogenic-promoting activities, thus allowing us to classify these molecules as neuroprotectors. Similarly, ω-3 PUFAs perform important actions in the formation of characteristic AD lesions, amyloid-β plaques (Aβ) and neurofibrillary tangles, reducing the development of these structures. Altogether, the aforementioned actions hinder cognitive decline and possibly reduce AD development. In addition, ω-3 PUFAs modulate the inflammatory response by inhibiting the production of pro-inflammatory molecules and promoting the synthesis of specialised pro-resolving mediators. Consequently, the present review assesses the mechanisms by which ω-3 PUFAs can act as therapeutic molecules and the effectiveness of their use in patients. Clinical evidence so far has shown promising results on ω-3 PUFA effects, both in animal and epidemiological studies, but remains contradictory in clinical trials. More research on these molecules and their neuroprotective effects in AD is needed, as well as the establishment of future guidelines to obtain more reproducible results on this matter.}, } @article {pmid40806766, year = {2025}, author = {Rebolledo-Pérez, L and Hernández-Bello, J and Martínez-Ramos, A and Castañeda-Arellano, R and Fernández-Quezada, D and Sandoval-García, F and Aguilar-García, IG}, title = {Substance Abuse and Cognitive Decline: The Critical Role of Tau Protein as a Potential Biomarker.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806766}, issn = {1422-0067}, mesh = {Humans ; *tau Proteins/metabolism ; *Substance-Related Disorders/metabolism/complications ; Biomarkers/metabolism ; Animals ; *Cognitive Dysfunction/metabolism/etiology ; Phosphorylation ; Alzheimer Disease/metabolism ; }, abstract = {Tau protein is essential for the structural stability of neurons, particularly through its role in microtubule assembly and axonal transport. However, when abnormally hyperphosphorylated or cleaved, Tau can aggregate into insoluble forms that disrupt neuronal function, contributing to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Emerging evidence suggests that similar Tau-related alterations may occur in individuals with chronic exposure to psychoactive substances. This review compiles experimental, clinical, and postmortem findings that collectively indicate a substance-specific influence on Tau dynamics. Alcohol and opioids, for instance, promote Tau hyperphosphorylation and fragmentation through the activation of kinases such as GSK-3β and CDK5, as well as proteases like caspase-3, leading to neuroinflammation and microglial activation. Stimulants and dissociatives disrupt insulin signaling, increase oxidative stress, and impair endosomal trafficking, all of which can exacerbate Tau pathology. In contrast, cannabinoids and psychedelics may exert protective effects by modulating kinase activity, reducing inflammation, or enhancing neuroplasticity. Psychedelic compounds such as psilocybin and harmine have been demonstrated to decrease Tau phosphorylation and facilitate cognitive restoration in animal models. Although the molecular mechanisms differ across substances, Tau consistently emerges as a convergent target altered in substance-related cognitive disorders. Understanding these pathways may provide not only mechanistic insights into drug-induced neurotoxicity but also identify Tau as a valuable biomarker and potential therapeutic target for the prevention or treatment of cognitive decline associated with substance use.}, } @article {pmid40806624, year = {2025}, author = {Șerban, M and Toader, C and Covache-Busuioc, RA}, title = {The Redox Revolution in Brain Medicine: Targeting Oxidative Stress with AI, Multi-Omics and Mitochondrial Therapies for the Precision Eradication of Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806624}, issn = {1422-0067}, mesh = {Humans ; *Oxidative Stress/drug effects ; *Mitochondria/metabolism/drug effects ; *Neurodegenerative Diseases/metabolism/therapy/drug therapy ; *Artificial Intelligence ; Oxidation-Reduction ; Antioxidants/therapeutic use/pharmacology ; Biomarkers/metabolism ; *Precision Medicine/methods ; Animals ; Reactive Oxygen Species/metabolism ; Brain/metabolism ; Multiomics ; }, abstract = {Oxidative stress is a defining and pervasive driver of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). As a molecular accelerant, reactive oxygen species (ROS) and reactive nitrogen species (RNS) compromise mitochondrial function, amplify lipid peroxidation, induce protein misfolding, and promote chronic neuroinflammation, creating a positive feedback loop of neuronal damage and cognitive decline. Despite its centrality in promoting disease progression, attempts to neutralize oxidative stress with monotherapeutic antioxidants have largely failed owing to the multifactorial redox imbalance affecting each patient and their corresponding variation. We are now at the threshold of precision redox medicine, driven by advances in syndromic multi-omics integration, Artificial Intelligence biomarker identification, and the precision of patient-specific therapeutic interventions. This paper will aim to reveal a mechanistically deep assessment of oxidative stress and its contribution to diseases of neurodegeneration, with an emphasis on oxidatively modified proteins (e.g., carbonylated tau, nitrated α-synuclein), lipid peroxidation biomarkers (F2-isoprostanes, 4-HNE), and DNA damage (8-OHdG) as significant biomarkers of disease progression. We will critically examine the majority of clinical trial studies investigating mitochondria-targeted antioxidants (e.g., MitoQ, SS-31), Nrf2 activators (e.g., dimethyl fumarate, sulforaphane), and epigenetic reprogramming schemes aiming to re-establish antioxidant defenses and repair redox damage at the molecular level of biology. Emerging solutions that involve nanoparticles (e.g., antioxidant delivery systems) and CRISPR (e.g., correction of mutations in SOD1 and GPx1) have the potential to transform therapeutic approaches to treatment for these diseases by cutting the time required to realize meaningful impacts and meaningful treatment. This paper will argue that with the connection between molecular biology and progress in clinical hyperbole, dynamic multi-targeted interventions will define the treatment of neurodegenerative diseases in the transition from disease amelioration to disease modification or perhaps reversal. With these innovations at our doorstep, the future offers remarkable possibilities in translating network-based biomarker discovery, AI-powered patient stratification, and adaptive combination therapies into individualized/long-lasting neuroprotection. The question is no longer if we will neutralize oxidative stress; it is how likely we will achieve success in the new frontier of neurodegenerative disease therapies.}, } @article {pmid40806521, year = {2025}, author = {Szablewski, L}, title = {Human Glucose Transporters in Health and Selected Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806521}, issn = {1422-0067}, mesh = {Humans ; *Neurodegenerative Diseases/metabolism/genetics/pathology ; *Glucose Transport Proteins, Facilitative/metabolism/genetics ; Animals ; Glucose/metabolism ; Alzheimer Disease/metabolism/genetics ; Huntington Disease/metabolism/genetics ; }, abstract = {Glucose is the main source of energy and the source of carbon for the biosynthesis of several molecules, such as neurotransmitters, for most mammalian cells. Therefore, the transport of glucose into cells is very important. There are described three distinct families of glucose transporters: facilitative glucose transporters (GLUTs), sodium-dependent glucose cotransporters (SGLTs), and a uniporter, the SWEET protein. Impaired function and/or expression of these transporters due to, for example, mutations in their genes, may cause severe diseases. Associations with the impaired function of glucose transporters have been described in the case of neurodegenerative diseases (NDs) such as Alzheimer's disease, Parkinson's disease, Huntington's disease, GLUT1-deficiency syndrome, stroke, and traumatic brain injury. Changes in the presence of glucose transporters may be a cause of NDs, and they may be the effect of NDs. On the other hand, in many cases of neurodegenerative diseases, changes in the expression of glucose transporters may be a targeted therapy in the treatment of patients with these diseases.}, } @article {pmid40806469, year = {2025}, author = {Wang, J and Shen, Y and Liao, P and Yang, B and Jiang, R}, title = {Roles of Ion Channels in Oligodendrocyte Precursor Cells: From Physiology to Pathology.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806469}, issn = {1422-0067}, support = {82401445//National Natural Science Foundation of China/ ; 82271249//National Natural Science Foundation of China/ ; 2024M752251//China Postdoctoral Science Foundation/ ; 2024NSFSC1636//Sichuan Science and Technology Program/ ; 2024HXBH013//Post doctor Research Fund of West China Hospital of Sichuan University/ ; ZYYC23002//1-3-5 Project for Disciplines of Excellence of West China Hospital of Sichuan University/ ; GZC20241141//Postdoctoral Fellowship Program of CPSF/ ; }, mesh = {Humans ; *Ion Channels/metabolism ; Animals ; *Oligodendrocyte Precursor Cells/metabolism/pathology ; Oligodendroglia/metabolism ; Cell Differentiation ; }, abstract = {Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer's disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases.}, } @article {pmid40806404, year = {2025}, author = {Yu, Y and Wang, C and Wang, B and Wang, X and Zhao, Q and Yan, Y and Liu, X}, title = {Clusterin Regulates the Mechanisms of Neuroinflammation and Neuronal Circuit Impairment in Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806404}, issn = {1422-0067}, support = {H2024206232//Natural Science Foundation of Hebei Province/ ; ZF2024142//The Hebei Provincial Department of Finance and the Health Commission will fund the 2024 government-funded clinical medicine excellent talent training project/ ; 20252051//Hebei Provincial Health Commission Medical Science Research Project Project/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Clusterin/metabolism ; Animals ; *Neuroinflammatory Diseases/metabolism/pathology ; Astrocytes/metabolism/pathology ; *Neurons/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with a multifaceted pathogenesis, which remains elusive, seriously affecting the quality of life of elderly patients and placing a heavy burden on affected individuals, their families, and society. As third-party synapses in brain networks, astrocytes play an important role in maintaining the normal function of neural networks, which contribute to the abnormal function of networks in AD. In recent years, numerous studies have shown that clusterin, a protein expressed by astrocytes, can participate in the progression of AD. Clusterin plays a significant role in many pathological processes of AD, such as lipid metabolism, AD pathological features, the imbalance in neural circuit excitatory inhibition, and neuroinflammation. Therefore, delving deeper into the association between clusterin and AD will help us to understand the mechanisms of disease better and provide a theoretical basis for early diagnosis and the development of treatment strategies for AD.}, } @article {pmid40806401, year = {2025}, author = {Nunkoo, VS and Jurcau, A and Les, M and Cristian, A and Militaru, M and Marge, C and Iovanovici, DC and Jurcau, MC}, title = {Circulating Biomarkers for the Early Diagnosis of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {26}, number = {15}, pages = {}, pmid = {40806401}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Biomarkers/blood ; Early Diagnosis ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Peptide Fragments/blood ; }, abstract = {With a rapidly growing incidence and prevalence, Alzheimer's disease (AD) is rapidly becoming one of the most disabling, lethal, and expensive diseases of the century. To diagnose AD as early as possible, the scientific world struggles to find reliable and non-invasive biomarkers that could predict the conversion of mild cognitive impairment to AD and delineate the ongoing pathogenic vicious pathways to be targeted with therapy. Research supports the use of blood biomarkers, such as Aβ1-42/Aβ1-40 ratio, phosphorylated tau181, and p-tau217 for diagnostic purposes, although the cut-offs are not clearly established and can depend on the assays used. For more accurate diagnosis, markers of neurodegeneration (neurofilament light) and neuroinflammation (glial fibrillary acidic protein) could be introduced in the biomarker panel. The recent approval of the Lumipulse G p-tau217/Aβ1-42 plasma ratio by the FDA for the early detection of amyloid plaques associated with Alzheimer's disease in adult patients, aged 55 years and older, exhibiting signs and symptoms of the disease represents a significant advancement in the diagnosis of Alzheimer's disease, offering a more accessible and less invasive way to diagnose this devastating disease and allow potentially earlier access to treatment options.}, } @article {pmid40805906, year = {2025}, author = {Fereshtehnejad, SM and Lökk, J}, title = {Healthcare Complexities in Neurodegenerative Proteinopathies: A Narrative Review.}, journal = {Healthcare (Basel, Switzerland)}, volume = {13}, number = {15}, pages = {}, pmid = {40805906}, issn = {2227-9032}, abstract = {Background/Objectives: Neurodegenerative proteinopathies, such as Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB), are increasingly prevalent worldwide mainly due to population aging. These conditions are marked by complex etiologies, overlapping pathologies, and progressive clinical decline, with significant consequences for patients, caregivers, and healthcare systems. This review aims to synthesize evidence on the healthcare complexities of major neurodegenerative proteinopathies to highlight current knowledge gaps, and to inform future care models, policies, and research directions. Methods: We conducted a comprehensive literature search in PubMed/MEDLINE using combinations of MeSH terms and keywords related to neurodegenerative diseases, proteinopathies, diagnosis, sex, management, treatment, caregiver burden, and healthcare delivery. Studies were included if they addressed the clinical, pathophysiological, economic, or care-related complexities of aging-related neurodegenerative proteinopathies. Results: Key themes identified include the following: (1) multifactorial and unclear etiologies with frequent co-pathologies; (2) long prodromal phases with emerging biomarkers; (3) lack of effective disease-modifying therapies; (4) progressive nature requiring ongoing and individualized care; (5) high caregiver burden; (6) escalating healthcare and societal costs; and (7) the critical role of multidisciplinary and multi-domain care models involving specialists, primary care, and allied health professionals. Conclusions: The complexity and cost of neurodegenerative proteinopathies highlight the urgent need for prevention-focused strategies, innovative care models, early interventions, and integrated policies that support patients and caregivers. Prevention through the early identification of risk factors and prodromal signs is critical. Investing in research to develop effective disease-modifying therapies and improve early detection will be essential to reducing the long-term burden of these disorders.}, } @article {pmid40804109, year = {2025}, author = {Jia, M and Liu, Z and Fan, X and Ahmad, S and Wang, Z and Zhu, X and Ai, H}, title = {Conformation-Dependent Binding Affinity of Small Molecules to Aβ42 Fibrils: Mechanistic Insights into Tracer Design.}, journal = {The journal of physical chemistry. B}, volume = {129}, number = {34}, pages = {8700-8711}, doi = {10.1021/acs.jpcb.5c04444}, pmid = {40804109}, issn = {1520-5207}, mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; *Peptide Fragments/chemistry/metabolism ; Binding Sites ; Humans ; Protein Binding ; Ligands ; *Small Molecule Libraries/chemistry/metabolism ; Protein Conformation ; Alzheimer Disease/metabolism ; }, abstract = {The β-amyloid (Aβ) deposits in Alzheimer's disease (AD) are primarily composed of Aβ42-derived fibrils, and Aβ42 fibrils exhibit polymorphism with diverse molecular structures. While small-molecule-based targeting strategies have achieved phased progress in AD diagnosis and treatment, the distribution and quantity of binding sites on Aβ42 fibrils, as well as the dynamic interaction mechanisms between these sites and different tracers, remain unclear. Additionally, the binding efficacy of small molecules to Aβ42 fibrils with distinct structures and their conformational dependence have not yet been elucidated. In this study, five novel ligands were selected as tracers to investigate their interactions with four representative Aβ42 fibril conformations. The results demonstrated significant differences in the capacities of these molecules to bind Aβ fibrils with varying conformations, revealing a pronounced conformation-dependent relationship. Notably, small molecule 1 (SM1) and SM3 exhibited robust binding affinities across all four Aβ fibril conformations, highlighting their potential as tracers. Furthermore, the binding sites of the υ-type (8EZE) Aβ fibril accommodating small molecules were first identified, and U-type (2BEG), S-type (2NAO), and LS-type (5OQV) Aβ fibrils were found to align with the ones reported previously for other ligands. Notably, strongly bound molecules induce structural deformation of the fibril. These findings provide critical insights for the rational design and modification of existing Aβ42 fibril-targeting ligands, facilitating the development of tracers with enhanced specificity and selectivity.}, } @article {pmid40803539, year = {2025}, author = {Ji, Y and Wang, M and Yang, C}, title = {Neurosteroids for the treatment of neurodegenerative disorders: We still have a long way to go.}, journal = {The Journal of steroid biochemistry and molecular biology}, volume = {254}, number = {}, pages = {106841}, doi = {10.1016/j.jsbmb.2025.106841}, pmid = {40803539}, issn = {1879-1220}, } @article {pmid40803248, year = {2025}, author = {Esparza-Moltó, PB and Goswami, AV and Bozkurt, S and Münch, C and Newman, LE and Moyzis, AG and Rojas, GR and Guan, D and Jones, JR and Gage, FH and Shadel, GS}, title = {ROS-dependent localization of glycolytic enzymes to mitochondria.}, journal = {Redox biology}, volume = {86}, number = {}, pages = {103812}, pmid = {40803248}, issn = {2213-2317}, support = {P30 AG068635/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Mitochondria/metabolism/enzymology/drug effects ; *Glycolysis ; *Reactive Oxygen Species/metabolism ; HEK293 Cells ; Oxidative Stress ; Alzheimer Disease/metabolism/pathology ; Fibroblasts/metabolism ; }, abstract = {Mitochondrial reactive oxygen species (mtROS) regulate cellular signaling pathways, but also cause oxidative stress when de-regulated during aging and pathological conditions such as neurodegenerative diseases. The dynamic redistribution of proteins between cellular compartments is a common mechanism to control their stability and biological activities. By targeting the BirA∗ biotin ligase to the outer mitochondrial membrane in HEK293 cells, we identified proteins whose labeling increased or decreased in response to treatment with menadione, consistent with a dynamic change in their mitochondrial localization in response to increased mtROS production. These proteins represent potential candidates for future studies of mitochondrial oxidative stress signaling. A subset of glycolytic enzymes was found in this screen and confirmed, by mitochondrial fractionation and imaging, to increase localization to mitochondria in response to menadione, despite no change in their overall abundance. Submitochondrial fractionation studies are consistent with import of a pool of these enzymes to the mitochondrial intermembrane space. Localization of glycolytic enzymes to mitochondria was also increased in cells grown under hypoxia or that express a mitochondria-targeted d-amino-acid oxidase (conditions that induce increased mtROS production), and inhibited basally under normal growth conditions by the mitochondrial antioxidant MnTBAP. Finally, primary Alzheimer's disease fibroblasts also had glycolytic enzymes associated with mitochondria that was reduced by antioxidants, consistent with increased mtROS altering their relative distribution between the cytoplasm and mitochondria. We speculate that the increased mitochondrial localization of glycolytic enzymes is an adaptive response to mtROS that alters glucose flux toward the antioxidant pentose phosphate pathway, creates distinct regulatory pools of mitochondrial metabolites or new metabolic circuits, and/or provides cytoprotection or other adaptive responses via moonlighting functions unrelated to their enzymatic activity.}, } @article {pmid40803039, year = {2025}, author = {Erickson, RP and Bernas, MJ and Witte, MH}, title = {Manual Lymph Drainage for Alzheimer's Dementia: A Clinical Trial Whose Time Has Come?.}, journal = {Lymphology}, volume = {58}, number = {2}, pages = {43-45}, pmid = {40803039}, issn = {2522-7963}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology ; Brain/pathology ; Clinical Trials as Topic ; *Manual Lymphatic Drainage/methods ; }, abstract = {Mounting evidence implicates brain lymphatic drainage in the pathogenesis of Alzheimer's disease and other dementias. Several recent basic and clinical science discoveries have suggested the impact of lymphatic therapy to stimulate lymph flow in the head and neck including improvement in cognition. Manual lymphatic drainage has potential as a simple inexpensive way to promote brain lymph drainage and is worthy of a well-designed clinical trial to evaluate its potential as a primary or adjunctive treatment of Alzheimer's disease at this time.}, } @article {pmid40802200, year = {2025}, author = {Talib, M and Siddiqui, N and Tripathi, PN and Chaudhary, A}, title = {Ameliorative Role of Phosphodiesterase-5 (PDE-5) Inhibitor "Avanafil" via Modulating cAMP & cGMP Pathway Against Alzheimer's Disease.}, journal = {Neurochemical research}, volume = {50}, number = {4}, pages = {258}, pmid = {40802200}, issn = {1573-6903}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Cyclic GMP/metabolism ; Male ; *Cyclic AMP/metabolism ; Rats ; *Phosphodiesterase 5 Inhibitors/therapeutic use/pharmacology ; Rats, Wistar ; Hippocampus/drug effects/metabolism ; *Pyrimidines/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Galactose ; }, abstract = {Alzheimer's disease (AD) is the utmost age-linked neuro-degenerative conditions, marked via gradual deterioration of cognitive abilities and continues to be a significant worldwide health issue. Etiology of AD is linked to neurobehavioral variations, deposition of Aβ, p-Tau, activations of glycogen synthase kinase-3 (GSK-3β), and fluctuations in cyclic nucleotides including cAMP & cGMP. As per evidence, PDE-5 inhibitors are able to boost cAMP & cGMP levels and other etiological hallmarks, which could be a novel AD cure. The main objective of present study was to examine therapeutic potential of Avanafil in a rat model of AD induced by administering 60 mg/kg of D-galactose (D-galac) and 10 mg/kg of Aluminium chloride (AlCl3) for a period of 42 days. Following this, 28 days of therapy with two different doses of Avanafil (3 mg/kg and 6 mg/kg) was given. Towards end of treatment, locomotor activity & Morris water maze were performed. Rats were then euthanized and hippocampus was isolated for biochemical parameters & histological investigation. Results revealed that both neurobehavioral parameters exhibits significant difference in treatment group as compared to toxic group. Alterations in level of AchE, Aβ (1-42), GSK-3β, p-Tau, tumor necrosis factor- alpha (TNF-α), IL-1β, & IL-6, cAMP, cGMP & BDNF, and oxidative stress were significantly reversed towards normal level in the treatment group when compared to toxic rats. Histopathological changes by H&E staining showed significant difference in treatment vs. toxic rats. The current investigation suggested that Avanafil improves memory by improving cAMP and cGMP pathways, implying that it may have therapeutic prospective in cognitive deficiencies linked with Alzheimer's disease.}, } @article {pmid40801914, year = {2025}, author = {Liguori, C}, title = {Sleep disturbances impact cognition and are highly prevalent in memory clinics.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {4}, pages = {1406-1408}, doi = {10.1177/13872877251366660}, pmid = {40801914}, issn = {1875-8908}, mesh = {Humans ; *Sleep Wake Disorders/epidemiology/psychology/complications/diagnosis ; Prevalence ; *Cognitive Dysfunction/epidemiology ; Surveys and Questionnaires ; *Cognition/physiology ; *Memory Disorders/epidemiology ; Female ; }, abstract = {Sleep questionnaires may help understand sleep habits and screen for sleep disorders. However, they can fail in diagnosing obstructive sleep apnea or identifying the chronotype and the total sleep time of patients admitted to a specialized memory clinic. Lam et al. showed the high prevalence of sleep disturbances in patients with cognitive impairment. They also highlighted the importance of combining subjective questionnaires with objective tests to identify sleep problems associated with poor cognitive performance, particularly in women. Consequently, recognizing sleep problems can help clinicians set personalized treatment strategies for improving sleep and preventing or slowing cognitive impairment.}, } @article {pmid40801842, year = {2025}, author = {Xie, F and Ye, Y and Hao, J and Liu, H and Richard, SA and He, S}, title = {Surgical advances in the treatment of Alzheimer's disease: A comprehensive review.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {3}, pages = {899-909}, doi = {10.1177/13872877251364397}, pmid = {40801842}, issn = {1875-8908}, mesh = {*Alzheimer Disease/surgery/therapy ; Humans ; Deep Brain Stimulation/methods ; Genetic Therapy/methods ; *Neurosurgical Procedures/methods ; Animals ; }, abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, represents a significant global health challenge with profound implications for patients and their families. Despite decades of intensive research efforts, no curative treatment for AD currently exists. In recent years, surgical interventions have emerged as a promising therapeutic avenue, offering potential for disease modification and symptom management. This comprehensive review critically evaluates the evolving landscape of surgical approaches in AD treatment, encompassing deep brain stimulation, focused ultrasound, gene therapy delivery systems, neural grafting techniques, and lymphatic-venous anastomosis. We systematically analyze the neurobiological mechanisms, clinical efficacy, safety profiles, and technical challenges associated with these interventions. Drawing upon an extensive review of 112 recent studies, this article provides a rigorous assessment of the current state of surgical therapies for AD, while identifying key knowledge gaps and future research directions that could advance the field toward more effective therapeutic strategies.}, } @article {pmid40801602, year = {2025}, author = {de Munter, J and Chaprov, K and Lang, E and Sitdikova, K and Wolters, EC and Svirin, E and Kassenova, A and Tsoy, A and Kramer, BW and Askarova, S and Schroeter, CA and Anthony, DC and Strekalova, T}, title = {Neuro-Cells Mitigate Amyloid Plaque Formation and Behavioral Deficits in the APPswe/PS1dE9 Model of Alzheimer Disease While Also Reducing IL-6 Production in Human Monocytes.}, journal = {Cells}, volume = {14}, number = {15}, pages = {}, pmid = {40801602}, issn = {2073-4409}, support = {101007642//HORIZON, EU/ ; AP23485236, BR24992841//the Ministry of Higher Education and Science of the Republic of Kazakhstan/ ; }, mesh = {*Alzheimer Disease/therapy/pathology/metabolism ; Animals ; *Monocytes/metabolism ; Humans ; *Interleukin-6/metabolism ; *Plaque, Amyloid/pathology/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Behavior, Animal ; Male ; *Neural Stem Cells ; Presenilin-1/metabolism ; }, abstract = {Neuroinflammation is a key feature of Alzheimer's disease (AD), and stem cell therapies have emerged as promising candidates due to their immunomodulatory properties. Neuro-Cells (NC), a combination of unmodified mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), have demonstrated therapeutic potential in models of central nervous system (CNS) injury and neurodegeneration. Here, we studied the effects of NC in APPswe/PS1dE9 mice, an AD mouse model. Twelve-month-old APPswe/PS1dE9 mice or their wild-type littermates were injected with NC or vehicle into the cisterna magna. Five to six weeks post-injection, cognitive, locomotor, and emotional behaviors were assessed. The brain was stained for amyloid plaque density using Congo red, and for astrogliosis using DAPI and GFAP staining. Gene expression of immune activation markers (Il-1β, Il-6, Cd45, Tnf) and plasticity markers (Tubβ3, Bace1, Trem2, Stat3) was examined in the prefrontal cortex. IL-6 secretion was measured in cultured human monocytes following endotoxin challenge and NC treatment. Untreated APPswe/PS1dE9 mice displayed impaired learning in the conditioned taste aversion test, reduced object exploration, and anxiety-like behavior, which were improved in the NC-treated mutants. NC treatment normalized the expression of several immune and plasticity markers and reduced the density of GFAP-positive cells in the hippocampus and thalamus. NC treatment decreased amyloid plaque density in the hippocampus and thalamus, targeting plaques of <100 μm[2]. Additionally, NC treatment suppressed IL-6 secretion by human monocytes. Thus, NC treatment alleviated behavioral deficits and reduced amyloid plaque formation in APPswe/PS1dE9 mice, likely via anti-inflammatory mechanisms. The reduction in IL-6 production in human monocytes further supports the potential of NC therapy for the treatment of AD.}, } @article {pmid40801286, year = {2025}, author = {Huang, J and Perrin, NA and Spira, AP and Szanton, SL and Rebok, GW and Budhathoki, C and Gooneratne, NS and Li, J}, title = {Sleep Disturbance and Cognitive Trajectories Among Older Adults with Subjective Cognitive Decline: The Roles of Age and Sleep Treatment.}, journal = {Sleep}, volume = {}, number = {}, pages = {}, doi = {10.1093/sleep/zsaf234}, pmid = {40801286}, issn = {1550-9109}, abstract = {STUDY OBJECTIVES: Growing evidence indicates that subjective cognitive decline (SCD), characterized by self-reported cognitive deterioration without measurable cognitive impairment, may be an early indicator of Alzheimer's Disease. This study investigated the association between baseline sleep disturbance and a 10-year trajectory of global cognitive performance in adults with SCD and examined if this association was moderated by age (50-64 years and ≥65 years) and sleep treatment. METHODS: Using six waves (2010-2020) of the Health and Retirement Study, we included individuals aged ≥50 years who reported SCD but had no objective cognitive impairment at baseline (2010) and had final wave of cognitive data (n=1,372). Latent growth curve modeling was employed to examine the associations between self-reported sleep disturbance and cognitive trajectories from 2010 to 2020, controlling for sociodemographic and health-related factors. RESULTS: In the full sample, baseline sleep disturbance was not significantly associated with cognitive change. However, a significant interaction between sleep disturbance and age group was found (β=-0.04, 95% CI [-0.08, -0.003]). Stratified analyses showed that poorer sleep was associated with faster cognitive decline in those aged ≥65 years (β=-0.04, 95% CI [-0.07, -0.005]; n=558), and receiving sleep treatment was associated with a reduced impact of sleep disturbance on cognitive decline (β=0.31, 95% CI [0.02, 0.60]). These associations were not significant in those aged 50-64 years (n=814). CONCLUSIONS: Sleep disturbance was an independent risk factor of future cognitive decline in older adults ≥65 years with SCD. Sleep treatment may mitigate this decline, offering a potential intervention strategy.}, } @article {pmid40801268, year = {2025}, author = {Ikanga, J and Patel, SS and Schwinne, M and Obenauf, C and Gikelekele, G and Epenge, E and Tshengele, N and Kavugho, I and Mampunza, S and Mananga, L and Teunissen, CE and Rojas, JC and Yohe, EO and Alonso, A and Gross, AL}, title = {Association between neuropsychiatric symptoms and neurodegeneration-related plasma biomarkers in older adults with and without clinical dementia in the Democratic Republic of the Congo.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70530}, pmid = {40801268}, issn = {1552-5279}, support = {//National Institutes of Health/ ; P30 AG066511/AG/NIA NIH HHS/United States ; R01AG070953 to AG/AG/NIA NIH HHS/United States ; R01AG030153 to AG/AG/NIA NIH HHS/United States ; P30AG066511/AG/NIA NIH HHS/United States ; RF1AG088003 to AG/AG/NIA NIH HHS/United States ; UL1TR002378//National Center for Advancing Translational Sciences/ ; //Emory Goizueta Alzheimer's disease Research Center (ADRC)/ ; }, mesh = {Humans ; Male ; Female ; *Biomarkers/blood ; Aged ; Democratic Republic of the Congo/epidemiology ; *Dementia/blood/psychology ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Neuropsychological Tests/statistics & numerical data ; Neurofilament Proteins/blood ; Psychiatric Status Rating Scales ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/blood ; }, abstract = {INTRODUCTION: Neuropsychiatric symptoms (NPS) are prevalent in dementia, but most studies focus on Western populations. This study examines the association between NPS and neurodegeneration-related plasma biomarkers in older adults with and without dementia in the Democratic Republic of the Congo (DRC). METHODS: Eighty-five individuals (≥65 years) underwent dementia adjudication using the Community Screening Instrument for Dementia (CSID) and Alzheimer's Questionnaire (AQ). Plasma biomarkers (amyloid β [Aβ] 42/40, phosphorylated-tau181 [p-tau181], neurofilament light [NfL], glial fibrillary acidic protein (GFAP), interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α]) were measured. NPS were assessed using the Geriatric Depression Scale (GDS), Beck Anxiety Inventory (BAI), and Neuropsychiatric Inventory Questionnaire (NPI) (for dementia cases). Logistic regressions examined associations between NPS and biomarkers, adjusting for age, sex, and education. RESULTS: NPS were common in dementia cases, with irritability (57.8%) and depression (90.7%) most frequent. GFAP was linked to irritability (odds ratio [OR] = 3.34, p = 0.01), and NfL and GFAP were associated with depressive symptoms (OR = 0.76, p = 0.04; OR = 1.98, p = 0.02, respectively). DISCUSSION: These findings highlight the burden of NPS in the DRC and suggest biomarker-driven mechanisms, emphasizing the need for further research in diverse populations. HIGHLIGHTS: Identifies neuropsychiatric symptoms as early indicators of Alzheimer's disease (AD) progression. Examines associations between depression and AD biomarkers in preclinical and prodromal stages. Highlights the role of amyloid and tau pathology in depression-related cognitive decline. Discusses implications for early intervention and personalized treatment strategies.}, } @article {pmid40801241, year = {2025}, author = {Jin, Z and Lu, Y and Tang, H and Cui, H}, title = {Integrating neuroinflammation biomarkers into the ATN(X) framework: Advances in Alzheimer's pathogenesis, diagnosis, and insights from non-human primate models.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70472}, pmid = {40801241}, issn = {1552-5279}, support = {82074535//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/diagnosis/metabolism/pathology ; Animals ; *Biomarkers/metabolism ; Humans ; Disease Models, Animal ; *Neuroinflammatory Diseases/metabolism/diagnosis ; *tau Proteins/metabolism ; Glial Fibrillary Acidic Protein/metabolism ; Primates ; }, abstract = {The amyloid/tau/neurodegeneration (ATN) biomarker framework has greatly progressed the diagnosis and staging of Alzheimer's disease (AD). However, recent research highlights neuroinflammation as an equally critical factor in AD pathology across humans, rodents, and non-human primates (NHPs). This review evaluates the combined use of ATN and neuroinflammatory biomarkers-such as glial fibrillary acidic protein (GFAP) (astrocytic marker) and triggering receptor expressed on myeloid cells 2 (TREM2)/ ionized calcium-binding adapter molecule 1 (IBA-1) (microglial markers)-in elucidating AD mechanisms, promoting early diagnosis, and shaping therapeutic strategies. It also summarizes the key features and translational potential of NHP models that closely mimic human AD pathology, highlighting the promising prospects of integrating these models with the ATN(X) biomarker system. These insights strengthen the link between biomarkers, NHP research, and clinical practice, opening new avenues for the early detection and treatment strategies of AD. HIGHLIGHTS: Neuroinflammation biomarkers, including glial fibrillary acidic protein (GFAP), triggering receptor expressed on myeloid cells 2 (TREM2)/sTREM2, and YKL-40, show strong clinical potential in Alzheimer's disease (AD). Incorporating neuroinflammation biomarkers into the ATN(X) framework may enhance diagnostic precision. Advanced non-human primate (NHP) models closely replicate human brain pathology, addressing key limitations of mouse models. Measuring ATN(X) biomarkers in NHPs may improve clinical translation and support early diagnosis of AD. Optimizing NHP models-including ApoE4 status, injection protocols, and gene-editing approaches-is crucial for reproducibility and efficiency.}, } @article {pmid40800505, year = {2024}, author = {Dong, M and Xie, L and Das, SR and Wang, J and Wisse, LEM and deFlores, R and Wolk, DA and Yushkevich, PA}, title = {Regional deep atrophy: Using temporal information to automatically identify regions associated with Alzheimer's disease progression from longitudinal MRI.}, journal = {Imaging neuroscience (Cambridge, Mass.)}, volume = {2}, number = {}, pages = {}, pmid = {40800505}, issn = {2837-6056}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; RF1 AG056014/AG/NIA NIH HHS/United States ; R01 AG069474/AG/NIA NIH HHS/United States ; R01 AG055005/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG070592/AG/NIA NIH HHS/United States ; R01 AG040271/AG/NIA NIH HHS/United States ; }, abstract = {Longitudinal assessment of brain atrophy, particularly in the hippocampus, is a well-studied biomarker for neurodegenerative diseases, such as Alzheimer's disease (AD). Estimating brain progression patterns can be applied to understanding the therapeutic effects of amyloid-clearing drugs in research and detecting the earliest sign of accelerated atrophy in clinical settings. However, most state-of-the-art measurements calculate changes directly by segmentation and/or deformable registration of MRI images, and may misreport head motion or MRI artifacts as neurodegeneration, impacting their accuracy. In our previous study, we developed a deep learning method DeepAtrophy that uses a convolutional neural network to quantify differences between longitudinal MRI scan pairs that are associated with time. DeepAtrophy has high accuracy in inferring temporal information from longitudinal MRI scans, such as temporal order or relative interscan interval. DeepAtrophy also provides an overall atrophy score that was shown to perform well as a potential biomarker of disease progression and treatment efficacy. However, DeepAtrophy is not interpretable, and it is unclear what changes in the MRI contribute to progression measurements. In this paper, we propose Regional Deep Atrophy (RDA), which combines the temporal inference approach from DeepAtrophy with a deformable registration neural network and attention mechanism that highlights regions in the MRI image where longitudinal changes are contributing to temporal inference. RDA has similar prediction accuracy as DeepAtrophy, but its additional interpretability makes it more acceptable for use in clinical settings, and may lead to more sensitive biomarkers for disease monitoring and progression understanding in preclinical AD.}, } @article {pmid40799992, year = {2025}, author = {Chu, J and Hu, H and Xu, W and Lu, X and Zhou, H and Hao, M and Wang, L and Li, S and Ji, W and Li, G and Luo, Y and Gao, J and Huang, D and Liu, Y and Yin, Y}, title = {Top-down engineered micron-cell derived nanovesicles encapsulating curcumin targeting the 3R strategy (remove, remodel, repair) for Alzheimer's disease therapy.}, journal = {Materials today. Bio}, volume = {34}, number = {}, pages = {102157}, pmid = {40799992}, issn = {2590-0064}, abstract = {Alzheimer's disease (AD), a global health crisis exacerbated by aging populations, demands innovative therapeutic strategies. Curcumin, a natural compound with anti-aging and anti-inflammatory properties, holds promise for AD treatment but is hindered by poor bioavailability. Here, we developed curcumin-loaded nanovesicles (NV-CUR) derived from brain-homing B16 melanoma cells to overcome these limitations. NV-CUR enhanced the solubility, stability, and blood‒brain barrier (BBB) penetration of curcumin, enabling systemic delivery in aged 3 × Tg AD mice. Our 3R strategy for removing senescent cells, remodeling the neuroinflammatory microenvironment, and repairing neuronal damage was comprehensively validated. NV-CUR effectively cleared p16[INK4a] (P16)-positive senescent microglia, suppressed senescence-associated secretory phenotypes (SASP), and reduced neuroinflammation (IL-1β, IL-6, and TNF-α). Concurrently, NV-CUR diminished amyloid-beta plaques, attenuated Tau hyperphosphorylation, and restored hippocampal neuronal integrity. Cognitive assessments revealed significant improvements in memory and exploratory behavior, whereas biosafety evaluations confirmed that there was no systemic toxicity. This study establishes NV-CUR as a mechanistically innovative, clinically translatable nanomedicine that aligns with the 3R paradigm, offering a multifaceted approach to combat AD pathogenesis.}, } @article {pmid40799764, year = {2025}, author = {Chakkarai, S and Sadowski, M and Yang, Q and Ray, A and Wang, R and Thomas, LF and Fuentes, RP and Tabar, MS and Cui, B and Jian, X and Nyquist, PA and Gill, D and Aiello, AE and Montine, TJ and Bukhari, S and Rogalski, E and Edland, SE and Haan, ME and Kawas, CH and Corrada, MM and Salardini, A and Chen, ZZ and Himali, JJ and Satizabal, CL and Gerszten, RE and Åsvold, BO and Fornage, M and Cruchaga, C and Habes, M and Chasman, DI and Launer, LJ and Flanagan, ME and Brumpton, BM and Georgakis, MK and Zaitlen, N and Ruiz, A and Debette, S and Seshadri, S and Sargurupremraj, M}, title = {Cross-tissue omics-guided drug repurposing triangulates novel targetable mechanisms for Alzheimer's disease and candidate genetic biomarkers for treatment stratification.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40799764}, issn = {2693-5015}, support = {R01 AG082360/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; R21 AG087907/AG/NIA NIH HHS/United States ; RF1 AG063507/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; R25 GM135043/GM/NIGMS NIH HHS/United States ; R01 NS017950/NS/NINDS NIH HHS/United States ; R01 AG021055/AG/NIA NIH HHS/United States ; }, abstract = {White matter hyperintensities (WMH) are covert magnetic resonance imaging (MRI) - markers of microvascular dysfunction and are primary vascular contributors to dementia, emphasizing its importance in prevention strategies. Here, we integrate gene expression and protein levels measured across plasma, cerebrospinal fluid (CSF), brain and multiple other tissues from population-based and biobank-scale data to triangulate druggable genes influencing WMH-burden and Alzheimer's disease (AD) and to map their spatial localization specifically in brain-cell types. Lowering the expression levels of CALCRL, MAP3K11, PKN2 and EPHB4 shows putative causal associations with reduced WMH-burden, and AD risk. These targets of clinically approved drugs, enriched in key cell types of the neurovascular unit and exhibiting cell-type specific effects in peripheral CD4 + T cell subsets, are implicated in regulating neuroimmune interactions and amyloid-β homeostasis. Gene-drug interaction analysis identifies higher levels of GLTPD2 modifying the antidepressants associated increase in dementia risk contributing to a 73.3% risk reduction relative to the use of drugs. Furthermore, pharmagenic pathway studies identify the coagulation cascade as a targetable pathway associated with AD risk (HR: 2.23, 95% CI:1.85-2.69), providing orthogonal support to emerging therapies targeting coagulation components in treating neurodegenerative disorders.}, } @article {pmid40799393, year = {2025}, author = {Araya, P and Niemeyer, B and Schade, K and Dunn, LN and Waugh, K and Busquet, N and Brindley, C and Brown, C and Winkler, C and Lyford, HR and Britton, EC and Ludwig, M and Siegenthaler, J and Galbraith, MD and Espinosa, JM and Sullivan, KD}, title = {Interferon signaling modulates Down syndrome-associated Alzheimer's disease pathology in a mouse model.}, journal = {iScience}, volume = {28}, number = {8}, pages = {113130}, pmid = {40799393}, issn = {2589-0042}, abstract = {Individuals with Down syndrome (DS), caused by trisomy of chromosome 21 (chr21, T21), are strongly predisposed to Alzheimer's disease (AD), due to triplication of the APP gene, with ∼100% penetrance of AD brain pathology by age 40 and variable onset of dementia thereafter. It remains unclear what role other triplicated genes play in the pathophysiology of DS-associated AD (DS-AD). Using mouse models of DS-AD, we demonstrate that triplication of other chr21 genes has paradoxical effects on learning and memory in DS-AD mice, exacerbating some phenotypes and attenuating others. Spatial transcriptomic analysis revealed genome-wide alterations typified by upregulation of interferon (IFN) signatures and elevated levels of disease-associated microglia with concomitant decreases in neurons in DS-AD animals. Finally, systemic treatment with a JAK inhibitor improved cognition and rescued gene expression changes in DS-AD animals, indicating that IFN may be a driver of pathophysiology in DS-AD that could be amenable to therapeutic intervention.}, } @article {pmid40798958, year = {2025}, author = {Zhang, Y and Ke, Z and Luo, J and Chen, Q and Jiang, X and Xiong, J and Deng, L}, title = {Betaine: A Promising Natural Product for Neurological and Psychiatric Diseases.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570159X375540250718094903}, pmid = {40798958}, issn = {1875-6190}, abstract = {Neurological and psychiatric diseases pose a considerable global burden. Exploring additional potential prevention strategies and therapies is ongoing. As a prevalent natural product and nutraceutical from food, betaine's pharmaceutical applications suggest benefits for both health and disease in multiple organs. Recently, its efficacy on neurological and psychiatric health has been proposed and has drawn considerable attention. This review aims to provide an updated, critical, and comprehensive profile of the promising medicinal roles of betaine in these diseases. In addition to its well-known osmotic protection, due to methyl donation, it regulates metabolism, alleviates oxidative stress, and reduces inflammation. To manifest neurological and psychiatric health benefits, betaine acts by affecting gamma-aminobutyric acid associated with its transporters, related neurotransmitters, downstream and neurological pathways, and other specific mechanisms in the nervous system. Betaine demonstrates therapeutic potential against various neurological and psychiatric diseases, such as epilepsy, neurocognitive disorders (including Alzheimer's disease), Parkinson's disease, stroke, multiple sclerosis, traumatic brain injury, depression, anxiety, schizophrenia, autism spectrum disorder, sleep disorders, fetal alcohol syndrome, syringomyelia, neonatal brain injury, neuropathic pain, and motor dysfunction. Despite the promising role of betaine in the treatment, diagnosis, and prevention of neuropsychiatric disorders, much of the present evidence appears to be fragmentary. Further studies elucidating the underlying mechanisms and direct clinical applications are required to obtain a deeper understanding of betaine and its underutilized potential. Overall, this review highlights the potential of betaine as a promising agent with benefits for neurological and psychiatric diseases, aiming to offer clues to advance this field.}, } @article {pmid40797227, year = {2025}, author = {Liang, J and Li, R and Wong, G and Huang, X}, title = {Lewy body dementia: exploring biomarkers and pathogenic interactions of amyloid β, tau, and α-synuclein.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {90}, pmid = {40797227}, issn = {1750-1326}, support = {32400781//National Natural Science Foundation of China/ ; No. BYYZ25014//President Foundation of Baiyun District People's Hospital of Guangzhou/ ; }, abstract = {Lewy body dementia (LBD) is a neurodegenerative disorder characterized by a combination of progressive dementia and spontaneous parkinsonian symptoms. As the second most prevalent form of neurodegenerative dementia after Alzheimer’s disease (AD), LBD necessitates a deeper understanding of its pathogenesis to enable the development of targeted therapeutic interventions. While numerous reviews focus on documenting the clinical manifestations and therapeutic modalities for LBD, animal models provide valuable insights into the underlying mechanisms and potential therapeutic strategies. In this review, we systematically analyze the hallmarks of LBD pathogenesis, genetic risk factors, clinical features, and treatment strategies. Importantly, we emphasize and critically evaluate the pivotal role of animal models in LBD research in advancing our understanding of this disorder, offering a comprehensive framework to elucidate the interactions among misfolded proteins and their role in LBD pathogenesis. Our review proposes new directions for LBD therapeutic management and facilitates the development of innovative pharmacological interventions.}, } @article {pmid40796907, year = {2025}, author = {Choi, J and Kim, D and Jeong, H and Hwang, J and Ramalingam, M and Han, S and Cho, HH and Kim, BC and Jeong, HS and Jang, S}, title = {A novel miR-4536-3p inhibition ameliorates Alzheimer's disease by reducing Aβ accumulation and tau phosphorylation.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {189}, pmid = {40796907}, issn = {1758-9193}, support = {RS-2020-KH088567//Korea Health Industry Development Institute/Republic of Korea ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *MicroRNAs/antagonists & inhibitors/metabolism/genetics ; *tau Proteins/metabolism ; Mice ; Phosphorylation/drug effects ; *Amyloid beta-Peptides/metabolism ; Humans ; Mice, Transgenic ; Disease Models, Animal ; Male ; Apoptosis/drug effects ; Signal Transduction ; Neuropeptides/metabolism ; Maze Learning ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive decline, amyloid-beta (Aβ) accumulation, and tau hyperphosphorylation. Effective therapies remain limited; therefore, recent studies have explored microRNAs as potential therapeutic targets. METHODS: miR-4536-3p inhibition was investigated using in vitro (SH-SY5Y cells) and in vivo (5xFAD mouse) AD models. Apoptosis, neuronal markers, and signaling pathways were assessed through functional assays. Cognitive effects were evaluated via the Morris water maze. RESULTS: miR-4536-3p inhibition increased an expression of Drebrin1 (DBN1), a key regulator of synaptic plasticity, but it reduced Aβ deposition, tau phosphorylation, and apoptosis. The treatment improved neuronal marker levels and significantly enhanced the spatial learning and memory of 5xFAD mice. Mechanistically, miR-4536-3p inhibition activated the PI3K/Akt/GSK3β signaling pathway, suppressing apoptosis and mitigating AD pathology. CONCLUSION: miR-4536-3p inhibition offers a promising therapeutic strategy for AD by restoring the DBN1 expression, reducing neurodegeneration, and improving cognitive outcomes through PI3K/Akt pathway modulation.}, } @article {pmid40796687, year = {2025}, author = {Kashiyama, R and Watanabe, H and Akasaka, T and Fujimoto, H and Murakami, M and Ooe, K and Toyoshima, A and Nakashima, K and Ono, M}, title = {Feasibility of targeted alpha therapy for Alzheimer's disease using [211]At-labeled agent targeting amyloid-β aggregates.}, journal = {Annals of nuclear medicine}, volume = {39}, number = {12}, pages = {1319-1325}, pmid = {40796687}, issn = {1864-6433}, support = {JP24wm0625512h//Japan Agency for Medical Research and Development/ ; JP25wm0625512h//Japan Agency for Medical Research and Development/ ; }, mesh = {*Alzheimer Disease/radiotherapy/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; Mice ; Feasibility Studies ; *Alpha Particles/therapeutic use ; *Protein Aggregates/radiation effects ; Tissue Distribution ; Benzofurans/chemistry/pharmacokinetics/therapeutic use ; Humans ; *Molecular Targeted Therapy/methods ; Male ; Isotope Labeling ; }, abstract = {OBJECTIVE: Amyloid-β (Aβ) aggregates have been recognized as therapeutic targets for Alzheimer's disease (AD). Targeted alpha therapy (TAT) using α-particles has the potential to be applied as a novel treatment approach for AD by reducing the quantity of Aβ aggregates. In this study, we developed a novel astatine-211-labeled pyridyl benzofuran (PBF) derivative, [[211]At]APBF-2, as a small molecule-based Aβ-TAT agent and evaluated its potential for in vivo use. METHODS: [[211]At]APBF-2 was synthesized in a one-step astatination process using the tributyltin precursor. In the Aβ aggregation inhibition assay, [[211]At]APBF-2 was added to a sample containing Aβ1-42 monomers and thioflavin-T (ThT) and the mixture was incubated for 24 h. The quantity of Aβ aggregates was evaluated by measuring ThT fluorescence intensity. The biodistribution of [[211]At]APBF-2 (25 kBq/100 μL) was evaluated using ddY mice (n = 5). RESULTS: [[211]At]APBF-2 was synthesized in radiochemical yield of 57% with a radiochemical purity of over 95%. In the in vitro assay, [[211]At]APBF-2 showed a dose-dependent decrease in ThT fluorescence intensity, suggesting the ability of [[211]At]APBF-2 to inhibit Aβ aggregation. In the biodistribution study using normal mice, the initial brain uptake of [[211]At]APBF-2 was observed (2.95% injected dose/g at 2 min), demonstrating favorable Blood-brain barrier permeability. CONCLUSIONS: These results suggest the feasibility of using [[211]At]APBF-2 as an Aβ-TAT agent for in vivo applications.}, } @article {pmid40795635, year = {2025}, author = {Zhou, W and Tian, L and Wang, X and Hou, G and Yu, J and Chen, M and Xu, C and Xue, L and Tan, X and Dai, R}, title = {Integrated untargeted and targeted metabolomics to reveal the mechanisms of herbal medicine HLXLD on Alzheimer's disease.}, journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences}, volume = {1265}, number = {}, pages = {124746}, doi = {10.1016/j.jchromb.2025.124746}, pmid = {40795635}, issn = {1873-376X}, mesh = {*Metabolomics ; Herbal Medicine ; *Alzheimer Disease/chemically induced/drug therapy/metabolism/pathology ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Animals ; Rats ; Disease Models, Animal ; Aluminum Chloride ; *Neuroprotective Agents/pharmacology/therapeutic use ; Neuroprotection/drug effects ; Male ; Rats, Sprague-Dawley ; Neurotransmitter Agents/analysis/metabolism ; Amino Acids/analysis/metabolism ; Arachidonic Acid/analysis/metabolism ; Lipids/analysis ; Lipid Metabolism ; Hypothalamus/metabolism/pathology ; }, abstract = {Huo-Luo-Xiao-Ling-Dan (HLXLD), a Chinese herbal medicine consisting of 11 herbs, has been shown to be effective in alleviating cognitive and memory impairment in Alzheimer's disease (AD). However, the underlying mechanisms require further investigation. This study aimed to clarify potential therapeutic mechanisms of HLXLD in the treatment of AD from a metabolic perspective. A rat model of AD induced by AlCl3 and D-gal was established, the Morris water maze (MWM) test and hippocampal histopathology were used to evaluate the pharmacological effect of the HLXLD on AD. Subsequently, untargeted metabolomics of brain tissues samples was performed by UHPLC-Q-Exactive-Orbitrap-MS, followed by multivariate statistical analysis. Targeted metabolomics by UHPLC-QQQ-MS was further employed to validate and supplement the untargeted metabolomics finding, involving neurotransmitters, amino acids, arachidonic acid and lipids, to elucidate the relationship between disease, herbal medicine and metabolism pathway. The study found that HLXLD could relieve the progression of AD and regulate metabolic imbalances. The levels of 26 metabolites decreased and 6 increased in brain tissues including lysine, taurine, fumaric acid, prostaglandin E2, choline and so on, these altered metabolites were primarily associated with amino acid metabolism, TCA cycle, arachidonic acid metabolism and lipid metabolism. The targeted metabolomics results showed that compared with the model group, the levels of 8 neurotransmitters, 21 amino acids, 7 arachidonic acids and 16 lipids in brain tissue, 9 neurotransmitters, 20 amino acids, 6 arachidonic acids and 2 lipids in plasma were changed. In summary, HLXLD could improve the levels of endogenous metabolites by regulating multiple metabolic pathways and play a role in energy supply, anti-neuroinflammatory and neuroprotective effects in AD treatment.}, } @article {pmid40794901, year = {2025}, author = {Tavakoli, E and Niciforos, E and Amid, P and Cuperfain, AB and Burhan, AM and Colman, S and Chu, L and Davies, SJC and Derkach, P and Gerretsen, P and Graff-Guerrero, A and Hussain, M and Ismail, Z and Kim, D and Krisman, L and Mulsant, BH and Pollock, BG and Rej, S and Rostas, A and Rajji, TK and Van Bussel, L and Kumar, S and Elmi, S}, title = {The impact of lifetime excessive alcohol use on behavioural and psychological symptoms of dementia.}, journal = {Alcohol and alcoholism (Oxford, Oxfordshire)}, volume = {60}, number = {5}, pages = {}, doi = {10.1093/alcalc/agaf048}, pmid = {40794901}, issn = {1464-3502}, support = {//The Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN)/ ; //Brain Canada Foundation/ ; //Centre for Aging and Brain Health Innovation/ ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; *Alcoholism/psychology/epidemiology/complications ; Alzheimer Disease/psychology ; Cross-Sectional Studies ; *Dementia/psychology/epidemiology ; Randomized Controlled Trials as Topic ; }, abstract = {INTRODUCTION: Excessive alcohol use (EAU) elevates the risk of dementia through various mechanisms, yet its impact on the behavioural and psychological symptoms of dementia (BPSDs) remains uncertain. METHODS: In this exploratory cross-sectional analysis of baseline data from the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov/NCT03672201), we included individuals with Alzheimer's disease and related dementias requiring BPSD treatment. We compared demographic characteristics and presentation of BPSDs (using the total and domain scores on the Neuropsychiatric Inventory-Clinician) in those with and without a lifetime history of EAU. RESULTS: Among 193 participants [mean (SD) age: 80.6 (9.7) years, male: 48.4%], those in the EAU group (n = 17) and in the comparator group (n = 176) had severe and comparable cognitive impairment, with a median Functional Assessment Staging Tool for Dementia score of 6e. Participants with EAU were significantly younger than comparators [mean age (SD): 72.9 (7.1) years vs. 81.4 (9.5) years] (t = -3.678, df = 181, P < .001), and were more frequently male (76.5% [13 of 17] vs. 46.6% [82 of 176]; P = .036). In a sensitivity analysis, there were no differences in the Neuropsychiatric Inventory-Clinician total or individual domain scores between those with EAU and a subsample of those without EAU matched for age, sex, and recruitment site. CONCLUSION: This exploratory study found that among individuals with Alzheimer's disease and related dementias and BPSDs, lifetime history of EAU is more frequent in younger males. Future studies may further examine the impact of EAU in individuals with BPSDs.}, } @article {pmid40794806, year = {2025}, author = {Yoon, DM and Plante, D and Fleming, V and Handen, B and Lao, P and Peven, J and Christian, B and Okonkwo, O and Laymon, C and Ances, B and Hom, C and Helsel, B and Hartley, SL and , }, title = {Preliminary Investigation of Obstructive Sleep Apnea and Alzheimer's Disease in Down Syndrome.}, journal = {Sleep}, volume = {}, number = {}, pages = {}, doi = {10.1093/sleep/zpaf044}, pmid = {40794806}, issn = {1550-9109}, abstract = {This study provided a preliminary examination of indices of obstructive sleep apnea (OSA) and sleep disruptions in adults with Down syndrome (DS), and their associations with Alzheimer's disease (AD) pathology and symptomatology. Ninety-three adults with DS (aged 25-61 years) from the Alzheimer Biomarker Consortium - Down Syndrome completed cognitive assessments, MRI and PET scans (assessing amyloid-beta [Aβ] and tau), and a one-night home sleep study using the WatchPAT-300 device. Study partners also reported on depressive symptoms and diagnoses. Correlational analyses examined relationships between sleep variables, PET biomarkers, and AD symptomatology (cognitive functioning and depressive mood), controlling for sociodemographics. Eighty-one participants (87%) completed valid WatchPAT data. Of these, 60 (74%) screened positive for OSA, and an additional 11 had a prior OSA diagnosis and used CPAP during the test night. Nearly half (45%) of those screening positive for OSA had no prior diagnosis, indicating under-detection. Among the 22 participants using OSA treatment, 50% continued to show sleep-disordered breathing, suggesting suboptimal treatment effectiveness. Higher wake percentage and shorter total sleep time were associated with greater Aβ and tau burden. Cognitive performance was negatively associated with wake percentage, total sleep time, and oxygenation indices (minimum oxygen, desaturation, and time ≤ 88% oxygen). Depressive symptoms were negatively related to total sleep time. These findings add preliminary evidence linking sleep disruption and OSA with AD-related pathology and symptomatology. Larger, longitudinal studies are needed to confirm these associations and evaluate whether improving sleep quality and treating OSA may help delay AD onset in this high-risk population.}, } @article {pmid40794238, year = {2025}, author = {Jellinger, KA}, title = {Comorbid pathologies and their impact on progressive supranuclear palsy: current view.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {40794238}, issn = {1435-1463}, support = {Society for the Promotion of Research in Experimental Neurology, Vienna, Austria//Society for the Promotion of Research in Experimental Neurology, Vienna, Austria/ ; }, abstract = {Progressive supranuclear palsy, a four-repeat tauopathy, is clinically characterized by early postural instability and falls, vertical supranuclear palsy, levodopa poorly-responsive parkinsonism, pseudobulbar palsy, and cognitive impairment. It is morphologically featured by accumulation of hyperphosphorylated tau protein in neurons and glia predominantly in the basal ganglia, brainstem tegmentum and frontal cortex, associated with degeneration of the extrapyramidal system and cortical atrophy. Isolated PSP neuropathology is uncommon, with nearly 70% showing co-neuropathologies including Alzheimer-type, Lewy body, TDP-43 pathologies, argyrophilic grains, and other tauopathies and neurodegenerative disorders (Parkinson disease, amyotrophic lateral sclerosis). The most common comorbid conditions are hypertension, cardiovascular and cerebrovascular diseases, diabetes mellitus, polyneuropathies, muscular and urological disorders. Due the increased prevalence of comorbidities and their eminent impact on the progress and outcome of the disease, clinical trials should account for them in their design and selection. However, currently little is known about co-pathologies in these patients. In view of the eminent burden of comorbidities and resulting therapeutic consequences, the frequency of the different co-pathologies in PSP and their clinical impact will be discussed. It should provide insight into their pathogenic backgrounds as a basis for adequate treatment procedures to improve the quality of life of patients with this fatal disease.}, } @article {pmid40792123, year = {2025}, author = {Zhi, N and Ren, R and Qi, J and Liu, X and Yun, Z and Lin, S and Hu, Y and Li, H and Xie, X and Wang, J and Li, J and Zhu, Y and Gao, M and Yang, J and Wang, Y and Jing, Y and Geng, J and Cao, W and Xu, Q and Yu, X and Zhu, Y and Zhou, Y and Wang, L and Gao, C and Li, B and Chen, S and Yuan, F and Dou, R and Liu, X and Li, X and Yin, Y and Chang, Y and Xu, G and Zhong, Y and Li, C and Wang, Y and Zhou, M and Wang, G}, title = {The China Alzheimer Report 2025.}, journal = {General psychiatry}, volume = {38}, number = {4}, pages = {e102020}, pmid = {40792123}, issn = {2517-729X}, abstract = {With the sustained growth of the economy and significant changes in social demographics, the issue of elderly-related diseases has increasingly drawn attention, particularly. Alzheimer's disease (AD), as a representative disease of neurodegenerative diseases, has become a major challenge, affecting the health and quality of life of the elderly population severely. In recent years, the incidence, prevalence and mortality rates of AD have increased in China, imposing substantial economic burdens on families, society and the entire healthcare system. To proactively address this challenge and respond to the national 'Healthy China Action' initiative, leading experts from authoritative institutions jointly authored the China Alzheimer Report 2025. Building on previous editions, this report updates epidemiological data on AD in China, thoroughly analyses the latest economic burdens of the disease and comprehensively evaluates the current status of AD diagnosis and treatment services, as well as the allocation of public health resources in our country. Its release reflects China's progress in AD research and prevention, underscores societal concern for elderly health and aims to provide scientific guidance and data support for AD prevention, diagnosis and treatment. It also facilitates academic exchanges and cooperation, enhancing public awareness and promoting active participation in elderly healthcare, towards achieving 'healthy ageing' in China.}, } @article {pmid40792047, year = {2025}, author = {Mannai, A and Ressaissi, A and Merghni, A and Chahdoura, H and Mnif, W and Alelyani, Z and Ben-Attia, M and El-Bok, S and Serralheiro, ML}, title = {Phytochemical Profile and Evaluation of Antioxidant Activity, Enzyme Inhibition and Cell Viability of Leaves Extracts of Three Tunisian Varieties of Diospyros kaki L.}, journal = {Food science & nutrition}, volume = {13}, number = {8}, pages = {e70775}, pmid = {40792047}, issn = {2048-7177}, abstract = {Because of their biological qualities, the leaves of Diospyros kaki L., also known as persimmon, have long been used in traditional Chinese medicine for the treatment of ischemic stroke, angina, internal hemorrhage, hypertension, atherosclerosis, and some infectious diseases. It has also been used in cosmetics, as well as in refreshing drink preparations. In the present study, we have compared the aqueous extract effects of the leaves of the three Tunisian varieties of D. kaki, namely Triumph, Jiro, and Rojo Brillante, prepared by decoction and then filtered. The obtained filtrates were lyophilized and kept cold until analysis. Phytochemical profile and biological activities were performed on the freeze-dried fractions of the different varieties of D. kaki. Analysis of the results shows that the leaf extracts of the three varieties are rich in total phenols and flavonoids (ranking: Rojo Brillante > Triumph > Jiro) and have a high antioxidant activity (EC50 values of 3.8, 8.0 and 12.1 μg/mL respectively for Rojo Brillante, Triumph and Jiro). Using a quadrupole time-of-flight interface and high-resolution tandem liquid chromatography, 29 secondary metabolites of D. kaki leaf decoctions were identified in the three varieties, including several polyphenols such as flavonoids, tannins, organic acids, and others. In addition, these extracts were found to inhibit the function of two key enzymes, acetylcholinesterase (IC50 values of 58, 96 and 210 μg/mL respectively for Rojo Brillante, Triumph and Jiro) and inhibition percentages of 3-hydroxy-3-methylglutaryl-CoA reductase were 61.44%, 57.35%, and 46.28% for Jiro, Triumph, and Rojo Brillante, respectively. However, we noted that these different extracts had no cytotoxic effect on human liver or breast cancer cells in culture until 10 μg/mL. The results reveal that the D. kaki leaves are a potential matrix for the launch of future nutraceuticals, cosmetics, and pharmaceutical specialties such as drugs to combat Alzheimer's disease or to reduce cholesterol levels, as well as an attractive source of ingredients beneficial to health. Comparative analysis of D. kaki leaves showed that the Rojo Brillante variety has a higher content of secondary metabolites than the other two varieties, thus increasing its antioxidant activity and enzyme inhibitory effect, although it is not as cytotoxic as the other two varieties.}, } @article {pmid40791780, year = {2025}, author = {Mahendrarajan, V and Lazarus, HPS and Muthukaliannan, GK and Varghese, S and Easwaran, N}, title = {Membrane vesicles from Red Complex bacteria: key players in oral pathogenesis, immune disruption, systemic diseases, and therapeutic insights.}, journal = {Frontiers in oral health}, volume = {6}, number = {}, pages = {1607931}, pmid = {40791780}, issn = {2673-4842}, abstract = {The oral cavity serves as a habitat for a diverse array of microorganisms, each performing distinct functions, thereby constituting a vibrant and intricate ecological community. The most common pathogenic bacteria in the oral ecosystem are the Red Complex group, which includes Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. These bacteria have several ways to inflict damage, such as creating biofilms and secreting nano-sized vesicles from their outer membrane, called Outer Membrane Vesicles (OMV). OMVs are nano structures that carry proteins, lipids, and toxins from the outer membrane of Gram-negative bacteria. The OMVs of Red Complex bacteria play a role in the onset and development of oral pathological conditions such as gingivitis and periodontitis. Additionally, a substantial body of evidence supports the notion that these OMVs may exert influence on systemic pathologies, including atherosclerosis, alzheimer's, rheumatoid arthritis, and diabetes mellitus. This review will discuss the formation and composition of Red Complex bacterial OMVs, their impacts on the oral environment, the immune response, and their correlations with various systemic diseases. The suggested treatment approach by probiotics and bioactives focuses on the genetic elements that induce the production of OMVs by the Red Complex bacteria, offering a potent means to hinder the advancement of diseases propagated through these OMVs.}, } @article {pmid40791767, year = {2025}, author = {Wang, X and Li, J and Fu, Q and Zheng, H and Duan, S and Gao, Y and Luo, H and Xu, Y}, title = {Cerebral Amyloid Angiopathy-Related Inflammation: Clinical Characteristics and Treatment Experience.}, journal = {Clinical interventions in aging}, volume = {20}, number = {}, pages = {1181-1190}, pmid = {40791767}, issn = {1178-1998}, mesh = {Humans ; *Cerebral Amyloid Angiopathy/complications/diagnosis/diagnostic imaging/therapy/drug therapy ; Male ; Female ; Aged ; Middle Aged ; Retrospective Studies ; Aged, 80 and over ; Adult ; *Inflammation/etiology ; Neuroimaging ; Cognitive Dysfunction/etiology ; }, abstract = {OBJECTIVE: The present study aims to analyze the clinical manifestations, laboratory results, neuroimaging features, treatment interventions, and outcomes in a cohort of patients with cerebral amyloid angiopathy-related inflammation (CAA-ri), providing a deeper understanding of this rare subtype of CAA and enhancing diagnostic precision in clinical practice. METHODS: We conducted a systematic retrospective review of clinical records from 13 consecutive patients who met the diagnostic criteria for probable CAA-ri and were evaluated at the First Affiliated Hospital of Zhengzhou University between January 2021 and August 2024. RESULTS: The study cohort comprised 13 patients (7 males, 6 females; mean age 65.2 years, range 42-81), predominantly presenting with subacute onset (53.8%, n=7). Cognitive impairment (61.5%, n=8) emerged as the most frequent clinical manifestation, followed by headache (46.2%, n=6), epileptic seizures (30.8%, n=4), and focal neurological deficits (23.1%, n=3). Neuroimaging findings across all patients demonstrated asymmetric white matter hyperintensities in conjunction with cortical-subcortical cerebral microbleeds. A subset of patients exhibited cortical superficial siderosis lobar hemorrhage, and/or punctate acute infarction. Among the nine patients who underwent lumbar puncture, five showed elevated cerebrospinal fluid (CSF) pressure and protein levels. All four patients assessed for CSF Alzheimer's disease biomarkers showed reduced Aβ42 and Aβ40 levels, alongside elevated total tau and phosphorylated tau levels. Furthermore, over 70% of the patients who treated with immunosuppressive therapy achieved favorable clinical outcomes. CONCLUSION: Clinical manifestations and neuroimaging abnormalities serve as pivotal non-invasive criteria for guiding clinicians in the diagnosis of CAA-ri. Timely initiation of immunosuppressive therapy in CAA-ri patients can lead to favorable outcomes.}, } @article {pmid40791424, year = {2025}, author = {Adaikkan, C and Islam, MR and Bozzelli, PL and Sears, M and Parro, C and Pao, PC and Sun, N and Kim, T and Abdelaal, K and Sedgwick, M and Kellis, M and Tsai, LH}, title = {A multimodal approach of microglial CSF1R inhibition and GENUS provides therapeutic effects in Alzheimer's disease mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40791424}, issn = {2692-8205}, support = {R01 AG069232/AG/NIA NIH HHS/United States ; R01 NS122742/NS/NINDS NIH HHS/United States ; R56 AG069232/AG/NIA NIH HHS/United States ; }, abstract = {The CSF1R inhibitor PLX3397, an FDA-approved treatment for a rare cancer, has been shown to reduce microglia count, lower inflammation, and increase synaptic markers in mouse models of Alzheimer's disease (AD). However, the effects of PLX3397 on neural function in AD remain largely unknown. Here, we characterized the effects of PLX3397 treatment in 5xFAD mice. While PLX3397 increased synaptic density, it reduced the percentage of neurons phase-locked to gamma oscillations. This neural decoupling was closely associated with gene expression changes related to synapse organization. We investigated whether Gamma ENtrainment Using Sensory (GENUS) stimulation could counterbalance the neural circuit alterations induced by PLX3397. GENUS + PLX3397 restored gamma phase-locking, reshaped gene expression signatures, and improved learning and memory better than either treatment alone in 5xFAD mice. These findings suggest that CSF1R inhibitors like PLX3397 may benefit from a multimodal approach combining microglial targeting with non-invasive sensory stimulation to support neural physiology and improve cognitive function in AD.}, } @article {pmid40791064, year = {2025}, author = {Rodrigues, CC and Carvalho, V and Sotero, FD and Mulroy, E and Guedes, LC}, title = {Efficacy and safety of cholinesterase inhibitors and memantine for cognitive symptoms in patients with Huntington's disease: A systematic review.}, journal = {Journal of Huntington's disease}, volume = {14}, number = {4}, pages = {331-339}, doi = {10.1177/18796397251367689}, pmid = {40791064}, issn = {1879-6400}, mesh = {Humans ; *Memantine/therapeutic use/adverse effects/pharmacology ; *Cholinesterase Inhibitors/therapeutic use/adverse effects/pharmacology ; *Huntington Disease/drug therapy/complications ; *Cognitive Dysfunction/drug therapy/etiology ; }, abstract = {BackgroundHuntington's Disease (HD) is an autosomal dominant neurodegenerative disorder. Clinical features encompass a broad spectrum of movement disorders, psychiatric and cognitive symptoms, often progressing to dementia and imposing a substantial burden on patients and their families. While cholinesterase inhibitors and memantine are often used for symptomatic treatment of Alzheimer's Disease and other dementias, there is currently no approved medication for treating cognitive symptoms in HD.ObjectiveWe aim to review, summarize, and appraise evidence from the literature for the use of cholinesterase inhibitors and memantine in the treatment of cognitive symptoms in patients with HD.MethodsA searched was conducted in PubMed and SCOPUS, from inception until February 2024, for Randomized Clinical Trials (RCTs), open-label, and case-control studies. Quality appraisal was performed using ROBINS-I and ROB2 for non-randomized studies and RCTs, respectively.ResultsFive eligible studies (three RCTs, one extension study, and one retrospective case-control), exploring the use of rivastigmine (n = 3), memantine (n = 1), and donepezil (n = 1) were found. Only two had a follow-up period longer than eight months. Previous cognitive functioning was not specified in three out of five studies. Cognitive measures varied widely, with Unified Huntington's Disease Rating Scale and Mini-Mental State Exam being used more frequently. None of the studies showed a significant improvement in cognitive function. Side effects occurred in up to 50% of patients and were usually considered mild.ConclusionsThere is insufficient evidence in the literature to support the use of cholinesterase inhibitors or memantine for cognitive symptoms in patients with HD.}, } @article {pmid40790925, year = {2025}, author = {Dodel, R and Frölich, L}, title = {Donanemab for Alzheimer's disease: from preclinical research to the clinical application.}, journal = {Expert review of neurotherapeutics}, volume = {25}, number = {10}, pages = {1151-1163}, doi = {10.1080/14737175.2025.2546868}, pmid = {40790925}, issn = {1744-8360}, mesh = {*Alzheimer Disease/drug therapy/physiopathology ; Humans ; Amyloid beta-Peptides/immunology ; *Antibodies, Monoclonal, Humanized/pharmacology/administration & dosage/adverse effects/therapeutic use ; Animals ; Cognitive Dysfunction/drug therapy ; }, abstract = {INTRODUCTION: Donanemab (Kisunla) is a humanized IgG1 monoclonal antibody specifically targeting a modified form of β-amyloid found predominantly within plaques (characterized as N-terminal pyroglutamate Aβ). Recently, it has gained approval for the use in early-stage Alzheimer's disease (AD) encompassing mild cognitive impairment due to AD or mild AD with confirmed brain amyloid pathology. AREAS COVERED: This drug profile discusses donanemab's function, clinical effectiveness, safety, tolerability, health economics, access challenges, and future prospects. This article is based on systematic review that was derived from PubMed. EXPERT OPINION: Donanemab is the third monoclonal antibody introduced for the treatment of individuals in the early stage of AD. While critical dialog continues regarding the potential impacts and role of antibody therapies, its approval signifies considerable progress in addressing the underlying pathology of AD. The authors are confident in the potential of antibodies against Aβ as a promising treatment option and foresee exciting advancements. However, further research is needed on trials extending beyond 18 months of follow-up, postmarketing surveillance, and the application of donanemab in combination with existing treatments and lifestyle interventions. Additionally, significant knowledge gaps and implementation limitations persist and must be addressed.}, } @article {pmid40790613, year = {2025}, author = {Li, B and Wang, S and Kerman, B and Hugo, C and Shwab, EK and Shu, C and Chiba-Falek, O and Arvanitakis, Z and N Yassine, H}, title = {Microglial States Are Susceptible to Senescence and Cholesterol Dysregulation in Alzheimer's Disease.}, journal = {Aging cell}, volume = {24}, number = {10}, pages = {e70189}, pmid = {40790613}, issn = {1474-9726}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; //Vranos Foundation/ ; P30AG72975/AG/NIA NIH HHS/United States ; R01 AG074003/AG/NIA NIH HHS/United States ; T32 GM087237/GM/NIGMS NIH HHS/United States ; RF1 AG076124/AG/NIA NIH HHS/United States ; R01AG055770/AG/NIA NIH HHS/United States ; R21AG056518/AG/NIA NIH HHS/United States ; R01 AG062335/AG/NIA NIH HHS/United States ; R01AG057522/AG/NIA NIH HHS/United States ; U01 MH119509/MH/NIMH NIH HHS/United States ; RF1 AG054012/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; R01 HG008155/HG/NHGRI NIH HHS/United States ; R01 AG058002/AG/NIA NIH HHS/United States ; //Tiny Foundation/ ; RF1 AG077695/AG/NIA NIH HHS/United States ; //Ms. Lynne Nauss/ ; U01 AG061356/AG/NIA NIH HHS/United States ; UG3 NS115064/NS/NINDS NIH HHS/United States ; R01AG15819/AG/NIA NIH HHS/United States ; R01AG054434/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; UH3 NS115064/NS/NINDS NIH HHS/United States ; R01 AG067063/AG/NIA NIH HHS/United States ; RF1 AG062377/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R01 AG054434/AG/NIA NIH HHS/United States ; AARFD-24-1313939/ALZ/Alzheimer's Association/United States ; R01 NS127187/NS/NINDS NIH HHS/United States ; R01 AG055770/AG/NIA NIH HHS/United States ; RF1AG076124/AG/NIA NIH HHS/United States ; P30AG066530/AG/NIA NIH HHS/United States ; RF1 AG054321/AG/NIA NIH HHS/United States ; GC-201711-2014197//Alzheimer's Drug Discovery Foundation/ ; U01 NS110453/NS/NINDS NIH HHS/United States ; R01 AG057522/AG/NIA NIH HHS/United States ; RF1AG077695/AG/NIA NIH HHS/United States ; R01AG067063/AG/NIA NIH HHS/United States ; R21 AG056518/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; *Microglia/metabolism/pathology ; Humans ; *Cholesterol/metabolism ; *Cellular Senescence ; }, abstract = {Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the ROSMAP and SEA-AD cohorts to uncover cell type-specific senescence pathologies. In ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex), microglia emerged as central contributors to AD-associated senescence phenotypes among non-neuronal cells. Homeostatic, inflammatory, phagocytic, lipid-processing, and neuronal-surveillance microglial states were associated with AD-related senescence in both ROSMAP (152,459 microglia nuclei from six brain regions) and SEA-AD (82,486 microglia nuclei) via integrative analysis. We assessed top senescence-associated bioprocesses and demonstrated that senescent microglia exhibit altered cholesterol-related processes and dysregulated cholesterol metabolism. We identified three gene co-expression modules representing cholesterol-related senescence signatures in postmortem brains. To validate these findings, we applied these signatures to snRNA-seq data from iPSC-derived microglia（iMGs) exposed to myelin, Aβ, apoptotic neurons, and synaptosomes. Treatment with AD-related substrates altered cholesterol-associated senescence signatures in iMGs. This study provides the first human evidence that dysregulated cholesterol metabolism in microglia drives cellular senescence in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to attenuate AD progression.}, } @article {pmid40790282, year = {2025}, author = {Higuchi, M and Tagai, K and Takahata, K and Endo, H}, title = {Advances in PET imaging of protein aggregates associated with neurodegenerative disease.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {9}, pages = {506-522}, pmid = {40790282}, issn = {1759-4766}, mesh = {Humans ; *Neurodegenerative Diseases/diagnostic imaging/metabolism ; *Positron-Emission Tomography/methods/trends ; *Protein Aggregates/physiology ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; alpha-Synuclein/metabolism ; *Protein Aggregation, Pathological/diagnostic imaging/metabolism ; }, abstract = {Neurodegenerative diseases such as Alzheimer disease (AD), Parkinson disease, frontotemporal lobar degeneration and multiple system atrophy (MSA) are characterized pathologically by deposition of specific proteins in the brain. Five major neurodegenerative disease-associated proteins - amyloid-β (Aβ), tau, α-synuclein, TAR DNA-binding protein 43 (TDP43) and fused in sarcoma (FUS) - are commonly encountered, and the disease specificity and neurotoxicity of the fibrillar protein assemblies are determined by factors such as the protein type, fibril structure, degree of multimerization and post-translational modifications. This article reviews the latest advances in PET technologies aimed at visualizing neurodegenerative proteinopathies, and highlights the importance of these technologies for emerging diagnostic and therapeutic approaches. PET allows Aβ deposition to be visualized throughout the natural history of AD and following anti-Aβ immunotherapies. However, whether this technology can visualize specific Aβ assembly subspecies primarily targeted by the treatment remains inconclusive. Various PET radiotracers can capture AD-type tau deposits, although only a few are known to react with non-AD tau pathologies, and cryo-electron microscopy has revealed the mode of binding of these compounds to different tau protofibrils. High-contrast PET imaging of α-synuclein lesions in MSA is a recent development in the field, and gradual progress is being made towards visualization of other, less abundant α-synuclein pathologies. Imaging of TDP43 and FUS deposits presents particular challenges, which might be overcome by establishing public-private partnerships focused on biomarker development.}, } @article {pmid40787376, year = {2025}, author = {Gebeş-Alperen, B and Evren, AE and Sağlik Özkan, BN and Karaburun, AC and Gundogdu-Karaburun, N}, title = {Novel Benzofuran-3-yl-methyl and Aliphatic Azacyclics: Design, Synthesis, and In Vitro and In Silico anti-Alzheimer Disease Activity Studies.}, journal = {ACS omega}, volume = {10}, number = {30}, pages = {32829-32843}, pmid = {40787376}, issn = {2470-1343}, abstract = {Neurological disorders represent a significant burden on human health, particularly as global life expectancy continues to rise. Among these conditions, Alzheimer's disease is notably prevalent. Of greater concern, if left untreated or unaddressed, Alzheimer's disease can progress to dementia, leading to severe cognitive decline and a substantial reduction in quality of life. In this study, 15 novel benzofuran-azacyclic hybrids were designed and synthesized. The final compounds were evaluated for their inhibitory potency on AChE and BACE-1 enzymes, and in silico studies were performed to clarify their binding modes. Finally, structure-activity relationships (SARs) were proposed for future studies. The results indicated that the most promising compound is 4m, which contains N-(2-hydroxyethyl)-piperazine and benzofuran moieties. These moieties effectively occupied the substrate channel of the AChE enzyme and the catalytic cleft of the BACE-1 enzyme. Additionally, compounds 4e (benzyl piperidine) and 4h (2-furoyl piperazine) showed dual inhibitory activity on both enzymes. In conclusion, the tubular form with a stopper group shows great potential for the treatment of Alzheimer's disease, as it blocks the entrance cavity of the AChE active pocket for the substrate and increases the stability of the inactive BACE-1 enzyme. Moreover, electrolytes, specifically sodium ions in this case, play a crucial role in stabilizing the 4m-BACE-1 protein complex. For further studies, we suggest that the tubular form with a stopper can serve as a potential pharmacophore and an appropriate starting point for drug development.}, } @article {pmid40786362, year = {2025}, author = {Chowdhury, A and Bhasin, G and Ganti, L}, title = {Bibliometric Analysis of the Epidemiological Research on Alzheimer's Disease Treatment.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e87484}, pmid = {40786362}, issn = {2168-8184}, abstract = {Alzheimer's disease presents a complex global health issue. It is characterized by a decline in cognitive function, starting with memory impairment, and extending to impact reasoning, language abilities, and spatial awareness. Despite decades of research, Alzheimer's disease remains a global challenge lacking long-term treatments. Institutions like the Karolinska Institutet, Columbia University, the University of California San Francisco (UCSF), and the University of Pittsburgh contribute significantly to Alzheimer's research, with a growth in publications in 2022 post-COVID-19. While current treatments offer symptomatic relief, there's a need for disease-modifying therapies targeting its mechanisms. This analysis aims to provide a comprehensive overview of the available research and medical literature on Alzheimer's disease by employing bibliometric methods to identify publication trends, leading research institutions, and the evolving focus from symptomatic treatments to disease-modifying therapies. This paper seeks to analyze the research papers on Alzheimer's disease and catalog the metadata associated with each paper.}, } @article {pmid40785177, year = {2025}, author = {Varshney, H and Gaur, K and Subhan, I and Fatima, J and Jyoti, S and I, M and Shahid, M and -, R and Siddique, YH}, title = {Neuroprotective Effects of Fenugreek Leaf Extract in a Drosophila Model of Alzheimer's Disease Expressing Human Aβ-42.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050385870250721072643}, pmid = {40785177}, issn = {1875-5828}, abstract = {INTRODUCTION: Much emphasis has been given to the biological activities of Fenugreek against various diseased conditions. This study investigated the effect of fenugreek leaf extract on behavioural and cognitive function of transgenic Drosophila having human Aβ-42 expression in the neurons, herein referred to as Alzheimer's disease model flies (AD flies). MATERIALS AND METHODS: AD flies were exposed to four different doses of fenugreek leaf extract (FE) containing i.e., 0.005, 0.010, 0.015 and 0.02 g/ml for 30 days. Thereafter, behavioural and cognitive assessment was done using climbing ability, activity pattern, aversive phototaxis and odour choice indexes. The life span of different groups of flies was also recorded. The effect of FE on the oxidative stress markers, acetylcholinesterase, monoamine oxidase (MAO) and caspase 3 and 9 activities was determined. The deposition of Aβ-42 aggregates in the brain tissue of the flies was studied by performing immunostaining. Also, the metabolic profile of different groups of flies was studied by performing LC-MS/MS. Compared with control flies, 22 selected metabolites were found to be upregulated and downregulated among transgenic AD flies and FE exposed AD flies compared to control. RESULTS: The findings of this study showed the neuroprotective role of fenugreek extract, which could be employed for the treatment of Alzheimer's disease. The AD flies exposed to FE showed a dose-dependent postponement in the decline of climbing ability, activity and cognitive impairments. A significant dose dependent increase in the life span was also noticed in the AD flies exposed to FE. A significant reduction in the oxidative stress, acetylcholinesterase, monoamine oxidase, and caspase-3&9 activities was also observed in a dose dependent manner. The results obtained from the immunostaining suggest the reduction in the deposition of Aβ-42 fibril, which was also confirmed by the docking studies showing the energetically favoured interaction useful for inhibiting the acetylcholinesterase and Aβ-42 aggregates. DISCUSSION: This study demonstrates the neurological potency of fenugreek leaf extract (FE) in a Drosophila model of AD due to its antioxidantive, anti-cholinesterase, and neuroprotective properties. Using a combination of behavioral, biochemical, histological, and metabolomic approaches, we evaluated the therapeutic potential of FE in mitigating AD-like symptoms in transgenic flies expressing Aβ-42. CONCLUSION: Fenugreek leaf extract may serve as a potential natural remedy for slowing down or alleviating the progression of AD.}, } @article {pmid40784967, year = {2025}, author = {Şener, B and Açıcı, K and Sümer, E}, title = {Improving early detection of Alzheimer's disease through MRI slice selection and deep learning techniques.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {29260}, pmid = {40784967}, issn = {2045-2322}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Deep Learning ; *Magnetic Resonance Imaging/methods ; Early Diagnosis ; Cognitive Dysfunction/diagnostic imaging/diagnosis ; Aged ; Brain/diagnostic imaging/pathology ; Male ; Female ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disorder marked by cognitive decline, memory loss, and behavioral changes. Early diagnosis, particularly identifying Early Mild Cognitive Impairment (EMCI), is vital for managing the disease and improving patient outcomes. Detecting EMCI is challenging due to the subtle structural changes in the brain, making precise slice selection from MRI scans essential for accurate diagnosis. In this context, the careful selection of specific MRI slices that provide distinct anatomical details significantly enhances the ability to identify these early changes. The chief novelty of the study is that instead of selecting all slices, an approach for identifying the important slices is developed. The ADNI-3 dataset was used as the dataset when running the models for early detection of Alzheimer's disease. Satisfactory results have been obtained by classifying with deep learning models, vision transformers (ViT) and by adding new structures to them, together with the model proposal. In the results obtained, while an accuracy of 99.45% was achieved with EfficientNetB2 + FPN in AD vs. LMCI classification from the slices selected with SSIM, an accuracy of 99.19% was achieved in AD vs. EMCI classification, in fact, the study significantly advances early detection by demonstrating improved diagnostic accuracy of the disease at the EMCI stage. The results obtained with these methods emphasize the importance of developing deep learning models with slice selection integrated with the Vision Transformers architecture. Focusing on accurate slice selection enables early detection of Alzheimer's at the EMCI stage, allowing for timely interventions and preventive measures before the disease progresses to more advanced stages. This approach not only facilitates early and accurate diagnosis, but also lays the groundwork for timely intervention and treatment, offering hope for better patient outcomes in Alzheimer's disease. The study is finally evaluated by a statistical significance test.}, } @article {pmid40784648, year = {2025}, author = {Zhang, F and Gou, J}, title = {Using multiple biomarkers for patient enrichment in two-stage clinical designs.}, journal = {Contemporary clinical trials}, volume = {156}, number = {}, pages = {108012}, doi = {10.1016/j.cct.2025.108012}, pmid = {40784648}, issn = {1559-2030}, mesh = {Humans ; *Biomarkers/analysis ; *Research Design ; *Alzheimer Disease/therapy/drug therapy ; *Precision Medicine/methods ; Sample Size ; *Clinical Trials as Topic/methods ; }, abstract = {Enrichment strategies play a critical role in modern clinical trial design, especially as precision medicine advances the focus on patient-specific efficacy. By targeting biomarker-defined populations most likely to benefit, these strategies improve efficiency, reduce sample sizes and costs, accelerate timelines, and minimize unnecessary exposure to treatment-related risks and side effects. Recent developments in enrichment design have introduced biomarker randomness and accounted for the correlation structure between treatment effect and biomarker, resulting in a two-stage threshold enrichment design. However, existing methods are limited to a single continuous biomarker. While incorporating multiple biomarkers can improve the accuracy of target population identification, no study has examined how to incorporate multiple continuous biomarkers into enrichment designs due to the challenges in determining multiple thresholds. To fully utilize information from all relevant biomarkers, we propose novel two-stage enrichment designs capable of handling two or more continuous biomarkers. Our framework accommodates two popular treatment effect metrics including average treatment effect (ATE) and the standardized ATE. We illustrate our method using a hypothetical clinical trial involving early-stage Alzheimer's patients and assess the impact of stage one sample size on threshold estimation through a simulation study. Overall, our proposed two-stage enrichment designs offer researchers greater flexibility in integrating multiple continuous biomarkers. The findings from our study provide valuable insights for the advancement of enrichment trial methodology.}, } @article {pmid40784620, year = {2025}, author = {Liu, L and Jiang, M and Zhang, Y and Lv, L and Wang, X and Yang, X}, title = {Acori Tatarinowii Rhizoma inhibited neuroinflammation in Alzheimer's disease rats by modulating the intestinal flora.}, journal = {Brain research}, volume = {1865}, number = {}, pages = {149878}, doi = {10.1016/j.brainres.2025.149878}, pmid = {40784620}, issn = {1872-6240}, mesh = {Animals ; *Gastrointestinal Microbiome/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; Male ; *Acorus ; Rats, Sprague-Dawley ; Rhizome ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Brain/drug effects/metabolism/pathology ; Drugs, Chinese Herbal/pharmacology ; *Plant Extracts/pharmacology ; Amyloid beta-Peptides ; }, abstract = {Alzheimer's disease (AD) is a degenerative disorder causing neuronal loss and cognitive deficits, which is associated with intestinal flora dysbiosis. Acori Tatarinowii Rhizoma (ATR) is the dried rhizome of Acorus tatarinowii Schott., and exhibits neuroprotective effects. We aimed to investigate the therapeutic mechanism of ATR in AD. AD rat models were constructed by intracerebroventricular injection of Aβ1-42, with gavage of ATR water extract (5, 10, and 20 mg/kg) for 21 days. Behavior tests, HE staining, immunohistochemistry, ELISA, immunofluorescence, and 16S rRNA sequencing were performed. In AD rats, ATR improved cognitive dysfunction and brain histopathological damage, with reduced Aβ1-42, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, malondialdehyde, ionized calcium binding adaptor molecule, and glial fibrillary acidic protein expression, and higher superoxide dismutase activity, indicating inhibition of neuroinflammation by ATR. Moreover, Ruminococcus was strongly associated with ATR treatment for AD, which mainly enriched in Carbohydrate metabolism, Amino acid metabolism, and Lipid metabolism. Meanwhile, Dorea was negatively correlated with behavioural indicators and positively correlated with inflammatory factors, whereas g_Adlercreutzia showed the opposite trend. These findings suggested that ATR may attenuate neuroinflammation and improved AD by modulating intestinal flora and inhibiting microglia and astrocyte activation, providing a scientific basis for its clinical application in AD.}, } @article {pmid40784614, year = {2025}, author = {Yang, Y and Zhang, L and Zhao, Y and Chen, Z and Wang, P and Yang, Z}, title = {Aβ-damaged neural stem cells migration and differentiation through Wnt3a/β-catenin pathway: Protective effects of 17β-E2.}, journal = {Neuroscience letters}, volume = {865}, number = {}, pages = {138350}, doi = {10.1016/j.neulet.2025.138350}, pmid = {40784614}, issn = {1872-7972}, mesh = {Animals ; *Neural Stem Cells/drug effects/metabolism ; *Wnt3A Protein/metabolism ; *beta Catenin/metabolism ; *Cell Movement/drug effects ; Rats, Sprague-Dawley ; *Cell Differentiation/drug effects ; *Amyloid beta-Peptides/toxicity ; Rats ; Female ; Cells, Cultured ; *Peptide Fragments/toxicity ; Signal Transduction/drug effects ; Neurogenesis/drug effects ; Glycogen Synthase Kinase 3 beta/metabolism ; }, abstract = {Alzheimer's disease (AD) is a widespread central nervous system degenerative disease in the elderly population. This study aims to uniquely targets this sex-specific vulnerability by investigating the effects of 17β-E2 on the differentiation and migration capabilities of Aβ-damaged NSCs and its potential mechanisms-a critical gap for female-focused AD therapies. Primary NSCs isolated from neonatal SD rats were treated with Aβ25-35 (60 μM) to mimic AD pathology, followed by 17β-E2 (100 nM) with or without BX795 (a Wnt3a/β-catenin inhibitor). Results showed that Aβ significantly suppressed Wnt3a, LRP6, and β-catenin mRNA/protein levels while increasing GSK-3β expression. 17β-E2 treatment reversed these effects, enhancing phosphorylated GSK-3β (Ser9) and β-catenin, which were abolished by BX795. Transwell assays demonstrated that 17β-E2 rescued Aβ-damaged migration deficits, accompanied by elevated p-MLC and Cdc42 protein levels. Furthermore, 17β-E2 promoted neuronal differentiation, increasing MAP2 + and βIII-tubulin + cells with enhanced dendritic complexity, whereas BX795 counteracted these benefits. These findings indicate that 17β-E2 mitigates Aβ-damaged NSCs dysfunction by activating the Wnt3a/β-catenin pathway via GSK-3β phosphorylation, highlighting its therapeutic potential for AD by enhancing neurogenesis and NSC mobility.}, } @article {pmid40784611, year = {2025}, author = {Maurice, T}, title = {Prevention of memory impairment and hippocampal injury with blarcamesine in an Alzheimer's disease model.}, journal = {Neuroscience letters}, volume = {865}, number = {}, pages = {138349}, doi = {10.1016/j.neulet.2025.138349}, pmid = {40784611}, issn = {1872-7972}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/prevention & control/pathology ; *Memory Disorders/prevention & control ; Mice ; *Hippocampus/drug effects/pathology/metabolism ; Amyloid beta-Peptides/toxicity ; Disease Models, Animal ; Male ; Peptide Fragments/toxicity ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice, Inbred C57BL ; }, abstract = {Alzheimer's disease (AD) is the most common dementia, with rising global prevalence, still incomplete pathogenetic understanding and very limited effective therapies. Recent advances in biomarker identification of Aβ peptides and phospho-tau protein, and in anti-Aβ immunotherapy are suggesting that more early intervention will be more effective. Alternative therapeutic strategies to anti-Aß immunotherapy have received comparably less attention, yet one specific approach toward upstream neuroprotection by improvement of intracellular calcium homeostasis, activation of endogenous neuroprotection and restoration of autophagy through sigma-1 receptor activation recently demonstrated positive clinical data with oral blarcamesine in a phase IIb/III trial in 508 patients with early AD. AD-preventive approaches beyond lifestyle interventions become attractive candidates when meeting criteria of: (i) record of effective early intervention in mild disease, (ii) record of human safety, (iii) ease of administration, (iv) scalability to population level, (v) relative cost-effectiveness considering longer-term preventive use at population level. Here, we assessed blarcamesine's efficacy at preventing memory impairment and brain oxidative injury in the mouse preclinical model induced by intracerebroventricular injection of aggregated Aβ25-35 peptide, that permitted a clean preventive approach before administration of the pathology-inducing amyloidogenic Aβ fragment. We observed significant preventions of Aβ25-35-induced memory impairments, for both spatial working and contextual long-term memories, and of Aβ25-35-induced increase in lipid peroxidation in the mouse hippocampi. These new insights, together with blarcamesine's clinical record in early AD render blarcamesine an attractive candidate for AD pharmacological prevention.}, } @article {pmid40784568, year = {2025}, author = {Yang, Y and Guan, PP and Wang, P}, title = {Triptolide induces the secretion of insulin, through which it alleviates the tauopathies of Alzheimer's disease via inhibiting the phosphorylation of tau.}, journal = {Biochemical pharmacology}, volume = {242}, number = {Pt 3}, pages = {117223}, doi = {10.1016/j.bcp.2025.117223}, pmid = {40784568}, issn = {1873-2968}, mesh = {Animals ; *Diterpenes/pharmacology/therapeutic use ; *Alzheimer Disease/metabolism/drug therapy ; *tau Proteins/metabolism/antagonists & inhibitors ; Phosphorylation/drug effects/physiology ; *Phenanthrenes/pharmacology/therapeutic use ; Mice ; *Insulin/metabolism ; Epoxy Compounds/pharmacology/therapeutic use ; Male ; *Tauopathies/metabolism/drug therapy ; Mice, Transgenic ; Mice, Inbred C57BL ; Humans ; }, abstract = {Triptolide (TP) has shown its therapeutic effects on Alzheimer's disease (AD) via decreasing the overloading of β-amyloid protein (Aβ). However, the roles and mechanisms of TP in the pathogenesis of tau have not been revealed until now. To this end, the current study aimed to assess the effects of TP on AD via tau-associated mechanisms. In detail, TP treatment decreases the phosphorylation of tau, which results in attenuating the cognitive decline of PS19 mice. In the mechanisms, we found that TP treatment elevates the levels of insulin, which lowers the blood glucose, leading to superior performance in the glucose tolerance test, inhibition of AMP-activated protein kinase (AMPK), and the change of serum triglycerides and cholesterol. The in vitro studies demonstrating that TP increases insulin production via cAMP-response element binding protein (CREB)- and pancreatic-duodenal homeobox factor 1 (PDX-1)-dependent mechanisms in MIN6 cells further supported the in vivo findings. By enhancing insulin production, TP upregulates protein O-GlcNAc modification and inhibits Ca[2+]/calmodulin-dependent protein kinase 2 (CaMK2) activity to reduce tau phosphorylation in both in vivo and in vitro experiments. Additionally, metabolic changes decrease the activity of the CCAAT/enhancer binding protein beta (C/EBPβ)/asparagine endopeptidase (AEP) signaling pathway, significantly reducing the associated neuroinflammation. Guided by these mechanisms, TP shows inhibitory effects on tau phosphorylation via an insulin secretion-dependent pathway.}, } @article {pmid40784411, year = {2025}, author = {Yang, J and Chen, Y and Dong, G and Ma, Y and Lin, R and Yuan, Y}, title = {Immune-metabolic perspective on the association of seven psychiatric disorders and five common auditory diseases: a bidirectional two-sample Mendelian randomization study and mediation analysis.}, journal = {Journal of affective disorders}, volume = {391}, number = {}, pages = {120044}, doi = {10.1016/j.jad.2025.120044}, pmid = {40784411}, issn = {1573-2517}, mesh = {Humans ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Depressive Disorder, Major/immunology/genetics ; *Mental Disorders/immunology/genetics/metabolism ; Mediation Analysis ; Autism Spectrum Disorder/immunology/genetics ; *Hearing Disorders/immunology/genetics ; Presbycusis/immunology/genetics ; Bipolar Disorder/immunology/genetics ; }, abstract = {INTRODUCTION: Although the relationship between psychiatric disorders and common auditory diseases has been discovered in observational studies, the causal linkage between them remains inconclusive. METHODS: The bidirectional two-sample Mendelian randomization (MR) analysis was performed, drawing on the most recent and expansive genome-wide association studies (GWAS) data for seven psychiatric disorders and five common auditory diseases. Additionally, a mediation analysis was conducted using data on 731 immune cell phenotypes and 1400 metabolite levels to explore potential mediating factors influencing the causal pathways. RESULTS: Autism Spectrum Disorder (ASD) could increase the risk of presbycusis (odds ratio [OR] = 1.161 [95 % confidence interval (CI), 1.042-1.295], P-value = 0.007) through CD25 on CD45RA- CD4 not regulatory T cell (Mediation effect β = 0.017), and Major Depressive Disorder (MDD) could increase the risk of vertigo (OR = 1.215 [95 % CI, 1.043-1.415], P-value = 0.012) through CD33+ HLA DR+ CD14dim Absolute Count (Mediation effect β = 0.007). Alzheimer's Disease (AD) could reduce the risk of presbycusis through four metabolite levels related to lipid metabolism. And Bipolar Disorder I (BD I) could reduce the risk of vertigo, as well as sudden sensorineural hearing loss (SSNHL) could reduce the risk of Post Traumatic Stress Disorder (PTSD). CONCLUSION: This study underscores the intricate causal links between psychiatric disorders and auditory diseases. Mediation analyses indicate that immune cells are facilitators of positive effects, while metabolite levels play a protective role. These insights offer potential pathways for more effective clinical diagnosis and treatment.}, } @article {pmid40784409, year = {2025}, author = {Sing, R and Shikha, D and Goswami, C}, title = {TRPM8 modulation alters uptake of Transferrin-mediated Fe[3+], mitochondrial Fe[2+] and intracellular Ca[2+]-levels in microglia.}, journal = {Neurochemistry international}, volume = {189}, number = {}, pages = {106031}, doi = {10.1016/j.neuint.2025.106031}, pmid = {40784409}, issn = {1872-9754}, mesh = {*Microglia/metabolism/drug effects ; *TRPM Cation Channels/metabolism ; Animals ; Mice ; *Mitochondria/metabolism/drug effects ; *Iron/metabolism ; *Calcium/metabolism ; *Transferrin/metabolism ; Cell Line ; }, abstract = {Microglia play an important role in the immunity of the central nervous system, crucial in maintaining homeostasis. However, under diseased conditions, this cell accumulates Fe[2+/3+], triggering inflammatory and neurotoxic effects that contribute to neurodegenerative disorders such as Alzheimer's and Parkinson's. Hence, the study of dysregulated microglial activation and overload of Fe[2+/3+] is crucial in the context of neurodegenerative conditions. Emerging research has identified cold-sensitive ion channels, i.e., TRPM8 in microglia, which can regulate key subcellular functions. This study explores the regulatory function of the TRPM8 in Fe[2+/3+] metabolism and its implications for potential ferroptosis in BV2 microglial cells. We used highly specific fluorescence probes, pharmacological modulators of TRPM8 and performed life cell imaging to understand the uptake of Transferrin-488, mitochondrial Fe[2+]-level, cellular Ca[2+]-levels in live BV2 cells under different experimental conditions. Our findings reveal that TRPM8 activation leads to enhanced Transferrin-488-mediated cytosolic Fe[3+]-uptake, disrupts mitochondrial superoxide levels, and promotes cell death. Interestingly, under inflammatory conditions induced by LPS treatment, TRPM8 exhibits a distinct functional role. These results position TRPM8 as an important regulator of microglial Fe[2+/3+] metabolism. This study indicates the involvement of TRPM8 in overload of Fe[2+/3+] leading to ferroptosis and potential for M1-M2 polarization in microglia. These findings impose TRPM8 as a potential therapeutic target for neurodegenerative diseases, and aging.}, } @article {pmid40782673, year = {2025}, author = {Sabbagh, MN and Kennedy, J and Majeed, J and Decourt, B}, title = {Alzheimer's disease: Clinical trials to watch.}, journal = {Med (New York, N.Y.)}, volume = {6}, number = {8}, pages = {100771}, doi = {10.1016/j.medj.2025.100771}, pmid = {40782673}, issn = {2666-6340}, mesh = {*Alzheimer Disease/drug therapy ; Humans ; Clinical Trials as Topic ; Oligonucleotides, Antisense/therapeutic use ; Glucagon-Like Peptide-1 Receptor Agonists ; Amyloid beta-Peptides/antagonists & inhibitors ; tau Proteins/antagonists & inhibitors ; }, abstract = {Second-generation anti-amyloid therapies (ATTs) offer new options for early Alzheimer's disease treatment, but with modest efficacy and documented adverse events. Here we highlight several ongoing clinical trials, aiming to develop therapeutic agents with higher efficacy and better safety profiles including third-generation ATTs, aggregation inhibitors, Sigma-1 receptor agonists, anti-tau antisense oligonucleotides, and GLP-1 receptor agonists.}, } @article {pmid40782185, year = {2025}, author = {Bergamo, G and Liguori, C}, title = {Are sleep disturbances modifiable risk factors for mild cognitive impairment and dementia? A systematic review of large studies.}, journal = {Sleep & breathing = Schlaf & Atmung}, volume = {29}, number = {4}, pages = {269}, pmid = {40782185}, issn = {1522-1709}, mesh = {Humans ; *Cognitive Dysfunction/epidemiology/diagnosis/etiology ; *Dementia/epidemiology/etiology/diagnosis ; Risk Factors ; *Sleep Wake Disorders/epidemiology/diagnosis/complications ; Aged ; }, abstract = {Studies have shown a connection between sleep disorders, mild cognitive impairment and dementia. In this context, the present systematic review aimed to determine in large studies whether sleep disturbances are modifiable risk factors for cognitive decline. Following the application of inclusion and exclusion criteria, this systematic review selected 15 studies, with large cohort of subjects included (more than 1000 participants), who were longitudinally observed. Studies predominantly used questionnaires and interviews to collect subjective data on sleep. Eleven studies were based on subjective measurements, one was based on the International Classification of Diseases - 9th Edition diagnosis codes, and three based on objective actigraphic measurements. No study used polysomnographic assessments for the evaluation of sleep disorders.The results of this systematic review showed that extreme sleep durations (either too short or too long), daytime sleepiness, circadian sleep-wake cycle disruption, and variation in sleep patterns are factors associated with an increased risk of developing cognitive decline and dementia. Actigraphy, as an objective instrument for monitoring the sleep-wake rhythm, provided further insights into the association between sleep problems and longitudinal cognitive decline. These findings emphasize the strong connection between sleep disturbances, circadian rhythm, and the risk of developing dementia and Alzheimer's disease (AD). Sleep disorders may serve as an early indicator for cognitive decline, also considering that they may represent a modifiable risk factor for dementia. Therefore, recognition and treatment of sleep problems should be included in the prevention strategies against cognitive decline, opening up new opportunities for the prevention and treatment of cognitive impairment and AD.}, } @article {pmid40780474, year = {2025}, author = {Manzoor, M and Iqbal, MO and Dan, W and Barkat, MQ and Iqbal Khan, MS and Syed, W and Al-Rawi, MBA and Ni, F}, title = {Syringaresinol from Cinnamomum cassia (L.) J.Presl ameliorates cognitive deficits and AD pathology via AMPK in a DM-AD mouse model.}, journal = {Journal of ethnopharmacology}, volume = {353}, number = {Pt A}, pages = {120374}, doi = {10.1016/j.jep.2025.120374}, pmid = {40780474}, issn = {1872-7573}, mesh = {Animals ; Male ; *AMP-Activated Protein Kinases/metabolism ; *Cinnamomum aromaticum/chemistry ; Mice ; *Cognitive Dysfunction/drug therapy/etiology ; Disease Models, Animal ; *Lignans/pharmacology/isolation & purification/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/etiology ; Oxidative Stress/drug effects ; *Diabetes Mellitus, Experimental/drug therapy/complications ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Maze Learning/drug effects ; }, abstract = {Syringaresinol (SYR), a major lignan in food analogous TCM (Cinnamomum cassia (L.) J.Presl) possesses antioxidant, anti-inflammatory, antidiabetic, and antiaging effects. However, its protective role and mechanisms in diabetes-related cognitive dysfunction (DM-AD) remain unclear. AIM OF THE STUDY: We aimed to assess the protective effects of SYR on metabolic dysfunction associated cognitive decline through the modulation of oxidative stress, neuroinflammation and AMPK activation. MATERIALS AND METHODS: This study involved extraction of C. cassia bark and isolation of SYR, structurally characterized by HR-MS and [1]H NMR. A DM-AD mouse model was established using HFD and STZ. In vivo assessments included body weight, food intake, fasting glucose, GTT, and ITT. Cognitive function was evaluated using Y-maze, MWM, and NOR tests. SYR's interaction with AMPK was examined through western blotting, molecular docking, and AMPK inhibitor experiments. Oxidative stress markers and neuroinflammatory cytokines were analyzed via biochemical assays and RT-PCR. RESULTS: SYR treatments at 5 and 15 mg/kg significantly improved metabolic parameters by reducing body weight gain, enhancing glucose tolerance and insulin sensitivity, and restoring hepatic lipid balance. It also alleviated cognitive impairments with improved memory and learning. Mechanistically, SYR activated AMPK, supported by phosphorylation and molecular docking (-8.7 kcal/mol). In addition, SYR also enhanced antioxidant defense and suppressed neuroinflammatory and increased anti-inflammatory cytokines in the DM-AD brain. Co-treatment with the AMPK inhibitor abolished SYR's cognitive and anti-inflammatory benefits to confirm AMPK's key role in neuroprotective effects of SYR. CONCLUSIONS: In conclusion, SYR demonstrates metabolic and neuroprotective effects comparable to metformin, primarily through AMPK activation therefore it could be used as a promising natural therapeutic candidate for DM-associated AD.}, } @article {pmid40780467, year = {2025}, author = {Sugandhi, VV and Gattu, K and Mundrathi, V and Khairnar, R and Arshad, T and Kumar, S and Cho, H}, title = {Intranasal delivery of rapamycin via brain-targeting polymeric micelles for Alzheimer's disease treatment.}, journal = {International journal of pharmaceutics}, volume = {683}, number = {}, pages = {126011}, pmid = {40780467}, issn = {1873-3476}, support = {R16 GM154661/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Sirolimus/administration & dosage/pharmacokinetics/chemistry ; Micelles ; *Alzheimer Disease/drug therapy/metabolism ; Administration, Intranasal ; Polyethylene Glycols/chemistry ; *Brain/metabolism/drug effects ; Mice ; Male ; Drug Carriers/chemistry ; Polyesters/chemistry ; Amyloid beta-Peptides/metabolism ; Humans ; *Immunosuppressive Agents/administration & dosage/pharmacokinetics ; Particle Size ; Maze Learning/drug effects ; Drug Delivery Systems ; Disease Models, Animal ; }, abstract = {Alzheimer's disease (AD) is a long-term neurological disorder associated with neuroinflammation and amyloid-beta (Aβ) aggregation, which leads to a decline in cognitive and behavioral changes. Rapamycin (Rapa) is an immunosuppressive drug effective in preventing organ rejection after a kidney transplant. In the last few years, orally delivered Rapa has emerged as a potential candidate for improving cognitive function in patients with AD. However, it is evident that long-term oral treatment of Rapa causes systemic toxicity, and although controversial, it may even trigger the aggregation of Aβ deposition. This study investigated the therapeutic potential of intranasally delivered brain-targeting polymeric micelles carrying Rapa. We successfully prepared Fibronectin CS1 peptide-conjugated poly(ethylene glycol)-block-poly(D, L-lactic acid) (FibCS1-PEG-b-PLA) micelles carrying Rapa, which were 98.08 ± 1.15 nm in particle size with a polydispersity index of 0.21 ± 0.01. FibCS1-PEG-b-PLA micelles showed a significant improvement for nasal permeation of Rapa across RPMI-2650 epithelial cells. Behavioral studies such as corner, novel object recognition and Morris Water Maze tests showed promising results towards the improvement of cognitive function in a 3xTg-AD mice model when treated with intranasal FibCS1-PEG-b-PLA micelles carrying RAPA at a dose of 0.2 mg/kg (q4dx5). The western blot and ELISA results of the brain tissues of 3xTg-AD mice treated with intranasal FibCS1-PEG-b-PLA micelles carrying Rapa showed significant reductions in Aβ and two pro-inflammation markers (e.g. interleukin (IL)-1β, tumor necrosis factor (TNF)-α). Here, we conclude that brain-targeting FibCS1-PEG-b-PLA micelles carrying Rapa were effective in reaching the brain via intranasal route, reduced pro-inflammatory markers and Aβ, and improved cognitive function in AD-induced mice.}, } @article {pmid40779804, year = {2025}, author = {Ferjančič Benetik, S and Proj, M and Knez, D and Košak, U and Meden, A and Krajšek, K and Pišlar, A and Horvat, S and Švajger, U and Tešić, N and Pulkrabkova, L and Soukup, O and Skarka, A and Andrys, R and Brazzolotto, X and Igert, A and Nachon, F and Dias, J and Detka, J and Gdula-Argasińska, J and Wyska, E and Szafarz, M and Manik, A and Płachtij, N and Musílek, K and Sałat, K and Obreza, A and Gobec, S}, title = {Targeting Neuroinflammation and Cognitive Decline: First-in-Class Dual Butyrylcholinesterase and p38α Mitogen-Activated Protein Kinase Inhibitors.}, journal = {Journal of medicinal chemistry}, volume = {68}, number = {16}, pages = {17378-17411}, pmid = {40779804}, issn = {1520-4804}, support = {U01 AG066722/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Humans ; Male ; Mice ; Alzheimer Disease/drug therapy ; *Butyrylcholinesterase/chemistry/metabolism ; *Cholinesterase Inhibitors/pharmacology/chemistry/therapeutic use ; *Cognitive Dysfunction/drug therapy ; Crystallography, X-Ray ; Lipopolysaccharides ; *Mitogen-Activated Protein Kinase 14/antagonists & inhibitors/metabolism ; Models, Molecular ; *Neuroinflammatory Diseases/drug therapy ; *Protein Kinase Inhibitors/pharmacology/chemistry/therapeutic use ; Structure-Activity Relationship ; }, abstract = {The currently approved drugs for the treatment of Alzheimer's disease (AD) fail to address its interconnected pathological processes. Inhibition of butyrylcholinesterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK) offers an innovative dual approach to mitigate two major drivers of neurodegeneration in AD: cholinergic deficit and neuroinflammation. Using structure-based drug design and a library of known p38α MAPK inhibitors, we developed first-in-class, selective dual BChE/p38α MAPK inhibitors with balanced activity against both targets. The X-ray crystal structures of the two most promising molecules bound to both enzymes were solved. Those ligands effectively reduced the production of proinflammatory markers in vitro and ex vivo in phytohemagglutinin/lipopolysaccharide neuroinflammation models. Remarkably, these compounds also significantly improved cognition in scopolamine- and lipopolysaccharide-induced models of cognitive dysfunction in mice. Because our dual-acting inhibitors target both the symptoms and the underlying neuropathology, they offer an innovative and comprehensive strategy to combat AD.}, } @article {pmid40779063, year = {2025}, author = {Bulai, IM and Ferraresso, F and Gladiali, F}, title = {Optimal control of monomers and oligomers degradation in an Alzheimer's disease model.}, journal = {Journal of mathematical biology}, volume = {91}, number = {3}, pages = {27}, pmid = {40779063}, issn = {1432-1416}, support = {20227TRY8H//Italian Ministry for Research and Education/ ; ECS 00000038//Italian Ministry for Research and Education/ ; ECS 00000038//Italian Ministry for Research and Education/ ; EU-CUP-J55F21004240001//Università degli Studi di Sassari/ ; EU-CUP-J55F21004240001//Università degli Studi di Sassari/ ; }, mesh = {*Alzheimer Disease/metabolism/therapy ; Humans ; *Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors ; Mathematical Concepts ; Brain/metabolism ; Computer Simulation ; Immunotherapy/methods ; *Models, Biological ; Protein Multimerization ; }, abstract = {The aggregation and accumulation of oligomers of misfolded Aβ-amyloids in the human brain is one of the possible causes for the onset of the Alzheimer's disease in the early stage. We introduce and study a new ODE model for the evolution of Alzheimer's disease based on the interaction between monomers, proto-oligomers, and oligomers of Aβ amyloid protein in a small portion of the human brain, based upon biochemical processes such as polymerization, depolymerization, fragmentation and concatenation. We further introduce the possibility of controlling the evolution of the system via a treatment that targets the monomers and/or the oligomers. We observe that a combined optimal treatment on both monomers and oligomers induces a substantial decrease of the oligomer concentration at the final stage. A single treatment on oligomers performs better than a single treatment on monomers. These results shed a light on the effectiveness of immunotherapy using anti-Aβ antibodies, targeting monomers or oligomers. Several numerical simulations show how the oligomer concentration evolves without treatment, with single monomer/oligomer treatment, or with a combined treatment.}, } @article {pmid40778542, year = {2025}, author = {Li, R and Xiong, W and Sun, C}, title = {Hippocampal neural stem cells in Alzheimer's disease: bridging neurogenesis, extracellular vesicles, and multimodal therapeutic paradigms.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-21}, doi = {10.1080/00207454.2025.2540989}, pmid = {40778542}, issn = {1563-5279}, abstract = {Alzheimer's disease (AD) presents a formidable challenge in neurodegenerative medicine because of its complex pathophysiology and the absence of effective disease-modifying therapies. Emerging evidence suggests that impaired adult hippocampal neurogenesis (AHN), a dynamic process essential for cognitive plasticity, is a mechanistic contributor to AD progression. This review highlights the role of hippocampal neural stem cells (NSCs) in the pathogenesis of AD, including the molecular mechanisms underlying the neurogenic decline in AD and their potential impact on cognitive resilience. We summarize current therapeutic approaches, including pharmacological agents and non-pharmacological interventions (e.g. exercise, cognitive training, dietary strategies, and neurostimulation therapies), and explore their influence on neurogenesis. Additionally, we explore the potential application of NSCs in AD treatment, specifically through the use of NSC-derived extracellular vesicles (NSC-EVs) as a novel therapeutic modality. By integrating insights from AHN research and cutting-edge therapeutic advancements, this review emphasizes the therapeutic potential of promoting neurogenesis to address cognitive decline and advance treatment strategies for AD.}, } @article {pmid40778306, year = {2025}, author = {Li, S and Huang, N and Wang, M and Huang, W and Shi, J and Luo, Y and Huang, J}, title = {GLP-1R as a potential link between diabetes and Alzheimer's disease.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1601602}, pmid = {40778306}, issn = {1663-4365}, abstract = {There is growing interest in the relationship between Alzheimer's disease (AD) and diabetes mellitus (DM), and the glucagon-like peptide-1 receptor (GLP-1R) may be an important link between these two diseases. The role of GLP-1R in DM is principally to regulate glycemic control by stimulating insulin secretion, inhibiting glucagon secretion, and improving insulin signaling, thereby reducing blood glucose levels. In AD, GLP-1R attenuates the pathological features of AD through mechanisms such as anti-inflammatory effects, the reduction in amyloid-beta (Aβ) deposition, the promotion of Aβ clearance, and improvements in insulin signaling. Notably, AD and DM share numerous pathophysiological mechanisms, most notably the disruption of insulin signaling pathways in the brain. These findings further underscore the notion that GLP-1R plays pivotal roles in both diseases. Taken together, these findings lead us to conclude that GLP-1R not only plays an important role in the treatment of DM and AD but also may serve as a bridge between these two diseases. Future research should focus on elucidating the detailed molecular mechanisms underlying the actions of GLP-1R in both diseases and exploring the development of GLP-1R agonists with dual therapeutic benefits for AD and DM. This could pave the way for innovative integrated treatment strategies to improve outcomes for patients affected by these intertwined conditions.}, } @article {pmid40778305, year = {2025}, author = {Zhang, X and Wijenayake, S and Hossain, S and Liu, Q}, title = {Estimating progression of Alzheimer's disease with extracellular vesicle-related multi-omics risk models.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1617611}, pmid = {40778305}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's Disease (AD) is heterogeneous and shows complex interconnected pathways at various biological levels. Risk scores contribute greatly to disease prognosis and biomarker discovery but typically represent generic risk factors. However, large-scale multi-omics data can generate individualized risk factors. Filtering these risk factors with brain-derived extracellular vesicles (EVs) could yield key pathologic pathways and vesicular vehicles for treatment delivery. METHODS: A list of 460 EV-related genes was curated from brain tissue samples in the ExoCarta database. This list was used to select genes from transcriptomics, proteomics, and DNA methylation data. Significant risk factors included demographic features (age, sex) and genes significant for progression in transcriptomics data. These genes were selected using Cox regression, aided by the Least Absolute Shrinkage and Selection Operator (LASSO), and were used to construct three risk models at different omics levels. Gene signatures from the significant risk factors were used as biomarkers for further evaluation, including gene set enrichment analysis (GSEA) and drug perturbation analysis. RESULTS: Nine EV-related genes were identified as significant risk factors. All three risk models predicted high/low risk groups with significant separation in Kaplan-Meier analysis. Training the transcriptomics risk models on EV-related genes yielded better AD classification results than using all genes in an independent dataset. GSEA revealed Mitophagy and several other significant pathways related to AD. Four drugs showed therapeutic potential to target the identified risk factors based on Connectivity Map analysis. CONCLUSION: The proposed risk score model demonstrates a novel approach to AD using EV-related large-scale multi-omics data. Potential biomarkers and pathways related to AD were identified for further investigation. Drug candidates were identified for further evaluation in biological experiments, potentially transported to targeted tissues via bioengineered EVs.}, } @article {pmid40778177, year = {2025}, author = {Villeneuve, S and Poirier, J and Breitner, JCS and Tremblay-Mercier, J and Remz, J and Raoult, JM and Yakoub, Y and Gallego-Rudolf, J and Qiu, T and Valdez, AF and Mohammediyan, B and Javanray, M and Metz, A and Sanami, S and Ourry, V and Wearn, A and Pastor-Bernier, A and Edde, M and Gonneaud, J and Strikwerda-Brown, C and Tardif, CL and Gauthier, CJ and Descoteaux, M and Dadar, M and Vachon-Presseau, É and Baril, AA and Ducharme, S and Montembeault, M and Geddes, MR and Soucy, JP and Rajah, N and Laforce, R and Bocti, C and Davatzikos, C and Bellec, L and Rosa-Neto, P and Baillet, S and Evans, AC and Collins, DL and Chakravarty, MM and Blennow, K and Zetterberg, H and Spreng, RN and Binette, AP and , }, title = {The PREVENT-AD cohort: accelerating Alzheimer's disease research and treatment in Canada and beyond.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40778177}, support = {P30 AG048785/AG/NIA NIH HHS/United States ; R01 AG068563/AG/NIA NIH HHS/United States ; R01 EB026299/EB/NIBIB NIH HHS/United States ; }, abstract = {The PREVENT-AD is an investigator-driven study that was created in 2011 and enrolled cognitively normal older adults with a family history of sporadic AD. Participants are deeply phenotyped and have now been followed annually for more than 12 years [median follow-up 8.0 years,SD 3.1]. Multimodal MRI, genetic, neurosensory, clinical, cerebrospinal fluid and cognitive data collected until 2017 on 348 participants who agreed to open sharing with the neuroscience community were already available. We now share a new release including 6 years of additional follow-up cognitive data, and additional MRI follow-ups, clinical progression, new longitudinal behavioral and lifestyle measures (questionnaires, actigraphy), longitudinal AD plasma biomarkers, amyloid-beta and tau PET, magnetoencephalography, as well as neuroimaging analytic measures from all MRI modalities. We describe the PREVENT-AD study, the data shared with the global research community as well as the model we created to sustain longitudinal follow-ups while also allowing new innovative data collection.}, } @article {pmid40778159, year = {2025}, author = {Khorsand, B and Ghanbarian, E and Rabin, L and Sajjadi, SA and Ezzati, A}, title = {Incremental Value of Plasma Biomarkers in Predicting Clinical Decline Among Cognitively Unimpaired Older Adults: Results from the A4 trial.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.07.22.25332015}, pmid = {40778159}, abstract = {OBJECTIVE: To evaluate the predictive utility of baseline plasma biomarkers and neuropsychological measures in identifying cognitively unimpaired older adults at risk of cognitive and functional decline over five years. BACKGROUND: The clinical and biological heterogeneity observed in Alzheimer's disease (AD) complicates design of trials and the identification of appropriate participants. Identifying practical tools to define more homogenous subgroups could enhance clinical trial enrichment and improve early detection. METHODS: We analyzed data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and its companion Evaluation of Amyloid Risk and Neurodegeneration (LEARN) observational study. The sample included 866 cognitively unimpaired, amyloid-positive individuals from the A4 trial (comprising participants randomized to receive Solanezumab or placebo) and 343 cognitively unimpaired, amyloid-negative individuals from LEARN. Cognitive/functional decline was defined as an increase of ≥0.5 in Clinical Dementia Rating-Global Score (CDR-GS) during a 240-week period. Using multiple logistic regression models, we evaluated the predictive value of demographic variables, APOE4 status, amyloid PET SUVR, plasma P-tau217, and Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (ADCS-PACC) in three groups: A4-Solanezumab, A4-placebo and LEARN. In a sub-study including 656 participants with available data, we assessed the incremental value of additional plasma biomarkers (Aβ42/Aβ40 ratio, GFAP, and NfL). RESULTS: Both plasma P-tau217 and ADCS-PACC significantly improved predictive performance over a base model with demographics and APOE4. The full model combining all predictor variables yielded the highest AUCs across A4 Solanezumab (0.80 ± 0.06), A4 Placebo (0.80 ± 0.06), and LEARN (0.78 ± 0.08). Adding other plasma biomarkers yielded small but consistent improvements in AUC (1-3%). CONCLUSIONS: Plasma P-tau217 and ADCS-PACC, individually and in combination, improved prediction of cognitive/functional decline in asymptomatic older adults. Predictive models incorporating these scalable and non-invasive measures improved clinical trial enrichment and earlier identification of at-risk individuals preclinical AD.}, } @article {pmid40778154, year = {2025}, author = {Guarnier, G and Reinelt, J and Molloy, EN and Mihai, PG and Einaliyan, P and Valk, S and Modestino, A and Ugolini, M and Mueller, K and Wu, Q and Babayan, A and Castellaro, M and Villringer, A and Scherf, N and Thierbach, K and Schroeter, ML}, title = {Cascaded Multimodal Deep Learning in the Differential Diagnosis, Progression Prediction, and Staging of Alzheimer's and Frontotemporal Dementia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40778154}, support = {U19 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Dementia is a complex condition whose multifaceted nature poses significant challenges in the diagnosis, prognosis, and treatment of patients. Despite the availability of large open-source data fueling a wealth of promising research, effective translation of preclinical findings to clinical practice remains difficult. This barrier is largely due to the complexity of unstructured and disparate preclinical and clinical data, which traditional analytical methods struggle to handle. Novel analytical techniques involving Deep Learning (DL), however, are gaining significant traction in this regard. Here, we have investigated the potential of a cascaded multimodal DL-based system (TelDem), assessing the ability to integrate and analyze a large, heterogeneous dataset (n=7,159 patients), applied to three clinically relevant use cases. Using a Cascaded Multi-Modal Mixing Transformer (CMT), we assessed TelDem's validity and (using a Cross-Modal Fusion Norm - CMFN) model explainability in (i) differential diagnosis between healthy individuals, AD, and three sub-types of frontotemporal lobar degeneration (ii) disease staging from healthy cognition to mild cognitive impairment (MCI) and AD, and (iii) predicting progression from MCI to AD. Our findings show that the CMT enhances diagnostic and prognostic accuracy when incorporating multimodal data compared to unimodal modeling and that cerebrospinal fluid (CSF) biomarkers play a key role in accurate model decision making. These results reinforce the power of DL technology in tapping deeper into already existing data, thereby accelerating preclinical dementia research by utilizing clinically relevant information to disentangle complex dementia pathophysiology.}, } @article {pmid40778134, year = {2025}, author = {Ackley, SF and Flanders, M and Murchland, A and Chen, R and Wang, J and Shah, SJ and Huey, ED and Glymour, MM}, title = {Evaluation of Amyloid Removal as a Surrogate for Cognitive Decline: Pilot Analysis in Individual-Level Data from the A4 Study of Solanezumab.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40778134}, support = {K00 AG068431/AG/NIA NIH HHS/United States ; R00 AG073454/AG/NIA NIH HHS/United States ; F99 AG083306/AG/NIA NIH HHS/United States ; P01 AG082653/AG/NIA NIH HHS/United States ; K99 AG088369/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Amyloid removal has been used as a surrogate outcome in Alzheimer's disease trials, allowing accelerated approval of aducanumab and lecanemab. The A4 (Alzheimer's Clinical Trial Consortium A4/LEARN) trial's individual-level data supports novel methods to evaluate amyloid's validity as a surrogate for cognitive decline. METHODS: In 812 participants, cognitive and functional change was measured using the CDR-SB score. Instrumental-variable analysis estimated the effect of amyloid reduction; mediation analysis quantified solanezumab's cognitive effect mediated by amyloid reduction. RESULTS: Each 10 centiloid reduction due to randomization to treatment was associated with 0.026 higher CDR-SB (95% CI: -0.013, 0.065). 14.6% of solanezumab's effect on cognition was mediated by amyloid reduction (95% CI: -122%, 208%). DISCUSSION: Estimates showing near-zero effects of amyloid reduction on cognitive decline suggest minimal impact of amyloid reduction in populations with little disease progression. Replication in anti-amyloid trials with larger treatment effects could guide treatment and regulatory decisions.}, } @article {pmid40777911, year = {2025}, author = {Shojapour, M and Asgharzade, S}, title = {Regenerative Medicine in the Treatment of Alzheimer's Disease: A Narrative Review.}, journal = {Iranian journal of public health}, volume = {54}, number = {7}, pages = {1399-1410}, pmid = {40777911}, issn = {2251-6093}, abstract = {Alzheimer's disease (AD) is one of the progressive neurodegenerative diseases, memory impairments and multiple cognitive and behavioral deficits characterize that. We aimed to evaluate the molecular mechanisms involved in the pathogenesis of AD. It introduces the regenerative medicine approach as a novel therapeutic strategy based on the pathogenesis of AD that would be efficient. Our data was collected using databases such as the Web of Science, PubMed, Scopus, and Google Scholar. We summarized the available therapeutic strategies to induce neurodegeneration that can increase the number of neurons and their survival and improve the plasticity of synapses and synaptic activity. There is a different approach to treatment. In first-line treatment, focusing declines the amyloid beta and hypophosphorylated tau protein accumulation. It inhibits acetylcholinesterase, but in regenerative medicine focusing on treatment via gene therapy, cell therapy, and tissue engineering. As a proposed solution for AD in recent years, the use of inhibitors of the pathogenesis of AD is known as a supportive therapeutic approach, but the multi-potential treatment of regenerative medicine has been able to provide promising results in treating neurodegenerative patients.}, } @article {pmid40777747, year = {2025}, author = {Mathew, LS and Marathe, A and Aman, A and Vats, A and Joy, T and Rao, YL}, title = {Bridging the molecular and clinical aspects of resveratrol in Alzheimer's disease: a review.}, journal = {3 Biotech}, volume = {15}, number = {9}, pages = {284}, pmid = {40777747}, issn = {2190-572X}, abstract = {Alzheimer's disease (AD) is a progressive brain disorder that affects neurological functioning specifically targeting cognition, memory and behaviour. Pathology starts with the accumulation of tau proteins which on phosphorylation can be destructive for brain function. With gold standard drugs like Donepezil, there have been several attempts made to discover adjuvant therapeutic molecules such as plant-based products that could not only ease the ill-toward effects of these drugs, but also lead to the betterment of the patients suffering from AD. These are crucial in the management of patients of AD, by associations with psychological vulnerabilities and the overall loss of health of such individuals 'Resveratrol' is one such plant-based molecule which is a stilbene polyphenol present in many of the commonly occurring plants. Resveratrol is reported to have anti-oxidant and anti-inflammatory properties which brings about the neuroprotection. Several studies have also been conducted that targets the signalling cascades involved during the progression of AD. This review attempts to give a collective information of its properties, its synthesis, metabolism and mechanisms that could drive researchers forward for its therapeutic applications during the treatment of Alzheimer's disease.}, } @article {pmid40777460, year = {2025}, author = {Kehmeier, MN and Famiano, A and Cullen, AE and Leonhardt, T and Ferguson, S and Snyder, M and McCurdy, CE and Tyrrell, D and Alkayed, NJ and Walker, AE}, title = {APOE4 genotype negates the benefits of 17β-estradiol on cerebrovascular endothelial and mitochondrial function.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.07.23.666474}, pmid = {40777460}, issn = {2692-8205}, support = {R00 AG068309/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Postmenopausal females who carry an APOEε4 allele are at higher risk of late-onset Alzheimer's Disease compared to age-matched APOEε4 males. Estrogen deficiency predisposes females to an increased risk of vascular, cognitive, and metabolic impairments. While estrogen and APOE genotype are known to impact metabolic and mitochondrial function in the brain, their cerebrovascular effects are less understood. Thus, the purpose of this study was to determine the interaction between APOE genotype and estrogen on cerebrovascular endothelial and mitochondrial function. METHODS: Young female homozygous APOEε3 and APOEε4 mice (n=19-20/group; ~6 months old) fed a high-fat diet were ovariectomized (OVX), OVX and supplemented with 17β-estradiol, or left intact. RESULTS: In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilation, which was rescued by 17β-estradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-estradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-estradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-estradiol in the APOEε4 mice. In cerebral arteries and arterioles, mitochondrial complexes I and I+II respiration were lower in APOEε4 mice compared with APOEε3 mice. 17β-estradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes, and pro-inflammatory factors. In contrast to other outcomes, we found that 17β-estradiol treatment was associated with lower cerebral artery stiffness in APOEε4 but not APOEε3 mice. CONCLUSIONS: Overall, these results indicate that the APOE genotype modulates the impact of estrogen on the cerebral vasculature. We found that 17β-estradiol enhances cerebrovascular endothelial and mitochondrial function in APOEε3 mice but not in APOEε4 mice. The results suggest that 17β-estradiol supplementation has more cerebrovascular benefit for APOEε4 non-carriers. NOVELTY & SIGNIFICANCE: What is known?: Females have twice the risk of Alzheimer's disease compared with males, and the APOE4 genetic variant is associated with a greater risk for Alzheimer's disease compared with the APOE3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction of APOE genotype and estrogens on cognitive function and other brain outcomes. What new information does this article contribute?: Vascular outcomes were not measured in previous studies examining the interaction between APOE genotype and estrogens. As such, we aimed to determine the impact of APOE4 genotype on the cerebrovascular response to estradiol. We found that estradiol improved cerebral artery endothelial function and mitochondrial respiration in APOE3 mice following ovariectomy. In contrast, APOE4 mice were refractory to the beneficial effects of estradiol on cerebrovascular endothelial and mitochondrial function. The broader implication of this research is that APOE genotype may be a consideration when prescribing hormone replacement therapy to menopausal females due to the impact on vascular outcomes.}, } @article {pmid40777445, year = {2025}, author = {Gu, J and Fuller, C and Carbonetto, P and He, X and Zheng, J and Li, H}, title = {Identifying the genetic basis and molecular mechanisms underlying phenotypic correlation between complex human traits using a gene-based approach.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40777445}, issn = {2692-8205}, support = {R01 AG058742/AG/NIA NIH HHS/United States ; R21 AG064357/AG/NIA NIH HHS/United States ; R21 AG071899/AG/NIA NIH HHS/United States ; }, abstract = {Phenotypic correlations between complex human traits have long been observed based on epidemiological studies. However, the genetic basis and underlying mechanisms are largely unknown. Here we developed a gene-based approach to measure genetic overlap between a pair of traits and to delineate the shared genes/pathways, through three steps: 1) translating SNP-phenotype association profile to gene-phenotype association profile by integrating GWAS with eQTL data using a newly developed algorithm called Sherlock-II; 2) measuring the genetic overlap between a pair of traits by a normalized distance and the associated p value between the two gene-phenotype association profiles; 3) delineating genes/pathways involved. Application of this approach to a set of GWAS data covering 59 human traits detected significant overlap between many known and unexpected pairs of traits; a significant fraction of them are not detectable by SNP based genetic similarity measures. Examples include Cancer and Alzheimer's Disease (AD), Rheumatoid Arthritis and Crohn's disease, and Longevity and Fasting glucose. Functional analysis revealed specific genes/pathways shared by these pairs. For example, Cancer and AD are co-associated with genes involved in hypoxia response and P53/apoptosis pathways, suggesting specific mechanisms underlying the inverse correlation between them. Our approach can detect yet unknown relationships between complex traits and generate mechanistic hypotheses and has the potential to improve diagnosis and treatment by transferring knowledge from one disease to another.}, } @article {pmid40777354, year = {2025}, author = {Ramanan, S and Johnson, GV}, title = {A Bioinformatic Analysis of BAG Protein Interactors and Pathways in Alzheimer's and Parkinson's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40777354}, issn = {2692-8205}, support = {R01 AG073121/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders. While the symptoms and general etiology may be different, these two diseases share significant common features in terms of their disease pathogenesis. Within the scope of neurodegenerative disorders, the Bcl-2 associated athanogene (BAG) family proteins and associated interactors have been a key area of focus. The BAG family is a group of proteins that contain at least one evolutionarily conserved BAG domain. Despite this similarity, their interactions and functions can vary widely. So far, research has predominantly scrutinized individual BAG proteins, rather than explore potential cooperative actions among family members. Some BAG family members may function together thereby indicating potential interactions within this family. Although connections among BAG members have been observed, their role in neurodegenerative disorders, such as AD and PD, remains largely uncharacterized. This mini review explores the common pathways, intersections, and differences within these interactions as well as their link to AD and PD. Using computational techniques to mine transcriptomic data, several groupings of pathways that these BAG family members are involved in were identified in the context of AD and PD. Understanding these pathways and their relationships may uncover potential gaps in current research and help identify novel therapeutic targets for the treatment of these neurodegenerative diseases.}, } @article {pmid40776985, year = {2025}, author = {Huang, Y and Lei, W and Shen, J and Sun, J}, title = {Tat-NR2B9c prevent cognitive dysfunction in mice modeling Alzheimer's Disease induced by Aβ1-42 via perturbing PSD-95 interactions with NR2B-subtype receptors.}, journal = {IBRO neuroscience reports}, volume = {19}, number = {}, pages = {317-322}, pmid = {40776985}, issn = {2667-2421}, abstract = {BACKGROUND: Alzheimer's Disease (AD) is one of common progressive and fatal neurodegenerative disorders,and its main clinical symptoms are progressive memory impairment and cognitive dysfunction. The Tat-NR2B9c, a peptide was known as postsynaptic density protein-95(PSD-95) inhibitors, has shown clinical efficacy as a neuroprotective effects in some diseases such as acute stroke and neuropathic pain.The aim of the study is to clarify whether Tat-NR2B9c has the same neuroprotective effects in AD. METHODS: Studies were performed in mice modeling AD induced by Aβ1-42. Animals were treated with drugs after modeling AD for 14 days,and the spatial learning and memory ability were assessed after drug treatment. Then, mice were euthanized for biochemical tests. RESULTS: The levels of PSD-95 and NR2B decreased,and the levels of N-methyl-d-aspartate receptor-postsynaptic density protein-95 interaction increased in hippocampus in AD mice. Tat-NR2B9c can improve spatial learning and memory ability in AD mice by perturbing PSD-95 interactions with NR2B-subtype but not inhibiting PSD-95 levels. CONCLUSION: Tat-NR2B9c can prevent cognitive dysfunction in mice modeling AD induced by Aβ1-42 via perturbing PSD-95 interactions with NR2B-subtype receptors.}, } @article {pmid40776228, year = {2025}, author = {Gao, T and Madanian, S and Templeton, J and Merkin, A}, title = {Clinical Decision Support for Alzheimer's: Challenges in Generalizable Data-Driven Approach.}, journal = {Studies in health technology and informatics}, volume = {329}, number = {}, pages = {1780-1781}, doi = {10.3233/SHTI251211}, pmid = {40776228}, issn = {1879-8365}, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Decision Support Systems, Clinical/organization & administration ; Magnetic Resonance Imaging/methods ; *Deep Learning ; Neural Networks, Computer ; Brain/diagnostic imaging ; }, abstract = {This paper reviews the current research on Alzheimer's disease and the use of deep learning, particularly 3D-convolutional neural networks (3D-CNN), in analyzing brain images. It presents a predictive model based on MRI and clinical data from the ADNI dataset, showing that deep learning can improve diagnosis accuracy and sensitivity. We also discuss potential applications in biomarker discovery, disease progression prediction, and personalised treatment planning, highlighting the ability to identify sensitive features for early diagnosis.}, } @article {pmid40775619, year = {2025}, author = {Ren, X and Edwards, L and Mann, E and Horiuchi, S and Tsuchiyagaito, A}, title = {Repetitive negative thinking, self-reflection, and perceived cognitive dysfunction in older adults: a cross-sectional study.}, journal = {BMC psychiatry}, volume = {25}, number = {1}, pages = {773}, pmid = {40775619}, issn = {1471-244X}, support = {P20 GM121312/GM/NIGMS NIH HHS/United States ; 2P20GM121312-06/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Aged ; Cross-Sectional Studies ; *Cognitive Dysfunction/psychology ; *Depression/psychology ; Aged, 80 and over ; *Rumination, Cognitive/physiology ; *Pessimism/psychology ; Japan ; *Thinking ; Middle Aged ; }, abstract = {As the global population ages, understanding cognitive dysfunction, including Alzheimer's Disease and other forms of dementia, is crucial. With the growing prevalence of these disorders, it is essential to identify and understand potential factors that maintain cognitive function and potentially delay severe cognitive dysfunction. This study examined the roles of repetitive negative thinking (RNT) and reflection in subjective cognitive dysfunction among older adults, with an additional consideration of their association with depressive symptoms. RNT, which is common in depression, has been associated with cognitive impairments. However, its unique influence on cognitive dysfunction is unclear. Conversely, reflection, considered to protect against adverse cognitive outcomes, is less explored. Using the Rumination Response Scale (RRS), we hypothesize that RNT may be more strongly linked to cognitive dysfunction than reflection, even when controlling for depressive symptoms. Two-hundred and seventy-six older adults (137 male, 139 female) from Japan participated in the study, providing measures of RRS-brooding (an index of RNT), RRS-reflection (an index of reflection), depressive symptoms, and self-reported cognitive dysfunction. The results showed higher reflection, but not RNT, was associated with greater subjective cognitive dysfunction [β = 0.28, p =.03], even after controlling for depressive symptoms. Importantly, the association between reflection and cognitive dysfunction demonstrated sex differences, with reflection significantly accounting for cognitive dysfunction in female [β = 0.46, p =.01] but not in male. These findings highlight the significance of evaluating specific subtypes of repetitive thoughts and sex differences when investigating the association with perceived cognitive dysfunction. Future research should continue to explore the mechanisms underlying these associations and the prevention and treatment of cognitive dysfunctions.}, } @article {pmid40775373, year = {2025}, author = {Kelleher-Andersson, J and Yoon, E and Green, C and McFarlane, C and Bagheri, D and Thomas, LP and Turner, RS}, title = {First-in-human study of neuron regenerative therapy NNI-362 to evaluate the safety, pharmacokinetics, and pharmacodynamics in healthy aged population.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {185}, pmid = {40775373}, issn = {1758-9193}, support = {U01 AG082687/AG/NIA NIH HHS/United States ; U01AG082687 (PI-Kelleher-Andersson)/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Aged ; Double-Blind Method ; Female ; Middle Aged ; *tau Proteins/blood ; *Nerve Regeneration/drug effects ; Biomarkers/blood ; }, abstract = {BACKGROUND: A placebo-controlled, double-blind Phase 1a trial examined the safety, tolerability, and pharmacokinetics of NNI-362 as well as the pharmacodynamic outcome of plasma phosphorylated tau[181] (p-tau[181]). METHODS: Oral NNI-362 and placebo were randomized in healthy, cognitively-unimpaired individuals (ages 50-72) at a 3:1 ratio, with sponsor, principal investigator, and subjects all blinded. Plasma levels of p-tau[181] were determined in the placebo and the two highest arms of 120 and 240 mg NNI-362. Plasma biomarker was examined for statistical change from baseline. RESULTS: NNI-362 treatment was safe and well tolerated in older individuals. NNI-362, at the two highest multiple doses, significantly reduced plasma p-tau[181] levels compared to pretreatment levels (P < 0.0012 to P < 0.0009), while no change occurred in placebo groups. CONCLUSIONS: These findings suggest in older subjects, oral NNI-362 appeared safe, well tolerated and reduced plasma p-tau[181]. Phase 2 studies of NNI-362 are warranted for Alzheimer's disease and age-related degenerative disorders. TRIAL REGISTRY NUMBER: NCT04074837. First registered: 2019-08-27.}, } @article {pmid40774425, year = {2025}, author = {Markley, AE and Stratton, KM and Cho, GY and Schmidt, NB and Suhr, J and Sheffler, JL and Nguyen, C and Schubert, FT and Quiles, JRG and Potter, MR and Meynadasy, MA and Irvin, SM and Allan, NP}, title = {Study design and protocol for cognitive anxiety sensitivity treatment for anxiety in adults with mild cognitive impairment or dementia.}, journal = {Contemporary clinical trials}, volume = {156}, number = {}, pages = {108044}, doi = {10.1016/j.cct.2025.108044}, pmid = {40774425}, issn = {1559-2030}, mesh = {Humans ; *Cognitive Dysfunction/psychology ; *Cognitive Behavioral Therapy/methods ; *Anxiety/therapy/psychology ; Aged ; Male ; Female ; Randomized Controlled Trials as Topic ; *Caregivers/psychology ; *Dementia/psychology ; Therapy, Computer-Assisted/methods ; Quality of Life ; *Alzheimer Disease/psychology ; }, abstract = {BACKGROUND: Anxiety is prevalent among older adults with mild cognitive impairment (MCI) and mild Alzheimer's disease and related disorders (ADRD) and may contribute to accelerated cognitive decline and increased care partner burden. Computerized Anxiety Sensitivity Treatment (CAST) is a novel, CBT-based intervention targeting anxiety sensitivity, which has not been widely tested in this population. METHODS: This randomized controlled trial (NCT05748613) will compare CAST to a health education control (HEC) in 194 dyads consisting of older adults with MCI/mild ADRD and their care partners. Primary outcomes include reductions in anxiety sensitivity and anxiety symptoms. Secondary outcomes include measures of mental health and well-being symptoms, improved cognitive performance, and decreased care partner burden. Participants will be assessed at baseline, during two intervention sessions, and follow-ups at 1-, 3-, and 6-months post-intervention. EXPECTED OUTCOMES: CAST will significantly lower anxiety sensitivity (AS) post-intervention and reduce anxiety compared to HEC. Secondary hypotheses propose that CAST will reduce other mental symptoms and improve cognitive functioning more effectively than HEC. Additionally, CAST will alleviate care partner distress and improve their quality of life compared to HEC, with the secondary hypothesis suggesting that these effects will be mediated by reductions in AS in older adults. Furthermore, reductions in AS from pre- to post-intervention will account for the effect of CAST on anxiety, and the secondary hypothesis suggesting that reductions in interoceptive fear conditioning will also contribute to the observed anxiety reduction. CLINICALTRIALS: gov registration: #NCT05748613.}, } @article {pmid40773904, year = {2025}, author = {Ahmad, SR and Zeyaullah, M and Zahrani, Y and Khan, MS and Muzammil, K and Dawria, A}, title = {Phytochemicals from Bacopa monnieri as small molecule modulators of MARK4: A multi-modal strategy for preventing Alzheimer's disease-causing tau aggregation.}, journal = {Journal of molecular graphics & modelling}, volume = {140}, number = {}, pages = {109135}, doi = {10.1016/j.jmgm.2025.109135}, pmid = {40773904}, issn = {1873-4243}, mesh = {*Bacopa/chemistry ; *Alzheimer Disease/drug therapy/metabolism/prevention & control ; Humans ; *tau Proteins/chemistry/metabolism ; *Phytochemicals/chemistry/pharmacology ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Thermodynamics ; *Protein Aggregates/drug effects ; }, abstract = {Neurodegenerative tauopathies, such as Alzheimer's disease, are closely associated with the dysregulation of tau phosphorylation, a process regulated in part by the serine/threonine kinase MARK4. In this study, we explored phytochemicals derived from Bacopa monnieri as potential natural inhibitors of MARK4. Using pressurized liquid extraction with an ethanol-water mixture, we efficiently extracted bioactive compounds from Bacopa leaves. LC-MS analysis identified 25 distinct phytoconstituents spanning flavonoids, triterpenoids, cucurbitacins, sterols, and alkaloids. In silico analysis revealed that several compounds, including oroxindin, cucurbitacin B, and bacosine, bind strongly to the catalytic pocket of MARK4. Molecular dynamics simulations confirmed their stability within the MARK4 active site, with oroxindin demonstrating the most favorable thermodynamic and conformational profile. Principal component and free energy landscape analyses further supported their capacity to stabilize MARK4 in low-energy conformations. Microscale thermophoresis further validated high-affinity binding of MARK4 with oroxindin, while other four compounds also show strong interaction with MARK4. MTT assays in SH-SY5Y cells confirmed the non-cytotoxic nature of all five lead compounds across a concentration range of 10 nM to 10 μM. Cellular assays revealed a significant reduction in Tau-GFP aggregates upon treatment with the compounds, particularly oroxindin. These results highlight oroxindin and other Bacopa monnieri phytochemicals as promising natural inhibitors of MARK4, with potential to attenuate tau pathology in neurodegenerative diseases.}, } @article {pmid40773726, year = {2025}, author = {Rajkumar, M and Presley, SID and Govindaraj, P and Girigoswami, K and Meenambigai, K and Deepak, P and Deepika, B and Elbehairi, SEI and Alfaifi, MY and Shati, AA and Menaa, F}, title = {Biomedical Prowess of Clitoria mariana (L.) Flower Methanolic Extract: A Comprehensive In Vitro, Ex Vivo, and In Vivo Evaluation.}, journal = {Chemistry & biodiversity}, volume = {22}, number = {12}, pages = {e01051}, doi = {10.1002/cbdv.202501051}, pmid = {40773726}, issn = {1612-1880}, mesh = {*Plant Extracts/chemistry/pharmacology/isolation & purification ; *Flowers/chemistry/metabolism ; Animals ; Humans ; Zebrafish/embryology ; *Anti-Bacterial Agents/pharmacology/chemistry/isolation & purification ; Methanol/chemistry ; Microbial Sensitivity Tests ; *Clitoria/chemistry ; *Antineoplastic Agents, Phytogenic/pharmacology/chemistry/isolation & purification ; *Antioxidants/pharmacology/chemistry/isolation & purification ; Staphylococcus aureus/drug effects ; *Cholinesterase Inhibitors/pharmacology/chemistry/isolation & purification ; Acetylcholinesterase/metabolism ; Cell Line, Tumor ; Butyrylcholinesterase/metabolism ; *Anti-Inflammatory Agents/pharmacology/chemistry/isolation & purification ; Drug Screening Assays, Antitumor ; Dose-Response Relationship, Drug ; Cell Survival/drug effects ; Cell Proliferation/drug effects ; }, abstract = {Clitoria mariana L., a medicinal plant widely distributed in Asia, has long been used in folk medicine. This study investigates the biomedical potential of its methanolic flower extract. Gas chromatography-mass spectrometry (GC-MS) and phytochemical analyses revealed the presence of alkaloids, phenolic compounds, and flavonoids. The phytoextract elicited significant antioxidant activity, as demonstrated by various assays, and displayed broad-spectrum antibacterial effects, producing the largest zones of inhibition (ZI) against Staphylococcus aureus, Micrococcus luteus, Escherichia coli, and Salmonella typhi, supported by MIC/MBC (minimum inhibition concentration/minimum bactericidal concentration) values indicative of bactericidal action. Notably, the phytoextract demonstrated marked cytotoxicity against various cancer cell lines, with the highest potency against MCF-7, followed by HeLa, A549, and PC-3, based on IC50 (concentration required to inhibit 50%) values. Its anti-inflammatory properties, comparable to aspirin (reference standard), increased with concentration. Additionally, the phytoextract showed promise in Alzheimer's disease (AD) treatment by inhibiting AChE (acetylcholinesterase) and BuChE (butyrylcholinesterase) activities more effectively than galantamine (GA), the standard drug. The zebrafish embryo assay evidenced its excellent biocompatibility. Overall, this study offers the first comprehensive phytochemical and pharmacological evaluation of C. mariana's methanolic extract, underscoring its potential relevance in managing inflammatory conditions.}, } @article {pmid40773100, year = {2025}, author = {Balki, S and Gautam, AS and Balaji, PG and Yadav, AK and Singh, RK}, title = {Montelukast attenuated memory decline, neuroinflammatory and neurodegenerative biomarkers in Aβ1-42 exposed model of alzheimer's disease in mice.}, journal = {Psychopharmacology}, volume = {}, number = {}, pages = {}, pmid = {40773100}, issn = {1432-2072}, support = {Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India//Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, India/ ; }, abstract = {Alzheimer's disease (AD) represents major cognitive and memory decline in the elderly patients. Although Montelukast has traditionally been used for the treatment of asthma, its role in prevention of neuropathological changes and memory decline in AD have recently been reported in literature. However, the brain availability through oral administration of Montelukast is limited due to its poor blood-brain barrier permeation. This study has highlighted that the intranasal administration of Montelukast can provide a considerable brain bioavailability of Montelukast in mice. In addition, intranasal administration of Montelukast showed a significant improvement of spatial and cognitive memory, prevention of Aβ accumulation, astrocyte activation, along with improved redox balance and neuronal density in the hippocampus and cortex regions in the amyloid-beta1-42 (Aβ1-42)-induced animal model of AD. These neuroprotective effects were found to be better through intranasal administration of Montelukast in comparison to its oral administration at the equivalent dose. These results suggest that Montelukast may be administered through intranasal route to achieve a significant therapeutic effect in the pathophysiology of AD.}, } @article {pmid40772428, year = {2025}, author = {French, SR and Arias, JC and Zahra, S and Ally, M and Escareno, C and Heitkamp, E and Vazquez, F and Hillis, M and Wiskoski, H and Ainapurapu, K and Culwell, G and Howell, C and Johnson, K and Kraemer, C and Pacanowski, J and Leon, L and Berman, S and Yanquez, F and Balderman, J and Sabat, J and Hung, O and Lucas, L and Vitali, F and Bedrick, EJ and Mushtaq, R and Altbach, M and Trouard, TP and Elahi, FM and Ashton, NJ and Dage, JL and Reiman, EM and Alexander, GE and Weinkauf, CC}, title = {Cognitive impairment and p-tau217 are high in a vascular patient cohort.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70565}, pmid = {40772428}, issn = {1552-5279}, support = {R01AG070987/AG/NIA NIH HHS/United States ; R01 HL159200/HL/NHLBI NIH HHS/United States ; //Doris Duke Foundation/ ; //University of Arizona Health Sciences Career Development Award/ ; //Arizona Alzheimer's Consortium/ ; P30 AG072980/AG/NIA NIH HHS/United States ; //U24 AG082930 Alzheimer Diagnosis in older Adults with Chronic Conditions ADACC Network/ ; CTR056039//Arizona Biomedical Research Commission/ ; CTR056056//Arizona Biomedical Research Commission/ ; U24 AG021886/AG/NIA NIH HHS/United States ; //Health Sciences, University of Arizona/ ; /DDCF/Doris Duke Charitable Foundation/United States ; }, mesh = {Humans ; Female ; Male ; *Cognitive Dysfunction/blood/diagnosis ; *tau Proteins/blood ; Aged ; Biomarkers/blood ; Cohort Studies ; *Alzheimer Disease/blood ; Mental Status and Dementia Tests/statistics & numerical data ; *Cardiovascular Diseases/complications/blood ; Prospective Studies ; Phosphorylation ; Middle Aged ; Aged, 80 and over ; Neuropsychological Tests ; }, abstract = {INTRODUCTION: Vascular comorbidities are modifiable contributors to cognitive impairment and Alzheimer's disease (AD), yet brain health outcomes are rarely evaluated in cardiovascular patients. METHODS: This study prospectively evaluated cognition and AD pathology in 162 community-dwelling adults with asymptomatic cardiovascular disease who did not have a clinical diagnosis of dementia or cognitive impairment. RESULTS: Twenty-nine percent of the cohort had Montreal Cognitive Assessment (MoCA) scores indicative of cognitive impairment or dementia after adjusting for age, sex, and education based on National Alzheimer's Coordinating Center normative data. AD blood biomarker phosphorylated tau217 was elevated in 55% of the cohort, significantly associated with decreased MoCA scores (β = -1.46, 95% confidence interval [CI] -2.53 to -0.39, p < 0.01), and accurately differentiated cognitive impairment (area under the curve 0.94, 95% CI 0.88-0.99). DISCUSSION: This level of undiagnosed cognitive impairment and AD pathology exceeds what would be expected in the general population and highlights a potential need for screening and future work to better identify treatment options. HIGHLIGHTS: Brain health outcomes are rarely evaluated in vascular patients. One hundred sixty-two adults with asymptomatic cardiovascular disease but without diagnoses of cognitive impairment or dementia were evaluated. Phosphorylated tau217 accurately differentiated cognitive impairment in patients with cardiovascular disease. High levels of cognitive impairment and Alzheimer's disease pathology are greatly underdiagnosed in the cardiovascular population.}, } @article {pmid40772264, year = {2025}, author = {Alrikabi, A and Allahyani, W and Shaghath, A and Alrashdi, J and Almoqhem, R and Alasmari, F and Al-Qerem, W and Albasher, G}, title = {Potential therapeutic effects of Ebixa, Ginkgo biloba, and selenium in a cadmium chloride-induced Alzheimer's disease manifestations in rats.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1634601}, pmid = {40772264}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by cognitive decline and neuronal damage. Cadmium exposure has been implicated in AD pathogenesis. This study aimed to investigate the potential therapeutic effects of Ebixa (memantine), Ginkgo biloba, and selenium in a cadmium-induced rat model of AD. Adult male Wistar rats were divided into six groups: control, control + Ginkgo-treated, cadmium chloride (CdCl2), CdCl2 + Ebixa-treated, CdCl2 + Ginkgo, and CdCl2 + Ginkgo + Selenium. Behavioral tests, including the Morris water maze and passive avoidance learning, were conducted. Additionally, biochemical analysis of acetylcholine (Ach), choline acetyltransferase (AchT), and acetylcholinesterase (AChE) levels in brain homogenates was performed. Histological sections of the cerebral cortex, cerebellum, and medulla were examined. Apoptotic assessment was conducted using the TUNEL assay. CdCl2 exposure resulted in cognitive deficits, reduced Ach levels, and neuronal damage, mirroring AD-like characteristics. Ebixa treatment improved spatial memory behavior as well as Ach, AchT and AChE levels in the brain. Ginkgo biloba and selenium co-administration increased the number of crossings in the Morris water maze test, suggesting memory preservation. Additionally, Ginkgo biloba exhibited potential cholinergic system protective effects. Histological analysis revealed neuroprotection in the cerebral cortex, cerebellum, and medulla. TUNEL assays demonstrated anti-apoptotic effects of both Ebixa and the combination of Ginkgo and selenium. Ebixa, Ginkgo biloba, and selenium showed promise in mitigating cognitive deficits and preserving neuronal structures in a CdCl2-induced AD manifestation in rats. These findings provide insights into potential therapeutic strategies for AD and warrant further investigation.}, } @article {pmid40771977, year = {2025}, author = {Park, H and Ni, M and Le, Y}, title = {Neuroinflammation and nutrition in Alzheimer's disease.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1622571}, pmid = {40771977}, issn = {1664-2295}, abstract = {The brain contains approximately 100 billion neurons and over 200 billion glial cells, which are integral to the neuronal networks that support normal brain function in the central nervous system. The complexity of the brain makes the diagnosis and treatment of neurodegenerative disease particularly challenging. Neuroinflammation and neuronal cell death contribute to the development of neurodegenerative diseases such as dementia. Dementia refers to a decline in memory and thinking ability, affecting approximately 55 million people worldwide. Owing to the association of multiple factors, including amyloid-β plaque, tau-fibrillary tangles, neuroinflammation, nutritional defects, and genetic mutations, the exact cause of the most common type of dementia, Alzheimer's disease, remains elusive. These multiple factors may cause damage to neurons and glial cells, leading to neurodegeneration. Very few therapeutics are available for neurodegenerative diseases due to the limited understanding of their pathogenesis, resulting in the lack of biomarkers and drug targets. Recent attention has shifted toward addressing modifiable risk factors such as unhealthy diets and lifestyles to delay the onset of Alzheimer's disease. Unhealthy diets that consist of saturated fatty acids and refined sugars, with other multiple risk factors, increase neuroinflammation and oxidative stress, furthering cognitive decline and progression of neurodegeneration. Mitigating these risk factors with antioxidants, anti-inflammatory-based nutrition, and multidomain lifestyle intervention, which may include physical exercise, cognitive stimulation, and social engagement, may delay the development of neurodegenerative diseases and cognitive decline. In this review, we focus on the role of neuroinflammation in contributing to neurodegeneration and dietary influence in Alzheimer's disease.}, } @article {pmid40771537, year = {2025}, author = {Sagar, R and Huang, Y and Dong, D and Boyd, RJ and Ahmed, W and Witwer, KW and Mahairaki, V}, title = {Profiling RNA Cargo in Extracellular Vesicles From hiPSC-Derived Neurons of Alzheimer's Disease Patients.}, journal = {Journal of extracellular biology}, volume = {4}, number = {8}, pages = {e70074}, pmid = {40771537}, issn = {2768-2811}, support = {RF1 AG083801/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a major neurodegenerative disorder that affects more than 55 million people, with an incidence that is projected to triple by 2050. Despite continuous advancements in the field, reliable treatment and early detection strategies remain elusive. Extracellular vesicles (EVs) play a major role in cellular communication throughout the body. In this study, we assessed the cargo of neuronal-specific EVs for their potential as AD biomarkers. We isolated EVs released from iPSC-derived excitatory glutamatergic neurons generated from eight AD patients (ADiNEVs) and six healthy controls (iNEVs). We performed RNA-sequencing and identified significant differences in RNA cargo between ADiNEVs and iNEVs. Notably, fewer small nuclear RNAs (snRNAs) were found in ADiNEVs. RNA transcripts significantly more abundant in ADiNEVs included MT-CO1, PRR32 and IGSF8 messenger RNAs. We also observed fewer XIST long noncoding RNAs and miR-7-5p microRNA content in ADiNEVs. These findings suggest that precision medicine approaches, such as characterising the content of EVs from a patient's own cells, could advance early detection and management of AD.}, } @article {pmid40771353, year = {2025}, author = {Moravveji, S and Sadia, H and Doyon, N and Duchesne, S}, title = {Sensitivity analysis of a mathematical model of Alzheimer's disease progression unveils important causal pathways.}, journal = {Frontiers in neuroinformatics}, volume = {19}, number = {}, pages = {1590968}, pmid = {40771353}, issn = {1662-5196}, abstract = {INTRODUCTION: Mathematical models serve as essential tools to investigate brain aging, the onset of Alzheimer's disease (AD) and its progression. By studying the representation of the complex dynamics of brain aging processes, such as amyloid beta (Aβ) deposition, tau tangles, neuro-inflammation, and neuronal death. Sensitivity analyses provide a powerful framework for identifying the underlying mechanisms that drive disease progression. In this study, we present the first local sensitivity analysis of a recent and comprehensive multiscale ODE-based model of Alzheimer's Disease (AD) that originates from our group. As such, it is one of the most complex model that captures the multifactorial nature of AD, incorporating neuronal, pathological, and inflammatory processes at the nano, micro and macro scales. This detailed framework enables realistic simulation of disease progression and identification of key biological parameters that influence system behavior. Our analysis identifies the key drivers of disease progression across patient profiles, providing insight into targeted therapeutic strategies. METHODS: We investigated a recent ODE-based model composed of 19 variables and 75 parameters, developed by our group, to study Alzheimer's disease dynamics. We performed single- and paired-parameter sensitivity analyses, focusing on three key outcomes: neural density, amyloid beta plaques, and tau proteins. RESULTS: Our findings suggest that the parameters related to glucose and insulin regulation could play an important role in neurodegeneration and cognitive decline. Second, the parameters that have the most important impact on cognitive decline are not completely the same depending on sex and APOE status. DISCUSSION: These results underscore the importance of incorporating a multifactorial approach tailored to demographic characteristics when considering strategies for AD treatment. This approach is essential to identify the factors that contribute significantly to neural loss and AD progression.}, } @article {pmid40771197, year = {2025}, author = {Cardillo, M and Katam, K and Suravajhala, P}, title = {Advancements in multi-omics research to address challenges in Alzheimer's disease: a systems biology approach utilizing molecular biomarkers and innovative strategies.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1591796}, pmid = {40771197}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is a growing global challenge, representing the most common neurodegenerative disorder and affecting millions of lives. As life expectancy continues to rise and populations expand, the number of individuals coping with the cognitive declines caused by AD is projected to double in the coming years. By 2050, we may see over 115 million people diagnosed with this devastating condition. Unfortunately, while we currently lack effective cures, there are preventative measures that can slow disease progression in symptomatic patients. Thus, research has shifted toward early detection and intervention for AD in recent years. With technological advances, we are now harnessing large datasets and more efficient, minimally invasive methods for diagnosis and treatment. This review highlights critical demographic insights, health conditions that increase the risk of developing AD, and lifestyle factors in midlife that can potentially trigger its onset. Additionally, we delve into the promising role of plant-based metabolites and their sources, which may help delay the disease's progression. The innovative multi-omics research is transforming our understanding of AD. This approach enables comprehensive data analysis from diverse cell types and biological processes, offering possible biomarkers of this disease's mechanisms. We present the latest advancements in genomics, transcriptomics, Epigenomics, proteomics, and metabolomics, including significant progress in gene editing technologies. When combined with machine learning and artificial intelligence, multi-omics analysis becomes a powerful tool for uncovering the complexities of AD pathogenesis. We also explore current trends in the application of radiomics and machine learning, emphasizing how integrating multi-omics data can transform our approach to AD research and treatment. Together, these pioneering advancements promise to develop more effective preventive and therapeutic strategies soon.}, } @article {pmid40771195, year = {2025}, author = {Ahmad, W and Choe, K and Ahmad, R and Park, TJ and Kim, MO}, title = {Ambroxol confers neuroprotection against scopolamine-induced Alzheimer's-like pathology by modulating oxidative stress, neuroinflammation, and cognitive deficits via Nrf-2/JNK/GSK-3β signaling pathways.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1607289}, pmid = {40771195}, issn = {1663-4365}, abstract = {Alzheimer's disease (AD) is the most common and costly chronic progressive neurodegenerative disorder, with the highest impact on public health worldwide. Pathological hallmarks of AD include progressive cognitive decline and memory impairment, dominantly mediated by oxidative neurodegeneration. Oxidative stress is commonly recognized as a key factor in the pathophysiological progression of AD. Despite significant advancements, a definitive and effective therapeutic intervention for AD remains elusive. In this study, we investigate the neuroprotective potential of ambroxol (Amb), known for its potent anti-inflammatory and antioxidant properties. Given ambroxol's potential neuroprotective effects, we explore the underlying molecular mechanisms, explicitly examining its role in attenuating scopolamine-induced oxidative stress-mediated activation of the c-Jun N-terminal kinase (JNK) pathway, as well as its modulation of Akt and glycogen synthase kinase-3 beta (GSK-3β) signaling, which is a key contributor to neuroinflammation, synaptic dysfunction and neurodegeneration. AD pathology is induced by scopolamine administration, leading to excessive lipid peroxidation (LPO) and reactive oxygen species (ROS) generation, which leads to a decline in critical antioxidant proteins, including nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1). However, ambroxol treatment effectively attenuated oxidative stress by reducing the production of reactive oxidative species while restoring the expression of key antioxidant proteins. Similarly, ambroxol attenuated oxidative stress-induced JNK activation and modulated Akt and GSK-3β alterations. Immunofluorescence and western blot analyses revealed that ambroxol attenuated reactive gliosis by suppressing the expression of GFAP and Iba-1, alongside the downregulation of key pro-inflammatory mediators, such as IL-1β, TNF-α, and phosphorylated NF-κB (p-p65). Scopolamine also compromised synaptic integrity and induced deficits in memory formation and spatial learning. In contrast, ambroxol promoted synaptic integrity by upregulating the expression of SNAP-23 and PSD-95, thereby ameliorating scopolamine-induced impairments in spatial learning and memory.}, } @article {pmid40770916, year = {2025}, author = {Zhu, M and Han, J and Liu, R and Zhu, C and Liang, F and Zhang, G and Ma, L and Jin, Y and Xu, S and Wang, Z}, title = {Blood-Brain Barrier-Crossing Photo-oxygenation Nanocomposite for the Selective Mapping and Disassembly of Amyloid-β Aggregates In Vivo.}, journal = {ACS applied materials & interfaces}, volume = {17}, number = {33}, pages = {46759-46770}, doi = {10.1021/acsami.5c11173}, pmid = {40770916}, issn = {1944-8252}, mesh = {*Blood-Brain Barrier/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; Mice ; *Nanocomposites/chemistry ; Alzheimer Disease/metabolism/drug therapy/pathology ; Stilbenes/chemistry/pharmacology ; Humans ; Reactive Oxygen Species/metabolism ; Mice, Transgenic ; }, abstract = {The accumulation of toxic amyloid-β (Aβ) aggregates in the brain underlies neuronal death and subsequent irreversible neurodegeneration in Alzheimer's disease (AD). Currently, optimized theranostic probes targeting Aβ aggregates are still rare. Herein, we synthesized a series of tetraphenylethylene (TPE) derivatives for the selective recognition and photo-oxygenation of Aβ aggregates. Among them, TPE-yne-Indo with a strong electron-withdrawing group (benzo[e]indolium) and an electron-donating group (N,N-dimethylaniline) can selectively recognize Aβ aggregates in solution (Kd = 310.5 nM, S/N = 6.1) and mapping Aβ plaques in brain slices. Theoretical calculations indicated that TPE-yne-Indo engaged in hydrophobic interactions with the amino acid residues Val-18 (V), Ala-21 (A), and His-13 (H) of Aβ. Notably, the binding with Aβ aggregates bestowed TPE-yne-Indo with higher reactive oxygen species (ROS) generation ability, boosting the photodynamic oxidation of Aβ aggregates. Furthermore, therapeutic nanocomposite with the lactoferrin receptor ligand (MSN@Lf&TPE-yne-Indo) was prepared to facilitate the blood-brain barrier (BBB) crossing process. In vivo assays showed that MSN@Lf&TPE-yne-Indo can selectively stain Aβ plaques and reduce Aβ deposition in the brain of APP/PS1 mice, alleviating symptoms of cognitive impairment and memory loss. This study provides a promising tool for the early diagnosis and treatment of AD.}, } @article {pmid40770806, year = {2025}, author = {Zhang, Y and Wang, J and Li, X and Guo, R and Wang, L and Liu, Y and Yu, Y and Kong, L}, title = {Huanglian Jiedu Decoction improves the"central-peripheral"inflammatory microenvironment and enhances the cognitive function of APP/PS1 mice by inhibiting the activation of NLRP3 inflammasome mediated by gut microbiota.}, journal = {Chinese medicine}, volume = {20}, number = {1}, pages = {123}, pmid = {40770806}, issn = {1749-8546}, support = {No. 2024-MSLH-289//Liaoning Provincial Science and Technology Program Joint Plan/ ; No. 320.6750.2024-18-60//the Wu Jieping Medical Foundation Special Research Fund/ ; No. zyzx2301//the Open fund of Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Liaoning University of Traditional Chinese Medicine/ ; 82404867//National Natural Science Foundation of China/ ; No. JYTQN2023471//Basic Research Project of Education Department of Liaoning Province/ ; }, abstract = {BACKGROUND: Huanglian Jiedu Decoction (HLJDD) is a representative formula for clearing heat and removing toxins, and some basic studies indicated that it can improve the learning cognitive ability of Alzheimer's disease (AD) mice, but the underlying molecular mechanism of its improvement in AD mice is still unclear, therefore, this paper delves into the mechanism of HLJDD to improve AD. PURPOSE: This study aims to investigate whether HLJDD can improve the "central-peripheral" inflammatory microenvironment in APP/PS1 mice, and to explore its relationship with gut microbiota and NLRP3 inflammatory vesicles activation. MATERIALS AND METHODS: In this paper, the fingerprint of HLJDD was established by high-performance liquid chromatography (HPLC) and the components of HLJDD were characterized by ultra-performance liquid chromatography-time-of-flight mass spectrometry (UPLC-O-TOF/MS). The potential signaling pathways of HLJDD against AD were preliminarily investigated through network pharmacology. Behavioral assessment, histopathological staining, immunofluorescence staining, immunohistochemical staining, and detection of central and peripheral inflammatory factors were used to explore the improvement of AD by HLJDD, in addition to which we examined the gut microbiota and expression of relevant inflammatory proteins. RESULTS: In this study, 137 chemical constituents, including flavonoids, terpenoids, and alkaloids, were first identified in HLJDD by HPLC fingerprinting and UPLC-Q-TOF/MS. In addition, 49 components were found in the brain tissue of APP/PS1 mice and 48 components were found in the plasma of APP/PS1 mice. Network pharmacology concluded that the relevant pathways for HLJDD treatment of AD include inflammatory pathways. We found that HLJDD was effective in improving the learning memory ability of APP/PS1 mice by in vivo mouse behavioral performance. Histopathological results showed that HLJDD had the effect of reducing AD-like pathological damage, and also found that HLJDD could significantly reduce the proportion of M1 type microglia and A1 type astrocytes, and increase the proportion of M2 type microglia and A2 type astrocytes, and the treatment of HLJDD also suppressed the infiltration of CD4[+] and CD8[+] T-cells in the brain, and inhibited Aβ deposition and reduced the expression of inflammatory factors in the brain, and alleviated central neuroinflammation. In addition, it was also found that HLJDD was able to reduce the expression of inflammatory factors in the peripheral blood and inhibit the peripheral immune response, and the results of gut microbiota also showed changes in gut microbiota after HLJDD treatment and verified the expression of inflammatory vesicle-associated proteins in the intestines, with significant upregulation of the expression of NLRP3, caspase-1, and ASC proteins in the model group, and significant downregulation of ZO-1 and occludin proteins, and reversal of the above changes after HLJDD intervention. CONCLUSION: Therefore, it is hypothesized that HLJDD improves the "central-peripheral" inflammatory microenvironment in APP/PS1 mice by inhibiting the activation of NLRP3 inflammatory vesicles mediated by gut microbiota.}, } @article {pmid40770529, year = {2025}, author = {Nakamichi, S and Yamada, L and Roselle, C and Horikawa, I and June, CH and Harris, CC}, title = {The senescence-inhibitory p53 isoform Δ133p53α: enhancing cancer immunotherapy and exploring novel therapeutic approaches for senescence-associated diseases.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {40770529}, issn = {2509-2723}, abstract = {Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while it does not inhibit, or may even promote, p53-mediated DNA repair. Owing to this selective inhibitory activity that preserves genome stability, Δ133p53α represents a promising target for enhancement in the prevention and treatment of diseases associated with increased senescence of normal cells. These diseases include Alzheimer's and other neurodegenerative diseases, premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS), and idiopathic pulmonary fibrosis (IPF). Current cell-based therapies, which are limited by increased cellular senescence, may also benefit from Δ133p53α-mediated improvements. As an initial application of Δ133p53α in improving therapeutic cells, we here introduce Δ133p53α-armored chimeric antigen receptor (CAR)-T cells. Based on our previous and ongoing studies using various types of senescent human cells in vitro, we also discuss the importance of further exploring the therapeutic potentials of Δ133p53α, with particular focus on HGPS and IPF. The development of mouse models facilitates in vivo evaluation of the therapeutic effects of Δ133p53α, potentially leading to future clinical applications.}, } @article {pmid40770492, year = {2025}, author = {Kim, J and Han, K and Jung, JH and Oh, SY and Park, KA and Min, JH}, title = {Optic neuritis as a link between autoimmunity and dementia risk.}, journal = {Communications medicine}, volume = {5}, number = {1}, pages = {335}, pmid = {40770492}, issn = {2730-664X}, support = {RS-2024-00341030//National Research Foundation of Korea (NRF)/ ; RS-2024-00439930//Korea Health Industry Development Institute (KHIDI)/ ; }, abstract = {BACKGROUND: Our limited understanding of dementia's complex pathogenesis confines treatment options primarily to symptom management rather than targeting underlying disease processes, underscoring the need for innovative treatment and preventive strategies. This study aimed to examine the relationship between optic neuritis (ON), an autoimmune inflammatory condition of the optic nerve, and the risk of developing dementia. METHODS: This nationwide, population-based cohort study was conducted in Korea, analyzing a cohort of 15,286 ON patients newly diagnosed between 2010 and 2017 who were age and sex matched against 76,430 controls without ON. Primary outcomes were incident cases of Alzheimer's disease, vascular dementia, or other types of dementia. Cox proportional hazards regression models were employed to assess the association between ON and dementia risk after adjusting for demographic characteristics, lifestyle factors, and other comorbidities. Dementia risk was assessed through hazard ratios (HRs), with an average follow-up period of 3.06 years. RESULTS: ON patients shows greater risks of all-cause dementia (HR: 1.258) and Alzheimer's disease (HR: 1.264). Associations between ON and dementia are prominent in younger patients and current smokers. CONCLUSION: This research suggests that autoimmunity, particularly in the form of ON, may significantly contribute to dementia development. This study implies that younger ON patients who smoke could be at a high risk of developing dementia, emphasizing the need for preventative strategies and additional research to establish causality. This work broadens the scope of known dementia risk factors and opens new avenues for research into autoimmune mechanisms as targets for therapeutic intervention.}, } @article {pmid40770370, year = {2025}, author = {Zhang, Y and Xu, Y and Song, Y and Wang, Y and Chen, M and Ji, X and Lin, Y and Gu, S}, title = {Lead-induced hypertension and cognitive dysfunction: brain amyloid pathology.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {720}, pmid = {40770370}, issn = {2047-783X}, support = {2022, ZDYF2022SHFZ101//This work was supported by the Key R & D Projects in Hainan Province/ ; }, mesh = {Animals ; Mice ; *Hypertension/chemically induced/pathology/metabolism ; *Brain/pathology/metabolism/drug effects ; *Cognitive Dysfunction/chemically induced/pathology/metabolism/drug therapy ; Mice, Transgenic ; *Lead/toxicity ; Spironolactone/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; *Alzheimer Disease/pathology ; Amlodipine/pharmacology/therapeutic use ; Receptors, Mineralocorticoid/metabolism ; Male ; Disease Models, Animal ; }, abstract = {BACKGROUND: Lead (Pb) exposure is a recognized environmental risk factor for cognitive decline and may aggravate Alzheimer's disease (AD) pathology through hypertension-related mechanisms. However, the specific role of mineralocorticoid receptor (MR) signaling in this process remains unclear. OBJECTIVES: This study investigated whether Pb-induced hypertension exacerbates amyloid pathology via MR activation, and evaluated the therapeutic effects of amlodipine and spironolactone in an AD mouse model. METHODS: APPSwDI transgenic mice were exposed to Pb acetate (25 mg/kg/day) for 8 weeks, with or without concurrent treatment with amlodipine or spironolactone. Cognitive behavior, blood pressure, renal function, neuroinflammation, oxidative stress, and brain amyloid deposition were assessed. RESULTS: Pb exposure significantly increased systolic blood pressure, impaired cognition, elevated IL-1β and IL-6 levels, and enhanced brain amyloid burden. MR expression in brain tissue was upregulated following Pb exposure. Both spironolactone and amlodipine improved cognitive performance and reduced neuroinflammation and oxidative stress. Spironolactone more effectively suppressed MR expression and amyloid deposition, though some group differences did not reach statistical significance. CONCLUSIONS: Pb exacerbates AD-like pathology through MR-related hypertensive and inflammatory mechanisms. MR antagonism by spironolactone offers greater neuroprotection than calcium channel blockade in this context. These findings suggest that targeting MR signaling may be a promising therapeutic strategy for environmentally induced AD risk.}, } @article {pmid40770222, year = {2025}, author = {Abuhantash, F and Welsch, R and Finkelstein, S and AlShehhi, A}, title = {Alzheimer's disease risk prediction using machine learning for survival analysis with a comorbidity-based approach.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {28723}, pmid = {40770222}, issn = {2045-2322}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; FSU-2021-005//Khalifa University of Science, Technology and Research/ ; }, mesh = {Humans ; *Alzheimer Disease/epidemiology/diagnosis ; Aged ; *Machine Learning ; Male ; Female ; Comorbidity ; Cognitive Dysfunction/epidemiology ; Survival Analysis ; Aged, 80 and over ; Neuroimaging ; Disease Progression ; Risk Factors ; }, abstract = {Alzheimer's disease (AD) presents a pressing global health challenge, demanding improved strategies for early detection and understanding its progression. In this study, we address this need by employing survival analysis techniques to predict transition time from Cognitive Normal (CN) to Mild Cognitive Impairment (MCI) in elderly individuals, considering the predictive value of baseline comorbidities. Leveraging data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) databases, we construct feature sets encompassing demographics, cognitive scores, and comorbidities. Various machine learning and deep learning methods for survival analysis are employed. Our top-performing model, fast random forest, achieves a concordance index of 0.84 when considering all feature modalities, with comorbidity data emerging as a significant predictor. The top features identified by the best-performing model include one demographic feature (age), seven cognitive scores (ADAS13, RAVLT learning, FAQ, ADAS11, RAVLT immediate, CDRSB, ADASQ4), and two comorbidities (Endocrine & Metabolic, Renal & Genitourinary). Age is highlighted as the most influential predictor, while cognitive scores are crucial indicators of Alzheimer's disease. External validation against the AIBL dataset affirms the robustness of our approach. Overall, our study contributes to a deeper understanding of the role of baseline comorbidities in AD risk prediction and emphasizes the importance of incorporating comprehensive feature assessment in clinical practice for early diagnosis and personalized treatment planning.}, } @article {pmid40770166, year = {2025}, author = {Lee, Y and Han, S and Lee, J and Cho, Y and Kim, JS and Jeon, Y and Cho, H and Yoo, H and Byun, Y and Kim, TK and Hong, JM and Kim, H and Park, SY and Yim, JH and Kim, SH and Jo, DG}, title = {A novel multi-target compound mitigates amyloid plaques, synaptic deficits, and neuroinflammation in Alzheimer's disease models.}, journal = {Archives of pharmacal research}, volume = {48}, number = {7-8}, pages = {745-764}, pmid = {40770166}, issn = {1976-3786}, support = {RS-2021-KS211513//Korea Institute of Marine Science and Technology promotion/ ; RS-2024-00399237//National Research Foundation of Korea/ ; RS-2024-00345742//National Research Foundation of Korea/ ; }, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Plaque, Amyloid/drug therapy/pathology/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; *Neuroinflammatory Diseases/drug therapy/pathology/metabolism ; *Synapses/drug effects ; Male ; Synaptic Transmission/drug effects ; *Hydrazines/pharmacology/chemistry ; }, abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid plaque accumulation, synaptic dysfunction, and neuroinflammation. This study reports the therapeutic potential of (S)-4-amino-5,5-difluoro-N'-methyl-N'-phenylpentanehydrazide hydrochloride (RA-058HM), a novel compound, in ameliorating these pathological features of AD in the 5xFAD mouse model. RA-058HM was administered orally for 8 weeks, and its multi-target effects - including relief from neuroinflammation, normalization of synaptic transmission, reduction of amyloidogenesis (plaque and soluble oligomers, as well as BACE1 levels), and rescue of cognitive function-were evaluated. To our knowledge, RA-058HM is the first compound to demonstrate simultaneous modulation of these key pathways in the 5xFAD model, highlighting its potential as a comprehensive disease-modifying therapy for AD. Behavioural tests revealed marked improvements in spatial and recognition memory in RA-058HM-treated 5xFAD mice, suggesting a reversal of cognitive deficits. At the molecular level, RA-058HM treatment reduced amyloidogenesis, as evidenced by decreased levels of amyloid precursor protein (APP) and β-secretase (BACE1) in the hippocampus, accompanied by reduced plaque formation, as detected by Thioflavin-S staining. Furthermore, synaptic transmission was restored to near-normal levels in RA-058HM-treated neurons, indicating that RA-058HM effectively rescues synaptic deficits without altering synaptic protein levels of PSD95 and synaptophysin. In addition, treatment of RA-058HM downregulated hippocampal levels of the NLRP3 inflammasome, TNF-α, and GFAP, suggesting a decrease in neuroinflammatory signaling and a modulation of glial activity. Restoration of mitochondrial motility in hippocampal neurons further suggests that RA-058HM may improve cellular energy dynamics. Collectively, these findings indicate that RA-058HM has multifaceted effects on AD pathology, targeting amyloid accumulation, synaptic transmission, neuroinflammation, and mitochondrial function. This study highlights RA-058HM as a promising candidate for AD therapy and underscores the potential of multi-targeted approaches in addressing the complex mechanisms underlying AD progression.}, } @article {pmid40770094, year = {2025}, author = {Aron, L and Ngian, ZK and Qiu, C and Choi, J and Liang, M and Drake, DM and Hamplova, SE and Lacey, EK and Roche, P and Yuan, M and Hazaveh, SS and Lee, EA and Bennett, DA and Yankner, BA}, title = {Lithium deficiency and the onset of Alzheimer's disease.}, journal = {Nature}, volume = {645}, number = {8081}, pages = {712-721}, pmid = {40770094}, issn = {1476-4687}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; DP2 AG072437/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; K01 AG051791/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; R01 AG069042/AG/NIA NIH HHS/United States ; R01 AG046174/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/pathology/metabolism/drug therapy/genetics/prevention & control ; Animals ; Mice ; *Lithium/deficiency/metabolism ; Disease Models, Animal ; Humans ; Glycogen Synthase Kinase 3 beta/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Brain/metabolism/pathology/drug effects ; Cognitive Dysfunction/metabolism/pathology ; tau Proteins/metabolism ; Female ; Microglia/pathology/metabolism/drug effects ; Aging/metabolism/pathology ; Transcriptome/drug effects ; Synapses/pathology/metabolism/drug effects ; Myelin Sheath/metabolism/pathology ; Axons/pathology/metabolism ; Aged ; }, abstract = {The earliest molecular changes in Alzheimer's disease (AD) are poorly understood[1-5]. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.}, } @article {pmid40769959, year = {2025}, author = {Shanok, NA and Derbin, B and Muzac, S and Cabeza, E and Leven, S and Rodriguez, R}, title = {The Effects of Deep TMS on QEEG Measures in Co-Occurring Major Depressive Disorder and Early-Stage Alzheimer's Disease: A Pilot Study.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {8919887251366637}, doi = {10.1177/08919887251366637}, pmid = {40769959}, issn = {1552-5708}, abstract = {Major Depressive Disorder (MDD) and Alzheimer's disease (AD) represent two of the most prevalent diseases worldwide. Notably, it is estimated that 30%-50% of individuals with AD have co-occurring MDD and there are overlapping symptoms across numerous domains. In this pilot study, a Deep TMS protocol (targeting the left frontal and bilateral temporal regions) was delivered for 36 sessions to patients with co-occurring MDD and early-stage AD (N = 12). All participants received the treatment and there was no control condition. The treatment yielded a response rate of 83.33% (defined by a ≥50% reduction in depressive symptoms on the Patient Health Questionnaire-9 [PHQ-9]) and a remission rate of 50.00% (PHQ-9 score of 4 or less following treatment). Further, participants displayed reductions in left prefrontal and right temporal delta power using QEEG analysis pre- and -post treatment. Alpha coherence was also enhanced in key areas. The observed shift in neurophysiological measures suggested reduced cortical slowing and dysconnectivity, which are hallmark traits in MDD and AD. This proof-of-concept study suggests that further research on the application of Deep TMS (paired with QEEG) for early-stage AD is warranted.}, } @article {pmid40768640, year = {2025}, author = {Bentivegna, M and Pomilio, C and Bellotto, M and Pérez, NG and Rossi, SP and Gregosa, A and Vota, D and Merech, F and Bonaventura, MM and Presa, J and Vinuesa, Á and Lux-Lantos, V and Alcón, SP and Saravia, F and Beauquis, J}, title = {Amyloid Beta Regulates Astrocytic Glucose Metabolism and Insulin Signaling in Experimental Models of Alzheimer's Disease.}, journal = {Aging and disease}, volume = {}, number = {}, pages = {}, doi = {10.14336/AD.2025.0484}, pmid = {40768640}, issn = {2152-5250}, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by amyloid beta (Aβ) plaques, neuroinflammation and cognitive impairment. Metabolic disturbances, particularly brain insulin resistance, are increasingly recognized as central features of AD pathophysiology. Astrocytes, essential for brain energy metabolism, exhibit a loss of homeostatic functions in AD, possibly promoting neurodegeneration. Even though the main astrocytic glucose transporters are non-insulin dependent, insulin may regulate astroglial glucose metabolism. Our objective was to evaluate insulin signaling and astrocyte metabolism in the PDAPP-J20 transgenic mouse model of familial AD and in mouse primary astrocyte cultures exposed to Aβ. Adult PDAPP-J20 mice showed hyperinsulinemia, hippocampal insulin resistance and astrocytic proinflammatory activation. The reactive glial phenotype was accompanied by decreased insulin receptor levels in this chronic setting. Exposure of primary astrocytes to Aβ induced proinflammatory activation, oxidative stress and loss of glutamate transporter EAAT2, crucial for neuroprotection. Even though Aβ-exposed astrocytes showed increased insulin receptor levels in this acute setting, insulin-induced phosphorylation of the receptor was hampered. Amyloid-treated astrocytes also showed increased glucose uptake, lactate release and glycogen storage. Insulin treatment was associated with a recovery of mitochondrial membrane potential and increased amyloid uptake, highlighting a pro-homeostatic role for the hormone. Our results highlight the interplay between insulin signaling and astrocyte metabolism at different experimental and temporal settings of amyloid pathology. Understanding these mechanisms may help to design therapeutic strategies aimed at restoring metabolic balance and mitigating neurodegeneration.}, } @article {pmid40768115, year = {2025}, author = {Birmann, PT and Zugno, GP and Sinott, A and Rodrigues, RR and Conceição, FR and Sousa, FSS and Collares, T and Seixas, FK and Savegnago, L}, title = {Komagataella pastoris KM71H Attenuates Cognitive Deficits and Depressive-Like Behavior by the TLR4/NF-κB Signaling Pathway in an Aβ1-40-Induced AD-Like Mouse Model.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {16448-16459}, pmid = {40768115}, issn = {1559-1182}, mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; *Toll-Like Receptor 4/metabolism ; *Signal Transduction/drug effects ; *Alzheimer Disease/metabolism/complications/drug therapy/chemically induced ; *NF-kappa B/metabolism ; Disease Models, Animal ; *Depression/drug therapy/metabolism/complications ; *Peptide Fragments/toxicity ; Male ; Mice ; *Cognitive Dysfunction/metabolism/drug therapy ; Behavior, Animal/drug effects ; Hippocampus/metabolism ; }, abstract = {Komagataella pastoris is a promising probiotic for modulating the microbiota-gut-brain axis, and growing evidence has demonstrated the relevance of this axis in the pathophysiology of neurological and psychiatric disorders, such as Alzheimer's disease and major depressive disorder. This study investigated the ameliorated cognitive impairment and antidepressive-like effect of K. pastoris treatment on an AD-like mouse model induced by amyloid β1-40 peptide (Aβ1-40). Behavioral tests revealed that Aβ1-40 administration (400 pmol/mouse, icv) increased immobility time in the tail suspension test, decreased spatial and working memory, and increased the time animals took to reach the chocolate cookies, and these behavioral changes were attenuated by the K. pastoris KM71H treatment (8 log CFU[-1]/mouse, ig). Biochemical changes also occurred as the applied protocol decreased reactive species and lipid peroxidation in the hippocampi and small intestine and reduced NRLP3, TLR4, Nfҡb, and IL-1β expression in the small intestine of mice. We believe that the ameliorated cognitive impairment and antidepressant effects of K. pastoris KM71H are due to its antioxidant activity and the modulation of the TLR4/NF-κB pathway, and our findings led us to conclude that K. pastoris KM71H is a promising therapeutic strategy for treating Alzheimer's disease and major depressive disorder.}, } @article {pmid40766949, year = {2025}, author = {Warren, A and Wynia, Z}, title = {Dementia-related stigma in physicians: a scoping review of stigma-reduction interventions.}, journal = {Frontiers in dementia}, volume = {4}, number = {}, pages = {1601462}, pmid = {40766949}, issn = {2813-3919}, abstract = {INTRODUCTION: Despite progress in dementia diagnosis and treatment, physician-held stigma remains a significant barrier to early recognition and effective care. Stigmatizing attitudes among healthcare professionals can negatively impact diagnosis rates, clinical interactions, and care quality for people living with dementia. METHODS: This scoping review was conducted following Arksey and O'Malley's framework. Peer-reviewed literature from 2014 to 2024 was systematically reviewed to identify and evaluate interventions aimed at reducing dementia-related stigma among physicians. A total of 14 studies met inclusion criteria, examining educational, skill-building, and person-centered approaches. RESULTS: Interventions included brief workshops, online modular training, and interdisciplinary methods integrating person-centered frameworks and behavior management tools. Validated outcome measures used in the studies included the Alzheimer's Disease Knowledge Scale (ADKS), the Dementia Negative Stereotype Scale (DNS), and the General Practitioners Confidence and Attitude Scale for Dementia (GPACS-D). Across studies, interventions were found to improve clinical confidence, reduce negative stereotypes, and enhance care quality. DISCUSSION: Findings highlight the importance of culturally sensitive and interdisciplinary interventions to address stigma, improve clinical confidence, and enhance care quality, particularly in low-resource settings. Notable gaps remain in understanding the long-term impact and scalability of such interventions. This review aims to contribute a deeper understanding of the barriers and facilitators to implementing dementia care practices, offering a conceptualization for enhanced physician education and improved health outcomes for persons with dementia. We offer recommendations for future research to develop tailored strategies that support stigma reduction and improve care delivery.}, } @article {pmid40766301, year = {2025}, author = {Gribsholt, SB and Horváth-Puhó, E and Elser, H and Laugesen, K and Skajaa, N and Fuglsang, CH and Henderson, V and Sørensen, HT}, title = {Obstructive sleep apnoea and risk of dementia: a Danish population-based cohort study.}, journal = {BMJ neurology open}, volume = {7}, number = {2}, pages = {e001174}, pmid = {40766301}, issn = {2632-6140}, abstract = {BACKGROUND: Obstructive sleep apnoea (OSA) is associated with adverse health outcomes. However, the association with dementia remains uncertain. Thus, we examined the association of OSA with all-cause dementia and Alzheimer's disease. METHODS: We conducted a Danish nationwide population-based cohort study using health registries. Patients with OSA were identified from 1995 to 2017. Furthermore, a propensity score-matched comparison cohort was defined. Propensity scores were computed based on age, sex, comorbidities and education. With follow-up until 2018, we computed incidence rates (IRs) and HRs for all-cause dementia and Alzheimer's disease. Subgroup analyses were conducted by sex, age, overweight/obesity, hypertension and continuous positive airway pressure (CPAP) treatment. RESULTS: We identified 62 928 patients with OSA and 62 928 in the propensity score-matched comparison cohort (76% male, median age 52 years). The IR for all-cause dementia was 1.27 (95% CI 1.17 to 1.37) per 1000 person-years in patients with OSA and 1.15 (95% CI 1.05 to 1.25) in the propensity score-matched comparison cohort, yielding an HR of 1.10 (95% CI 0.98 to 1.24). The HR for Alzheimer's disease was 1.16 (95% CI 0.94 to 1.43). Among individuals with overweight/obesity, the HR for all-cause dementia was 0.71 (95% CI 0.51 to 0.99), while it was 1.17 (95% CI 1.03 to 1.33) in those without. CPAP treatment attenuated associations. CONCLUSION: Our findings support a modest association between OSA and dementia, including Alzheimer's disease, motivating early clinical detection of OSA as a potentially modifiable risk factor for subsequent dementia. The finding that the dementia hazard was not increased in the setting of overweight or obesity requires further study and points to the need for research on mechanisms underlying the association between OSA and dementia.}, } @article {pmid40765720, year = {2025}, author = {Hamilton, JL and Fuller, RLM and Modi, N and Sampaio, C}, title = {Utilizing MCID for evaluating clinical relevance of AD therapeutic interventions.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70138}, pmid = {40765720}, issn = {2352-8737}, abstract = {UNLABELLED: With the recent approval of disease-modifying treatments for mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) by the United States Food and Drug Administration (FDA), Medicines and Healthcare products Regulatory Agency (MHRA), European Medicine Agency's Committee for Medicinal Products for Human Use (EMA/CHMP) entities, there is a growing sense of urgency and renewed efforts to reassess and understand what constitutes a clinically meaningful benefit in the context of new treatments for AD care, despite the discordance between regulatory entities in regulatory decision-making. While the concept of minimal clinically important difference (MCID) was introduced many years ago, there remains an ongoing debate about how best to evaluate and define clinical benefit in the context of emerging and new therapies for dementia. In this perspective piece, we assess how MCID can be applied to common endpoints and identify areas where MCID application or generation could be useful to enable a better valuation of therapeutic innovation. We offer recommendations for greater consistency in measures used to define MCID, and encourage the prioritized use of patient-reported measures in early AD to build fieldwide consensus for MCID estimation methods and application in AD. HIGHLIGHTS: There is no gold standard or field-wide consensus on what constitutes a clinically meaningful change in Alzheimer's disease (AD) progression trajectories.Anchor-based minimal clinically important difference (MCID) may be used as a tool that can be leveraged for greater contextualization of the clinical relevance of a treatment effect.Patient-reported outcomes (PROs) should be used to define MCID, particularly within mild cognitive impairment (MCI), prodrome/mild AD groups.Greater consistency is needed in the outcome measures used to detect cognitive and functional change to define MCID. This will enable MCID comparisons and support replications of MCID estimates across AD populations.Observational data can augment the clinical characterization and impact of treatment effect and help establish a "ground truth" MCID.MCID estimates for AD outcomes may be used in regulatory submissions to help contextualize the importance of a statistically significant treatment effect.}, } @article {pmid40765614, year = {2025}, author = {Li, X and Lu, X and Ou, J and Lyu, H and Liu, Y and Zhang, J}, title = {Effect of acupuncture on episodic memory for amnestic mild cognitive impairment based on hippocampal subregion: study protocol of a randomized, controlled trial.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1536291}, pmid = {40765614}, issn = {1664-2295}, abstract = {BACKGROUND: The hippocampus is a key brain region for episodic memory, and impairment of episodic memory is the earliest feature of amnestic mild cognitive impairment (aMCI). Preserving the structure and function of the hippocampus plays a key role in preventing progression to Alzheimer's disease (AD). Therefore, early intervention is crucial, and acupuncture could significantly improve episodic memory in aMCI, but the mechanism is not clear. Accordingly, this experiment aims to explore the mechanism of acupuncture to improve episodic memory in aMCI based on the hippocampal subregion. METHODS: A randomized, controlled, blinded research will be performed. 150 aMCI participants will be assigned to the verum acupuncture group, sham acupuncture group, and waiting group; 50 healthy controls will also be recruited. Patients in the acupuncture group will receive real acupuncture treatment or placebo acupuncture three times per week, 36 sessions over 12 consecutive weeks in total. Patients in the waiting group will receive the same verum acupuncture treatment for compensation after the trials are finished. The primary outcome will be the auditory-verbal learning test. Secondary outcomes will include Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Hamilton Depression Scale (HAMD), and functional magnetic resonance imaging data. Outcomes will be measured at baseline and 12 weeks after randomization. Repeated measurement analysis of variance will be used to explore the intervention effect. DISCUSSION: This protocol will provide theoretical support for the neural mechanisms by which acupuncture improves episodic memory in aMCI. We hope that this study will provide objective evidence and offer alternative treatment options for the early treatment of aMCI. CLINICAL TRIAL REGISTRATION: ChiCTR2400084308.}, } @article {pmid40765028, year = {2025}, author = {Kudpaje, M and Joghee, S and Ram Kumar, RM}, title = {Exosomes as a Nanotheranostic Platform in Brain Diseases.}, journal = {The European journal of neuroscience}, volume = {62}, number = {3}, pages = {e70215}, doi = {10.1111/ejn.70215}, pmid = {40765028}, issn = {1460-9568}, support = {D.O. NO.BT/HRD/35/02/2006//Department of Biotechnology, Government of India/ ; }, mesh = {Humans ; *Exosomes/metabolism ; Animals ; *Theranostic Nanomedicine/methods ; *Drug Delivery Systems/methods ; *Brain Diseases/therapy/drug therapy ; Blood-Brain Barrier/metabolism ; }, abstract = {Exosomes, nanoscale extracellular vesicles (30-150 nm), play a critical role in intercellular communication by transporting bioactive molecules, including proteins, lipids, and nucleic acids. These vesicles have emerged as a transformative tool for drug delivery in brain diseases, particularly due to their ability to cross the blood-brain barrier (BBB), a major challenge in treating central nervous system (CNS) disorders. Recent studies have highlighted the potential of exosome-based therapies in treating neurodegenerative diseases such as Alzheimer's and Parkinson's, neuroinflammatory conditions, and brain tumors like glioblastoma. Exosomes can be engineered to enhance their targeting precision by modifying their surface to selectively deliver therapeutic agents to specific brain cells, including neurons, glial cells, and endothelial cells. This review explores the latest advancements in optimizing exosome-mediated drug delivery, focusing on surface modifications and other strategies to improve targeting efficiency and therapeutic outcomes. Additionally, exosomes are being investigated as diagnostic biomarkers for early disease detection and monitoring, offering a noninvasive alternative to traditional methods. Despite their promise, challenges such as large-scale production, cargo loading, safety concerns, and regulatory barriers remain. This review provides an overview of the current state of exosome-based therapies, critically evaluates the ongoing challenges, and explores future directions for optimizing their use in brain disease treatment, emphasizing enhancing targeted delivery and therapeutic efficacy.}, } @article {pmid40764790, year = {2025}, author = {Sepúlveda-Rivera, V and Olivieri-Henry, G and Morales-González, H and Ruiz-Adames, J and Herrero-Rivera, C and Rentas-Echeverria, A and Cardona-Berdecia, V and Soler-Llompart, C and Sala-Morales, AC and Pérez-Montero, G and Blanco-Ruiz, E and Godoy-Vitorino, F}, title = {Gut microbiota distinguishes aging hispanics with Alzheimer's disease: associations with cognitive impairment and severity.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {28505}, pmid = {40764790}, issn = {2045-2322}, support = {U54 MD007600/MD/NIMHD NIH HHS/United States ; S21MD001830/MD/NIMHD NIH HHS/United States ; P20GM103475//National Institute Of General Medical Sciences of the National Institutes of Health/ ; U54GM133807//National Institute Of General Medical Sciences of the National Institutes of Health/ ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Aging ; *Alzheimer Disease/microbiology ; Case-Control Studies ; *Cognitive Dysfunction/microbiology ; Dysbiosis/microbiology ; *Gastrointestinal Microbiome ; Hispanic or Latino ; Puerto Rico ; Severity of Illness Index ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that begins with memory loss and can lead to death. In Puerto Rico, AD is the fourth leading cause of death, while in the United States, it ranks fifth. Research suggests the gut microbiome contributes to the pathophysiology of AD by promoting inflammation and amyloid buildup in the brain. This study examined the composition and diversity of the gut microbiota in Puerto Ricans with AD compared to controls and its relationship with cognitive impairment severity and APOE status. We recruited 100 participants (50 AD, 50 controls), who underwent clinical and cognitive assessments (MoCA/CDR). While overall microbial diversity and richness showed no significant differences, specific bacterial taxa exhibited subtle differential abundance. Faecalibacterium and Bacteroides were moderately significant and increased on controls compared to AD. Moreover, individuals carrying the APOE E4 allele exhibited lower abundances of butyrate-producing bacteria and an enrichment of potentially pro-inflammatory genera, including Eggerthella and Lachnoclostridium. These findings suggest that gut microbiota dysbiosis may contribute to cognitive decline and AD progression, highlighting the potential for microbiome-targeted therapeutic interventions in AD prevention and treatment.}, } @article {pmid40764372, year = {2025}, author = {Lin, CH and Lane, HY}, title = {Sodium benzoate treatment decreased amyloid beta peptides and improved cognitive function among patients with Alzheimer's disease: secondary analysis of a randomized clinical trial.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {264}, pmid = {40764372}, issn = {2158-3188}, support = {NHRI-EX113-11133NI//National Health Research Institutes (NHRI)/ ; DMR-114-188//China Medical University Hospital (CMUH)/ ; MOST 111-2314-B-182A-024-MY3//Ministry of Science and Technology, Taiwan (Ministry of Science and Technology of Taiwan)/ ; CMRPG8M1311, CMRPG8M1361, CMRPG8N1201, CMRPG8N1121, CMRPG8N1212//Chang Gung Memorial Hospital (CGMH)/ ; CMRPG8M1311, CMRPG8M1361, CMRPG8N1201, CMRPG8N1121, CMRPG8N1212//Chang Gung Memorial Hospital (CGMH)/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/blood/psychology ; *Amyloid beta-Peptides/blood/drug effects ; Male ; Female ; *Sodium Benzoate/administration & dosage/pharmacology/therapeutic use ; Aged ; Double-Blind Method ; *Cognition/drug effects ; *Peptide Fragments/blood/drug effects ; Middle Aged ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {With the recent approval of anti-amyloid beta (Aβ) monoclonal antibody infusion therapies for Alzheimer's disease (AD), more feasible and safter Aβ-reducing approaches are anticipated. Previous studies showed that 750-mg/day or 1000-mg/day (but not 500-mg/day) sodium benzoate treatment improved cognitive function in AD patients with excellent safety and that benzoate decreased Aβ burden in an animal AD model. The current study aimed to explore whether oral sodium benzoate was able to reduce Aβ peptides in AD patients and whether Aβ before treatment was correlated with cognitive improvement after treatment. This secondary analysis used data from a double-blind trial, in which 149 patients with mild AD were randomized to receive oral placebo or one of three benzoate doses (500, 750, or 1000 mg/day). Cognitive function and plasma Aβ 1-40 and Aβ 1-42 levels were measured before and after treatment. When compared to placebo, benzoate therapy at effective doses (750 and 1000 mg/day) reduced Aβ 1-40 and the sum of both Aβ peptides (Aβ 1-40 plus Aβ 1-42) in AD patients. Moreover, higher Aβ 1-42 levels at baseline were associated with better cognitive improvements after benzoate treatment at effective doses in the patients. The findings suggest that sodium benzoate therapy can reduce Aβ 1-40 and the total Aβ in AD patients and higher Aβ 1-42 levels before treatment predict better cognitive improvements. Due to its superior safety and convenient administration, sodium benzoate has the potential to be a novel Aβ-reducing therapy for AD treatment. TRIAL REGISTRATION: Name of trial registry: NMDA Enhancer for the Treatment of Mild Alzheimer's Disease. Identifying number: ClinicalTrials.gov Identifier: NCT03752463 (https://clinicaltrials.gov/ct2/show/NCT03752463). Registration date: 2018-11-21.}, } @article {pmid40764129, year = {2025}, author = {Zhang, B and Lu, H and Li, WP and Liu, DM and Zhang, X and Zhan, SH and Li, KC and Wang, Y and Yang, QX and Gu, XS and Xu, TS}, title = {[The application value of olfactory brain imaging combined with olfactory-stimulating and brain-invigorating acupuncture in the early diagnosis and treatment of Alzheimer's disease].}, journal = {Zhonghua nei ke za zhi}, volume = {64}, number = {8}, pages = {801-806}, doi = {10.3760/cma.j.cn112138-20240918-00587}, pmid = {40764129}, issn = {0578-1426}, mesh = {*Alzheimer Disease/therapy/diagnosis ; Humans ; *Acupuncture Therapy ; Early Diagnosis ; Brain ; }, } @article {pmid40764088, year = {2025}, author = {Liu, H and Chen, Y and Zhang, J and Chen, X}, title = {Adaptive immunity in the neuroinflammation of Alzheimer's disease.}, journal = {Chinese medical journal}, volume = {138}, number = {17}, pages = {2116-2129}, pmid = {40764088}, issn = {2542-5641}, mesh = {*Alzheimer Disease/immunology/metabolism ; Humans ; *Adaptive Immunity/immunology/physiology ; Immunity, Innate/immunology ; Animals ; *Neuroinflammatory Diseases/immunology ; *Inflammation/immunology ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia and is a growing public health challenge. Neuroinflammation has been proposed as a prominent pathological feature of AD and has traditionally been attributed to the innate immune system. However, emerging evidence highlights the involvement of adaptive immunity, particularly T and B lymphocytes, in the neuroinflammatory processes of AD. It remains unclear how adaptive immune responses, originally intended to protect the body, contribute to chronic inflammation and neuronal dysfunction in AD. Here, we review the roles of adaptive immunity, cellular composition, and niches and their contribution to AD development and progression. Notably, we synthesize the crosstalk between adaptive immunity and the innate immune system of the central nervous system (CNS), which is mainly mediated by glial cells and myeloid cells, and their interrelationships with amyloid-β (Aβ)/Tau pathology. We hypothesized that the alterations observed in innate immunity in AD mirror age-related immune alterations, whereas the dysregulation of adaptive immunity contributes more accurately to disease-specific immune responses. Targeting adaptive immunity in the context of neuroinflammation may provide new insights into potential therapeutic strategies designed to modulate immune responses, thereby facilitating the diagnosis, intervention, and treatment of AD.}, } @article {pmid40763898, year = {2025}, author = {Porel, P and Hunjan, G and Singh, S and Aran, KR}, title = {Is the renin-angiotensin system a friend or foe in neurological diseases? Unveiling its role and therapeutic potential.}, journal = {Ageing research reviews}, volume = {112}, number = {}, pages = {102854}, doi = {10.1016/j.arr.2025.102854}, pmid = {40763898}, issn = {1872-9649}, mesh = {Humans ; *Renin-Angiotensin System/physiology/drug effects ; Animals ; *Nervous System Diseases/drug therapy/metabolism/physiopathology ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use/pharmacology ; Angiotensin Receptor Antagonists/therapeutic use/pharmacology ; Neurodegenerative Diseases/drug therapy ; }, abstract = {The renin-angiotensin system (RAS), an important regulator of body fluid and cardiovascular homeostasis, is gradually implicated in the pathogenesis of neurological diseases due to its dysregulation. In addition to their traditional functions, components of the RAS, especially angiotensin-II (Ang-II), enhance neuroinflammation, oxidative stress, and neuronal injury. Ang-II exacerbates blood-brain barrier (BBB) disruption, promotes glial activation, and contributes to neurodegeneration via the Angiotensin type 1 (AT1) receptor (AT1R) and causes neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease (HD), epilepsy, depression, and anxiety. The angiotensin (1-7) axis mediated by the Mas receptor appears to be neuroprotective, however, as it reverses the negative effects of Ang-II. In experimental models and clinical trials, blocking RAS specifically by angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) has demonstrated promise in reducing neuroinflammation and neuronal damage, especially in stroke and neurodegenerative diseases. In the current era of research, neuropharmacologists have new optimism due to emerging evidence of the promising potential of RAS-modulating drugs, such as ARBs and ACEIs, in the treatment of various neurological diseases. Since RAS imbalance causes neuroinflammation, neuronal damage, and cognitive decline in conditions including AD, PD, and MS, these drugs may offer a new treatment approach. In the current era of neuropharmacology, this technique is novel since it enables more targeted therapies to address the root causes of neurodegeneration. This review explores the molecular pathways of RAS dysregulation in various neurological diseases, highlighting its therapeutic potential and paving the way for future treatment strategies.}, } @article {pmid40763881, year = {2025}, author = {Garbo, S and Raucci, A and Zwergel, C and Handzlik, J and Battistelli, C}, title = {Beyond Antibodies: Reinventing Alzheimer's Treatment for the Next Decade.}, journal = {Drug discovery today}, volume = {30}, number = {9}, pages = {104445}, doi = {10.1016/j.drudis.2025.104445}, pmid = {40763881}, issn = {1878-5832}, } @article {pmid40763582, year = {2026}, author = {Zuo, Z and Xiao, Z and Zhang, L and Deng, S and He, X and Mu, Y and Wang, P and Feng, Y and Wang, Z and Li, S and Yang, X and Xu, J and Guo, K and Guo, W and Shuai, X and Hu, X and Zheng, H}, title = {Engineered peripheral CD4 T cells delivery across the BBB promote intracerebral Treg conversion unleashes microglial phagocytotic activity for Alzheimer's disease treatment.}, journal = {Biomaterials}, volume = {325}, number = {}, pages = {123574}, doi = {10.1016/j.biomaterials.2025.123574}, pmid = {40763582}, issn = {1878-5905}, mesh = {Animals ; *Alzheimer Disease/therapy/immunology/pathology ; *T-Lymphocytes, Regulatory/immunology/cytology ; *Microglia/immunology ; *Blood-Brain Barrier/metabolism ; Mice ; *CD4-Positive T-Lymphocytes/immunology/transplantation ; *Phagocytosis ; Amyloid beta-Peptides/metabolism/immunology ; Mice, Transgenic ; Disease Models, Animal ; Mice, Inbred C57BL ; Peptide Fragments ; Brain/pathology ; }, abstract = {Alzheimer's disease (AD) affects thirty million individuals worldwide, but a viable treatment has yet to be identified. During disease progression, peripheral immune cells, including peripheral T cells, infiltrate the brain. Although CD4[+] regulatory T cells have been demonstrated to exhibit neuroprotective efficacy in AD, the precise roles of these cells in the brain remain elusive. Here, we report that β-amyloid (Aβ) 1-42 antigen-specific CD4[+] T cells spontaneously cross the blood-brain barrier (BBB) into the brain in an APP/PS1 mouse model. To promote parenchymal Treg conversion from infiltrated CD4[+] T cells and minimize the perturbations of the brain microenvironment, we engineered an Aβ1-42 antigen-specific CD4[+] T cell-based nanodelivery system to release the compound AS2863619, a CDK8/19 inhibitor (eTc-AS), which can bypass the BBB and selectively induce the conversion of CD4[+] T cells into Treg cells within the brain region. These cells demonstrated notable pathological amelioration in APP/PS1 mice, in part by interacting with microglia or recruited macrophage via PD-L1/PD-1 signaling. Our study reveals valuable engineered T cell therapies and suggests an immune checkpoint mechanism underlying the neuroprotective function of the Treg-microglia like cell interplay in AD.}, } @article {pmid40763193, year = {2025}, author = {Lv, L and Fazio-Eynullayeva, E and Mystkowski, P and McKay, C and Al-Zubeidi, T and Miller, J and McKee, S and Bottomley, C and Floegel, C and Hyde, R and Aly, A}, title = {Experiences of patient and care partner dyads in early Alzheimer's disease: a mixed-method study in the United States.}, journal = {Neurodegenerative disease management}, volume = {15}, number = {5}, pages = {223-234}, pmid = {40763193}, issn = {1758-2032}, mesh = {Humans ; *Alzheimer Disease/psychology/economics/therapy ; Male ; Female ; Aged ; United States ; *Caregivers/psychology ; Aged, 80 and over ; Middle Aged ; Surveys and Questionnaires ; }, abstract = {AIMS: Understanding the holistic experience of patients with early Alzheimer's disease (AD) and their care partners is important to identify unmet needs. This study aimed to describe and compare patient-care partner dyad experiences and perspectives in early AD. PATIENTS & METHODS: Experiences of patients and their care partners (dyads) were explored using a survey, qualitative interviews, and social media listening. Each dyad completed a 25-minute quantitative online survey exploring their perceptions of symptoms, comorbidity impact, financial burden, and preferred treatment characteristics. Data were analyzed descriptively and comparatively. RESULTS: 150 patient-care partner dyads completed the survey. Patients and care partners frequently reported memory-related issues and cognitive challenges (68% and 77%, respectively); approximately 19% of responses were discordant, with patients often under-reporting symptoms. Managing comorbidities worsened overall well-being of patients (41%) and care partners (40%). Treatments slowing AD progression (patients: 99%; care partners: 96%) and improving symptoms (patients: 95%; care partners: 93%) were important. Approximately 26% of respondents experienced significant negative financial impacts. CONCLUSIONS: Patients and care partners perceived early AD impacts similarly whereas some symptoms were perceived differently. There was a shared desire for disease-modifying treatments. Limited financial impact may reflect preserved functionality and limited use of disease-modifying treatments.}, } @article {pmid40762111, year = {2025}, author = {Cao, F and Zhang, P and Zheng, Z and Wang, P and Wang, Y and Shi, Q and Zhang, D and Xu, L}, title = {Celastrol treatment attenuates the inflammatory response in Alzheimer's disease model mice.}, journal = {Neurological research}, volume = {}, number = {}, pages = {1-7}, doi = {10.1080/01616412.2025.2534077}, pmid = {40762111}, issn = {1743-1328}, abstract = {OBJECTIVE: Alzheimer's disease (AD) is the most common neurodegenerative disease. Unfortunately, current effective therapeutics for AD are limited, and thus, the discovery of novel anti-AD agents is urgently needed. Celastrol, a plant-derived triterpene, has both antioxidant and anti-inflammatory activities. METHODS AND RESULTS: Here, we found that celastrol treatment promoted microglial M2 polarization and inhibited inflammatory factor expression in both in vivo and in vitro experiments. Celastrol treatment significantly improved cognitive function in AD mice by regulation the TLR4/NFκB pathway, overexpression TLR4 reversed the protective effect of CEL to cognitive function in AD model mice. Suggesting that TLR4/NFκB plays a crucial role in regulating the inflammatory response. CONCLUSION: Taken together, the results indicate that celastrol treatment attenuated the inflammatory response in AD mice by promoting microglial M2 polarization via the TLR4/NFκB pathway.}, } @article {pmid40762089, year = {2025}, author = {Chatanaka, MK and Pascual Lorén, M and Diamandis, EP}, title = {Is screening for Alzheimer's disease ready for prime time? Ask Wilson and Jungner.}, journal = {Critical reviews in clinical laboratory sciences}, volume = {62}, number = {8}, pages = {631-645}, doi = {10.1080/10408363.2025.2533860}, pmid = {40762089}, issn = {1549-781X}, mesh = {Humans ; *Alzheimer Disease/diagnosis/epidemiology ; *Mass Screening/methods ; Early Diagnosis ; }, abstract = {Population screening is an effective strategy for disease prevention, early diagnosis and treatment; however, the benefits and harms of disease screening need to be carefully evaluated before clinical implementation. Various national and international bodies, including the U.S. Preventive Services Task Force (USPSTF), periodically develop recommendations for screening after reviewing the available published evidence and, in some instances, expert opinions. In 1968, Wilson and Jungner formulated a set of 10 rules that must be considered and fulfilled before introducing screening for any disease into clinical practice. Alzheimer's disease (AD), a devastating chronic disease that affects millions of people worldwide and is the most common cause of dementia, has recently been reviewed in the context of population screening. Data and predictions show that the prevalence of AD is steadily increasing and will likely become one of the most common causes of death by 2060. Currently, there are no effective curative therapeutic options for this disease, but new developments have allowed earlier detection at asymptomatic and early symptomatic stages. New classes of disease-modifying therapeutics show promise of slowing the progression of the disease. These new developments prompted us to examine the near-future feasibility of screening for presymptomatic or early symptomatic AD by considering the general screening principles of Wilson and Jungner. In 2020, USPSTF published a guideline regarding screening for cognitive impairment, an AD symptom, and concluded that the current evidence is insufficient to assess the balance of benefits and harms and did not recommend screening for cognitive impairment in older adults. This was recapitulated in 2024 by the Canadian Task Force on Preventive Health Care (CTFPHC). After careful consideration, and despite the recent significant biological, diagnostic and therapeutic advances for AD, screening does not seem to be justified at present, due to numerous reasons, such as lack of trained professionals and specialized clinics to handle the anticipated highly increased workload, the huge cost, the ineffectiveness and side effects of current therapy, the lack of long-term therapy studies, and the disagreement among experts as to whom to test and treat and when (at either asymptomatic or early symptomatic stages).}, } @article {pmid40762084, year = {2025}, author = {Wang, X and Xia, Y and Guo, MS and Wu, J and Dilidaer, A and Gao, J and Dong, TT and Zhu, Y and Tsim, KWK}, title = {The Tacrine-Induced Endoplasmic Reticulum Stress in AChE-Expressed Cells Leads to Improper Assembly and Transport of the Oligomeric Enzyme: Reversal by Trehalose.}, journal = {Journal of neurochemistry}, volume = {169}, number = {8}, pages = {e70178}, pmid = {40762084}, issn = {1471-4159}, support = {ZDSYS201707281432317//Shenzhen Science and Technology Innovation Committee/ ; HMRF18SC06//Health and Medical Research Fund, Food and Health Bureau of Hong Kong/ ; HMRF20SC07//Health and Medical Research Fund, Food and Health Bureau of Hong Kong/ ; 16100921//Hong Kong GRF/ ; T13-605/18-W//Hong Kong GRF Theme-based Research Scheme/ ; ITCPD/17-9//Hong Kong Innovation and Technology Fund/ ; }, mesh = {*Trehalose/pharmacology ; *Tacrine/toxicity/pharmacology ; *Endoplasmic Reticulum Stress/drug effects/physiology ; Animals ; *Acetylcholinesterase/metabolism/biosynthesis/genetics ; *Cholinesterase Inhibitors/pharmacology/toxicity ; Mice ; Cell Line, Tumor ; Humans ; Protein Transport/drug effects ; Neurons/drug effects ; }, abstract = {Alzheimer's disease (AD) is the most common dementia with progressive loss of cognitive functions. Acetylcholinesterase (AChE) inhibitors have been approved as conventional pharmacotherapies for AD. Tacrine was the first AChE inhibitor introduced into clinics for AD; however, it was withdrawn from use in 2013 because of safety concerns. In cultured neurons, as well as in mice, tacrine was found to induce endoplasmic reticulum (ER) stress and finally lead to cell apoptosis: the event was triggered by binding the inhibitor to the intracellular enzyme serving as a pharmacological chaperone. Trehalose, a known ER stress reducer, was shown here to ameliorate the ER stress induced by tacrine in AChE-overexpressed NG108-15 cells, with the increased level of C/EBP homologous protein (CHOP) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α). In tetrameric G4 AChE overexpressed cells, the tacrine-exposed cultures revealed considerable G1/G2 forms of AChE accumulated in the ER fraction, whereas the treatment of trehalose decreased the accumulation of G1/G2 AChE. Meanwhile, trehalose reduced the ER stress induced by other AChE inhibitors, for example, lycobetaine, bis(3)-cognitin, daurisoline, and dauricine, in the cultured neuronal cells. Besides, this tacrine-induced ER stress was identified in all AChE isoforms, as well as in butyrylcholinesterase (BChE) expressing cells. Thus, we proposed that the AChE inhibitors, particularly tacrine, could act as 'chemical/pharmacological chaperones' during AChE biosynthesis in the ER, disrupting the proper folding of AChE in neurons as a result of ER stress. Trehalose possesses the ability to relieve ER stress by promoting the proper assembly of AChE. The results provide guidance for the drug design and discovery of AChE inhibitors for AD treatment.}, } @article {pmid40761983, year = {2025}, author = {DiGiovanni, A and Shehaj, A and Millar, D and Tse, C and Rizk, E}, title = {Utility of Pharmacological Agents for Diabetes Mellitus in the Prevention of Alzheimer's Disease: Comparison of Metformin, Glucagon-Like Peptide-1 (GLP-1) Agonists, Insulin, and Sulfonylureas.}, journal = {Cureus}, volume = {17}, number = {7}, pages = {e87350}, pmid = {40761983}, issn = {2168-8184}, abstract = {BACKGROUND: Metformin is a drug primarily used for the treatment of diabetes mellitus (DM), but it also offers clinical benefits that extend beyond glycemic control. Existing literature provides an unclear conclusion as to whether metformin's benefits extend to preventing neurodegeneration, such as in Alzheimer's disease (AD). METHODS: A retrospective database study was conducted to evaluate the likelihood of developing AD in DM patients taking metformin compared to those taking glucagon-like peptide (GLP-1) analogs, sulfonylureas, and short-acting insulin variants. An analysis was also run to assess whether metformin has a protective benefit for AD and mortality when used in those with DM compared to those without DM. RESULTS: In analyses totaling greater than 2.5 million patients, those on metformin had lower A1C percentages and a decreased mortality risk when compared to sulfonylureas (HR = 0.519, (CI: (0.493,0.546)), and short-acting insulins (HR = 0.372, (CI: (0.364,0.380)). Metformin use for DM was associated with a statistically significant increased likelihood of AD diagnosis compared to GLP-1 use (HR = 2.228, CI: (1.036,4.794)) but an insignificant difference compared to both sulfonylureas and insulins. Those with DM were at a significantly higher risk of being diagnosed with Alzheimer's compared to those without DM (HR = 1.826, (CI: 1.579, 2.111)). CONCLUSIONS: Metformin, previously thought to have significant benefits in preventing neurodegeneration, may not be the optimal pharmacologic agent of choice, particularly in patients with DM, if neurodegeneration is a primary concern in treatment decision-making based on other risk factors.}, } @article {pmid40761698, year = {2025}, author = {Zhou, B and Li, J and Wu, A and Wang, X and Cheng, L and Yang, G and Gao, D and Zhu, C}, title = {Insights into targeted ferroptosis in mechanisms, biology, and role of Alzheimer's disease: an update.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1587986}, pmid = {40761698}, issn = {1663-4365}, abstract = {Ferroptosis is a newly discovered form of programmed cell death, primarily caused by an imbalance between iron-dependent oxidative damage and antioxidant defense mechanisms within the cell. It differs from previously reported forms of cell death, such as apoptosis, necrosis, and autophagy, in terms of morphology, biochemistry, and genetics. Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by pathological features including neurofibrillary tangles (NFTs), senile plaques (SPs), and abnormal iron deposition, suggesting that ferroptosis may be involved in its disease progression. Although recent studies have made significant progress, the mechanisms underlying neuronal ferroptosis in AD remain incompletely understood. This review, based on elucidating the process and regulatory mechanisms of cellular ferroptosis, explores, and supplements the correlation between iron overload and redox imbalance with the main pathological mechanisms of AD, providing new insights for the treatment of AD and the development of new drugs.}, } @article {pmid40761545, year = {2025}, author = {Zhu, H and Yang, W and Suo, Y and Liu, Y and Zhan, X and Zhou, J and Chen, Z and Wu, X and Yin, X and Bao, B}, title = {Nanomaterials engineered for photothermal therapy in neural tumors and neurodegenerative diseases: biomaterial design, clinical mechanisms and applications.}, journal = {Frontiers in bioengineering and biotechnology}, volume = {13}, number = {}, pages = {1631627}, pmid = {40761545}, issn = {2296-4185}, abstract = {The rising incidence of neural tumors and neurodegenerative diseases cause significant health, emotional, and financial burdens. Conventional treatments like surgery and chemotherapy often lack effectiveness. However, advancements in nanotechnology, particularly photothermal therapy (PTT), offer new hope. PTT is widely studied for neural tumors and neurodegenerative diseases due to its simplicity, rapid recovery, combined therapeutic potential, and compatibility with imaging techniques. This innovative approach could revolutionize the diagnosis and treatment of neural tumors and neurodegenerative diseases, addressing current limitations and improving outcomes. In this article, we offer a comprehensive overview of the rational design and engineering of various nanomaterials designed specifically for PTT applications in neural tumors and neurodegenerative diseases, including organic platforms such as liposomes, dopamine, etc. and inorganic platforms such as gold nanomaterials, carbon nanomaterials, etc. A comparative analysis of these platforms examines their biocompatibility and potential for biodegradation. It also assesses their manufacturing scalability, cost-effectiveness, regulatory challenges, and ultimate potential for clinical translation. We also update the therapeutic advances of PTT in neural tumors (Glioma, Peripheral nerve sheath tumors, Spinal metastases from in situ tumors and brain metastases) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease), and systematically summarize the mechanisms of PTT application in neural tumors and neurodegenerative diseases. In the end, we provide an in-depth discussion of the advantages and disadvantages of PTT and the perspectives for its application in the above neurological disorders.}, } @article {pmid40761402, year = {2025}, author = {Zampatti, S and Peconi, C and Farro, J and Piras, F and Pellicano, C and Caltagirone, C and Giardina, E}, title = {Pharmacogenetics or predictive genetics? APOE testing blurs the lines.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1627239}, pmid = {40761402}, issn = {1663-9812}, abstract = {The integration of pharmacogenetics into personalized medicine enables the optimization of drug selection and dosage, maximizing therapeutic benefits while minimizing the risk of adverse drug reactions. The association between APOE alleles and ARIA, a known adverse reaction in Alzheimer's disease patients treated with anti-amyloid monoclonal antibodies, has led to the inclusion of APOE genotyping among conventional pharmacogenetic tests. Given the dual role of APOE alleles, the widespread implementation of this genetic test requires caution and should be accompanied by appropriate genetic counselling. APOE genotyping is uniquely positioned at the intersection of pharmacogenetics and germline testing: it provides insight not only into drug safety (specifically the risk of Amyloid-Related Imaging Abnormalities) but also into familial risk for developing Alzheimer's disease. Carriers of risk alleles, especially homozygotes, face the highest risk and require close monitoring. While APOE genotyping can inform treatment decisions, it also raises ethical concerns due to the broader implications of disclosing genetic risk information for neurodegenerative diseases. Identifying a high-risk APOE genotype in a patient substantially impacts family members. Therefore, patients considered for treatment with anti-amyloid monoclonal antibodies should receive comprehensive pre- and post-test genetic counseling that goes beyond traditional standards, as currently provided for other peculiar tests. Such counseling ensures that patients are adequately informed about potential outcomes, psychological impacts, and familial implications. It also supports ethical decision-making and facilitates truly informed consent, helping to prevent deterministic or overly simplistic interpretations of genetic risk.}, } @article {pmid40760852, year = {2025}, author = {Duchesne, S and Potvin, O and Hudon, C and Bocti, C}, title = {A brain health framework with application to the study of neurodegeneration.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {3}, pages = {960-972}, pmid = {40760852}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/pathology ; *Brain/pathology/physiopathology ; Models, Neurological ; *Neurodegenerative Diseases/pathology ; }, abstract = {An all-encompassing framework seems necessary for understanding brain health in the context of neurodegeneration, particularly due to Alzheimer's disease (AD). We argue that current views, dominated by the amyloid-beta hypothesis, oversimplify the complexity of brain degeneration. We propose a multi-scale, multi-entity approach, treating the brain as a complex system composed of interacting subsystems across various scales, from the nanoscale (genes and proteins) to the macroscale (cognition) and beyond. By redefining brain health through mathematical complexity, we emphasize the importance of integrating diverse biological, environmental, and lifestyle factors to account for the heterogeneity in AD presentations. This framework suggests that failures at different levels of brain function can lead to cascading effects that influence neurodegenerative trajectories. Additionally, it calls for a shift toward personalized treatment approaches that target multiple yet specific pathological mechanisms affecting an individual. We propose computational models as essential tools for simulating and testing these complex interactions. Through this framework, we aim to provide a deeper understanding of neurodegeneration, and advocate for more comprehensive and multi-factorial approaches in both research and clinical practice to advance the treatment of brain health disorders such as AD.}, } @article {pmid40760799, year = {2025}, author = {Li, Z and Kang, Y and Li, S and Guo, S and Zheng, H}, title = {Unveiling the Relationship Between Oral Microbiota and Alzheimer's Disease: A Genetic Instrumental Variable Analysis via Mendelian Randomization.}, journal = {Brain and behavior}, volume = {15}, number = {8}, pages = {e70753}, pmid = {40760799}, issn = {2162-3279}, mesh = {Mendelian Randomization Analysis ; *Alzheimer Disease/genetics/microbiology ; *Microbiota ; *Tongue/microbiology ; *Saliva/microbiology ; Humans ; }, abstract = {BACKGROUND: The potential relationship between oral microbiota (OM) and Alzheimer's disease (AD) is increasingly recognized, but the exact causal relationship between them remains uncertain. This study aims to reveal the causal relationship between OM and AD. METHODS: A two-sample Mendelian randomization (MR) approach was employed to examine the association between 594 OM exposures and AD outcomes. Effect estimates were derived from external genome-wide association study (GWAS) summary statistics, primarily utilizing inverse-variance weighted (IVW) analysis. Sensitivity analyses were conducted to assess the robustness of the findings. In addition, we genetically mapped SNPs corresponding to OM in the MR analysis to identify genes that may link OM to AD. RESULTS: A total of 48 OM exposures exhibited statistically significant associations with AD outcomes (p ≤ 0.05). Of these, 30 were identified at the genus level, 12 at the species level, and six at the family level. Genetic function analyses indicated that OM-related genes are closely linked to the regulation of neurobiological functions, supporting a potential role for OM in the pathogenesis of AD. CONCLUSION: The findings presented here provide genetic evidence for a causal relationship between OM and AD, offering insights that may guide the future development of prevention and treatment strategies targeting OM in the context of AD.}, } @article {pmid40760788, year = {2025}, author = {Ke, S and Yan, J and Li, B and Feng, X}, title = {Causal Association Between Immune Cell Traits and Risk of Multiple Malignant and Nonmalignant CNS Diseases: A Mendelian Randomization and Single-Cell Transcriptomic Analysis.}, journal = {Brain and behavior}, volume = {15}, number = {8}, pages = {e70632}, pmid = {40760788}, issn = {2162-3279}, mesh = {Humans ; Mendelian Randomization Analysis ; Single-Cell Analysis ; Quantitative Trait Loci/genetics ; Glioblastoma/genetics/immunology ; *Central Nervous System Diseases/genetics/immunology ; Transcriptome ; Gene Expression Profiling ; Brain Neoplasms/genetics/immunology ; }, abstract = {BACKGROUND: The influence of immune cell traits (ICTs) on the onset of multiple brain diseases has been previously investigated; however, it is limited by the sample size or colocalization evidence. Besides, the impact remains inconclusive. METHODS: We performed a Mendelian randomization (MR) study to elucidate the causal correlation between significant ICTs and diverse brain disorders and explored the biomarkers linked to glioblastoma (GBM), a form of solid tumor, by integrating expression quantitative trait locus (eQTL) and single-cell RNA sequencing (scRNA-seq) analyses. The nonnegative matrix factorization (NMF) method was utilized to reclassify malignant cells into distinct cell states. Related functional analyses at the scRNA-seq level were also performed. RESULTS: We examined 731 ICTs across 13 brain disorders; impacts from these ICTs varied a lot across different brain diseases. Such ICTs mainly involved T/natural killer (NK) cell activation, B cell differentiation, and myeloid cell suppression or activation. Pleiotropy or heterogeneity in current results has been checked and excluded via sensitivity analyses. Specifically, colocalization analyses demonstrated protective roles of distinct ICTs in T/B/NK cell panels for amyotrophic lateral sclerosis (ALS) and GBM, while myeloid and human leukocyte antigen (HLA)-associated traits were associated with increased risk of Alzheimer's disease (AD), and then two memory cell traits were linked to the increased risk of major depressive disease (MDD). By NMF, we identified six distinct cell states within GBM cells. Furthermore, we established an eight-marker glioblastoma risk signature (GBRS) using scRNA-seq and eQTL data, with higher GBRS scores observed in the NFkB cluster and EGFR cluster, indicating their highlighted aggression among malignant cells. Epigallocatechin gallate could be an effective treatment candidate targeting the EGFR cluster via markers of SQLE and VCP. CONCLUSION: Our findings identified causal effects of distinct ICTs on both malignant and nonmalignant brain diseases and underscored the pivotal role of neuroinflammation in their etiology. With combined evidence from eQTL and scRNA-seq, GBM could be better characterized and managed.}, } @article {pmid40760693, year = {2025}, author = {Iwatsubo, T and Sperling, RA and Algeciras-Schimnich, A and Arai, H and Barron, AM and Benzinger, TLS and Carrillo, MC and Chen, C and Choi, SH and Fontana, IC and Graff-Radford, J and Grill, JD and Heidebrink, J and Hu, CJ and Ihara, R and Ikeuchi, T and Iwata, A and Ip, FCF and Fitri, FI and Jack, CR and Jeong, JH and Jia, J and Kandiah, N and Kim, S and Kowa, H and La Joie, R and Niimi, Y and Noritake, R and Okonkwo, OC and Palmqvist, S and Rafii, MS and Raman, R and Shen, Y and Simuni, T and Snyder, HM and Sriwannopas, O and Stoeckel, LE and van der Flier, WM and Wang, H and Wilcock, DM and Zetterberg, H and Zhou, J and Mahinrad, S and Sexton, CE}, title = {Modernizing diagnosis of Alzheimer's disease: A review of global trends and Asia-specific perspectives.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70536}, pmid = {40760693}, issn = {1552-5279}, support = {//Gates Ventures/ ; R01AG070028/NH/NIH HHS/United States ; //Eisai/ ; //European Union's Horizon 2020 research and innovation programme/ ; //Roche Nederland/ ; R01 AG066203/AG/NIA NIH HHS/United States ; R01 AG070028/AG/NIA NIH HHS/United States ; //Combinostics/ ; #ADSF-21-831377-C/ALZ/Alzheimer's Association/United States ; U19 AG073153/AG/NIA NIH HHS/United States ; //Pasman stichting/ ; //Health∼Holland/ ; //anonymous donor/ ; R01AG077507/NH/NIH HHS/United States ; //Alzheimer Nederland/ ; //Biogen/ ; U19AG078109/NH/NIH HHS/United States ; //Alexander family professorship/ ; MRP/042/18X//Innovation and Technology Commission - Hong Kong/ ; R01 AG077507/AG/NIA NIH HHS/United States ; #ADSF-21-831376-C/ALZ/Alzheimer's Association/United States ; //Familjen Rönströms Stiftelse/ ; //Edwin Bouw fonds/ ; #2022-01018//Vetenskapsrådet/ ; R01 AG085592/AG/NIA NIH HHS/United States ; U19AG032438/NH/NIH HHS/United States ; //Alzheimer's Drug Discovery Foundation/ ; 2021ZD0201805//The Science and Technology Innovation 2030-Major Project/ ; #2019-02397//Vetenskapsrådet/ ; JP20dk0207048h002//Japan Agency for Medical Research and Development/ ; R01AG027161/NH/NIH HHS/United States ; JP24K10653//Japan Society for the Promotion of Science/ ; JP19dk0207048h001//Japan Agency for Medical Research and Development/ ; //Fujifilm/ ; JP24dk0207060//Japan Agency for Medical Research and Development/ ; R01 AG062167/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; //Eli Lilly-NL/ ; JP23dk0207054h0003//Japan Agency for Medical Research and Development/ ; #2023-00356//Vetenskapsrådet/ ; //Innovative Health Initiative/ ; JP24dk0207054h0004//Japan Agency for Medical Research and Development/ ; //UK Dementia Research Institute at UCL/ ; P30AG072931/NH/NIH HHS/United States ; //Novarti-NL/ ; R01 AG027161/AG/NIA NIH HHS/United States ; 2021ZD0201802//The Science and Technology Innovation 2030-Major Project/ ; //Erling-Persson Family Foundation/ ; R01AG066203/NH/NIH HHS/United States ; //GHR Foundation/ ; U19 AG024904/AG/NIA NIH HHS/United States ; Z201100005520017//Beijing Municipal Science and Technology Commission, Adminitrative Commission of Zhongguancun Science Park/ ; R61AG066543/NH/NIH HHS/United States ; JP21dk0207054h0001//Japan Agency for Medical Research and Development/ ; 23re0122003//Japan Agency for Medical Research and Development/ ; //Philips/ ; MRP/097/20X//Innovation and Technology Commission - Hong Kong/ ; //Swedish State Support for Clinical Research/ ; JP24dk0207069h0001//Japan Agency for Medical Research and Development/ ; 25dk0207068h0003//Japan Agency for Medical Research and Development/ ; //Hersenstichting/ ; R01AG062167/NH/NIH HHS/United States ; //Stichting Equilibrio/ ; JPND2021-00694//EU Joint Programme - Neurodegenerative Disease Research/ ; JP23dk0207048h005//Japan Agency for Medical Research and Development/ ; //Life-MI/ ; #ADSF-21-831381-C/ALZ/Alzheimer's Association/United States ; //Topsector Life Sciences & Health/ ; //Avid Radiopharmaceuticals/ ; //Davis Alzheimer's Prevention Project/ ; //GIESKES-STRIJBIS FONDS/ ; //Stichting Dioraphte/ ; JP21dk0207048h0003//Japan Agency for Medical Research and Development/ ; U19 AG078109/AG/NIA NIH HHS/United States ; P01AG003991/NH/NIH HHS/United States ; //Stiftelsen för Gamla Tjänarinnor/ ; //Cure Alzheimer's Fund/ ; Z201100005520016//Beijing Municipal Science and Technology Commission, Adminitrative Commission of Zhongguancun Science Park/ ; //European Union's Horizon Europe research and innovation programme/ ; //European Partnership on Metrology/ ; R01AG085592/NH/NIH HHS/United States ; U19AG073153/NH/NIH HHS/United States ; U19AG024904/NH/NIH HHS/United States ; RF1 AG052324/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; //Olav Thon Stiftelsen/ ; /ZONMW_/ZonMw/Netherlands ; RF1AG052324/NH/NIH HHS/United States ; //Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; FO2022-0270//Hjärnfonden/ ; JP22dk0207054h0002//Japan Agency for Medical Research and Development/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; R61 AG066543/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; JP22dk0207048h004//Japan Agency for Medical Research and Development/ ; #ADSF-24-1284328-C/ALZ/Alzheimer's Association/United States ; }, mesh = {*Alzheimer Disease/diagnosis/therapy ; Humans ; Biomarkers ; Asia ; Early Diagnosis ; }, abstract = {The landscape of Alzheimer's disease (AD) and related dementias (ADRD) diagnosis is evolving rapidly, driven by advances in disease understanding, biomarker tools, and disease-modifying therapies. Modern diagnostic approaches emphasize biological precision, early detection, and dynamic frameworks that adapt to treatment-induced changes in disease biology. These frameworks enable opportunities for personalized interventions-encompassing pharmacological and non-pharmacological strategies-and for enhanced clinical trial design. However, implementing these advancements globally is influenced by diverse cultural, infrastructural, and regulatory factors. The 2024 Alzheimer's Association International Conference Advancements: Modernizing Diagnosis, held in Japan, provided a unique platform to explore these global dynamics, particularly from an Asian perspective. This article highlights key discussions from the conference, exploring the role of biomarker-based diagnostic frameworks in shaping the future of AD/ADRD research, diagnosis, and treatment. We highlight regional challenges and successes and emphasize ethical considerations and practical strategies needed to ensure equitable access to diagnostic and therapeutic innovations. HIGHLIGHTS: Advances in biomarkers are reshaping Alzheimer's disease diagnosis and treatment. Modern diagnostic frameworks highlight biological precision, early detection, and dynamic frameworks. The 2024 Alzheimer's Association International Conference Advancements: Modernizing Diagnosis explored challenges and opportunities in global biomarker implementation. The conference explored geographic-specific impacts, focusing on Asia.}, } @article {pmid40760649, year = {2025}, author = {Chen, W and Chen, Y and Tang, Q and Kong, D and Xu, M and Yang, Y and Li, Q and Yang, M}, title = {Analysis of risk-factors associated with hospital-acquired pneumonia in patients with alzheimer's disease based on gender differences.}, journal = {BMC geriatrics}, volume = {25}, number = {1}, pages = {587}, pmid = {40760649}, issn = {1471-2318}, support = {2022172//Health Commission of Chengdu/ ; 2024141//Health Commission of Chengdu/ ; S23012//Sichuan medical association/ ; 2022-YF05-01867-SN//Chengdu Science and Technology Bureau/ ; 24CXTD11//Health Commission of Sichuan Province/ ; 62373079//The National Natural Science Foundation of China/ ; 2024ZYD0039//Science and Technology Department of Sichuan Province/ ; SYYXHPT202420//Sichuan Medical Association/ ; }, mesh = {Humans ; Male ; Female ; *Alzheimer Disease/epidemiology/diagnosis/complications ; Aged ; Risk Factors ; Sex Factors ; Aged, 80 and over ; *Healthcare-Associated Pneumonia/epidemiology/diagnosis ; *Cross Infection/epidemiology/diagnosis ; }, abstract = {BACKGROUND: Pneumonia is an important cause of death in patients with Alzheimer's disease (AD), and understanding the factors associated with hospital-acquired pneumonia (HAP) is essential for preventing the development of HAP in AD patients. This study aimed to elucidate the specific risk factors related to HAP in AD patients based on gender differences. METHODS: A total of 1066 patients with Alzheimer's disease (483 males, 583 females), who were admitted to a large psychiatric hospital for the first time between 2013 and 2023, were included in the study. The association between HAP and patients' personal characteristics, medication use and blood test results among genders was analysed. Finally, binary logistic regression was used to identify the independent risk factors for men and women. RESULTS: The infection rate of HAP in male AD patients was significantly higher than that in females, at 41.8% and 23.3%, respectively (χ[2] = 41.726, P < 0.001). Regression results showed that in male patients, HAP was independently correlated with age, apolipoprotein A1 level and lymphocyte count, whereas in female patients, HAP was independently correlated with age, albumin, low-density lipoprotein cholesterol and neutrophil count. CONCLUSION: This study suggests that older AD patients are more susceptible to HAP; the infection rate of HAP in male patients with Alzheimer's disease is higher than that in females, and there are differences in the factors associated with the occurrence of HAP between male and female patients. It is suggested that prevention and treatment strategies for hospital-acquired pneumonia in individuals with Alzheimer's disease could consider age and gender differences.}, } @article {pmid40760501, year = {2025}, author = {Yu, L and Wang, X and Doan, TH and Fan, Y and Bussiere, T and Bacskai, BJ and Kastanenka, KV}, title = {Aducanumab binds high molecular weight soluble Aβ oligomers and restores intracellular calcium levels.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {180}, pmid = {40760501}, issn = {1758-9193}, support = {R01 AG066171/AG/NIA NIH HHS/United States ; PYJH2024314//Advanced Program of The Affiliated Hospital of Xuzhou Medical University/ ; }, mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Calcium/metabolism ; Mice, Transgenic ; Humans ; *Antibodies, Monoclonal, Humanized/pharmacology ; Neurons/drug effects/metabolism ; Mice ; Astrocytes/drug effects/metabolism ; Molecular Weight ; Cells, Cultured ; *Peptide Fragments/metabolism ; Alzheimer Disease/metabolism ; Coculture Techniques ; Brain/metabolism/drug effects ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) accumulation, leading to the formation of neurotoxic soluble oligomers (AβOs) that impair calcium homeostasis in neurons and astrocytes. Aducanumab, a fully human monoclonal antibody targeting aggregated Aβ, has been approved for AD treatment due to its ability to reduce amyloid plaque burden. However, its specificity toward different AβO species and its functional impact on calcium homeostasis remain unclear. METHODS: We investigated aducanumab's ability to recognize and immunodeplete low-molecular-weight (LMW) and high-molecular-weight (HMW) AβOs using three Aβ preparations: (1) transgenic conditioned media (TgCM) from cultured Tg2576 neurons, (2) synthetic Aβ42-derived diffusible ligands (ADDLs), and (3) TBS-soluble fractions from aged Tg2576 mouse brain. Size exclusion chromatography and ELISA were used to characterize AβO species. Multiphoton calcium imaging of neuron-astrocyte co-cultures was performed to assess the impact of aducanumab on AβO-induced calcium overload. RESULTS: Aducanumab preferentially bound and immunodepleted HMW AβOs in ADDLs and the TBS-soluble fraction of Tg2576 mouse brain extracts but did not recognize LMW AβOs in TgCM. In calcium imaging experiments, all three AβO preparations induced calcium overload in neuron-astrocyte co-cultures. Immunodepletion with aducanumab prevented calcium overload in cultures exposed to ADDLs and Tg2576 brain extracts but not in those treated with immunodepleted TgCM, indicating that aducanumab selectively neutralizes HMW AβOs. CONCLUSIONS: Our findings demonstrate that aducanumab specifically targets HMW AβOs, mitigating their neurotoxic effects by restoring intracellular calcium homeostasis. These results provide mechanistic insight into aducanumab's therapeutic action and support its potential role in modifying AD pathology by selectively neutralizing Aβ species.}, } @article {pmid40760500, year = {2025}, author = {Hamadelseed, O and Skutella, T}, title = {Stem cell-based therapeutic strategies for down syndrome and Alzheimer's disease.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {420}, pmid = {40760500}, issn = {1757-6512}, mesh = {Humans ; *Down Syndrome/therapy/pathology ; *Alzheimer Disease/therapy/pathology ; *Stem Cell Transplantation/methods ; Animals ; }, abstract = {BACKGROUND: Down syndrome (DS) and Alzheimer's disease (AD) are two distinct yet interconnected neurological conditions that share overlapping pathological features, including amyloid-beta plaque accumulation, neuroinflammation, and progressive neurodegeneration. Individuals with DS are at increased risk of developing AD-like dementia owing to the overexpression of the amyloid precursor protein-encoding gene on chromosome 21. Despite significant research efforts, effective disease-modifying treatments remain unavailable for both conditions, necessitating the exploration of novel therapeutic approaches. METHODS: We analyzed and synthesized the existing literature on stem cell therapy as a treatment for DS and AD. We conducted a comprehensive search of PubMed, Google Scholar, and Web of Science databases, focusing on recent, high-quality, and peer-reviewed studies on stem cell therapy in DS and AD. RESULTS: The findings indicate that stem cell therapy represents a promising therapeutic approach for both conditions. Preclinical trials using neural, mesenchymal, and induced pluripotent stem cells have shown their potential to mitigate disease pathology, restore neuronal function, modulate neuroinflammation, enhance neurogenesis, and improve cognitive performance in DS and AD models; these findings suggest the viability of stem cell-based interventions as a disease-modifying strategy. However, despite promising findings, the efficacy and safety of these approaches require further validation through well-designed human clinical trials before clinical translation. Furthermore, AD research in stem cell therapy is currently more advanced than DS research, with a greater number of preclinical and early clinical investigations. In fact, people with DS have been previously excluded from clinical trials. CONCLUSIONS: While both DS and AD share common neurodegenerative mechanisms and are potential candidates for stem cell therapeutic approaches, the therapeutic focus varies. This study underscores the potential of stem cell therapy as a novel disease-modifying approach for both conditions while emphasizing the need for further research to refine therapeutic protocols, address ethical and safety concerns, and evaluate the feasibility of translating these therapies into clinical practice.}, } @article {pmid40759310, year = {2025}, author = {Mao, YF and Chen, L and Liu, JY and Guo, ZY and Lu, PL and Chen, YX}, title = {Intranasal insulin administration shows limited tau-targeted effects in early-stage APP/PS1 Alzheimer's mice.}, journal = {Neuroscience letters}, volume = {865}, number = {}, pages = {138337}, doi = {10.1016/j.neulet.2025.138337}, pmid = {40759310}, issn = {1872-7972}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/pathology/genetics ; Administration, Intranasal ; *tau Proteins/metabolism ; *Insulin/administration & dosage/pharmacology ; Mice ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Brain/metabolism/drug effects ; Disease Models, Animal ; Phosphorylation ; Male ; }, abstract = {Brain insulin signaling deficits contribute to multiple pathologicalfeatures of Alzheimer's disease (AD).Intranasal insulin has demonstrated therapeutic potential, but its underlying mechanisms remain unclear. This study investigated whether intranasal insulinmodulates tau pathology in early-stage APPswe/PS1dE9 (APP/PS1) mice.After six weeks of treatment, no significant changes in total or phosphorylated tau levels were observed. However, there was a trend toward improvement in dysregulated signaling pathways associated with tau kinases. These findings suggest that the protective effect of nasal insulin in early AD may not primarily be against tau-related neurotoxicity.}, } @article {pmid40759295, year = {2025}, author = {Song, ZY and Yu, WJ and Jin, YJ and Zhou, MF and He, CX and Li, Z and He, JW and Chen, Q and Li, P and Yi, Y and Cheng, SW}, title = {Baicalin alleviates pathological changes in Alzheimer's disease comorbid with type 2 diabetes: Targeting metabolic dysregulation and neuroinflammation.}, journal = {Journal of ethnopharmacology}, volume = {353}, number = {Pt A}, pages = {120352}, doi = {10.1016/j.jep.2025.120352}, pmid = {40759295}, issn = {1872-7573}, mesh = {Animals ; *Flavonoids/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Diabetes Mellitus, Type 2/drug therapy/metabolism/complications/pathology ; Male ; Rats ; Rats, Sprague-Dawley ; Molecular Docking Simulation ; *Diabetes Mellitus, Experimental/drug therapy/metabolism/complications ; Streptozocin ; *Neuroinflammatory Diseases/drug therapy ; Lipid Metabolism/drug effects ; Disease Models, Animal ; }, abstract = {Derived from the plant Scutellaria baicalensis Georgi, baicalin is a naturally occurring flavonoid, has demonstrated anti-inflammatory, neuroprotective, hypoglycemic, and lipid-lowering properties. While its effects on Alzheimer's disease (AD) or type 2 diabetes mellitus (T2DM) have been studied individually, its therapeutic role in AD comorbid with T2DM remains unclear. AIM OF THE STUDY: This study aims to explore the potential therapeutic mechanisms associated with baicalin through a rat model featuring AD combined with T2DM. MATERIALS AND METHODS: A dual-pathology rat model was developed using a streptozotocin (STZ) and a high-fat dietary regimen injections to induce T2DM, followed by intracerebroventricular STZ to induce AD pathology. Behavioral tests, biochemical assays, histological analyses, qPCR, and Western blotting were used to evaluate baicalin's effects. Untargeted metabolomics was applied to profile metabolic alterations, while network pharmacology and molecular docking were integrated to predict key targets and pathways. Finally, cellular thermal shift assay (CETSA) was conducted to validate the direct binding of baicalin to core proteins. RESULTS: Baicalin significantly improved cognitive performance, ameliorated glucose and lipid metabolism, and suppressed neuroinflammation in AD-T2DM rats. Metabolomics identified disruptions in energy metabolism, amino acid metabolism, and purine metabolism pathways. Network pharmacology analysis revealed ALDH2, NOS2, GOT1, GPT, and XDH as key targets associated with these metabolic disturbances. Molecular docking demonstrated strong binding affinities between baicalin and the identified targets. qPCR confirmed the regulation of ALDH2 and NOS2 gene expression by baicalin, and CETSA experiments further validated the thermal stabilization of these proteins, supporting direct interactions in vivo. CONCLUSIONS: Baicalin exerts therapeutic effects by targeting ALDH2 and NOS2 to modulate arginine and proline metabolism and regulate key metabolites such as GABA and L-arginine. This mechanism improves neuronal function and insulin sensitivity, highlighting baicalin as a promising multi-target treatment for AD with T2DM.}, } @article {pmid40759059, year = {2025}, author = {Xie, Y and Li, C and Zhang, Y and Liu, X and Wang, W and Zheng, L and Gu, X}, title = {Fisetin alleviates Aβ-induced neuronal cell ferroptosis by regulating Sirt6-mediated deacetylation modification.}, journal = {Journal of neuroimmunology}, volume = {407}, number = {}, pages = {578699}, doi = {10.1016/j.jneuroim.2025.578699}, pmid = {40759059}, issn = {1872-8421}, mesh = {Animals ; *Ferroptosis/drug effects/physiology ; Mice ; *Sirtuins/metabolism ; *Flavonols/pharmacology ; *Amyloid beta-Peptides/toxicity ; *Neurons/drug effects/metabolism ; Acetylation/drug effects ; *Neuroprotective Agents/pharmacology ; NF-E2-Related Factor 2/metabolism ; Cell Line ; Kelch-Like ECH-Associated Protein 1/metabolism ; *Flavonoids/pharmacology ; Cell Survival/drug effects ; Hippocampus/drug effects/metabolism ; *Peptide Fragments/toxicity ; }, abstract = {BACKGROUND: Ferroptosis contributes to Alzheimer's disease (AD) pathology. Fisetin, a flavonoid with neuroprotective properties, has shown potential in reducing oxidative stress and inflammation. This study investigates the protective effects and underlying molecular pathways of fisetin against amyloid-β (Aβ)-induced ferroptosis in neuronal cells. METHODS: HT22 mouse hippocampal neuronal cells were pre-incubated with fisetin before exposure to amyloid-β (Aβ). Cell viability was evaluated by Cell Counting Kit-8 (CCK-8) assay, and lipid peroxidation was measured with the C11-BODIPY probe. Protein expression patterns were determined via Western blot analysis. Co-immunoprecipitation (CoIP) and ubiquitination assays were used to explore the interactions between Sirtuin 6 (Sirt6), nuclear factor erythroid 2-related factor 2 (Nrf2), and kelch-like ECH-associated protein 1 (Keap1). RESULTS: Fisetin pre-treatment significantly alleviated Aβ-induced ferroptosis in HT22 cells. Sirt6 upregulation was observed following fisetin treatment, and silencing Sirt6 reversed its protective effects on Aβ-induced neuronal cell ferroptosis. Mechanistically, Sirt6 deacetylated Nrf2 and enhanced its stability by preventing its degradation through Keap1-mediated ubiquitination. As expected, fisetin alleviated Aβ-induced ferroptosis in neuronal cells through activation of the Sirt6/Nrf2 axis. CONCLUSION: Fisetin alleviated Aβ-induced neuronal cell ferroptosis by activating the Sirt6/Nrf2 axis. These results underscore fisetin's therapeutic potential for AD by targeting ferroptosis, providing a new strategy for disease intervention.}, } @article {pmid40758321, year = {2025}, author = {Hoidy, WH and Essa, SM and Al-Saadi, MH}, title = {Pro-inflammatory/Anti-Inflammatory Interleukin Imbalance in Iraqi Alzheimer's Patients: Implications for Post-Conflict Environmental Exposures.}, journal = {The European journal of neuroscience}, volume = {62}, number = {3}, pages = {e70214}, doi = {10.1111/ejn.70214}, pmid = {40758321}, issn = {1460-9568}, mesh = {Humans ; *Alzheimer Disease/blood/immunology/metabolism ; Male ; Female ; Aged ; Iraq ; Middle Aged ; *Environmental Exposure/adverse effects ; Interleukin-1beta/blood ; *Interleukins/blood ; Interleukin-10/blood ; Iraq War, 2003-2011 ; Inflammation ; Aged, 80 and over ; Interleukin-6/blood ; Amyloid beta-Peptides/metabolism ; Interleukin-4/blood ; }, abstract = {The role of inflammatory processes has been increasingly recognized in the pathology of Alzheimer's disease (AD), especially in populations with particular environmental exposures. This study examined the profiles of pro-inflammatory (IL-1β, IL-6) and anti-inflammatory (IL-4, IL-10) interleukins in a cohort of 112 Iraqi AD patients and a control group of 240 age-matched subjects. Peripheral blood samples were obtained and analyzed using quantitative real-time PCR and ELISA methods, with correlations made to cognitive performance and degree of amyloid burden. AD patients showed significant upregulation of IL-1β (2.8-fold, p < 0.001) and IL-6 (3.2-fold, p < 0.001) as well as downregulation of IL-10 (0.6-fold, p < 0.01). Interleukin 4 expression was unchanged. Striking correlations were found between pro-inflammatory cytokine expression and cognitive decline measured by the MMSE scores. Increased expression of IL-1β was associated with higher PET imaging-derived amyloid-β deposition. Carriers of the APOE ε4 allele showed a greater degree of inflammatory marker dysregulation compared to non-carriers. A combined model with multiple interleukins achieved superb distinguishing capacity (AUC = 0.94) between AD patients and healthy controls. This study suggests that dysregulation of inflammation likely plays a considerable role in the pathogenesis of AD in the Iraqi population, possibly modified by specific environmental exposures due to decades of conflict. The connection made between peripheral inflammatory markers and central AD pathology underscores the potential value of interleukin expression profiles as accessible biomarkers for prognosis and monitoring. Thus, the connection made between peripheral inflammatory markers and central AD pathology underscores the potential value of interleukin expression profiles as easily obtainable biomarkers for diagnosis and monitoring, which may inform future development of targeted treatment strategies aimed at modulating inflammation in specific populations.}, } @article {pmid40757693, year = {2025}, author = {Chen, WX and Huang, QY and Sun, JH and Yang, XY and Pei, H and Cao, Y and Li, H and Ma, LN}, title = {The mechanism of Yizhi Qingxin formula to improve neuroinflammation in Alzheimer's disease by regulating the TLR4/NF‑κB/NLRP3 pathway.}, journal = {Journal of Asian natural products research}, volume = {}, number = {}, pages = {1-19}, doi = {10.1080/10286020.2025.2539987}, pmid = {40757693}, issn = {1477-2213}, abstract = {Yizhi Qingxin formula (YQF) is a traditional Chinese medicine for the treatment of Alzheimer's disease (AD). This study explored the mechanism of YQF to improve AD-related neuroinflammation in vivo and in vitro. The behavioral tests, immunohistochemical analysis and Western blot were performed. The present results showed that YQF ameliorated cognitive deficits, reduced hippocampal Aβ deposition, and decreased the number of GFAP and Iba1-positive cells. The results also indicated that YQF suppressed neuroinflammatory cytokines (TNF-α, IL-1β, IL-6) by inhibiting TLR4/NF-κB/NLRP3 pathway. In summary, YQF provides a multi-targeted strategy for AD-related neuroinflammation, which may address limitations of single-pathway therapies.}, } @article {pmid40757649, year = {2025}, author = {Siguier, PLM and Planton, M and Pages, B and Gérard, F and Rafiq, M and Wolfrum, M and Archambault, O and Damour, A and Guidolin, V and Pefferkorn, P and Danet, L and Virchien, L and Magnin, E and Richard-Mornas, A and Sauvée, M and Thomas-Antérion, C and Mouton, S and Jucla, M and Pariente, J}, title = {Neurodevelopmental Vulnerability in Alzheimer's Disease and Frontotemporal Dementia.}, journal = {European journal of neurology}, volume = {32}, number = {8}, pages = {e70322}, pmid = {40757649}, issn = {1468-1331}, support = {ANR-21-CE28-0020-01//Agence Nationale de la Recherche/ ; }, mesh = {Humans ; *Alzheimer Disease/epidemiology/complications/physiopathology/diagnosis ; *Frontotemporal Dementia/epidemiology/diagnosis/physiopathology ; Female ; Male ; Aged ; Middle Aged ; *Neurodevelopmental Disorders/epidemiology/complications ; Prospective Studies ; Age of Onset ; Neuropsychological Tests ; }, abstract = {BACKGROUND: Neurodevelopmental disorders (NDDs) may influence the course of Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, prior studies have focused on specific pairs of NDDs and variants of AD/FTD. Adopting a dimensional approach to NDDs and considering the heterogeneity of AD/FTD, we investigated the association between a neurodevelopmental vulnerability (DV) and the clinical presentation and age at onset of AD/FTD. METHODS: We prospectively and consecutively recruited 84 AD/FTD participants and 41 matched controls. AD/FTD participants were classified into typical (amnestic AD, behavioral FTD) and atypical (primary progressive aphasia, frontal and posterior variants of AD, right temporal variant of FTD, amnestic FTD) presentations. Participants underwent a neuropsychological assessment and answered a novel questionnaire on NDDs symptoms. Using k-means clustering based on the questionnaire, participants were assigned to a DV+ (with neurodevelopmental vulnerability) or a DV- (without) cluster. This data-driven approach enabled an unbiased classification of individuals with a DV, beyond traditional diagnostic labels. RESULTS: DV frequencies did not differ between the AD/FTD (18%) and control (15%) χ[2] = 0.205; p = 0.651); and between typical (21%) and atypical (11%) subgroups (Fisher's test, p = 0.184). However, in DV+ patients, symptom onset occurred 8.0 years earlier than in DV- patients (95% CI [-14, -3.0]; p = 0.005), with a median onset age of 58 years (IQR: 15). CONCLUSIONS: A DV could favor early-onset AD/FTD, but may not affect susceptibility to typical and atypical variants of AD/FTD. The underlying neurophysiological processes involved require future investigation, with implications for precision medicine and individualized treatment strategies. STUDY REGISTRATION NUMBERS: RnIPH 2023-71 and Research Ethics Committee file No. 2023_765.}, } @article {pmid40757035, year = {2025}, author = {Gooding, DC and Carter, FP and Zuelsdorff, M and Gee, A and Anthony, RL and Boustead, B and Russell, T and Chin, NA and Clark, L and Cornelius, K and Asthana, S and Johnson, SC and Gleason, CE}, title = {Guided by the community: Insights on recruitment science from the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) Project.}, journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging}, volume = {1}, number = {2}, pages = {}, pmid = {40757035}, issn = {2997-3805}, support = {P30 AG062715/AG/NIA NIH HHS/United States ; R01 AG027161/AG/NIA NIH HHS/United States ; R01 AG054059/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Although Alzheimer's disease and related dementias (ADRDs) are disproportionately high in Black/African American (AA) individuals, this population is under-included in biomarker studies and clinical trials. This underrepresentation contributes to health disparities in treatment and disease outcomes. The Wisconsin Alzheimer's Disease Research Center (ADRC) and the Wisconsin Registry for Alzheimer's Prevention (WRAP) at the University of Wisconsin-Madison have been successfully conducting the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) Project since 2016. The AA-FAIM Project aims to promote the timely, valid detection of ADRD for Black/AA groups and to increase their inclusion in ADRD research. METHOD: We describe the infrastructure and engagement strategies of AA-FAIM, a longitudinal research program focused on examining and reducing the health disparities observed in Black/AA individuals facing risk for ADRD. We describe practical, sustainable methods used to meet our recruitment, enrollment, participation, and retention goals. RESULTS: We report enrollment numbers as evidence of the effectiveness of this work. We attribute our success to several strengths. First, AA-FAIM incorporates the principles of community-based participatory research (CBPR), including strong community partnerships and an active, engaged advisory board. Second, the program is guided by the Participant and Relationship-Centered Research Engagement (PRCRE) and the STEPS models. Third, AA-FAIM uses creative, culturally respectful programs. Fourth, a key element is the partnership between the Academy and the people embedded within the community. DISCUSSION: We discuss our experiences establishing and maintaining the AA-FAIM Project and offer insights to increase the representation and inclusion of Black/AA individuals in ADRD studies.}, } @article {pmid40756364, year = {2025}, author = {Xie, J and Cao, K and Liu, L and Zhang, L and Yang, Y and Gong, H and Luo, H}, title = {Mn3O4 nanozyme-based anti-inflammatory therapy modulates microglial phenotype by downregulating TLR4/NOX2 expression and further alleviates Alzheimer's disease pathology.}, journal = {Theranostics}, volume = {15}, number = {15}, pages = {7467-7488}, pmid = {40756364}, issn = {1838-7640}, mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Microglia/drug effects/metabolism ; *Toll-Like Receptor 4/metabolism ; Mice ; *Manganese Compounds/pharmacology/administration & dosage ; *Oxides/pharmacology/administration & dosage ; Mice, Transgenic ; *Anti-Inflammatory Agents/pharmacology/administration & dosage ; *NADPH Oxidase 2/metabolism/genetics ; Reactive Oxygen Species/metabolism ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Lipopolysaccharides ; Down-Regulation/drug effects ; Humans ; Phenotype ; }, abstract = {Rationale: Evidence shows that neuroinflammation mediated by microglial activation plays an important role in Alzheimer's disease (AD) pathogenesis. However, the relationship between microglial phenotype and fibrillar β-amyloid (fAβ) pathology in anti-inflammatory treatment of AD remains unclear. Methods: We designed a water-soluble Mn3O4 nanozymes and demonstrated its ability to reverse lipopolysaccharide (LPS)-induced microglial transition from M1 to M2 phenotype by clearing reactive oxygen species (ROS). Results: In 5×FAD transgenic mice, intranasal (IN) instillation of Mn3O4 nanozymes initially promoted M2 microglial polarization and significantly reduced neuroinflammation after 4 weeks of treatment. After 8 weeks of continuous treatment, they further alleviate fAβ pathology and improved learning and memory deficits in 5×FAD mice. The excellent anti-inflammatory effect of Mn3O4 nanozymes is achieved by inhibiting the Toll-like receptor 4 (TLR4)/nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase isoform 2 (NOX2) pathway to clear ROS. Conclusions: This study reveals the molecular mechanism of Mn3O4 nanozymes modulating microglia phenotype to attenuate neuroinflammation primarily through inhibition of the TLR4/NOX2 pathway and highlights the temporal sequence of anti-inflammatory treatment in regulating microglial phenotype and improving fAβ pathology, providing new insights for the anti-inflammatory treatment of AD and other neurological diseases.}, } @article {pmid40756032, year = {2025}, author = {Demirhan, I and Necip, A and Oner, E and Gumuscu, N and Demirci, O and Gok, Y and Doni, NY and Işık, M and Rudrapal, M and Khan, J and Ibrahim, RM}, title = {Imidazolium salts carrying two positive charges: design, synthesis, characterization, molecular docking, antibacterial and enzyme inhibitory activities.}, journal = {Frontiers in cellular and infection microbiology}, volume = {15}, number = {}, pages = {1579916}, pmid = {40756032}, issn = {2235-2988}, mesh = {*Imidazoles/pharmacology/chemical synthesis/chemistry ; Molecular Docking Simulation ; *Anti-Bacterial Agents/pharmacology/chemical synthesis/chemistry ; Microbial Sensitivity Tests ; Drug Design ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Bacteria/drug effects ; *Enzyme Inhibitors/pharmacology/chemical synthesis/chemistry ; Salts/pharmacology/chemical synthesis/chemistry ; Acetylcholinesterase/metabolism ; Structure-Activity Relationship ; }, abstract = {INTRODUCTION: The discovery of alternative drugs has gained importance due to the many side effects of these drugs used for treatment. METHODS: Herein, the synthesis of a series of unsymmetrical imidazolium salts containing 4-acetylphenyl/4-formylphenyl and bioactive heterocyclic groups such as morpholine, piperidine, pyrrole or pyridine was reported. 4-(1-H-imidazol-1-yl)acetophenone and 4-(1-H-imidazol-1-yl)benzaldehyde were used as salt precursors. Alkyl halides containing heterocyclic groups such as 2-morpholinoethyl hydrochloride, 2-pyrrolidinoethyl hydrochloride, 2-piperidinoethyl hydrochloride and pyridin-2-ylmethyl bromide hydrobromide were used. Thus, there are two positively charged nitrogens in the structure of these salts synthesized by the quaternization method. The structures of all salts were fully characterized by [1]H, [13]C NMR, FTIR spectroscopic and elemental analysis methods. the a series of imidazolium salts (1a-d and 2a-d) were designed, synthesized and fully characterized by spectroscopic methods. RESULTS: The inhibitory effect against AChE of the series compounds was evaluated as in vitro and in silico studies. The results indicated that the compounds showed remarkably potent inhibitory effects on AChE with K I values ranging from 0.63 ± 0.04 μM to 11.23 ± 1.05 μM and IC50 values spanning from 0.82 ± 0.06 μM to 14.75 ± 0.82 μM. The antimicrobial activities of the synthesized compounds were measured by inhibition of bacterial growth expressed as minimum inhibitory concentration (MIC) values. It was observed that the synthesized compounds exhibited antimicrobial activity especially against Gram negative bacteria. In addition, the results of molecular docking studies of bacteria supported our antimicrobial results. CONCLUSIONS: The results suggested that the synthesized compounds showed the potential to be antimicrobial and acetylcholinesterase inhibitors.}, } @article {pmid40756022, year = {2025}, author = {Hirose, S and Kobayashi, R and Hatakeyama, S and Kawakatsu, S and Suzuki, A and Kawanishi, C and Utsumi, K}, title = {Corticobasal degeneration preceded by cognitive impairment and apathy: An autopsy case report.}, journal = {PCN reports : psychiatry and clinical neurosciences}, volume = {4}, number = {3}, pages = {e70174}, pmid = {40756022}, issn = {2769-2558}, abstract = {BACKGROUND: Corticobasal degeneration (CBD) presents with a range of clinical phenotypes, making diagnosis challenging. We report the clinical course of a patient with autopsy-confirmed CBD who initially presented with cognitive impairment and apathy, without motor symptoms. CASE PRESENTATION: A 51-year-old man presented to our hospital with decreased motivation, amnesia, and executive dysfunction. Memory disturbance and frontal lobe dysfunction were evident on examination. No motor symptoms such as Parkinsonism, apraxia, or oculomotor abnormalities were apparent. Magnetic resonance imaging and brain perfusion imaging revealed mild atrophy and hypoperfusion in the left frontal lobe. Based on these findings, he was initially diagnosed with behavioral variant frontotemporal dementia. However, due to the presence of memory impairment, Alzheimer's disease was also considered in the differential diagnosis. At the age of 53 years, he began experiencing frequent falls, followed by rapid progression of extrapyramidal symptoms. Dopamine-transporter (DAT) imaging revealed a marked reduction in DAT availability in the striatum. The patient died of aspiration pneumonia at the age of 55 years. Neuropathological examination confirmed the diagnosis of CBD, showing abundant tau pathology in the frontal lobes and basal ganglia. CONCLUSION: In this case, abundant tau pathology in the frontal lobe corresponded with early cognitive impairment, including frontal lobe dysfunction, whereas abundant tau pathology in the basal ganglia corresponded with rapid exacerbation of extrapyramidal symptoms and marked reduction in DAT availability. Clinicians should be aware that patients with CBD without motor symptoms may seek treatment at outpatient clinics specializing in dementia.}, } @article {pmid40756017, year = {2025}, author = {Feng, Q and Chen, F and Liu, R and Li, D and Feng, H and Yang, J}, title = {Mesenchymal stem cell application in Alzheimer's disease.}, journal = {Regenerative therapy}, volume = {30}, number = {}, pages = {439-445}, pmid = {40756017}, issn = {2352-3204}, abstract = {Alzheimer's disease (AD) is a type of degenerative disease that primarily affects in the central nervous system of elderly or pre-elderly individuals. The symptoms of Alzheimer's disease include memory impairment, aphasia, loss of function, dementia, and impairment of visual spatial ability, which in turn affects the physical health of patients. Mesenchymal stem cell therapy is a branch of regenerative medicine that primarily utilizes stem cells or their derivatives to stimulate the body's own healing process and repair damaged, diseased, or injured tissues. Its utilization in the treatment of autoimmune diseases and neurological disorders has been extensively documented. This review summarizes the preclinical and clinical applications of mesenchymal stem cells in AD, their underlying mechanisms and the application limitations of their application and potential solutions. It is hoped that researchers in this field will find it a useful foundation for further study of mesenchymal stem cell therapy.}, } @article {pmid40756009, year = {2025}, author = {Huang, H and Xuan, Y and Ma, ZC}, title = {Safety Profile of Intravenous Ferulic Acid Nanoparticles: Acute Toxicity and Neurological Effects in Sprague-Dawley Rats.}, journal = {Nanotechnology, science and applications}, volume = {18}, number = {}, pages = {319-358}, pmid = {40756009}, issn = {1177-8903}, abstract = {BACKGROUND: Ferulic acid (FA) exhibits therapeutic potential for various disorders, but its clinical application is hindered by poor bioavailability and solubility. This study aimed to develop and evaluate FA-loaded lipid nanoparticles (FA-LNPs) as a safe and efficient drug delivery system. METHODS: FA-LNPs were prepared via an optimized active loading method. The Morris water maze test was conducted to evaluate FA efficacy against LPS-induced cognitive impairment in rats. Comprehensive neurotoxicity assessment was performed in three brain regions (striatum, hippocampus, and cerebellum-brain stem) using multiple staining techniques (LFB, GFAP, IBA-1, and Fluoro-Jade) to evaluate myelin integrity, glial activation, and neuronal degeneration. Acute toxicity, pharmacokinetics, and network pharmacology analysis were conducted to assess safety profiles and potential mechanisms. RESULTS: FA-LNPs were successfully prepared using an optimized active loading method, achieving high drug loading (≥4 mg/mL), superior encapsulation efficiency (EE%) ≥80%, and uniform particle size distribution (<200 nm, PDI=0.053), zeta potential of +5.97 mV (Quality Factor = 1.701), excellent storage stability over two weeks, and was scaled up for batch production. The Morris water maze test revealed an effective FA concentration of 50 mg/kg, with FA-LNPs achieving 46.5 mg/kg through active loading method. Toxicological studies demonstrated favorable safety profiles. Pharmacokinetic analysis showed a prolonged elimination half-life (12.8 ± 1.88 hours) and moderate systemic clearance (0.535 ± 0.0851 L/h/kg). Short-term administration did not elicit significant neuroprotection. Network pharmacology analysis identified 141 potential therapeutic targets and five key proteins (EGFR, ESR1, PTGS2, CTNNB1, and STAT3), with molecular docking confirming favorable binding energies (-7.6 to -5.2 kcal/mol). CONCLUSION: FA-LNPs enhanced FA's bioavailability without apparent systemic toxicity or neurotoxicity. While safe for short-term use, longer treatment durations may be necessary to observe potential neuroprotective benefits and toxicity. This study provides a foundation for further investigation of FA-LNPs as a promising drug delivery system for neurological disorders.}, } @article {pmid40756002, year = {2025}, author = {Dastgheib, ZA and Lithgow, BJ and Moussavi, ZK}, title = {Differential Impact of Repetitive Transcranial Magnetic Stimulation on Alzheimer's Disease Symptomology: Evidence from Electrovestibulography Does repetitive transcranial magnetic stimulation treatment alter Alzheimer's disease symptomology? a clue to show who will benefit.}, journal = {Cognitive neurodynamics}, volume = {19}, number = {1}, pages = {120}, pmid = {40756002}, issn = {1871-4080}, abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has shown promise in enhancing cognitive function through neuroplasticity. This study investigates the impact of rTMS on Alzheimer's disease (AD) and AD with cerebrovascular disease (AD-CVD) symptomologies, using Electrovestibulography (EVestG). METHODOLOGY: Participants were recruited from a randomized, double-blind, placebo-controlled clinical trial on rTMS efficacy for mild to moderate AD. Thirty-five individuals who volunteered for the EVestG study (28 received active rTMS and 7 the sham treatment) were recorded at baseline, post-treatment, and two months' follow-up. EVestG recordings were analyzed to calculate normalized probability (NP) values for AD and AD-CVD symptomologies and compare with standard cognitive outcome. RESULTS: Changes in NP values from pre to post active treatment showed improved participants exhibited opposite trends in AD and AD-CVD symptomologies compared to non-improved participants with a decrease in NPAD-CVD and a slight increase in NPAD value. Significant associations were found between changes in cognitive score and NP values, even after adjusting for age, sex, and multiple comparisons, indicating that patients with higher certainty of AD diagnosis (versus AD-CVD) were more likely to benefit from rTMS. CONCLUSION: These findings suggest rTMS cognitive improvement may result from reduced AD-CVD symptomatology, especially in patients with higher certainty of AD diagnoses, potentially due to increased cerebral blood flow (CBF). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11571-025-10310-5.}, } @article {pmid40755499, year = {2025}, author = {Wang, X and Hou, R and Chen, Z and Wang, X and Malek, M and Wang, H}, title = {The Beneficial Effects of Berberine on Brain Functions in Age-Related Neurological Disorders: From Molecular Signaling to Treatment.}, journal = {Food science & nutrition}, volume = {13}, number = {8}, pages = {e70563}, pmid = {40755499}, issn = {2048-7177}, abstract = {Berberine (BBR), a naturally occurring compound with diverse medicinal properties, is emerging as a compelling candidate for managing age-related central nervous system conditions. Preclinical studies have extensively explored its impact on neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease, revealing its capacity to modulate key pathological processes. Mechanistically, BBR is shown to mitigate neuroinflammation, oxidative stress, and endoplasmic reticulum stress, thereby reducing neuronal damage and apoptosis. While these mechanistic insights and preclinical data are robust, clinical evidence remains nascent, necessitating further rigorous investigation to fully understand BBR's therapeutic efficacy and translate its promise into clinical practice. This narrative review provides a comprehensive examination of BBR's application in treating neurological conditions, emphasizing its molecular signaling pathways and critically evaluating the current translational landscape. It also identifies promising directions for future research into BBR's neuroprotective roles.}, } @article {pmid40755338, year = {2025}, author = {Liu, C and Xie, Q and Xu, JP and Hua, KY and Zhao, WJ}, title = {Neuregulin 2 reversed astrocytosis in the spinal cord in a mouse model of Alzheimer's disease.}, journal = {Folia neuropathologica}, volume = {63}, number = {2}, pages = {138-147}, doi = {10.5114/fn.2025.151824}, pmid = {40755338}, issn = {1509-572X}, mesh = {Animals ; *Alzheimer Disease/pathology/drug therapy/metabolism ; Disease Models, Animal ; Mice ; *Spinal Cord/pathology/drug effects/metabolism ; Mice, Transgenic ; *Gliosis/pathology/drug therapy/metabolism ; *Astrocytes/drug effects/pathology/metabolism ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is classified as a neurodegenerative disorder without efficacious therapeutic interventions. Accumulating evidence has demonstrated the deposition of b-amyloid peptide (Ab) in the spinal cord in several mouse AD models. Neuregulin 2 (Nrg2), structurally homologous to neuregulin 1 (Nrg1), exerts a regulatory influence over various biological processes within the nervous system. However, the neuroprotective role of Nrg2 in the spinal cord in AD remains unclear. MATERIAL AND METHODS: Reverse transcription PCR (RT-PCR) was employed to confirm the expression of mutated amyloid precursor protein (APP) in APPswe mice. Immunohistochemical staining was used to compare the differences between wild-type and APPswe mice in APP and GFAP expression. We applied western blot to test the changes of ErbB4, Akt1, and Erk1/2 activation, as well as that of GFAP in response to recombinant Nrg2 (rNrg2) treatment in the spinal cord in APPswe mice. RESULTS: In the current study, we observed that mutated APP mRNA level was upregulated, and astrocytes were activated in the spinal cord of APPswe transgenic mice. rNrg2 treatment down-regulated astrocyte activation, as indicated by the reduced level of GFAP. Meanwhile, Nrg2 treatment enhanced the phosphorylation-mediated activation of ErbB4, Akt1, and Erk1/2 in most of the spinal cord segments. CONCLUSIONS: These combined results suggest the involvement of astrocytosis in the spinal cord of APPswe transgenic mice. Neuregulin 2, when administered exogenously, may represent a potential strategy for preventing and treating AD-induced astrocytosis in the spinal cord.}, } @article {pmid40755109, year = {2025}, author = {Poszwa, J and Słowikowski, B and Owecki, W and Szymanowicz, O and Jagodziński, PP and Kozubski, W and Dorszewska, J}, title = {Integration of Neuroimaging and Molecular Biomarkers in the Diagnosis of Alzheimer's Disease and Frontotemporal Dementia: The Promise of fMRI.}, journal = {Current Alzheimer research}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115672050390340250716061313}, pmid = {40755109}, issn = {1875-5828}, abstract = {INTRODUCTION: Dementia is a set of acquired and progressive neuropsychiatric disorders. The most common types of dementia include Alzheimer's Disease (AD) and Frontotemporal Dementia (FTD). Early intravital diagnosis of both types of dementia is difficult. Both molecular and neuroimaging markers are important for the diagnosis of different types of dementia. METHODS: This review employed freely accessible databases, including PubMed, Google Scholar, and ScienceDirect, using keywords such as molecular parameters, neuroimaging factors, dementia, FTD, Alzheimer's disease, and fMRI. RESULTS: Among the molecular markers of dementia, there are parameters common to its various types and enabling their differentiation. These parameters include both genetic and biochemical factors. Markers include genetic factors that help differentiate AD (APP, PSEN1, PSEN2) from FTD (e.g., TARDBP, FUS, MAPT). Simultaneously, there are important biochemical parameters differentiating AD (amyloid-beta (Aβ), neurofibrillary tangles) from FTD (TDP-43, FUS, and different forms of tau protein aggregates). Currently, there is growing interest in neuroimaging studies in the differential diagnosis of dementia. Positron Emission Tomography (PET) imaging enables the quantification and localization of Aβ deposits in the brain through the selective binding of the Pittsburgh Compound-B (PiB) ligand. This method has become the standard in AD diagnostics. In the context of magnetic resonance imaging studies, it is worth noting the search for structural differences between AD (mainly affecting the temporal lobe, including the hippocampus and entorhinal cortex, and the parietal lobe) and FTD (primarily involving the prefrontal cortex, anterior temporal lobes, and subcortical structures, as well as exhibiting an anteroposterior gradient of atrophy). However, the method of the future appears to be functional Magnetic Resonance Imaging (fMRI), especially since functional changes precede structural changes in the development of dementia. DISCUSSION: The review encompasses the basic diagnostic criteria for AD and FTD dementia, as well as molecular and neuroimaging parameters important for the intravital diagnosis of these dementias. It seems that the use of fMRI can contribute to both early diagnosis and early introduction of targeted treatment in developing dementia. Although it is not yet widely used clinically, its diagnostic value is increasingly recognized. CONCLUSION: The benefits of fMRI studies complementing molecular markers in the diagnosis of dementia were highlighted.}, } @article {pmid40755106, year = {2025}, author = {Saini, M and Rohilla, S and Kumar, R}, title = {Revolutionizing Therapeutic Approaches Against Pathophysiology of Alzheimer's Disease: A Therapeutic Review.}, journal = {Current aging science}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118746098376646250715094707}, pmid = {40755106}, issn = {1874-6128}, abstract = {Alzheimer's disease (AD) is a multifactorial neuron-degenerative old age illness, which deteriorates the neuronal cells of the brain ultimately leading to dementia, decreased thinking ability and intricacy in performing daily routine activities. In most of the cases, AD is suspected to be caused by a combination of numerous factors, like environmental, genetic and lifestyle affecting the brain functioning. The present permitted treatments include N-methyl-Daspartate (NMDA) receptor antagonists, cholinesterase inhibitors, and their combinations, which provide only momentary and symptomatic relief. Nowadays, clinical research is interested, in the pathology of Alzheimer's disease to target the metabolism of abnormal tau protein, removal of beta-amyloid inflammatory response, the cholinergic neuron, and free radical damage, and treatments that can either stop or modify the course, of AD. Globally, efforts are continued to search new targets to invent new options for the treatment of AD. The present review critically discusses about various treatment strategies for the patients presented with AD. Moreover, herbal drug and new drug candidates, along with nanoformulations for the treatments of AD and the role of AI-based technology in searching therapy for AD have been delineated in the present article. We concluded that preventing amyloid-β (Aβ) synthesis, enhancing the removal of Aβ deposition, or preventing Aβ aggregation can suppress AD. Moreover, herbal medicines have become an attractive alternative to cure this disease with numerous beneficial effects with little side effects. Novel approaches using AI are therefore required to create treatments with novel targets that may not only cure symptoms but also prevent disease development at an early stage to improve the quality of patients' lives.}, } @article {pmid40755103, year = {2025}, author = {Beigh, S and Alsahag, M and Alisaac, A and Dar, SA and Alyami, MH and Ajlan, SE and Malak, HA and Alshehri, AA}, title = {Ginkgolide as a Promising Multi-Target Therapeutic for Alzheimer's Disease: Targeting ApoE4 and Beyond.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113816128386836250723134001}, pmid = {40755103}, issn = {1873-4286}, abstract = {INTRODUCTION: The progressive neurodegenerative disease known as Alzheimer's disease (AD) is typified by neuroinflammation, amyloid-beta buildup, and cognitive impairment. Current pharmacological treatments merely alleviate symptoms, despite extensive research, which underscores the need for innovative, multi-target medicines. Since apolipoprotein E4 (ApoE4) is a significant genetic risk factor linked to the development of AD, it is a potentially effective treatment target. With their neuroprotective qualities, natural substances like ginkgolide may help treat some diseases. This study investigates ginkgolide's potential as a multi-target treatment for AD, with a particular emphasis on how it interacts with the ApoE4 N-terminal domain. METHODS: The interaction between Ginkgolide and ApoE4 (PDB ID: 8AX8) was assessed using pharmacokinetic profiling, molecular docking, and molecular dynamics (MD) simulations. MD simulations were used to determine stability, and AutoDock Vina was used to obtain the binding affinity. To predict pharmacokinetics and toxicity, SwissADME and PkCSM were employed. The effectiveness of ginkgolide was contextualized using comparative docking with curcumin and resveratrol. RESULTS: Ginkgolide formed sustained hydrophobic contacts with important sites and demonstrated a substantial binding affinity (-7.1 kcal/mol) to ApoE4. MD simulations verified negligible fluctuations and complex stability over 100 ns. Pharmacokinetics showed no significant toxicity risks, good gastrointestinal absorption, and favorable blood-brain barrier permeability. In terms of binding affinity and stability, ginkgolide fared better than curcumin and resveratrol, indicating its greater therapeutic potential. DISCUSSION: The results indicate that ginkgolide effectively binds and stabilizes the ApoE4 N-terminal domain, supporting its potential role in modulating a key pathological factor in Alzheimer's disease. Its superior pharmacokinetic profile and interaction dynamics compared to curcumin and resveratrol suggest a broader therapeutic relevance. These in silico insights provide a mechanistic basis for further investigation into ginkgolide's neuroprotective effects. CONCLUSION: The results demonstrated ginkgolide as a potentially effective multi-target treatment for AD through ApoE4 regulation. It is a better option than other natural chemicals because of its potent binding affinity, stability, and pharmacokinetics. These findings highlight the value of in silico methods in the early stages of drug discovery and the need for additional experimental support before they can be used in clinical settings.}, } @article {pmid40754996, year = {2025}, author = {Stam, R}, title = {Low frequency magnetic field exposure and neurodegenerative disease: systematic review of animal studies.}, journal = {Electromagnetic biology and medicine}, volume = {44}, number = {4}, pages = {566-580}, doi = {10.1080/15368378.2025.2540435}, pmid = {40754996}, issn = {1536-8386}, mesh = {Animals ; *Magnetic Fields/adverse effects ; *Neurodegenerative Diseases/etiology/pathology/therapy ; Humans ; Disease Models, Animal ; }, abstract = {Epidemiological studies have found an association between occupational exposure to low frequency magnetic fields and the occurrence of motor neuron disease and Alzheimer's disease. No association has been found for Parkinson's disease and the evidence for multiple sclerosis is insufficient. Animal models studying the effects of low frequency magnetic fields on neurodegenerative disease induction or progression could provide more evidence on causation and the underlying mechanisms. A systematic search and review was conducted of peer-reviewed research articles involving animal experiments on the effects of low frequency magnetic field exposure on behavioural and neuroanatomical outcomes relevant for neurodegenerative diseases in humans. Firstly, experimental studies in naive animals do not support a causal relationship between exposure to low frequency magnetic fields and the induction of neuropathology relevant for Alzheimer's disease, but the number of studies relevant for motor neuron disease, multiple sclerosis and Parkinson's disease is too limited to draw conclusions. Secondly, experimental studies in existing animal models for neurodegenerative disease support a therapeutic (beneficial) effect of low frequency magnetic field treatment on behavioural and neuroanatomical abnormalities relevant for dementia (including Alzheimer's disease), multiple sclerosis and Parkinson's disease and no effect on disease progression in models relevant for motor neuron disease.}, } @article {pmid40754917, year = {2025}, author = {Zhang, Y and Li, L and Zhu, A and Xiao, W and Wang, Q}, title = {[Protective effects of escin and dextromethorphan on Alzheimer disease in Caenorhabditis elegans models].}, journal = {Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences}, volume = {57}, number = {4}, pages = {764-771}, pmid = {40754917}, issn = {1671-167X}, mesh = {Animals ; *Caenorhabditis elegans/genetics/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Disease Models, Animal ; *Dextromethorphan/pharmacology ; Amyloid beta-Peptides/metabolism/genetics ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Animals, Genetically Modified ; Memantine/pharmacology ; }, abstract = {OBJECTIVE: To investigate whether escin (ESC) and dextromethorphan (DEX) have the protective effects on the progression and symptoms of Alzheimer disease (AD). METHODS: The AD model of Caenorhabditis elegans (C. elegans) was established by transgenic amyloid β-protein (Aβ protein). Different concentrations of ESC or DEX or 50 μmol/L memantine (MEM) were used to treat the AD model worms, and their lifespan was detected. The movement ability of AD model C. elegans was evaluated by body bending frequency and head swinging frequency. The changes in cognitive functions of AD model C. elegans before and after treatment were detected by chemotaxis experiments. The changes in Aβ protein and reactive oxygen species (ROS) content in C. elegans were detected. The changes in gene pathways related to oxidative stress were detected by Real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: At high dose 1 000 μmol/L, ESC or DEX treatment showed no significant effects on the activity of C. elegans. Compared with untreated worms, the survival time of AD model C. elegans in the 20 μmol/L ESC and 60 μmol/L DEX intervention groups was significantly extended. In the middle stage of AD progression, the body bending frequency and head swinging frequency of AD model worms after ESC or DEX treatment was significantly increased compared with the untreated control group with DEX being more effective in the recovery of head swinging frequency. For the early cognitive function tests, the chemotaxis index of ESC or DEX treated worms was significantly higher than that of the untreated worms, which correlated with marked reductions in the Aβ protein levels. The reactive oxygen species content in the drug intervention group was also lower than that in the control group. RT-qPCR results showed that ESC could inhibit oxidative stress in the AD model C. elegans by a 2-fold upregulation of skn1 expression. CONCLUSION: ESC and DEX could improve the reductions of movement ability and cognitive function in the AD model worms and delay the aggravation of AD-related symptoms. ESC delays the progression of AD possibly by activating the SKN-1/Nrf2 pathway to protect against oxidative injury in the AD model.}, } @article {pmid40754800, year = {2025}, author = {Barbour, AJ}, title = {Screening antiseizure medications to break the cycle between neuronal hyperexcitability and Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {3}, pages = {994-996}, pmid = {40754800}, issn = {1875-8908}, support = {R01 AG077692/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/drug therapy/complications/genetics ; Animals ; *Anticonvulsants/therapeutic use/pharmacology ; Mice ; Disease Models, Animal ; Humans ; *Seizures/drug therapy ; *Neurons/drug effects ; Male ; Female ; }, abstract = {Epilepsy is commonly comorbid with Alzheimer's disease and is now well established to accelerate disease course. In the present study, Knox and colleagues evaluated the efficacy of several antiseizure medications (ASMs) in mitigating seizure induction in two aged Alzheimer's disease mouse models with distinct etiologies. They found differential responses to seizure induction and ASM treatment across sexes and models. These results reveal a complex interplay between sex, Alzheimer's disease risk genes, and neuronal hyperexcitability that suggest a tailored approach to seizure control may maximize therapeutic benefit in Alzheimer's disease.}, } @article {pmid40754079, year = {2025}, author = {Shao, X and Cao, X and Fan, T and Yan, C and Wang, C and Wang, J and Bai, M and Cui, C and Wang, X and Guan, P and Fan, L and Hu, X}, title = {Tannic acid-derived carbon dots: Dual-function inhibitors against β-amyloid fibrosis and bacterial infections.}, journal = {International journal of biological macromolecules}, volume = {322}, number = {Pt 1}, pages = {146516}, doi = {10.1016/j.ijbiomac.2025.146516}, pmid = {40754079}, issn = {1879-0003}, mesh = {*Tannins/chemistry/pharmacology ; *Carbon/chemistry/pharmacology ; *Amyloid beta-Peptides/metabolism/chemistry/antagonists & inhibitors ; *Anti-Bacterial Agents/pharmacology/chemistry ; Humans ; *Quantum Dots/chemistry ; Blood-Brain Barrier/metabolism/drug effects ; *Bacterial Infections/drug therapy ; Animals ; Alzheimer Disease/drug therapy/metabolism ; Peptide Fragments ; Polyphenols ; }, abstract = {Alzheimer's disease is a puzzle that has been plaguing mankind for a long time, and amyloid plaque cascade and microbial infection are now widely accepted hypotheses of pathogenicity. In this work, we prepared carbon dots TACDs by solvothermal carbonization using tannic acid and o-Phenylenediamine as precursors. TACDs have abundant functional groups and large conjugated structures, and binds to Aβ42 through hydrophobic interactions, hydrogen bonding, electrostatic interaction and π-π stacking to efficiently inhibit the self-assembly and mis-folding of Aβ42. The existence of a good binding and co-localization capacity between TACDs and the Aβ42 species. TACDs have good biocompatibility and TACDs can rapidly enter the cells within 0.5 h. In an in vitro blood-brain barrier model, TACDs show good BBB penetration ability. Moreover, TACDs have good antibacterial ability and can achieve a dual function. The above results will provide the foundation for the application of polyphenol-derived carbon dots in AD diagnosis and treatment.}, } @article {pmid40753965, year = {2025}, author = {Jia, L and Hao, L and Zhang, HL}, title = {Cognitive performance correlated with hemoglobin level in patients with chronic kidney disease: a data analysis from the National Health and Nutrition Examination Survey (NHANES) 2011- 2014.}, journal = {Kidney & blood pressure research}, volume = {50}, number = {1}, pages = {1-26}, pmid = {40753965}, issn = {1423-0143}, abstract = {INTRODUCTION: Given the increased incidence of renal anemia and cognitive dysfunction in patients with chronic kidney disease (CKD), the association between hemoglobin levels and cognitive function in these patients remains elucidated. An optimal level of hemoglobin for the best cognitive performance in CKD has yet to be determined. METHODS: A retrospective cross-sectional study was conducted using data from 2011-2014 of the National Health and Nutrition Examination Survey (NHANES). Enrolled subjects for analysis were divided into the CKD and the non-CKD groups. The Animal Fluency Test (AF), Digit Symbol Substitution Test (DSST), Consortium to Establish a Registry for Alzheimer's Disease Word Learning Test (CERAD-WL) and Word List Recall Test (CERAD-DR) were used to evaluate cognitive performances. We quantified the association between hemoglobin levels and cognitive function in patients with CKD and non-CKD subjects by using the logistic regression analysis. Plotted curves and inflection points were calculated by a recursive algorithm. RESULTS: The ratio of cognitive impairment was higher in the CKD group than in the non-CKD group. Hemoglobin levels were correlated with CERAD-DR and DSST in patients with CKD. For non-CKD subjects, the hemoglobin level was not correlated with any test results. The potential range of the hemoglobin level was 11.0 - 12.7 mg/dL for keeping better cognitive performance of patients with CKD. CONCLUSION: Hemoglobin levels are associated with cognitive performance in patients with CKD. The treatment of renal anemia would be meaningful to reduce cognitive impairment in CKD.}, } @article {pmid40753124, year = {2025}, author = {Peng, W and Li, C and Ma, Y and Dai, W and Fu, D and Liu, L and Liu, L and Yu, N and Liu, J}, title = {Integrating Time and Frequency Domain Features of fMRI Time Series for Alzheimer's Disease Classification Using Graph Neural Networks.}, journal = {Interdisciplinary sciences, computational life sciences}, volume = {}, number = {}, pages = {}, pmid = {40753124}, issn = {1867-1462}, support = {62472202//National Natural Science Foundation of China/ ; 61972185//National Natural Science Foundation of China/ ; 62172444//Natural Science Foundation of Jilin Province/ ; 62472450//Natural Science Foundation of Jilin Province/ ; }, abstract = {Accurate and early diagnosis of Alzheimer's Disease (AD) is crucial for timely interventions and treatment advancement. Functional Magnetic Resonance Imaging (fMRI), measuring brain blood-oxygen level changes over time, is a powerful AD-diagnosis tool. However, current fMRI-based AD diagnosis methods rely on noise-susceptible time-domain features and focus only on synchronous brain-region interactions in the same time phase, neglecting asynchronous ones. To overcome these issues, we propose Frequency-Time Fusion Graph Neural Network (FTF-GNN). It integrates frequency- and time-domain features for robust AD classification, considering both asynchronous and synchronous brain-region interactions. First, we construct a fully connected hypervariate graph, where nodes represent brain regions and their Blood Oxygen Level-Dependent (BOLD) values at a time series point. A Discrete Fourier Transform (DFT) transforms these BOLD values from the spatial to the frequency domain for frequency-component analysis. Second, a Fourier-based Graph Neural Network (FourierGNN) processes the frequency features to capture asynchronous brain region connectivity patterns. Third, these features are converted back to the time domain and reshaped into a matrix where rows represent brain regions and columns represent their frequency-domain features at each time point. Each brain region then fuses its frequency-domain features with position encoding along the time series, preserving temporal and spatial information. Next, we build a brain-region network based on synchronous BOLD value associations and input the brain-region network and the fused features into a Graph Convolutional Network (GCN) to capture synchronous brain region connectivity patterns. Finally, a fully connected network classifies the brain-region features. Experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate the method's effectiveness: Our model achieves 91.26% accuracy and 96.79% AUC in AD versus Normal Control (NC) classification, showing promising performance. For early-stage detection, it attains state-of-the-art performance in distinguishing NC from Late Mild Cognitive Impairment (LMCI) with 87.16% accuracy and 93.22% AUC. Notably, in the challenging task of differentiating LMCI from AD, FTF-GNN achieves optimal performance (85.30% accuracy, 94.56% AUC), while also delivering competitive results (77.40% accuracy, 91.17% AUC) in distinguishing Early MCI (EMCI) from LMCI-the most clinically complex subtype classification. These results indicate that leveraging complementary frequency- and time-domain information, along with considering asynchronous and synchronous brain-region interactions, can address existing approach limitations, offering a robust neuroimaging-based diagnostic solution.}, } @article {pmid40752775, year = {2025}, author = {Meshram, HK and Gupta, SK and Gupta, A and Nagori, K and Ajazuddin, }, title = {Next-generation CRISPR gene editing tools in the precision treatment of Alzheimer's and Parkinson's disease.}, journal = {Ageing research reviews}, volume = {111}, number = {}, pages = {102851}, doi = {10.1016/j.arr.2025.102851}, pmid = {40752775}, issn = {1872-9649}, mesh = {Humans ; *Gene Editing/methods ; *Parkinson Disease/therapy/genetics ; *Alzheimer Disease/therapy/genetics ; *CRISPR-Cas Systems/genetics ; Animals ; *Genetic Therapy/methods ; *Precision Medicine/methods ; }, abstract = {Emerging gene-editing technologies, such as the CRISPR system, represent a potential pathway for precision medicine targeting the genetic and molecular causes of diseases. Second-generation CRISPR technologies, including base editing, prime editing, and engineered Cas variants, have improved fidelity and offer alternative strategies for precise gene correction, transcriptional repression or activation, and modulation of pathological pathways in neurodegeneration. These tools can correct single-nucleotide mutations, reduce pathological protein accumulation, and modulate neuroinflammatory responses, all integral to the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD), both chronic, progressive neurodegenerative disorders. Unfortunately, currently available treatments are limited and primarily palliative. Preclinical studies have shown promising results, with improvements in cognitive and motor deficits in animal models. However, significant challenges must be addressed to ensure safe and effective delivery to the CNS, minimize off-target effects, and address ethical concerns. Current clinical investigations aim to translate these findings into available therapeutic options. This review also identifies the biological mechanisms, therapeutic use cases, and current limitations of next-generation CRISPR systems as tools in the context of AD and PD, providing both therapeutic and research capabilities through their unique strengths. Ultimately, the future of transactional neurogenomics will determine the clinical possibilities of CRISPR-based strategies for advancing neurodegenerative disease management beyond palliative and symptomatic treatment, toward a feasible mechanistic form of disease modification.}, } @article {pmid40752028, year = {2025}, author = {Liew, KY and Aumeeruddy, MSUIZ and Goh, NY and Kong, BH and Tang, YQ and Ng, ST and Tan, CS and Fung, SY}, title = {Antioxidant Activity and Total Terpenoid Content of Tropicoporus linteus Cultivar (Agaricomycetes) Cold Water Extract and In Silico Assessment of Potential Neuroprotective Compounds.}, journal = {International journal of medicinal mushrooms}, volume = {27}, number = {11}, pages = {51-61}, doi = {10.1615/IntJMedMushrooms.2025059827}, pmid = {40752028}, issn = {1940-4344}, mesh = {*Antioxidants/pharmacology/chemistry/isolation & purification ; Molecular Docking Simulation ; *Terpenes/chemistry/pharmacology/isolation & purification ; *Neuroprotective Agents/chemistry/pharmacology/isolation & purification/pharmacokinetics ; Alzheimer Disease/drug therapy ; *Basidiomycota/chemistry ; Humans ; Amyloid Precursor Protein Secretases/metabolism ; Computer Simulation ; }, abstract = {Tropicoporus linteus (formerly Phellinus linteus) is a medicinal fungus used in China, Korea and Japan for its therapeutic properties. This study assessed the antioxidant capabilities of cold-water extract (xSHTM) from a T. linteus cultivar (SH02), and its terpenoid content. The potential of bioactive compounds in T. linteus as treatment against Alzheimer's disease (AD) was also explored with pharmacokinetic prediction via SwissADME and molecular docking. xSHTM is found to have high superoxide anion scavenging capability (expressed as trolox equivalents (35.10 ± 2.58) mmol/g), and its terpenoid content is expressed as 490.12 ± 31.51 mg LE/g of extract. SwissADME was used to screen all 68 of the compounds contained in T. linteus according to PubChem to identify their pharmacokinetic properties. Nine bioactive compounds are selected based on their gastrointestinal absorption, lipophilicity, water solubility, violation of Lipinski's rule, and the ability to cross the blood-brain barrier (BBB) to proceed with molecular docking against common AD treatment targets, acetylcholinesterase (AChE) and β-secretase (BACE1), which revealed 4 compounds with high binding affinity (expressed as Kcal/mol). Phellilin B and phellilane L showed binding affinities of -8.8 and -8.0, respectively, when docked against AChE, while phellinulin L, phellinulin K and phellilin B showed binding affinities of -7.4, -7.3 and -7.1 respectively when docked against BACE1.}, } @article {pmid40751793, year = {2025}, author = {Santana, RA and McWhirt, JM and Brewer, GJ}, title = {Treatment of age-related decreases in GTP levels restores endocytosis and autophagy.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {40751793}, issn = {2509-2723}, support = {RF1 AG058218/DK/NIDDK NIH HHS/United States ; }, abstract = {Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimer's model mice and a novel genetically encoded fluorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free GTP colocalized in the mitochondria decreased with age accompanied by the accumulation of free GTP-labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while bafilomycin inhibition of autophagy raised GTP levels. Twenty-four-hour supplementation of aged neurons with the NAD precursor nicotinamide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endocytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal Aβ aggregates, improved viability, and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy deficits that impair autophagy and endocytosis. GTP deficits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path.}, } @article {pmid40751388, year = {2025}, author = {Saberi, Z and Rostamkhani, N and Saghatchi Zanjani, M and Salimi, M and Andalib, S and Rashidzadeh, H and Jafari Anarkooli, I and Karami, Z}, title = {Neuroprotective effect of rosuvastatin-loaded nanoemulsions against lipopolysaccharide-induced neuroinflammation and oxidative stress.}, journal = {Journal of drug targeting}, volume = {}, number = {}, pages = {1-11}, doi = {10.1080/1061186X.2025.2538037}, pmid = {40751388}, issn = {1029-2330}, abstract = {Neuroinflammation is a pathophysiological feature of several neurological disorders, including Parkinson's disease, Alzheimer's disease and traumatic brain injury, resulting from various intrinsic and environmental triggers. However, effective treatments are hindered by challenges in drug delivery to the central nervous system, primarily due to the blood-brain barrier. In this study, we investigated the potential of rosuvastatin-loaded nanoemulsions for neuroinflammation treatment. The mean diameter and zeta potential of developed RSV-NEs were 124.8 ± 1.23 nm and -40.5 ± 3.2 mV, respectively. TEM analysis revealed the spherical morphology and uniformity of nano-droplets. A cell viability study on the PC12 cell line confirmed the safety of RSV-NEs up to the concentration of 300 µg/mL. The protective efficacy of orally administrated RSV-NEs against LPS-induced neuroinflammation and oxidative stress was assessed in SD rats. According to histopathological assessments, LPS-induced damage was prevented by RSV-NEs through a neuroprotective effect linked to a reduction in GFAP[+] cells. Moreover, TBARS levels in the rat brain cortex decreased by 3.9 times, and the cerebellum's SH increased by 1.7 times in the RSV-NEs-treated group compared to the LPS group. These findings suggest that utilising nanoemulsion delivery systems may offer improved efficacy for CNS disorders, addressing significant challenges in the management of neuroinflammatory diseases.}, } @article {pmid40751333, year = {2025}, author = {Cimen, YA and Elibol, B and Korkmaz, ND and Yuzgulec, M and Kinsiz, B and Kutlu, S and Ustunova, S}, title = {The Impact of Ketogenic Diet Consumption on the Sporadic Alzheimer's Model Through MT1/MT2 Regulation.}, journal = {Journal of neuroscience research}, volume = {103}, number = {8}, pages = {e70070}, doi = {10.1002/jnr.70070}, pmid = {40751333}, issn = {1097-4547}, support = {20220409//Bezmialem Vakıf Üniversitesi/ ; }, mesh = {Animals ; *Diet, Ketogenic/methods ; Male ; *Alzheimer Disease/metabolism/diet therapy ; Rats, Sprague-Dawley ; Rats ; *Receptor, Melatonin, MT2/metabolism ; *Receptor, Melatonin, MT1/metabolism ; Melatonin/metabolism ; Disease Models, Animal ; Hippocampus/metabolism ; Corpus Striatum/metabolism ; }, abstract = {Melatonin and its receptors play a primary role in regulating circadian rhythms, which are frequently disrupted in patients with Alzheimer's disease (AD). Furthermore, there is increasing evidence that the use of a ketogenic diet (KD) delays the onset of AD. Therefore, we aimed to investigate whether KD has an ameliorative effect on AD through the regulation of melatonin receptors. In this study, male Sprague-Dawley rats were divided into three groups: sham, AD, and KD. At the end of KD supplementation, behavioral parameters were determined by the Morris Water Maze. Melatonin levels, protein expression levels, and immunoreactivity of MT1-MT2 in thehippocampus and striatum were determined by ELISA, Western blotting, and immunofluorescence staining, respectively. As a result, KD improved memory decline in AD rats. Also, KD increased melatonin levels in the hippocampus but did not affect striatum melatonin levels. MT1 expression tended to increase in the hippocampus of the AD group, while MT2 expression decreased. On the contrary, KD treatment increased both MT1 and MT2 expressions. In the striatum, there was no change in MT1 expression in the AD and KD groups, but MT2 expression increased in the AD group compared with the sham group and was suppressed in the KD group. In addition, KD treatment reduced streptozotocin-induced apoptosis and neuroinflammation in the hippocampus and striatum. Our results suggest that KD may improve AD-associated inflammation and apoptosis by altering melatonin levels and the expression of MT2 receptors in the hippocampus and striatum. Therefore, KD may be a promising preventive and therapeutic option for AD.}, } @article {pmid40750068, year = {2025}, author = {Košak, U and Knez, D and Pišlar, A and Horvat, S and Žakelj, S and Igert, A and Dias, J and Nachon, F and Brazzolotto, X and Gobec, S}, title = {N-Propargylpyrrolidine-based butyrylcholinesterase and monoamine oxidase inhibitors.}, journal = {Chemico-biological interactions}, volume = {420}, number = {}, pages = {111681}, doi = {10.1016/j.cbi.2025.111681}, pmid = {40750068}, issn = {1872-7786}, mesh = {*Butyrylcholinesterase/metabolism/chemistry ; *Pyrrolidines/chemistry/pharmacology/metabolism ; Humans ; *Cholinesterase Inhibitors/chemistry/pharmacology/metabolism/chemical synthesis ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology/metabolism ; Animals ; *Monoamine Oxidase/metabolism/chemistry ; Crystallography, X-Ray ; Molecular Docking Simulation ; Amyloid beta-Peptides/toxicity ; Structure-Activity Relationship ; Peptide Fragments/toxicity ; }, abstract = {Butyrylcholinesterase (BChE) inhibitors are or could be used for the treatment of Alzheimer's disease, canine cognitive dysfunction, depression, multiple sclerosis, heroin abuse and metabolic disorders. Monoamine oxidase (MAO) inhibitors are or could be used for the treatment of depression, anxiety, Alzheimer's disease, Parkinson's disease, cancer, cardiovascular disease and chronic inflammatory diseases. We have designed, synthesized, and evaluated ten new N-propargylpyrrolidine-based inhibitors of these enzymes. Sulfonamide 10 is the most potent human (h)BChE (IC50 = 0.203 μM) of the series, and secondary carboxamide 1 is a time-dependent and irreversible inhibitor of hMAO-A (IC50 = 6.42 μM) and hMAO-B (IC50 = 7.83 μM). The X-ray crystal structures of carboxamide 4 [IC50(hBChE) = 3.89 μM] and sulfonamide 10 with hBChE confirmed our previous observation that carboxamides and sulfonamides have distinct binding poses in the active site of hBChE. The X-ray crystal structure of the complex of pyrrolidine 4 with hBChE also revealed a distinct binding pose compared to its direct piperidine analogue (PDB code 5LKR). Furthermore, compounds 1 and 10 should be able to cross the blood-brain barrier, exhibit low cytotoxicity (>50 μM) in two cell lines and protect against amyloid β1-42-induced neuronal cell death.}, } @article {pmid40749808, year = {2025}, author = {Wang, M and Zhang, L and Huang, W and Huang, J and Luo, Y and Huang, N}, title = {The potential of acupuncture in the treatment of Alzheimer's disease: An exploration from traditional Chinese medicine to modern technology.}, journal = {Complementary therapies in medicine}, volume = {93}, number = {}, pages = {103222}, doi = {10.1016/j.ctim.2025.103222}, pmid = {40749808}, issn = {1873-6963}, mesh = {*Alzheimer Disease/therapy ; Humans ; *Acupuncture Therapy/methods ; *Medicine, Chinese Traditional/methods ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with the highest prevalence worldwide, and it places considerable life and economic burdens on patients and their families. Currently, treatments for AD only delay symptoms, fail to reverse disease progression, and are often accompanied by significant side effects. Acupuncture, a nonpharmacological therapeutic method originating from China, has a history of thousands of years and is characterized by safety and economy. In recent years, the potential of acupuncture use in AD treatment has received widespread attention. With the rapid development of modern science and technology, the mechanism of action of acupuncture in the treatment of AD has gradually become increasingly clear. Therefore, we searched the databases of China National Knowledge Infrastructure (CNKI), PubMed and Web of Science for relevant studies on acupuncture for AD in recent years. According to the literature, acupuncture can improve cognitive function in AD patients through various mechanisms, such as reducing β-amyloid deposition, inhibiting Tau protein hyperphosphorylation, and attenuating neuroinflammation, and shows good therapeutic potential. Future studies should further explore in depth the mechanisms of acupuncture in treating AD through the rational use of modern science and technology techniques, with the aim of providing new strategies for the treatment of AD.}, } @article {pmid40749181, year = {2025}, author = {Galić, M and Ćilerdžić, J and Stajic, M}, title = {Mushrooms: Potential Agents for the Prevention and Slowdown of Alzheimer's Disease: A Review.}, journal = {International journal of medicinal mushrooms}, volume = {27}, number = {10}, pages = {7-19}, doi = {10.1615/IntJMedMushrooms.2025059428}, pmid = {40749181}, issn = {1940-4344}, mesh = {*Alzheimer Disease/prevention & control/drug therapy ; *Agaricales/chemistry ; Humans ; *Neuroprotective Agents/therapeutic use/pharmacology ; Animals ; *Biological Products ; Dietary Supplements ; }, abstract = {Alzheimer's disease as a neurodegenerative disorder is characterized by a decline in cognitive abilities that makes it difficult or impossible to perform ordinary tasks. It is the most common form of dementia and its exact causes are still unknown. Approximately 45.0 million people are affected by this disease, which is the leading cause of death worldwide. Although numerous commercial drugs are available on the world market, many of them have mutagenic, toxic, carcinogenic and other side effects. Therefore, today the world's trend is use of natural products without any harmful effects. Edible and medicinal mushrooms as producers of numerous biologically active compounds, such as polysaccharides, proteins, sterols, terpenoids, etc., could be a safe and effective neuroprotective agents and a promising therapy for patients with Alzheimer's disease. Mushrooms are highly valued functional foods and diet supplementation with them could significantly reduce the risk of apparence of Alzheimer's disease or slow down its development. The results of numerous studies have shown that the addition of mushrooms to the diet not only increases the effectiveness of conventional drugs but also reduces their harmful effects. However, despite numerous studies on mushrooms' medicinal properties, much more in vivo research and clinical trials are still needed to fully understand the potential of mushrooms for the prevention and treatment of Alzheimer's disease, as well as to determine their optimal administration. Reviewing all the results so far and considering future necessary studies were the main aims of this review article.}, } @article {pmid40748474, year = {2025}, author = {Suhaili, INA and Yow, HY and Mah, SH and Zaman Huri, H and Tan, SLJ}, title = {Alzheimer's disease: unraveling role of xanthone derivatives and nanocarriers.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40748474}, issn = {1432-1912}, support = {FP010-2024//Ministry of Higher Education Malaysia under the Fundamental Research Grant Scheme (FRGS 2024-1)/ ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and neuronal loss. Xanthones, a class of polyphenolic compounds, have shown potential neuroprotective effects in AD due to their antioxidant, anti-inflammatory, and acetylcholinesterase inhibitory properties. However, their therapeutic use is limited by low bioavailability and restricted blood-brain barrier (BBB) penetration. This review highlights the novelty of bridging the therapeutic findings of xanthone derivatives with brain-targeted nano-based delivery systems, while identifying gaps for pre-clinical development. A literature review was conducted focusing on the pathophysiology of AD, current therapeutic strategies, the pharmacological properties of xanthone derivatives and recent advancements in nano-based drug delivery systems for xanthone delivery to the brain. The literature search was performed across the PubMed database to identify relevant articles published until January 2025. Evidence from preclinical studies suggests that xanthone derivatives possess multiple neuroprotective properties that can weaken the AD pathophysiology. These compounds can reduce oxidative stress, suppress neuroinflammatory responses, and improve neurotransmission. Besides improving the solubility, recent nanoformulations of α-mangostin, particularly polymer nanoparticles, have demonstrated the potential to overcome the BBB through the enhancement of low-density lipoprotein receptor expression in microglia. Animal studies show improved cognitive outcomes and neuroprotection when xanthones are delivered via nanocarriers, highlighting their disease-modifying potential. Xanthone-loaded nanocarriers represent a promising disease-modifying strategy for AD as they enhance bioavailability and therapeutic outcomes. Future validation of nanoformulations through clinical trials and development of multi-targeted approaches paves the way for innovative and patient-centered neurotherapies, holding significant promise for AD treatment.}, } @article {pmid40747637, year = {2025}, author = {Zimmer, AR and Bourourou, M and Lesage, F and Hamel, E}, title = {Neurovascular coupling and functional connectivity changes through the Alzheimer's disease spectrum: Effects of simvastatin treatment.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70402}, pmid = {40747637}, issn = {1552-5279}, support = {MOP-126001//Canadian Institutes of Health Research (CIHR)/ ; 436352//Canadian Institutes of Health Research (CIHR)/ ; //Canadian Consortium on Neurodegeneration in Aging/ ; //McGill Healthy Brains Healthy Lives/ ; //Canada First Research Excellence Fund/ ; //Quebec's Ministère de l'Économie et de l'Innovation/ ; //Fonds de recherche du Québec-Santé/ ; 88887.363553/2019-00//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/PRINT)/ ; RGPIN-2017-06140//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {*Simvastatin/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/physiopathology ; Animals ; Mice, Transgenic ; *Neurovascular Coupling/drug effects ; Mice ; Disease Models, Animal ; *Brain/drug effects/physiopathology ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Male ; Humans ; *Nerve Net/drug effects/physiopathology ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a leading cause of dementia, with vascular dysfunction being an early pathogenic event. Cardiovascular interventions show therapeutic promise, hence may improve neurovascular coupling (NVC) and resting-state functional connectivity (RSFC) hemodynamic responses. METHODS: NVC and RSFC were recorded longitudinally in control and AD transgenic mice treated or not with simvastatin (SV) using optical imaging of intrinsic signals (OIS), together with memory testing. RESULTS: AD mice showed early decreases in NVC and bilateral connectivity (BC) in motor and cingulate cortex, and hypoconnectivity within the sensory-motor network. Early default-mode network (DMN) hyperconnectivity was followed by hypoconnectivity, together with a decreased BC in somatosensory (S) cortex. SV restored NVC, prevented aberrant DMN hyperconnectivity, improved BC of S, and preserved memory. DISCUSSION: Our results indicate that OIS can detect early AD-related changes in NVC and RSFC, and that a preventive cardiovascular strategy may bear therapeutic promise in at-risk individuals. HIGHLIGHTS: Optical imaging of intrinsic signals captures Alzheimer's disease (AD) progression and response to therapy. Neurovascular coupling (NVC) and resting-state functional connectivity (RSFC) disruptions precede memory decline in AD transgenic mice. Simvastatin prevented NVC and AD-specific RSFC disruptions and protected memory. This study supports translational value of hemodynamic signal in early AD detection.}, } @article {pmid40747287, year = {2025}, author = {Kwon, D and Kim, D}, title = {Effects of cognitive stimulation group programs in patients with mild Alzheimer's disease.}, journal = {The British journal of occupational therapy}, volume = {88}, number = {8}, pages = {467-478}, pmid = {40747287}, issn = {1477-6006}, abstract = {OBJECTIVES: This study examined the effects of a cognitive stimulation group program on cognitive functions, depression, activities of daily living (ADL), and quality of life in patients with mild Alzheimer's disease (AD). METHODS: Sixty patients with mild AD were randomized into the experimental or control groups (30 in each). Both groups underwent conventional occupational therapy for 30 minutes, followed by a 50-minute session of a cognitive stimulation group program for the experimental group and a cognitive workbook group program for the control group. Interventions for both groups were carried out for 4 weeks, five times a week, and once a day. RESULTS: After the interventions, both groups showed significant differences in cognitive functions, depression, ADL, and quality of life (p < 0.01, p < 0.001), with the experimental group demonstrating slightly higher scores in all assessment items. Significant intergroup differences were found in the scores for memory, the shortened Korean version of the Boston Naming Test, the Elderly Seoul Verbal Learning Test, the Korean version of the Trail Making Test Part A (depression), the Korean version of the Instrumental ADL scale, and quality of life (p < 0.05, p < 0.01, p < 0.001). CONCLUSION: It has been shown that the cognitive simulation group program can be an effective intervention method to reduce the depression of mild AD patients and improve cognitive function, ADL, and quality of life. In addition, it is significant that various enjoyable activities were organized for each cognitive domain to induce active participation and motivation of the subjects. It is expected that this study can be usefully used as a guideline for the treatment of AD patients in the future.}, } @article {pmid40746342, year = {2025}, author = {Kwon, HS and Park, KH and Lee, JS and Choi, H and Lee, CN and Lim, JS and Jang, JW and Shim, Y and Choi, SH and Yang, DW}, title = {Nationwide Survey on the Awareness of Mild Cognitive Impairment.}, journal = {Dementia and neurocognitive disorders}, volume = {24}, number = {3}, pages = {198-207}, pmid = {40746342}, issn = {2384-0757}, abstract = {BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI), particularly due to Alzheimer's disease (AD), is an important stage for early intervention. We aim to assess awareness among the general population of MCI and AD, and evaluate their willingness to pay for treatment that delays the progression to dementia. METHODS: A nationwide cross-sectional telephone survey was conducted from August 29 to 31, 2022, targeting adults aged ≥18 years in the Republic of Korea. In toto, 1,006 respondents were randomly selected via a proportional allocation based on age, sex, and region. The survey consisted of 11 questions covering demographic information, awareness of MCI and AD, understanding of diagnostic procedures, such as amyloid positron emission tomography (PET), and willingness to pay for disease-modifying treatment. RESULTS: Among the respondents, 41.3% had heard of MCI, but only 12.0% were well informed. Some 77.0% stated that if they experienced cognitive decline, they would visit a hospital. Only 12.4% of respondents knew the important role of amyloid PET in diagnosing MCI due to AD. Regarding the treatment costs of disease-modifying drugs, 42.1% were willing to pay <600,000 KRW (approximately 420 USD) per month, while 18.4% were unwilling to pay. Older age and lower socioeconomic status were significantly associated with decreased willingness to pay (p<0.001). CONCLUSIONS: Public awareness of MCI is limited, and willingness to pay decreases with older age and lower socioeconomic status. Targeted education and strategies are therefore required to increase awareness and reduce disparities.}, } @article {pmid40745950, year = {2026}, author = {Jeong, YJ and Lee, HJ and Kim, JS and Kim, SJ and Jo, U and Park, JY and Jun, SJ and Lee, WS and Song, M and Kim, D and Cho, G and Song, JH and Hoe, HS}, title = {Digital Therapeutics for Alzheimer's and Parkinson's Diseases: Current Trends and Future Perspectives.}, journal = {Medicinal research reviews}, volume = {46}, number = {1}, pages = {316-327}, pmid = {40745950}, issn = {1098-1128}, mesh = {*Alzheimer Disease/physiopathology/therapy ; *Parkinson Disease/physiopathology/therapy ; Humans ; *Software/trends ; *Digital Health/trends ; Executive Function/physiology ; Cognition/physiology ; Motor Activity/physiology ; Machine Learning/trends ; Virtual Reality Exposure Therapy/trends ; Clinical Trials as Topic ; }, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD), which are characterized by the accumulation of misfolded protein aggregates and cognitive/motor dysfunction, are the most prevalent neurodegenerative diseases (NDDs). Despite strategic investigations aimed at augmenting the pharmaceutical pipeline, available drugs for AD and PD merely slow disease progression without curing or treating the underlying pathology. Recent technological advances have given rise to digital therapeutics (DTx): software systems that aim to prevent, cure, and manage specific diseases, including NDDs. For AD and PD, the majority of DTx focus on enhancing cognitive/executive function and motor-related functions, respectively. In this review, we describe the status of therapeutic development for AD and PD, as well as the characteristics and status of DTx targeting these NDDs. In addition, we address the limitations and challenges of DTx and their implications for the treatment of AD and PD. Ultimately, this review provides insights into the potential of DTx as a therapeutic modality and future directions for the development of DTx targeting AD and PD.}, } @article {pmid40745641, year = {2025}, author = {Bao, S and Zheng, F and Jiang, L and Wang, Q and Lyu, Y}, title = {TA-SSM net: tri-directional attention and structured state-space model for enhanced MRI-Based diagnosis of Alzheimer's disease and mild cognitive impairment.}, journal = {BMC medical imaging}, volume = {25}, number = {1}, pages = {309}, pmid = {40745641}, issn = {1471-2342}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Cognitive Dysfunction/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Aged ; *Deep Learning ; Male ; Female ; Imaging, Three-Dimensional ; *Image Interpretation, Computer-Assisted/methods ; Neuroimaging/methods ; Brain/diagnostic imaging ; Aged, 80 and over ; }, abstract = {Early diagnosis of Alzheimer's disease (AD) and its precursor, mild cognitive impairment (MCI), is critical for effective prevention and treatment. Computer-aided diagnosis using magnetic resonance imaging (MRI) provides a cost-effective and objective approach. However, existing methods often segment 3D MRI images into 2D slices, leading to spatial information loss and reduced diagnostic accuracy. To overcome this limitation, we propose TA-SSM Net, a deep learning model that leverages tri-directional attention and structured state-space model (SSM) for improved MRI-based diagnosis of AD and MCI. The tri-directional attention mechanism captures spatial and contextual information from forward, backward, and vertical directions in 3D MRI images, enabling effective feature fusion. Additionally, gradient checkpointing is applied within the SSM to enhance processing efficiency, allowing the model to handle whole-brain scans while preserving spatial correlations. To evaluate our method, we construct a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), consisting of 300 AD patients, 400 MCI patients, and 400 normal controls. TA-SSM Net achieved an accuracy of 90.24% for MCI detection and 95.83% for AD detection. The results demonstrate that our approach not only improves classification accuracy but also enhances processing efficiency and maintains spatial correlations, offering a promising solution for the diagnosis of Alzheimer's disease.}, } @article {pmid40745201, year = {2025}, author = {Xiaoying, M and Zhiming, H and Mingwen, S and Hong, W and Tao, Y and Jun, X and Na, G}, title = {Uncovering active ingredients and mechanisms of Pholiota adiposa in the treatment of Alzheimer's disease based on network pharmacology and bioinformatics.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {27981}, pmid = {40745201}, issn = {2045-2322}, support = {2024MS0604//the Presidential Foundation of the Liaoning Academy of Agricultural Sciences/ ; 2022JH2/101300160//Applied Basic Research Program of Liaoning Province/ ; 2024XTCX0403//the Fundamental Research Funds of Liaoning Academy of Agricultural Sciences/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Network Pharmacology/methods ; *Computational Biology/methods ; Molecular Docking Simulation ; *Drugs, Chinese Herbal/pharmacology/chemistry/therapeutic use ; Machine Learning ; Molecular Dynamics Simulation ; }, abstract = {Pholiota adiposa is recognized for its health benefits, particularly in Alzheimer's disease (AD), but its molecular mechanism remains elusive. Our study employs network pharmacology and machine learning to uncover its therapeutic potential. We constructed a network of AD-relevant target proteins using databases like TCMSP, CTD, and GeneCards, and performed gene enrichment and functional analysis with DAVID, GO, and KEGG via Hiplot. Targets were identified through Cytoscape's degree analysis and the Aging Atlas database for aging-related genes. Clinical targets were confirmed with GEO, and molecular docking was executed using AutoDock Vina. LASSO regression and random forest algorithms were applied for target model selection, and molecular dynamics simulations were run with Gromacs2022.3. Our findings suggest Pholiota adiposa modulates key proteins involved in AD, including STAT3, PRKCA, NF-κB1, and CDK1, potentially inhibiting protein phosphorylation and influencing neuronal membrane synthesis and RNA polymerase II activity. KEGG analysis revealed its impact on cancer pathways, indicating a multifaceted role. High-degree targets like STAT3 and NF-κB1 were identified as effective, with TERT showing a significant role in aging. Machine learning confirmed the diagnostic importance of STAT3 and NFKB1 in AD. Molecular docking highlighted the affinity of Pholiota adiposa for these targets, with carnosol, carnosic acid, and clovane diol as key components. Carnosol, in particular, induced a conformational change in STAT3, enhancing its efficacy. Pholiota adiposa shows promise as a therapeutic agent in AD treatment by modulating various pathways and signaling mechanisms, as demonstrated through network pharmacology and machine learning analyses. This study underscores its potential in managing neurodegenerative diseases.}, } @article {pmid40744715, year = {2025}, author = {Ying, C and He, Y and Guo, Y and Fan, F and Wang, B and Gao, J and Li, Y and Zhang, Y}, title = {Application of Traditional Chinese Medicine in Alzheimer's Disease Treatment: A Focus on the Wnt/[Formula: see text]-Catenin Pathway.}, journal = {The American journal of Chinese medicine}, volume = {53}, number = {6}, pages = {1641-1683}, doi = {10.1142/S0192415X25500624}, pmid = {40744715}, issn = {1793-6853}, mesh = {*Alzheimer Disease/drug therapy/metabolism/genetics/etiology ; Humans ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Wnt Signaling Pathway/drug effects/genetics ; *Medicine, Chinese Traditional/methods ; Animals ; Amyloid beta-Peptides/metabolism ; *Neuroprotective Agents/therapeutic use ; *Phytotherapy ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by cognitive decline. Its etiology and pathogenesis are complex and multifactorial, with neurotoxicity induced by the abnormal aggregation of amyloid-beta (A[Formula: see text]) protein widely recognized as a central pathological hallmark. Current pharmacological treatments provide only limited symptomatic relief and are often associated with dose-dependent adverse effects. In contrast, Traditional Chinese Medicine (TCM) has garnered growing attention due to its distinctive therapeutic profile, and in particular, its multi-target and multi-pathway synergistic mechanisms. The Wnt/[Formula: see text]-catenin signaling pathway plays a crucial role in intracellular signal transduction and is closely associated with several key pathological processes involved in AD. This review provides a comprehensive analysis of the molecular interplay between the Wnt/[Formula: see text]-catenin signaling pathway and the pathogenesis of AD, as well as a specific focus on how natural compounds, herbal monomers, and classical TCM formulations modulate this pathway. Accumulating evidence suggests that TCM exerts neuroprotective effects by regulating Wnt/[Formula: see text]-catenin signaling to thereby suppress A[Formula: see text] deposition, preserve synaptic structure and tissue homeostasis, modulate cell proliferation and apoptosis, and maintain metabolic and redox homeostasis. Additionally, the review discusses key challenges, such as improving blood-brain barrier permeability and enhancing bioavailability, and outlines future directions involving advanced delivery systems and optimized administration routes. These insights provide a robust scientific foundation for the development of Wnt/[Formula: see text]-catenin-targeted therapies and highlight the potential of TCM in the clinical treatment of AD.}, } @article {pmid40744389, year = {2025}, author = {Nelson, VK and Begum, MY and Suryadevara, PR and Madhuri Kallam, SD and Panda, SP and Bodapati, A and Sanga, V and Bishoyi, AK and Ballal, S and Monsi, M and Walia, C and Prasad, GVS and Abomughaid, MM and Shukla, S and Chauhan, P and Jha, NK}, title = {Natural bioactive compounds as modulators of autophagy: A herbal approach to the management of neurodegenerative diseases.}, journal = {European journal of pharmacology}, volume = {1005}, number = {}, pages = {178003}, doi = {10.1016/j.ejphar.2025.178003}, pmid = {40744389}, issn = {1879-0712}, mesh = {Humans ; *Autophagy/drug effects ; *Neurodegenerative Diseases/drug therapy/pathology/metabolism ; Animals ; *Biological Products/therapeutic use/pharmacology ; *Neuroprotective Agents/therapeutic use/pharmacology ; }, abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Polyglutamine (polyQ), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) disease are a significant health concern that affects millions of people every year worldwide. The main pathological hallmark of various NDs is the formation of misfolded protein aggregation and accumulation of inclusion bodies. These protein aggregates are mainly responsible for producing toxic effects and initiating neuronal cell death, ultimately promoting various NDs. On the other hand, the patients suffering from these kinds of diseases live in impaired conditions, imposing a substantial financial burden on the family. However, the current treatment strategies can only offer temporary relief from the disease symptoms and can't reverse the disease completely. Hence, there is an urgent need for specific and novel drug treatment that can significantly eradicate NDs. Ubiquitin proteasome system (UPS) and autophagy are the two essential intracellular defensive mechanisms that are involved in clearing the protein aggregates, pathogens, and damaged organelles from the cytoplasm and maintaining protein homeostasis. Nevertheless, UPS is inefficient in removing some kinds of organelles and aggregating-prone proteins, specifically in neuronal and glial cells. Under this kind of circumstance, the autophagy mechanism plays a vital role in eliminating the accumulated protein aggregates and other toxic elements from the cytoplasm of the neuronal cells that initiate oxidative stress. However, in NDs, the autophagy function is impaired, and the protein aggregates can't be eliminated effectively. Hence, forced up-regulation of autophagy function by applying various external agents could be a potential therapeutic strategy to control NDs like AD, PD, HD, and ALS. In this review, we focused on different kinds of plant-derived compounds that induce autophagy. We also discussed the role of these plant-derived autophagy modulators in various NDs. In this way, the current review will be a standalone reference to the researchers working in this area.}, } @article {pmid40743720, year = {2025}, author = {Ali, A and Ganeshpurkar, A and Ganeshpurkar, A and Dubey, N}, title = {In Silico Investigation of Ganoderic Acid A Targeting Amyloid-Beta and Tau Protein Aggregation in Alzheimer's Disease.}, journal = {International journal of medicinal mushrooms}, volume = {27}, number = {9}, pages = {85-92}, doi = {10.1615/IntJMedMushrooms.2025059137}, pmid = {40743720}, issn = {1940-4344}, mesh = {*tau Proteins/metabolism/chemistry ; *Alzheimer Disease/drug therapy/metabolism ; *Amyloid beta-Peptides/metabolism/chemistry ; *Lanosterol/analogs & derivatives/pharmacology/chemistry ; Molecular Docking Simulation ; Humans ; Computer Simulation ; Protein Aggregates/drug effects ; Protein Binding ; *Reishi/chemistry ; Heptanoic Acids ; }, abstract = {Alzheimer's disease (AD) represents a significant challenge in neurodegenerative disorders, characterized by the accumulation of amyloid-beta (Aβ) plaques and tau protein tangles in the brain. Current treatments provide symptomatic relief but do not halt disease progression. ganoderic acid A, derived from Ganoderma lucidum, has shown to act as a dual inhibitor of Aβ and tau protein aggregation through in vitro and animal model studies. This study aims to explore the therapeutic potential of ganoderic acid A using in silico methods to predict its binding affinity and mode of interaction with Aβ and tau proteins. Analysis included molecular docking simulations using computational models to evaluate the binding of ganoderic acid A to Aβ and tau proteins. Various tools were employed to predict the binding energy, interaction sites (Autodock), and MD (CABSflex 2.0) of these complexes. Ganoderic acid A demonstrated favorable binding energies and interactions with both Aβ and tau proteins. The compound exhibited potential dual inhibition capabilities by forming stable complexes with critical residues involved in Aβ aggregation and tau protein hyperphosphorylation. The findings suggest that ganoderic acid A holds promise as a dual inhibitor of Aβ and tau protein aggregation in AD. By targeting these key pathological processes, ganoderic acid A may offer therapeutic benefits in halting or slowing disease progression. Confirming these predictions and advancing ganoderic acid A as a possible AD treatment will require additional experimental validation, including in vitro and in vivo research.}, } @article {pmid40742404, year = {2025}, author = {Chen, X and Zhou, XY and Lan, C and Fu, HJ and Li, ZC and Chen, MY and Wen, YP and Yu, L and Qin, DL and Wu, AG and Wu, JM and Zhou, XG}, title = {Araloside A Induces Raf/MEK/ERK-Dependent Autophagy to Mitigate Alzheimer's and Parkinson's Pathology in Cellular and C. elegans Models.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {16061-16080}, pmid = {40742404}, issn = {1559-1182}, support = {2024YFHZ0361//The Department of Science and Technology of Sichuan Province/ ; SKL-KF202311//The Open Project Program of State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China/ ; 81801398//the National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Caenorhabditis elegans/metabolism/drug effects ; *Autophagy/drug effects ; *Alzheimer Disease/pathology/drug therapy/metabolism ; *Parkinson Disease/pathology/drug therapy/metabolism ; Humans ; *MAP Kinase Signaling System/drug effects ; *raf Kinases/metabolism ; *Oleanolic Acid/pharmacology/analogs & derivatives/therapeutic use ; Disease Models, Animal ; Animals, Genetically Modified ; Neurons/drug effects/metabolism/pathology ; alpha-Synuclein/metabolism ; }, abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by pathological protein aggregation and oxidative stress, leading to progressive neurodegeneration. Enhancing autophagy, the primary intracellular pathway for clearing misfolded proteins, represents a promising therapeutic strategy. In this study, we identify Araloside A (ARA), a triterpenoid saponin derived from Aralia elata, as a potent autophagy inducer that alleviates AD- and PD-related pathology. In neuronal cell models, ARA promotes autophagosome formation, increases LC3-II and Beclin-1 levels, and decreases P62, indicating enhanced autophagic activity. Mechanistic investigations reveal that ARA directly binds to Raf, MEK, and ERK proteins and activates autophagy in a Raf/MEK/ERK-dependent manner. This activation facilitates the clearance of APP, total Tau, phosphorylated Tau, and α-synuclein, thereby reducing cytotoxicity. Furthermore, in transgenic Caenorhabditis elegans models of AD and PD, ARA treatment alleviates protein aggregation and behavioral deficits via ERK-dependent autophagy. Together, these findings identify ARA as a natural compound that enhances autophagic clearance of neurotoxic aggregates via Raf/MEK/ERK pathway activation, offering promising therapeutic insights for neurodegenerative proteinopathies.}, } @article {pmid40742252, year = {2026}, author = {Morgan, TM and Snyder, B}, title = {Pharmacokinetics and Bioavailability of a Novel Rivastigmine Nasal Spray Compared to Rivastigmine Oral Capsule in Healthy Men.}, journal = {Journal of clinical pharmacology}, volume = {66}, number = {1}, pages = {e70086}, doi = {10.1002/jcph.70086}, pmid = {40742252}, issn = {1552-4604}, support = {AC76937//Lachesis Biosciences and AusIndustry/ ; ACTRN12619001513101//Australian New Zealand Clinical Trials Registry/ ; }, mesh = {Humans ; Male ; Rivastigmine ; Adult ; Cross-Over Studies ; Biological Availability ; Administration, Oral ; Young Adult ; Middle Aged ; Nasal Sprays ; Adolescent ; *Phenylcarbamates/pharmacokinetics/administration & dosage/adverse effects/blood ; Capsules ; Administration, Intranasal ; Area Under Curve ; *Cholinesterase Inhibitors/pharmacokinetics/administration & dosage/adverse effects/blood ; }, abstract = {To compare the pharmacokinetics, bioavailability, tolerability, and safety of a novel 4 mg rivastigmine nasal spray to 3 mg rivastigmine oral capsule, a single-dose, open-label, randomized, crossover study was conducted in 16 fasted healthy young men (18 to 55 years). Mean (SD) rivastigmine Cmax was 8.39 (6.8) and 13.77 (10.7) ng/mL for oral and nasal, respectively. Rivastigmine AUC0-inf was 19.6 (14.9) and 40.6 (24.4) ng h/mL for oral and nasal, respectively. The ratio of LS means (nasal test / oral reference; 90% C.I.) for rivastigmine Cmax was 185.83% (134.22, 257.28) and for rivastigmine AUC0-inf was 257.35% (197.26, 335.73). Rivastigmine tmax for nasal (0.7 h) was significantly lower than oral (1.2 h, P < .05), however, NAP226-90 tmax for nasal (1.9 h) and oral (1.8 h) were similar. NAP226-90 Cmax was 3.93 (1.1) and 3.01 (0.8) ng/mL for oral and nasal, respectively. NAP226-90 AUC0-inf was 22.9 (5.3) and 23.2 (5.1) ng h/mL for oral and nasal, respectively. Median NAP226-90 to rivastigmine AUC0-inf ratio for nasal (0.55) was significantly lower than oral (1.38, P < .05) because nasal bypassed first-pass metabolism. Both single-dose treatments were safe and well tolerated. Nasal and throat irritation were mostly perceived as mild and transient following nasal administration. The 4 mg rivastigmine nasal spray had 1.5- and 2.0-fold higher dose normalized rivastigmine Cmax and AUC0-inf, respectively, and 2.5-fold lower NAP226-90 to rivastigmine AUC0-inf ratio compared to 3 mg oral capsule. This nasal spray has good potential to improve the local and gastrointestinal tolerability of rivastigmine treatment in Alzheimer's and Parkinson's disease dementia patients.}, } @article {pmid40741047, year = {2025}, author = {Yang, Y and Chen, H and Liu, Q and Niu, Y and Mao, C and Wang, R}, title = {Elucidating molecular pathogenesis and developing targeted therapeutic interventions for cerebrovascular endothelial cell-mediated vascular dementia.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1623050}, pmid = {40741047}, issn = {1663-4365}, abstract = {Vascular dementia (VaD) ranks as the second most prevalent subtype of dementia, surpassed only by Alzheimer's disease (AD). The maintenance of neurological function and cerebral homeostasis critically depends on precisely regulated blood flow within the intricately organized cerebrovascular network. Disruptions in cerebral hemodynamics may impair neurovascular homeostasis, thereby inducing pathophysiological cascades characterized by oxidative stress, neuroinflammation, and neuronal degeneration. Emerging evidence identifies cerebrovascular dysregulation and impaired neurovascular coupling (NVC) as primary pathogenic mechanisms underlying VaD, emphasizing the necessity to elucidate their complex interplay. Cerebrovascular endothelial cells exhibit remarkable heterogeneity, serving dual roles as both architectural components of the blood-brain barrier (BBB) and functional regulators of NVC. Furthermore, pericytes residing abluminal on capillary endothelia demonstrate critical involvement in hemodynamic modulation through contractile regulation of microvascular tone, while concurrently maintaining BBB integrity through dynamic paracrine signaling. This study examines cerebrovascular endothelial-neuronal interactions within the neurovascular unit (NVU) framework, analyzing their bidirectional regulatory mechanisms and therapeutic potential in cognitive dysfunction remediation. The pathophysiological progression of VaD manifests through multiple interdependent pathways, including cerebral hypoperfusion, oxidative stress cascades, neuroinflammatory responses, mitochondrial dysregulation, and electrolyte homeostasis perturbations. Through three interventional axes: (1) BBB fortification strategies; (2) cerebral hemodynamic optimization and NVC enhancement; (3) nanotherapeutic platforms integrating endothelial-specific molecular targets we systematically evaluate endothelial-centric therapeutic paradigms. This multi-modal approach proposes novel mechanistic insights and clinical translation frameworks for VaD management.}, } @article {pmid40740995, year = {2025}, author = {Zhang, Y and Zhang, T and Zhao, M and Li, P and Liu, T and Xie, J}, title = {Pharmacological mechanisms and potential clinical applications of Dihydromyricetin in neurological disorders.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1618623}, pmid = {40740995}, issn = {1663-9812}, abstract = {Neurological disorders (e.g., Alzheimer's disease, Parkinson's disease, and stroke) have complex pathogenesis and affect a substantial proportion of the population; yet, available treatments have poor or limited efficacy, and the patients have a poor prognosis, with high morbidity and mortality. Dihydromyricetin (DHM), a flavonoid compound extracted from plants, has received widespread attention in recent years because of its diverse pharmacological effects. In vitro and in vivo studies have revealed its substantial antioxidant, anti-inflammatory, and neuroprotective properties, making it a promising candidate for the treatment of central nervous system disorders through multiple mechanisms and pleiotropic effects. Therefore, there is an urgent need to develop novel therapeutic strategies. DHM is an attractive candidate for the management of neurological disorders, but there is a lack of a systematic summary of the knowledge status and gaps. Therefore, to address this challenge, we systematically reviewed the pharmacological mechanisms of DHM in central nervous system disorders and its potential applications in related conditions. We analyzed the therapeutic potential and current challenges of DHM to provide a reference for its development and application as a novel therapeutic agent. The review suggests that DHM possesses significant potential for the management of neurological disorders.}, } @article {pmid40740514, year = {2025}, author = {Wang, J and Mao, Y and Liu, X and Hao, W and , }, title = {Learning Patient-Specific Spatial Biomarker Dynamics via Operator Learning for Alzheimer's Disease Progression.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {40740514}, issn = {2331-8422}, support = {R35 GM146894/GM/NIGMS NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder with substantial heterogeneity in progression and treatment response. Despite recent therapeutic advances, predictive models capable of accurately forecasting individualized disease trajectories remain limited. Here, we present a machine learning-based operator learning framework for personalized modeling of AD progression, integrating longitudinal multimodal imaging, biomarker, and clinical data. Unlike conventional models with prespecified dynamics, our approach directly learns patient-specific disease operators governing the spatiotemporal evolution of amyloid, tau, and neurodegeneration biomarkers. Using Laplacian eigenfunction bases, we construct geometry-aware neural operators capable of capturing complex brain dynamics. Embedded within a digital twin paradigm, the framework enables individualized predictions, simulation of therapeutic interventions, and in silico clinical trials. Applied to AD clinical data, our method achieves high prediction accuracy exceeding 90% across multiple biomarkers, substantially outperforming existing approaches. This work offers a scalable, interpretable platform for precision modeling and personalized therapeutic optimization in neurodegenerative diseases.}, } @article {pmid40740460, year = {2025}, author = {Fu, HX}, title = {Effects of repetitive transcranial magnetic stimulation on electroencephalogram and memory function in patients with mild cognitive impairment.}, journal = {World journal of psychiatry}, volume = {15}, number = {7}, pages = {106761}, pmid = {40740460}, issn = {2220-3206}, abstract = {BACKGROUND: Mild cognitive impairment (MCI) is a high-risk precursor to Alzheimer's disease characterized by declining memory or other progressive cognitive functions without compromising daily living abilities. AIM: To investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with MCI. METHODS: This retrospective analysis involved 180 patients with MCI who were admitted to The First Hospital of Shanxi Medical University from January 2021 to June 2023. Participants were allocated into the research (n = 98, receiving rTMS) and control groups (n = 82, receiving sham stimulation). Memory tests, cognitive function assessments, event-related potential-P300 tests, and electroencephalogram (EEG) examinations were conducted pre-treatment and post-treatment. Further, memory quotient (MQ), cognitive function scores, and EEG grading results were compared, along with adverse reaction incidences. RESULTS: Pre-treatment MQ scores, long-term and short-term memory, as well as immediate memory scores, demonstrated no notable differences between the groups. Post-treatment, the research group exhibited significant increases in MQ scores, long-term memory, and short-term memory compared to baseline (P < 0.05), with these improvements being statistically superior to those in the control group. However, immediate memory scores exhibited no significant change (P > 0.05). Further, the research group demonstrated statistically better post-treatment scores on the Revised Wechsler Memory Scale than the control group. Furthermore, post-treatment P300 latency and amplitude improved significantly in the research group, surpassing the control group. EEG grading in the research group improved, and the incidence of adverse reactions was significantly lower than in the control group. CONCLUSION: Patients with MCI receiving rTMS therapy demonstrated improved memory and cognitive functions and EEG grading and exhibited high safety with fewer adverse reactions.}, } @article {pmid40740038, year = {2025}, author = {Zheng, M and Yang, M and Li, X and Tian, L and Zhou, S and Wang, G and Gao, W}, title = {Attenuation of Tacrine Combined With Rosmarinic Acid.}, journal = {Phytochemical analysis : PCA}, volume = {36}, number = {7}, pages = {2022-2038}, doi = {10.1002/pca.70009}, pmid = {40740038}, issn = {1099-1565}, support = {2060302//Key Project at the Central Government Level/ ; ZYYCXTD-D-202005//Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine/ ; 81872956//National Natural Science Foundation of China/ ; 82173929//National Natural Science Foundation of China/ ; }, mesh = {Rosmarinic Acid ; *Depsides/pharmacology/administration & dosage ; *Cinnamates/pharmacology/administration & dosage ; Animals ; *Tacrine/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Mice ; Male ; Disease Models, Animal ; Neuroprotective Agents/pharmacology ; Microglia/drug effects/metabolism ; Galactose ; Brain/drug effects/metabolism/pathology ; Mice, Inbred C57BL ; Amyloid beta-Peptides/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of dementia among the elderly in the world. With the increase of human life expectancy, its incidence is also increasing year by year. Tacrine (TAC) is the first acetylcholine inhibitor approved for the treatment of AD. Although TAC has obvious anti-AD activity, it was eventually delisted due to acute liver injury caused by its strong hepatotoxicity. Rosmarinic acid (RA) has shown good activity in both neuroprotection and hepatoprotection. PURPOSE AND STUDY DESIGN: In this study, the combination of RA and TAC was explored, and a high dose of d-galactose was used to build an AD mouse model, which was given at the same time for 4 weeks in order to alleviate TAC hepatotoxicity and enhance the intervention of AD in mice through RA. In particular, we pay attention to the key role of Aβ and microglia in the pathogenesis of AD, so we evaluate the ability of RA combined with TAC in alleviating chronic neuroinflammation induced by Aβ plaque in the brain of AD mice and enhancing the ability of microglia to clear Aβ plaque. RESULTS: The results show that the combination of RA and TAC has the best intervention effect on AD compared with the single use of the two drugs, and it is basically positively correlated with RA dose. RA + TAC significantly improved body weight, organ index, and behavioral state of AD mice. Further analysis showed that RA + TAC enhanced the antioxidant level of hippocampus and serum of AD mice, alleviated the pathological damage of hippocampus, significantly improved cholinergic system, reduced the expression levels of AB plaque and neurotoxic Aβ1-41 and Aβ1-42 in the brain, and significantly increased the level of neuroprotective protein trigger receptor expressed on myeloid cells 2 (TREM2), which mediated the phagocytosis of microglia. More importantly, the combination therapy of RA and TAC decreased the expression of M1 microglia marker (ionized calcium-binding adapter molecule 1 [Iba-1]), increased the expression of M2 microglia marker Arg-1, and promoted the release of anti-inflammatory compounds. In addition, RA + TAC also inhibited the mRNA expression of TLR4 and NF-κB related to neuroinflammation. In the aspect of liver function, RA reduced cell death mediated by Caspase-3 by regulating the expression of bcl-2/bax, alleviated TAC-induced liver injury in mice, and made the serum indexes of ALT, AST, ALP, TBIL, and γ-GT reflecting liver function closer to the normal range. CONCLUSION: The combination of RA and TAC shows the potential to reduce the hepatotoxicity of TAC and is expected to enhance its therapeutic effect on AD.}, } @article {pmid40739944, year = {2025}, author = {Hardy, J}, title = {Alzheimer's Disease: Treatment Challenges for the Future.}, journal = {Journal of neurochemistry}, volume = {169}, number = {8}, pages = {e70176}, pmid = {40739944}, issn = {1471-4159}, mesh = {*Alzheimer Disease/drug therapy/therapy/metabolism ; Humans ; Animals ; Amyloid beta-Peptides/metabolism/immunology/antagonists & inhibitors ; }, abstract = {The approvals of the first anti-amyloid antibodies for the treatment of Alzheimer's disease have changed both the clinical and research landscape for the disease. These antibodies, lecanemab and donanemab, mark a turning point for our understanding of the disease pathogenesis and for the treatment of this prevalent disorder. This review discusses what they imply for disease pathogenesis and what is needed to progress from the current imperfect therapies toward safe and better, disease halting therapies. The research over the next period will involve drug development, largely aimed at reducing the side effects of the anti-amyloid therapies, biomarker and genetic research to try and identify patients earlier in the disease process, and neuropathological research in individuals who have received treatment to try and understand the pathological substrates of the continuing clinical decline in the disease.}, } @article {pmid40739673, year = {2025}, author = {Zheng, X and Yuan, W and Li, L and Ma, H and Zhu, M and Li, X and Feng, X}, title = {Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) to tackle central nervous system diseases: role as a promising approach.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {690}, pmid = {40739673}, issn = {2047-783X}, mesh = {Humans ; *Proprotein Convertase 9/metabolism/genetics ; *PCSK9 Inhibitors/therapeutic use ; *Central Nervous System Diseases/drug therapy/metabolism ; Animals ; }, abstract = {Atherosclerosis-associated disease (ASD) represents a complex pathological condition, characterized by the formation of atherosclerotic plaques within the arterial walls, encompassing cholesterol depositions, which is primarily attributed to elevated levels of low-density lipoprotein-cholesterol (LDL-C). A log-linear association between the absolute magnitude of LDL-C exposure and ASD risk has been widely studied. High levels of LDL-C have been acknowledged as the predominant culprit. The previous research findings have demonstrated that PCSK9 inhibitors (PCSK9i) can remarkably diminish the risk of ASD. The current research has primarily focused on the relevance of PCSK9 to the cardiovascular system and lipid metabolism; however, an increasing body of evidence shows that PCSK9 is pivotal in pathogenic processes in other organ systems. Yet, PCSK9's impact on the brain is complex and not fully clarified, although several recent studies emphasize a putative role of its impact on various neurodegenerative disorders. Among neurological disorders, not only stroke but neurogenesis, neural cell differentiation, central LDL receptor metabolism, neural cell apoptosis, neuroinflammation, alcohol use disorder (AUD), amyotrophic lateral sclerosis(ALS), and Alzheimer's Disease (AD) are related to PCSK9. PCSK9 expression in brain is low but greatly upregulated in neurological disorders. Therefore, PCSK9 is a promising pathway for the treatment of central nervous diseases. This review comprehensively describes evidence from the previous research on the effects of PCSK9i on the central nervous system, with a focus on the clinical potential of PCSK9i. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop treatments for the neurological diseases based on PCSK9i.}, } @article {pmid40737743, year = {2025}, author = {Liu, J and Liu, K and Cui, X and Ji, Y and Ding, Z and Chang, Z and Zhang, J and Wang, X and Liu, Y}, title = {From gut to brain: donepezil and nimodipine combination therapy improves cognitive deficits in Alzheimer's disease via gut microbiota and metabolites.}, journal = {Biochemical and biophysical research communications}, volume = {778}, number = {}, pages = {152418}, doi = {10.1016/j.bbrc.2025.152418}, pmid = {40737743}, issn = {1090-2104}, mesh = {*Gastrointestinal Microbiome/drug effects ; *Donepezil/pharmacology/therapeutic use/administration & dosage ; Animals ; *Alzheimer Disease/drug therapy/metabolism/microbiology ; Male ; Drug Therapy, Combination ; Rats ; *Brain/drug effects/metabolism ; Rats, Sprague-Dawley ; *Cognitive Dysfunction/drug therapy/metabolism ; Feces/microbiology ; Hippocampus/drug effects/pathology/metabolism ; }, abstract = {Donepezil (DNP) is often combined with nimodipine (NMD) for the treatment of Alzheimer's disease (AD). However, its underlying mechanisms remain poorly understood. This study integrated pharmacodynamics, microbiomics, and fecal metabolomics analysis to explore the therapeutic potential and mechanism of DNP + NMD in AD. The results showed that DNP + NMD significantly reduced the contents of serum inflammatory cytokines interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) as well as the contents of nitric oxide synthase (NOS), glycogen synthase kinase-3β (GSK-3β) and acetylcholinesterase (AChE) in the hippocampus, alleviated neuronal damage in hippocampal tissues and effectively improved cognitive deficits of AD rats. Furthermore, DNP + NMD greatly increased the relative abundance of beneficial bacteria (Lactobacillus and Prevotellaceae_Prevotella) and decreased the relative abundance of harmful bacteria (Ruminococcus and Akkermansia). Fecal metabolomic analyses indicated that DNP + NMD regulated 28 fecal differential metabolite levels mainly through six key pathways, including linoleic acid metabolism, arachidonic acid metabolism, unsaturated fatty acid biosynthesis, steroid hormone biosynthesis, saturated fatty acid biosynthesis, primary bile acid biosynthesis, pantothenic acid biosynthesis, and coenzyme A biosynthesis pathway. Moreover, Spearman's correlation analysis revealed significant associations between affected metabolites and specific gut microbes. In general, our research sheds light that DNP + NMD exerts a neuroprotective effect against AD by ameliorating the gut microbiota and fecal metabolic disorders, uncovering novel mechanistic insights and therapeutic targets for AD intervention.}, } @article {pmid40737409, year = {2025}, author = {Zou, F and Liu, Y and Luo, Y and Xu, T}, title = {A wearable spatiotemporal controllable ultrasonic device with amyloid-β disaggregation for continuous Alzheimer's disease therapy.}, journal = {Science advances}, volume = {11}, number = {31}, pages = {eadw1732}, pmid = {40737409}, issn = {2375-2548}, mesh = {*Alzheimer Disease/therapy/metabolism/pathology ; Animals ; *Amyloid beta-Peptides/metabolism/chemistry ; Mice ; Disease Models, Animal ; *Wearable Electronic Devices ; Microglia/metabolism ; Humans ; Brain/metabolism/pathology ; Plaque, Amyloid/metabolism ; *Ultrasonic Therapy/instrumentation ; Mice, Transgenic ; *Protein Aggregates ; }, abstract = {The rising prevalence of Alzheimer's disease (AD) due to an aging population has made the search for effective treatments more urgent than ever. Previous studies have demonstrated that continuous ultrasound can depolymerize amyloid proteins, offering potential relief from AD. In this study, we present a portable, fully integrated wearable ultrasound system designed to promote amyloid protein depolymerization. The system comprises a flexible honeycomb ultrasonic array patch, a flexible printed circuit, and an interactive terminal control system to facilitate the treatment process. Our results demonstrate that the system effectively reduces amyloid proteins in the brain, improves cognitive function in a familial Alzheimer's disease (FAD) mouse model, enhances microglial phagocytosis of amyloid-β plaques, and shifts microglia polarization from M1 to M2. These changes contribute to a mitigated inflammatory environment in the brain. This innovative approach may pave the way for noninvasive, personalized treatments for AD, potentially transforming therapeutic strategies in neurodegenerative disorders.}, } @article {pmid40736488, year = {2025}, author = {Johnston, EM and Lounsbery, JL}, title = {Benzgalantamine (Zunveyl) for the Treatment of Mild to Moderate Alzheimer Disease.}, journal = {American family physician}, volume = {112}, number = {1}, pages = {22-23}, pmid = {40736488}, issn = {1532-0650}, } @article {pmid40735986, year = {2025}, author = {Akocak, S and Lolak, N and Ammara, A and Güler, ÖÖ and Supuran, CT}, title = {Exploring the Carbonic Anhydrase Activation Properties of 4-arylazo-3,5- diamino-1H-pyrazoles against hCA I, II, IV, and VII isoenzymes.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266373008250723064558}, pmid = {40735986}, issn = {1873-4294}, abstract = {INTRODUCTION: CAs serve as crucial enzymes involved in a variety of physiological processes, including brain metabolism and cognitive function. hCA VII, a brain-associated isoform, plays an important role in modulating cerebral metabolism. Activating hCA VII may provide therapeutic benefits in Alzheimer's disease and other neurodegenerative or age-related illnesses. This study proposes to add to the growing interest in CAAs by developing innovative drugs with selective activation characteristics that target brain-associated CA isoforms. METHOD: A series of 4-arylazo-3,5-diamino-1H-pyrazoles have been produced by reacting aniline and aniline derivatives with a malononitrile solution at 0-5 °C, resulting in compounds 1(a-m). Then, arylazo malononitrile compounds were added with hydrazine monohydrate to obtain 4- arylazo-3,5-diamino-1H-pyrazole derivatives 2(a-m). The activity of the synthesized compounds was examined on human CA isoforms I, II, IV, and VII to determine activation potency and selectivity. RESULTS: The synthesized compounds demonstrated a wide spectrum of strong micromolar activation on human CA isoforms, with particularly encouraging results for hCA VII. The discovered activators showed a high selectivity profile for the brain-associated hCA VII isoform, indicating their potential use in neurological methods of therapy. DISCUSSION: Among the most compelling findings of this study is the unprecedented potency of several synthesized derivatives, particularly 2i and 2m, in selectively activating hCA VII far beyond the benchmark histamine, positioning them as promising pharmacological candidates for addressing CA-related neurological disorders. CONCLUSION: The research successfully discovered potent and selective CAAs with specific activity against hCA VII, a key enzyme in brain metabolism. These outcomes offer novel possibilities for developing medicinal products for neurological disorders and provide critical molecules for further study into CAAs. Furthermore, the study advances our understanding of enzyme activation kinetics and gives significant insights into the future of enzyme-based treatment research.}, } @article {pmid40735980, year = {2025}, author = {Agarwal, U and Tonk, RK and Verma, S}, title = {Pathogens Association with Alzheimer Disease: Emerging Concepts and New Perspectives.}, journal = {Current gene therapy}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115665232389348250722073721}, pmid = {40735980}, issn = {1875-5631}, abstract = {Alzheimer's Disease (AD) represents a significant global health challenge, distinguished by a complex pathology that involves the accumulation of abnormal proteins in the brain, leading to neuronal loss and brain atrophy. Recent research has indicated a potential association between various pathogens and the development of AD, suggesting that infectious pathogens may play a role in its pathology. The study focuses on the exploration of pathogens linked to AD. It aims to enhance the understanding of the disease's etiopathogenesis, which refers to the causes and development of the condition. The findings from this analysis have the potential to contribute to improved diagnostic methods and treatment strategies for AD. Overall, the manuscript highlights the importance of exploring infectious pathogens relating to neurodegenerative disorders. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to March 2025. Articles were searched based on keywords related to reviews and research exploring the association/link between different pathogens and AD, emerging interventions, preventive strategies, and limitations in study design. This study indicates that various viruses, bacteria, and fungi are significant contributors to the condition, while parasites and prions play a lesser role. Notably, the variability in pathogen species among patients could provide insights into the evolution and severity of clinical symptoms associated with the disease. Additionally, some studies propose that after modification, certain fungi may actually reduce the amyloid burden in Alzheimer's patients. However, it is crucial to emphasize that there is currently no definitive evidence supporting the notion that treating infections alone can prevent or cure AD. The prevention and treatment of pathogens, including viruses, bacteria, and fungi, as well as infectious prions, may play a significant role in reducing the risk of AD. Effective management of these pathogens can help to control and prevent further damage in individuals who have already been diagnosed with AD. There is a pressing need for additional pre-clinical and clinical research to deepen the understanding of the pathophysiological connections between pathogens and AD.}, } @article {pmid40735445, year = {2025}, author = {Khan, W and Khan, MS and Qasem, SN and Ghaban, W and Saeed, F and Hanif, M and Ahmad, J}, title = {An explainable and efficient deep learning framework for EEG-based diagnosis of Alzheimer's disease and frontotemporal dementia.}, journal = {Frontiers in medicine}, volume = {12}, number = {}, pages = {1590201}, pmid = {40735445}, issn = {2296-858X}, abstract = {The early and accurate diagnosis of Alzheimer's Disease and Frontotemporal Dementia remains a critical challenge, particularly with traditional machine learning models which often fail to provide transparency in their predictions, reducing user confidence and treatment effectiveness. To address these limitations, this paper introduces an explainable and lightweight deep learning framework comprising temporal convolutional networks and long short-term memory networks that efficiently classifies Frontotemporal dementia (FTD), Alzheimer's Disease (AD), and healthy controls using electroencephalogram (EEG) data. Feature engineering has been conducted using modified Relative Band Power (RBP) analysis, leveraging six EEG frequency bands extracted through power spectrum density (PSD) calculations. The model achieves high classification accuracies of 99.7% for binary tasks and 80.34% for multi-class classification. Furthermore, to enhance the transparency and interpretability of the framework, SHAP (SHapley Additive exPlanations) has been utilized as an explainable artificial intelligence technique that provides insights into feature contributions.}, } @article {pmid40735383, year = {2025}, author = {Luca, A and Luca, M and Ferri, R and Barbanti, M and Malaguarnera, R and Pecorino, B and Scollo, P and Serretti, A}, title = {Medical Comorbidities in Alzheimer's Disease: An Autopsy Confirmed Study with a Focus on Sex-Differences?.}, journal = {Clinical neuropsychiatry}, volume = {22}, number = {3}, pages = {207-214}, pmid = {40735383}, issn = {2385-0787}, abstract = {OBJECTIVE: Systemic comorbidities are common in Alzheimer's disease (AD) and may influence disease progression, severity, and management. Aim of the study was to assess the prevalence of comorbid medical conditions in a large cohort of AD patients, focusing on sex differences. METHOD: AD patients from the NIMH Alzheimer Disease Genetics Initiative were enrolled. Data on multimorbidity, demographics, disease characteristics, and clinical assessments were collected from interviews, medical records, and examinations. Univariate and multivariate logistic regression models were performed to identify possible associations between comorbidities and sex. Subgroup analysis was performed for patients with autopsy-confirmed AD. RESULTS: Four hundred and twenty-four AD patients (295 women; mean age: 78.4±8.3 years) were included. Men had a higher prevalence of heart disease, diabetes, chronic obstructive pulmonary disease and smoking, whereas thyroid disease, hypertension and depression were more common in women (all p<0.05). Except for hypertension, all associations found in the univariate analysis were confirmed in the multivariate analysis after adjustment for age. Subgroup analysis of autopsy-confirmed cases confirmed these findings. CONCLUSIONS: Our findings support the importance of considering sex-specific comorbidities in AD for precision medicine and emphasize the need for comprehensive assessment of comorbidities to improve clinical outcomes, treatment strategies and health equity.nt.}, } @article {pmid40734951, year = {2025}, author = {Yang, JC and Kuo, PJ and Chang, C and Wang, YM and Ou, YC and Cheng, YC and Wu, SC and Chien, PC and Hsieh, CH and Lin, WC}, title = {Linking Lymphedema, Chronic Inflammation, Oxidative Stress, Alzheimer Disease, and Potential Role of Lymphaticovenous Anastomosis.}, journal = {Plastic and reconstructive surgery. Global open}, volume = {13}, number = {7}, pages = {e6955}, pmid = {40734951}, issn = {2169-7574}, abstract = {BACKGROUND: Lymphedema and Alzheimer disease (AD) share common mechanisms involving oxidative stress and chronic inflammation. However, the link between these 2 conditions and the impact of lymphaticovenous anastomosis (LVA) has not been fully explored. This study aimed to evaluate their association by examining changes in AD biomarkers, inflammatory cytokines, and oxidative stress markers before and after LVA. METHODS: Twenty-four patients with unilateral lower limb lymphedema who underwent LVA as primary treatment and 18 healthy controls were recruited. Exclusion criteria included previous LVA, liposuction, or excisional surgery. Venous blood samples were obtained before and 1 month after LVA. RESULTS: After matching, 15 patients remained in each group. The lymphedema group had significantly elevated levels of t-tau (p < 0.001), amyloid beta (Aβ)1-40 (P = 0.033), Aβ1-42 (P = 0.033), Aβ1-42 × t-tau (P < 0.001), and Aβ1-42/Aβ1-40 ratio (P = 0.021) compared with controls. One month post-LVA, there were significant reductions in t-tau (P = 0.007) and Aβ1-42 × t-tau (P = 0.002), and a notable increase in brain-derived neurotrophic factor (P = 0.006). Post-LVA samples also showed significant improvements in antioxidative enzymes, antioxidant capacity, and reductions in lipid peroxidation. Inflammatory cytokine levels were also significantly reduced, indicating decreased oxidative stress and inflammation. The median follow-up period was 6.3 months. CONCLUSIONS: Findings suggest a possible association between lymphedema and increased AD risk possibly linked to elevated oxidative stress and inflammation. LVA may modulate this risk by reducing AD biomarkers and systemic inflammation/oxidative stress, supporting further investigation into its neuroprotective potential.}, } @article {pmid40734473, year = {2025}, author = {Prajapat, M and Sarma, P and Kaur, G and Choudhary, G and Jain, S and Kamal, R and Bains, O and Sangwan, N and Prakash, A and Medhi, B}, title = {Therapeutic potential of 6BIO and DKK1-LRP6 inhibitor in Wnt/β-catenin pathway modulation for amyloid-β-induced Alzheimer's disease model.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {857-878}, doi = {10.1177/13872877251362787}, pmid = {40734473}, issn = {1875-8908}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; Amyloid beta-Peptides/toxicity ; Humans ; *Low Density Lipoprotein Receptor-Related Protein-6/antagonists & inhibitors/metabolism ; Male ; Rats, Wistar ; *Wnt Signaling Pathway/drug effects/physiology ; Rats ; Peptide Fragments/toxicity ; Disease Models, Animal ; Cell Line, Tumor ; *Intercellular Signaling Peptides and Proteins/metabolism ; }, abstract = {BackgroundThe Wnt/β-catenin signaling pathway plays a crucial role in central nervous system development, with emerging evidence linking its dysregulation to the progression of Alzheimer's disease (AD).ObjectiveThis study investigates the activation of Wnt signaling by targeting GSK3β and the DKK1/LRP6 interaction using a combination of 6BIO (6Bromoindirubin-3-oxime) and a novel gallocyanine derivative (8e) modulator.MethodsWe identified the interaction energy scores of both modulators with target proteins through an in-silico approach. Furthermore, the effects of 6BIO (10 µM) and 8e (20 µM) were assessed in SH-SY5Y cells treated with Aβ1-42 (20 µM). The efficacy of these modulators was also evaluated in male Wistar rats through dose-ranging studies. An Alzheimer's disease model was established via intracerebroventricular injection of Aβ1-42, followed by treatment with 6BIO (23.8 µg/kg/day, i.p.) and 8e (4.2 mg/kg/day, i.p.).ResultsBoth modulators demonstrated favorable binding energy scores and dynamic simulation results against the targeted proteins. In Aβ1-42-treated SHSY5Y cells, the combination of 6BIO and 8e significantly reduced reactive oxygen species production and apoptotic activity while modulating protein expression. In vivo study, rats treated with combination of 6BIO and 8e modulators exhibited improved neurobehavioral activity compared to AD model rats, along with altered expression of DKK1, β-catenin, p-tau, and pGSK3β. Additionally, decreased oxidative stress and apoptosis markers.ConclusionsThese findings suggest that the combined targeting of GSK3β and LRP6 represents a promising therapeutic strategy for AD. The combination of 6BIO and 8e shows potential as a novel modulator and warrants further investigation in clinical trials to assess its therapeutic efficacy.}, } @article {pmid40734451, year = {2025}, author = {Wang, H and Yang, Q and Ge, C and Liu, J and Mistry, H and Jia, YF and He, G}, title = {Integrated transcriptomic and proteomic analysis identifies FBXW7 as a key regulator of tau homeostasis in Alzheimer's disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {542-560}, doi = {10.1177/13872877251361042}, pmid = {40734451}, issn = {1875-8908}, mesh = {*F-Box-WD Repeat-Containing Protein 7/genetics/metabolism ; *Alzheimer Disease/metabolism/genetics ; Humans ; *tau Proteins/metabolism/genetics ; Proteomics/methods ; Homeostasis/physiology ; *Transcriptome ; Male ; Animals ; Mice ; Female ; }, abstract = {BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder driven by complex, incompletely understood genetic and pathogenic factors. E3 ubiquitin ligases (E3s), crucial for protein degradation, are implicated in AD, but their specific contributions to its progression remain to be elucidated.ObjectiveThis study aimed to identify dysregulated E3s in AD and elucidate the role of a hub E3, FBXW7, in its pathogenesis and tau protein regulation.MethodsWe integrated four datasets to identify differentially expressed E3s (DE-E3s) in AD and performed functional enrichment and PPI network analyses. Machine learning identified hub E3s and stratified AD patients into molecular subtypes. Furthermore, we validated the expression and functional role of FBXW7 using western blot, immunoprecipitation-mass spectrometry (IP-MS), and co-immunoprecipitation (Co-IP).ResultsWe identified 42 DE-E3s primarily enriched in protein ubiquitination and Notch signaling pathways. FBXW7 and ENC1 emerged as hub E3s, stratifying patients into two subtypes. Subtype I exhibited enrichment of inflammatory pathways, suggesting immune dysregulation. Conversely, subtype II displayed activation of pathways associated with synaptic dysfunction and neuronal loss, potentially representing distinct primary pathological features. Furthermore, we observed decreased FBXW7 expression in AD models compared to controls. Notably, FBXW7 interacted with Tau protein. Overexpression of FBXW7 reduced the levels of both total Tau and p-Tau Ser262, and this reduction in Tau levels was reversed by MG132 treatment.ConclusionsThis study comprehensively identified E3s associated with AD, with our findings highlighting FBXW7 as a potential key regulator of AD pathogenesis through its modulation of tau protein levels.}, } @article {pmid40734422, year = {2025}, author = {Miles, LA and Masters, CL}, title = {The structural foundations of anti-amyloid-β immunotherapies: Unravelling antibody-antigen interactions in Alzheimer's disease treatment.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {393-408}, doi = {10.1177/13872877251361049}, pmid = {40734422}, issn = {1875-8908}, mesh = {*Alzheimer Disease/immunology/drug therapy/therapy ; Humans ; *Amyloid beta-Peptides/immunology/metabolism/antagonists & inhibitors ; *Immunotherapy/methods ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Antibodies, Monoclonal/therapeutic use ; Structure-Activity Relationship ; }, abstract = {BackgroundAnti-amyloid-β (Aβ) immunotherapies are emerging as treatments for Alzheimer's disease (AD).ObjectiveThis review examines the structure-activity relationships of anti-Aβ therapeutics tested in phase 3 trials.MethodsWe analyzed crystallographic data and molecular models to elucidate the Aβ binding mechanisms of donanemab, lecanemab, aducanumab, bapineuzumab, gantenerumab, solanezumab, and crenezumab.ResultsLecanemab recognizes minimally degraded Aβ missing 1-2 residues, avoiding common Aβ in circulation and further degraded material sequestered in plaques. Bapineuzumab buries the N-terminus of Aβ requiring Asp1 and is reactive with benign, common Aβ. Donanemab buries the truncated N-Glu3 terminus with strong contacts engaging the cyclized pyro-Glu3 modification. Gantenerumab shows lecanemab-like properties but also binds common Aβ. Aducanumab likely needs mAb-mAb cooperation to scavenge a spectrum of Aβ oligomers explaining higher doses. Solanezumab and crenezumab target a pre-amyloid epitope resulting in off-target engagement, including monomers and likely excluding Aβ-ApoE complexes.ConclusionsPreventing primary Aβ nucleation failed due to limitations imposed by the blood-brain barrier, intracellular aggregation routes, and the natural abundance of Aβ. Anti-Aβ monoclonal antibody therapies in clinical use capture Aβ at various stages of decay where post translational modifications have been used effectively as proxies for time spent in vivo. By targeting a relatively labile epitope of aging Aβ, lecanemab selects more biologically active species of Aβ avoiding both benign monomers and old fortified species. This focal point may account for the significant cognitive effects of lecanemab. The structure of aducanumab suggests a broadly neutralizing role has evolved for natural immunity to AD.}, } @article {pmid40734174, year = {2025}, author = {Zare, A and Salehi, S and Bader, JM and Wiessler, AL and Prokesch, M and Albrecht, V and Villmann, C and Mann, M and Briese, M and Sendtner, M}, title = {Axonal tau reduction ameliorates tau and amyloid pathology in a mouse model of Alzheimer's disease.}, journal = {Translational neurodegeneration}, volume = {14}, number = {1}, pages = {39}, pmid = {40734174}, issn = {2047-9158}, support = {BR4910/2-2//Deutsche Forschungsgemeinschaft/ ; SE697/5-2//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Animals ; *tau Proteins/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology/genetics ; Disease Models, Animal ; *Axons/metabolism/pathology ; Mice ; Mice, Knockout ; Humans ; *Plaque, Amyloid/pathology/metabolism ; Brain/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Cells, Cultured ; Neurons/metabolism ; Mice, Transgenic ; }, abstract = {BACKGROUND: Pathological deposition of hyperphosphorylated tau in the brain closely correlates with the course of Alzheimer's disease (AD). Tau pathology occurs in axons of affected neurons and tau removal from axons might thus be an early intervention strategy. METHODS: We investigated the role of the RNA-binding protein hnRNP R in axonal localization and local translation of Mapt mRNA in neurons cultured from hnRNP R knockout mice. hnRNP R knockout mice were crossed with 5×FAD mice, an AD mouse model, and the effects of hnRNP R loss on the deposition of phospho-tau and amyloid-β plaques were evaluated. We designed antisense oligonucleotides (MAPT-ASOs) to block the binding of hnRNP R to Mapt mRNA. Cultured mouse and human neurons were treated with MAPT-ASOs and axonal Mapt mRNA and tau protein levels were quantified. MAPT-ASO was injected intracerebroventricularly into 5×FAD mice followed by quantification of phospho-tau aggregates and amyloid-β plaques in their brains. Protein changes in brains of 5×FAD mice treated with the MAPT-ASO were measured by mass spectrometry. RESULTS: Mapt mRNA and tau protein were reduced in axons but not cell bodies of primary neurons cultured from hnRNP R knockout mice. Brains of 5×FAD mice deficient for hnRNP R contained less phospho-tau aggregates and amyloid-β plaques in the cortex and hippocampus. Treatment of neurons with MAPT-ASOs to block hnRNP R binding to Mapt similarly reduced axonal tau levels. Intracerebroventricular injection of a MAPT-ASO reduced the phospho-tau and plaque load and prevented neurodegeneration in the brains of 5×FAD mice, accompanied by rescue of proteome alterations. CONCLUSION: Lowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.}, } @article {pmid40733241, year = {2025}, author = {Asim, A and Jastrzębski, MK and Kaczor, AA}, title = {Dual Inhibitors of Acetylcholinesterase and Monoamine Oxidase-B for the Treatment of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {14}, pages = {}, pmid = {40733241}, issn = {1420-3049}, support = {2021/43/B/NZ7/01732//National Science Center/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism/enzymology ; *Monoamine Oxidase Inhibitors/chemistry/therapeutic use/pharmacology ; Humans ; *Cholinesterase Inhibitors/chemistry/therapeutic use/pharmacology ; *Monoamine Oxidase/metabolism/chemistry ; *Acetylcholinesterase/metabolism/chemistry ; Structure-Activity Relationship ; Animals ; Molecular Structure ; }, abstract = {Alzheimer's disease (AD) is a multi-factorial neurodegenerative disease with a complex pathomechanism that can be best treated with multi-target medications. Among the possible molecular targets involved in AD, acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) are well recognized because they control the neurotransmitters responsible for memory processes. This review discusses the current understanding of AD pathology, recent advances in AD treatment, and recent reports in the field of dual AChE/MAO-B inhibitors for treating AD. We provide a classification of dual inhibitors based on their chemical structure and describe active compounds belonging to, i.a., chalcones, coumarins, chromones, imines, and hydrazones. Special emphasis is given to the computer-aided strategies of dual inhibitors design, their structure-activity relationships, and their interactions with the molecular targets at the molecular level.}, } @article {pmid40732328, year = {2025}, author = {Alghamdi, MA}, title = {From Molecules to Medicines: The Role of AI-Driven Drug Discovery Against Alzheimer's Disease and Other Neurological Disorders.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {7}, pages = {}, pmid = {40732328}, issn = {1424-8247}, support = {IMSIU-DDRSP2501//Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University/ ; }, abstract = {The discovery of effective therapeutics against Alzheimer's disease (AD) and other neurological disorders remains a significant challenge. Artificial intelligence (AI) tools are of considerable interest in modern drug discovery processes and, by exploiting machine learning (ML) algorithms and deep learning (DL) tools, as well as data analytics, can expedite the identification of new drug targets and potential lead molecules. The current study was aimed at assessing the role of AI-based tools in the discovery of new drug targets against AD and other related neurodegenerative diseases and their efficacy in the discovery of new drugs against these diseases. AD represents a multifactorial neurological disease with limited therapeutics available for management and limited efficacy. The discovery of more effective medications is limited by the complicated pathophysiology of the disease, involving amyloid beta (Aβ), neurofibrillary tangles (NFTs), oxidative stress, and inflammation-induced damage in the brain. The integration of AI tools into the traditional drug discovery process against AD can help to find more effective, safe, highly potent compounds, identify new targets of the disease, and help in the optimization of lead molecules. A detailed literature review was performed to gather evidence regarding the most recent AI tools for drug discovery against AD, Parkinson's disease (PD), multiple sclerosis (MLS), and epilepsy, focusing on biological markers, early diagnoses, and drug discovery using various databases like PubMed, Web of Science, Google Scholar, Scopus, and ScienceDirect to collect relevant literature. We evaluated the role of AI in analyzing multifaceted biological data and the properties of potential drug candidates and in streamlining the design of clinical trials. By exploring the intersection of AI and neuroscience, this review focused on providing insights into the future of AD treatment and the potential of AI to revolutionize the field of drug discovery. Our findings conclude that AI-based tools are not only cost-effective, but the success rate is extremely high compared to traditional drug discovery methods in identifying new therapeutic targets and in the screening of the majority of molecules for clinical trial purposes.}, } @article {pmid40732267, year = {2025}, author = {Liu, C and Wang, X and Xu, W and Yu, S and Zhang, Y and Xu, Q and Tan, X}, title = {Study on the Pharmacological Efficacy and Mechanism of Dual-Target Liposome Complex AD808 Against Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {7}, pages = {}, pmid = {40732267}, issn = {1424-8247}, support = {32471351//National Science Foundation of China/ ; }, abstract = {Background/Objectives: To study the efficacy and pharmacological mechanism of the dual-target liposome complex AD808 in the treatment of Alzheimer's disease. Methods: Using APP/PS1 mouse models, the therapeutic efficacy and pharmacological mechanism of AD808 on Alzheimer's disease were studied through water maze tests, brain tissue staining, immunofluorescence, and ELISA for inflammatory and neurotrophic factors. Results: AD808 exhibited significant pharmacodynamic effects in improving behavioral and cognitive abilities (70% reduction in escape latency) and repairing damaged nerve cells (90% reduction in Aβ plaque) in Alzheimer's disease mice. The efficacy of the liposome complex AD808 was significantly better than that of ST707 or gh625-Zn7MT3 alone. AD808 significantly reduced brain inflammation (57.3% and 61.5% reductions in TNF-α and IL-1β, respectively) in AD (Alzheimer's disease) mouse models and promoted the upregulation of neurotrophic factors and nerve growth factors (142.8% increase in BDNF, 275.9% in GDNF, and 111.3% in NGF-1) in brain homogenates. By activating the PI3K/AKT signaling pathway in brain microglia, AD808 upregulated TREM2 protein expression and removed Aβ amyloid plaques in the brain. Additionally, it promoted the transition of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, regulated the M1/M2 balance, released anti-inflammatory and neurotrophic factors, reduced chronic inflammation, and enhanced neurological repair. Based on these results, the potential pharmacological mechanism of AD808 against Alzheimer's disease was proposed. Conclusions: As a dual-target liposome complex, AD808 has shown promising therapeutic potential in the treatment of Alzheimer's disease, providing a new strategy for innovative drug development.}, } @article {pmid40732244, year = {2025}, author = {Wiśniewski, K and Zglejc-Waszak, K and Antonowski, T and Szablinska-Piernik, J and Juskiewicz, J and Lahuta, L and Jozwik, M and Wojtkiewicz, J}, title = {Analysis of Scyllo-Inositol in a Wistar Rat Animal Model-A Preliminary Study.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {18}, number = {7}, pages = {}, pmid = {40732244}, issn = {1424-8247}, support = {RID/SP/0025/2024/01//the Minister of Science under "the Regional Initiative of Excellence Program/ ; }, abstract = {Background: Scyllo-inositol (SCI) is a naturally occurring carbocyclic sugar implicated in many biological processes. Studies have highlighted the potential of using SCI in Alzheimer's therapy. However, in order to fully use this compound in the treatment of neurovegetative diseases, its pharmacokinetics must be thoroughly understood. Objectives: We undertook the task of analyzing SCI in a Wistar rat animal model. The aim of this study was to observe the changes in SCI concentration after oral administration. Methods: All rats received 10 mg/kg of SCI as a solution in distilled water by oral gavage. Estimated parameters were based on the serum concentration of SCI observed in six individual rats with regard to time. Results: The first peak concentration appeared at 30 min for SCI. Thereafter, the serum SCI concentration increased rapidly and reached its highest level after approximately 1.5 h. There was no second peak in SCI concentration. The elimination half-life was determined to be 10.07 h and the mean residence time was 14.52 h. There were no side effects of SCI supplementation noticed during the study. Conclusions: Although our results present an analysis of SCI immediately after oral administration up to 48 h, further studies are necessary.}, } @article {pmid40731203, year = {2025}, author = {Gao, H and Jensen, K and Nesbitt, J and Ostroot, M and Cary, GA and Wiley, J and Trushin, S and Watzlawik, JO and Springer, W and Galkin, A and Baloni, P and Funk, C and Trushina, E}, title = {Mitochondrial complex I deficiency induces Alzheimer's disease-like signatures that are reversible by targeted therapy.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {8}, pages = {e70519}, pmid = {40731203}, issn = {1552-5279}, support = {RF1AG55549/NH/NIH HHS/United States ; //Michael J. Fox Foundation for Parkinson's Research/ ; W81XWH-17-1-0248//Department of Defense Congressionally Directed Medical Research Programs/ ; R01 NS131322/NS/NINDS NIH HHS/United States ; RF1 AG062135/AG/NIA NIH HHS/United States ; R01NS112381/NH/NIH HHS/United States ; R56 AG062556/AG/NIA NIH HHS/United States ; //Ted Nash Long Life Foundation/ ; R01NS110085/NH/NIH HHS/United States ; RO1AG062135/NH/NIH HHS/United States ; U54 AG065187/AG/NIA NIH HHS/United States ; RO1AG59093/NH/NIH HHS/United States ; R01NS131322/NH/NIH HHS/United States ; U54NS110435/NH/NIH HHS/United States ; R56AG062556/NH/NIH HHS/United States ; RF1NS085070/NH/NIH HHS/United States ; Emory-Sage-SGC-JAX U54AG065187//National Institute of Health Target Enablement to Accelerate Therapy Development for Alzheimer's Disease Consortia/ ; R01 NS110085/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/drug therapy ; *Electron Transport Complex I/deficiency/genetics ; Mice ; Disease Models, Animal ; Female ; Humans ; Male ; Mice, Knockout ; *Mitochondrial Diseases/genetics/metabolism/complications ; Mitochondria/metabolism ; Brain/metabolism ; Transcriptome ; }, abstract = {INTRODUCTION: Mitochondrial dysfunction is implicated in Alzheimer's disease (AD), but whether it drives AD-associated changes is unclear. We assessed transcriptomic alterations in the brains of Ndufs4[-/-] mice, a model of mitochondrial complex I (mtCI) deficiency, and evaluated the therapeutic effects of the neuroprotective mtCI inhibitor CP2. METHODS: Cortico-hippocampal tissue from Ndufs4[-/-] and wild-type mice was subjected to transcriptomic analysis, followed by cross-species comparisons to human late-onset AD and familial AD mouse datasets. RESULTS: Knockout of Ndufs4-mediated mtCI deficiency disrupted mitochondrial homeostasis, energy metabolism, and synaptic gene expression, recapitulating transcriptomic signatures of AD. CP2 treatment partially reversed these changes, with female Ndufs4[-/-] mice showing greater compensatory adaptations and treatment responses. DISCUSSION: Loss of mtCI activity alone is sufficient to induce AD-like molecular changes in the brain, independent of amyloid beta or phosphorylated tau. CP2-mediated rescue highlights the potential of targeting mitochondria as a therapeutic strategy for AD. Sex-specific responses suggest important considerations for personalized therapeutics. HIGHLIGHTS: Activity of mitochondrial complex I (mtCI) affects broad mitochondrial and neuronal transcriptional networks. A reduction of mtCI activity is sufficient to induce transcriptomic changes reminiscent of those observed in late-onset Alsheimer's disease (AD) patients and familial mouse models of AD. Pharmacological targeting of mtCI mediates neuroprotective signaling. Male and female mice have differential responses to the loss of mtCI activity and to the mitochondria-targeted therapeutics. Mitochondria play a key role in AD development and treatment.}, } @article {pmid40731005, year = {2025}, author = {Ghaderi Yazdi, B and Razlighi, QR}, title = {Translation of task-evoked negative BOLD response into aging and Alzheimer's disease: a systematic review of the current literature.}, journal = {Journal of translational medicine}, volume = {23}, number = {1}, pages = {850}, pmid = {40731005}, issn = {1479-5876}, support = {R01AG085972/AG/NIA NIH HHS/United States ; R01AG057962/AG/NIA NIH HHS/United States ; K01AG044467/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging/blood ; *Magnetic Resonance Imaging ; *Aging/physiology ; *Oxygen/blood ; Cognitive Dysfunction/physiopathology ; }, abstract = {BACKGROUND: Aging, mild cognitive impairment (MCI), Alzheimer's disease (AD), and individuals at risk for AD are associated with impaired negative blood-oxygen-level-dependent (BOLD) response (NBR) in task-evoked functional magnetic resonance imaging (fMRI) studies. In addition, autosomal dominant AD patients have exhibited NBR alterations in the default mode network (DMN) regions nearly a decade before any accumulation of amyloid-β (Aβ) or tau and subsequent memory decline. Studies examining exclusively the NBR are rare in clinical settings, but some existing studies using task-evoked fMRI also report alterations in the NBR. However, in many studies, NBR is often disregarded, left lingering in the shadows, or, more generally, masked out as a bothersome noise. METHODS: We reviewed the Embase, Scopus, and PubMed databases, and forward and backward citation tracking for studies published up to 6/11/2024. Included articles detailed the use of task-evoked fMRI (tb-fMRI) to investigate aging, AD, mild cognitive impairment (MCI), and early tau or Aβ deposition, with all results reported on NBR. FINDINGS: From 319 records identified for aging, 154 records for tau or Aβ, and 159 records for AD and MCI, 42, 14, and 9 papers were included, respectively. Forward and backward citation tracking added 44, 3, and 55 papers, respectively resulting in 167 studies with 11310 individuals. A significantly reduced magnitude of NBR in some regions of the DMN in healthy aging compared with young participants and individuals with elevated Aβ levels, MCI, and AD compared to healthy aging was found in 57, 12, 17, and 14 studies, respectively. INTERPRETATION: This review highlights the DMN NBR's importance in the AD continuum and underscores its potential as an early diagnostic biomarker when pharmacological treatment options can still alter the disease course.}, } @article {pmid40730714, year = {2025}, author = {Xia, X and Aye, S and Frisell, O and Aho, E and Handels, R and Li, Y and Wimo, A and Winblad, B and Eriksdotter, M and Skillbäck, TB and Kern, S and Zetterberg, H and Jönsson, L}, title = {The Cost-Effective Price of Lecanemab for Patients with Early Alzheimer's Disease in Sweden.}, journal = {PharmacoEconomics}, volume = {43}, number = {10}, pages = {1251-1266}, pmid = {40730714}, issn = {1179-2027}, support = {101112145//The Innovative Health Initiative Joint Undertaking/ ; 2021-02680//VINNOVA/ ; 2024-03573//Vetenskapsrådet/ ; 2023-00356//Vetenskapsrådet/ ; 2022-01018//Vetenskapsrådet/ ; 2019-02397//Vetenskapsrådet/ ; 2019-02075//Vetenskapsrådet/ ; 2019-02075_15//Vetenskapsrådet/ ; FO2024-0287//Swedish Brain Foundation/ ; FO2024-0097//Swedish Brain Foundation/ ; FO2024-0339//Swedish Brain Foundation/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; ALFGBG-81392//Swedish State Support for Clinical Research/ ; ALFGBG-771071//Swedish State Support for Clinical Research/ ; ALFGBG-1005471//Swedish State Support for Clinical Research/ ; ALFGBG-965923//Swedish State Support for Clinical Research/ ; AF-842471//Alzheimerfonden/ ; AF-737641//Alzheimerfonden/ ; AF-929959//Alzheimerfonden/ ; AF-939825//Alzheimerfonden/ ; 2024-03599//Swedish Research Council/ ; }, mesh = {Humans ; Sweden ; *Alzheimer Disease/drug therapy/economics ; *Antibodies, Monoclonal, Humanized/economics/therapeutic use ; Cost-Effectiveness Analysis ; Markov Chains ; Quality-Adjusted Life Years ; *Drug Costs ; Models, Economic ; Quality of Life ; Male ; Female ; Age Factors ; Sex Factors ; }, abstract = {INTRODUCTION: We sought to estimate the cost-effective price for lecanemab for treating early Alzheimer's disease in Sweden from the perspective of formal care payers. METHODS: We developed a Markov model with states defined by disease severity and care setting. The model was populated by integrated clinical and economic data from Swedish registers. We included patients with biomarker-confirmed Alzheimer's disease and fitted survival models for transitions between model states. Costs in 2023 Swedish kronor (SEK), life-years (LYs), and quality-adjusted LYs (QALYs) over a 10-year time horizon were estimated for standard of care and for lecanemab in addition to standard of care, assuming a maximum treatment duration of 3 years with lecanemab and no treatment effect after treatment stops. We also explored the impact of different assumptions regarding treatment efficacy and duration. RESULTS: Treatment with lecanemab over 3 years resulted in 0.13 LYs gained, 0.17 QALYs gained, and a net cost increase of 87,146 SEK (€1 = 11.5 SEK, $US1 = 10.6 SEK) due to administration and monitoring, before considering the cost of drug. The cost-effective price of lecanemab at a willingness-to-pay level of 1 million SEK per QALY was 33,886 SEK per year of treatment. The health gain, net costs, and cost-effective price of lecanemab varied significantly by treatment duration, potential residual effects, and patient characteristics. CONCLUSIONS: The future price of lecanemab in European countries is unknown. However, treatment with lecanemab is unlikely to be cost effective in Sweden at the levels of current list prices in the USA.}, } @article {pmid40730660, year = {2025}, author = {Kumar, S and Song, K and Wang, J and Baghel, MS and Zeng, Y and Shen, K and Zheng, J and Crane, J and Demehri, S and Gao, P and Jain, A and Skolasky, RL and Wong, P and Cao, X and Wan, M}, title = {Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis.}, journal = {Nature aging}, volume = {5}, number = {9}, pages = {1771-1789}, pmid = {40730660}, issn = {2662-8465}, support = {P01AG066603//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P01 AG066603/AG/NIA NIH HHS/United States ; R01AG068226//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG072090/AG/NIA NIH HHS/United States ; R01AG072090//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 AG068226/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Serum Amyloid P-Component/metabolism ; *Amyloidosis/metabolism/pathology ; *Adipocytes/metabolism/pathology ; Mice ; Mice, Transgenic ; *Aging/pathology/metabolism ; Alzheimer Disease/metabolism/pathology ; C-Reactive Protein/metabolism ; Amyloid beta-Peptides/metabolism ; *Bone Marrow Cells/metabolism ; Humans ; Mice, Inbred C57BL ; Male ; }, abstract = {The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on organ aging. Here, we demonstrate that both transgenic Alzheimer's disease (AD) mice and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits. Senescent BMAds acquire a secretory phenotype, markedly increasing secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAds in vivo and promotes insoluble amyloid formation from soluble amyloid-β (Aβ) peptides in in vitro and ex vivo three-dimensional (3D) BMAd-based cultures. Combined SAP/PTX2 and Aβ treatment promotes osteoclastogenesis but inhibits osteoblastogenesis. Transplanting senescent BMAds into the bone marrow cavity of young mice induces bone loss, which is reversed by senolytic treatment. Finally, depleting SAP/PTX2 in aged mice abolishes marrow amyloid deposition and rescues low bone mass. Thus, senescent BMAds drive age-related skeletal amyloidosis and bone deficits via SAP/PTX2.}, } @article {pmid40730291, year = {2025}, author = {Magdalena, R and Ferrada, L and Ramírez, E and Smith-Ghigliotto, JF and Salazar, K and Nualart, F}, title = {Dehydroascorbic acid impairs neurite growth through RIPK1-associated caspase activation.}, journal = {Free radical biology & medicine}, volume = {239}, number = {}, pages = {406-416}, doi = {10.1016/j.freeradbiomed.2025.07.036}, pmid = {40730291}, issn = {1873-4596}, mesh = {*Receptor-Interacting Protein Serine-Threonine Kinases/metabolism/genetics ; *Neurites/drug effects/metabolism/pathology ; Animals ; *Dehydroascorbic Acid/pharmacology ; Enzyme Activation/drug effects ; Apoptosis/drug effects ; Reactive Oxygen Species/metabolism ; Imidazoles/pharmacology ; Indoles/pharmacology ; *Caspases/metabolism ; Mice ; Amino Acid Chloromethyl Ketones/pharmacology ; Ascorbic Acid ; Antioxidants/pharmacology ; Humans ; }, abstract = {Axonal and neurite loss is a common event in neurodegenerative diseases, such as Alzheimer's disease or amyotrophic lateral sclerosis, which are enhanced by oxidative damage and reactive oxygen species (ROS) production. In the central nervous system, vitamin C can be found as ascorbic acid (AA), its reduced form, or dehydroascorbic acid (DHA), its oxidized form. Vitamin C mainly acts as an antioxidant agent, and homeostasis in the brain is maintained through its recycling between neurons and astrocytes. However, DHA accumulation under pathophysiological conditions has been associated with changes in neuronal metabolism and necroptotic cell death through RIPK1 activation. Furthermore, recent studies show that DHA accumulation induces significant neurite loss; however, it is unknown whether this effect is associated with RIPK1 activation. Here, we show that DHA treatment on neurospheres (NE) in vitro induces significant neurite shortening and reduced branching, effects associated with early RIPK1 activation and inhibited through Necrostatin-1s and zVAD-FMK treatment, suggesting the activation of apoptotic mechanisms. Finally, we propose DHA, the oxidized form of vitamin C, impairs neurite growth through ripk1-associated caspase activation.}, } @article {pmid40729740, year = {2025}, author = {Hu, L and Li, J and Guo, H and Su, L and Dong, P and Huang, J and Liu, Y and Liu, X and Luo, Z and Xiong, W and Ju, Z and Zhou, Q and Wang, H and Wang, W}, title = {SENP6 Maintains Mitochondrial Homeostasis by Regulating Mitochondrial Protein Import Through deSUMOylation of TOM40.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {40}, pages = {e03408}, pmid = {40729740}, issn = {2198-3844}, support = {2021YFA08049000//National Key Research and Development Program of China/ ; 32430049//National Natural Science Foundation of China/ ; 82370576//National Natural Science Foundation of China/ ; 82370596//National Natural Science Foundation of China/ ; 32170772//National Natural Science Foundation of China/ ; 32270810//National Natural Science Foundation of China/ ; 92049304//National Natural Science Foundation of China/ ; 82030039//National Natural Science Foundation of China/ ; 82071340//National Natural Science Foundation of China/ ; 82401526//National Natural Science Foundation of China/ ; 2022A1515140040//Guangdong Basic and Applied Basic Research Foundation/ ; 2023B1515120089//Guangdong Basic and Applied Basic Research Foundation/ ; 2021A1515011227//Guangdong Basic and Applied Basic Research Foundation/ ; 2022A0505050041//Guangdong Basic and Applied Basic Research Foundation/ ; }, mesh = {*Mitochondria/metabolism/genetics ; Animals ; Mice ; Homeostasis ; Sumoylation ; Humans ; Mitochondrial Precursor Protein Import Complex Proteins/metabolism ; Alzheimer Disease/metabolism/genetics ; *Cysteine Endopeptidases/metabolism/genetics ; *Mitochondrial Proteins/metabolism ; Protein Transport ; Mice, Transgenic ; Proteostasis ; }, abstract = {SUMOylation, a reversible post-translational modification, regulates various mitochondrial processes, including biogenesis, dynamics, mitophagy, and the mitochondrial unfolded protein response. Although SUMOylation is shown to be triggered by mitochondrial protein import failure in yeast, its impact on mammalian mitochondrial protein import remains unclear. Here, it is demonstrated that SENP6 knockdown-induced SUMOylation causes loss of mitochondrial proteostasis, which impairs mitochondrial morphology and function. Mechanistically, SENP6 knockdown dampens TOM complex assembly by SUMOylating TOM40, thereby hindering the mitochondrial protein import process, including TOM40 precursor, and ultimately disrupts mitochondrial homeostasis. Additionally, it is observed that CCCP treatment resulted in a decrease of SENP6 within mitochondria fraction, accompanied by increased TOM40 SUMOylation in the brains of 3×Tg-Alzheimer's disease (AD) mice or Aβ1-42 peptide-stimulated cells. Collectively, the results suggest that Aβ1-42 accumulation may enhance TOM40 SUMOylation by suppressing SENP6, thereby impairing mitochondrial homeostasis through protein import failure and potentially contributing to the pathological process of AD. This study elucidates the role of TOM40 SUMOylation/deSUMOylation in regulating the mitochondrial import process during mitochondrial stress.}, } @article {pmid40728824, year = {2025}, author = {Helal, MM and Almosilhy, NA and Hamam, NG and Abdelbaset, MAA and Shelbaya, AN and Musse, HAY and Prasad, A}, title = {Sacubitril/Valsartan Reduces the Risk of All-Cause Dementia in Patients with Heart Failure: A Systematic Review and Meta-Analysis.}, journal = {Drugs & aging}, volume = {42}, number = {10}, pages = {907-920}, pmid = {40728824}, issn = {1179-1969}, mesh = {Humans ; *Heart Failure/drug therapy/complications ; *Biphenyl Compounds/therapeutic use/adverse effects ; Drug Combinations ; *Aminobutyrates/therapeutic use/adverse effects ; *Valsartan/therapeutic use/adverse effects ; *Dementia/prevention & control ; *Angiotensin Receptor Antagonists/therapeutic use/adverse effects ; Neprilysin/antagonists & inhibitors ; }, abstract = {BACKGROUND: Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), has become a cornerstone therapy for heart failure (HF) since its approval over a decade ago. However, concerns have emerged about potential cognitive risks, as neprilysin inhibition may contribute to the accumulation of amyloid-beta (Aβ) in the brain-a hallmark of Alzheimer's disease, the most common form of dementia. OBJECTIVE: Given the already elevated risk of dementia in patients with HF and the widespread use of sacubitril/valsartan, this meta-analysis aimed to evaluate whether its use is associated with an increased risk of all-cause dementia in HF populations. METHODS: A systematic literature search was conducted on 23 March 2025, to identify eligible studies comparing the risk of dementia in patients receiving sacubitril/valsartan versus those receiving placebo, no treatment, or other HF medications. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model. RESULTS: Six studies, comprising 101,074 participants and published between 2017 and 2024, were included in the meta-analysis. Treatment with sacubitril/valsartan was associated with a significant 15% reduction in the risk of all-cause dementia (RR = 0.85; 95% CI: 0.74-0.98; p = 0.02). Leave-one-out sensitivity and subgroup analyses confirmed the robustness of the findings. CONCLUSIONS: This meta-analysis suggests that sacubitril/valsartan is associated with a reduced risk of dementia in patients with HF, helping to alleviate previous concerns about potential cognitive adverse effects. These findings support the continued use of sacubitril/valsartan as a foundational therapy in this high-risk population.}, } @article {pmid40728549, year = {2025}, author = {Al Saihati, HA and Alazabi, NI and Bakeer, RM and Abol-Fetouh, GM and Ahmed-Farid, OA and Alshedi, AF and Alsabeelah, NF}, title = {Optimizing predictive biomarkers for alzheimer's disease: muscarinic M1 antagonist-induced synaptic signaling disruptions and bee venom intervention through cholinergic modulation and multiregression dose selection.}, journal = {Metabolic brain disease}, volume = {40}, number = {6}, pages = {244}, pmid = {40728549}, issn = {1573-7365}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/chemically induced ; Rats ; *Bee Venoms/pharmacology/therapeutic use ; Biomarkers/metabolism ; Male ; Oxidative Stress/drug effects ; Rats, Wistar ; *Receptor, Muscarinic M1/antagonists & inhibitors/metabolism ; Scopolamine ; Dose-Response Relationship, Drug ; *Muscarinic Antagonists/pharmacology ; Neuroprotective Agents/pharmacology ; Memantine/pharmacology ; Disease Models, Animal ; Brain/metabolism/drug effects ; Maze Learning/drug effects ; }, abstract = {Alzheimer's (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neurochemical imbalances. The present study aims to ensure the correct dosage of scopolamine (SC) for inducing AD using Quality by Design to optimize the predictive biomarker acetylcholine esterase. Further, neuroprotective effects will be assessed with variable doses of bee venom (BV) by analyzing its effect on cognitive function, neurochemical markers, and oxidative stress. The goal of this study is to improve models of AD and learn more about how BV can protect neurons in a dose-dependent way during treatment. Methods: The rats were randomly divided into six groups (n = 6): Control, SC -induced AD, SC + Memantine (1 mg/kg bwt p.o.), and three BV doses (5, 10, 15 µl/kg, i.p, every other day) to study dose-dependent effects combined with SC. Memantine and BV were given to the animals two months before they developed AD, which happened on its own 14 days after treatment. After four days of behavioral assessment using the Morris Water Maze to evaluate cognitive function, the animals were humanely sacrificed. Blood and brain samples were collected for the measurement of serum liver and kidney function markers, oxidative and nitrosative stress parameters, cellular energy metabolites, amino acid profiles, neurotransmitters, and inflammatory markers in brain tissue. Results and Conclusion: The most remarkable neuroprotective effect was found in the group treated with BV medium and high dose showed a plateau, beyond which no more improvement was shown. These findings point toward a promising therapeutic approach for BV in the cognitive decline of AD.}, } @article {pmid40727792, year = {2025}, author = {Wang, N and Liu, W and Zhou, L and Liu, W and Liang, X and Liu, X and Xu, Z and Zhong, T and Wu, Q and Jiao, X and Chen, J and Ning, X and Jiang, X and Zhao, Q}, title = {Retraction of "Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3β for the Treatment of Alzheimer's Disease".}, journal = {ACS omega}, volume = {10}, number = {28}, pages = {31208}, doi = {10.1021/acsomega.5c06137}, pmid = {40727792}, issn = {2470-1343}, abstract = {[This retracts the article DOI: 10.1021/acsomega.2c03368.].}, } @article {pmid40727583, year = {2025}, author = {Matuszewska, M and Wilkaniec, A and Gąssowska-Dobrowolska, M and Cieślik, M and Olech-Kochańczyk, G and Pałasz, E and Gawinek, E and Strawski, M and Czapski, GA}, title = {Inhibition of BET proteins modulates amyloid-beta accumulation and cognitive performance in middle-aged mice prenatally exposed to maternal immune activation.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1619583}, pmid = {40727583}, issn = {1662-5099}, abstract = {INTRODUCTION: Given the complex etiological basis of Alzheimer's disease (AD), it is reasonable to hypothesize that neuronal dysfunction and death result from the interplay of numerous factors, both genetic and environmental. Accumulating evidence implicates the immune system and inflammation as key components of the pathomechanism of AD. In the present study, we analyzed the effect of maternal immune activation (MIA) on AD-related pathological changes in middle-aged 12-month-old offspring mice. Additionally, we investigated whether the inhibition of bromodomain and extraterminal domain (BET) proteins, which are readers of the histone acetylation code, could influence these changes. METHODS: In our study, we administered a viral mimetic, polyinosinic-polycytidylic acid (PIC), on gestation day 17 to induce MIA in wild-type C57BL/6J mice. The BET protein inhibitor, OTX-015 (Birabresib), was administered orally to 12-month-old male offspring for 14 days. Subsequently, behavioral, genetic, and immunochemical analyses were conducted. RESULTS: Our results demonstrated several MIA-evoked molecular alterations in the brains of middle-aged offspring. We observed an increase in App gene expression (qPCR) and amyloid-β (Aβ) levels (ELISA), while the levels and phosphorylation of Tau protein remained unchanged (WB). The mRNA levels of selected microglial markers were also elevated in the MIA group. Treatment with OTX-015 improved memory, as observed in the novel object recognition test, and reduced Aβ levels, but did not alter the expression of inflammatory genes or amyloidogenesis-related genes. DISCUSSION: Our findings suggest that inhibition of BET proteins may effectively attenuate neuropathological alterations in the aged brain.}, } @article {pmid40727259, year = {2025}, author = {Sun, W and Zhu, A and Chang, H and Xia, J and Gao, J and Zhang, Z and Chi, F and Zhu, Y and Bao, X}, title = {Causal associations and shared genetic etiology between neurodegenerative diseases and constipation.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251362469}, pmid = {40727259}, issn = {2542-4823}, abstract = {BACKGROUND: There is increasing evidence suggesting a correlation between neurodegenerative diseases (NDDs) and constipation; however, their genetic relationship and causal mechanisms remain inadequately elucidated. OBJECTIVE: We aim to investigate the causal link and shared genetic basis between NDDs and constipation. METHODS: We obtained summary statistics from large-scale genome-wide association studies, encompassing five NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Lewy body dementia (LBD), as well as constipation. The primary analysis employed five Mendelian randomization methods to evaluate causal effects, while linkage disequilibrium score regression (LDSC) and high-definition likelihood (HDL) were utilized to investigate genetic correlations. Additionally, significant pleiotropic SNPs were identified using pleiotropic analysis under the composite null hypothesis (PLACO) and functional mapping and annotation (FUMA). Finally, enrichment analysis was conducted to explore the biological pathways associated with the identified pleiotropic genes. RESULTS: MR analysis revealed a significant causal relationship between AD and an enhanced risk of constipation was demonstrated (OR = 1.043, 95% CI: 1.015-1.073, p = 0.003), while no causality was found between PD, MS, ALS, LBD, and the risk of constipation (p > 0.05). LDSC and HDL analysis revealed a significant positive genetic correlation between AD and constipation. Using PLACO combined with FUMA, we identified 30 overlapping pleiotropic loci, with pathway enrichment analysis revealing important biological pathways related to Aβ metabolism and processing, tau protein process, and the complement and coagulation cascades. CONCLUSIONS: Our study indicates that AD is a contributing factor to constipation and uncovers the complex genetic mechanisms linking AD and constipation, which holds significant implications for diagnosis and treatment of both conditions.}, } @article {pmid40727044, year = {2025}, author = {Jiang, Q and Liu, Y and Wei, Y and Kuan, G and Ma, L and Wang, H and Wang, Y and Lou, H}, title = {The underlying mechanism of physical exercise on neurodegenerative diseases: the mediating role of psychological stress and resilience: a systematic review.}, journal = {Frontiers in psychology}, volume = {16}, number = {}, pages = {1474579}, pmid = {40727044}, issn = {1664-1078}, abstract = {Theories and experiments have shown that physical exercise can improve mental resilience and resist the negative effects of psychological stress. Neurodegenerative diseases are a collection of diseases in which progressive changes in the structure and function of neurons result in progressive disorders of cognitive and motor function, greatly reducing the quality of life of the patient. The latest research suggests that psychological factors such as psychological stress and resilience also have an impact on the onset, symptoms, and course of Neurodegenerative diseases. However, the specific mechanisms in the above pathways are unclear, so this study introduced psychological factors such as psychological stress and resilience and explore the mechanism of physical exercise in improving NDDs by influencing psychological factors such as psychological stress and resilience. This review examined four electronic databases (PubMed, Web of Science, Cochrane Library, and CNKI) up to May 2024, selecting a total of 95 articles. A logical analysis approach was employed to evaluate the literature. The findings revealed that: (1) Exercise can enhance resilience by reducing negative emotions or fulfilling individual needs, thereby diminishing the harmful effects of stress, a key risk factor for NDDs. (2) Exercise alleviates NDDs through neurobiological pathways such as improving immune function, regulating endocrine and neurotransmitter levels, and modifying neuronal structure. (3) Long-term, regular high-intensity exercise effectively enhances resilience and helps prevent and treat NDDs. Exercise has a positive impact on the prevention and treatment of NDDs. Clarifying the mechanisms by which exercise improves NDDs is crucial for providing new theoretical insights into the diagnosis, prevention, and treatment of psychologically induced NDDs, as well as offering practical guidance and feasible strategies for using exercise to prevent and mitigate NDDs.}, } @article {pmid40726797, year = {2025}, author = {Mondal, S and An, J and Bera, T and Banerjee, M and Debnath, S and Mandal, D and Sikder, A and Guha, S and Kim, JS and Singh, NDP}, title = {Engineering a Green Fluorescent Protein-Core-Inspired NIR-Photocage: Exploring meso-GFP-PRPG toward Alzheimer's Disease Therapeutics.}, journal = {ACS central science}, volume = {11}, number = {7}, pages = {1062-1070}, pmid = {40726797}, issn = {2374-7943}, abstract = {NIR light-activated photocage with inherent protein tagging ability is unprecedented in contemporary photochemistry. Herein, we introduce a series of protein-taggable NIR-photocages derived from green fluorescent protein (GFP) chromophore analogs with spatiotemporal control for releasing the caged bioactive molecules. Through molecular engineering of the GFP chromophoric scaffold, a series of meso-substituted oxazolone-photocages (meso-GFP-PRPG) were judiciously designed and synthesized. These photocages, anchored with electron-donating groups (EDG) and electron-withdrawing groups (EWG), accommodate diverse payloads, including aliphatic carboxylic acids, expanding the possibilities for tailoring their properties and applications. Notably, under anaerobic conditions, irradiation of meso-GFP-PRPG leads to fast and efficient release of caged molecules. Insightful experimental and theoretical investigations revealed that photorelease is predominantly driven by the triplet state photochemistry in anaerobic conditions. The concept's theranostic potential was demonstrated by the conditional release of valproic acid, a neuroprotective agent for Alzheimer's disease (AD) treatment. meso-GFP-PRPG (15E) showed enhanced NIR emission with Aβ oligomers and fibrils (30-37 fold vs ThT) and effectively degraded amyloid fibrils under 640 nm light, offering a promising targeted treatment approach for neurodegenerative disorders.}, } @article {pmid40726790, year = {2025}, author = {Ma, M and Zhao, Y}, title = {Protein-Taggable Near-Infrared Photocages for Theranostics of Alzheimer's Disease.}, journal = {ACS central science}, volume = {11}, number = {7}, pages = {1024-1025}, pmid = {40726790}, issn = {2374-7943}, abstract = {Protein-tagged near-infrared-activatable photocages have been developed for the simultaneous diagnosis and treatment of Alzheimer's disease.}, } @article {pmid40726727, year = {2025}, author = {Rao, SP and Imam-Fulani, AO and Xie, W and Phillip, S and Chennavajula, K and Bhilare, KD and Lind, EB and Zhang, Y and Vince, R and Lee, MK and More, SS}, title = {Oral Prodrug of a Novel Glutathione Surrogate Reverses Metabolic Dysregulation and Attenuates Neurodegenerative Process in Transgenic Alzheimer's Mice.}, journal = {ACS pharmacology & translational science}, volume = {8}, number = {8}, pages = {2448-2464}, pmid = {40726727}, issn = {2575-9108}, support = {R01 AG062469/AG/NIA NIH HHS/United States ; R01 AG077743/AG/NIA NIH HHS/United States ; RF1 AG062135/AG/NIA NIH HHS/United States ; }, abstract = {Glycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer's disease (AD). Reduced glutathione levels in AD lead to increased oxidative stress, including glycation-induced pathology. Previously, we showed that the accumulation of reactive 1,2-dicarbonyls such as methylglyoxal, the major precursor of nonenzymatic glycation products, was reduced by the increased function of GSH-dependent glyoxalase-1 enzyme in the brain. In this two-pronged study, we evaluate the therapeutic efficacy of an orally bioavailable prodrug of our lead glyoxalase substrate, pro-ψ-GSH, for the first time in a transgenic Alzheimer's disease mouse model. This prodrug delivers pharmacodynamically relevant brain concentrations of ψ-GSH upon oral delivery. Chronic oral dosing of pro-ψ-GSH effectively reversed the cognitive decline observed in the APP/PS1 mouse model. The prodrug successfully mirrors the robust effects of the parent drug, i.e., reducing amyloid pathology, glycation stress, neuroinflammation, and the resultant neurodegeneration, in these mice. We also report the first metabolomics study of such a treatment that yields key biomarkers linked to the reversal of AD-related metabolic dysregulation. Collectively, this study demonstrates the neuroprotective effect of pro-ψ-GSH in a symptomatic preclinical model of AD and paves the way for further preclinical advancement of such therapeutics. Metabolomic signatures identified could prove beneficial in the development of treatment-specific, clinically translatable biomarkers.}, } @article {pmid40726442, year = {2025}, author = {Ehtezazi, T and Sarker, SD}, title = {Phytochemical Nanoparticles for the Treatment of Neurological Disorders.}, journal = {Phytochemical analysis : PCA}, volume = {36}, number = {7}, pages = {1918-1935}, pmid = {40726442}, issn = {1099-1565}, mesh = {Humans ; *Phytochemicals/therapeutic use/chemistry ; *Nanoparticles/chemistry ; *Nervous System Diseases/drug therapy ; Animals ; *Neurodegenerative Diseases/drug therapy ; Alzheimer Disease/drug therapy ; Curcumin/therapeutic use ; }, abstract = {Neurological disorders impose a significant burden on the healthcare systems. The latest published data by WHO indicated that stroke was the second leading cause of death globally in 2020, with Alzheimer's disease (AD) and other dementias in the seventh position. The treatment of neurological disorders is challenging because of the complex nature of the disease, as well as limited accessibility to this target organ due to several biological barriers. There is a wide range of treatment options for neurological disorders. Small drug molecules, antibodies, and stem cells have been employed for the treatment of neurodegenerative diseases such as AD, but currently, there is no effective treatment for AD. As conventional drugs have not been successful in achieving therapeutic outcomes, natural products such as curcumin, stemming from traditional medicines, have been tested for the treatment of neurodegenerative diseases such as AD. However, this compound has not shown significant therapeutic effects for the treatment of brain diseases, mainly due to rapid clearance from the body. Therefore, phytochemical nanoparticles have been developed. In this review article, the rationale has been provided for the use of nanoparticles for the treatment of neurodegenerative diseases with emphasis on phytochemical nanoparticles.}, } @article {pmid40726148, year = {2025}, author = {Rahman, AU and Esa, M and Panichayupakaranant, P}, title = {The therapeutic potential of pomegranate in the prevention and management of noncommunicable diseases.}, journal = {Food & function}, volume = {16}, number = {16}, pages = {6313-6345}, doi = {10.1039/d5fo01999k}, pmid = {40726148}, issn = {2042-650X}, mesh = {*Pomegranate/chemistry ; Humans ; *Noncommunicable Diseases/prevention & control ; *Plant Extracts/pharmacology/chemistry ; Fruit/chemistry ; Animals ; Neoplasms/prevention & control ; }, abstract = {Noncommunicable diseases (NCDs), including cardiovascular diseases, cancer, respiratory conditions, and metabolic and central nervous system disorders, are the leading causes of morbidity and mortality worldwide. These diseases are primarily driven by unhealthy diets and sedentary lifestyles. Pomegranate (Punica granatum L.), a fruit rich in diverse functional phytoconstituents, has emerged as a promising natural therapeutic agent for the prevention and management of NCDs. Every part of the fruit harbors distinct bioactive compounds that contribute to its health-promoting properties. The peels are particularly rich in punicalagins, the arils are abundant in anthocyanins and ellagic acid, and the seeds contain significant amounts of punicic acid, ellagic acid, and quercetin. Pomegranate peel extracts and juice demonstrate cardioprotective effects through inhibition of angiotensin-converting enzyme (ACE) activity, reduction of inflammatory cytokines, e.g., interleukins and TNF-α, and improvements in lipid profiles. Additionally, their anticancer properties are associated with the upregulation of pro-apoptotic markers (Bax, cytochrome c, caspases 3 and 9, and p53) and the downregulation of tumor-promoting and inflammatory markers (Bcl-2, MMP-2, MMP-9, GOLPH-3, and N-cadherin), as well as the attenuation of reactive oxygen species (ROS) generation. Moreover, pomegranate extracts have exhibited hypoglycemic, nephroprotective, hepatoprotective, antidepressant, anti-Alzheimer's, and anti-Parkinson's properties, as demonstrated in in vitro and in vivo studies, and clinical trials. Recent investigations have identified key bioactive constituents, including punicalagin, ellagic acid, gallic acid, and urolithin A, as major contributors to these therapeutic effects. This review provides an overview of the metabolomic profile of pomegranate, its therapeutic potential, safety, and quality control assessments, and strategies to enhance the stability and bioavailability of its active constituents, thus underscoring its potential as a natural intervention for the prevention and treatment of NCDs.}, } @article {pmid40725913, year = {2025}, author = {Ugwu, OP and Okon, MB and Alum, EU and Ugwu, CN and Anyanwu, EG and Mariam, B and Ogenyi, FC and Eze, VHU and Anyanwu, CN and Ezeonwumelu, JOC and Egba, SI and Uti, DE and Onohuean, H and Aja, PM and Ugwu, MN}, title = {Unveiling the therapeutic potential of the gut microbiota-brain axis: Novel insights and clinical applications in neurological disorders.}, journal = {Medicine}, volume = {104}, number = {30}, pages = {e43542}, pmid = {40725913}, issn = {1536-5964}, mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; Probiotics/therapeutic use ; *Nervous System Diseases/therapy/microbiology ; *Dysbiosis/therapy/complications ; *Brain ; Fecal Microbiota Transplantation/methods ; Prebiotics/administration & dosage ; *Brain-Gut Axis/physiology ; }, abstract = {Over the last several years, the gut microbiota-brain axis has been the focus of medical study, demonstrating the bidirectional nature of gut and brain communication and the resulting influence on neurological and mental health. Trillions of microorganisms, particularly those found in the gastrointestinal tract, contribute the most to the pathophysiology recovery of organs that are critical to human health, such as digestive processes and metabolism, immune responses, and even cognitive function. Dysbiosis (a disturbance in the microbiome balance) has been identified as one of the risk factors for neuropsychiatric illnesses such as depression, anxiety, autism spectrum disorder, Parkinson's disease, and Alzheimer's disease. Therapeutic strategies aimed at the gut microbiota, such as probiotics, dietary modifications, prebiotics, and fecal microbiota transplantation, will eventually offer ways to alleviate symptoms associated with these disorders by restoring microbial balance, modulating the immune response, and influencing the production of major neurotransmitters. Innovative drug carriers, such as microbially-derived nanoparticles and probiotics that target particular parts of the gut or microbial communities, may improve pharmaceutical treatment efficacy and specificity. The resolution of difficulties such as ethical concerns, unexpected repercussions, and peak performance optimization in a clinical setting is critical for the advancement of this subject.}, } @article {pmid40725728, year = {2025}, author = {Riachi, R and Khalife, E and Kędzia, A and Niechciał, E}, title = {Understanding Insulin Actions Beyond Glycemic Control: A Narrative Review.}, journal = {Journal of clinical medicine}, volume = {14}, number = {14}, pages = {}, pmid = {40725728}, issn = {2077-0383}, abstract = {Insulin, traditionally recognized for its pivotal role in glycemic regulation, exerts extensive effects beyond glucose homeostasis, influencing multiple physiological systems. This narrative review explores the multifaceted actions of insulin, emphasizing its impact on skeletal muscle remodeling, protein and lipid metabolism, growth, reproductive health, and the central nervous system. Methods: An in-depth review of articles with evidence-based research discussing insulin actions beyond glycemic control was conducted in this review paper. Results: Insulin directly influences lipid and protein metabolism as well as growth hormone levels. This hormone provides a protective effect on the skeletal and central nervous systems, helping to maintain homeostasis and potentially reducing the risk of certain disorders such as Alzheimer's disease. The significance of insulin balance in the reproductive system is also crucial, with recent research indicating that insulin plays a role in worsening symptoms and complications associated with polycystic ovary syndrome. This review underscores the importance of maintaining proper insulin levels to lower the risk of insulin resistance. Ongoing research aims to deepen our understanding of insulin's functions, which are essential for preventing specific diseases and developing new treatment strategies. Conclusions: Insulin's action extends far beyond glucose metabolism, affecting many systems and preventing pathological changes in some.}, } @article {pmid40725270, year = {2025}, author = {Tahri, A and Niccolai, E and Amedei, A}, title = {Neurosteroids, Microbiota, and Neuroinflammation: Mechanistic Insights and Therapeutic Perspectives.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40725270}, issn = {1422-0067}, mesh = {Humans ; *Gastrointestinal Microbiome ; *Neuroinflammatory Diseases/metabolism/microbiology/therapy ; Animals ; *Neurosteroids/metabolism ; *Neurodegenerative Diseases/metabolism/microbiology ; Brain/metabolism ; Inflammation ; }, abstract = {The gut-brain axis (GBA) represents a complex bidirectional communication network that links the gut microbiota (GM) and the central nervous system (CNS). Recent research has revealed that neurosteroids (NSs) play crucial roles in modulating neuroinflammatory responses and promoting neuroprotection. Meanwhile, GM alterations have been associated with various neuroinflammatory and neurodegenerative conditions, such as multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. This review aims to provide a comprehensive overview of the intricate interactions between NS, GM, and neuroinflammation. We discuss how NS and metabolites can influence neuroinflammatory pathways through immune, metabolic, and neuronal mechanisms. Additionally, we explore how GM modulation can impact neurosteroidogenesis, highlighting potential therapeutic strategies that include probiotics, neuroactive metabolites, and targeted interventions. Understanding these interactions may pave the way for innovative treatment approaches for neuroinflammatory and neurodegenerative diseases, promoting a more integrated view of brain health and disease management.}, } @article {pmid40725224, year = {2025}, author = {Scarano, N and Musumeci, F and Casini, B and Brullo, C and D'Ursi, P and Fossa, P and Schenone, S and Cichero, E}, title = {Alzheimer's Disease Etiology Hypotheses and Therapeutic Strategies: A Perspective.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40725224}, issn = {1422-0067}, support = {FRA2023//University of Genoa/ ; }, mesh = {*Alzheimer Disease/etiology/therapy/metabolism/drug therapy/pathology ; Humans ; Animals ; Neuroprotective Agents/therapeutic use ; Neurotransmitter Agents/metabolism ; Risk Factors ; Cholinesterase Inhibitors/therapeutic use ; }, abstract = {Alzheimer's disease (AD) is a progressive, complex, multifactorial, neurodegenerative disease and accounts for most cases of dementia. The currently approved therapy includes cholinesterase inhibitors, NMDA-receptor antagonists and monoclonal antibodies. However, these medications were gradually discovered to be ineffective in removing the root of AD pathogenesis, having only symptomatic effects. Thus, the priority remains prevention and clarifying AD etiology. A better understanding of the neuroprotective mechanisms undertaken by specific genes is crucial to guide the design of novel therapeutic agents via selective ligands and precision medicine. In this review, we present a perspective of the physiological phase of the AD spectrum, of risk factors in AD with a focus on therapeutic approaches in three categories: neurotransmitters/ion modulations, peptide deposit control and aspecific treatments, followed by a discussion of treatment limitations. An overview of innovative strategies and non-pharmaceutical ancillary support is given.}, } @article {pmid40725167, year = {2025}, author = {Abdul-Nasir, S and Chau, CT and Nguyen, TT and Bajgai, J and Rahman, MH and Hwang-Un, K and You, IS and Kim, CS and Seo, BA and Lee, KJ}, title = {Hydrogen Gas Attenuates Toxic Metabolites and Oxidative Stress-Mediated Signaling to Inhibit Neurodegeneration and Enhance Memory in Alzheimer's Disease Models.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40725167}, issn = {1422-0067}, mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy ; *Oxidative Stress/drug effects ; *Hydrogen/pharmacology ; Mice ; Disease Models, Animal ; Astrocytes/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; Hippocampus/metabolism/drug effects ; Mice, Transgenic ; Signal Transduction/drug effects ; Male ; *Memory/drug effects ; Hydrogen Peroxide/metabolism ; Memory Disorders/drug therapy ; Maze Learning/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition in which amyloid-beta (Aβ) plaques trigger oxidative stress (OS) and neuroinflammation, causing memory loss. OS and neurodegeneration can also be caused by reactive astrocytes, thereby promoting AD via toxic metabolite accumulation in the astrocytic urea cycle. However, the effect of molecular hydrogen (H2) on this cycle remains unknown. Therefore, we investigated whether H2 treatment could reduce OS-induced neurodegeneration and memory loss. 5xFAD (n = 14) and wild-type (n = 15) mice were randomized into four groups and treated with either 3% hydrogen gas (H2) or vehicle for 60 days. Cognitive behaviors were evaluated using the Morris water maze and Y-maze tests. In addition, we used biochemical assays to measure ammonia and hydrogen peroxide (H2O2) levels in the hippocampi of the mice and AβO-treated primary mouse astrocytes. Aβ, γ-aminobutyric acid (GABA), and the expression of inflammatory markers were evaluated using immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). We observed that H2 treatment significantly prevented cognitive deficits, oxidative stress, the accumulation of toxic metabolites, and the increase in inflammatory markers in 5xFAD mice. These results suggest that H2 therapy can mitigate toxic metabolites in the astrocytic urea cycle, thereby reducing neurodegeneration and memory loss in AD.}, } @article {pmid40725005, year = {2025}, author = {Heller, E and McGurran, L and Brown, JK and Love, K and Hobbs, M and Kim-Han, JS and Han, BH}, title = {Aβ40 Improves Cerebrovascular Endothelial Function via NOX4-Dependent Hydrogen Peroxide Release.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40725005}, issn = {1422-0067}, support = {851-075//A.T. Still University/ ; }, mesh = {*NADPH Oxidase 4/metabolism ; Animals ; *Hydrogen Peroxide/metabolism ; *Amyloid beta-Peptides/pharmacology/metabolism ; Mice ; *Endothelial Cells/metabolism/drug effects ; *Peptide Fragments/pharmacology/metabolism ; Reactive Oxygen Species/metabolism ; Cell Line ; Nitric Oxide/metabolism ; Brain/metabolism/blood supply ; Alzheimer Disease/metabolism ; Cell Survival/drug effects ; }, abstract = {Alzheimer's disease (AD) is associated with an abnormal accumulation of amyloid β (Aβ) fibrils in the brain parenchyma and cerebrovasculature, which leads to cognitive impairment and cerebrovascular dysfunction. Cerebrovascular endothelial cells play a crucial role in regulating cerebral blood flow, vascular permeability, and neurovascular function. Reactive oxygen species (ROS), particularly those generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), contribute to vascular dysfunction and amyloid deposition in the Alzheimer's disease (AD) brain. However, the role of the NOX4 isoform in AD pathogenesis remains to be examined. In the present study, we found that NOX4 among the NOX isoforms is predominantly expressed in bEnd.3 mouse brain endothelial cells. Treatment with Aβ40 significantly enhanced the release of H2O2 and NO, and increased the endothelial cell viability. To test the involvement of NOX4 in Aβ40-induced H2O2 production, we utilized pharmacological inhibitors of NOX isoforms. Aβ40-induced H2O2 production was attenuated in the presence of the pan-NOX inhibitor, apocynin, or the NOX1/4-selective inhibitors, setanaxib and GKT136901. Since only the NOX4 isoform is expressed in bEnd.3 cells, these results indicate that NOX4 is responsible for the release of H2O2 stimulated by Aβ40. Taken together, the present study demonstrated that Aβ40 peptide exerts beneficial effects in bEnd.3 endothelial cells via the NOX4-dependent mechanism.}, } @article {pmid40724974, year = {2025}, author = {Gagliardi, S and Hotchkin, T and Hillmer, G and Engelbride, M and Diggs, A and Tibebe, H and Izumi, C and Sullivan, C and Cropp, C and Lantz, O and Marquez, D and Chang, J and Ezaki, J and Zestos, AG and Riley, AL and Izumi, T}, title = {Oxidative Stress in HIV-Associated Neurodegeneration: Mechanisms of Pathogenesis and Therapeutic Targets.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40724974}, issn = {1422-0067}, support = {R41 NS113702/NS/NINDS NIH HHS/United States ; R41 MH139088/MH/NIMH NIH HHS/United States ; 7R15AI172610-02/NH/NIH HHS/United States ; R15 AI172610/AI/NIAID NIH HHS/United States ; P30AI117970//DC CFAR/ ; }, mesh = {Humans ; *Oxidative Stress/drug effects ; *HIV Infections/complications/metabolism/drug therapy/virology ; Reactive Oxygen Species/metabolism ; *Neurodegenerative Diseases/metabolism/etiology/drug therapy ; Animals ; *AIDS Dementia Complex/metabolism/drug therapy ; Antioxidants/therapeutic use ; }, abstract = {Treatment for HIV infection has become more manageable due to advances in combination antiretroviral therapy (cART). However, HIV still significantly affects the central nervous system (CNS) in infected individuals, even with effective plasma viral suppression, due to persistent viral reservoirs and chronic neuroinflammation. This ongoing inflammation contributes to the development of HIV-associated neurocognitive disorders (HANDs), including dementia and Alzheimer's disease-like pathology. These complications are particularly prevalent among the aging population with HIV. This review aims to provide a comprehensive overview of HAND, with a focus on the contribution of oxidative stress induced by HIV-mediated reactive oxygen species (ROS) production through viral proteins such as gp120, Tat, Nef, Vpr, and reverse transcriptase. In addition, we discuss current and emerging therapeutic interventions targeting HAND, including antioxidant strategies and poly (ADP-ribose) polymerase (PARP) inhibitors. These are potential adjunctive approaches to mitigate neuroinflammation and oxidative damage in the CNS.}, } @article {pmid40724820, year = {2025}, author = {Tomaszewska-Zaremba, D and Gajewska, A and Misztal, T}, title = {Anti-Inflammatory Effects of Cannabinoids in Therapy of Neurodegenerative Disorders and Inflammatory Diseases of the CNS.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40724820}, issn = {1422-0067}, mesh = {Humans ; *Cannabinoids/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Animals ; *Inflammation/drug therapy ; Central Nervous System/drug effects ; *Central Nervous System Diseases/drug therapy ; }, abstract = {Many neurodegenerative diseases are associated with immune system disorders, while neurodegenerative processes often occur in inflammatory conditions of the Central Nervous System (CNS). Cannabinoids exhibit significant therapeutic potential due to their dual ability to modulate both neural and immune functions. These compounds have a broad spectrum of action, allowing them to target multiple pathological mechanisms underlying neurodegenerative and inflammatory CNS diseases. The present review outlines the therapeutic potential of cannabinoids, with a focus on their anti-inflammatory properties, in the treatment of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, as well as inflammatory CNS disorders like multiple sclerosis and HIV-associated dementia.}, } @article {pmid40724803, year = {2025}, author = {Ivanova, P and Kortenska, L and Angelova, VT and Tchekalarova, J}, title = {The Novel Melatonin Analog Containing Donepezil Fragment Prevents Cognitive Impairments and Associated Oxidative Stress in a Hybrid Rat Model of Melatonin Deficiency and icvAβ1-42.}, journal = {International journal of molecular sciences}, volume = {26}, number = {14}, pages = {}, pmid = {40724803}, issn = {1422-0067}, support = {grant number KP-06-N63/11; 14.12.2022 and IC-SK/03/2025-2026.//the Bulgarian National Science Fund, Bulgarian Academy of Sciences/ ; }, mesh = {Animals ; *Melatonin/analogs & derivatives/pharmacology ; *Donepezil/chemistry/pharmacology ; *Oxidative Stress/drug effects ; Rats ; *Amyloid beta-Peptides/toxicity ; *Cognitive Dysfunction/drug therapy/metabolism/prevention & control ; *Peptide Fragments ; Male ; Disease Models, Animal ; Alzheimer Disease/drug therapy/metabolism ; Hippocampus/metabolism/drug effects ; }, abstract = {Alzheimer's disease (AD) is the most common cause of dementia in older adults and is becoming a major public health crisis as life expectancy increases worldwide. A major contributor to this disease is a deficiency in melatonin signaling. We have recently synthesised a series of melatonin analogs containing donepezil fragments. These compounds have been tested both in silico and in vitro. In this study, a particularly potent compound, 3a, was evaluated in a hybrid rat model of melatonin deficiency and AD. Rats underwent pinealectomy followed one week later by bilateral intracerebroventricular infusion of Aβ1-42 (1 µg/µL). A 14-day subchronic treatment with compound 3a was started simultaneously with the neurotoxin infusion. Melatonin was used as a reference drug, while a matched sham group received vehicle treatment. One week after the Aβ1-42 infusion, the rats' cognitive functions were assessed using two Y-maze protocols, object recognition and object location tests. Markers of oxidative stress, including hippocampal glutathione, superoxide dismutase, and malondialdehyde, were assessed by ELISA. Compound 3a effectively prevented cognitive impairment induced by the AD model, and its effects were comparable to those of melatonin. In addition, this melatonin analogue with a donepezil fragment reduced AD-associated oxidative stress and suppressed model-associated increased Aβ1-42 levels in the hippocampus. Our findings suggest that melatonin analogs containing donepezil fragments are promising therapeutic options for targeting oxidative stress associated with AD.}, } @article {pmid40723783, year = {2025}, author = {Muñoz de León-López, CA and Navarro-Lobato, I and Khan, ZU}, title = {The Role of Astrocytes in Synaptic Dysfunction and Memory Deficits in Alzheimer's Disease.}, journal = {Biomolecules}, volume = {15}, number = {7}, pages = {}, pmid = {40723783}, issn = {2218-273X}, support = {PID2022-136954OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; PROYEXCEL-00422//Junta de Andalucía/ ; CTS-586-G-FEDER//Fondo Europeo de Desarrollo Regional/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology/physiopathology ; *Astrocytes/metabolism/pathology ; Humans ; *Synapses/metabolism/pathology ; Animals ; *Memory Disorders/metabolism/pathology ; Neuronal Plasticity ; Synaptic Transmission ; Amyloid beta-Peptides/metabolism ; }, abstract = {Astrocytes are the most abundant glial cells in the brain. They play critical roles in synapse formation and function, neurotransmitter release and uptake, the production of trophic factors, and energy supply for neuronal survival. In addition to producing proteases for amyloid-β degradation, astrocytes express various receptors, transporters, gliotransmitters, and other molecules that enable them to sense and respond to external signals. They are also implicated in amyloid-β clearance. In Alzheimer's disease, excessive accumulation of amyloid-β induces the polarization of astrocytes into the A1 phenotype, promoting the release of inflammatory cytokines and mitochondrial reactive oxygen species, leading to alterations in astrocytic functions. Under such conditions, gliotransmitter release, glutamate neurotransmission, AMPA receptor trafficking, and both Hebbian and non-Hebbian forms of synaptic plasticity-biological activities essential for synaptic functions-are compromised. Moreover, astrocytes are essential for learning, memory, and synaptic plasticity, and alterations in their function are associated with memory deficits in Alzheimer's disease. This review provides an overview of the current understanding of the defects in astrocytes that lead to altered synaptic functions, neuronal structural plasticity, and memory deficits in Alzheimer's disease.}, } @article {pmid40722053, year = {2025}, author = {Rajan, R and Singh, M and Suzuki, K and Matsumura, K}, title = {Design of Zwitterionic Conjugated Polymers as Protein Aggregation Inhibitors.}, journal = {Langmuir : the ACS journal of surfaces and colloids}, volume = {41}, number = {31}, pages = {20623-20630}, doi = {10.1021/acs.langmuir.5c02043}, pmid = {40722053}, issn = {1520-5827}, mesh = {*Protein Aggregates/drug effects ; *Amyloid beta-Peptides/chemistry/antagonists & inhibitors/metabolism ; *Polyethylene Glycols/chemistry/pharmacology ; *Peptide Fragments/chemistry/antagonists & inhibitors ; *Polymers/chemistry/pharmacology ; Humans ; Betaine/analogs & derivatives ; }, abstract = {Protein aggregation and misfolding is the root cause of several neurodegenerative diseases, including Alzheimer's disease, and can be mitigated using small molecules, peptides, and conjugated or zwitterionic polymers. However, polymers that are both conjugated and zwitterionic have not been evaluated as protein aggregation/misfolding inhibitors. Herein, to bridge this gap, we prepare polymers with a conjugated backbone bearing zwitterionic sulfobetaine moieties and poly(ethylene glycol) chains and examine their abilities to inhibit protein aggregation. These polymers not only strongly inhibit the aggregation of amyloid β peptide (Aβ42) and other proteins but also actively disrupt and solubilize pre-established amyloid fibrils. This dual functionality enables almost complete fibril disaggregation at concentrations lower than those required for existing alternatives and results in protective capability extension across a broad spectrum of proteins. The results open new avenues for advancing neurodegenerative disease treatment strategies and represent considerable progress in the development of biomedical materials.}, } @article {pmid40722027, year = {2025}, author = {Hua, Z and Zhou, N and Zhou, Z and Fu, Z and Guo, R and Akogo, HY and Yang, J and Yu, M and Jiang, Y and Lan, S and Chang, H and Ma, J and Cui, H}, title = {Intranasal administration of stem cell derivatives for the treatment of AD animal models: a systematic review and meta-analysis.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {409}, pmid = {40722027}, issn = {1757-6512}, support = {H2021206321//Natural Science Foundation of Hebei Province/ ; }, abstract = {BACKGROUND: Alzheimer’s disease (AD) is a neurodegenerative disorder with increasing prevalence and limited efficacy of current therapies. Stem cell-derived therapies have attracted attention for their potential neurodegenerative and reparative effects. Intranasal administration provides a non-invasive route that bypasses the blood-brain barrier and delivers stem cell derivatives directly to the brain. Although studies have shown that the intranasal administration of stem cell derivatives alleviates symptoms in animal models of AD, a comprehensive meta-analysis evaluating their therapeutic efficacy is yet to be conducted. This study aims to evaluate the efficacy of intranasal stem cell derivatives therapies in AD animal models and provide a foundation for clinical translation. METHODS: We conducted a systematic literature search across four databases (Pubmed, Embase, Web of Science and Cochrane Library) using subject terms and complementary keywords. After applying inclusion and exclusion criteria, data were extracted using Origin 2024 software and analysed using Review Mange 5.4. The SYRCLE tool was applied to assess study quality and evaluate the potential risk of bias systematically. RESULTS: This meta-analysis of 14 studies investigated the efficacy of intranasal stem cell-derived therapies in animal models of Alzheimer’s disease (AD). Using predominantly mouse and rat models from diverse geographical locations and employing various stem cell types (bone marrow, umbilical cord blood, adipose tissue, hiPSCs), the analysis revealed a significant reduction in amyloid-beta (Aβ) deposition (SMD = -2.69, p < 0.0001). Subgroup analyses indicated that stem cell source, stem cell derivative types and Aβ detection method were not primary drivers of heterogeneity. Furthermore, treatment significantly reduced inflammatory markers IL-1β (SMD = -0.92, p = 0.008) and IBA-1 (SMD = -1.68, p = 0.006), suggesting an anti-inflammatory effect. Auxiliary outcomes CD68 and GFAP also exhibited decreased expression levels. Improved cognitive function was evident, as measured by increased target quadrant dwell time (MD = 10.17, p < 0.00001) and decreased escape latency (MD = -15.74, p = 0.003) in behavioral experiments, and enhanced recognition in the Novel Object Recognition Test (NORT) (SMD = 1.10, p = 0.006). Nissl staining demonstrated a significant reduction in neuronal cell death (SMD=-3.33,p < 0.00001),suggesting a role in neuronal repair.Together, these findings support the potential of intranasal stem cell-derived therapies to improve Alzheimer’s disease pathology, neuronal repair, and cognition in animal models. CONCLUSION: Intranasal administration of stem cell derivatives has demonstrated efficacy in Alzheimer’s disease (AD) animal models, leading to reductions in amyloid-beta (Aβ) deposition, cognitive improvement, repair neurons and attenuation of inflammatory responses. However, limitations such as potential publication bias and heterogeneity among existing studies are noted. Due to insufficient data and study limitations, additional preclinical and clinical trials are required to confirm these results and explore the therapy’s long-term safety and efficacy. GRAPHICAL ABSTRACT: [Image: see text]}, } @article {pmid40716511, year = {2025}, author = {Feng, NN and Li, L and Liu, LZ and He, RB and Xian, XH and Liu, LR and Hu, YY and Li, WB}, title = {Ceftriaxone ameliorates tau phosphorylation and mislocalization in APP/PS1 AD mice by inhibiting endoplasmic reticulum stress.}, journal = {Neuropharmacology}, volume = {279}, number = {}, pages = {110600}, doi = {10.1016/j.neuropharm.2025.110600}, pmid = {40716511}, issn = {1873-7064}, mesh = {Animals ; *tau Proteins/metabolism ; *Endoplasmic Reticulum Stress/drug effects ; Phosphorylation/drug effects ; Mice ; Hippocampus/drug effects/metabolism ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics ; *Alzheimer Disease/metabolism/drug therapy ; *Ceftriaxone/pharmacology ; Mice, Inbred C57BL ; Presenilin-1/genetics ; Male ; Disease Models, Animal ; Glycogen Synthase Kinase 3 beta/metabolism ; *Neuroprotective Agents/pharmacology ; Synaptosomes/drug effects/metabolism ; }, abstract = {Tau phosphorylation and mislocalization are hallmark pathological features of Alzheimer's disease (AD), with endoplasmic reticulum stress (ERS) contributing to tauopathy. We previously showed that ceftriaxone (Cef) improves cognition in APP/PS1 AD mice through regulating GLT-1-mediated glutamate homeostasis. Here, we examined Cef's neuroprotection against ERS-related tauopathy. C57BL/6J and APP/PS1 AD mice were used. Cognitive functions were assessed by new object recognition (NOR), new location recognition (NLR) and Morris water maze (MWM) tests. Hippocampal synaptosomes were isolated using the Syn-PER™ Synaptic Protein Extraction Kit. Western blot analysis evaluates the protein levels of ERS markers, total and phosphorylated tau (Ser396/Ser262/Thr181), and Gsk3β. Transmission electron microscopy examined the endoplasmic reticulum ultrastructural changes of the hippocampus. Confocal 3D-reconstructed imaging assessed the phosphorylated tau (Ser396) distribution on the dendrites in the hippocampal region. The results showed that Cef treatment effectively reduced protein levels of ERS markers and restored endoplasmic reticulum ultrastructural integrity of hippocampus. Simultaneously, Cef treatment significantly alleviated tau phosphorylation levels, decreased accumulation of total and phosphorylated tau in synaptosomes, reduced phosphorylated tau (Ser396) distribution in dendritic compartments and inhibited Gsk3β activity in the hippocampus of APP/PS1 AD mice. Tunicamycin, a promoter of ERS, exacerbated cognitive impairments, tau phosphorylation levels and mislocalization, and Gsk3β activity, and notably, this exacerbation was inhibited by Cef treatment. Simultaneously, the ERS activation significantly inhibited Cef's above benefits on APP/PS1 AD mice. In conclusion, Cef improves cognitive impairment by alleviating ERS, decreasing Gsk3β activity, and reducing tau phosphorylation and mislocalization in the hippocampus of APP/PS1 AD mice.}, } @article {pmid40715899, year = {2025}, author = {Suk-In, N and Promphet, N and Rodthongkum, N and Ummartyotin, S}, title = {Cellulose nanocrystals from waste cotton fabric and polyvinyl alcohol composite hydrogel for non-invasive colorimetric sensing of cysteine.}, journal = {Mikrochimica acta}, volume = {192}, number = {8}, pages = {526}, pmid = {40715899}, issn = {1436-5073}, mesh = {*Cysteine/urine/analysis ; *Colorimetry/methods ; *Cellulose/chemistry ; *Polyvinyl Alcohol/chemistry ; *Cotton Fiber ; *Nanoparticles/chemistry ; Humans ; Limit of Detection ; *Hydrogels/chemistry ; Copper/chemistry ; }, abstract = {Cellulose nanocrystals (CNCs) were successfully extracted and purified from cotton fabric waste via alkali treatment and acid hydrolysis. The resulting nanostructure was characterized using transmission electron microscopy (TEM) and X-ray diffraction spectroscopy (XRD), confirming the successful isolation of CNCs. A PV/Cu[2+]-CNCs/CNFs/PVA hydrogel was then synthesized through chemical crosslinking of polyvinyl alcohol (PVA), cellulose nanofibrils (CNFs), cellulose nanocrystals (CNCs), and borax. The incorporation of CNCs as a reinforcing agent significantly enhanced the hydrogel's surface area and water absorption capacity, leading to a substantial improvement in the colorimetric sensitivity of the sensor. This hydrogel was employed as a non-invasive colorimetric sensor for urinary cysteine detection, utilizing an indicator-displacement assay (IDA) with pyrocatechol violet/copper ion (PV/Cu[2+]) as the indicator. Upon exposure to cysteine, the sensor exhibited a distinct color change from greenish-blue to orange-red. The sensor demonstrated a linear detection range of 0-0.6 g/L and a limit of detection (LOD) of 0.017 g/L, effectively encompassing the clinical cut-off level for cysteine in human urine (0.25 g/L), relevant for Alzheimer's disease indication. Eventually, this sensor was validated for cysteine determination in artificial urine samples, confirming its practical applicability.}, } @article {pmid40720733, year = {2025}, author = {Li, W and Zha, X and Zhang, X and Dai, H and Pu, S and Yao, X and Hui, W and Xu, R and Bao, J and Yu, J and Wei, Y and Huang, J and Guo, N and Xu, M and Zhao, J and Cheng, B and Luo, Z}, title = {Enhanced Positron Emission Tomography Imaging of β-Amyloid through Focused Ultrasound-Mediated Gallium-68 Radiotracer Delivery across the Blood-Brain Barrier.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {15}, pages = {3070-3081}, doi = {10.1021/acschemneuro.5c00476}, pmid = {40720733}, issn = {1948-7193}, mesh = {Animals ; *Blood-Brain Barrier/metabolism/diagnostic imaging ; *Positron-Emission Tomography/methods ; *Gallium Radioisotopes ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Hippocampus/metabolism/diagnostic imaging ; Brain/metabolism/diagnostic imaging ; Radiopharmaceuticals ; }, abstract = {Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening is an innovative approach for enhancing the delivery of central nervous system drugs. [68]Ga radiotracers are advantageous for imaging due to their ideal half-life and imaging properties; however, their limited ability to traverse the BBB constrains their application in brain imaging. This study investigates the application of FUS to selectively deliver the [68]Ga radiotracer, [[68]Ga]STZL4110, into the hippocampus for β-amyloid positron emission tomography (PET) imaging in an Alzheimer's disease (AD) mouse model. The synthesis and radiolabeling of [[68]Ga]STZL4110 were accomplished, demonstrating robust binding to β-amyloid, as validated by Thioflavin T assays and in vitro autoradiography with both wild-type (WT) and APP/PS1 AD mouse brain sections. Cavitation activity measurements confirmed effective and consistent BBB opening post-FUS treatment, ensuring targeted delivery without vascular damage, as supported by histological analysis. Quantitative PET imaging revealed the successful detection of β-amyloid deposition following FUS treatment. Initially, [[68]Ga]STZL4110 showed a low volume of distribution in the right hippocampus of AD mice. FUS application significantly enhanced BBB permeability, leading to a 74% increase in [[68]Ga]STZL4110 uptake in the targeted right hippocampus of APP/PS1 mice compared with the left hippocampus, whereas no significant change was observed in WT mice. These findings suggest that combining FUS with [[68]Ga]STZL4110 could significantly enhance the sensitivity and specificity of [68]Ga PET imaging for β-amyloid. FUS-mediated PET imaging may potentially address the challenge of effective brain imaging with radiotracers that traditionally exhibit a low penetration of the BBB.}, } @article {pmid40720390, year = {2025}, author = {Hwang, J and Choi, J and Cha, SY and Lee, IS and Yoon, JH and Jung, DJ and Lee, CW and Kim, SR and Lee, JH and Jeon, B and Park, JH and Maeng, S and Park, H}, title = {Memory improving effect of silkworm larva on insulin resistance related cognitive impairment model.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0328847}, pmid = {40720390}, issn = {1932-6203}, mesh = {Animals ; *Bombyx/chemistry ; *Insulin Resistance ; Larva/chemistry ; *Cognitive Dysfunction/drug therapy/physiopathology ; Disease Models, Animal ; Male ; Hippocampus/drug effects/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; *Memory/drug effects ; Rats ; Blood Glucose/metabolism ; Diet, High-Fat/adverse effects ; }, abstract = {Hongjam (HJ) is the steamed and freeze-dried powder of larva-stage silkworm (Bombyx mori) rich in protein, unsaturated fatty acids, and minerals. Silkworm products have traditionally been used for medical purposes, and their effectiveness in diabetic and neurodegenerative diseases has been studied. In particular, the anti-inflammatory-antioxidant, blood sugar-lowering, and neuroprotective effects are expected to be useful for the prevention and treatment of dementia, especially in a model of dementia related to insulin resistance. Most animal models of Alzheimer's disease (AD) are based on genetic factors and research based on these models does not explain the pathophysiology of sporadic AD. Therefore, no drug can effectively delay the progression of AD. We hypothesized that HJ may improve cognitive function in an insulin resistance model which is considered one of the causes of sporadic AD. Insulin resistance was induced by a high-fat diet and streptozotocin injection. Additionally, the effect of HJ was tested in in vitro cultured hippocampal slices treated with an N-methyl-D-aspartate antagonist. At the given dose, HJ did not affect on the body weight but lowered blood glucose concentration, improved spatial memory in the Morris water maze and avoidance memory in the passive avoidance tests which was related to hippocampal brain-derived neurotrophic factor. In hippocampal slices, HJ strengthened long-term potentiation, which was suppressed by AP5. Thus, HJ improved cognitive functions in an insulin-resistance related dementia model and may be useful in treating sporadic AD.}, } @article {pmid40720331, year = {2025}, author = {Royall, DR and Palmer, RF}, title = {Affliction class moderates the dementing impact of amyloidopathy.}, journal = {Neuropsychology}, volume = {39}, number = {7}, pages = {587-598}, pmid = {40720331}, issn = {1931-1559}, support = {R01 AG080548/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; //Julia and Van Buren Parr Endowment/ ; //National Institutes of Health; National Institute on Aging/ ; }, mesh = {Humans ; Positron-Emission Tomography ; Male ; Female ; Aged ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aged, 80 and over ; Severity of Illness Index ; Biomarkers ; Disease Progression ; Neuroimaging ; }, abstract = {OBJECTIVE: The treatment of dementia is increasingly likely to focus on dementia-related biomarkers. Unfortunately, there is variability with regard to biomarker-related effects. This analysis tests an algorithm capable of identifying persons adversely impacted by any dementia-related biomarker in this case, amyloidopathy as estimated by positron emission tomography (PET). METHOD: N = 1,737 subjects of the Alzheimer's disease neuroimaging initiative were assigned to amyloidopathy-affliction classes. Moderation effects were tested by chi-square difference. RESULTS: 39.3% of subjects with (+) PET results were assigned to the afflicted class. The afflicted subjects had greater dementia severity and higher amyloid burdens. These effects persisted at 36 months. Furthermore, the association between amyloid burden and dementia severity was moderated by affliction class. Afflicted nondemented cases with positive PET findings were more likely to convert to clinical "Alzheimer's disease" over 48 months, by Cox's F: F(312, 154) = 1.27, p = .05. PET assessed amyloid burden was not related to dementia severity in resilient PET (+) cases. CONCLUSION: Our approach could allow for more accurate prediction of biomarker effects and guide precision interventions against specific biomarkers. (PsycInfo Database Record (c) 2025 APA, all rights reserved).}, } @article {pmid40720180, year = {2025}, author = {Mehta, NV and Kapadia, A and Khambete, M and Abhyankar, A}, title = {The Evolution of AChE Inhibitors in Alzheimer's Disease: From Single-Target to Multi-Target Ligands.}, journal = {Chembiochem : a European journal of chemical biology}, volume = {26}, number = {17}, pages = {e202500053}, doi = {10.1002/cbic.202500053}, pmid = {40720180}, issn = {1439-7633}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Ligands ; *Acetylcholinesterase/metabolism ; Blood-Brain Barrier/metabolism ; Animals ; }, abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disease marked by cognitive decline, neuronal degeneration, and the accumulation of intracellular neurofibrillary tangles, extracellular amyloid plaques, and neuroinflammation. Current treatment strategies, such as acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate receptor antagonists, offer symptomatic relief but fail to stop disease progression. The development of multi-target-directed ligands (MTDLs) has gained attention as a method to address the complex pathology of AD. This review provides a detailed account of the journey of AChE inhibitors from single-target ligands to MTDLs, emphasizing the structural changes that improve target specificity, blood-brain barrier penetration, and therapeutic impact. By exploring these advancements, the review highlights the potential of MTDLs to overcome the limitations of traditional single-target approaches and contribute to the discovery of more effective anti-Alzheimer therapies along with discussing potential pitfalls.}, } @article {pmid40720133, year = {2025}, author = {Zeltzer, E and Schonhaut, DR and Mundada, NS and Blazhenets, G and Soleimani-Meigooni, DN and Cho, H and Ranasinghe, KG and Windon, C and Yadollahikhales, G and Apgar, C and Gatsonis, C and Carrillo, MC and Hanna, L and Romanoff, J and Hillner, BE and Koeppe, RA and March, A and Siegel, BA and Smith, K and Whitmer, RA and Iaccarino, L and Rabinovici, GD and La Joie, R}, title = {Concordance Between Amyloid-PET Quantification and Real-World Visual Reads.}, journal = {JAMA neurology}, volume = {82}, number = {9}, pages = {952-962}, pmid = {40720133}, issn = {2168-6157}, support = {P30 AG062422/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Cross-Sectional Studies ; *Positron-Emission Tomography/methods/standards ; Female ; Aged ; Male ; *Cognitive Dysfunction/diagnostic imaging/metabolism ; Aged, 80 and over ; *Alzheimer Disease/diagnostic imaging/metabolism ; Aniline Compounds ; Radiopharmaceuticals ; *Brain/diagnostic imaging/metabolism ; }, abstract = {IMPORTANCE: With increased payer coverage and the advent of antiamyloid therapies, clinical use of amyloid positron emission tomography (PET) is likely to increase to help guide the diagnosis and treatment of patients with cognitive impairment. However, unlike most previous research studies, in clinical practice, scan acquisition is less standardized, interpretation typically relies purely on visual reads rather than scan quantification, and patients have more frequent comorbidities, all of which might compromise test accuracy. OBJECTIVE: To compare visual interpretation of amyloid-PET in real-world clinical settings to scan interpretation based on central quantification, in order to assess the accuracy of clinical reads. This cross-sectional quality improvement study used data from the Imaging Dementia-Evidence for Amyloid Scanning study, collected between February 2016 and January 2018 and analyzed between December 2021 and April 2023. The setting included 294 imaging facilities in the US. Medicare beneficiaries 65 years or older with cognitive decline for whom Alzheimer disease was a diagnostic consideration were recruited by dementia specialists from their clinical practices. EXPOSURES: Amyloid-PET with [18F]florbetapir, [18F]florbetaben, or [18F]flutemetamol. MAIN OUTCOMES AND MEASURES: PET scans were visually interpreted as positive or negative by local radiologists or nuclear medicine physicians following approved guidelines. Independently, scans were centrally processed and quantified using the standardized Centiloid (CL) scale. We applied an a priori autopsy-based threshold of 24.4 CL to quantitatively define scan positivity. RESULTS: Of 18 293 participants included in the parent study, scan images were available for 10 774 (59%), of which Centiloids were successfully calculated for 10 361 (96%). Median (IQR) patient age was 75 (71-80) years; 5245 patients (51%) were female, 6500 (63%) had mild cognitive impairment, and 3861 (37%) had dementia). Participants self-reported the following races and ethnicities: 1 Alaska Native (0%), 23 American Indian (0.2%), 188 Asian (1.8%), 316 Black (3.1%), 449 Hispanic or Latino (4.3%), 8 Native Hawaiian or Other Pacific Islander (0.1%), and 9125 White (88.2%). A total of 6332 scans (61%) were visually read as positive, and 6121 (59%) were quantitatively positive. Agreement between visual reads and quantitative classification was 86.3% (95% CI, 85.7%-87.0%; Cohen κ = 0.72; 95% CI, 0.70-0.73). A total of 5519 (53%) scans were positive visually and quantitatively (V+/Q+), 3416 (33%) were negative by both (V-/Q-), 813 (8%) were V+/Q-, and 602 (6%) were V-/Q+. Female sex (female: 4581/5241 [87.4%]; male: 4354/5109 [85.2%]; P =.001), White race (White race: 7900/9125 [86.6%]; non-White race: 1035/1225 [84.5%]; P =.046), and use of [18F]flutemetamol and [18F]florbetaben ([18F]flutemetamol: 559/628 [89.0%]; [18F]florbetaben: 2664/3032 [87.9%]; [18F]florbetapir: 5712/6690 [85.4%]; P <.001), compared with [18F]florbetapir, were associated with higher visual-quantitative concordance. Scans within a 10- to 40-CL borderline positivity zone were more likely to be discordant. CONCLUSIONS AND RELEVANCE: This cross-sectional study found high concordance between local visual reads and central quantification of clinical amyloid-PET scans, supporting the validity of amyloid-PET visual reads in real-world clinical practice.}, } @article {pmid40719892, year = {2025}, author = {Yu, Q and Li, L and Yu, S and Han, J and Cheng, Q and Cui, Z and Chen, H and Li, M and Lu, Z}, title = {Mitochondrial Damage and Autophagy Dysregulation in Alzheimer's Disease: Mechanisms and Therapeutic Opportunities.}, journal = {Neurochemical research}, volume = {50}, number = {4}, pages = {251}, pmid = {40719892}, issn = {1573-6903}, support = {tsqnz20240852//Taishan Scholars Program of Shandong Province/ ; 2022CXGC010507//Key Technology Research and Development Program of Shandong Province/ ; }, mesh = {*Alzheimer Disease/metabolism/pathology/drug therapy ; Humans ; *Mitochondria/metabolism/pathology/drug effects ; *Autophagy/physiology/drug effects ; Animals ; Mitophagy/physiology/drug effects ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive neurodegeneration and a variety of cognitive deficits. Of note, mitochondrial malfunctions occur early in the disease's development. Mitophagy impairment leads to the build-up of damaged mitochondria inside the cells, causing malfunction and eventual death of the cells. This review summarizes the mechanisms linking mitochondrial damage and autophagy dysregulation to AD and highlights potential therapeutic opportunities. We summarize how mitochondrial dysfunction contributes to AD, including defects in mitochondrial biogenesis, impaired dynamics, the impact of AD-related protein aggregates on mitochondrial integrity, and defective axonal transport. We also explore the roles of mitophagy in AD, including its function in the removal of harmed proteins and organelles. Finally, we highlight the therapeutic strategies for the treatment of AD, targeting molecular components involved in mitochondrial damage and autophagy dysregulation in AD, i.e., antioxidants, mitochondrial modulators, and mitophagy enhancers.}, } @article {pmid40719827, year = {2025}, author = {Yde Ohki, CM and Walter, NM and Smigielski, L and Bender, A and Rickli, M and Walitza, S and Grünblatt, E}, title = {Assessing the effects of methylphenidate in proliferation and Wnt activity of neuronal stem cells from attention deficit/hyperactivity disorder patients.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {40719827}, issn = {1435-1463}, abstract = {As the most common neurodevelopmental and mental disorder around the world, attention-deficit/hyperactivity disorder (ADHD) affects primarily children and adolescents. Both genetic (polygenicity) and environmental variables interplay in the etiology of this disorder. The Wnt signaling pathway, which regulates proliferation and differentiation during neurodevelopment, has been implicated in ADHD. Clinically, individuals with ADHD may exhibit delays in structural and functional brain development. Available evidence suggests that methylphenidate (MPH) treatment can potentially improve these delays. However, the molecular and cellular mechanisms underlying ADHD and the therapeutic targets of MPH are not yet completely elucidated. In a pilot investigation, the proliferation of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) was significantly lowered in ADHD male patients. Yet, we did not observe any variations in proliferation rates during the iPSC stage. To extend the earlier results, we increased the sample size to include females, explored whether MPH may improve NSC proliferation in ADHD and clarified the role of the Wnt pathway. To do so, iPSC and NSC proliferation from five ADHD patients and five controls was assessed. The results corroborated our previous findings of decreased proliferation in ADHD NSCs. Conversely, ADHD NSC proliferation was modestly regulated by MPH treatment at 10 nM, which also showed modulatory effects on Wnt signaling in this group. Interestingly, no increase in proliferation was seen when DKK1 blocked Wnt signaling before MPH treatment. These findings suggest MPH regulates the canonical Wnt pathway and may partially explain ADHD-related neurodevelopmental abnormalities and MPH-specific benefits.}, } @article {pmid40718958, year = {2025}, author = {Plantera, L and Immig, K and Fritsche, AK and Reinicke, M and Zemer, A and Monsonego, A and Ceglarek, U and Bechmann, I}, title = {Exploring the Impact of a High-Fat Diet on Brain Homeostasis: A Comprehensive Analysis of the Absence of Inflammation.}, journal = {Molecular nutrition & food research}, volume = {69}, number = {20}, pages = {e70168}, pmid = {40718958}, issn = {1613-4133}, mesh = {Animals ; *Diet, High-Fat/adverse effects ; Male ; Mice, Inbred C57BL ; Microglia/drug effects/metabolism ; *Brain/metabolism/drug effects ; Female ; *Homeostasis ; *Phytosterols/pharmacology ; Mice ; Inflammation ; Cytokines/metabolism ; Neuroinflammatory Diseases ; Weight Gain/drug effects ; Membrane Glycoproteins/metabolism ; Receptors, Immunologic ; }, abstract = {Excessive fat consumption increases the risk of Alzheimer's disease (AD), potentially through diet-induced neuroinflammation. Microglia, the brain's immune cells, are affected by obesity and diet. Phytosterols (PS), plant-derived cholesterol-like compounds, accumulate in the brain with age, and their content correlates with dietary intake. We hypothesize that the accumulation of PS modulates microglial activation and exerts anti-inflammatory effects. We investigated the effects of a normal diet (ND), high-fat diet (HFD), HFD with 2% PS (HFD+2% PS), and HFD with 4% PS (HFD+4% PS) on neuroinflammation in female and male C57BL/6J mice. Flow cytometry (FC) of microglia showed no significant regulation of pro- (IFN-γ, IL-1β, TNF-α) and anti-inflammatory (IL-10) cytokines due to diet, but sex- and age-dependent differences were observed. Immunofluorescence staining showed no TREM2 upregulation, indicating a lack of microglial activation in response to HFD. PS supplementation significantly reduced HFD-induced weight gain, suggesting metabolic effects. Contrary to existing research, we found no evidence of HFD-induced neuroinflammation or microglial activation. However, the reduction in weight gain with PS supplementation suggests potential metabolic benefits, which could have implications for the treatment of obesity. The potential effects on neuroinflammation remain unclear.}, } @article {pmid40718314, year = {2025}, author = {Auti, ST and Kulkarni, YA}, title = {Beneficial Effects of Caraway Oil in Aluminium Chloride-Induced Neurotoxicity.}, journal = {Cureus}, volume = {17}, number = {6}, pages = {e86783}, pmid = {40718314}, issn = {2168-8184}, abstract = {PURPOSE: Alzheimer's disease (AD) is characterized by cognitive decline and memory impairment, amyloid plaques, and neurofibrillary tangles (NFT). Current therapies provide symptomatic treatment but do not address the exact cause of the disease. Caraway oil, derived from Carum carvi, is rich in carvone and limonene with reported anticholinesterase, antioxidant, and neuroprotective properties. This study aimed to evaluate the neuroprotective effect of caraway oil in an aluminum chloride-induced rat model of neurotoxicity. METHODS: Albino Wistar rats were randomized into five groups: normal control, disease control (aluminum chloride, 100 mg/kg), standard (donepezil, 1 mg/kg), and caraway oil treatment groups (100 and 200 mg/kg). Treatments were administered orally for 42 days. Behavioral assessments included locomotor activity, the Morris water maze, the elevated plus maze, and passive avoidance tests. Acetylcholinesterase (AChE) activity and oxidative stress markers were assessed in the hippocampus and cortex. RESULTS: Caraway oil administration significantly improved locomotor activity and spatial memory in rats at 100 mg/kg and 200 mg/kg. The oil showed a significant effect on oxidative stress parameters in the hippocampus and cortex. AChE activity was also improved significantly (p<0.001) after caraway oil treatment. CONCLUSION: Caraway oil demonstrated significant neuroprotective effects in aluminum chloride-induced neurotoxicity, improving cognitive and behavioral functions and reducing oxidative stress. These findings suggest that caraway oil may have therapeutic potential in the management of AD.}, } @article {pmid40717971, year = {2025}, author = {Rong, Y and Li, Q and Du, Y and Wang, W and Su, W and Zhang, J and He, W}, title = {Preclinical evidence and potential mechanisms of tanshinone ⅡA on cognitive function in animal models of Alzheimer's disease: a systematic review and meta-analysis.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1603861}, pmid = {40717971}, issn = {1663-9812}, abstract = {BACKGROUND: Tanshinone ⅡA (Tan ⅡA) is a monomer extracted from Salvia miltiorrhiza Bunge. Animal studies have demonstrated its potential in providing cognitive protection in Alzheimer's disease (AD), but the overall effects remain inconclusive, and its multiple mechanisms have not been systematically summarized. OBJECTIVE: This systematic review and meta-analysis (SR/MA) aimed to evaluate the overall effects of Tan ⅡA on cognitive function in AD animal models and to summarize the mechanisms. METHODS: Seven databases (PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Chinese Biological Medical Disc, Chongqing VIP, and Wanfang databases) and grey literature were retrieved. Risk of bias was evaluated following the Systematic Review Center for Laboratory Animal Experiments. The mean difference (MD) or standard mean difference (SMD) with 95% confidence intervals (CIs) were used to evaluate the effect of Tan ⅡA on cognitive function, neuropathology, neuroinflammation, oxidative stress, apoptosis, and neural/synaptic plasticity, with P < 0.05 considered a significant difference. The effect and potential mechanisms of Tan ⅡA were demonstrated by performing multiple subgroup analyses. RESULTS: Nineteen studies involving 581 AD animals were identified. The included studies showed satisfactory reporting quality but had certain risks of bias in methodology. Tan ⅡA ameliorated cognitive deficits, evidenced by reducing escape latency (MD = -17.94 s; 95% CI: -22.92 to -12.96) and increasing time spent in the target quadrant (MD = 10.69 s; 95% CI: 7.32-14.07). It attenuated neuropathological damage by reducing amyloid-β (Aβ) plaques in thioflavine S staining (SMD = -3.46; 95% CI: -5.65 to -1.26) and increasing neuronal density in Nissl staining (SMD = 2.82; 95% CI: 2.11-3.52) and NeuN staining (SMD = 2.89; 95% CI: 1.71-4.08). Tan ⅡA also demonstrated anti-inflammatory effects through downregulation of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6)] and antioxidant stress properties by increasing superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels while reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Additionally, it exhibited antiapoptotic effects by increasing the B-cell lymphoma-2/Bcl-2-associated X protein (Bcl-2/Bax) ratio and decreasing Caspase-3 expression. Moreover, treatment improved neuronal/synaptic plasticity by upregulating postsynaptic density-95 (PSD-95) and brain-derived neurotrophic factor (BDNF) levels. CONCLUSION: Tan ⅡA could improve cognitive function and neuropathology through multiple mechanisms. This suggests that Tan IIA may serve as a viable candidate for the development of therapeutic strategies for AD. https://www.crd.york.ac.uk/PROSPERO/view/CRD42024588415.}, } @article {pmid40717894, year = {2025}, author = {Yu, M and Ma, H and Lai, X and Wu, J and Shen, M and Yan, J}, title = {Stem cell extracellular vesicles: a new dawn for anti-inflammatory treatment of neurodegenerative diseases.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1592578}, pmid = {40717894}, issn = {1663-4365}, abstract = {Mesenchymal stem cell-derived extracellular vesicles, as carriers for intercellular communication, are rich in bioactive substances such as proteins and nucleic acids, and show unique potential in the treatment of neurodegenerative diseases. Their vesicular structure, with a diameter of 30-150 nm, can penetrate the blood-brain barrier and modulate the activity of microglia and astrocytes by delivering functional molecules. This process inhibits the release of pro-inflammatory factors and enhances the expression of anti-inflammatory mediators, thereby alleviating neuroinflammation in the pathological process of neurodegenerative diseases. As natural drug carriers, extracellular vesicles can improve the targeted delivery efficiency of therapeutic molecules. However, their specific anti-inflammatory mechanisms remain not fully understood and require further exploration. This article discusses the anti-inflammatory effects in the context of neurodegenerative diseases and provides a summary and outlook on the anti-inflammatory actions associated with extracellular vesicles from past research.}, } @article {pmid40717814, year = {2025}, author = {Righes, G and Semenzato, L and Koutsikos, K and Zanato, V and Pinton, P and Giorgi, C and Patergnani, S}, title = {The role of autophagy in the pathogenesis and treatment of multiple sclerosis.}, journal = {Autophagy reports}, volume = {4}, number = {1}, pages = {2529196}, pmid = {40717814}, issn = {2769-4127}, abstract = {Autophagy is a crucial cellular process responsible for the degradation and recycling of damaged or unnecessary components, maintaining cellular homeostasis and protecting against stress. Dysregulation of autophagy has been implicated in a variety of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Various types of autophagy exist, each with distinct mechanisms, such as macroautophagy, mitophagy, lipophagy, and chaperone-mediated autophagy. These processes are essential for the removal of toxic substrates like protein aggregates and dysfunctional mitochondria, which are vital for neuronal health. In neurodegenerative diseases, the impairment of these clearance mechanisms leads to the accumulation of harmful substances, which accelerate disease progression. Modulating autophagy has emerged as a promising therapeutic strategy, with ongoing studies investigating molecules that can either stimulate or regulate this process. However, despite its potential, significant challenges remain in translating preclinical findings into clinically effective treatments. In this review, we will explore the different types of autophagy, their roles in neurodegenerative diseases, and the therapeutic potential associated with modulating these processes.}, } @article {pmid40717739, year = {2025}, author = {Kenaan, N and Alshehabi, Z}, title = {A review on recent advances in Alzheimer's disease: The role of synaptic plasticity.}, journal = {AIMS neuroscience}, volume = {12}, number = {2}, pages = {75-94}, pmid = {40717739}, issn = {2373-7972}, abstract = {Alzheimer's Disease (AD) remains a significant global health challenge, characterized by progressive neurodegeneration and a decline in cognitive abilities such as memory and learning. Despite being the main cause of dementia worldwide, the precise mechanisms that underlie neuronal dysfunction and synaptic plasticity impairment in AD remain elusive. However, while genetic mutations, dietary factors, and immune dysregulation are implicated in AD pathogenesis, the current therapeutic approaches are largely centered around acetylcholinesterase inhibitors (AChEIs). Nevertheless, this cholinergic hypothesis of AD is no longer satisfactory in describing this disease and has demonstrated a limited efficacy. Hence, new treatment approaches should be developed, and that requires us to view AD from a new perspective. Herein, in our review, we present the latest studies that discussed possible AD pathologies and pharmacotherapies. Additionally, we highlight that the emerging treatments that precisely targets brain regions associated with enhancing neuroplasticity have delivered promising results and seem to be more effective than older treatments. Finally, by viewing AD as a complex interplay of various factors that ultimately cause synaptic dysfunction and cognitive decline, we can develop more effective therapeutic interventions and ultimately alleviate the significant burden of this debilitating disease for both patients and their families.}, } @article {pmid40717666, year = {2025}, author = {Nakamura, Y and Adachi, J and Hirota, N and Iba, K and Sasajima, C and Shimizu, K and Nakai, M and Takahashi, K}, title = {Brexpiprazole's impacts on patients and caregivers in agitation in Alzheimer's dementia.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70522}, pmid = {40717666}, issn = {1552-5279}, support = {//Otsuka Pharmaceutical Co., Ltd/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/complications/psychology ; *Caregivers/psychology ; Male ; Female ; Double-Blind Method ; *Psychomotor Agitation/drug therapy/etiology ; Aged ; *Thiophenes/therapeutic use ; *Quinolones/therapeutic use ; Aged, 80 and over ; Treatment Outcome ; Middle Aged ; Neuropsychological Tests ; Japan ; }, abstract = {INTRODUCTION: We evaluated the impacts of brexpiprazole treatment on patient neuropsychiatric symptoms and caregiver distress in Japanese patients with agitation in Alzheimer's dementia (AAD). METHODS: In a phase 2/3 multicenter, double-blind study, patients were randomized to receive brexpiprazole 1 or 2 mg/day, or placebo (3:4:4) for 10 weeks. The Neuropsychiatric Inventory (NPI) was used for evaluation. The areas of patient symptoms and caregiver distress were defined as NPI and NPI-Distress, respectively. RESULTS: At Week 10, the differences of brexpiprazole 1 and 2 mg versus placebo for NPI total score were -1.2 (p = 0.5891) and -8.4 (p < 0.0001), and those for NPI-Distress total score were -1.1 (p = 0.2292) and -3.9 (p < 0.0001), respectively. In brexpiprazole 2 mg versus placebo, NPI and NPI-Distress agitation/aggression score showed ≥ 2 and ≥ 1 point improvement, respectively. DISCUSSION: Brexpiprazole is suggested to improve patient symptoms and to reduce caregiver distress in the treatment of AAD in Japanese patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03620981 HIGHLIGHTS: Brexpiprazole improved symptoms of patients with agitation in Alzheimer's dementia. The improvements included not only agitation, but also various behavioral and psychological symptoms of dementia scores. The improvements of patient symptoms led to the reduction of caregiver distress. Our study suggests that brexpiprazole is beneficial for both patients and caregivers.}, } @article {pmid40717576, year = {2026}, author = {Liu, Y and Sun, Y and Zhao, P and Liu, Z and Wang, Y and Wang, Y and Zhao, R and Wang, C and Wang, S}, title = {Near-Infrared Fluorescent Probe for the Early Diagnosis of Alzheimer's Disease.}, journal = {Medicinal research reviews}, volume = {46}, number = {1}, pages = {5-39}, doi = {10.1002/med.70000}, pmid = {40717576}, issn = {1098-1128}, support = {//We sincerely thank the Key R&D Program of Gansu Province, under Grant No.24YFWA010; the Talent Innovation and Entrepreneurship Project of Lanzhou City, under Grant No. 2020-RC-43; the Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital, under Grant No. CY2024-MS-A15 and No. CY2024-MS-B17; the Inner Mongolia Science and Technology Plan Project, under Grant No. 2021GG0339./ ; }, mesh = {*Alzheimer Disease/diagnosis/metabolism/diagnostic imaging ; Humans ; *Fluorescent Dyes/chemistry ; Early Diagnosis ; Animals ; Biomarkers/metabolism ; Spectroscopy, Near-Infrared/methods ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a common progressive neurodegenerative disease characterized by abnormal deposition of amyloid-β protein (Aβ) and the formation of neurofibrillary tangles (NFT). Although there are drugs available for clinical treatment, they do not fundamentally cure AD, so early diagnosis and intervention for AD are essential. In recent years, near-infrared fluorescent (NIRF) probes have been widely used in diagnosing AD due to their advantages of high tissue penetration, low autofluorescence interference, and non-invasiveness. This paper reviewed the recent progress of NIRF probes in AD. We described the effects of NIRF probes on AD biomarkers, including Aβ protein, Tau tangles, mitochondrial viscosity, reactive oxygen species, copper ions, zinc ions, and so on. In detail, we also described the optical properties, in vitro detection, and in vivo imaging of NIRF probes based on different dyes and their derivatives, such as curcumin, Boron dipyrromethene, Quinoline, and Donor-Acceptor. Despite significant progress, NIRF probes remain challenging in imaging and treating AD in vivo. Their selectivity and sensitivity need to be improved due to the complex structure of brain tissue and interfering factors. In conclusion, studying NIRF probes provides us with new ideas. Through further optimization, these probes may be used for early diagnosis and treatment detection of AD to better cope with the challenges brought by AD.}, } @article {pmid40717475, year = {2025}, author = {Hsiao, CH and Wu, CE and Wang, CM and Lin, TY and Wu, RY and Wu, MJ and Lin, SH and Sung, PS}, title = {Intracerebral hemorrhage risk in Alzheimer's disease patients on anticoagulants: A nationwide cohort study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {769-777}, doi = {10.1177/13872877251362362}, pmid = {40717475}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/epidemiology/drug therapy/complications ; Female ; Male ; *Cerebral Hemorrhage/epidemiology/chemically induced ; Aged ; Taiwan/epidemiology ; *Anticoagulants/adverse effects/therapeutic use ; Cohort Studies ; Aged, 80 and over ; Risk Factors ; Incidence ; Middle Aged ; Databases, Factual ; }, abstract = {BackgroundThe risk of intracerebral hemorrhage (ICH) in Alzheimer's disease (AD) patients undergoing anticoagulation (AC) remains unclear.ObjectiveThis nationwide cohort study assessed ICH risk in AC-treated AD patients.MethodsUsing Taiwan's National Health Insurance Research Database, we identified 1638 AC-treated AD patients and established four matched cohorts: AD with AC, AD without AC, non-AD with AC, and non-AD without AC. We applied inverse probability of treatment weighting (IPTW) and competing risks regression (CRR) to adjust for confounders and mortality risk. Cox proportional hazards regression estimated ICH risk.ResultsThe ICH incidence per 100 person-years was 2.21 in AD patients with AC, 1.03 without AC, 1.71 in non-AD with AC, and 0.28 in non-AD without AC. After IPTW adjustment, compared to non-AD without AC, AD patients with AC had the highest ICH risk (aHR 1.94, 95% CI: 1.44-2.61), followed by non-AD with AC (aHR 1.84, 95% CI: 1.51-2.23) and AD without AC (aHR 1.74, 95% CI: 1.42-2.11). ICH risk in AC-treated AD patients was comparable to non-AD with AC. Subgroup analysis showed higher ICH risk in females and those with hyperlipidemia, diabetes, heart failure, chronic kidney disease, or cancer.ConclusionsAD is associated with increased ICH risk, which is further elevated by AC use. These findings highlight the need for individualized risk-benefit evaluation, particularly in high-risk populations.}, } @article {pmid40717228, year = {2025}, author = {Gertz, MA and Aras, MA and Bart, N and Brannagan, TH and Griffin, JM and Kontorovich, AR and Rosen, AM}, title = {Unravelling the myriad physiologic roles of transthyretin: critical considerations for treating transthyretin amyloidosis.}, journal = {Annals of medicine}, volume = {57}, number = {1}, pages = {2536755}, pmid = {40717228}, issn = {1365-2060}, mesh = {Humans ; *Prealbumin/genetics/metabolism/physiology ; *Amyloid Neuropathies, Familial/therapy/genetics/physiopathology/drug therapy/metabolism ; Animals ; }, abstract = {BACKGROUND: Transthyretin (TTR) is a highly conserved protein with crucial and broadly protective physiologic roles across organ systems and diseases. Evidence shows that TTR contributes to neuroprotection, cognition, glucose regulation, pregnancy, muscle development, and bone mineralization. In several disease states, including diabetes, Alzheimer's disease, Lewy body dementia, cerebrovascular disease, and osteoporosis, higher TTR levels may be protective. Numerous studies have shown that low levels of TTR are associated with increased mortality overall and in relation to cardiovascular disease and several malignancies. PURPOSE: There is a growing portfolio of approved and investigational transthyretin amyloidosis (ATTR) treatments that differ in their mechanisms and effects on circulating TTR. When selecting an ATTR therapy, clinicians must decide whether to stabilize and preserve TTR and its functions or knockdown and drastically reduce TTR. This review summarizes the vital physiologic roles of TTR in health and disease. We consider the potential effects on normal biologic pathways that may occur while therapeutically suppressing TTR and discuss clinical decisions concerning ATTR therapies in the context of the summarized literature. DISCUSSION: TTR is essential for a broad range of physiologic processes and may confer clinically protective effects in neurologic and other organ systems. While a link between low TTR and severe disease and mortality is well established, it remains unclear whether long-term TTR suppression via ATTR therapies increases risk of disease. Clinical decisions in ATTR, however, should reflect the current understanding of the roles of TTR and the patient's clinical history. CONCLUSION: TTR serves vital physiologic roles across organ systems. Given its clinically protective properties, continued investigation into the potential long-term impact of TTR suppression via knockdown or gene editing therapies is prudent. ATTR treatment selection should reflect an awareness of the physiologic importance of TTR, as well as consideration of the potential long-term impact of chronic TTR suppression.}, } @article {pmid40715349, year = {2025}, author = {Ebrahimifar, A and Ahmadi, S and Rostamzadeh, J and Rahimi, K}, title = {Vanadyl sulfate restores memory impairment in streptozotocin-induced rat model of sporadic alzheimer's disease by repressing FoxO1 gene expression.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {27293}, pmid = {40715349}, issn = {2045-2322}, mesh = {Animals ; *Alzheimer Disease/drug therapy/chemically induced/genetics/metabolism ; Male ; Rats ; Streptozocin ; *Forkhead Box Protein O1/genetics/metabolism ; Rats, Wistar ; Disease Models, Animal ; Hippocampus/metabolism/drug effects ; *Memory Disorders/drug therapy ; *Gene Expression Regulation/drug effects ; HMGA1a Protein/genetics/metabolism ; Maze Learning/drug effects ; }, abstract = {Impaired brain insulin signaling is a risk factor for the pathogenesis of Alzheimer's disease (AD). FoxO1 and HMGA1 transcription factors are involved in the pathogenesis of both type 2 diabetes (T2D) and Alzheimer's disease (AD). This study aimed to assess the effect of vanadyl sulfate (VS) on impaired memory and hippocampal FoxO1 and HMGA1 RNA expression in sporadic AD (sAD) model in rats. Thirty-two male Wistar rats (250 ± 10 g) were divided into sham, AD, and VS 0.5 and 0.75 treated groups. The animals were subjected to two bilateral intracerebroventricular (icv) injections of either citrate buffer or streptozotocin (STZ) at 72-hour intervals. The VS-treated groups were treated with either 0.5 or 0.75 mg/ml oral VS for 3 weeks. The target quadrant entry latency, path length, and time and distance traveled in the target quadrants were assessed with the Morris water maze (MWM). Hippocampal tissues were analyzed for FoxO1 and HMGA1 RNA expressions. Group differences and group‒time interactions were analyzed via mixed two-way repeated-measures ANOVA. VS treatment in icv STZ rats restored impaired spatial memory. Hippocampal FOXO1 and HMGA1 RNA expressions were significantly lower in VS-treated and sham groups compared to AD control. VS can restore impaired spatial memory in sAD rats, possibly via the repression of FoxO1 and HMGA1 RNA expression in hippocampus.}, } @article {pmid40713860, year = {2025}, author = {Lancaster, TM and Murphy, K and Chandler, H}, title = {Reductions in brainstem volume as a key macrostructural indicator in at-risk populations for Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {177}, pmid = {40713860}, issn = {1758-9193}, support = {PNU-80762-CU-14//European Regional Development Fund/ ; 104943/Z/14/Z//Wellcome Trust/United Kingdom ; 104943/Z/14/Z//Wellcome Trust/United Kingdom ; WT224267//Wellcome/ ; WT224267//Wellcome/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/pathology/genetics ; *Brain Stem/pathology/diagnostic imaging ; Aged ; Male ; Female ; Magnetic Resonance Imaging ; Middle Aged ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Organ Size ; }, abstract = {BACKGROUND: Alterations to brain macrostructure, assessed via T1-weighted magnetic resonance imaging are observed in preclinical models of Alzheimer's disease (AD), reflecting susceptibility, prodromal stages of AD or correlates of early AD pathophysiology. While changes in cingulate and medial temporal lobe structures may be functionally implicated in cognitive decline, little is known about the viability of brain-based biomarkers that support autonomic functions implicated in preclinical AD risk such as the brainstem. METHODS: In a series of multiple linear regressions, we assess the volume of the brainstem in two asymptomatic at-AD-risk samples, assessed via the presence of either mild cognitive impairment (MCI, N = 148), or extremely high polygenic risk (N = 13) with matched demographics (mean age = 67 [range 58-76], in both cases). We further determine the strength of the association, compared to 150 other structural MRI features. RESULTS: We observed brainstem volume reductions (MCI: b = -0.29, P = 0.018; Genetic risk: b = -1.29, P = 0.002) in both samples. The magnitude of each preclinical AD marker (MCI / AD-polygenic risk)- brainstem association was empirically larger (Z > 2.3, P < 0.05, in both cases) than 150 frequently segmented MRI features. We further replicate the negative AD-polygenic risk score- brainstem association in UK Biobank (N = 31968; b = -0.002, P = 0.03), with weaker evidence that the association was larger than all other MRI features (Z = 1.622; P = 0.052). CONCLUSIONS: These observations suggest that AD risk, assessed via the presence of MCI or extremely high AD-polygenic risk score is linked to reduced brainstem volume before most typically observed morphological brain alterations. This conforms with evidence implicating the brainstem as one of the earliest sites of morphological neurodegeneration and provides a plausible biological mechanism linking prodromal autonomic symptoms to AD risk in later life. These observations warrant future investigation into the molecular correlates of AD-linked brainstem dysfunction, assessment as a candidate biomarker, and the exploration of brainstem mediated treatment strategies in AD prevention.}, } @article {pmid40713733, year = {2025}, author = {Li, H and Bai, L}, title = {Advances in mesenchymal stem cell and exosome-based therapies for aging and age-related diseases.}, journal = {Stem cell research & therapy}, volume = {16}, number = {1}, pages = {401}, pmid = {40713733}, issn = {1757-6512}, support = {No. 2022YFA1103803//National Key Research and Development Project/ ; 2021-I2M-1-035//Chinese Academy of Medical Sciences Initiative for Innovative Medicine/ ; }, mesh = {Humans ; *Exosomes/transplantation/metabolism ; *Mesenchymal Stem Cells/metabolism/cytology ; *Aging ; *Mesenchymal Stem Cell Transplantation/methods ; Animals ; *Osteoporosis/therapy ; Primary Ovarian Insufficiency/therapy ; Atherosclerosis/therapy ; *Alzheimer Disease/therapy ; }, abstract = {Mesenchymal stem/stromal cells (MSCs) and their exosomes (MSC-Exos) have great potential for tissue repair and regenerative medicine, which can improve the symptoms and prognosis of aging-related diseases and potentially slow the aging process through multiple pathways. This comprehensive review summarizes the characterization of MSCs and MSC-Exos from various tissue sources and their applications in treating diseases associated with aging, such as premature ovarian failure (POF), Alzheimer's disease (AD), atherosclerosis (AS), and osteoporosis (OP). MSCs exert therapeutic effects through multiple mechanisms, including differentiation into various cell types, secretion of bioactive molecules, and immune response regulation. MSC-Exos, which contain a diverse array of proteins, miRNAs, and other biomolecules, can deliver MSC-derived bioinformatics to target cells and demonstrate comparable therapeutic benefits to MSCs. This review highlights the signaling pathways and molecular mechanisms underlying the therapeutic efficacy of MSCs and MSC-Exos in age-related diseases, and further discusses the importance of MSC and MSC-Exo tissue source selection for specific disease applications and the potential of combination therapies and preconditioning strategies to enhance their therapeutic outcomes. Despite promising preclinical and clinical results, challenges such as uneven distribution, in vivo environmental maladaptation, apoptosis, and immune responses need to be addressed before widespread clinical application. Future research requires multidisciplinary collaboration to further elucidate the mechanisms of action and develop optimized therapeutic strategies for the prevention and treatment of age-related pathologies using MSCs and MSC-Exos.}, } @article {pmid40713730, year = {2025}, author = {Budda, B and Mitra, A and Park, L and Long, H and Kurnellas, M and Bien-Ly, N and Estacio, W and Burgess, B and Chao, G and Schwabe, T and Paul, R and Kenkare-Mitra, S and Rosenthal, A}, title = {Development of AL101 (GSK4527226), a progranulin-elevating monoclonal antibody, as a potential treatment for Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {174}, pmid = {40713730}, issn = {1758-9193}, support = {R44AG050363//National Institutes of Health/ ; R44AG050363//National Institutes of Health/ ; }, mesh = {*Progranulins/metabolism/blood ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Male ; Rats ; Female ; *Antibodies, Monoclonal/pharmacology/therapeutic use/pharmacokinetics ; Adaptor Proteins, Vesicular Transport/metabolism ; Rats, Sprague-Dawley ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid plaques, tau tangles, and neuronal loss. Progranulin (PGRN) is a secreted immune regulator, lysosomal chaperone, and neuronal survival factor. Genetic polymorphisms that reduce PGRN levels are associated with an increased risk for AD and other neurodegenerative disorders. The receptor sortilin binds and targets PGRN for lysosomal degradation, resulting in a reduction of extracellular PGRN. AL101 (GSK4527226) is a monoclonal antibody that binds to the sortilin receptor and is being developed as a potential PGRN-elevating therapy for AD. METHODS: Cell-based in vitro studies examined the interaction of AL101 with sortilin and its effect on PGRN levels. In vivo studies evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of AL101 in rats and nonhuman primates. A phase 1 study in healthy volunteers assessed PK, safety, tolerability, and PD biomarkers after intravenous or subcutaneous dosing of AL101. RESULTS: Cell-based assays showed that AL101 increased PGRN levels by decreasing cell surface sortilin levels and partially blocking the sortilin-PGRN interaction. Preclinical studies in rats and monkeys demonstrated that AL101 decreased cell surface sortilin levels on white blood cells and increased PGRN levels by up to 2-fold in cerebrospinal fluid (CSF) and up to 4-fold in blood. In the phase 1 study in healthy volunteers, both single and multiple doses of AL101 led to significant increases in plasma and CSF PGRN levels, providing additional support for its potential as a PGRN-elevating therapy. LIMITATIONS: The first-in-human dose-finding study was aimed at investigating the safety and tolerability of AL101 and was not sufficiently powered to detect changes in exploratory outcomes, such as neurodegeneration biomarkers. Clinical studies are needed to evaluate AL101 in AD patients. CONCLUSIONS: AL101 was shown to bind sortilin and decrease cell surface sortilin levels, leading to consistent elevations of PGRN across in vitro, preclinical, and human studies. These results support continued development of AL101 and its investigation as a potential treatment for AD and other neurodegenerative conditions where PGRN could play a role. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04111666. Registered on October 1, 2019. https://clinicaltrials.gov/ct2/show/NCT04111666 .}, } @article {pmid40712813, year = {2025}, author = {Tan, Q and Liu, Z and Zheng, J and Wang, Y and Wu, H and Wang, Q and Liang, Y}, title = {Experimental validation, molecular docking, proteomic analysis and network pharmacology reveal Morroniside promoting neurogenesis and improving cognitive impairment via Notch1/Hes1 pathway in intracerebroventricular-streptozotocin mice.}, journal = {Journal of ethnopharmacology}, volume = {353}, number = {Pt A}, pages = {120322}, doi = {10.1016/j.jep.2025.120322}, pmid = {40712813}, issn = {1872-7573}, mesh = {Animals ; *Transcription Factor HES-1/metabolism/genetics ; *Neurogenesis/drug effects ; Molecular Docking Simulation ; *Receptor, Notch1/metabolism ; Mice, Inbred C57BL ; Proteomics ; Network Pharmacology ; Mice ; Male ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Disease Models, Animal ; Streptozocin ; Neuroprotective Agents/pharmacology ; Signal Transduction/drug effects ; Hippocampus/drug effects/metabolism ; *Alzheimer Disease/drug therapy ; Cognition/drug effects ; Cornus/chemistry ; Glycosides ; }, abstract = {ETHNOPHARMACOLOGY RELEVANCE: Alzheimer's disease (AD) is a widely occurred neurodegenerative disease and Notch1/Hes1 pathway based neural stem cell (NSC) proliferation and neurogenesis are very crucial to restore cognitive ability. Cornus officinalis Sieb. et Zucc, a famous traditional Chinese herb remedy was widely used to tonify kidney and essence to ameliorate AD symptoms. Morroniside (MOR), a prominent bioactive component of Cornus officinalis Sieb. et Zucc has demonstrated promising neuroprotective properties, while its function of neurogenesis to improve cognitive ability largely remains unclear. AIM OF THE STUDY: This study aimed to reveal the role of MOR promoting neurogenesis and improving cognitive function via Notch1/Hes1 pathway thus to discover more neuropharmacological merit of MOR for AD treatment. MATERIALS AND METHODS: An AD model was induced in C57BL/6 mice by bilateral intracerebroventricular injection of streptozotocin (ICV-STZ). The mice were divided into control, model, low-dose, high-dose, DAPT + MOR, and donepezil groups. Cognitive functions were assessed using open field test, novel object recognition test, and Morris water maze (MWM). Histopathological changes were evaluated by Nissl and hematoxylin-eosin (HE) staining. Immunofluorescence double-labeling was performed to detect the expression of neurogenesis biomarkers in dentate gyrus. qRT-PCR and Western blotting were employed to measure the mRNA levels and Notch1, Hes1 expression. Molecular docking and dynamics simulations were performed to assess the binding affinity and stability between MOR and Notch1/Hes1 proteins. Proteomic analysis combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were integrated to verify the effects of MOR on including Notch1/Hes1 pathway for neurogenesis. RESULTS: MOR (20 and 40 mg/kg) significantly improved cognitive function of ICV-STZ mice from the behavioral tests. Histological analysis showed that MOR enhanced neuronal survival in the hippocampus, improved cellular arrangement and structure, and reduced oxidative stress. Immunofluorescence results indicated that MOR promoted NSC proliferation and neurogenesis, as evidenced by the elevated number of BrdU/Nestin and DCX/Ki67 double-positive cells. Mechanistically, MOR upregulated the mRNA and protein expression of Notch1 and Hes1 in the hippocampus and increased the expression of downstream Cyclin D1 and CDK4. Molecular docking and dynamics simulations further supported stable binding of MOR to Notch1 and Hes1. Proteomics combined with GO and KEGG enrichment further confirmed MOR (40 mg/kg, ∗P < 0.05) could significantly regulated multiple signaling pathways including Notch1 to ameliorate AD symptoms. CONCLUSION: This work demonstrated MOR could promote neural stem cell proliferation and neurogenesis by activating Notch1/Hes1 pathway, thereby enhancing learning and memory abilities in ICV-STZ mice. Such findings will further promote the clinical application of MOR for AD treatment.}, } @article {pmid40712769, year = {2025}, author = {Košak, U and Knez, D and Benetik, SF and Sokolov, PM and Pišlar, A and Horvat, S and Stojan, J and Lv, B and Zhang, W and Wang, Y and Wang, Q and Igert, A and Dias, J and Nachon, F and Brazzolotto, X and Sun, H and Gobec, S}, title = {Chiral switch of a butyrylcholinesterase inhibitor for the treatment of Alzheimer's disease.}, journal = {Chemico-biological interactions}, volume = {420}, number = {}, pages = {111670}, doi = {10.1016/j.cbi.2025.111670}, pmid = {40712769}, issn = {1872-7786}, mesh = {*Alzheimer Disease/drug therapy ; *Butyrylcholinesterase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/therapeutic use/pharmacology/metabolism ; Animals ; Humans ; Stereoisomerism ; Mice ; Acetylcholinesterase/metabolism/chemistry ; *Sulfonamides/chemistry/therapeutic use/pharmacology ; Male ; Crystallography, X-Ray ; }, abstract = {Butyrylcholinesterase (BChE) is a viable drug target to alleviate the symptoms of Alzheimer's disease (AD). We recently developed and biologically evaluated racemic N-benzylpiperidine-based naphthalene-2-sulfonamide 2, a nanomolar BChE inhibitor with procognitive effects. To optimize it, we performed a chiral switch. Using semi-preparative chiral HPLC, we isolated the pure enantiomers (R)-(-)-2 and (S)-(+)-2 and confirmed that (R)-(-)-2 is the eutomer and (S)-(+)-2 is the distomer with respect to human (h)BChE inhibition. Notably, (R)-(-)-2 is a less potent inhibitor of human acetylcholinesterase (hAChE) than both racemate 2 and (S)-(+)-2, which is advantageous, since AChE inhibition is associated with undesirable peripheral parasympathomimetic adverse effects. The crystal structures of hBChE in complexes with each enantiomer revealed distinct binding poses. The crystal structure of hBChE in complex with (R)-(-)-2 confirmed our previous hypothesis that only the (R)-(-)-2 is bound in the active site of hBChE when the racemate is crystallized. The synthesis of (R)-2 hydrochloride has a higher overall yield (73 %) than the synthesis of racemate 2 hydrochloride (64 %) and is safer as it avoids the use of LiAlH4. (R)-(-)-2 has in vivo efficacy in mice with scopolamine-induced AD-like symptoms, and (R)-(-)-2 is less toxic in mice (LD50 = 169 mg/kg) than racemate 2 (LD50 = 112 mg/kg). These results support the chiral switch from racemate 2 to (R)-(-)-2 as a safer and more selective lead compound in the anti-AD drug development pipeline.}, } @article {pmid40711709, year = {2025}, author = {Chen, R and Gao, H and Zhu, T and Zheng, N and Jin, Y and Li, M and Lu, Z}, title = {Syringaldehyde Ameliorates Cognitive Dysfunction in APP/PS1 Mice by Stabilizing the NLRP3 Pathway.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {15844-15858}, pmid = {40711709}, issn = {1559-1182}, support = {202134029//Jinan Clinical Medical Science and Technology Innovation Plan/ ; tsqnz20240852//Taishan Scholars Program of Shandong Province/ ; 82272414//the National Natural Science Foundation of China/ ; 2022CXGC010507//the Key Research and Development Program of Shandong Province, China/ ; }, mesh = {Animals ; *Cognitive Dysfunction/drug therapy/metabolism ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Mice, Transgenic ; Mice ; *Benzaldehydes/pharmacology/therapeutic use ; *Signal Transduction/drug effects ; Hippocampus/drug effects/pathology/metabolism ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Presenilin-1/metabolism ; Plaque, Amyloid/pathology/metabolism ; Alzheimer Disease/drug therapy/metabolism ; Male ; Oxidative Stress/drug effects ; Neurons/drug effects/metabolism/pathology ; Maze Learning/drug effects ; Mice, Inbred C57BL ; }, abstract = {This study aimed to assess the therapeutic efficacy of syringaldehyde (SYD) in Alzheimer's disease (AD) and to investigate its potential underlying molecular mechanisms. The potential of SYD for AD treatment was first explored through a network pharmacology approach. APPswe/PS1dE9 (APP/PS1) transgenic mice were treated with SYD via intraperitoneal injection for 9 weeks, and cognitive and behavioral functions were evaluated using the Y-maze, Morris water maze, and novel object recognition tests. Histopathological analysis was conducted to assess neuronal changes and amyloid plaque deposition in the hippocampus using immunofluorescence, hematoxylin and eosin staining, Nissl staining, and Congo red staining. RNA sequencing and transcription factor prediction analyses were utilized to identify the potential molecular mechanisms underlying SYD's therapeutic effects. In addition, in vitro experiments were performed on HT22 hippocampal neuronal cells, including ROS assay, TUNEL assay, and quantitative reverse transcription PCR, to validate the mechanisms suggested by the in vivo results. The results demonstrated that SYD treatment significantly reduced amyloid plaque deposition in the hippocampus of APP/PS1 mice, promoted neuronal repair, and improved cognitive performance. Further analysis indicated that these therapeutic effects were mediated by SYD's ability to enhance resistance to oxidative stress, alleviate neuronal damage, and inhibit the NF-κB/IL-1β/NLRP3 inflammatory pathway, thereby counteracting neuroinflammation induced by neuronal activation. In conclusion, this study provides strong evidence for the potential of SYD to ameliorate cognitive impairment and reduce amyloid plaque deposition in AD, highlighting its promising role as a therapeutic agent in the treatment of Alzheimer's disease.}, } @article {pmid40710322, year = {2025}, author = {Koch-Paszkowski, J and Sennett, C and Pula, G}, title = {Alzheimer's Disease-Thrombosis Comorbidity: A Growing Body of Evidence from Patients and Animal Models.}, journal = {Cells}, volume = {14}, number = {14}, pages = {}, pmid = {40710322}, issn = {2073-4409}, mesh = {*Alzheimer Disease/complications/epidemiology/pathology ; Humans ; Animals ; Disease Models, Animal ; *Thrombosis/complications/epidemiology/pathology ; Comorbidity ; Brain/pathology/blood supply ; }, abstract = {BACKGROUND/OBJECTIVES: A growing body of evidence is amassing in the literature suggesting a correlation between Alzheimer's disease (AD) and thrombotic vascular complications, which led to the suggestive hypothesis that thrombosis may contribute to AD onset and progression by damaging the neurovasculature and reducing the cerebral blood flow. In turn, low cerebral blood flow is likely to contribute to neurodegeneration by reducing nutrient and oxygen supply and impairing toxic metabolite removal from the brain tissue. METHODS: We searched the literature for studies in animal models of AD or patients diagnosed with the disease that reported circulating markers of platelet hyperactivity or hypercoagulation, or histological evidence of brain vascular thrombosis. RESULTS: Platelet hyperactivity and hypercoagulability have been described in multiple animal models of AD, and histological evidence of neurovascular thrombosis has also been reported. Similarly, clinical studies on patients with AD showed circulating markers of platelet hyperactivity and hypercoagulation, or histological evidence of neurovascular thrombosis collected from post-mortem brain tissue samples. CONCLUSIONS: Taken together, a convincing picture is emerging that suggests a strong correlation between systemic or neurovascular thrombosis and AD. Nonetheless, a mechanistic role for haemostasis dysregulation and neurovascular damage in the onset or the progression of AD remains to be proven. Future research should focus on this important question in order to clarify the mechanisms underlying AD and identify a treatment for this disease.}, } @article {pmid40710114, year = {2025}, author = {Nazir, S and Dogan, M and Wei, Y and Pan, G}, title = {Electrochemical Immunosensor Using COOH-Functionalized 3D Graphene Electrodes for Sensitive Detection of Tau-441 Protein.}, journal = {Biosensors}, volume = {15}, number = {7}, pages = {}, pmid = {40710114}, issn = {2079-6374}, mesh = {*Graphite/chemistry ; *Biosensing Techniques ; *tau Proteins/analysis ; Humans ; Electrodes ; *Electrochemical Techniques ; Immunoassay ; Alzheimer Disease/diagnosis ; Limit of Detection ; Amyloid beta-Peptides ; }, abstract = {Early diagnosis of Alzheimer's disease (AD) is essential for effective treatment; however current diagnostic methods are often complex, costly, and unsuitable for point-of-care testing. Graphene-based biosensors offer an alternative due to their affordability, versatility, and high conductivity. However, graphene's conductivity can be compromised when its carbon lattice is oxidized to introduce functional groups for biomolecule immobilization. This study addresses this challenge by developing an electrochemical immunosensor using carboxyl-modified commercial graphene foam (COOH-GF) electrodes. The conductivity of graphene is preserved by enabling efficient COOH modification through π-π non-covalent interactions, while antibody immobilization is optimized via EDC-NHS carbodiimide chemistry. The immunosensor detects tau-441, an AD biomarker, using differential pulse voltammetry (DPV), achieving a detection range of 1 fM-1 nM, with a limit of detection (LOD) of 0.14 fM both in PBS and human serum. It demonstrates high selectivity against other AD-related proteins, including tau-217, tau-181, amyloid beta (Aβ1-40 and Aβ1-42), and 1% BSA. These findings underscore its potential as a highly sensitive, cost-effective tool for early AD diagnosis.}, } @article {pmid40709649, year = {2025}, author = {Radanovic, M and Passos Neto, CEB and Monteiro, LH and Forlenza, OV}, title = {Transactive response DNA-binding protein 43 (TDP-43) proteinopathy: the complex biological and clinical findings in limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathological changes, limbic-predominant amnestic neurodegenerative syndrome, and other mixed age-related major neurocognitive disorders.}, journal = {Current opinion in psychiatry}, volume = {38}, number = {5}, pages = {341-347}, doi = {10.1097/YCO.0000000000001025}, pmid = {40709649}, issn = {1473-6578}, mesh = {Humans ; *TDP-43 Proteinopathies/pathology/diagnosis/genetics ; *Neurodegenerative Diseases/pathology ; *DNA-Binding Proteins/metabolism ; *Limbic System/pathology ; *Aging ; Dementia ; }, abstract = {PURPOSE OF REVIEW: As the term limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy (LATE) was coined in 2019, more than 200 articles addressing the subject were published. This review aims to provide an updated synthesis of knowledge regarding LATE-NC as a cause of age-related neurodegeneration and cognitive decline while addressing the challenges posed by overlapping neuropathologies in aging populations. RECENT FINDINGS: LATE-NC is marked by TDP-43 deposition in limbic structures, such as the amygdala and hippocampus, and is often associated with cognitive decline resembling Alzheimer's disease, though with a slower progression in isolated cases. The frequent coexistence of LATE-NC with other neuropathologies, particularly Alzheimer's disease neuropathologic changes (ADNC) and Lewy body dementia (LBD), exacerbates dementia severity and complicates diagnosis and treatment. Recent efforts have established clinical criteria for in-vivo diagnosis, including neuroimaging markers like hippocampal atrophy and limbic hypometabolism. Genetic studies have identified key risk genes, including GRN, TMEM106B, SORL1, and APOE, while biomarker development in cerebrospinal fluid (CSF) and blood remains in its early stages. SUMMARY: The review highlights the importance of multidisciplinary research and clinical approaches in addressing the complexities of neurodegenerative diseases involving TDP-43 proteinopathy, enhancing diagnostic accuracy, and developing effective treatments tailored to individual patient profiles.}, } @article {pmid40709644, year = {2025}, author = {Radanovic, M and Passos Neto, CEB and Monteiro, LH and Forlenza, OV}, title = {TDP-43 proteinopathy: the complex biological and clinical findings in LATE-NC, LANS, and other mixed age-related major neurocognitive disorders.}, journal = {Current opinion in psychiatry}, volume = {38}, number = {5}, pages = {361-367}, doi = {10.1097/YCO.0000000000001027}, pmid = {40709644}, issn = {1473-6578}, mesh = {Humans ; *TDP-43 Proteinopathies/diagnosis/pathology/physiopathology/genetics ; DNA-Binding Proteins/metabolism ; *Aging ; *Cognitive Dysfunction ; Dementia ; }, abstract = {PURPOSE OF REVIEW: Since the term limbic-predominant age-related TDP-43 encephalopathy (LATE) was coined in 2019, more than 200 articles addressing the subject were published. This review aims to provide an updated synthesis of knowledge regarding LATE-NC as a cause of age-related neurodegeneration and cognitive decline while addressing the challenges posed by overlapping neuropathologies in aging populations. RECENT FINDINGS: LATE-NC is marked by TDP-43 deposition in limbic structures, such as the amygdala and hippocampus, and is often associated with cognitive decline resembling Alzheimer's disease, though with a slower progression in isolated cases. The frequent coexistence of LATE-NC with other neuropathologies, particularly Alzheimer's disease neuropathologic changes (ADNC) and Lewy body dementia (LBD), exacerbates dementia severity and complicates diagnosis and treatment. Recent efforts have established clinical criteria for in-vivo diagnosis, including neuroimaging markers like hippocampal atrophy and limbic hypometabolism. Genetic studies have identified key risk genes, including GRN , TMEM106B , SORL1 , and APOE , while biomarker development in cerebrospinal fluid (CSF) and blood remains in its early stages. SUMMARY: The review underscores the need for multidisciplinary research and clinical approaches to address the complexities of neurodegenerative diseases involving TDP-43 proteinopathy, improve diagnostic accuracy, and develop effective treatments tailored to individual patient profiles.}, } @article {pmid40709598, year = {2025}, author = {Kaur, G and Mankoo, OK and Kaur, A and Mann, S and Priyadarshi, N and Singh, PP and Goyal, B and Singhal, NK and Goyal, D}, title = {The Synergistic Potential of Rationally Designed Phenol-Triazole Derivatives to Attenuate Aβ/Cu[2+]-Aβ Aggregation and Reactive Oxygen Species.}, journal = {ACS chemical neuroscience}, volume = {16}, number = {15}, pages = {3020-3037}, doi = {10.1021/acschemneuro.5c00386}, pmid = {40709598}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism ; *Reactive Oxygen Species/metabolism ; Animals ; *Copper/metabolism ; Rats ; PC12 Cells ; *Peptide Fragments/metabolism ; *Triazoles/pharmacology/chemistry ; Chelating Agents/pharmacology ; Clioquinol/pharmacology/chemistry ; Protein Aggregates/drug effects ; Phenols/pharmacology/chemistry ; Protein Aggregation, Pathological/metabolism/drug therapy ; }, abstract = {Alzheimer's disease (AD) is a neurological disorder characterized by a spectrum of symptoms such as memory loss and cognitive decline. AD is a multifaceted disease, and designing multipotent ligands is an effective strategy for AD treatment. In this regard, the pharmacophore moiety of clioquinol (CQ, metal chelator) was employed to design the multifunctional phenol-triazole derivatives 4(a-p). In particular, 4k with an o-I group on the phenyl ring displayed a noteworthy higher inhibition (inhibition efficiency 4k = 90.5%, IC50 = 6.51 ± 0.01 μM) against Aβ42 aggregation as compared to 38.1% noted for CQ. Furthermore, 4k significantly disassembled the preformed Aβ42 fibrils (Aβf, 92.5%), chelated Cu[2+] ions, and inhibited Cu[2+]-mediated Aβ42 aggregation. Compound 4k ceases the production of reactive oxygen species (ROS) as it acts as an antioxidant due to the presence of a phenolic hydroxyl group. Compound 4k has a sufficient safety-efficacy profile and alleviates the cytotoxicity by Aβ42 aggregates in PC-12 cells. For studying the modulation in the fibrillary architecture, hydrodynamic size, and structural transition of Aβ42 in the presence of 4k, we resorted to transmission electron microscopy (TEM), dynamic light scattering (DLS), and circular dichroism (CD), respectively. The molecular dynamics (MD) simulations depicted a notable reduction in the conformational transformations in the Aβ42 monomer (Aβm) and Aβf on the incorporation of 4k. Compound 4k modulates Aβ42 fibrillation by maintaining a helix conformation and simultaneously reduces the sampling of β-sheet structures in Aβm, consistent with the CD results. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis depicted a favorable binding of 4k to Aβm (-42.12 ± 7.14 kcal/mol) and Aβf (-74.42 ± 4.98 kcal/mol) with a significant contribution of van der Waals interactions to the binding free energy. The 4k-induced deformation in Aβf chains noted in the conformational snapshots depicts its destabilization potential against Aβf. Finally, our results uncovered the potential of phenol-triazole derivatives as a promiscuous ligand for targeting various pathological conditions in AD. The key insights into the prevention of conformational transitions in Aβm and destabilization of Aβf by 4k illuminated by experimental and computational studies are central to unraveling the molecular understanding of amyloid aggregation as well as designing future therapeutic candidates against multifaceted AD.}, } @article {pmid40709526, year = {2025}, author = {Sharma, N and Kim, D and Sharma, H and Kim, MI and Lee, H and Kim, M and Ryoo, N and Kang, MJ and Pyun, JM and Park, YH and Ryu, J and Oh, HJ and Yang, HS and Kim, HR and Kim, GH and Han, S and Yang, Y and Youn, YC and Teunissen, C and Zetterberg, H and Scheltens, P and An, SSA and Kim, YB and Kim, S and , }, title = {Unveiling blood biomarkers for neuronal hyperplasticity: Insights from AD molecular subtyping, a comprehensive review.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70475}, pmid = {40709526}, issn = {1552-5279}, support = {RS-2023-00251396//National Research Foundation of Korea/ ; RS-2021-NR060117//Ministry of Education/ ; 2021R1A6A1A03038996//Ministry of Education/ ; RS-2025-02292973//Korea Institute of Marine Science & Technology Promotion (KIMST)/ ; }, mesh = {Humans ; *Biomarkers/blood ; *Alzheimer Disease/blood/pathology/classification/diagnosis ; *Neurons/pathology ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, predominantly affecting the aging population. Early detection through biomarkers is essential for early intervention. Recent sub-classification of AD through extensive cerebrospinal fluid (CSF) proteomic analyses revealed distinct characteristics of each subtype, necessitating tailored therapeutic strategies. While CSF proteomics has identified potential biomarkers, the need for non-invasive and cost-effective substitutions highlights the importance of blood-based biomarkers (BBMs). This review is a comprehensive review that categorizes potential BBMs based on neuronal hyperplasticity (subtype 1), underlining their role in refining subtype classification and enabling precision medicine. Early AD is often marked by cortical and hippocampal hyperactivity, followed by hypoactivity during later stages of neurodegeneration. While the exact mechanisms remain unclear, factors like Ca[2+], glutamate, amyloid beta, tau, genetic factors, and impaired glial function play a role. Advancements in blood-based diagnostics would improve detection, individual treatment strategies, and evaluation of therapeutic response, eventually reducing the burden of AD on health-care systems. HIGHLIGHTS: Alzheimer's disease (AD; subtype 1) exhibits neuronal hyperplasticity, mild cortical atrophy, and moderate microglial activation. The neuronal hyperplasticity subtype of AD is characterized by an upregulation of synaptic and plasticity-related proteins, distinguishing it from other AD subtypes. Identifying biomarkers specific to neuronal hyperplasticity would enable real-time monitoring of therapeutic responses, allowing for individualized therapy as opposed to a "one-size-fits-all" strategy. The treatments based on neuronal hyperactivity reduction, restoration of synaptic plasticity, and anti-inflammation/metabolic dysfunction would be useful in this AD subtype. Blood-based biomarkers offer a cost-effective and accessible alternative to cerebrospinal fluid and neuroimaging methods.}, } @article {pmid40709497, year = {2025}, author = {Liu, W and Guo, J and Dong, Y and Li, J and Wang, Y}, title = {Efficacy of probiotic supplementation in influencing cognitive function in Alzheimer's disease: A systematic review and meta-analysis.}, journal = {Journal of food science}, volume = {90}, number = {7}, pages = {e70037}, doi = {10.1111/1750-3841.70037}, pmid = {40709497}, issn = {1750-3841}, mesh = {*Probiotics/administration & dosage ; Humans ; *Alzheimer Disease/psychology/drug therapy/microbiology ; *Cognition/drug effects ; Aged ; Gastrointestinal Microbiome/drug effects ; Randomized Controlled Trials as Topic ; *Dietary Supplements ; Male ; Female ; Aged, 80 and over ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral changes. Emerging evidence suggests that the gut microbiota influences central nervous system function. Probiotic interventions may offer a promising therapeutic approach by modulating the gut microbiota composition and potentially improving cognitive outcomes in AD patients. This meta-analysis aimed to assess the effects of probiotic supplementation on cognitive function in AD patients by analyzing randomized controlled trials (RCTs). Following PRISMA 2020 guidelines and registered with PROSPERO (CRD42024508725), we conducted a comprehensive search across PubMed, Embase, Cochrane Library, and ClinicalTrials.gov through April 9th, 2024. Only double-blind RCTs comparing probiotic supplementation to placebo in patients aged 65 or older with clinically diagnosed AD were included. Primary outcomes were cognitive function scores from validated tools like MMSE and TYM. Our stringent inclusion criteria identified four double-blind RCTs with 251 participants aged 65 or older with clinically diagnosed AD. Statistical analysis using a random-effects model revealed significant cognitive improvement in probiotic-treated groups compared to placebo controls (Standardized Mean Difference [SMD] = 0.67; 95% CI [0.14, 1.19]; P < 0.05), though substantial heterogeneity was observed (I[2] = 79.16%). Subgroup analyses indicated that probiotic formulation type, dosage, and baseline AD severity may influence cognitive outcomes. While these findings suggest probiotics may offer cognitive benefits for AD patients, the high heterogeneity and limited study number necessitate additional well-designed clinical trials to confirm these promising results and establish optimal treatment protocols for clinical implementation.}, } @article {pmid40709486, year = {2025}, author = {Munn, EE and Montelongo, A and Patel, VK and Fodstad, JC and Ciccarelli, MR and Ptomey, LT and Pangelinan, MM}, title = {A meta-analysis and systematic review of interventions to prevent or treat cognitive decline related to Alzheimer's disease in adults with Down syndrome.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70471}, pmid = {40709486}, issn = {1552-5279}, mesh = {Humans ; *Down Syndrome/complications ; *Alzheimer Disease/complications/therapy ; *Cognitive Dysfunction/therapy/prevention & control/etiology ; Adult ; Cognitive Behavioral Therapy ; }, abstract = {Down syndrome (DS) is a leading genetic risk factor for Alzheimer's disease (AD). Although prevention and treatment of AD are well documented for those without DS, less is known about individuals with DS. This review evaluates the efficacy of AD and dementia interventions in people with DS. It includes 26 articles with 1417 participants ages 18-69 in the qualitative synthesis and 17 articles with 1118 participants in the meta-analysis. Four types of interventions demonstrated small-to-moderate effects: pharmacological (n = 19), exercise (n = 5), environmental (n = 1), and cognitive training (n = 1). Significant treatment effects were observed across interventions (t(66) = 4.67, p < 0.0001, d = 0.29, 95% confidence interval [CI]: 0.16-0.40); however, high heterogeneity (I[2] = 93.8% CI = 92.8-94.7) was noted, which was not explained by intervention type or outcome. The meta-analysis indicates that interventions enhance AD-related cognitive and behavioral outcomes, emphasizing the need for further research to address heterogeneity. This review was registered with PROSPERO: CRD42024567026. HIGHLIGHTS: This study is the first to comprehensively review both pharmacological and non-pharmacological interventions for Alzheimer's disease (AD) in individuals with Down syndrome (DS), extending previous reviews by including a meta-analysis and examining key mediating variables. Donepezil, the most studied pharmacological treatment, showed significant cognitive and behavioral improvements in individuals with DS, especially with longer treatment periods. However, further trials are needed to explore its efficacy in combination with non-pharmacological interventions. All seven non-pharmacological studies reported significant improvement, suggesting that even small doses of exercise and cognitive training can be effective and feasible for individuals with DS. Online formats may enhance scalability and reduce barriers to participation. Significant heterogeneity in cognitive assessments across studies highlights the need for standardized, sensitive assessments to enable meaningful comparisons of intervention effects. Additional studies are required to determine the long-term efficacy of pharmacological interventions like Donepezil and to assess the sustained impact of non-pharmacological interventions on key AD-related cognitive domains such as memory, language, and executive function.}, } @article {pmid40709360, year = {2025}, author = {Zhang, Y and Wang, Y and Xu, K and Zhang, C and Lv, P and Bai, Y and Wang, S}, title = {Repetitive transcranial magnetic stimulation across neurodegenerative diseases: a systematic review and dose-response meta-analysis.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1615734}, pmid = {40709360}, issn = {1663-4365}, abstract = {OBJECTIVE: We summarized the existing clinical evidence of repetitive transcranial magnetic stimulation (rTMS) for Parkinson's Disease (PD) and Alzheimer's Disease (AD) and conducted a series of dose-response meta-analyses to determine the curve relationship between the number of pulses and the effect size of the treatment. METHODS: Existing evidence was retrieved from five databases, and relevant outcome data on rTMS treatment for motor and non-motor symptoms of PD and AD were collected. Data were analyzed using R software to assess effect size using standardized mean differences (SMD) and 95% confidence intervals (CI). Heterogeneity testing was performed to assess differences in efficacy among the evidence, and restricted cubic spline (RCS) was used to fit the dose-response curves. RESULTS: A total of 51 publications were included, involving 1,938 subjects. We found that for PD patients, the total number of rTMS pulses showed significant bell-shaped curves in TUG (χ[2] = 6.87, df = 2, p = 0.03), FOGQ (χ[2] = 15.17, df = 2, p = 0.001), BDI (χ[2] = 14.33, df = 2, p = 0.001), HAMD (χ[2] = 12.63, df = 2, p = 0.001), and HAMA (χ[2] = 6.06, df = 2, p = 0.04). For AD patients, the total number of rTMS pulses demonstrated significant bell-shaped curves for MMSE (χ[2] = 8.76, df = 2, p = 0.01) and MoCA (χ[2] = 6.79, df = 2, p = 0.03). CONCLUSION: Our dose-response meta-analysis results show that rTMS demonstrates significant efficacy in certain motor and non-motor symptoms of PD and AD. The number of rTMS pulses presents a typical bell-shaped curve for these symptoms, indicating that more number of rTMS pulses is not always better; beyond a certain threshold, increasing the number of rTMS pulses correlates negatively with therapeutic efficacy.}, } @article {pmid40709087, year = {2025}, author = {Wang, G and Zhou, X and Pang, X and Ma, K and Li, L and Song, Y and Hou, D and Wang, X}, title = {Pharmacological effects, molecular mechanisms and strategies to improve bioavailability of curcumin in the treatment of neurodegenerative diseases.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1625821}, pmid = {40709087}, issn = {1663-9812}, abstract = {With the global population aging, the incidence of neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, has been progressively increasing. However, effective therapeutic strategies and clinical drugs for these disorders remain scarce. Curcumin, a natural polyphenolic compound primarily derived from the herbaceous plant Curcuma longa L., has been proposed as a promising candidate for ND treatment based on the excellent antioxidant, anti-inflammatory and neuroprotective properties. Its pharmacological activities encompass scavenging reactive oxygen species, mitigating toxic protein aggregation and cytotoxicity, repairing mitochondrial dysfunction, and inhibiting excessive neuronal apoptosis. Compared with synthetic drugs, curcumin demonstrates a more favorable safety profile with fewer side effects. Nevertheless, its clinical application is substantially hindered by poor bioavailability, which stems from low aqueous solubility, inefficient intestinal absorption, and rapid metabolism and systemic elimination. Conventional administration methods often fail to achieve effective concentrations in vivo. Further clinical trials are also required to validate the therapeutic efficacy and potential adverse effects in human subjects. This article systematically reviews the pathogenesis of NDs and the knowledge on curcumin including pharmacological effects, neuroprotective mechanisms, functions across specific NDs and advanced strategies to enhance the bioavailability, with the aim of promoting the development and clinical translation of curcumin-based therapeutics for NDs.}, } @article {pmid40708863, year = {2025}, author = {Nagarajan, R and Lyu, J and Kambali, M and Wang, M and Pearce, RA and Rudolph, U}, title = {Noncanonical sustained actions of propofol reverse surgery-induced microglial activation and cognitive impairment in aged mice.}, journal = {PNAS nexus}, volume = {4}, number = {7}, pages = {pgaf213}, pmid = {40708863}, issn = {2752-6542}, abstract = {Perioperative neurocognitive disorder is a major concern in aged individuals, and currently, treatment options are limited. Chronic intermittent propofol (CIP) has been shown to have neuroprotective effects in aged mice and in a mouse model of Alzheimer's disease. Here, we investigated whether CIP could reverse surgery-induced cognitive deficits and propose a mechanism of action. Male and female mice (21-24 months old) underwent exploratory laparotomy under isoflurane anesthesia. Animals were administered either CIP (75 mg/kg i.p.) or vehicle every fifth day throughout the experiment. Cognitive function was assessed using a battery of behavioral tests: the Y-maze test (spatial working memory), the novel object recognition test (recognition memory), the Morris water maze (spatial learning and memory), and trace and contextual fear conditioning (nondeclarative associative memory). Expression of α5-GABAA receptors, markers of apoptosis, and a microglial activation marker were assessed in the hippocampus using western blotting. The amount of α5-GABAA receptor subunits in cell-surface membranes was determined by biotinylation followed by western blotting. CIP induced a sustained redistribution of α5-GABAA receptors to the cell-surface membranes. Laparotomy led to an increased expression of the microglial activation marker Iba-1 and of proapoptotic markers, and impaired cognitive functions. CIP prevented these molecular and cognitive changes. Perioperative CIP redistributes α5-GABAA receptors to cell-surface membranes and thus prevents or reverses surgery-induced increases in markers of microglial activation, apoptosis, and cognitive dysfunction. Increasing the number or activity of α5-GABAA receptors on cell-surface membranes may be an effective therapeutic strategy to reduce postoperative morbidity in elderly patients.}, } @article {pmid40708572, year = {2025}, author = {Pan, Y and Ji, N and Jiang, L and Zhou, Y and Feng, X and Li, J and Zeng, X and Wang, J and Shen, YQ and Chen, Q}, title = {GPCRs identified on mitochondrial membranes: New therapeutic targets for diseases.}, journal = {Journal of pharmaceutical analysis}, volume = {15}, number = {7}, pages = {101178}, pmid = {40708572}, issn = {2214-0883}, abstract = {G protein-coupled receptors (GPCRs) are the largest family of membrane proteins in eukaryotes, with nearly 800 genes coding for these proteins. They are involved in many physiological processes, such as light perception, taste and smell, neurotransmitter, metabolism, endocrine and exocrine, cell growth and migration. Importantly, GPCRs and their ligands are the targets of approximately one third of all marketed drugs. GPCRs are traditionally known for their role in transmitting signals from the extracellular environment to the cell's interior via the plasma membrane. However, emerging evidence suggests that GPCRs are also localized on mitochondria, where they play critical roles in modulating mitochondrial functions. These mitochondrial GPCRs (mGPCRs) can influence processes such as mitochondrial respiration, apoptosis, and reactive oxygen species (ROS) production. By interacting with mitochondrial signaling pathways, mGPCRs contribute to the regulation of energy metabolism and cell survival. Their presence on mitochondria adds a new layer of complexity to the understanding of cellular signaling, highlighting the organelle's role as not just an energy powerhouse but also a crucial hub for signal transduction. This expanding understanding of mGPCR function on mitochondria opens new avenues for research, particularly in the context of diseases where mitochondrial dysfunction plays a key role. Abnormalities in the phase conductance pathway of GPCRs located on mitochondria are closely associated with the development of systemic diseases such as cardiovascular disease, diabetes, obesity and Alzheimer's disease. In this review, we examined the various types of GPCRs identified on mitochondrial membranes and analyzed the complex relationships between mGPCRs and the pathogenesis of various diseases. We aim to provide a clearer understanding of the emerging significance of mGPCRs in health and disease, and to underscore their potential as therapeutic targets in the treatment of these conditions.}, } @article {pmid40708508, year = {2025}, author = {Rana, A and Malviya, R and Rajput, S and Sridhar, SB and Wadhwa, T}, title = {Trends in Nanoparticle-based Strategies for the Management of Neuroinflammation.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273373041250707012835}, pmid = {40708508}, issn = {1996-3181}, abstract = {Neuroinflammation, characterised by an overactive immune system in the brain and spinal cord, has now been tied to several neurodegenerative diseases. Here, immune cells invade into the brain, activating astrocytes and microglia. Neuroinflammation is a common symptom of many neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This inflammatory reaction occurs within the central nervous system (CNS). Neurological dysfunction results from the inflammatory response, which arises in reaction to any kind of brain injury. Regulating neuroinflammation can be useful for controlling brain disorders associated with neuroinflammation. Several targeted drug delivery systems attempt to treat neuroinflammation caused by neurodegenerative illnesses or brain tumours by targeting the microglia and other immune cells in the central nervous system. Therefore, biodegradable and biocompatible NPs (nanoparticles) could be developed as a treatment for neurodegenerative diseases caused by neuroinflammation or as a less invasive means of transporting other drugs across the blood-brain barrier. Numerous applications of gold nanoparticles (AuNPs) in the treatment of neurological diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are studied in this article. To prevent neuroinflammation and microglia over-activation, some NPs have recently been found to be effective anti-inflammatory medication carriers that cross the blood-brain barrier.}, } @article {pmid40707875, year = {2025}, author = {Wang, C and Bu, X and Cao, M and Lian, Y and Ling, H and You, M and Yi, J and Gao, X and Wu, D and Li, Y}, title = {Mir-199a-3p aggravates neuroinflammation in an Alzheimer's disease transgenic mouse model by promoting M1-polarization microgliaMir-199a-3p M1.}, journal = {BMC neuroscience}, volume = {26}, number = {1}, pages = {45}, pmid = {40707875}, issn = {1471-2202}, support = {yzjj2023qn15//President Foundation of Zhujiang Hospital, Southern Medical University/ ; 2018A0303130216//Natural Science Foundation of Guangdong Province/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; *MicroRNAs/metabolism/genetics ; *Microglia/metabolism ; Mice, Transgenic ; Mice ; *Neuroinflammatory Diseases/metabolism/genetics/pathology ; Disease Models, Animal ; Hippocampus/metabolism ; Male ; Cytokines/metabolism ; }, abstract = {Chronic neuroinflammation, driven by M1-polarized microglia, is a core pathological mechanism of Alzheimer's disease (AD). Elevated expression levels of miR-199a-3p and pro-inflammatory cytokines were detected in the hippocampi of AD transgenic mice and in LPS-stimulated BV2 microglial cells. We hypothesized that miR-199a-3p exacerbates neuroinflammation by promoting M1 microglial polarization in AD progression. M1 （AD）。 AD LPS BV2 miR-199a-3p 。 miR-199a-3p AD M1 。 OBJECTIVE: To explore the role of miR-199a-3p in AD-associated neuroinflammation. miR-199a-3p AD 。 METHODS: AD transgenic (APPswe/PSEN1dE9) mice and LPS-treated BV2 cells were used to assess miR-199a-3p effects in vivo and in vitro. Inflammatory cytokines and markers for microglial cell typing were detected. Transcriptome sequencing was performed on miR-199a-3p-modulated BV2 cells, and the sequencing data were cross-analyzed with public databases to predict miR-199a-3p-mediated pathways.AD （APPswe/PSEN1dE9） LPS BV2 miR-199a-3p 。。 miR-199a-3p BV2 ，， miR-199a-3p 。 RESULTS: Intracerebroventricular administration of miR-199a-3p agomir exacerbated amyloid deposition and impaired cognitive function in AD mice, and promoted microglial polarization toward the M1 phenotype. Conversely, treatment with miR-199a-3p antagomir attenuated AD pathology and suppressed M1 polarization. In LPS treated BV2 cells, miR-199a-3p mimics promoted M1 polarization, while inhibitors reversed this effect. Transcriptome analysis revealed that miR-199a-3p downregulated WDR76, subsequently suppressing cell cycle-associated pathways, IL-17 signaling, and FOXO pathways, resulting in an increase in the proportion of M1 type microglia. miR-199a-3p agomir AD ， M1 。， miR-199a-3p AD M1 。 LPS BV2 ，miR-199a-3p M1 ，。，miR-199a-3p WDR76，、 IL-17 FOXO ， M1 。 CONCLUSION: MiR-199a-3p aggravates neuroinflammation of AD by promoting M1-polarization microglia. These findings highlight miR-199a-3p as a potential therapeutic target for AD.}, } @article {pmid40707826, year = {2025}, author = {Chun, MY and Jeon, J and Chung, SJ and Kim, J}, title = {Association between osteoporosis and risk of dementia: a Korean women nationwide population-based cohort study.}, journal = {Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA}, volume = {36}, number = {10}, pages = {1987-1997}, pmid = {40707826}, issn = {1433-2965}, support = {RS-2024-00345524//National Research Foundation of Korea/ ; }, mesh = {Humans ; Female ; Aged ; Republic of Korea/epidemiology ; *Dementia/epidemiology/etiology/physiopathology ; Retrospective Studies ; Bone Density/physiology ; *Osteoporosis, Postmenopausal/epidemiology/physiopathology/complications ; Risk Factors ; Risk Assessment/methods ; Incidence ; Bone Diseases, Metabolic/epidemiology/physiopathology/complications ; Aged, 80 and over ; Mass Screening/methods ; Follow-Up Studies ; }, abstract = {UNLABELLED: Brief rationale: dementia and osteoporosis share risk factors and are rising in aging populations. MAIN RESULTS: osteoporosis significantly increases the risk of all-cause dementia, Alzheimer's disease dementia, and vascular dementia in Korean older women. Significance of the paper: early detection and treatment of osteoporosis may reduce dementia risk. PURPOSE: Dementia and osteoporosis share common risk factors and are increasing in prevalence in the aging population. This study aimed to investigate the impact of osteoporosis on dementia and its subtypes in women using data from a population-based, health-screening cohort, with a follow-up period of more than 10 years. METHODS: This retrospective study included 66-year-old Korean women who participated in the "National Screening Program for Transitional Ages" from 2010 to 2011. Participants were categorized based on spine bone mineral density T-scores into three groups: normal (T-score ≥ - 1.0 standard deviation [SD]; 18.7%), osteopenia (- 2.5 SD < T-score < - 1.0 SD; 42.5%), and osteoporosis (T-score ≤ - 2.5 SD; 38.8%). Incident dementia cases were evaluated until 2021 using national healthcare claims databases. Fine-Gray subdistribution hazard models were used to assess the risks of all-cause dementia including Alzheimer's disease (AD) dementia and vascular dementia (VaD), accounting for death as a competing risk. RESULTS: The study included 131,872 dementia-free women aged 66 years. Over an average follow-up of 10.4 ± 1.8 years, 9399 individuals developed all-cause dementia (7.1%). Osteoporosis was associated with increased risks for all-cause dementia (adjusted subdistribution hazard ratio [asHR] 1.14; 95% confidence interval [CI] 1.08-1.21; p < 0.001), AD dementia (asHR 1.14; 95% CI 1.08-1.22; p < 0.001), and VaD (asHR 1.42; 95% CI 1.08-1.87; p = 0.013), compared to normal. CONCLUSION: Our findings highlight an association between osteoporosis and increased risks of developing all-cause dementia, AD dementia, and VaD. Further research is needed to explore the effects of early identification and treatment of osteoporosis in preventing dementia.}, } @article {pmid40706971, year = {2025}, author = {Alshehri, GH and Al-Kuraishy, HM and Al-Gareeb, AI and Fawzy, MN and Waheed, HJ and Papadakis, M and Alexiou, A and El-Saber Batiha, G}, title = {A novel therapeutic prospect: a dual-acting tirzepatide for Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {1003}, number = {}, pages = {177979}, doi = {10.1016/j.ejphar.2025.177979}, pmid = {40706971}, issn = {1879-0712}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Animals ; *Glucagon-Like Peptide 1/metabolism/therapeutic use/analogs & derivatives ; *Neuroprotective Agents/therapeutic use/pharmacology ; Signal Transduction/drug effects ; Brain/drug effects/metabolism ; Cognition/drug effects ; Insulin/metabolism ; Insulin Resistance ; Tirzepatide ; }, abstract = {Alzheimer's disease (AD), the leading cause of dementia, involves microglial activation, pro-inflammatory cytokine release, and impaired insulin signaling via insulin receptor substrate 1 (IRS-1) inhibition. Brain insulin resistance (BIR) is a key factor in AD progression, disrupting synaptic plasticity and neuronal function. Additionally, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) signaling, which regulate insulin pathways, are compromised in AD. GLP-1/GIP receptor activation or their analogs, such as tirzepatide, show potential in mitigating AD neuropathology. However, the precise neuroprotective mechanisms of tirzepatide remain unclear. This mini-review explores tirzepatide's potential therapeutic effects in AD, focusing on its role in restoring insulin signaling, reducing neuroinflammation, and improving cognitive function. Understanding these mechanisms could offer new insights into AD treatment strategies.}, } @article {pmid40706880, year = {2025}, author = {Duan, K and Qin, C and Zhang, Y and Li, D and Zhang, J and Li, F}, title = {Scorpion venom heat-resistant synthetic peptide regulates Nrf-2 to alleviate neuronal pyroptosis in an AD model induced by endoplasmic reticulum stress under PM2.5 exposure.}, journal = {Toxicon : official journal of the International Society on Toxinology}, volume = {265}, number = {}, pages = {108504}, doi = {10.1016/j.toxicon.2025.108504}, pmid = {40706880}, issn = {1879-3150}, mesh = {Animals ; *Particulate Matter/toxicity ; *Pyroptosis/drug effects ; *NF-E2-Related Factor 2/metabolism ; Mice ; *Endoplasmic Reticulum Stress/drug effects ; *Alzheimer Disease/drug therapy ; *Scorpion Venoms/pharmacology ; Neurons/drug effects ; Rats ; Disease Models, Animal ; PC12 Cells ; *Peptides/pharmacology ; Amyloid beta-Peptides ; Male ; Oxidative Stress/drug effects ; Peptide Fragments ; }, abstract = {In recent years, the impact of fine particulate matter (PM2.5) on the nervous system, particularly on neurodegenerative diseases, has garnered widespread attention. Epidemiological studies have shown that exposure to PM2.5 is closely associated with the development and progression of Alzheimer's disease (AD). However, the mechanisms through which PM2.5 exacerbates AD remain unclear. Scorpion venom heat-resistant synthetic peptide (SVHRSP) is a pharmacologically active product synthesised from the amino acid sequence of scorpion venom heat-resistant peptide. In this study, we investigated the mechanism through which PM2.5 exposure aggravates neuronal pyroptosis and validated the protective effects of SVHRSP against AD. PC12 and HT22 neuronal cells were used to construct in vitro models of AD. Mice were stereotactically injected with Aβ25-35 protein to induce AD. Subsequently, PM2.5 exposure-induced changes in ER stress, pyroptosis, and oxidative stress in AD models, were detected through in vivo and in vitro experiments. The results indicated that PM2.5 exposure aggravated cognitive impairment, ER stress, and pyroptosis in mice with AD. Conversely, treatment with SVHRSP counteracted the damage induced by PM2.5 exposure. At a mechanistic level, PM2.5 might enhance oxidative stress and trigger pyroptosis by suppressing the expression of Nrf-2. These findings offer novel insights into the mechanisms through which PM2.5 exposure hastens the progression of AD and propose a promising strategy for the pharmacological treatment of AD.}, } @article {pmid40706761, year = {2025}, author = {Ohno, M}, title = {BACE1 as an early biomarker and its relevance to risk factors for Alzheimer's disease.}, journal = {Brain research bulletin}, volume = {230}, number = {}, pages = {111475}, doi = {10.1016/j.brainresbull.2025.111475}, pmid = {40706761}, issn = {1873-2747}, mesh = {Humans ; *Alzheimer Disease/metabolism/diagnosis ; *Amyloid Precursor Protein Secretases/metabolism ; *Aspartic Acid Endopeptidases/metabolism ; Biomarkers/metabolism ; Animals ; Risk Factors ; Amyloid beta-Peptides/metabolism ; }, abstract = {While the β-secretase BACE1 is responsible for the rate-limiting initial step to generate amyloid-β (Aβ) peptides, BACE1 inhibitor clinical trials have been halted due to a lack of efficacy and/or safety concerns at symptomatic/prodromal stages of Alzheimer's disease (AD). These trials were often targeted at high levels of BACE1 inhibition (>70 %) and ended up with signs of mild cognitive worsening instead of expected improvement. BACE1 concentration and activity are elevated in the cerebrospinal fluid and plasma/serum as well as brains of patients with mild cognitive impairment and AD dementia. Interestingly, recent evidence suggests that these fluid-based biomarkers reflective of BACE1 elevation may be associated with yet asymptomatic pathological changes in preclinical AD populations who are at high-risk for developing AD. Consistent with these findings, it has been demonstrated that exposures to major environmental and genetic risks such as diabetes, sleep disturbances, seizure, vascular disorders, stress, apolipoprotein E4, etc. converge on BACE1 elevation in humans and animal models, which may contribute to triggering sporadic AD. Moreover, vicious cycles exist between BACE1/Aβ elevations and certain prognostic conditions, further accelerating disease progression. Conversely, protective factors for AD are associated with reduced BACE1 level/activity. This review provides an overview of BACE1 alterations as common responses to a broad battery of AD risk and protective factors. The findings validate BACE1 as a biomarker for preclinical AD status that may be useful for earlier diagnosis and identifying subpopulations of individuals under AD risks who would benefit from preventive low-dose BACE1 inhibitor treatment with a higher probability.}, } @article {pmid40705095, year = {2025}, author = {Wang, C and Wang, L and Liu, X and Wang, J and Chen, M and Li, J}, title = {Ponicidin attenuates Aβ1-42-induced hippocampal cell injury through SIRT1 and PI3K/Akt pathways.}, journal = {Molecular biology reports}, volume = {52}, number = {1}, pages = {752}, pmid = {40705095}, issn = {1573-4978}, support = {PW2022B-04//The Scientific Research Program of Shanghai Pudong New Area Health Commission (the Youth Program)/ ; ZQZR202427//the scientific research project of Shanghai Zhongqiao Vocational and Technical University/ ; }, mesh = {*Amyloid beta-Peptides/metabolism/toxicity ; *Sirtuin 1/metabolism ; *Hippocampus/drug effects/metabolism/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Animals ; Signal Transduction/drug effects ; *Peptide Fragments/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Mice ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; Neuroprotective Agents/pharmacology ; Cell Line ; Cell Survival/drug effects ; Neurons/drug effects/metabolism ; Alzheimer Disease/metabolism/drug therapy ; *Diterpenes/pharmacology ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) accumulation that leads to synaptic dysfunction and neuronal death. Ponicidin, a natural diterpenoid, possesses anti-inflammatory and neuroprotective properties. However, its potential effects on Aβ-induced neurotoxicity remain unclear. This study investigated whether ponicidin ameliorates Aβ1-42-induced hippocampal neuronal injury by modulating SIRT1 and PI3K/Akt signaling pathways. METHODS: HT22 cells were exposed to Aβ1-42 to establish an in vitro AD model, followed by treatment with ponicidin. Cell viability, apoptosis, oxidative stress, and inflammatory responses were assessed using MTT assay, flow cytometry, ROS detection, and ELISA. Western blotting and qRT-PCR were performed to evaluate the expression of SIRT1, the components of the PI3K/Akt pathway, and neuroinflammation. RESULTS: Ponicidin significantly attenuated Aβ1-42-induced cytotoxicity, reduced oxidative stress, and suppressed apoptosis and inflammatory cytokine release. Mechanistically, ponicidin upregulated SIRT1 expression and activated PI3K/Akt pathway. The protective effects of ponicidin were reversed by the PI3K/Akt inhibitor EX-527, confirming the involvement of this pathway. CONCLUSION: These findings suggest that ponicidin exerts neuroprotective effects against Aβ1-42-induced hippocampal injury by enhancing SIRT1 and activating PI3K/Akt signaling, highlighting its potential as a therapeutic candidate for AD.}, } @article {pmid40703204, year = {2025}, author = {Ramanan, VK and Heckman, MG and Hofrenning, EI and Przybelski, SA and Graff-Radford, J and Lowe, VJ and Machulda, MM and Murray, ME and Algeciras-Schimnich, A and Figdore, DJ and Bennett, DA and Knopman, DS and Jack, CR and Petersen, RC and Ross, OA and Vemuri, P and , }, title = {Combating Genetic Heterogeneity for Polygenic Prediction of Susceptibility to Brain β-Amyloid Deposition: Beyond APOE.}, journal = {Neurology. Genetics}, volume = {11}, number = {4}, pages = {e200266}, pmid = {40703204}, issn = {2376-7839}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVES: The APOE (apolipoprotein E) ε4 allele is the strongest known genetic risk factor for sporadic Alzheimer disease (AD) and for brain amyloidosis, an early marker of disease pathophysiology. However, APOE ε4 is present in only 25% of the general population and is by itself inadequate for explaining susceptibility to amyloid accumulation or AD diagnosis. Existing studies have been limited by potential confounding due to inclusion of individuals carrying APOE ε4 or ε2 (which has a modest protective association). We hypothesized that genome-wide association study (GWAS) and genetic risk score (GRS) analyses in APOE ε3/ε3 individuals would uniquely identify novel predictors of β-amyloid pathology in older adults. METHODS: We analyzed data from the Mayo Clinic Study of Aging (MCSA), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Rush Religious Orders Study and Memory and Aging Project. Frequency of APOE ε3/ε3 in those samples ranged from 48% to 61%. A GWAS was performed across 1,496 individuals with amyloid PET to identify candidate variants for GRS generation. Postmortem neuropathologic data (N = 710) were used to refine the variant list to capture high-likelihood true associations. An independent sample (N = 641) with plasma p-tau181 data was used for validation. RESULTS: The GWAS identified previously implicated (e.g., PICALM and RBFOX1) and novel potential associations with amyloid PET burden. A non-APOE GRS of top variants was strongly associated with amyloid PET levels in the MCSA (p = 4.34 × 10[-9], β = 5.88) and ADNI (p = 1.87 × 10[-8], β = 12.1) cohorts. In both cohorts, this non-APOE amyloid GRS outperformed a comparator GRS (based on variants associated with clinically diagnosed AD dementia risk) in explaining phenotypic variation. The non-APOE amyloid GRS was also associated with postmortem neuropathologic β-amyloid and neurofibrillary tangle burden and in an independent sample was associated with plasma p-tau181 concentrations (a robust indicator of cerebral amyloidosis). DISCUSSION: Our non-APOE amyloid GRS, which appropriately includes variants associated with amyloid deposition in APOE ɛ4/ɛ2 noncarriers, may advance personalized prediction of genetic susceptibility to β-amyloid accumulation within the large segment of the population that is APOE ε3/ε3. This may have future implications for risk modification, trial enrollment, and treatment selection.}, } @article {pmid40702815, year = {2025}, author = {Huo, Z and Yip, BH and Lee, AT and Cheng, ST and Chan, WC and Fung, AW and Ma, SL and Cheng, CP and Lai, FH and Wong, SY and Lam, LC}, title = {Healthcare utilization and economic costs of neurocognitive disorders in community-dwelling older Chinese adults: A comparison with 9 Asian economies.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {515-528}, doi = {10.1177/13872877251361057}, pmid = {40702815}, issn = {1875-8908}, mesh = {Humans ; Aged ; Male ; Female ; *Independent Living/economics ; *Health Care Costs/statistics & numerical data ; Hong Kong/epidemiology ; Cross-Sectional Studies ; Middle Aged ; *Neurocognitive Disorders/economics/epidemiology/therapy ; *Patient Acceptance of Health Care/statistics & numerical data ; Aged, 80 and over ; China/epidemiology ; *Cost of Illness ; East Asian People ; }, abstract = {BackgroundIt is increasing recognized that care for people with neurocognitive disorders (NCDs) is costly, and cost of NCDs can be highly context dependent.ObjectiveTo evaluate the healthcare utilization and economic costs of NCDs in Hong Kong, cross referencing with other Asian metropolitan cities.Methods461 older adults aged ≥60 (major NCD: 68, mild NCD: 264, normal cognition: 129) were recruited from a population-based cross-sectional survey, Hong Kong Mental Morbidity Survey for Older People. Healthcare utilization was collected by Resource Utilization of Dementia. Per person cost was estimated from a societal perspective and expressed in 2022 US dollars. Cost-associative factors were explored. Our findings were compared to cost-of-illness evidence in major Asian metropolitan cities by a systematic review.ResultsAnnual costs per community-living adult with mild and major NCD were US$5677 (95%CI: 4985-6465) and US$12,841 (9940-16,590) in Hong Kong. For those with major NCD, costs doubled in severer stages, and diagnosed cases incurred nearly 30% more costs than hidden cases. Dementia cost in Hong Kong was lower than other high-income Asian economies and mainland China, mainly due to methodological heterogeneities and lower utilization of social care services.ConclusionsThe great economic burden of NCDs in Hong Kong reflects a striking social and care needs, particularly in moderate and severe stages. Care planning should prepare for the blowout needs being revealed by hidden cases and the diversified needs by different stages and family caregivers. Region- and population-specific studies with rigor design are warranted to estimate cost-effectiveness of upcoming treatment strategies.}, } @article {pmid40702688, year = {2025}, author = {Song, X and Wang, Y and Zheng, K}, title = {Taurine ameliorates viral encephalitis by restoring PRKN-mediated mitophagy.}, journal = {Autophagy}, volume = {21}, number = {11}, pages = {2523-2525}, pmid = {40702688}, issn = {1554-8635}, mesh = {Animals ; *Mitophagy/drug effects ; Mice ; Humans ; *Encephalitis, Viral/drug therapy/metabolism/pathology ; Mitochondria/metabolism/drug effects ; Activating Transcription Factor 4/metabolism ; Herpesvirus 1, Human ; }, abstract = {Mitophagy is a selective type of autophagy that removes damaged mitochondria to maintain mitochondrial homeostasis and regulate the antiviral immune response. Despite increasing evidence that herpes simplex virus type 1 (HSV-1) infection causes mitochondrial damage, the regulatory mechanisms governing mitochondrial homeostasis and its biological implications in the context of HSV-1 infection and viral encephalitis remain unclear. In our recent work, we find that HSV-1 infection causes the accumulation of damaged mitochondria via defective mitophagy in vitro and in brain tissue of mice. The viral proteins ICP34.5 and US11 inhibit the EIF2S (eukaryotic translation initiation factor 2 subunit alpha)-ATF4 (activating transcription factor 4) axis to transcriptionally suppress PRKN/Parkin expression and subsequently impede PRKN-dependent mitophagy. Consequently, modulation of mitophagy significantly affects HSV-1 infection and NFKB/NF-κB-mediated neuroinflammation, as well as the severity of viral encephalitis in mice. Moreover, taurine, a metabolite differentially regulated by HSV-1 infection, transcriptionally promotes PRKN-mediated mitophagy, thereby limiting HSV-1 infection both in vitro and in vivo. This work reveals a protective function of mitophagy in restricting viral encephalitis and highlights the ATF4-PRKN axis as a potential therapeutic approach for the treatment of neurotropic virus-related diseases.Abbreviations: Aβ: amyloid β protein; AD: Alzheimer disease; ATF4: activating transcription factor 4; EIF2AK2/PKR: eukaryotic translation initiation factor 2 alpha kinase 2; EIF2S1: eukaryotic translation initiation factor 2 subunit alpha; HSE: herpes simplex encephalitis; HSV-1: herpes simplex virus type 1.}, } @article {pmid40702549, year = {2025}, author = {Zhang, P and Song, C and Shi, J and Wei, Z and Wang, J and Huang, W and Zhang, R and Wang, J and Yang, X and Wang, G and Gao, X and Zhang, Y and Chen, H and Wang, H}, title = {Endothelium-specific endoglin triggers astrocyte reactivity via extracellular vesicles in a mouse model of Alzheimer's disease.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {84}, pmid = {40702549}, issn = {1750-1326}, support = {82204374//National Natural Science Foundation of China/ ; 2022M722140//China Postdoctoral Science Foundation/ ; zyyzdxk-2023070//NATCM's Project of High-level Construction of Key TCM Disciplines/ ; STAR project 20230101//Shanghai Jiao Tong University Trans-med Awards Research/ ; QKHZYD-[2025]030//Central Government Guidance Funds for Local Scientific and Technological Development/ ; KFKT2024-02//Open Funds of Shanghai Jiao Tong University School of Medicine and Affiliated Hospital of Hebei University of Engineering/ ; }, mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Astrocytes/metabolism ; *Extracellular Vesicles/metabolism ; Mice ; Disease Models, Animal ; Humans ; *Endoglin/metabolism ; *Endothelial Cells/metabolism ; Mice, Transgenic ; Brain/metabolism ; Male ; Female ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder with a complex etiology that extends beyond the well-documented amyloid-β and tau pathologies. Growing evidence implicates cerebrovascular dysfunction, particularly brain microvascular endothelial cells (BMECs) dysfunction, as an early contributor to AD pathogenesis. However, how BMECs influence on neighboring astrocytes needs to be further explored. METHODS: We employed a multi-omics approach integrating bulk RNA sequencing of human BMECs with proteomic analysis of cerebrospinal fluid (CSF) from AD patients and cerebrovascular endothelial extracellular vesicles (CEEVs). The role of identified candidate proteins was investigated in vitro and in vivo utilizing CEEVs transplantation and BMEC-astrocyte co-cultures. Endothelial cell-specific knockdown or treatment with a monoclonal antibody was used to assess the functional consequences on cognitive impairment and AD pathology via two-photon imaging and behavioral experiments on APP/PS1 mice. RESULTS: The elevated endothelium-specific protein Endoglin (ENG) was identified in the brain and serum of AD individuals and APP/PS1 mice, and the supernatant of injured BMECs. ENG was released and delivered to adjacent astrocytes via CEEVs, and subsequently upregulated TGFBRI/Smad3 pathway in astrocytes, leading to astrocyte reactivity and the release of pro-inflammatory cytokines. Endothelial cell-specific ENG knockdown or treating with ENG monoclonal antibody Carotuximab significantly suppressed reactive astrocytes, reduced neuroinflammation, and improved cognitive performance of APP/PS1 mice. CONCLUSIONS: This study reveals a novel mechanism by which BMECs-derived ENG, delivered via CEEVs, drives astrocyte reactivity. These findings redefine the role of cerebrovascular dysfunction in AD pathogenesis and identify ENG as both a potential biomarker and a promising therapeutic target for AD.}, } @article {pmid40702219, year = {2025}, author = {Jamshidiha, S and Rezaee, A and Hajati, F and Golzan, M and Chiong, R}, title = {An explainable transformer model for Alzheimer's disease detection using retinal imaging.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {26773}, pmid = {40702219}, issn = {2045-2322}, support = {A24/2676//University of New England, Australia/ ; A24/2676//University of New England, Australia/ ; }, mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Retina/diagnostic imaging/pathology ; Algorithms ; Aged ; Male ; Female ; Artificial Intelligence ; Image Processing, Computer-Assisted/methods ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions worldwide. In the absence of effective treatment options, early diagnosis is crucial for initiating management strategies to delay disease onset and slow down its progression. In this study, we propose Retformer, a novel transformer-based architecture for detecting AD using retinal imaging modalities, leveraging the power of transformers and explainable artificial intelligence. The Retformer model is trained on datasets of different modalities of retinal images from patients with AD and age-matched healthy controls, enabling it to learn complex patterns and relationships between image features and disease diagnosis. To provide insights into the decision-making process of our model, we employ the Gradient-weighted Class Activation Mapping algorithm to visualise the feature importance maps, highlighting the regions of the retinal images that contribute most significantly to the classification outcome. These findings are compared to existing clinical studies on detecting AD using retinal biomarkers, allowing us to identify the most important features for AD detection in each imaging modality. The Retformer model outperforms a variety of benchmark algorithms across different performance metrics by margins of up to 11%.}, } @article {pmid40701934, year = {2025}, author = {Ataman Sadık, D and Cansız, CS and Turğut, M and Dağ, Ç and Duman, M}, title = {Investigation of Methylsulfonamide's Capability to Prevent Zn[2+]-Induced Aβ Peptide Aggregation Based on Zn[2+] Coordination within the Zinc Binding Region of Aβ for Treatment of Alzheimer's Disease (AD).}, journal = {ACS chemical neuroscience}, volume = {16}, number = {15}, pages = {2945-2957}, doi = {10.1021/acschemneuro.5c00238}, pmid = {40701934}, issn = {1948-7193}, mesh = {*Amyloid beta-Peptides/metabolism ; *Zinc/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Sulfonamides/pharmacology ; *Peptide Fragments/metabolism ; Humans ; Protein Aggregates/drug effects ; Protein Aggregation, Pathological/metabolism ; }, abstract = {There is no cure for Alzheimer's disease (AD) with the currently suggested therapies. Thus, designing and synthesis of new drugs for the treatment of Alzheimer's disease for safe and effective therapy have become an important task. Metal ions such as Zn[2+], Cu[2+], and Fe[3+] are known to increase the rate of Aβ aggregation and exist in amyloid plaques at high concentrations. Aβ oligomers, whether formed on the way to amyloid fibril formation or formed off-pathway due to the interaction of Aβ monomers with Zn[2+], are considered to be the most neurotoxic aggregates. Using NMR and SPR, this study reports the methylsulfonamide inhibition of Zn[2+]-induced Aβ1-16 dimer formation via methylsulfonamide coordination of Zn[2+] within the Zn[2+] binding region of Aβ, (11EVHH14) and inhibit the H14-Zn[2+] coordination between the 11EVHH14 regions of two Aβ peptides, preventing their interactions and hence the Aβ dimer formation. According to the results of this study, methylsulfonamide has the potential to be used as a drug in Alzheimer's disease for the prevention of the formation of the Zn[2+]-induced toxic Aβ oligomers formed during Aβ aggregation.}, } @article {pmid40701789, year = {2025}, author = {Mukherjee, S and Reddy, A and Dutta, N and Vaiphei, KK and Vivek, and Kumar, A and Gulbake, A}, title = {Exploring the potential of repurposed deferoxamine: bridging challenges and novel formulation opportunities.}, journal = {Nanomedicine (London, England)}, volume = {20}, number = {16}, pages = {2117-2141}, pmid = {40701789}, issn = {1748-6963}, mesh = {Humans ; *Deferoxamine/therapeutic use/chemistry/pharmacokinetics/pharmacology ; *Drug Repositioning ; Neoplasms/drug therapy ; Nanoparticles/chemistry ; Animals ; Drug Carriers/chemistry ; Drug Compounding ; Drug Delivery Systems ; }, abstract = {Since the FDA approval of deferoxamine mesylate (Desferal) in 1968, the characteristic low plasma half-life, low plasma protein binding (PB), constrained volume of distribution (Vd), and variety of adverse effects made the dosing, bioavailability, and patient compliance as the main hurdle for clinical application of Deferoxamine (DFO). Nevertheless, these pharmacokinetic and pharmacodynamic constraints have been lessened by recent developments in novel drug carrier systems, which has resulted in an increased acceptance of DFO. The effective use of this drug in the treatment of Alzheimer, Parkinson, cancer, wound healing, and ferroptosis has further increased its clinical importance. According to our literature search on various reputed databases such as ScienceDirect, Nature, Wiley, ACS, etc. accumulating results of last 18 years, there has been a significant increase in the overall number of studies conducted on various novel formulations and strategies regarding DFO e.g. polymeric nanoparticles, micelles, nanofibers, conjugates, photothermal therapy, etc. Clinical trial applications found on clinicaltrials.gov have doubled since 2020, and patent applications found on Google Patent have climbed by 320% since 2011. These results demonstrate DFO's versatility and its potential for usage not just in traditional applications but also as a repurposed therapeutic agent.}, } @article {pmid40701551, year = {2025}, author = {Shukla, S and Shukla, S and Sharma, S and Vasudeva, N and Khatri, R and Lather, A and Hooda, T}, title = {Neuroprotective Role of Eupalitin in Streptozotocin-Induced Diabetic Rats: In Silico and In Vivo Studies.}, journal = {Planta medica}, volume = {91}, number = {12}, pages = {664-675}, doi = {10.1055/a-2654-7657}, pmid = {40701551}, issn = {1439-0221}, mesh = {Animals ; *Neuroprotective Agents/pharmacology/therapeutic use/chemistry ; *Diabetes Mellitus, Experimental/drug therapy ; Molecular Docking Simulation ; Male ; Rats ; Acetylcholinesterase/metabolism ; Streptozocin ; Rats, Wistar ; Oxidative Stress/drug effects ; Lipid Peroxidation/drug effects ; Brain/drug effects/metabolism ; Glutathione/metabolism ; Donepezil ; Memory/drug effects ; Amyloid beta-Peptides/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative condition with marked cognitive loss and impaired thinking abilities as well as spatial memory, working memory, and communication skills. Numerous studies have found that both type 1 and type 2 diabetes lead to neuropathological and neurobehavioral problems, which lead to notable cognitive dysfunction and deterioration in memory. The aims of this study are to find out the neuroprotective potential of eupalitin on memory in streptozotocin-induced diabetic rats and to evaluate its in silico binding affinity on acetylcholinesterase by using molecular docking studies. Eupalitin (dose 1 mg/kg/day) was used to study the behavior model and other biochemical parameters measurement in acute as well as chronic streptozotocin (STZ)-induced diabetic rats. Eupalitin treatment increased the level of acetylcholinesterase (AChE) and lipid peroxidation and decreased glutathione in STZ-infused diabetic rat's brain tissue, suggesting that this substance may modulate cognitive function that is altered by oxidative stress. Results were comparable to standard drugs metformin and donepezil. Docking score and molecular mechanics generalized born surface area (MMGBSA) study results of eupalitin in comparison with donepezil possess superior predicted binding affinity toward AChE. The level of Aβ (1 - 42) was considerably lower in the eupalitin-treated group than in the STZ-treated group during both the acute and chronic phases of treatment, but results were more prominent in the case of chronic-level treatment. In silico studies showed the binding affinity toward AChE. This result concluded that eupalitin antioxidant potential may be utilized as a therapy for diabetes mellitus (DM)-related cognitive impairment.}, } @article {pmid40701395, year = {2025}, author = {Yang, FG and Liang, YL and Wang, X and Wang, JT and Gao, W and Ye, QY and Li, XY and Yang, Y and Li, HL}, title = {The evolution of Alzheimer's disease: From mitochondria to microglia.}, journal = {Ageing research reviews}, volume = {111}, number = {}, pages = {102838}, doi = {10.1016/j.arr.2025.102838}, pmid = {40701395}, issn = {1872-9649}, mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Microglia/metabolism/pathology ; *Mitochondria/metabolism/pathology ; Animals ; Oxidative Stress/physiology ; }, abstract = {Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder worldwide. Recent studies highlights that mitochondrial dysfunction drives alterations in microglial function, serving as a pivotal mechanism in the pathogenesis and progression of AD. Increasingly, there is evidence that mitochondrial dysfunction encompasses energy metabolism deficits, heightened oxidative stress, impaired mitochondrial dynamics, disrupted autophagy, and calcium homeostasis imbalances. These impairments modulate microglial activation states, precipitating exacerbated neuroinflammation, altered phagocytic capacity, and increased cellular apoptosis, collectively contributing to microglial dysfunction. This paper presents a narrative review on the relationship between mitochondrial dysfunction and AD, elucidating the impact of mitochondrial impairment on microglia. It summarizes therapeutic strategies that target mitochondria to modulate microglial function, aiming to prevent and treat AD. The goal is to provide new perspectives and insights for AD research and treatment, contributing to improving patients' quality of life and prognosis.}, } @article {pmid40701259, year = {2025}, author = {Dai, H and Huang, Y and Liu, Y and He, X and Guo, J and Prosperi, M and Bian, J}, title = {Variational temporal deconfounder network for individualized treatment effect estimation with longitudinal observational data.}, journal = {Journal of biomedical informatics}, volume = {169}, number = {}, pages = {104880}, pmid = {40701259}, issn = {1532-0480}, support = {RF1 AG084178/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; U01 AG088076/AG/NIA NIH HHS/United States ; R01 AG080991/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; R01 AG084236/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; R01 AG080624/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; R01 AG083039/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; R01 AG079280/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; R01 AI172875/AI/NIAID NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; RF1 AG077820/AG/NIA NIH HHS/United States ; R01 AG076234/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; R01 AG089445/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Precision Medicine/methods ; *Electronic Health Records ; Longitudinal Studies ; Treatment Outcome ; Alzheimer Disease/therapy ; Algorithms ; }, abstract = {OBJECTIVE: By leveraging real-world electronic health record (EHR) data, this study set out to estimate individualized treatment effects (ITE) in longitudinal observational settings to advance personalized medicine, addressing key challenges that are often observed in real-world clinical scenarios and pose statistical challenges, including hidden confounding and dynamic treatment regimens. METHODS: We propose the Variational Temporal Deconfounder Network (VTDNet), a novel framework designed to account for time-varying hidden confounding using a variational recurrent transformer-based autoencoder. Specifically, VTDNet comprises three critical components: a temporal Encoder-Decoder structure to capture hidden representation, a Treatment Block that captures interdependencies among multiple treatments, and a Potential Outcome Block that predicts both factual and counterfactual outcomes. We assess the effectiveness of the proposed framework using a synthetic dataset and two real-world datasets: MIMIC-III, an EHR dataset focusing on intensive care settings, and NACC, emphasizing neurodegenerative disease, collected using a standardized protocol from participants enrolled in Alzheimer's Disease Research Center (ADRC) clinical cores. RESULTS: Experimental results on the synthetic dataset demonstrate superior accuracy under varying levels of confounding. On real-world EHR datasets, VTDNet achieves lower root mean squared error, mean absolute error, and influence function precision in the estimation of heterogeneous effects compared to existing state-of-the-art methods. CONCLUSION: The proposed VTDNet offers a robust framework for estimating individualized treatment effects in longitudinal settings, effectively accommodating irregular time points and high-dimensional data while addressing hidden confounders through a deep generative approach. It holds significant potential to advance personalized medicine and support real-world evidence generation. Future work will aim to extend VTDNet to continuous treatment scenarios, such as dose-response analysis, to further broaden its applicability in clinical practice.}, } @article {pmid40701134, year = {2025}, author = {Wu, N and Shao, Y and Wu, Z and Zhu, S and Wang, P and Zhu, Z and Zhang, C and Wu, C and Huo, X and Lin, H and Zhang, G}, title = {Electric field variations across DLPFC targeting methods in TMS therapy for Alzheimer's disease.}, journal = {NeuroImage. Clinical}, volume = {48}, number = {}, pages = {103847}, pmid = {40701134}, issn = {2213-1582}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology/diagnostic imaging ; *Transcranial Magnetic Stimulation/methods ; Male ; Female ; Aged ; Magnetic Resonance Imaging/methods ; *Dorsolateral Prefrontal Cortex/diagnostic imaging/physiopathology ; Middle Aged ; Aged, 80 and over ; }, abstract = {BACKGROUND: The dorsolateral prefrontal cortex (DLPFC) is crucial for cognitive control and a primary target for transcranial magnetic stimulation (TMS) in Alzheimer's disease (AD). However, understanding the distribution of TMS-induced electric field (E-field) across different targeting methods remains limited, as does its relationship to therapeutic outcomes. OBJECTIVE: This study assesses differences in TMS-induced E-field using functional versus anatomical targeting methods for DLPFC stimulation. METHODS: Functional and anatomical targets were identified in 30 (11 M/19F) AD patients and 30 (13 M/17F) age-matched healthy controls (HCs) using T1 and fMRI data. E-field characteristics, including magnitude (EROI) and normal component (E⊥), were calculated via SimNIBS software for comparisons across stimulation targets. RESULTS: Functional targeting showed greater spatial dispersion compared to anatomical targeting in both groups. Significant E-field differences were observed between the functional target and adjacent anatomical regions when the coil was positioned over the functional target in both groups. Optimal coil orientation exhibited directional specificity: parallel alignment with the LOI E-field produced higher field intensity in the functional target compared to the anatomical target (AD patients: P < 0.001; HCs: P = 0.052), while perpendicular orientation maintained functional stability with reduced anatomical interference (both groups: P < 0.001). And significant variations in E-field ratios were observed across coil orientations. CONCLUSION: This study reveals key E-field disparities across DLPFC targeting approaches and establishes coil orientation optimization as a critical strategy to improve TMS precision, offering actionable insights for developing personalized protocols in AD therapy that may enhance treatment efficacy while minimizing adverse effects.}, } @article {pmid40700403, year = {2025}, author = {Hook, V and Podvin, S and Yoon, MC and Phan, VV and Florio, J and Spencer, B and Mosier, C and Cheng, A and Ahuett, S and Almaliti, J and Gerwick, WH and Rissman, RA and O'Donoghue, AJ}, title = {Neutral pH-Selective Inhibition of Cytosolic Cathepsin B: A Novel Drug Targeting Strategy for Traumatic Brain Injury and Alzheimer's Disease.}, journal = {ACS chemical biology}, volume = {20}, number = {8}, pages = {1841-1848}, pmid = {40700403}, issn = {1554-8937}, support = {R01 NS109075/NS/NINDS NIH HHS/United States ; R21 AT013004/AT/NCCIH NIH HHS/United States ; }, mesh = {*Cathepsin B/antagonists & inhibitors/metabolism ; Hydrogen-Ion Concentration ; *Brain Injuries, Traumatic/drug therapy/metabolism/enzymology ; Animals ; *Alzheimer Disease/drug therapy/metabolism/enzymology ; Humans ; *Cytosol/metabolism/enzymology/drug effects ; Mice ; Lysosomes ; }, abstract = {Cathepsin B contributes to the behavioral deficits and neuropathology that occur in traumatic brain injury (TBI) and Alzheimer's disease (AD). TBI and AD patients display elevated levels of cathepsin B that correlate with the severity of injury or cognitive deficits, respectively. In animal models of TBI and AD, cathepsin B gene knockout ameliorates behavioral deficits and improves neuropathology. While cathepsin B is normally located in acidic lysosomes, during TBI and AD, lysosomal leakage results in the translocation of cathepsin B to the neutral pH environment of the cytosol, thereby initiating neurodegeneration. Neutral pH-selective inhibitors are hypothesized to specifically target the pathogenic cytosolic cathepsin B without affecting its normal lysosomal form. Therefore, this review focuses on a novel strategy to utilize pH-dependent substrate cleavage properties of cathepsin B for the design of a neutral pH-selective inhibitor. Investigation of the enzymatic properties of cathepsin B at different pH conditions led to the development of Z-Arg-Lys-AOMK, a neutral pH-selective inhibitor that does not affect the enzyme's activity at normal lysosomal acidic pH. Z-Arg-Lys-AOMK potently inhibits cathepsin B at nM concentrations and effectively inhibits cellular cathepsin B in neuronal cell cultures at similar levels. In mice subjected to controlled cortical impact (CCI) brain injury, a model of TBI, cytosolic cathepsin B activity was significantly elevated in the brain. Treatment of the CCI-TBI mice with Z-Arg-Lys-AOMK reduced cytosolic cathepsin B activity and resulted in less motor dysfunction. These findings show that pH-dependent cleavage properties of cathepsin B can be utilized for the development of selective inhibitors to target the neutral cytosolic form of cathepsin B. The new concept of pH-selective inhibitors of cathepsin B reveals novel opportunities for targeting pathogenic, cytosolic cathepsin B involved in brain disorders.}, } @article {pmid40700397, year = {2025}, author = {Jamal, QMS and Alharbi, AH and Ahmad, V and Ahmad, K}, title = {Integrated in silico identification of cholinesterase inhibitors from Nyctanthes arbor-tristis.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0328457}, pmid = {40700397}, issn = {1932-6203}, mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology ; Butyrylcholinesterase/metabolism/chemistry ; Molecular Dynamics Simulation ; Humans ; Acetylcholinesterase/metabolism/chemistry ; Molecular Docking Simulation ; Computer Simulation ; Alzheimer Disease/drug therapy ; *Plant Extracts/chemistry/pharmacology ; }, abstract = {Alzheimer's disease (AD) remains a major neurodegenerative disorder, characterized by cognitive decline alongside functional impairments that affect daily living. Natural therapeutic alternatives have spurred the search for novel inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), two well-established targets in AD therapy. This study utilizes an in silico methodology to investigate new cholinesterase inhibitors sourced from Nyctanthes arbor-tristis, a plant known for its abundant bioactive phytochemicals. Through virtual screening, molecular dynamics simulations (MDS), free energy landscape analysis, and ADMET predictions, eight compounds have been identified as potential inhibitors of AChE and/or BChE. These compounds include Apigenin, Arborside-B, Arbortristoside-D, Arbortristoside-E, Nicotiflorin, Arborside-A, Beta-amyrin, and Nyctanthic acid. These compounds exhibited robust binding affinities compared to the control, advantageous ADMET profiles, and sustained stability throughout 200 ns of MDS and energy assessments, highlighting their potential as viable drug candidates for further exploration. Further experimental studies are required to validate their therapeutic efficacies, thereby confirming their potential as neurological therapeutics for the treatment of AD and related disabilities.}, } @article {pmid40699791, year = {2025}, author = {Klein, BY and Gofrit, ON and Greenblatt, CL}, title = {Testing Protein Stress Signals in Peripheral Immunocytes Under the Same Treatment Capable of Decreasing the Incidence of Alzheimer's Disease in Bladder Cancer Patients.}, journal = {Current issues in molecular biology}, volume = {47}, number = {6}, pages = {}, pmid = {40699791}, issn = {1467-3045}, abstract = {Several studies showed that the incidence of Alzheimer's disease (AD) is significantly lower in patients with non-muscle invasive bladder cancer (NMIBC) treated with intravesical bacillus Calmette-Guérin (BCG) instillations compared to treatment by alternative methods. Hypothetically, failure to clear misfolded and aggregated proteins (i.e., beta-amyloid) in AD brains and peripheral blood mononuclear cells (PBMCs) implicates BCG in upgrading the unfolded protein response (UPR). To test this hypothesis, pre- versus post-BCG PBMC proteins of the UPR pathway were compared in six NMIBC patients by capillary immunoelectrophoresis on an Abby instrument. PERK, the endoplasmic reticulum (ER) resident kinase, a stress-activated sensor, and its substrate alpha component of the eIF2 translation factor (eIF2a) complex inactivation were considered as potentially proapoptotic via a downstream proapoptotic transcription factor only if persistently high. GAPDH, a glycolytic marker of innate immunocyte training by BCG, and eight other UPR proteins were considered antiapoptotic. Summation of antiapoptotic %change scores per patient showed that the older the age, the lower the antiapoptotic %change. Higher antiapoptotic scores were observed upon a longer time from BCG treatment (with the exception of the patient in her ninth decade of life). Studies with more individuals could substantiate that BCG enhances the antiapoptotic aggregate-clearance effect of the UPR in PBMCs of NMIBC patients, which hypothetically protects brain cells against AD.}, } @article {pmid40698680, year = {2025}, author = {Rohilla, S and Goyal, G}, title = {Computer-aided Drug Design for Alzheimer's Disease: Recent Advancements and Future Perspectives.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115680266343814250713100224}, pmid = {40698680}, issn = {1873-4294}, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder marked by a decline in cognitive function and memory loss, primarily resulting from cholinergic dysfunction, the accumulation of amyloid plaques, the formation of tau tangles, and the progressive degeneration of neurons. While existing treatments offer limited symptomatic relief, they do not effectively halt or reverse the underlying progression of the disease, presenting a major global challenge in Alzheimer's research. Developing therapeutic strategies for AD remains complex, largely due to the inability of current medications to significantly slow neurodegeneration. Traditional drug discovery processes are often lengthy, costly, and inefficient, further complicating the search for effective treatments. To overcome these obstacles, researchers have turned to a combination of computational approaches alongside conventional drug design techniques. These integrated methodologies help accelerate the discovery process by significantly reducing both time and costs. This review delves into the underlying physiological and pathological mechanisms of Alzheimer's disease, while identifying potential drug targets such as acetylcholinesterase, butyrylcholinesterase, β-Secretase (BACE-1), A2A adenosine receptor, Dickkopf-1 protein, glycogen synthase kinase-3β, indoleamine 2,3-dioxygenase, monoamine oxidase-B, NMDA receptor, Wnt inhibitory factor, cyclindependent kinase-5, glutaminyl cyclase, and cathepsin-B. Furthermore, the review examines various computer-aided drug design (CADD) methodologies, including structure-based and ligandbased approaches, virtual screening, pharmacophore modeling, molecular modelling, and simulation techniques. These computational strategies are playing an increasingly important role in Alzheimer's research, particularly in drug discovery. By investigating promising drug candidates and lead molecules that target key proteins involved in Alzheimer's pathogenesis, the review highlights their binding modes with these targets and assesses the chemical properties essential for the development of effective clinical candidates. The aim is to provide researchers with critical insights and tools to design novel compounds with the necessary chemical and physical characteristics required for the successful treatment of Alzheimer's disease.}, } @article {pmid40698455, year = {2025}, author = {Topalis, V and Voros, C and Ziaka, M}, title = {Targeting Inflammation in Alzheimer's Disease: Insights Into Pathophysiology and Therapeutic Avenues-A Comprehensive Review.}, journal = {Journal of geriatric psychiatry and neurology}, volume = {}, number = {}, pages = {8919887251361578}, doi = {10.1177/08919887251361578}, pmid = {40698455}, issn = {1552-5708}, abstract = {Alzheimer's Disease (AD) is the most common dementia, affecting mainly older adults, particularly over 65. Characterized by progressive cognitive decline-including deficits in memory, executive functions, and language, alongside behavioral disturbances-AD arises from complex pathophysiological mechanisms. These include neurotransmitter imbalances, cholinergic deficits, amyloid-beta (Aβ) toxicity, tau protein hyperphosphorylation, oxidative stress, synaptic dysfunction, and neuroinflammatory processes. Growing evidence highlights the protective role of microglia in AD pathology through their immune functions, phagocytic clearance of Aβ proteins, and trophic support to promote tissue repair and maintain cerebral homeostasis, as alterations in their response to Aβ are linked to an increased risk of AD. However, disruptions in homeostasis or tissue alterations may trigger microglial activation, leading to detrimental effects such as increased inflammatory activity, impaired microglial-mediated clearance, synapse loss, and neuronal damage. Astrocytes, a distinct type of glial cell with homeostatic functions, also exhibit neuroprotective effects. However, the presence of Aβ may result in astrocyte reactivity, leading to neurotoxic effects associated with disturbances of calcium levels, activation of proinflammatory pathways, gliotransmission, altered tau metabolism, and impaired clearance of Aβ. Despite substantial research, AD remains challenging to diagnose early and lacks effective treatments. Given its multifactorial nature, therapeutic approaches primarily aim to slow progression and remain limited in achieving a definitive cure. While most current strategies focus on mitigating the toxic effects of Aβ and tau proteins, growing interest has emerged in addressing neuroinflammation as a potential means to delay or prevent neurodegeneration. Targeting neuroinflammation could open new therapeutic avenues for the treatment of AD.}, } @article {pmid40698100, year = {2025}, author = {Singh, D and Singhal, S and Kanaujiya, V and Ranjan, A and Mani, VE and Paliwal, VK and Jain, V and Aishwarya, A and Agarwal, R}, title = {Ganglion Cell Layer Thickness as a Biomarker for Amyotrophic Lateral Sclerosis Functional Outcome: An OCT study.}, journal = {Romanian journal of ophthalmology}, volume = {69}, number = {2}, pages = {200-207}, pmid = {40698100}, issn = {2501-2533}, mesh = {Humans ; *Tomography, Optical Coherence/methods ; *Amyotrophic Lateral Sclerosis/physiopathology/diagnosis ; Male ; Middle Aged ; Female ; *Retinal Ganglion Cells/pathology ; *Visual Acuity/physiology ; *Nerve Fibers/pathology ; Adult ; *Optic Disk/pathology ; Aged ; Intraocular Pressure/physiology ; Biomarkers ; }, abstract = {AIM: This study aims to evaluate various optical coherence tomography (OCT) parameters in patients diagnosed with amyotrophic lateral sclerosis (ALS). METHODS: Assessment of BCVA was done using Snellen charts, and subjective refraction was done to achieve a BCVA for distance and near. Measurement of intraocular pressure (IOP) was done with Goldman applanation tonometry. Stereoscopic fundus examination was performed using a 90D lens to assess the status of the optic nerve and retina, ruling out any ocular pathology. The patients were then subjected to OCT scanning to measure optic nerve head and macular parameters. Optical coherence tomography was performed using CIRRUS™ HD OCT (500-21822) (version 8.0.0.518) (Carl Zeiss Meditec, Dublin, CA, USA). The analyzed area was centered manually, and the absence of segmentation errors was confirmed for each scan. RESULTS: RE Avg RNFL and LE Avg RNFL showed weak correlations with ALSFRS, indicated by Pearson Correlation coefficients of 0.073 and -0.026, respectively. The p-values (0.637 and 0.86) suggested that these correlations were not statistically significant. RE Avg GCL and LE Avg GCL, on the other hand, exhibited moderate positive correlations with ALSFRS scores, with correlation coefficients of 0.337 (RE) and 0.389 (LE). These correlations were statistically significant, as indicated by p-values of 0.021 and 0.006, respectively, suggesting a substantial association between GCL thickness and ALS functional outcomes. DISCUSSION: All patients in our study were clinically diagnosed cases of ALS, as per the El Escorial criteria. Age group-wise analysis showed statistically significant thinning overall as well as quadrant-wise RNFL parameters in patients less than 50 years compared to age-matched controls, indicating that the pathological process occurring in larger motor neurons in ALS might also be happening in smaller sensory neurons of the retina, causing thinning, which was not due to age-related process. Although GCIPL thinning was occurring in our cases, though statistically not significant compared to control, the significant positive correlation observed between GCIPL and ALS functional outcome and between RNFL and GCIPL measurements highlighted the fact that though the axonal degeneration in retinal neurons might not be translating to the same extent in ganglion cells in ALS, the subtle thinning of GCIPL correlated strongly with functional disability in patients with ALS, implying better functional scores with higher values of GCIPL parameters. CONCLUSION: In summary, GCL measurements in both eyes showed a notable relationship with ALSFRS, whereas RNFL did not appear to correlate significantly.}, } @article {pmid40697975, year = {2025}, author = {Gogu, P and Bharti, J and Yadav, JP and Grishina, M and Verma, A and Kumar, V and Singh, AK and Verma, A and Kumar, P and Khalilullah, H and Jaremko, M and Emwas, AH and Dwivedi, AR and Pathak, P}, title = {Exploring GPR120/FFAR4 pharmacology: Unveiling novel therapeutic avenues through molecular signaling pathways for Alzheimer's disease intervention.}, journal = {Brain, behavior, & immunity - health}, volume = {48}, number = {}, pages = {101061}, pmid = {40697975}, issn = {2666-3546}, abstract = {G-protein-coupled receptors (GPCRs) are a major class of membrane proteins involved in numerous physiological and pathological processes. Among them, free fatty acid receptor 4 (FFAR4/GPR120), activated by long-chain free fatty acids, has shown anti-inflammatory effects and is expressed in the brain-implicating its role in neurodegenerative diseases like Alzheimer's disease (AD). AD is characterized by brain atrophy, cognitive decline, and neuroinflammation, involving complex signaling networks. This review explores the pharmacological relevance of GPR120/FFAR4 in AD, focusing on its involvement in neuroinflammatory, amyloidogenic, and intracellular signaling cascades. Targeting GPR120 may help modulate chronic inflammation and amyloid-β accumulation. Additionally, activation of nuclear receptors and regulation of pathways such as MAPK, NLRP3, PPARs, and cAMP have shown promise in mitigating AD pathology. Despite the complexity of brain signaling, GPR120 emerges as a compelling multitarget therapeutic receptor. These insights provide a foundation for developing novel anti-inflammatory strategies in AD treatment.}, } @article {pmid40697447, year = {2025}, author = {Senanayake, D and Yapa, P and Dabare, S and Munaweera, I}, title = {Precision targeting of the CNS: recent progress in brain-directed nanodrug delivery.}, journal = {RSC advances}, volume = {15}, number = {32}, pages = {25910-25928}, pmid = {40697447}, issn = {2046-2069}, abstract = {The therapeutic drug penetration into brain tissues meets limitations through the restrictive function of the blood-brain barrier (BBB) within the central nervous system (CNS). The advancement of nanocarrier engineering techniques allows scientists to develop nanoscale delivery vehicles that successfully cross the BBB. This review analyses modern brain-delivery nanodrug delivery platforms by examining the properties and distribution of liposomes and polymeric nanoparticles, dendrimers, solid lipid nanoparticles, and exosomes. Organizations use specific physicochemical approaches designed for each platform to boost brain penetration and enhance therapeutic drug distribution for improving drug effectiveness. An analysis is presented of the various procedures to cross or bypass the BBB where receptor-mediated transcytosis joins focused ultrasound, as well as magnetic targeting and chemical modifications. The article presents therapeutic developments regarding neurological treatment of Alzheimer's disease, alongside Parkinson's disease and glioblastoma. Early laboratory success has produced promising results, yet challenges persist during the translation of these findings for clinical use because of safety issues as well as compatibility problems and difficulties with scaling up manufacturing processes. Finally, it discusses regulatory advancements and describes active market trends in nanomedicine that focus on precise delivery techniques and combination treatment methods, and brain-targeted delivery systems. The innovations combined present an optimistic future for CNS drug development because they create substantial opportunities to reshape neurological disorder treatments.}, } @article {pmid40697193, year = {2025}, author = {Zhang, L and Wu, Y and Jin, Q and Wang, C}, title = {Association between genetically proxied PPARG activation and early onset Alzheimer's disease: A drug target Mendelian randomization study.}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251359579}, pmid = {40697193}, issn = {2542-4823}, abstract = {BACKGROUND: Early-onset Alzheimer's disease (EOAD), which has an onset before the age of 65, is overshadowed by the more prevalent late-onset Alzheimer's disease (LOAD). Nevertheless, rather than being merely a form of LOAD that occurs at a prematurely defined younger age, EOAD differs from LOAD in multiple ways. Given these disparities, understanding the potential treatment options for EOAD becomes crucial. OBJECTIVE: We aim to assess anti-diabetic drugs' potential utility in treating EOAD and LOAD from a novel perspective via drug-targeted Mendelian randomization (MR) analysis. METHODS: Through Summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) analysis, we assessed the associations between anti-diabetic drug targets (including DPP-4 inhibitor, Thiazolidinedione, GLP1R agonist, Sulfonylureas, SLC5A2 inhibitor, and Insulin/Insulin analog) and AD outcomes (EOAD and LOAD). We utilized two types of genetic instruments to represent the exposure to anti-diabetic drugs: eQTLs of genes encoding drug target proteins and genetic variants within or near genes encoding these target proteins associated with HbA1c from genome-wide association studies. RESULTS: SMR analysis showed that enhanced PPARG gene expression in the blood was a protective factor for EOAD (OR = 0.733, 95%CI = 0.548-0.979, p = 0.035). Additionally, an IVW-MR association was found between HbA1c mediated by PPARG and EOAD (OR = 0.295, 95%CI = 0.092-0.949, p = 0.041). CONCLUSIONS: This study suggests that Thiazolidinedione therapy could help suppress the development of EOAD, supporting further exploration of PPARG-targeted anti-diabetic drug development.}, } @article {pmid40696527, year = {2025}, author = {Jeon, SY and Wang, SM and Roh, HW and Kim, KY and Chang, YY and Kim, E and Bae, JN and Ryu, SH}, title = {Practical Guide of the Korean Association for Geriatric Psychiatry to Anti-Amyloid Monoclonal Antibody Therapy for Alzheimer's Disease: Focused on Lecanemab.}, journal = {Journal of Korean medical science}, volume = {40}, number = {28}, pages = {e215}, pmid = {40696527}, issn = {1598-6357}, support = {//Korean Association for Geriatric Psychiatry/Korea ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/pathology ; Republic of Korea ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Amyloid beta-Peptides/antagonists & inhibitors/immunology ; Aged ; Antibodies, Monoclonal/therapeutic use ; }, abstract = {The advent of anti-amyloid monoclonal antibody (mAb) therapies represents a paradigm shift in the treatment of Alzheimer's disease (AD), from symptomatic relief to disease modification. Lecanemab, a humanized mAb targeting soluble Aβ protofibrils and plaque, received regulatory approval in Korea in July 2024, following global randomized controlled trial data demonstrating its efficacy to reduce amyloid burden and slow cognitive decline. However, the introduction of such therapies into routine clinical realm presents several practical and systemic challenges, particularly in the context of Korea's unique healthcare infrastructure and reimbursement environment. In response, the Korean Association for Geriatric Psychiatry has developed the first comprehensive domestic guidance to facilitate the safe, evidence-based, and patient-centered use of anti-amyloid mAb therapies, first focused on lecanemab. This practical guide goes beyond simple eligibility criteria. It provides detailed recommendations on clinical and imaging-based candidate selection, amyloid-related imaging abnormalities (ARIA) risk stratification and monitoring protocols, infusion workflows, adverse event management strategies, and multidisciplinary coordination within hospital systems. It also emphasizes shared decision-making and outlines how to navigate situations where treatment is not appropriate, such as in patients with advanced dementia, high-risk magnetic resonance imaging findings, or poor treatment adherence, reinforcing that non-treatment can also represent a legitimate, evidence-based clinical decision. The guidance further highlights the urgent need to generate real-world data that reflect the treatment experiences of Korean patients. Multicenter collaboration will be essential for collecting data on adherence rates, ARIA incidence, cognitive outcomes, and functional trajectories, which in turn can inform policy decisions, insurance reimbursement models, and future updates to clinical guidelines. This publication represents the first nationwide roadmap in Korea to support clinicians in the appropriate integration of monoclonal antibody therapies for AD. By combining scientific rigor, operational feasibility, and ethical sensitivity, it aims to promote safe and responsible adoption of disease-modifying treatment across various clinical settings.}, } @article {pmid40696469, year = {2025}, author = {Oosthoek, M and Vijverberg, EGB and Blujdea, ER and Veld, SGJGI and Avilés, MP and Zsadanyi, SE and Hok-A-Hin, YS and Visser, A and van der Flier, WM and Barkhof, F and Del Campo, M and Schut, MC and Bejanin, A and Alcolea, D and Teunissen, CE and Vermunt, L}, title = {CHIT1 and DDAH1 levels relate to amyloid-related imaging abnormalities risk profile in Alzheimer's disease patients.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {169}, pmid = {40696469}, issn = {1758-9193}, support = {WE.03-2018-05//Alzheimer Nederland/ ; WE.03-2018-05//Alzheimer Nederland/ ; NR170065//Selfridges Group Foundation/ ; NR170065//Selfridges Group Foundation/ ; PI21/00791, PI14/01126, PI17/01019, PI20/01473, PI13/01532, PI16/01825, PI18/00335, PI19/00882, PI18/00435, PI22/00611, INT19/00016, INT23/00048, PI17/01896 and AC19/00103//Fondo de Investigaciones Sanitario/ ; PI21/00791, PI14/01126, PI17/01019, PI20/01473, PI13/01532, PI16/01825, PI18/00335, PI19/00882, PI18/00435, PI22/00611, INT19/00016, INT23/00048, PI17/01896 and AC19/00103//Fondo de Investigaciones Sanitario/ ; Program 1, Alzheimer Disease//CIBERNED program/ ; Program 1, Alzheimer Disease//CIBERNED program/ ; NIA grants 1R01AG056850-01A1; R21AG056974; and R01AG061566),//Office of Dietary Supplements/ ; NIA grants 1R01AG056850-01A1; R21AG056974; and R01AG061566),//Office of Dietary Supplements/ ; 2017-SGR-547, SLT006/17/125, SLT006/17/119, SLT002/16/408//Generalitat de Catalunya/ ; 2017-SGR-547, SLT006/17/125, SLT006/17/119, SLT002/16/408//Generalitat de Catalunya/ ; 20141210, 044412 and 20142610//Fundació la Marató de TV3/ ; 20141210, 044412 and 20142610//Fundació la Marató de TV3/ ; }, mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/genetics ; Male ; Female ; Aged ; Biomarkers/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; *Hexosaminidases/cerebrospinal fluid ; Cohort Studies ; Proteomics ; Peptide Fragments/cerebrospinal fluid ; Chitinase-3-Like Protein 1 ; }, abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIA) are a common and potentially dangerous side effect in anti-amyloid therapies, creating a need for tools to assess ARIA risk. Several patient factors have been linked to ARIA; namely the presence of microbleeds (MBL[+]), APOE E4 carriership (APOE4[+]), and extremely low CSF Aβ42 concentrations (A[L]). We hypothesize that studying the CSF proteome of Alzheimer's disease (AD) dementia patients from a high-risk group (MBL[+]APOE4[+]A[L]) can inform on the biological underpinnings of ARIA risk and aid the progress of ARIA risk biomarkers. METHODS: We utilized CSF proteomic data of AD (n = 156) and cognitively unimpaired individuals (CU n = 100) of the Amsterdam Dementia Cohort. The proteome of the defined high-risk (n = 13) was compared to low-risk AD group (n = 23), using age and sex corrected linear regressions followed by gene ontology analysis. For biomarker prioritization, we selected proteins that were abnormal in the high-risk group versus low-risk and CU patients. The biomarkers were validated in an independent cohort (high risk n = 14, low risk n = 9) analyzed using customized multiplex panels. Lastly, we assessed biomarker lead co-expression. RESULTS: Ninety-four proteins differentiated in the high-risk group compared to low-risk (p < 0.05), none surviving FDR correction. These proteins were enriched for synapse-related proteins and axonogenesis. CHIT1 (vs. low-risk AD: FC = 1.0, p = 0.014, vs. CU: FC = 2.4, p < 0.001) and DDAH1 (vs. low-risk AD: FC=-0.31, p = 0.046, vs. CU: FC = 0.5, p < 0.001) were prioritized as biomarker. DDAH1 protein changes replicated in an independent cohort (FC=-0.37, p = 0.010), and CHIT1 replicated on a trend level (FC = 0.70, p = 0.104). DDAH1 levels had the highest co-expression with synaptic process, energy utilization and RNA-binding cell signaling related proteins (R > 0.8). CONCLUSIONS: The findings suggest that in the high risk group, there is a lack of upregulation in synapse and axonogenesis related proteins. High CSF CHIT1 and less increased CSF DDAH1 levels within AD relate to ARIA risk. From the literature, the link to ARIA risk for CHIT1 could be its contribution to innate immunity or vascular amyloid deposition, and for DDAH1 to blood-brain barrier integrity. Biomarker assays are available to assess the potential of CHIT1 and DDAH1 in trials and treatment studies in the clinical setting.}, } @article {pmid40695613, year = {2025}, author = {Sun, M and Wang, X and Lu, Z and Yang, Y and Lv, S and Miao, M and Chen, WM and Wu, SY and Zhang, J}, title = {Evaluating GLP-1 receptor agonists versus metformin as first-line therapy for reducing dementia risk in type 2 diabetes.}, journal = {BMJ open diabetes research & care}, volume = {13}, number = {4}, pages = {}, pmid = {40695613}, issn = {2052-4897}, mesh = {Humans ; *Metformin/therapeutic use ; *Diabetes Mellitus, Type 2/drug therapy/complications ; Male ; Female ; *Dementia/prevention & control/epidemiology/etiology ; *Glucagon-Like Peptide-1 Receptor Agonists ; *Hypoglycemic Agents/therapeutic use ; Retrospective Studies ; Aged ; Middle Aged ; Risk Factors ; Follow-Up Studies ; Incidence ; Aged, 80 and over ; }, abstract = {INTRODUCTION: No direct comparisons have evaluated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus metformin as first-line antidiabetic therapy for preventing dementia in patients with type 2 diabetes mellitus (T2DM). This study aimed to assess the comparative effectiveness of GLP-1 RAs and metformin in reducing dementia risk. RESEARCH DESIGN AND METHODS: This retrospective cohort study used data from a global health research network between 2004 and 2024. Patients with T2DM initiating GLP-1 RAs or metformin as first-line monotherapy were included. Propensity score matching was employed to balance baseline characteristics. Dementia incidence was analyzed using Cox proportional hazards models, with sensitivity analyses to confirm robustness. RESULTS: Among 87,229 matched patients per cohort, GLP-1 RA use was associated with a significantly lower risk of overall dementia (adjusted HR (AHR) 0.90; 95% CI 0.85 to 0.95), Alzheimer's disease (AD) (AHR 0.88; 95% CI 0.83 to 0.94), and non-vascular dementias (non-VaDs) (AHR 0.75; 95% CI 0.70 to 0.81) compared with metformin. No significant difference was observed for VaD. Subgroup analyses showed consistent benefit across age and sex, with the strongest effect among older adults and females. CONCLUSIONS: GLP-1 RAs were more effective than metformin in reducing the risk of dementia-especially AD and non-vascular types-highlighting their potential as a preferred first-line treatment in T2DM. Further randomized trials are warranted to validate these findings.}, } @article {pmid40695276, year = {2025}, author = {Li, Y and Pereda Serras, C and Blumenfeld, J and Xie, M and Hao, Y and Deng, E and Chun, YY and Holtzman, J and An, A and Yoon, SY and Tang, X and Rao, A and Woldemariam, S and Tang, A and Zhang, A and Simms, J and Lo, I and Oskotsky, T and Keiser, MJ and Huang, Y and Sirota, M}, title = {Cell-type-directed network-correcting combination therapy for Alzheimer's disease.}, journal = {Cell}, volume = {188}, number = {20}, pages = {5516-5534.e18}, pmid = {40695276}, issn = {1097-4172}, support = {R01 AG060393/AG/NIA NIH HHS/United States ; R01 AG078164/AG/NIA NIH HHS/United States ; P01 AG073082/AG/NIA NIH HHS/United States ; R01 AG057683/AG/NIA NIH HHS/United States ; RF1 AG076647/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/drug therapy/genetics/pathology/metabolism ; Animals ; Mice ; Humans ; Disease Models, Animal ; Drug Therapy, Combination ; Irinotecan/therapeutic use/pharmacology ; Neurons/metabolism/drug effects ; Transcriptome/drug effects ; Gene Regulatory Networks/drug effects ; Neuroglia/metabolism/drug effects ; Nitriles/therapeutic use/pharmacology ; Triazoles/therapeutic use/pharmacology ; Single-Cell Analysis ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Male ; Mice, Transgenic ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records. Using this framework, letrozole and irinotecan were identified as a potential combination therapy, each targeting AD-related gene expression changes in neurons and glial cells, respectively. In an AD mouse model with both Aβ and tau deposits, this combination therapy significantly improved memory performance and reduced AD-related pathologies compared with vehicle and single-drug treatments. Single-nucleus transcriptomic analysis confirmed that the therapy reversed disease-associated gene networks in a cell-type-specific manner. These results highlight the promise of cell-type-directed combination therapies in addressing multifactorial diseases like AD and lay the groundwork for precision medicine tailored to patient-specific transcriptomic and clinical profiles.}, } @article {pmid40695043, year = {2025}, author = {Kritika, and Sanjay, and Lee, HJ}, title = {Eriocitrin and its derivatives against Alzheimer's disease: Cumulative accounts of in vitro and in vivo studies.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {190}, number = {}, pages = {118362}, doi = {10.1016/j.biopha.2025.118362}, pmid = {40695043}, issn = {1950-6007}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Animals ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Flavanones/therapeutic use/pharmacology/chemistry ; *Brain/drug effects/metabolism/pathology ; }, abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease (ND), and its adversities are not limited to the brain. Due to complex and interconnected pathologies with other NDs, an effective treatment for multidimensional AD-related adversities has yet to be reported. Several phytoconstituents have been reported and are currently being studied for their bioactive potential in AD. Eriocitrin, a dihydroflavonoid compound present in citrus fruits, such as lemons, limes, lemon peels, grapefruit, and vegetables, and processed items, such as beverages and wine, along with its derivatives hesperetin, hesperidin, eriodictyol, and homoeriodictyol, has been reported to possess various neuroprotective bioactivities, including anti-inflammatory, anti-oxidative, anti-amyloidogenic, anti-tau phosphorylation, and anti-apoptotic properties, in several in vitro and in vivo models. However, a comprehensive review summarizing and correlating the multidimensional bioactive potentials of eriocitrin and its derivatives against AD has yet to be compiled. This review extensively discusses the in-depth role of eriocitrin and its derivatives in ameliorating different AD-related signaling pathways both in vitro and in vivo, and summarizes the incorporation of eriocitrin like different plant-based flavonoids in long-term dietary practice to combat AD and other similar NDs. Additionally, this review suggests examining various nano-formulations of eriocitrin and its derivatives for their anti-AD effects in comparison to the parent compound. Furthermore, in-depth in vitro and in vivo studies, along with different clinical trials, should be conducted to fully elucidate the true potential of eriocitrin and its derivatives in AD pathology.}, } @article {pmid40694204, year = {2025}, author = {Goleij, P and Khazeei Tabari, MA and Poudineh, M and Sanaye, PM and Khan, H and Kumar, AP and Larsen, DS and Daglia, M}, title = {Therapeutic potential of melatonin-induced mitophagy in the pathogenesis of Alzheimer's disease.}, journal = {Inflammopharmacology}, volume = {33}, number = {8}, pages = {4553-4575}, pmid = {40694204}, issn = {1568-5608}, mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; *Melatonin/pharmacology/therapeutic use ; *Mitophagy/drug effects/physiology ; Humans ; Animals ; Mitochondria/drug effects/metabolism ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Neuroprotective Agents/pharmacology ; Mice ; Neurons/metabolism/drug effects ; }, abstract = {Neurons rely heavily on functional mitochondria for energy production. Mitochondrial dysfunction is a key player in age-related neurodegenerative diseases like Alzheimer's disease (AD). In AD, damaged mitochondria accumulate early, worsening the disease. This dysfunction disrupts cellular balance in neurons, leading to energy deficiencies, calcium imbalances, and oxidative stress. These issues further aggravate the harmful effects of amyloid beta (Aβ) plaques and tau tangles, ultimately leading to synaptic dysfunction, memory loss, and cognitive decline. While a complex link exists between mitochondrial dysfunction and AD hallmarks like Aβ plaques and tau tangles, the exact cause-and-effect relationship remains unclear. Additionally, recent evidence suggests impaired mechanisms for mitophagy in AD. Mitophagy is crucial for neuronal health, and studies have found changes to proteins involved in this process, mitochondrial dynamics, and mitochondrial production in AD. Impaired mitophagy might also be linked to problems with how cells fuse waste disposal compartments (autophagosomes) with lysosomes, and issues with maintaining proper acidity within lysosomes. Interestingly, melatonin, a hormone known for regulating sleep, has recently emerged as a potential neuroprotective agent. Studies using a mouse model of AD showed that melatonin treatment improved cognitive function by enhancing mitophagy. These findings suggest that melatonin's ability to improve mitophagy may be a promising avenue for future AD therapies. Therefore, in this review, we discuss the therapeutic effect of melatonin on mitochondrial dysfunction, especially mitophagy, in AD.}, } @article {pmid40694170, year = {2025}, author = {Shah, Z and Iqbal, A and Badshah, SL and Mir, MA and Sohni, S and Ullah, H and Shah, SA and Bashir, N and Ayaz, M and Daglia, M}, title = {Macroalgae Polysaccharides Enhance Brain Health by Mitigating Scopolamine-induced Oxidative Stress and Inflammation Via Nrf-2/TLR4/NF-kB Pathways.}, journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology}, volume = {20}, number = {1}, pages = {74}, pmid = {40694170}, issn = {1557-1904}, mesh = {Animals ; *Polysaccharides/pharmacology/isolation & purification ; *Oxidative Stress/drug effects/physiology ; Scopolamine/toxicity ; Mice ; NF-kappa B/metabolism ; Male ; NF-E2-Related Factor 2/metabolism ; Toll-Like Receptor 4/metabolism ; *Seaweed/chemistry ; *Neuroprotective Agents/pharmacology/isolation & purification ; *Brain/drug effects/metabolism ; Signal Transduction/drug effects ; Inflammation/chemically induced/metabolism/drug therapy ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder commonly associated with memory loss and difficulties in performing daily activities, particularly in the aging brain. PURPOSE OF THE STUDY: This study aimed to evaluate the neuroprotective effects of macroalgae-derived polysaccharides from seaweed against scopolamine-induced amnesia, oxidative stress, and amyloid plaque (Aβ) production in rodents, following standard experimental protocols. METHODS: Three novel polysaccharides were extracted from Chara vulgaris, Cladophora glomerata, and Spirogyra crassa, namely: methylated pectin-type polysaccharides (PS1), methylated pectin-type polysaccharides (homo galacturonan and rhamno galacturonan, PS2), Ulvan-type polysaccharide, and xyloglucan polysaccharides (PS3). These polysaccharides were characterized using a variety of analytical techniques, including SEM, FTIR, XRD, [1]H-NMR, and [13]C-NMR. The polysaccharides were administered at a dose of 30 mg/kg to male albino mice exposed to scopolamine (1 mg/kg) for three weeks. To assess their neuroprotective effects, Morris Water Maze (MWM) and Y-maze tests, antioxidant enzyme assays (Catalase, GSH, LPO), and western blotting were performed. RESULTS: The results showed that all three polysaccharides significantly (p ≤ 0.001) mitigated redox imbalance and reduced (p ≤ 0.001) microglial activation, thereby decreasing scopolamine-induced neuroinflammation and amyloid beta (Aβ) accumulation. Additionally, these polysaccharides improved neuronal synapses and cognitive function by modulating the NRf-2/TLR4/NF-kB signaling pathway. DATA ANALYSIS: The data analysis and graph generation were performed using GraphPad Prism software, version 5.0, with a significance level set at a p-value of < 0.05. CONCLUSION: The findings highlighted the potential of these three novel natural polysaccharides as promising candidates for the treatment of scopolamine-induced oxidative stress-mediated neurodegenerative disorders, such as Alzheimer's disease.}, } @article {pmid40693114, year = {2025}, author = {Xiao, S and Wei, X and Han, B and Shi, X and Wei, C and Liang, R and Sun, J and Zhang, Z and Han, Z and Shen, L}, title = {Quantitative analysis of targeted lipidomics in the hippocampus of APP/PS1 mice employing the UHPLC-MS/MS method.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1561831}, pmid = {40693114}, issn = {1663-4365}, abstract = {BACKGROUND: Alzheimer's disease (AD) is marked by the pathological features of amyloid-β plaque accumulation, as well as intracellular neurofibrillary tangles formation in the patients' brain. Aberrant lipid metabolism is increasingly recognized as one of the important contributors to AD. PURPOSE: The main goal of this research was to conduct quantitative detection of targeted lipidomics in hippocampal tissue of APPSwe/PS1dE9 mice in order to identify lipid metabolic biomarkers of early-onset AD mice. METHODS: Our approach departs from conventional lipid detection methods, employing a highly accurate quantificational Ultra High Performance Liquid Chromatography Tandem Mass Spectrometry (UHPLC-MS/MS) technique to analyze targeted lipid biomarkers. The innovative method was utilized to detect targeted lipids in the hippocampus of AD and wild-type mice. Statistical method was performed by Student's t-test and multivariate analysis. Differential metabolites were identified through fulfilling the standard of Variable Importance in Projection surpassing one and the significance probability lower than 0.05 thresholds. RESULTS: Both groups utilized identical methodologies and adhered strictly to standardized treatment protocols. Sphingolipids (SPs), Glycerophospholipids (GPs), Glycolipids, Glycerides (GLs), Sterol Lipids (STs), and Free Fatty Acid (FA) were identified as prominent lipids exhibiting alterations in the hippocampus of AD models. Regarding glycolipid and glycerolipid composition, monogalactosyldiacylglycerols (MGDGs) and Triacylglycerols (TGs) constituted a significant proportion (p < 0.05, VIP > 1). Among glycerophospholipids, phosphatidylethanolamines (PEs) and phosphatidylcholines (PCs) emerged as significant constituents (p < 0.05, VIP > 1). Furthermore, hexosylceramides (HexCers) and ceramides (Cers) in the AD model's hippocampus, the prominent sphingolipids in the hippocampus of AD mice, existed as the two primary changed lipid metabolites. The levels of some TGs in GLs and CEs in STs showed a significant elevation (p < 0.05, VIP > 1). In contrast, most kinds of MGDGs, HexCers, Cers, PEs and FA (18:2) demonstrated a notable decrease in the hippocampus of AD group (p < 0.05, VIP > 1). CONCLUSION: The present research represents the important quantitative identification of distinct lipid biomarker profiles within the hippocampal portion of 7.5-month-aged AD mice. It encompasses glycolipid, GLs, GPs, SPs, STs, and FAs using a targeted HPLC-MS method for quantification. These findings suggest potential diagnostic lipid biomarkers in hippocampus of early-onset AD mice related to cellular membrane integrity, atherosclerosis, oxidative stress damage, and inflammation.}, } @article {pmid40692324, year = {2025}, author = {Pereira da Silva, AM and Falcão, L and Virgilio, F and Rodrigues Menezes, I and Leite, M and Farias, E and Nascimento, M and Lee Han, M and Mota Telles, JP and de Souza Franco, E and de Sousa Maia, MB}, title = {Efficacy and APOE ε4-stratified risk of donanemab in Alzheimer's disease: A systematic review and meta-analysis of randomized clinical trials.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {477-493}, doi = {10.1177/13872877251361044}, pmid = {40692324}, issn = {1875-8908}, mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; Randomized Controlled Trials as Topic ; *Apolipoprotein E4/genetics ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Treatment Outcome ; }, abstract = {BackgroundDonanemab, a monoclonal antibody targeting amyloid-β (Aβ) plaques, has shown the ability to reduce cerebral amyloid burden in early Alzheimer's disease (AD). However, uncertainties remain regarding its clinical relevance, particularly in relation to tau pathology, APOE ε4 genotype, and methodological limitations in existing trials.ObjectiveTo conduct a systematic review and exploratory meta-analysis to evaluate the efficacy, safety, and tolerability of donanemab in patients with mild to moderate AD.MethodsWe conducted a systematic review and exploratory meta-analysis following PRISMA guidelines. Randomized controlled trials comparing donanemab to placebo in individuals aged ≥65 years with biomarker-confirmed mild to moderate AD were included. Outcomes included cognitive measures (ADAS-Cog13, MMSE, CDR-SB, iADRS, ADCS-iADL) and adverse events (ARIA-E, ARIA-H, infusion reactions, discontinuations). Random-effects models were used to estimate pooled mean difference (MD) or risk ratio (RR) with 95% confidence intervals. Subgroup analyses were performed by baseline tau burden and APOE ε4 genotype.ResultsThree trials (n = 2054) were included. Donanemab modestly reduced cognitive decline compared to placebo: ADAS-Cog13 (MD, -1.86), CDR-SB (MD, -0.36), MMSE (MD, 0.64), and iADRS (MD, 3.19), with similar effects across tau subgroups. The risk of ARIA-E was markedly increased (RR, 12.39), especially among APOE ε4 homozygotes. Infusion reactions (RR, 11.90) and discontinuations (RR, 3.22) were also more frequent.ConclusionsDonanemab demonstrated modest cognitive benefits, the clinical significance of which remains uncertain. Independent, longer-term trials with rigorous methodology and active comparators are warranted to more clearly define its therapeutic value in the treatment of AD.}, } @article {pmid40692317, year = {2025}, author = {Yin, M and Ding, S and Zhao, M and Liu, J and Su, W and Fu, M and Wu, M and Ma, C and Sun, X and Kong, Y}, title = {The global, regional, and national burden and attributable risk factors of Alzheimer's disease and other dementias, 1990-2021: A systematic analysis for the Global Burden of Disease Study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {1}, pages = {192-206}, doi = {10.1177/13872877251360221}, pmid = {40692317}, issn = {1875-8908}, mesh = {Humans ; Risk Factors ; *Alzheimer Disease/epidemiology ; *Global Burden of Disease/trends ; Female ; Male ; Cross-Sectional Studies ; Aged ; *Dementia/epidemiology ; Middle Aged ; Incidence ; Aged, 80 and over ; Disability-Adjusted Life Years ; Global Health ; Adult ; }, abstract = {BackgroundDementia is a syndrome characterized by a decline in cognitive function, with Alzheimer's disease (AD) being the most common type. Updated global statistics on the burden of AD and other dementias provide critical insights for guiding prevention and treatment strategies.ObjectiveTo estimate the global, regional, and national burden and attributable risk factors of AD and other dementias from 1990 to 2021.MethodsThis cross-sectional study utilized the 2021 Global Burden of Disease (GBD) dataset from 204 countries and territories. The analysis focused on individuals aged 40 years and older with AD and other dementias and included data on incidence, all-cause and cause-specific mortality, disability-adjusted life years (DALYs), and estimated annual percentage changes (EAPCs). These trends were stratified by region, country, age, sex, and Socio-Demographic Index (SDI).ResultsFrom 1990 to 2021, global DALYs attributable to AD and other dementias rose from 3.83 million to 9.84 million. Age-standardized rates (ASRs) of incidence and DALYs increased for both sexes, with a more pronounced rise in males. ASRs for incidence, prevalence, and DALYs were positively correlated with SDI. Smoking was identified as the primary risk factor for dementia burden among males, whereas obesity was the leading risk factor for females.ConclusionsThe global burden of AD and other dementias has significantly increased from 1990 to 2021, especially in high-SDI regions. While females have a higher overall risk, the burden has grown more rapidly in males. These findings highlight the need for targeted interventions to address aging populations and reduce dementia risk factors.}, } @article {pmid40691719, year = {2025}, author = {Rafii, MS and Aisen, PS}, title = {Amyloid-lowering immunotherapies for Alzheimer disease: current status and future directions.}, journal = {Nature reviews. Neurology}, volume = {21}, number = {9}, pages = {490-498}, pmid = {40691719}, issn = {1759-4766}, mesh = {Humans ; *Alzheimer Disease/therapy/immunology/drug therapy/metabolism ; *Immunotherapy/methods/trends ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies, Monoclonal/therapeutic use ; Animals ; }, abstract = {The treatment of Alzheimer disease (AD) has crossed a pivotal threshold, marked by the landmark approvals of the first-ever disease-modifying therapies. These immunotherapies, specifically monoclonal antibodies (mAbs) that target various amyloid-β (Aβ) species including proto-fibrillar and fibrillar forms, substantially lower levels of Aβ in the brain. The therapies have collectively demonstrated the ability to slow cognitive and clinical decline in large placebo-controlled trials, ushering a new era in the management of AD. Here, we review recent progress made in bringing amyloid-lowering mAb therapies to the clinic and explore future directions in this rapidly evolving field. We also delve into the current understanding of AD as a biological continuum, from its asymptomatic preclinical stage to its clinically overt dementia stage. We explore how this conceptualization provides a regulatory framework to evaluate amyloid-lowering mAbs across the entire spectrum of the disease. Additionally, we review key factors that affect the integration of these treatments into clinical practice.}, } @article {pmid40691577, year = {2025}, author = {Kim, HB and Yoo, S and Kwak, H and Ma, SX and Kim, R and Lee, M and Ha, N and Pyo, S and Kwon, SG and Cho, EH and Lee, SM and Jang, J and Kim, WK and Park, HC and Baek, M and Park, Y and Park, JY and Park, JW and Hwang, SW and Hwang, JI and Seong, JY}, title = {Inhibition of FAM19A5 reverses synaptic loss and cognitive decline in mouse models of Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {168}, pmid = {40691577}, issn = {1758-9193}, mesh = {Animals ; Humans ; Male ; Mice ; Rats ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Cognitive Dysfunction/metabolism/drug therapy ; Disease Models, Animal ; Excitatory Postsynaptic Potentials/drug effects ; Hippocampus/metabolism/drug effects/pathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurons/metabolism/drug effects ; *Synapses/drug effects/pathology/metabolism ; }, abstract = {BACKGROUND: FAM19A5 is a secretory protein primarily expressed in neurons. Although its role in synaptic function has been suggested, the precise molecular mechanisms underlying its effects at the synapse remain unclear. Given that synaptic loss is a critical hallmark of Alzheimer's disease (AD), elucidating the mechanisms involving FAM19A5 could provide valuable insights into reversing synaptic loss in AD. METHODS: The binding partner of FAM19A5 was identified through co-immunoprecipitation experiments of mouse brain tissue. The effect of FAM19A5 on spine density in hippocampal neurons was evaluated using immunocytochemistry by overexpressing FAM19A5, treating neurons with FAM19A5 protein, and/or an anti-FAM19A5 antibody NS101. Target engagement of NS101 was determined by measuring FAM19A5 levels in mouse, rat, and human plasma at specific time points post NS101 injection using ELISA. Changes in spine density and dynamics in P301S tauopathy mice were assessed via Golgi staining and two-photon microscopy after NS101 administration. The synaptic strengthening of hippocampal neurons in APP/PS1 amyloidopathy mice after NS101 treatment was assessed by measuring miniature excitatory postsynaptic currents (mEPSCs) and field excitatory postsynaptic potentials (fEPSPs). Cognitive performance in AD mice after NS101 treatment was measured using the Y-maze and Morris water maze tests. RESULTS: FAM19A5 binds to LRRC4B, a postsynaptic adhesion molecule, leading to reductions in spine density in mouse hippocampal neurons. Inhibiting FAM19A5 function with NS101 increased spine density. Intravenous administration of NS101 increased spine density in the prefrontal cortex of P301S mice, which initially showed reduced spine density compared to wild-type (WT) mice. NS101 normalized the spine elimination rate in P301S mice, restoring the net spine count to levels comparable to WT mice. NS101 treatment enhanced the frequency of mEPSCs and fEPSPs in the hippocampal synapses of APP/PS1 mice, leading to improved cognitive function. The increases in plasma FAM19A5 levels upon systemic NS101 administration suggest that the antibody effectively engages its target and facilitates the transport of FAM19A5 from the brain. CONCLUSIONS: This study demonstrated that inhibiting FAM19A5 function with an anti-FAM19A5 antibody restores synaptic integrity and enhances cognitive function in AD, suggesting a novel therapeutic strategy for AD. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT05143463 , Identifier: NCT05143463, Release date: 3 December 2021.}, } @article {pmid40690192, year = {2025}, author = {Jiang, S and Arnold, SE and Betensky, RA}, title = {Design and Analysis of N-Of-1 Trials That Incorporate Sequential Monitoring.}, journal = {Statistics in medicine}, volume = {44}, number = {15-17}, pages = {e70177}, doi = {10.1002/sim.70177}, pmid = {40690192}, issn = {1097-0258}, support = {P30AG066512/NH/NIH HHS/United States ; UL1 TR002345/NH/NIH HHS/United States ; R01NS094610/NH/NIH HHS/United States ; P01AG036694/NH/NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Sample Size ; *Research Design ; *Randomized Controlled Trials as Topic/methods/statistics & numerical data ; Computer Simulation ; Cross-Over Studies ; Alzheimer Disease/drug therapy ; }, abstract = {For many diseases and disorders, such as Alzheimer's disease, patients demonstrate considerable heterogeneity in their responses to treatment interventions. One treatment may be most effective for some patients, while another may be most effective for others, and neither may be effective for another subset of patients. This potentially renders the conventional parallel group design highly inefficient. An attractive alternative is the N-of-1 design, also called the multi-crossover randomized controlled trial. In this design, each participant serves as their own control in a series of randomized blocks of treatment assignments. We propose novel designs for both the single-person and multi-person N-of-1 trials that employ sequential monitoring. In particular, we allow for early stopping for a single participant as soon as there is sufficient evidence of a preferred treatment for them, and early stopping for the group of participants as soon as there is sufficient evidence of a preferred treatment for the population of patients. We provide sample size calculations and decision rules for terminating the trial early and illustrate their properties in simulation studies. We apply our proposed methods to N-of-1 studies of brain tumor excisions and of methylphenidate in mild cognitive impairment.}, } @article {pmid40690160, year = {2025}, author = {Sompol, P and Jicha, GA and Hinman, JD and Brickman, AM and Greenberg, SM and Arfanakis, K and Buckwalter, MS and Llorente, IL and Williamson, JD and Wolf, MS and Smith, EE and Gupta, A and Flanagan, ME and Vazquez, MA and Burns, JM and Carmichael, ST and Barone, FC}, title = {Advancing clinical trial readiness in white matter disease and related dementias: key steps for future research progress.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {40690160}, issn = {2509-2723}, support = {K23 AG055666/AG/NIA NIH HHS/United States ; R33 AG068483/AG/NIA NIH HHS/United States ; R21AG074146/AG/NIA NIH HHS/United States ; }, abstract = {White matter disease, a broad-spectrum term that covers various types of white matter lesions and degeneration, is strongly related to age-related neurodegenerative disorders including Alzheimer's disease (AD), and vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's related dementias (ADRD). There is no specific treatment for white matter disease. Therefore, basic research and clinical studies are essential for future outcomes. Since its formation in 2020, the Albert Research Institute for White Matter and Cognition (ARIWMC) mission has been to support white matter research by providing a forum for communication where basic and clinical scientists meet to discuss and debate new knowledge and guidelines for studying white matter in dementia. The 4th annual ARIWMC workshop was held on May 31-June 2, 2023, where researchers met to set strategies for clinical trial readiness. Significant discussion by participants advocated research on multiple levels, including molecular, cellular, metabolic, behavioral, and risk factors that contribute to disease etiology and regeneration processes. Moreover, participants also addressed identifying and validating biomarkers and functional studies in animal models and human trials that are key steps for treatment development. Other areas that were discussed included epidemiological studies and pragmatic clinical trials where health care researchers and everyday medical practice support risk factor management or healthy lifestyle, and prevention trials could mitigate the incident of the disease. In summary, this workshop fostered a better understanding of how white matter lesions contribute to cognitive impairment from bench-to-biomarker-to-bedside-to-translational approaches which will facilitate and support the discovery and development of therapies and prevention strategies that facilitate a healthy brain and reduce white matter-related pathologies associated with and contributing to VCID and ADRD.}, } @article {pmid40689211, year = {2025}, author = {Yang, Z and Zhang, FR and Ren, L and Bai, JM and Wang, SC and Li, XY and Yang, HJ and Xiao, HH}, title = {Multi-omics reveal the neuroprotective mechanisms of Xinshubao tablet against scopolamine-induced cognitive dysfunction in mice.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1596728}, pmid = {40689211}, issn = {1663-9812}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatments. Xinshubao tablet (XSB), a traditional Chinese medicine, contains several bioactive compounds with notable neuroprotective effects. Our previous studies have demonstrated that XSB can alleviate cognitive deficits in vascular dementia (VaD) models, suggesting its potential as a therapeutic candidate for AD. METHODS: In this study, scopolamine-induced AD-like mice were orally administered with varying doses of XSB (0.13 g/kg, 0.26 g/kg and 0.52 g/kg) for 28 days. Behavior tests, H&E, Nissl, immunofluorescence staining, and Western blot assays were performed to evaluate the neuroprotection of XSB on AD-like mice. Then, fecal 16S rDNA sequencing, serum metabolomics, and hippocampal mRNA sequencing (mRNA-seq) analysis were performed to investigate the underlying mechanisms. RESULTS AND DISCUSSION: The results revealed that oral administration of XSB improved cognitive function, mitigated neuropathological damage, and alleviated dysfunction in the cholinergic system in AD-like mice. XSB treatment also enhanced gut microbiota diversity, increased the abundance of Enterococcus, Actinobacteriota, Coriobacteriales, and Eggerthellaceae, but reduced the abundance of Helicobacter rodentium and Lachnospiraceae. Integrating mRNA-seq and metabolomics data highlighted key regulatory pathways including the biosynthesis of unsaturated fatty acids, tyrosine metabolism, and glycerophospholipid metabolism. Furthermore, XSB treatment reduced the expression of TNF-α, IL-1β, MPO, enhanced SOD, GSH activities, reduced malondialdehyde (MDA) levels, upregulated the expression of BDNF, SYN, PSD95, and improved synaptic density. Transformation of XSB derived fecal microbiota (XSB-FM) effectively alleviated cognitive dysfunction and intestinal barrier injures. In conclusion, XSB may exert its neuroprotective effects via the microbiota-metabolite-brain axis, thereby improving neuroinflammation, neurotransmission, and synaptic integrity. These findings support the potential of XSB as a multifactorial therapeutic strategy for cognitive deficits in AD.}, } @article {pmid40689203, year = {2025}, author = {Mi, X and Ruan, X and Lin, R and Huang, S and Cai, P and Chen, X and Liao, J and Dai, X}, title = {Intranasal administration of Ganoderma lucidum-derived exosome-like nanovesicles ameliorates cognitive impairment by reducing inflammation in a mouse model of Alzheimer's disease.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1572771}, pmid = {40689203}, issn = {1663-9812}, abstract = {BACKGROUND/OBJECTIVES: Although Alzheimer's disease (AD) is the most prevalent dementia in late life, with amyloid beta (Aβ) deposition and neuroinflammation are recognized among its primary pathological features. Currently, there is currently still a lack of effective therapeutic drugs for AD. Ganoderma lucidum (G. lucidum) is abundant in active ingredients that harbor anti-inflammatory properties in both central nervous system and the periphery. We attempted to determine whether G. lucidum contained exosome-like nanovesicles (GLENVs) and whether these GLENVs can alleviate cognitive impairment. METHODS: We extracted GLENVs by the differential ultracentrifugation method and identified the components by liquid chromatography-mass spectrometry (LC-MS). The 5×FAD mice underwent a 3-month intranasal administration of GLENVs and their behavioral and pathological changes were evaluated. RESULTS: GLENVs were successfully extracted and identified to contain multiple ganoderic acids; intranasal administration allowed GLENVs to penetrate the blood-brain barrier to exert their effects directly. The 3-month GLENVs treatment effectively ameliorated the impairment in the memory and learning of the 5×FAD mice. The GLENVs treatment also reduced Aβ deposition in the cortex and hippocampus of 5×FAD mice, overactivated microglia, reactive astrocytes, and pro-inflammatory factors, and inhibited the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway. Moreover, GLENVs exerted no adverse effects on liver and kidney function. CONCLUSION: GLENVs may be a promising candidate for AD treatment.}, } @article {pmid40688757, year = {2025}, author = {Sur, TK and Mondal, T and Noreen, Z and Johnson, J and Nunlee-Bland, G and Loffredo, CA and Korba, BE and Chandra, V and Jana, SS and Kwabi-Addo, B and Sarkar, S and Ghosh, S}, title = {Developing non-invasive molecular markers for early risk assessment of Alzheimer's disease.}, journal = {Biomarkers in neuropsychiatry}, volume = {12}, number = {}, pages = {}, pmid = {40688757}, issn = {2666-1446}, support = {U54 MD007597/MD/NIMHD NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease, with no standard biomarker(s) to detect or confirm its risk at an early stage. The prevalence of AD increases exponentially worldwide in people of ages over 65 and older. Current improvements have unveiled the disease's pathophysiology and clinical diagnostic tests, targeting the neurological changes (neurodegeneration, amyloid precursor protein metabolism and tangle pathology) with precise PET/MRI imaging and xMAP/SIMOA (Multiplex simultaneous detection/single molecule array) to identify and quantify β-amyloids (Aβ40, Aβ42), total tau (T-tau) and phosphorylated tau (P-tau) proteins in the brain and cerebrospinal fluid (CSF) of patients. However, their utility for diagnosis in routine clinical practice is still challenging because of cost, accessibility, standardization, procedural limitation, and regulatory approval. Further research is needed to establish affordable, patient-friendly, easy, quick, and robust biomarkers for early AD detection, progression, and therapeutic management. Research on blood-based preclinical diagnosis and clinical practice for AD has advanced significantly in the last decade. Emerging literature supports the importance of new molecular biomarkers and signature genes from blood to detect and predict AD in advance. This review examines the potential applications of these blood-based target biomarkers for early disease detection, co-morbid condition risk prediction, and treatment management of AD.}, } @article {pmid40708156, year = {2024}, author = {Ghosh, P and Iyer, PK}, title = {Conjugated Polyelectrolytes: Illuminating the Path to Neurodegenerative Disorders Detection and Treatment.}, journal = {ACS applied materials & interfaces}, volume = {16}, number = {16}, pages = {20034-20054}, doi = {10.1021/acsami.3c17890}, pmid = {40708156}, issn = {1944-8252}, mesh = {Humans ; *Polyelectrolytes/chemistry/therapeutic use ; Amyloid beta-Peptides/metabolism/chemistry ; *Neurodegenerative Diseases/diagnosis/drug therapy/metabolism ; Alzheimer Disease/diagnosis/drug therapy/metabolism ; Animals ; }, abstract = {Conjugated polyelectrolytes (CPEs) have gained extensive attention for their potential efficacy in protein misfolding disease (PMD) studies. This comprehensive review article explores the importance of CPEs in PMD research and treatment strategies. CPEs have unique features and capabilities, such as selective binding to disease-specific biomarkers like amyloid-beta (Aβ) aggregates which allows for noninvasive imaging methods to detect and identify early pathological alterations. They also induce unique fluorescence responses upon interaction with Aβ aggregates, enabling real-time monitoring of aggregation kinetics. The exceptional selectivity of CPEs has been demonstrated by their strategic chemical modification, by conjugating them with certain specific ligands, enhancing their diagnostic precision. Thus, CPEs hold immense potential to serve in the diagnosis and treatment of neurodegenerative diseases such as Alzheimer's due to their versatility.}, } @article {pmid40703689, year = {2024}, author = {Kim, H and Lee, H}, title = {Current status and significance of research on sex differences in neuroscience: a narrative review and bibliometric analysis.}, journal = {Ewha medical journal}, volume = {47}, number = {2}, pages = {e16}, pmid = {40703689}, issn = {2234-2591}, abstract = {This review aims to highlight the importance of research on structural, functional, molecular-biological, and disease-specific sex differences in the brain, and to examine current bibliometric indicators related to research on sex differences. The Web of Science Core Collection was searched for related articles from 2010 to 2023. Structural and functional brain differences according to sex, including variations in communication patterns between hemispheres, may play a role in mental disorders. Sex differences in neurotransmitters such as serotonin, dopamine, and γ-aminobutyric acid contribute to disparities in mental health, addiction, and neurodevelopmental conditions. Neurodevelopmental disorders such as autism spectrum disorder and schizophrenia exhibit sex-based differences in prevalence, symptoms, brain changes, and neurotransmitter disruptions under hormonal influence. There is a growing body of research on depression, adolescence, the hippocampus, the amygdala, and cognition, highlighting the importance of considering sex/gender factors. Recent studies on sex differences in brain diseases have identified variations in brain structure, function, and neurophysiological substances, as well as in hormones and genes between the sexes. The incidence of psychiatric disorders such as autism spectrum disorder, depression, anxiety, and Alzheimer's disease is increasingly being linked to sex differences, and the need for research into the mechanisms underlying these differences is gaining recognition. However, there remains a significant gap in sex-specific neuroscience research related to the diagnosis, treatment, prevention, and management of these conditions. Advancing inclusive research will require comprehensive training, a consensus on methodology, diverse perspectives through collaborative frameworks, governmental/institutional support, and dedicated funding to create suitable research environments and implementation strategies.}, } @article {pmid40969174, year = {2024}, author = {Matz, LM and Shah, NS and Porterfield, L and Stuyck, OM and Jochum, MD and Kayed, R and Taglialatela, G and Urban, RJ and Buffington, SA}, title = {Gut pathobiont enrichment observed in a population predisposed to dementia, type 2 diabetics of Mexican descent living in South Texas.}, journal = {Frontiers in microbiomes}, volume = {3}, number = {}, pages = {}, pmid = {40969174}, issn = {2813-4338}, support = {P30 ES030285/ES/NIEHS NIH HHS/United States ; R01 HD109095/HD/NICHD NIH HHS/United States ; T32 AG067952/AG/NIA NIH HHS/United States ; UL1 TR001439/TR/NCATS NIH HHS/United States ; }, abstract = {Type 2 diabetes (T2D) is a common forerunner of neurodegeneration and accompanying dementia, including Alzheimer's Disease (AD), yet the mechanisms underlying this comorbidity remain unresolved. Individuals of Mexican descent living in South Texas have increased prevalence of comorbid T2D and early onset AD, despite low incidence of the APOE-ε4 risk variant among the population and an absence of a similar predisposition among relatives residing in Mexico - suggesting a role for environmental factors in coincident T2D and AD susceptibility. We therefore sought to test if differences in gut community structure could be observed in this population prior to any AD diagnosis. Here, in a small clinical trial (ClinicalTrials.gov Identifier NCT04602650), we report evidence for altered gut microbial ecology among subjects of Mexican descent living in South Texas with T2D (sT2D) compared to healthy controls without T2D (HC), despite no differences in expressed dietary preferences. We performed metataxonomic 16S rRNA gene amplicon sequencing of study participant stool samples. Although no significant decrease in microbial alpha diversity was observed between sT2D gut communities versus those of HC, body mass index was identified as a driver of gut community structure. Intriguingly, we observed a significant negative association of Faecalibacterium with T2D and an increase in the abundance of pathobionts Escherichia-Shigella, Enterobacter, and the erysipelotrichial species Clostridia innocuum among sT2D gut microbiota, as well as differentially abundant gene and metabolic pathways. Future large-scale, longitudinal sequencing efforts of the gut microbiome of individuals with T2D who go onto develop AD might identify key actors among "disease state" microbiota that contribute to increased susceptibility to comorbid dementia among type 2 diabetics. Finally, we identified candidate microbiome-targeted approaches for the treatment of T2D.}, } @article {pmid40766919, year = {2024}, author = {Tucker, M and Liao, GY and Keely, A and Park, JY and Rosenfeld, M and Wezeman, J and Mangalindan, R and Ratner, D and Darvas, M and Ladiges, W}, title = {Behavioral and neuropathological features of Alzheimer's disease are attenuated in 5xFAD mice treated with intranasal GHK peptide.}, journal = {Aging pathobiology and therapeutics}, volume = {6}, number = {3}, pages = {102-108}, pmid = {40766919}, issn = {2690-1803}, support = {R01 AG057381/AG/NIA NIH HHS/United States ; R01 AG067193/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease and a leading cause of morbidity and mortality. Efforts to find disease modifying treatments have met with limited success. The naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine), in its Cu-bound form, supports angiogenesis, remodeling, and tissue repair, has anti-inflammatory and antioxidant properties, and has been shown to improve cognitive performance in aging mice. These features raised the question of whether GHK-Cu could alleviate neurodegeneration observed in AD. Male and female 5xFAD transgenic mice on the C57BL/6J background at 4 months of age were given 15 mg/kg GHK-Cu intranasally 3 times per week for 3 months until 7 months of age. Results showed that intranasal GHK-Cu treatment delayed cognitive impairment, reduced amyloid plaques, and lowered MCP1-mediated inflammation levels in the frontal cortex and hippocampus. These observations provide the rationale for conducting additional studies to investigate the potential of GHK-Cu peptide as a promising treatment for AD.}, } @article {pmid40703952, year = {2023}, author = {Rezakhani, L and Salimi, Z and Zarei, F and Moradpour, F and Khazaei, MR and Khazaei, M and Pourjalili, M}, title = {Protective Effects of Statins against Alzheimer Disease.}, journal = {Ewha medical journal}, volume = {46}, number = {4}, pages = {e17}, pmid = {40703952}, issn = {2234-2591}, abstract = {Alzheimer disease (AD) is a common neurodegenerative disorder, characterized by memory impairment, dementia, and diminished cognitive function. This disease affects more than 20 million people worldwide. Amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) are important pathological markers of AD. Multiple studies have indicated a potential association between elevated cholesterol levels and increased risk of AD, suggesting that lowering the cholesterol level could be a viable strategy for AD treatment or prevention. Statins, potent inhibitors of cholesterol synthesis, are widely used in clinical practice to decrease the plasma levels of LDL cholesterol in patients with hyperlipidemia. Statins are known to play a neuroprotective role in limiting Aβ pathology through cholesterol-lowering therapies. In addition to Aβ plaques and neurofibrillary tangles, the brains of AD patients exhibit signs of oxidative stress, neuroinflammatory responses, and synaptic disruption. Consequently, compounds with antioxidant, anti-inflammatory, and/or neuroprotective properties could be beneficial components of AD treatment strategies. In addition to lowering LDL cholesterol, statins have demonstrated therapeutic efficacy in various forms, including antioxidant, anti-inflammatory, and neuroprotective effects. These properties of statins are potential mechanisms underlying their beneficial effects in treating neurodegenerative diseases. Therefore, this review was conducted to provide an overview of the protective effects of statins against AD.}, } @article {pmid40688669, year = {2025}, author = {Zhu, RK and Shi, J and Zhou, HJ and Ge, L and Yin, WH and Zeng, H and Wang, XW}, title = {Biological applications of graphene-based nanomaterials in neurodegenerative diseases.}, journal = {Materials today. Bio}, volume = {33}, number = {}, pages = {102064}, pmid = {40688669}, issn = {2590-0064}, abstract = {Neurodegenerative diseases (NDDs) have become a major challenge in global public health due to neurotoxicity caused by progressive neuronal degeneration and abnormal protein aggregation, which has attracted widespread attention. Graphene-based nanomaterials provide innovative solutions for the early diagnosis and precise treatment of NDDs by virtue of their ultra-high conductivity, large specific surface area and multifunctional properties. In this paper, we systematically discuss the key applications of these materials in the diagnosis and treatment of NDDs, and deeply analyze the technological breakthroughs and clinical translation challenges. The core of this paper is to illustrate that graphene-based nanomaterials are expected to reshape the paradigm of NDDs diagnosis and treatment through cross-scale technological innovations, promoting the synergistic development of early diagnosis, personalized treatment and real-time monitoring, and providing a transformative strategy for overcoming NDDs.}, } @article {pmid40688579, year = {2025}, author = {Zhang, G and Zhao, W and Lv, S and Wang, Z and Yi, Y and Ma, H and Lu, Y and Yan, W and Teng, J}, title = {Emerging trends in Alzheimer's disease diagnosis and prediction using artificial intelligence: A bibliometric analysis of the top cited 100 articles.}, journal = {Digital health}, volume = {11}, number = {}, pages = {20552076251362098}, pmid = {40688579}, issn = {2055-2076}, abstract = {BACKGROUND: AD is a significant public health challenge, and AI technologies, including deep learning and machine learning, offer the potential to dramatically improve diagnostic and predictive accuracy. These technologies are widely applied in AD research. However, comprehensive literature summaries of this field remain limited. This study uses bibliometric analysis to examine research hotspots, trends, future development potential, and limitations in AI-based AD diagnosis and prediction. METHODS: We conducted a bibliometric analysis of 100 top cited studies on AI-based diagnosis and prediction of AD, using data from the WoSCC. We performed the analysis using CiteSpace 6.3.R2, VOSviewer 1.6.19, Scimago Graphica 1.0.39, Microsoft Excel 2021, and R package Bibliometrix running in RStudio, visualizing the results through graphical representations. RESULTS: It was found that the top cited 100 articles came from 51 journals and 31 countries. The journal with both the highest number of published articles and the greatest citation frequency was NEUROIMAGE, while PROTEIN ENGINEERING DESIGN & SELECTION boasted the highest average citation rate. The country with the largest volume of published articles was the United States, followed by China and the United Kingdom. In terms of institutions, the University of North Carolina had produced the most publications. The keywords identified fall into 9 categories. The most frequently occurring keywords are "Alzheimers disease", "mild cognitive impairment", "classification", "MRI", "deep learning", "diagnosis", "dementia", "biomarkers", "brain atrophy", "machine learning", "voxel based morphometry", "prediction", and "patterns". CONCLUSION: AI-based technologies for AD diagnosis and prediction are becoming indispensable clinical tools. Future research should leverage AI to identify novel AD biomarkers, enabling precision diagnosis and treatment. However, our bibliometric analysis has limitations: language and citation biases may skew interpretation of emerging AI-AD trends.}, } @article {pmid40688402, year = {2025}, author = {Espinoza, C and Salinas, M and Morocho, A and Morales, A and Verdezoto, B}, title = {Mortality from Alzheimer's Disease and Other Dementias in Ecuador during the Period 2012-2022.}, journal = {Clinical practice and epidemiology in mental health : CP & EMH}, volume = {21}, number = {}, pages = {e17450179376076}, pmid = {40688402}, issn = {1745-0179}, abstract = {INTRODUCTION: Alzheimer's disease (AD) is a growing concern worldwide in healthcare. In Ecuador, the increasing life expectancy has raised the prevalence of age-related diseases, including dementias. The main objective of this study was to analyze the mortality from AD and other dementias in Ecuador from 2012 to 2022. METHODOLOGY: A retrospective, descriptive time series analysis was conducted on adult subjects with AD and other dementias across various geographic regions of Ecuador during the 2012-2022 period. A sample of 855,122 individuals registered in the databases of the National Institute of Statistics and Censuses (INEC) was analyzed. RESULTS: Out of the total evaluated subjects, 4,836 deaths were due to AD (0.56%) and 1,317 deaths from other types of dementia (0.15%). For AD, the distribution of deaths by sex showed a predominant trend in women (n=3,008) within the group aged 65 years or older (n=4,749). For other dementias, women were also the main group (n=766), along with those aged 65 years and older (n=1,294). The national mortality rate showed an upward trend during this decade, increasing from 2.2 per 100,000 inhabitants in 2012 to 4.86 per 100,000 inhabitants in 2022. DISCUSSION: This study reveals a worrying increase in mortality from Alzheimer's disease (AD) and other dementias in Ecuador between 2012 and 2022, especially among women, adults over 65 years of age, and residents of the Sierra region. Several factors that could negatively influence cognitive function were observed. These findings are consistent with global trends and suggest that biological, environmental, and social variables, such as aging, postmenopausal hormonal changes, chronic exposure to hypoxic altitude conditions, and unequal access to health services, could play a key role in this disease. CONCLUSION: Mortality from Alzheimer's disease and other dementias in Ecuador showed a sustained increase between 2012 and 2022, reflecting a growing burden of these pathologies in the population and the urgent need to strengthen prevention, early diagnosis, and comprehensive treatment strategies. The disproportionate impact on women, adults over 65 years of age, and residents of the Sierra region suggests the involvement of various biological, environmental, and social determinants of health, which requires more rigorous surveillance and a differentiated approach for these particularly vulnerable populations.}, } @article {pmid40687177, year = {2025}, author = {Zhang, Y and Lv, Y and Yang, T and Liu, Q and Guo, Q}, title = {Insulin resistance and Alzheimer's disease: Exploring research hotspots and frontiers from a bibliometric and visual analysis (2005-2024).}, journal = {Journal of Alzheimer's disease reports}, volume = {9}, number = {}, pages = {25424823251361056}, pmid = {40687177}, issn = {2542-4823}, abstract = {BACKGROUND: Alzheimer's disease (AD) and insulin resistance (IR) share intersecting pathological pathways, with IR increasingly implicated in AD pathogenesis. Systematic bibliometric analyses mapping the evolution of this interdisciplinary field remain limited. OBJECTIVE: To quantify global research trends, collaboration networks, knowledge structures, and emerging frontiers in IR-AD research from 2005-2024. METHODS: We analyzed 2676 publications from the Web of Science Core Collection. Using VOSviewer, CiteSpace, and bibliometrix R package, we conducted quantitative analyses and visualized multiple dimensions including annual publications/citations, countries/regions, institutions, journals, authors, references, and keywords. RESULTS: Annual publications grew steadily, peaking at 267 in 2022. The United States dominated productivity (942 papers, 35.2%) and citations (88,170). The University of Kentucky was the top institution (53 papers), while the Journal of Alzheimer's Disease led in output (214 papers) and co-citations (8046). Keyword analysis revealed three clusters: metabolic dysregulation, molecular pathology, and neuroimmune responses. Emerging frontiers highlight neuroimmune mechanisms, with current hotspots focusing on NLRP3 inflammasome activation, gut-brain axis dysregulation, glucose transporter impairment, and therapeutic repurposing of GLP-1 agonists. CONCLUSIONS: These findings underscore IR-AD as a critical intersection of metabolic and neurodegenerative pathways, advocating for targeted therapies addressing neuroinflammation and cerebral metabolism. By delineating global trends, this study provides a roadmap for future research to bridge translational gaps in AD pathogenesis and treatment.}, } @article {pmid40686359, year = {2025}, author = {Ashwin, JV and Shahi, MK and Singh, A and Kumar, ST}, title = {Efficacy and safety of dextromethorphan-bupropion combination (AXS-05) in the treatment of depression: A systematic review and network meta-analysis.}, journal = {Indian journal of pharmacology}, volume = {57}, number = {4}, pages = {262-268}, pmid = {40686359}, issn = {1998-3751}, mesh = {Adult ; Humans ; *Bupropion/adverse effects/therapeutic use/administration & dosage ; *Depressive Disorder, Major/drug therapy ; *Dextromethorphan/adverse effects/therapeutic use/administration & dosage ; Drug Combinations ; Randomized Controlled Trials as Topic ; Treatment Outcome ; }, abstract = {This network meta-analysis evaluated the efficacy and safety of the dextromethorphan-bupropion combination (AXS-05) in treating major depressive disorder (MDD). Data were retrieved from multiple databases, including PubMed, Embase, Scopus, Google Scholar, and ClinicalKey, yielding 60 records. After removing duplicates and excluding irrelevant studies, such as reviews, case reports, posters, and studies focusing on unrelated populations (e.g., Alzheimer's dementia), two randomized controlled trials (RCTs) - Tabuteau et al. (2022) and Iosifescu et al. (2022) - were selected for final analysis. The inclusion criteria focused on RCTs published between 2014 and 2024, involving adult participants (18-65 years) diagnosed with MDD, and reporting on the efficacy and safety of the dextromethorphan-bupropion combination. Studies that did not focus on MDD, were not in English, or lacked control groups were excluded. The findings indicate superior efficacy of the dextromethorphan-bupropion combination, with remission rates of 46.5% and 39.5%, compared to 16.2% for Bupropion alone and 17.3% for placebo. Despite a higher incidence of mild to moderate adverse events (72.9% vs. 64.6% for Bupropion), the combination's safety profile remained comparable, with no significant increase in treatment discontinuation. These results suggest that AXS-05 is a promising treatment for MDD, warranting further investigation in larger, diverse populations to confirm its long-term efficacy and safety.}, } @article {pmid40686118, year = {2025}, author = {Chen, SL and Wang, ZC and Chen, GZ and Zheng, HB and Huang, SE}, title = {[Causal effects of chronic kidney disease on Alzheimer's disease and its prevention based on "kidney-brain interaction" theory].}, journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica}, volume = {50}, number = {12}, pages = {3431-3440}, doi = {10.19540/j.cnki.cjcmm.20250306.501}, pmid = {40686118}, issn = {1001-5302}, mesh = {Humans ; *Alzheimer Disease/prevention & control/etiology/genetics ; *Renal Insufficiency, Chronic/complications/genetics ; *Kidney/physiopathology/metabolism ; *Brain/metabolism/physiopathology ; Genome-Wide Association Study ; Medicine, Chinese Traditional ; Mendelian Randomization Analysis ; }, abstract = {Based on the traditional Chinese medicine(TCM) theory of "kidney-brain interaction", a two-sample Mendelian randomization(MR) analysis was conducted to investigate the causal effects of chronic kidney disease(CKD) on Alzheimer's disease(AD) and analyze the potential mechanisms of kidney-tonifying and essence-replenishing TCM to improve AD. From the perspective that CKD is closely related to the core pathogenesis of AD, namely "kidney deficiency, essence loss, and marrow reduction", genome-wide association study(GWAS) data was used, with the inverse variance weighting(IVW) method as the main approach to reveal the causal association between CKD and AD. Sensitivity analysis was conducted to evaluate the robustness of the results. To further investigate the causal effects of CKD on AD, two different AD datasets were used as outcomes, and the urinary albumin-to-creatinine ratio(UACR) data was used as the exposure for a supplementary analysis. On this basis, the modern scientific mechanism of the kidney-tonifying and essence-replenishing method for improving AD was further explored. The IVW analysis show that CKD(ieu-b-2: OR=1.084, 95%CI[1.011, 1.163], P=0.024; ieu-b-5067: OR=1.001, 95%CI[1.000, 1.001], P=0.002) and UACR(ieu-b-2: OR=1.247, 95%CI[1.021, 1.522], P=0.031; ieu-b-5067: OR=1.001, 95%CI[1.000, 1.003], P=0.015) both have significant causal effects on AD in different datasets, with CKD increasing the risk of AD. The sensitivity analysis further confirmed the reliability of the results. Genetic studies have shown that CKD has a significant causal effect on AD, suggesting that controlling CKD is an important intervention measure for preventing and treating AD. Therefore, further research on CKD's role in AD is crucial in clinical practice. The research enriches the theoretical implication of "kidney-brain interaction", deepens the understanding of AD' etiology, and provides further insights and directions for the prevention and treatment of AD with TCM, specifically from a kidney-based perspective.}, } @article {pmid40685770, year = {2025}, author = {Farooq, U and Islam, M and Batool, Z and Mali, SN and Jawarkar, RD and Gurav, SS and Alharthy, RD and Şenol, H and Sadeghian, N and Taslimi, P and Shafiq, Z and Schenone, S}, title = {Design, Synthesis, In Vitro, and In Silico Studies of 5-(Diethylamino)-2-Formylphenyl Naphthalene-2-Sulfonate Based Thiosemicarbazones as Potent Anti-Alzheimer Agents.}, journal = {Archiv der Pharmazie}, volume = {358}, number = {7}, pages = {e70050}, pmid = {40685770}, issn = {1521-4184}, support = {//This Project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under grant no. GPIP: 46-665-2024./ ; }, mesh = {*Alzheimer Disease/drug therapy/enzymology ; *Cholinesterase Inhibitors/chemical synthesis/pharmacokinetics ; Monoamine Oxidase Inhibitors/chemical synthesis/pharmacokinetics ; *Thiosemicarbazones/chemical synthesis/pharmacokinetics ; Molecular Docking Simulation ; *Nootropic Agents/chemical synthesis/pharmacokinetics ; Humans ; *Drug Design ; }, abstract = {Alzheimer's disease (AD) is known as one of the more devastating neurodegenerative diseases diagnosed in older people. Cholinesterase inhibitors (ChEI) can be used as an effective palliative treatment for AD. An extensive range of new biologically active 4-(diethylamino) salicylaldehyde-based thiosemicarbazone derivatives 5(a-u) was synthesized and evaluated as inhibitors of cholinesterase (ChE) and monoamine oxidase (MAO) enzymes. 2,3-Dichloro-substituted compound 5u was the most potent inhibitor of AChE and MAO-A with IC50 values of 12.89 and 96.25 nM, respectively. In contrast, the 2,3-dichlorophenyl-substituted compound 5a was the most powerful inhibitor of BChE, with an IC50 value of 124.72 nM. Structure-activity analysis revealed that the electron-withdrawing substituents on the phenyl ring play a crucial role in the inhibition potential of synthesized compounds. Compound 5a showed the strongest binding with 4BDS (-11.3 kcal/mol) via hydrogen bonds and π-interactions. Compound 5u exhibited high affinity with 1B41 (-8.2 kcal/mol), 2Z5X (-8.6 kcal/mol), and 2V5Z (-7.8 kcal/mol), forming key hydrogen bonds, salt bridges, and π-interactions, highlighting its multi-target potential. In silico ADME, pharmacokinetics, and drug-likeness studies were conducted and compared with the standard drugs galantamine and clorgyline.}, } @article {pmid40685632, year = {2025}, author = {Huang, Y and Xu, T and Wang, L and Xiang, R and Zhou, M and Yu, H and Liu, D and Chen, Z}, title = {Application of machine learning reveals diagnostic biomarkers related to pyroptosis in Alzheimer's disease and analysis of immune infiltration.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {1}, pages = {361-373}, doi = {10.1177/13872877251360033}, pmid = {40685632}, issn = {1875-8908}, mesh = {*Alzheimer Disease/genetics/diagnosis/immunology/metabolism ; Humans ; *Pyroptosis/genetics ; *Machine Learning ; Biomarkers/metabolism ; Molecular Docking Simulation ; Brain/metabolism/pathology ; Gene Expression Profiling ; }, abstract = {BackgroundAlzheimer's disease (AD) is characterized by complex pathological mechanisms, with pyroptosis potentially contributing to neuroinflammation.ObjectiveTo identify pyroptosis-related genes (PRGs) in AD and explore their role in neuroinflammation, aiming to provide potential biomarkers and therapeutic targets for precision medicine in AD treatment.MethodsTranscriptomic data from AD brain tissues (GEO database) were analyzed using multi-omics integration and machine learning. Key PRGs were screened via weighted gene co-expression network analysis (WGCNA), LASSO regression, random forest, and SVM-RFE algorithms. Molecular subtypes and therapeutic potential were assessed through unsupervised clustering and molecular docking.ResultsAnalysis identified 609 differentially expressed genes (DEGs), with upregulated genes enriched in DNA transcription and mitosis-related pathways. Six core PRGs (MIB1, TUG1, GATA1, CA1, CFH, IL17A) demonstrated strong diagnostic accuracy (AUC > 0.85). Unsupervised clustering revealed two AD subtypes: a high-risk subtype with activated pyroptosis-inflammatory pathways and distinct immune microenvironment features (p < 0.05). Molecular docking confirmed stable binding between CFH and the anti-AD drug candidate fludrocortisone (binding energy < -7 kcal/mol).ConclusionsPyroptosis modulates neuroinflammation to drive AD progression. CFH and other PRGs serve as promising biomarkers and therapeutic targets, advancing precision strategies for AD subtyping and intervention.}, } @article {pmid40685475, year = {2025}, author = {Shin, S and Kim, M and Hong, SH}, title = {Economic Evaluation of Lecanemab for Early Symptomatic Alzheimer's Disease in South Korea.}, journal = {PharmacoEconomics - open}, volume = {9}, number = {5}, pages = {793-804}, pmid = {40685475}, issn = {2509-4254}, support = {2023//Health Fellowship Foundation/ ; }, abstract = {BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) exerts a considerable economic burden on South Korea's aging population. Lecanemab, an amyloid-targeting therapy, has demonstrated efficacy in mitigating cognitive decline in early-stage AD but remains non-reimbursed in South Korea due to concerns over its economic feasibility. This study aimed to examine the cost-effectiveness of lecanemab using nationwide claims data for cost estimation within the South Korean healthcare system. Considering the substantial societal burden of AD, we also evaluated the cost-effectiveness of lecanemab from a limited societal perspective. METHODS: A Markov state transition cohort model was developed to compare costs and outcomes of lecanemab combined with standard of care (SoC) versus SoC alone. The model simulated five stages of AD progression: mild cognitive impairment, mild AD, moderate AD, severe AD, and death. Transition probabilities between health states were derived from data provided by the National Alzheimer's Coordinating Center. Formal medical costs and long-term care costs were obtained from the national claims database, while drug cost and other medical expenses were derived from previous studies. Additional cost components such as opportunity cost of caregiver time, out-of-pocket expenses, and time and travel costs for hospital visits were included in the limited societal perspective. Korean-specific utilities for patients and caregivers differentiated by states of AD progression and care settings were obtained from the published literature. Effectiveness was measured in quality-adjusted life years (QALYs) over a lifetime horizon. Scenario analyses were conducted by varying compositions of the cohort, age of onset, and drug pricing. RESULTS: The incremental cost-effectiveness ratio (ICER) of lecanemab combined with SoC was 198,171,820 Korean Won (KRW)/QALY from the healthcare payer perspective and 181,185,820 KRW/QALY from the limited societal perspective, which significantly exceeded South Korea's willingness-to-pay (WTP) threshold of 30 million KRW/QALY. Sensitivity analyses revealed that the ICER was highly influenced by variations in treatment effect and discount rates. The result of scenario analyses suggested that targeting lecanemab to patients with mild AD or implementing price reductions could substantially improve its cost-effectiveness. CONCLUSIONS: Lecanemab's high cost poses a challenge to its inclusion in the National Health Insurance formulary under South Korea's current WTP thresholds. Strategic price adjustments and patient targeting are essential to enhance its economic viability. These findings provide valuable insights for policymakers and stakeholders in balancing treatment outcomes and resource allocation for AD management.}, } @article {pmid40685330, year = {2025}, author = {Far, BF and Akbari, M and Habibi, MA and Katavand, M and Nasseri, S}, title = {CRISPR Technology in Disease Management: An Updated Review of Clinical Translation and Therapeutic Potential.}, journal = {Cell proliferation}, volume = {58}, number = {11}, pages = {e70099}, pmid = {40685330}, issn = {1365-2184}, mesh = {Humans ; *CRISPR-Cas Systems/genetics ; *Gene Editing/methods ; *Genetic Therapy/methods ; Neoplasms/therapy/genetics ; Disease Management ; COVID-19/therapy ; SARS-CoV-2 ; *Translational Research, Biomedical ; Nervous System Diseases/therapy/genetics ; Animals ; Immunotherapy/methods ; }, abstract = {CRISPR-Cas9 technology has rapidly advanced as a transformative genome-editing platform, facilitating precise genetic modifications and expanding therapeutic opportunities across various diseases. This review explores recent developments and clinical translations of CRISPR applications in oncology, genetic and neurological disorders, infectious diseases, immunotherapy, diagnostics, and epigenome editing. CRISPR has notably progressed in oncology, where it enables the identification of novel cancer drivers, elucidation of resistance mechanisms, and improvement of immunotherapies through engineered T cells, including PD-1 knockout CAR-T cells. Clinical trials employing CRISPR-edited cells are demonstrating promising results in hematologic malignancies and solid tumours. In genetic disorders, such as hemoglobinopathies and muscular dystrophies, CRISPR-Cas9 alongside advanced editors like base and prime editors show significant potential for correcting pathogenic mutations. This potential was affirmed with the FDA's first approval of a CRISPR-based therapy, Casgevy, for sickle cell disease in 2023. Neurological disorders, including Alzheimer's, ALS, and Huntington's disease, are increasingly targeted by CRISPR approaches for disease modelling and potential therapeutic intervention. In infectious diseases, CRISPR-based diagnostics such as SHERLOCK and DETECTR provide rapid, sensitive nucleic acid detection, particularly valuable in pathogen outbreaks like SARS-CoV-2. Therapeutically, CRISPR systems target viral and bacterial genomes, offering novel treatment modalities. Additionally, CRISPR-mediated epigenome editing enables precise regulation of gene expression, expanding therapeutic possibilities. Despite these advances, significant challenges remain, including off-target effects, delivery methodologies, immune responses, and long-term genomic safety concerns. Future improvements in editor precision, innovative delivery platforms, and enhanced safety assessments will be essential to fully integrate CRISPR-based interventions into standard clinical practice, significantly advancing personalised medicine.}, } @article {pmid40685037, year = {2025}, author = {Wang, T and Gao, C and Dong, X and Li, L}, title = {Therapeutic potential of traditional chinese medicine polysaccharides in alzheimer's disease via modulation of gut microbiota: A review.}, journal = {International journal of biological macromolecules}, volume = {321}, number = {Pt 2}, pages = {146160}, doi = {10.1016/j.ijbiomac.2025.146160}, pmid = {40685037}, issn = {1879-0003}, mesh = {Animals ; Humans ; *Alzheimer Disease/drug therapy/microbiology ; *Drugs, Chinese Herbal/therapeutic use/pharmacology/chemistry ; *Gastrointestinal Microbiome/drug effects ; *Medicine, Chinese Traditional ; *Polysaccharides/therapeutic use/pharmacology/chemistry ; }, abstract = {Alzheimer's disease (AD) is a chronic and progressively deteriorating neurodegenerative condition characterized by a strong association with gut microbiome imbalances. It is estimated that by 2025, there will be 35 million patients worldwide, imposing a substantial burden on society. Currently, AD treatments predominantly rely on single-target approaches aimed at alleviating symptoms, which exhibit limited efficacy and fail to influence disease progression. Consequently, there is an urgent need to investigate novel therapeutic strategies to enhance treatment outcomes. Polysaccharides derived from traditional Chinese medicine (TCMPs) are renowned for their capacity to target multiple pathways and function as potent natural immune regulators, delivering comprehensive treatment effects. TCMPs possess prebiotic properties and can be fermented by the intestinal flora, promoting the proliferation of beneficial bacteria, inhibiting pathogens, and exerting anti-inflammatory, antioxidant, and Aβ-deposition inhibitory effects within the intestine. This article provides a systematic review of the interplay between gut microbiota, AD, and TCMPs, showcasing specific TCMP examples that demonstrate significant anti-AD effects mediated through gut flora modulation. The aim is to deepen understanding of TCMPs' role in AD therapy involving gut microbiota and to propose innovative strategies for optimizing AD treatment.}, } @article {pmid40684900, year = {2026}, author = {Liu, Q and Siadat, SD}, title = {MicroRNA-155 in neurodegeneration.}, journal = {Clinica chimica acta; international journal of clinical chemistry}, volume = {578}, number = {}, pages = {120506}, doi = {10.1016/j.cca.2025.120506}, pmid = {40684900}, issn = {1873-3492}, mesh = {Humans ; *MicroRNAs/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/diagnosis ; Exosomes/metabolism ; Animals ; Biomarkers/metabolism ; }, abstract = {MicroRNA-155 (miR-155) is recognized for its multifaceted roles in neuroinflammation and neurodegeneration. This abstract explores the emerging significance of miR-155, both as an intracellular regulator and encapsulated within exosomes, as a biomarker and therapeutic target in neurodegenerative disorders. Dysregulation of miR-155 is implicated in various conditions, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis, where it modulates key pathways involved in neuronal survival, synaptic plasticity, and immune cell activation. Specifically, miR-155 has been shown to influence microglial activation, cytokine production, and the clearance of protein aggregates, all critical processes in neurodegenerative pathogenesis. Exosomal miR-155, released by various cell types including immune cells and neurons, offers a particularly exciting avenue. These nanovesicles facilitate intercellular communication, delivering their cargo, including miR-155, to recipient cells and influencing their function. As such, exosomal miR-155 levels in biofluids like cerebrospinal fluid and blood are being investigated as potential non-invasive diagnostic and prognostic biomarkers for neurodegenerative diseases. Furthermore, the ability of exosomes to cross the blood-brain barrier makes them attractive vehicles for targeted delivery of therapeutic agents. This review highlights the dual promise of miR-155 and exosomal miR-155: first, as readily measurable indicators of disease progression and response to treatment, and second, as actionable targets for novel therapeutic strategies aimed at modulating neuroinflammation and protecting neuronal integrity.}, } @article {pmid40684705, year = {2025}, author = {Yu, J and Ma, D and Li, S and Yang, S and Li, T and Kong, L and Liu, Y and Zang, J and Yu, Y and Li, X}, title = {Construction of ROS-responsive cascade-targeted liposomes and investigation of their anti-AD effects.}, journal = {International immunopharmacology}, volume = {163}, number = {}, pages = {115234}, doi = {10.1016/j.intimp.2025.115234}, pmid = {40684705}, issn = {1878-1705}, mesh = {*Reactive Oxygen Species/metabolism ; Liposomes ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Microglia/drug effects/metabolism ; *Resveratrol/pharmacology/administration & dosage/therapeutic use/pharmacokinetics ; Blood-Brain Barrier/metabolism/drug effects ; Mice ; Polyethylene Glycols/chemistry ; *Antioxidants/pharmacology/administration & dosage ; *Anti-Inflammatory Agents/pharmacology ; Humans ; *Neuroprotective Agents/pharmacology/administration & dosage ; Male ; Oxidative Stress/drug effects ; Brain/metabolism/drug effects ; }, abstract = {Oxidative stress is considered a critical factor in the pathogenesis of Alzheimer's disease (AD). The interaction between oxidative stress and neuroinflammation is closely associated with the production of beta-amyloid (Aβ). Although many drugs exhibit potent anti-inflammatory and antioxidant properties, their poor water solubility and limited ability to penetrate the blood-brain barrier (BBB) often result in reduced efficacy, making accurate AD treatment challenging. Previous studies have shown that borneol (Bor) can enhance BBB permeability, while the MG1 peptide can specifically target M1-type microglial cells. In this study, we constructed reactive oxygen species (ROS)-responsive cascade-targeting liposomes (ROS@Res-Lip) using DSPE-PEG2000-MG1 and DSPE-TK-PEG2000-Bor co-modification. This design aimed to reduce ROS accumulation and enhance BBB penetration by incorporating ROS-responsive thioketal (TK) bonds and Bor, while leveraging the MG1 peptide to improve the targeting of resveratrol (Res) to M1-type microglia. As a result, the drug concentration in the brain was significantly increased, thereby improving therapeutic efficacy. Our findings demonstrate that ROS@Res-Lip can achieve anti-inflammatory, antioxidant, and neuroprotective effects by targeting M1-type microglia and promoting the conversion of M1-type microglia to M2-type microglia.}, } @article {pmid40684632, year = {2025}, author = {Li, M and Li, C and He, M and Chen, L and Wang, Q}, title = {Neurotoxic effects of Cis-bifenthrin on microbe-gut-brain axis: Disruption of neurolipid balance in Xenopus laevis.}, journal = {Ecotoxicology and environmental safety}, volume = {302}, number = {}, pages = {118675}, doi = {10.1016/j.ecoenv.2025.118675}, pmid = {40684632}, issn = {1090-2414}, mesh = {Animals ; *Xenopus laevis ; *Gastrointestinal Microbiome/drug effects ; *Brain/drug effects/metabolism ; *Pyrethrins/toxicity ; Female ; *Water Pollutants, Chemical/toxicity ; Bile Acids and Salts/metabolism ; Lipopolysaccharides/metabolism ; }, abstract = {The neurotoxic effects of cis-bifenthrin (cis-BF) on amphibians and its molecular mechanisms are unclear despite its common presence in aquatic environments. In present study, female Xenopus laevis were subjected to a three-month treatment with environmentally relevant concentrations of 60 and 300 ng/L cis-BF. Metabolomic analysis of brain tissue revealed differential metabolites enriching bile acid (BA) synthesis, impacting β-amyloid protein deposition. Reduced polyunsaturated fatty acids (PUFAs), essential for membrane integrity, were observed. Elevated amyloid β-protein and lipopolysaccharide (LPS) levels suggested potential Alzheimer's-like symptoms induced by cis-BF. Given PUFAs and BAs are processed via enterohepatic circulation, a notable decrease in the abundance of genera linked to PUFAs and BAs metabolism was observed. Gut metabolomics revealed decreased concentrations of PUFAs and secondary BAs across cis-BF treatment groups, attributed to changes in associated microbial communities. Cis-BF exposure raised intestinal LPS levels and plasma proinflammatory cytokines, resulting in intestinal damage. This facilitated the entry of LPS into the bloodstream and brain tissue, indicating a cytokine-LPS interaction that promotes LPS transit to the brain through the bloodstream. Our study suggests that cis-BF-induced alterations in gut microbiota and metabolism may trigger Alzheimer's-related neurological disorders in Xenopus laevis via the gut-brain axis by inducing neurolipid disorder and inflammation.}, } @article {pmid40684252, year = {2025}, author = {Idris, M and Saini, F and Ivain, P and Baksh, RA and Bianchi, LA and Pape, SE and Zetterberg, H and Wijeratne, PA and Strydom, A}, title = {Staging of Alzheimer's disease progression in Down syndrome using mixed clinical and plasma biomarker measures with machine learning.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70446}, pmid = {40684252}, issn = {1552-5279}, support = {MR/S011277/1/MRC_/Medical Research Council/United Kingdom ; MR/S005145/1/MRC_/Medical Research Council/United Kingdom ; MR/R024901/1/MRC_/Medical Research Council/United Kingdom ; 098330/Z/12/Z//Wellcome Trust Strategic Award/ ; //Baily Thomas Charitable Fund/ ; //Fondation Jérôme Lejeune/ ; AS-CP-18-0020//Alzheimer's Society/ ; 2023-00356//Swedish Research Council/ ; 101053962//Swedish Research Council/ ; 2022-01018//Swedish Research Council/ ; 2019-02397//Swedish Research Council/ ; ALFGBG-71320//Swedish State Support for Clinical Research/ ; 201809-2016862//Alzheimer's Drug Discovery Foundation/ ; //AD Strategic Fund/ ; ADSF-21-831376-C/ALZ/Alzheimer's Association/United States ; ADSF-21-831381-C/ALZ/Alzheimer's Association/United States ; ADSF-21-831377-C/ALZ/Alzheimer's Association/United States ; ADSF-24-1284328-C/ALZ/Alzheimer's Association/United States ; //European Partnership on Metrology/ ; 22HLT07//European Union's Horizon Europe Research and Innovation Programme/ ; //The Bluefield Project/ ; //Cure Alzheimer's Fund/ ; //Erling-Persson Family Foundation, Familjen Rönströms Stiftelse/ ; //Stiftelsen för Gamla Tjänarinnor/ ; FO2022-0270//Hjärnfonden/ ; 860197//Marie Skłodowska-Curie/ ; UKDRI-1003//UK Dementia Research Institute/ ; //Olav Thon Stiftelsen/ ; //UCLH Biomedical Research Centre/ ; JPND2021-00694//EU Joint Programme - Neurodegenerative Disease Research/ ; //H2020 Marie Skłodowska-Curie/ ; 101053962//HORIZON EUROPE European Research Council/ ; 2023-00356//Vetenskapsrådet/ ; 101053962//Vetenskapsrådet/ ; 2023-00356//Vetenskapsrådet/ ; 2022-01018//Vetenskapsrådet/ ; 2019-02397//Vetenskapsrådet/ ; //The Alzheimer's Society/ ; //National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre/ ; UKDRI-1003//UK Dementia Research Institute at UCL/ ; }, mesh = {Humans ; *Down Syndrome/blood/complications ; *Biomarkers/blood ; *Alzheimer Disease/blood/diagnosis ; Female ; *Disease Progression ; Male ; Middle Aged ; *Machine Learning ; Amyloid beta-Peptides/blood ; Adult ; tau Proteins/blood ; Neurofilament Proteins/blood ; Peptide Fragments/blood ; Neuropsychological Tests ; Aged ; Cross-Sectional Studies ; }, abstract = {INTRODUCTION: Adults with Down syndrome (DS) have a high risk for Alzheimer's disease (AD). Although the sequence of plasma biomarker and cognitive changes in AD in DS is well studied, their related trajectories are not fully characterized. Data-driven methods can estimate disease progression from cross-sectional data. METHODS: In 57 adults with DS and no AD, we used the event-based model to sequence plasma biomarker and cognitive changes in preclinical AD. Generalized additive models assessed the relationship between age and plasma biomarkers. RESULTS: The earliest changes occurred in the amyloid beta 42/40 ratio, followed by memory changes. Later alterations in neurofilament light and tau concentrations preceded executive and visuomotor function changes, with glial fibrillary acidic protein levels changing last. The highest rate of plasma biomarker changes occurred between ages 39 and 52. CONCLUSION: Changes in DS follow a pattern similar to that of sporadic and familial AD. Event-based modeling offers individual-level staging, potentially optimizing diagnosis and clinical trial patient selection. HIGHLIGHTS: The pre-clinical stages of Alzheimer's disease (AD) development in Down syndrome (DS) are not well defined, despite the extremely high prevalence of AD. Better understanding of early AD progression would aid in diagnostics and treatment. Data-driven methods, such as the event-based model, can aid in clarifying the sequence of cognitive and plasma biomarker changes in the early stages of AD while accounting for baseline variability. We find that plasma amyloid beta 42/40 ratio and memory changes precede changes in plasma biomarker levels of neurodegeneration, with changes in executive and visuomotor functions occurring later, before neuroinflammatory marker changes. Combining plasma biomarkers could be a useful measure of preclinical AD for trials, particularly in individuals between 39 and52 years of age.}, } @article {pmid40684196, year = {2025}, author = {Choi, Y and Kim, PW and Jung, IC and Kim, AR and Park, HJ and Kwon, O and Lee, JH and Kim, JH}, title = {Acupuncture for patients with mild cognitive impairment: a randomized, patient-assessor-blinded, sham-controlled pilot study.}, journal = {BMC complementary medicine and therapies}, volume = {25}, number = {1}, pages = {277}, pmid = {40684196}, issn = {2662-7671}, support = {K16122 and KSN2122211//Korea Institute of Oriental Medicine/ ; K16122 and KSN2122211//Korea Institute of Oriental Medicine/ ; }, mesh = {Humans ; *Cognitive Dysfunction/therapy ; *Acupuncture Therapy/methods ; Pilot Projects ; Male ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; Neuropsychological Tests ; Treatment Outcome ; }, abstract = {BACKGROUND: Mild cognitive impairment (MCI) is the transitional stage between normal aging and early dementia. Although acupuncture is a promising non-pharmacological treatment, higher-quality evidence is needed to confirm its effectiveness. METHODS: A randomized, patient- and assessor-blinded, sham-controlled, pilot clinical trial was conducted to evaluate the feasibility of acupuncture for treating MCI. In total, 30 participants were randomized into acupuncture and sham acupuncture groups. The participants underwent 24 treatment sessions over 12 weeks. The primary outcome was a change in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) score over 12 weeks, whereas the secondary outcomes included the Seoul Neuropsychological Screening Battery (SNSB-II) score. Adverse events and the success of blinding were also assessed. RESULTS: Of the 30 participants, 28 completed the study. Participants in the acupuncture and sham acupuncture groups exhibited a decrease in ADAS-cog scores from 10.27 ± 4.03 and 11.47 ± 3.85 at baseline to 5.78 ± 3.04 and 6.27 ± 2.83 at week 12, respectively. Both groups exhibited clinically meaningful improvements, with no significant difference between groups (P = 0.6590). The SNSB-II memory domain exhibited a moderate effect size favoring acupuncture (Cohen's d = 0.57, P = 0.1317). No intervention-related adverse events were reported, and participant blinding was adequate throughout the trial. CONCLUSIONS: The 12-week acupuncture treatment is feasible for patients with MCI and may improve memory. Although the primary outcomes did not reach statistical significance, the secondary outcomes suggested potential benefits. Larger confirmatory trials are warranted to investigate the effectiveness of acupuncture in patients with MCI. TRIAL REGISTRATION: Clinical Research Information Service (cris.nih.go.kr) KCT0001938 (Registered on June 3, 2016).}, } @article {pmid40682852, year = {2025}, author = {Guan, X and Zha, L and Zhu, X and Rao, X and Huang, X and Xiong, Y and Guo, Y and Zhang, M and Zhou, D and Tu, Q and Wu, J and Wang, X and Hua, F and Xu, J}, title = {Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review).}, journal = {International journal of molecular medicine}, volume = {56}, number = {4}, pages = {}, pmid = {40682852}, issn = {1791-244X}, mesh = {Humans ; *Calgranulin B/metabolism ; *Calgranulin A/metabolism ; *Cognitive Dysfunction/metabolism/drug therapy ; *Neuroinflammatory Diseases/metabolism/drug therapy ; Animals ; Biomarkers/metabolism ; Molecular Targeted Therapy ; }, abstract = {The complex of proteins S100A8/A9 has been recognized as a major initiator of cognitive disorder onset, including, but not restricted to, neuroinflammation. Cognitive impairment or decline in memory, attention and executive function has been on the rise and is a major public health priority. Several neurological conditions that affect the brain and cognitive processes, including central nervous system diseases such as Alzheimer's disease and stroke, and systemic diseases, such as sepsis and systemic lupus erythematosus, are associated with S100A8/A9. Experiments have progressively demonstrated that S100A8/A9 plays a role in cognitive decline, as it regulates cognitive domains, including sleep, learning, memory, and emotion control, via several mechanisms. In this review, a critical overview of the role of S100A8/A9 in the treatment of neurocognitive diseases is provided, including the regulation of brain function and the pathogenesis of diseases, and potential novel therapies are suggested. It is necessary to study S100A8/A9 alone as an alternative marker for the diagnosis and treatment of neurocognitive diseases, and in line with the requirements of therapy for cognitive impairment. As S100A8/A9 research continues, the understanding and treatment of neurocognitive diseases may improve.}, } @article {pmid40682719, year = {2025}, author = {Ryu, HS and Sanjay, and Choi, SK and Lee, KH and Jang, SS and Yang, SY and Kwon, YS and Ku, SK and Lee, HJ}, title = {Golden Oyster Mushroom Extract Ameliorates Oxidative Stress-Induced Cell Death in Neurons and Scopolamine-Induced Cholinergic System Impairment in Mice.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {15494-15508}, pmid = {40682719}, issn = {1559-1182}, support = {(RS-2023-00236592)//This research was supported by Korea Institute of Marine Science & Technology Promotion (KIMST) funded by the Ministry of Oceans and Fisheries/ ; }, mesh = {Animals ; *Oxidative Stress/drug effects ; *Scopolamine/toxicity ; Cell Death/drug effects ; *Neurons/drug effects/pathology/metabolism ; Mice ; Neuroprotective Agents/pharmacology ; Male ; Hydrogen Peroxide/toxicity ; Acetylcholine/metabolism ; Cell Line ; Cholinergic Neurons/drug effects/pathology ; Acetylcholinesterase/metabolism ; }, abstract = {Impaired cholinergic system is an important therapeutic target to develop drugs against Alzheimer's disease (AD), as cholinergic signal transduction is associated with the memory, learning, and behavior of an individual. Acetylcholine (ACh) is an important neurotransmitter and is degraded by an enzyme, acetylcholinesterase (AChE), blocking neuronal signal transmission, which leads to amnesia or memory loss. Oxidative stress (OS) also worsens AD pathology by damaging lipids, proteins and DNA of the neuronal cells, leading to neuronal cell death. Golden oyster mushroom (GOM), an edible mushroom native to the regions of Japan, Korea, Russia, and China, has been reported to possess several bioactivities. However, there is no study reported till date, studying the anti-amnesic properties of GOM. The objectives of this study were to assimilate the in vitro neuroprotective and in vivo anti-amnesic properties of GOM. The GOM at 0.1, 0.5, 1, 5, and 10 mg/ml was nontoxic and was able to prevent H2O2 (500 µM) and glutamate (5 mM)-induced OS-mediated cell death in HT-22 cells. In addition, all the selected concentrations of GOM extract (50, 100, and 200 mg/kg, 28 days) were able to prevent scopolamine (ACh receptor antagonist, 1 mg/kg, 1 h post-treatment after the 7[th], 14[th], and 28[th] administrations)-induced cholinergic system impairment, memory loss, histopathological alteration, antioxidant defense system disruption, and reduced memory susceptibility markers in C57BL mice compared to the positive control tacrine (10 mg/kg, 28 days). In conclusion, GOM extract emerged as a natural AChE inhibitor and could be seen as a potential therapeutic AD agent.}, } @article {pmid40682580, year = {2025}, author = {Degan, S and Feng, Y and Colton, C and Schmidt, S and Peterchev, AV and Turner, DA}, title = {Cerebral Blood Flow Responses to Extracranial Alternating Current Brain Stimulation in CVN Mouse Model of Alzheimer's Disease: A Pilot Study Determining Optimal Dose.}, journal = {Neuromodulation : journal of the International Neuromodulation Society}, volume = {}, number = {}, pages = {}, pmid = {40682580}, issn = {1525-1403}, support = {R01 AG074999/AG/NIA NIH HHS/United States ; R01 AG081774/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: Insufficient metabolic supply in response to neural demand is a key mechanism of degeneration in Alzheimer's disease [AD]. However, extracranial alternating current [AC] stimulation can increase cerebral blood flow [CBF] and metabolic substrate supply to the brain. In this work, we investigate in an initial, pilot study the optimal dosage of extracranial AC brain stimulation appropriate for long-term treatment to retard degeneration in a mouse AD model [CVN]. MATERIALS AND METHODS: We applied extracranial AC (0.5-2.0 mA; 10 Hz; 20-second bursts) to CVN and control C57Bl/6 mice while measuring CBF and intracerebral electric field in vivo in anesthetized animals, and behavioral responses in awake animals. RESULTS: We found a significant, diffuse increase in cortical CBF (2.6% increase at 0.75 mA) and intracerebral electric field (6.36mV/mm gradient at 0.75 mA) in response to extracranial AC brain stimulation in both CVN and control mice. In awake, behaving mice, the optimal dose of stimulation was 0.75 mA (in 30-second bursts), causing no adverse behavioral effects. CONCLUSION: Scheduled (at fixed times) or demand-triggered (during dynamic metabolic need) bursts of extracranial brain stimulation could enhance CBF to improve brain metabolic supply. The goal of this potential AD treatment is to alleviate mismatches between neural metabolic demand and brain substrate supply, to prevent AD phenotypic disease progression. Based on these pilot data, 0.75 mA is an optimal stimulation treatment dose leading to an appreciable net change in CBF, at a moderate intracranial electrical field, while also indicating behavioral tolerability, now being implemented in a long-term treatment trial.}, } @article {pmid40681915, year = {2025}, author = {Shah, A and Estilo, A and Sheridan, PL and Kalu, U and Chen, D and Chang, D and Slomkowski, M and Lee, D and Hefting, N and Hobart, M and Behl, S and Such, P and Brubaker, M and Grossberg, GT}, title = {Safety and Tolerability of Brexpiprazole in Participants with Agitation Associated with Dementia due to Alzheimer's Disease: Pooled Analysis of Three Randomized Trials and an Extension Trial.}, journal = {CNS drugs}, volume = {39}, number = {10}, pages = {1011-1023}, pmid = {40681915}, issn = {1179-1934}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/complications/drug therapy ; *Antipsychotic Agents/adverse effects/therapeutic use/administration & dosage ; Clinical Trials, Phase III as Topic ; *Dementia/drug therapy/etiology ; Double-Blind Method ; *Psychomotor Agitation/drug therapy/etiology ; *Quinolones/adverse effects/therapeutic use/administration & dosage ; Randomized Controlled Trials as Topic ; *Thiophenes/adverse effects/therapeutic use/administration & dosage ; }, abstract = {BACKGROUND AND OBJECTIVE: Older adults with dementia are particularly vulnerable to antipsychotic side effects. Brexpiprazole, an atypical antipsychotic, is approved in a number of countries for the treatment of agitation associated with dementia due to Alzheimer's disease. This pooled analysis aimed to evaluate the safety and tolerability of brexpiprazole in this patient population. METHODS: Data were included from three Phase 3, 12-week, randomized, double-blind, placebo-controlled trials and a Phase 3, 12-week, active-treatment extension trial in participants with agitation associated with dementia due to Alzheimer's disease. Safety outcomes included treatment-emergent adverse events (TEAEs), weight change, suicidality, extrapyramidal symptoms, and cognitive dysfunction. Two datasets were considered: a 12-week dataset that pooled data from the three randomized trials for brexpiprazole 0.5-3 mg/day and placebo, and a 24-week dataset that combined data from the parent randomized trial and the extension trial for brexpiprazole 2-3 mg/day. RESULTS: Over 12 weeks, 335/655 (51.1%) participants on brexpiprazole and 178/388 (45.9%) participants on placebo reported ≥ 1 TEAE, which led to discontinuation in 41 (6.3%) and 13 (3.4%) participants, respectively. Headache was the only TEAE with incidence ≥ 5% (brexpiprazole, 50 [7.6%] participants; placebo, 36 [9.3%] participants). The incidences of cerebrovascular TEAEs (brexpiprazole, 0.5%; placebo, 0.3%), cardiovascular TEAEs (3.7%; 2.3%), extrapyramidal symptom-related TEAEs (5.3%; 3.1%), and somnolence/sedation TEAEs (3.7%; 1.8%) were generally similar between treatment groups. Six (0.9%) participants on brexpiprazole and 1 (0.3%) participant on placebo died; causes of death were not considered related to brexpiprazole and were generally in line with those expected in Alzheimer's disease. Over 24 weeks, 110/226 (48.7%) participants on brexpiprazole reported ≥ 1 TEAE, which led to discontinuation in 19 (8.4%) participants. Headache was the only TEAE with incidence ≥ 5% (18 [8.0%] participants). No participants died during the extension trial. Over 12 and 24 weeks, mean changes in weight, suicidality, and extrapyramidal symptoms were minimal, with no worsening of cognition. CONCLUSIONS: Considering pooled data from > 1000 participants on brexpiprazole or placebo, brexpiprazole appears to be generally well tolerated for up to 24 weeks in participants with agitation associated with dementia due to Alzheimer's disease. STUDY REGISTRATION: ClinicalTrials.gov identifiers: NCT01862640, NCT01922258, NCT03548584, NCT03594123.}, } @article {pmid40680978, year = {2025}, author = {Zhang, Y and Liu, M and Wang, Y and Hu, D and Wu, S and Zhao, B and Zhou, B and Yang, L}, title = {Nasal nanotherapeutics for central nervous system disorders: Bridging the translational gap in central nervous system drug delivery.}, journal = {European journal of pharmacology}, volume = {1003}, number = {}, pages = {177958}, doi = {10.1016/j.ejphar.2025.177958}, pmid = {40680978}, issn = {1879-0712}, mesh = {Humans ; Administration, Intranasal ; *Central Nervous System Diseases/drug therapy/metabolism ; Animals ; *Drug Delivery Systems ; *Central Nervous System Agents/administration & dosage/pharmacokinetics ; *Nanoparticles ; }, abstract = {Neurological disorders such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), cerebrovascular accidents, brain tumors, and functional impairments are becoming an increasingly urgent global health concern, particularly as aging populations expand worldwide. The blood-brain barrier significantly limits current treatment strategies, such as pharmacological therapies (oral or systemic), neurosurgical procedures, and neuromodulation. This highly selective barrier prevents most small-molecule drugs and virtually all biologics from reaching effective concentrations within the central nervous system (CNS), thereby restricting their therapeutic potential. Therefore, traditional drug delivery methods face challenges in effectively delivering therapeutic agents to the CNS. Intranasal delivery circumvents this limitation through direct nose-to-brain transport via olfactory/trigeminal pathways, achieving higher cerebrospinal fluid drug bioavailability compared to intravenous routes. In this review, we present a comprehensive elucidation of the pathophysiology of CNS disorders and the intricate mechanisms governing drug transport from the nasal cavity. Significantly advancing the field, we provide an exhaustive overview of cutting-edge nanocarriers and inhalation devices specifically designed for inhalable formulations, highlighting their unique advantages and limitations. This review combines clinical and engineering insights to evaluate innovative treatment methods through intranasal delivery, while identifying critical research pathways for improving central nervous system therapies.}, } @article {pmid40680673, year = {2025}, author = {Meng, D and Luo, G and Liu, P}, title = {Copper metabolism and cuproptosis in Alzheimer's disease: mechanisms and therapeutic potential.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {190}, number = {}, pages = {118354}, doi = {10.1016/j.biopha.2025.118354}, pmid = {40680673}, issn = {1950-6007}, mesh = {*Alzheimer Disease/metabolism/drug therapy/pathology ; *Copper/metabolism ; Humans ; Animals ; *Brain/metabolism/pathology/drug effects ; Oxidative Stress ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder with an increasing incidence rate year by year. The pathogenesis of AD is complex and closely related to protein misfolding and aggregation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and other factors. Cuproptosis is a newly discovered form of programmed cell death caused by excessive intracellular copper. Unlike other known forms of cell death, it shows significant potential in the treatment of neurodegenerative diseases. Copper binds to the acylated components of the tricarboxylic acid cycle, causing protein toxicity stress, which ultimately leads to cell cuproptosis. AD is characterized by pathological features such as β-amyloid plaque formation and excessive phosphorylation of tau protein, which are closely linked to the cuproptosis mechanism. However, the specific relationship between the pathogenesis of AD and copper metabolism remains unclear. This article summarizes the metabolism of copper in the brain, the mechanisms of cuproptosis, and the pathogenesis of cuproptosis in AD, and also discusses the regulation of cuproptosis in the treatment of AD. This article provides a basis for targeted research on cuproptosis in AD.}, } @article {pmid40680380, year = {2025}, author = {Wang, B and Li, W and Hong, C and Jin, F and Xu, B and Guo, Z and Chen, S and Zhang, Q}, title = {Amyloid β (Aβ) inhibits retinal angiogenesis in Alzheimer's disease via LncRNA-XIST/miRNA-126-5p/VEGF axis.}, journal = {Immunobiology}, volume = {230}, number = {4}, pages = {153097}, doi = {10.1016/j.imbio.2025.153097}, pmid = {40680380}, issn = {1878-3279}, mesh = {*Alzheimer Disease/metabolism/genetics/pathology ; *MicroRNAs/genetics/metabolism ; *RNA, Long Noncoding/genetics/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism/genetics ; *Vascular Endothelial Growth Factor A/genetics/metabolism ; Mice ; Disease Models, Animal ; Humans ; Retina/pathology/metabolism ; Signal Transduction ; *Retinal Neovascularization/metabolism/genetics ; Gene Expression Regulation ; *Neovascularization, Pathologic ; Angiogenesis ; }, abstract = {Alzheimer's disease (AD) is often accompanied by retinal lesions, in which Amyloid β (Aβ) is a key mediator. Vascular dysfunction is always associated with the malignant progression of AD, but the precise mechanisms remain poorly understood. The aim of this study is to investigate how Aβ regulates retinal angiogenesis in AD models through the LncRNA-XIST/miR-126-5p/VEGF axis. The research results showed that in the retina of AD model mice, the expression of Aβ and miR-126-5p increased, while the expression of LncRNA-XIST and VEGF decreased. In vitro experiments demonstrated that Aβ treatment downregulated LncRNA-XIST and VEGF expression in RF/6 A cells, while upregulating miR-126-5p and significantly suppressing angiogenesis. Overexpression of LncRNA-XIST can reverse the inhibitory effect of Aβ on angiogenesis, while further overexpression of miR-126-5p can counteract the pro-angiogenic effect of LncRNA-XIST. The dual-luciferase reporter assay results showed that Aβ repressed the transcriptional activity of the LncRNA-XIST promoter by targeting the -800 to -600 fragment. Mechanism studies have revealed that LncRNA-XIST competitively binds to miR-126-5p, preventing its binding to VEGF mRNA and upregulating VEGF expression. In vivo experiments demonstrated that miR-126-5p inhibitor resulted in elevated expression of LncRNA-XIST and VEGF in the mouse retina. This study reveals the molecular mechanism by which Aβ regulates retinal angiogenesis in AD models through the LncRNA-XIST/miR-126-5p/VEGF axis, providing a potential new strategy for targeted therapy of AD-related retinal lesions.}, } @article {pmid40680313, year = {2025}, author = {Hamuľaková, S and Gucký, A and Mezencev, R and Kožurková, M and Bednáriková, Z and Marek, J and Soukup, O and Janoušek, J and Gažová, Z}, title = {Inhibition of amyloid fibrillization of amyloid β peptide by 4,7-disubstituted coumarin derivatives.}, journal = {Bioorganic & medicinal chemistry}, volume = {129}, number = {}, pages = {118302}, doi = {10.1016/j.bmc.2025.118302}, pmid = {40680313}, issn = {1464-3391}, mesh = {*Coumarins/pharmacology/chemistry/chemical synthesis ; *Amyloid beta-Peptides/antagonists & inhibitors/metabolism ; Humans ; Structure-Activity Relationship ; Cell Line, Tumor ; Blood-Brain Barrier/metabolism ; *Antioxidants/pharmacology/chemistry/chemical synthesis ; Molecular Structure ; Cell Survival/drug effects ; *Peptide Fragments/metabolism/antagonists & inhibitors ; Dose-Response Relationship, Drug ; Protein Aggregates/drug effects ; }, abstract = {Coumarins are well-known for their unique chemical structure and a wide range of biological effects. Various substituted coumarin-based compounds have emerged as promising candidates for the development of novel therapeutic agents against numerous diseases. This study was focused on the synthesis of new 4,7-disubstituted coumarin derivatives and investigation of their ability to inhibit the aggregation of Aβ40 peptide, their cytotoxic effect on SH-SY5Y cells, their antioxidant properties, and their ability to penetrate the blood-brain barrier (BBB). The results revealed that the trihydroxy derivatives 5a-c had been the most effective inhibitors of Aβ aggregation, promoting the formation of non-toxic, amorphous aggregates instead. Importantly, no significant decrease in the viability of SH-SY5Y neuroblastoma cells was observed after treatment with the studied coumarins. Among them, coumarin 5a demonstrated the strongest antioxidant activity, while compound 5b also exhibited good antioxidant properties, along with the best inhibition of Aβ aggregation (IC50 = 13.5 μM), and adequate permeability across the blood-brain barrier. These findings suggest that compound 5b is a promising candidate for further investigation in Alzheimer's disease pharmacotherapy.}, } @article {pmid40679987, year = {2025}, author = {Li, B and Golovynska, I and Stepanov, YV and Golovynskyi, S and Golovynskyi, A and Kolesnik, D and Stepanova, LI and Lai, P and Lin, F and Qu, J}, title = {Transcranial photobiomodulation therapy with 808 nm light changes expression of genes and proteins associated with neuroprotection, neuroinflammation, oxidative stress, and Alzheimer's disease: Whole RNA sequencing of mouse cortex and hippocampus.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0326881}, pmid = {40679987}, issn = {1932-6203}, mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/therapy ; *Hippocampus/metabolism/radiation effects ; *Oxidative Stress/radiation effects/genetics ; Mice ; *Low-Level Light Therapy/methods ; *Neuroprotection/genetics/radiation effects ; *Neuroinflammatory Diseases/genetics ; *Cerebral Cortex/metabolism/radiation effects ; Mice, Inbred BALB C ; Sequence Analysis, RNA ; Male ; Gene Expression Regulation/radiation effects ; Gene Regulatory Networks ; }, abstract = {Light therapy, using red and near-infrared (NIR) irradiation, is currently applied for the treatment of various neurodegenerative diseases, such as Alzheimer's disease (AD). Transcranial photobiomodulation therapy (tPBMT) can alleviate neurodegeneration, neuronal loss, and β-amyloid peptide plaque burden. Alternatively, potential early inhibition of oxidative stress, neuroinflammation, apoptosis, and amyloidogenic cellular pathways may constrain pathological changes with aging. In this research, we conduct an 808-nm tPBMT with a 30-day course of daily 1-hour sessions for mice and assess its influence on molecular mechanisms related to the potential onset of neurodegeneration. To comprehensively identify molecular mechanisms of tPBMT on the brain cells, the next-generation whole RNA sequencing of over 30,000 mRNA of the cortex and hippocampus of BALB/c mice is performed. After tPBMT, transcriptional alterations are found in 1,005 genes in the hippocampus and 1,482 genes in the cortex. Pathway-gene enrichment network analysis identifies genes associated with about 20 pathways of neurodegeneration, and a disease-gene network is constructed. Particularly, tPBMT alters the transcription and expression of the essential genes associated with oxidative stress (NF-κBIα, JUN, JUND, and PKC genes), inflammation (DOCK4/6, IL-1RAPL1, and TNFαIP6), and apoptosis (CASP3, TNFαIP6, AKT3, CDKN1A, CYP51, RASA2, and RESTAT). Additionally, 808-nm light modulates the main risk genes for AD (BACE1, BACE2, PSEN2, APH1B, GATA2, YY2, RELA, STAT3, JUN, JUND, ARNTL, CREB3L1, CELF2, E2F4, ELK3, and CEBPD), involved in APP processing supporting AD development. Moreover, the APP concentration is reduced after tPBMT. Hence, PBMT may help inhibit the development of different neurodegeneration types and maintain normal brain conditions.}, } @article {pmid40679583, year = {2025}, author = {Sun, X and Zhong, G and Zeng, Y and Xu, T and Liu, Y}, title = {Fully Integrated Wearable Biosensor for Multiple In Situ Phosphorylated Tau Protein Detection.}, journal = {Analytical chemistry}, volume = {97}, number = {29}, pages = {15941-15948}, doi = {10.1021/acs.analchem.5c02541}, pmid = {40679583}, issn = {1520-6882}, mesh = {*Biosensing Techniques/instrumentation ; *tau Proteins/analysis/metabolism ; *Wearable Electronic Devices ; Humans ; *Alzheimer Disease/diagnosis ; Phosphorylation ; *Electrochemical Techniques/instrumentation ; Limit of Detection ; }, abstract = {Early diagnosis is critical for the prevention and treatment of Alzheimer's disease (AD), as it allows for timely detection and intervention. Here, we developed a fully integrated wearable electrochemical sensing patch for early screening of AD, which combines sample collection and detection within a device. This wearable patch integrates a custom-developed microneedle sampling system with a wearable multimodal electrochemical biosensor. Such a microneedle sampling system can deliver interstitial fluid (ISF) to the detection area through a microneedle array, where the electrochemical sensing system can directly detect AD-related biomarkers P-tau181 and P-tau217 in situ with detection limits of 0.058 and 0.079 pg/mL. Additionally, the sensing patch includes a Bluetooth module, enabling the transmission of detection results to a mobile phone APP for display and further detection control. This fully integrated wearable electrochemical sensing patch provides a promising strategy for early multiple in situ diagnosis of AD.}, } @article {pmid40678834, year = {2025}, author = {Islam, MR and Rauf, A and Akter, S and Akter, H and Al-Imran, MIK and Fakir, MNH and Thufa, GK and Islam, MT and Hemeg, HA and Abdulmonem, WA and Aljohani, ASM and Iriti, M}, title = {Neuroprotective Potential of Curcumin in Neurodegenerative Diseases: Clinical Insights Into Cellular and Molecular Signaling Pathways.}, journal = {Journal of biochemical and molecular toxicology}, volume = {39}, number = {8}, pages = {e70369}, pmid = {40678834}, issn = {1099-0461}, mesh = {*Curcumin/therapeutic use/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Signal Transduction/drug effects ; Animals ; Oxidative Stress/drug effects ; }, abstract = {Progressive neuronal loss and dysfunction characterize neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, and Huntington's diseases, spinal cord injury, and stroke, making them difficult to treat. Curcumin, a bioactive substance derived from the turmeric plant (Curcuma longa), is interesting due to its potential neuroprotective properties. This review thoroughly shows the cellular and molecular signaling mechanisms that curcumin utilizes to provide neuroprotective effects in NDs. Curcumin regulates several signaling pathways linked to neuroprotection, such as those that reduce oxidative stress, prevent Aβ formation, and decrease neuroinflammation. NF-κB suppression reduces inflammatory responses, while Nrf2 activation boosts antioxidant response element expression. Furthermore, curcumin enhances autophagy and neurotrophic factor expression, facilitating the removal of harmful protein aggregates. The function of curcumin as a metal chelator is emphasized particularly to iron and other metal dysregulations linked to neurodegenerative processes. Curcumin's capacity to regulate metal ion homeostasis is essential since the pathophysiology of NDs is significantly influenced by metal-induced oxidative stress and toxic buildup. It shows potential therapeutic effects by reducing oxidative damage and chelating excess metals. Clinical research indicates that curcumin can penetrate the blood-brain barrier, making it an effective treatment option. The regulation of these pathways reduces neuronal damage and improves neurons' survival and functionality. In addition, curcumin's anti-inflammatory properties and low toxicity make it a promising long-term treatment option for NDs. Therefore, this review emphasizes the potential of curcumin as a targeted neuroprotective compound, presenting recent clinical insights and experimental data. Future studies should optimize curcumin formulations and delivery systems to enhance its bioavailability and therapeutic efficacy.}, } @article {pmid40678772, year = {2025}, author = {Choi, SH and Shim, Y and Kim, S and Yang, DW and Park, KH and Kim, J and Youn, YC}, title = {The Care Pathway for Patients with Mild Cognitive Impairment in Korea: A Survey of Dementia Specialists.}, journal = {Dementia and geriatric cognitive disorders extra}, volume = {15}, number = {1}, pages = {99-107}, pmid = {40678772}, issn = {1664-5464}, abstract = {INTRODUCTION: Mild cognitive impairment (MCI) represents a loss of memory or other cognitive function while maintaining the ability to independently perform most activities of daily living. This study assessed how Korean specialists in dementia care diagnosed and treated patients with MCI symptoms. METHODS: A questionnaire on the current management of MCI was developed by 6 experts in MCI care. Specialists in MCI care (n = 24: 14 neurologists/10 psychiatrists) verbally answered questions relating to their experience/views in caring for MCI patients. RESULTS: Respondents diagnosed MCI using the Seoul Neuropsychological Screening Battery (79%) and the Consortium to Establish a Registry for Alzheimer's Disease - Korea (21%) neuropsychological battery tests. All or nearly all respondents also assessed patients with Mini-Mental State Examination, Geriatric Depression Scale, Clinical Dementia Rating, Activities of Daily Living (ADL), and Instrumental ADL tests. All respondents used MRI or CT for differential diagnosis of diseases causing MCI, about one-third used amyloid PET. Most respondents (96%) treated patients with MCI due to Alzheimer's disease (AD) with medication, commonly choline alfoscerate (71%) and donepezil (53%), mainly as combination therapy. Unmet needs included patient/caregiver education (63%) and time constraints for consulting patients (54%). Most respondents considered that increased amyloid-β testing for patients with MCI due to AD or subjective cognitive decline is likely to increase. CONCLUSIONS: This survey described the current management of MCI due to AD, identified unmet needs and considered possible future developments in the changing landscape of early AD treatment. Early detection and diagnosis and continued development of emerging preventative or therapeutic interventions are critical for MCI outcomes.}, } @article {pmid40678242, year = {2025}, author = {Batista, AF and Presumey, J and Singh, B and Schroeder, MK and Khan, K and Spooner, E and Li, S and Carroll, MC and Lemere, CA}, title = {Global C3 lowering in adulthood protects against hippocampal dysfunction and cognitive impairment in aged mice.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40678242}, issn = {2693-5015}, support = {R01 NS136122/NS/NINDS NIH HHS/United States ; RF1 AG060057/AG/NIA NIH HHS/United States ; R01 AR074105/AR/NIAMS NIH HHS/United States ; R21 AG044713/AG/NIA NIH HHS/United States ; R01 AI130307/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Complement component 3 (C3) is increasingly recognized for its role in neurodegenerative processes; however, its specific impact on age-related hippocampal dysfunction remains poorly understood. This study investigates the effects of inducible C3 knockdown in adulthood on hippocampal function using a novel mouse model. METHODS: We developed a chimeric floxed C3 mouse line (C3[fl/fl]) and crossed it with Rosa-26-Cre-ERT2+/- mice, resulting in C3[fl/fl] ; Rosa-26-Cre-ERT2[+/-] (C3iKO) mice that allow for global C3 knockdown via Tamoxifen (TAM) administration at any age. Young adult female and male C3iKO mice were treated with TAM or corn oil (CO) as a control, to induce global C3 lowering in 4 cohorts of mice. Serum C3 levels were monitored throughout the lifespan for all cohorts. Other outcome measures varied by cohort and included behavior, C3 mRNA and protein levels in brain, C1q levels, immune gene expression in brain, gliosis, synaptic changes in hippocampus. RESULTS: TAM treatment led to a sustained reduction in C3 levels in serum, liver, and brain tissues of C3iKO mice. Global C3 lowering was associated with reduced expression of C1q, C4b, IFNa, IFNb,and APOE, and increase expression of homeostatic genes Tgfb1 and Tgfbr1 in mouse brain one-year following TAM treatment. Notably, C3 lowering in adulthood conferred significant neuroprotection against age-related cognitive decline, which corresponded to increased hippocampal synaptic density and dendritic spine formation and increased pre-synaptic proteins in hippocampal synaptosomes. Moreover, long-term potentiation (LTP) impairments induced by Aβ-oligomers were rescued following C3 knockdown, highlighting potential therapeutic implications. CONCLUSION: Our C3iKO mouse model was consistently effective in lowering C3 levels in the brain and periphery in mice. The findings reported here demonstrate that global C3 lowering in adulthood, after brain development, protected the brain against age-associated hippocampal dysfunction and cognitive decline, suggesting that complement modulation may provide a neuroprotective strategy against brain aging. The C3iKO model provides a valuable platform for understanding the role of complement C3 in age-related neurodegenerative conditions, including Alzheimer's disease. Further studies are needed to better understand these neuroprotective effects in models of neurodegeneration and to assess the therapeutic potential of complement modulation in the brain.}, } @article {pmid40677108, year = {2025}, author = {Hakim, MA and Sanni, A and Osman, ST and Hamdy, NA and Purba, WT and Bhuiyan, MMAA and Onigbinde, S and El-Khordagui, LK and El-Yazbi, A and Mechref, Y}, title = {Serum Proteome Profiling of Diabetic Patients Treated With DPP4 and SGLT2 Inhibitors Shows Improved Cognitive and Cardiovascular Functions.}, journal = {Proteomics}, volume = {25}, number = {14}, pages = {e70000}, doi = {10.1002/pmic.70000}, pmid = {40677108}, issn = {1615-9861}, support = {D-0005//Robert A. Welch Foundation/ ; //The CH Foundation/ ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/drug therapy/blood ; Male ; Female ; *Sodium-Glucose Transporter 2 Inhibitors/therapeutic use/pharmacology ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/pharmacology ; Middle Aged ; *Proteome/analysis/metabolism ; Metformin/therapeutic use ; *Cognition/drug effects ; Aged ; Hypoglycemic Agents/therapeutic use/pharmacology ; Proteomics/methods ; Cardiovascular Diseases/drug therapy ; Dipeptidyl Peptidase 4 ; }, abstract = {Type 2 diabetes (T2D) is a complex metabolic disorder with rising global prevalence, leading to major complications such as cognitive decline, cardiovascular disease, and systemic inflammation. Although advances in T2D pharmacotherapy have shown promise in addressing these complications, the underlying protective mechanisms remain unclear, especially as they appear to be independent of glycemic control. In this study, we performed a comprehensive proteomic analysis using LC-MS/MS to explore the molecular effects of newer antidiabetic drugs, specifically dipeptidyl peptidase 4 (DPP4) and sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is), when combined with metformin, the first-line treatment for T2D. Serum samples from 76 individuals were analyzed, including 16 healthy subjects, 32 T2D patients on metformin monotherapy, and 28 T2D patients receiving combination therapy. We identified and quantified 505 low-abundance proteins, followed by statistical analysis and ingenuity pathway analysis. Our findings revealed significant changes in key biological pathways related to synaptogenesis, insulin-like growth factor transport, and neurovascular coupling signaling. These results were further validated using parallel reaction monitoring. Notably, pathways associated with cognitive function and cardiovascular health were adversely affected in T2D patients on metformin monotherapy but showed improvement with combination therapy. These results suggest that the combination of DPP4 and SGLT2is offers a therapeutic advantage, underscoring the importance of personalized treatment strategies in managing T2D complications. Summary: Type 2 diabetes (T2D) is a chronic metabolic disorder that contributes to the progression of cognitive impairment, cardiovascular diseases, and renal dysfunction. Cognitive decline in T2D patients can also increase the risk of developing neurological conditions like Alzheimer's disease. Recently developed antidiabetic drugs have shown promising cardiovascular and renal health effects, such as dipeptidyl peptidase 4 (DPP4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is). However, the precise mechanisms by which these drugs influence biological pathways related to cognitive function and central nervous system (CNS) development remain unclear. In this study, we explored the impact of these newer antidiabetic drugs in combination with metformin, compared to metformin monotherapy and healthy controls, by investigating differentially expressed proteins and their role in cognitive processes. Our findings reveal that DPP4 and SGLT2is activate key biological pathways-such as synaptogenesis, insulin-like growth factor regulation, and neurovascular coupling-that are either suppressed or not enriched in the metformin-only group. These pathways are critical for maintaining and regulating CNS function and cognitive health.}, } @article {pmid40676911, year = {2025}, author = {Chhipa, RR and Kurien, BT and Scofield, RH and Wolf, RF and Huang, H and Sundaram, P}, title = {Amytrapper Catheter: A Prototype Extracorporeal Device That Traps Blood Amyloid-β in a Rat Model of Alzheimer's Disease.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {40}, number = {}, pages = {15333175251361265}, pmid = {40676911}, issn = {1938-2731}, support = {R44 AG057327/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Alzheimer Disease/blood/therapy ; *Amyloid beta-Peptides/blood ; Disease Models, Animal ; Rats ; Male ; *Catheters ; }, abstract = {Alzheimer's disease (AD) presents a pressing global health challenge, with amyloid-β (Aβ) accumulation in the brain being a hallmark feature. While monoclonal antibodies targeting Aβ have shown cognitive benefits, safety concerns remain. Here, we introduce the Amytrapper catheter, a novel extracorporeal device developed by Recombinant Technologies to trap circulating Aβ using a retro-inverso peptide conjugated to polyethylene glycol. Through in vivo experiments using a rat model of AD, we demonstrate significant reductions in blood Aβ levels and behavioral improvements following Amytrapper catheter treatment. This innovative approach holds promise as a disease-modifying therapy for AD, offering a complementary strategy to existing treatments and advocating for further clinical development.}, } @article {pmid40676897, year = {2025}, author = {Sánchez-Soblechero, A and Gil, M and Rojo, JM and Muñiz, R and Hoyos-Alonso, MC and Olazarán, J}, title = {Trends of antipsychotic prescribing for people with dementia in Spain.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {1}, pages = {104-111}, doi = {10.1177/13872877251359682}, pmid = {40676897}, issn = {1875-8908}, mesh = {Humans ; *Antipsychotic Agents/therapeutic use ; Spain/epidemiology ; *Dementia/drug therapy/epidemiology ; Male ; Female ; Retrospective Studies ; Aged ; Aged, 80 and over ; *Practice Patterns, Physicians'/trends ; *Drug Prescriptions/statistics & numerical data ; Middle Aged ; }, abstract = {BackgroundAntipsychotic medications are frequently prescribed in people with dementia (PwD), despite concern regarding risk-benefit balance.ObjectiveTo describe the evolution of antipsychotic prescribing for PwD in Spain, with special interest in the effect of administration regulatory warnings (2004 and 2008).MethodsLongitudinal retrospective study using the national Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP). We included patients with incident dementia during the study period (January 1, 2002 to December 31, 2018) and excluded those with major psychiatric conditions, mental retardation, or previous use of antipsychotics. Paper-based and electronic prescriptions of antipsychotics were collected. Annual prevalence of prescribing was obtained for single medications and antipsychotic group. All calculations were conducted for the total sample and stratified by sex. The results were compared with those of other countries.ResultsAntipsychotic prescribing doubled during the study period, raising from 12.6% (2002) to 23.8% (2018). A mild decrease of prescribing was observed from 2004 to 2007, followed by steady increase from 2007 on. This increase was due to atypical antipsychotic use, specifically quetiapine, which grew from 0.2% (2002) to 16.4% (2018) and was more frequently utilized in men. Spain prevalence of antipsychotics doubled the UK's.ConclusionsBetter designed warnings appear as a key means to rationalize use of antipsychotics in Spain and other countries, ideally as part of national dementia strategies. Dearly needed non-pharmacological approaches for comprehensive treatment of neuropsychiatric symptoms could be generalized as a first step through nursing home and day care networks. Quetiapine requires the agencies' urgent attention.}, } @article {pmid40676867, year = {2025}, author = {Chen, G and McKay, NS and Gordon, BA and Joseph-Mathurin, N and Liu, J and Schindler, SE and Hassenstab, J and Doering, S and Aschenbrenner, AJ and Wang, Q and LaMontagne, PJ and Keefe, SJ and Massoumzadeh, P and Cruchaga, C and Xiong, C and Morris, JC and Benzinger, TL}, title = {Baseline and longitudinal changes in cortical thickness and hippocampal volume predict cognitive decline.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {106}, number = {4}, pages = {1452-1462}, pmid = {40676867}, issn = {1875-8908}, support = {R01 AG043434/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; S10 RR022984/RR/NCRR NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; R01 AG021910/AG/NIA NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; P50 MH071616/MH/NIMH NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; U24 RR021382/RR/NCRR NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Hippocampus/pathology/diagnostic imaging ; Male ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Female ; Aged ; Magnetic Resonance Imaging ; Longitudinal Studies ; Middle Aged ; Aged, 80 and over ; *Cerebral Cortex/pathology/diagnostic imaging ; *Brain Cortical Thickness ; Organ Size ; Neuropsychological Tests ; Disease Progression ; }, abstract = {BackgroundAs we transition to disease-modifying treatment for Alzheimer's disease (AD), identifying individuals most at risk for future cognitive decline is crucial. Amyloid PET, cerebrospinal fluid and more recently blood-based biomarkers can identify the first stage of AD. However, changes detectable by PiB-PET may precede the onset of the dementia by 20-30 years. MRI is a widely available tool for detecting longitudinal changes in brain structure, such as cortical thickness and hippocampal volume and may provide additional insight into which patients are at greatest risk to develop cognitive decline.ObjectiveTo determine how well the hippocampal volume and cortical thickness, without specific AD biomarkers, can predict cognitive decline.MethodsMRI data from 344 participants (cognitively unimpaired or mild cognitive impairment, age 50-86) were used to evaluate if changes in cortical thickness and hippocampal volume predict cognitive decline, measured by a global cognitive composite score. A random coefficient model was employed to calculate longitudinal changes in cortical thickness and hippocampal volume and assess their ability to predict cognitive decline.ResultsBaseline cortical thickness as well as hippocampal volume predicted cognitive decline, regardless of baseline cognitive status. In individuals unimpaired at baseline, decreases in cortical thickness and hippocampal volume independently predicted cognitive decline. For participants with baseline mild impairment, decreases in hippocampal volume predicted further cognitive decline.ConclusionsThese findings indicate that MRI could serve as an effective tool for identifying individuals at elevated risk of cognitive decline, a growing public health concern as global populations continue to age.}, } @article {pmid40676669, year = {2025}, author = {Li, B and Wang, L and Xiao, Y and Tang, Z and Wang, Y and Sun, T and Qi, X}, title = {Modulation of neuronal α1-adrenergic receptor reduces tauopathy and neuroinflammation by inhibiting the STING/NF-κB/NLRP3 signaling pathway in Alzheimer's disease mice.}, journal = {Journal of neuroinflammation}, volume = {22}, number = {1}, pages = {187}, pmid = {40676669}, issn = {1742-2094}, support = {Qiankehe Basic-[2024] Youth 228//the Guizhou Provincial Science and Technology Program Project/ ; Qiankehe Platform Talents-GCC[2023]035//the Guizhou Provincial Science and Technology Program Project/ ; QianJiaoji [2024]92//the Guizhou Provincial Department of Education Youth Science and Technology Talent Project/ ; 82260263//This research was funded by the Chinese National Natural Science Foundation/ ; }, mesh = {Animals ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Mice ; *Alzheimer Disease/metabolism/pathology/genetics ; *Signal Transduction/physiology/drug effects ; NF-kappa B/metabolism ; Mice, Transgenic ; *Neuroinflammatory Diseases/metabolism/pathology ; *Tauopathies/metabolism/pathology/genetics ; *Receptors, Adrenergic, alpha-1/metabolism/genetics/biosynthesis ; *Neurons/metabolism/pathology ; Humans ; Mice, Inbred C57BL ; Membrane Proteins/metabolism ; Male ; Disease Models, Animal ; }, abstract = {BACKGROUND: Neuroinflammation is closely associated with the pathological progression of Alzheimer's disease (AD). The α1-adrenergic receptor (ADRA1), a G protein-coupled receptor, has been identified as a critical therapeutic target in inflammatory disorders. However, its precise mechanistic role in AD pathogenesis remains unclear. METHODS: To investigate ADRA1's role in AD, we employed 3xTg-AD and wild-type (WT) mice, modulating neuronal ADRA1 expression via intracerebroventricular delivery of adeno-associated viruses. Cognitive function, tau pathology, neuronal morphology, and activation of the STING/NF-κB/NLRP3 signaling pathway were evaluated using behavioral tests, Western blot, Golgi-Cox staining, immunohistochemistry, and immunofluorescence. In vitro AD models were established using Aβ42 oligomer-stimulated SH-SY5Y cells and primary murine neurons, along with SH-SY5Y cells transfected with full-length human tau (SH-SY5Y/htau). Pharmacological antagonists, inhibitors, lentiviral transduction, co-immunoprecipitation, and calcium flux assays were utilized to dissect ADRA1-mediated molecular mechanisms in tauopathy and neuroinflammation. RESULTS: Hippocampal ADRA1 expression was significantly elevated in 10-month-old 3xTg-AD mice. Neuronal ADRA1 knockdown suppressed STING/NF-κB/NLRP3 pathway activation, ameliorated tauopathy and neuroinflammation, restored neuronal structure/function, and improved cognitive deficits in 3xTg-AD mice. Conversely, ADRA1 overexpression in C57/BL6 mice induced tauopathy, neuroinflammation, and cognitive impairment. Mechanistically, ADRA1 interacts with CXCR4 to form heterodimers, triggering cytoplasmic Ca[2]⁺ overload and subsequent STING/NF-κB/NLRP3 pathway activation. CONCLUSIONS: ADRA1 critically mediates tauopathy and neuroinflammation through STING/NF-κB/NLRP3 signaling. These results identify ADRA1 as a promising therapeutic target for AD prevention and treatment.}, } @article {pmid40676541, year = {2025}, author = {Zhang, Y and Xu, K and Wang, Y and Shen, Y and Liu, Z and Zhang, C and Zhou, Y and Lv, P and Bai, Y and Wang, S}, title = {Efficacy of repetitive transcranial magnetic stimulation in cognitive impairment of neurodegenerative diseases: a systematic review and meta-analysis.}, journal = {BMC neurology}, volume = {25}, number = {1}, pages = {295}, pmid = {40676541}, issn = {1471-2377}, mesh = {Humans ; *Transcranial Magnetic Stimulation/methods ; *Cognitive Dysfunction/therapy/etiology ; *Neurodegenerative Diseases/therapy/complications/psychology ; Randomized Controlled Trials as Topic/methods ; Treatment Outcome ; *Alzheimer Disease/therapy/psychology ; *Parkinson Disease/therapy/complications/psychology ; }, abstract = {OBJECTIVE: Currently, there is a lack of reliable evidence to prove the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the cognitive and emotional domains of neurodegenerative diseases (ND), leading to the absence of a unified and effective rTMS treatment protocol or stimulation targets. This systematic review and meta-analysis summarizes existing evidence to evaluate the efficacy of rTMS targeting the dorsolateral prefrontal cortex (DLPFC) and non-DLPFC in the cognitive and emotional aspects of ND. METHODS: For two common types of ND Alzheimer's disease (AD) and Parkinson's disease (PD), we included 17 relevant randomized controlled trials (RCTs) from five databases. Search terms included rTMS, Parkinson's disease, Alzheimer's disease, cognitive impairment, and randomized controlled studies. Two independent reviewers assessed the risk of bias in the included literature, performed data extraction, and evaluated the evidence. Treatment effects were assessed using the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Hamilton Depression Rating Scale (HAMD), the Hamilton Anxiety Rating Scale (HAMA), and Activities of Daily Living (ADL). Data were analyzed using R software to evaluate effect sizes and 95% confidence interval (CI). Heterogeneity tests were conducted to assess differences in treatment effects between DLPFC and non-DLPFC. RESULTS: We screened 3,467 articles and identified 17 studies that met the inclusion criteria. The pooled results showed significant effects: MoCA (MD: 2.13, 95% CI [0.75, 3.52], p < 0.001); MMSE (MD: 1.16, 95% CI [0.91, 1.41], p = 0.0075); HAMD (MD: -2.63, 95% CI [-6.45, -1.20], p = 0.14); HAMA (SMD: -0.62, 95% CI [-0.91, -0.33], p < 0.001); ADL (MD: -0.56, 95% CI [-1.10, 2.22], p = 0.48). CONCLUSION: rTMS has a positive effect on cognitive impairment and emotional abnormalities associated with ND. There is a significant difference in MoCA scores between rTMS applied to DLPFC and non-DLPFC. DLPFC may serve as a reliable stimulation target for treating non-motor symptoms related to ND (such as cognitive and emotional issues), which is beneficial for developing an rTMS treatment protocol with broad applicability for ND. However, due to the small number of included studies and the indirect nature of the comparison methods, we should interpret these results with caution.}, } @article {pmid40676466, year = {2025}, author = {Hu, H and Brys, M and Ruberg, SJ and Qu, Y}, title = {Estimand Endpoints for Longitudinal Measures of Continuous Disease Progression with an Alzheimer's Disease Example.}, journal = {Therapeutic innovation & regulatory science}, volume = {59}, number = {6}, pages = {1413-1420}, pmid = {40676466}, issn = {2168-4804}, mesh = {*Alzheimer Disease/drug therapy/physiopathology ; Humans ; *Disease Progression ; Longitudinal Studies ; Quality of Life ; *Endpoint Determination/methods ; }, abstract = {The ICH E9 (R1) Addendum provides a framework to define an estimand and perform sensitivity analysis. The clinical endpoint (i.e., variable, response, outcome) is one of the important estimand attributes. In our opinion, the selection of the endpoint in Alzheimer's disease requires more exploration beyond what is used currently. The change in a cognitive and functional assessment scale from baseline to a specific time point of interest is often used as a primary or key secondary endpoint in clinical trials. However, such a change from baseline to the time point of interest may not reflect the benefit of the treatment over the course of treatment duration and may be difficult to intuitively understand by patients and clinicians. For two patients with the same change from baseline, the patient with rapid disease progression in the beginning is considered to have overall worse quality of life compared to the other patient with slow disease progression in the beginning but rapid progression toward the end. We explore time-averaged measurement (TAM) as a new endpoint and propose using the relative change to quantify the treatment difference. Estimands under the ICH E9 (R1) Addendum were considered by using various strategies in handling intercurrent events and used corresponding methods for handling missing data. We illustrate the use of TAM and compare the results with other commonly used estimand endpoints (the change from baseline, the relative disease progression model, and the slope of disease progression) for different estimands and imputation methods from retrospective analyses of a historical study.}, } @article {pmid40675957, year = {2025}, author = {Vaghari, D and Mohankumar, G and Tan, K and Lowe, A and Shering, C and Tino, P and Kourtzi, Z}, title = {AI-guided patient stratification improves outcomes and efficiency in the AMARANTH Alzheimer's Disease clinical trial.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {6244}, pmid = {40675957}, issn = {2041-1723}, support = {/WT_/Wellcome Trust/United Kingdom ; U19 AG024904/AG/NIA NIH HHS/United States ; 221633/Z/20/Z//Wellcome Trust (Wellcome)/ ; INF\R2\202107//Royal Society/ ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/diagnosis ; Male ; Female ; Aged ; Amyloid beta-Peptides/metabolism ; Treatment Outcome ; Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Aspartic Acid Endopeptidases/antagonists & inhibitors ; Aged, 80 and over ; Prognosis ; Cognitive Dysfunction/drug therapy ; Patient Selection ; Cognition/drug effects ; }, abstract = {Alzheimer's Disease (AD) drug discovery has been hampered by patient heterogeneity, and the lack of sensitive tools for precise stratification. Here, we demonstrate that our robust and interpretable AI-guided tool (predictive prognostic model, PPM) enhances precision in patient stratification, improving outcomes and decreasing sample size for a AD clinical trial. The AMARANTH trial of lanabecestat, a BACE1 inhibitor, was deemed futile, as treatment did not change cognitive outcomes, despite reducing β-amyloid. Employing the PPM, we re-stratify patients precisely using baseline data and demonstrate significant treatment effects; that is, 46% slowing of cognitive decline for slow progressive patients at earlier stages of neurodegeneration. In contrast, rapid progressive patients did not show significant change in cognitive outcomes. Our results provide evidence for AI-guided patient stratification that is more precise than standard patient selection approaches (e.g. β-amyloid positivity) and has strong potential to enhance efficiency and efficacy of future AD trials.}, } @article {pmid40675659, year = {2025}, author = {Singla, P and Argoff, CE}, title = {How Common Is Pain in Neurologic Disorders and Why Should Neurologists Care?.}, journal = {Neurologic clinics}, volume = {43}, number = {3}, pages = {457-465}, doi = {10.1016/j.ncl.2025.04.001}, pmid = {40675659}, issn = {1557-9875}, mesh = {Humans ; *Neurologists ; *Nervous System Diseases/complications/therapy ; *Pain Management/methods ; *Pain/etiology ; *Chronic Pain/therapy/etiology ; }, abstract = {This article explores the link between chronic pain and neurologic disorders, focusing on how pain affects conditions like Alzheimer's disease, Parkinson's disease, multiple sclerosis, and post-stroke pain. The article highlights the need to recognize pain as an important symptom in these conditions and encourages neurologists to take an active role in managing pain. By understanding how pain works and using a team approach, health care providers can improve the quality of life for patients and create better treatment plans for chronic pain related to neurologic disorders.}, } @article {pmid40675338, year = {2025}, author = {Shtilbans, A}, title = {Combination Supplement Therapy: A New Frontier in Treatment of Neurodegenerative Diseases.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.tjnut.2025.07.004}, pmid = {40675338}, issn = {1541-6100}, abstract = {This review highlights the importance and potential beneficial effects of dietary supplements, including taurine, tauroursodeoxycholic acid (TUDCA), curcumin, coenzyme Q10, creatine, and N-acetylcysteine, in the management of neurodegenerative diseases. Studies in preclinical models have consistently shown significant potential of these supplements in mitigating neurodegenerative pathology. Through a range of mechanisms targeting different molecular pathways, these supplements demonstrate therapeutic outcomes in preclinical models of conditions such as Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, and Huntington disease. This review discusses published data on each of these supplements in the context of neurodegenerative diseases. It also discusses a combination therapy concept and proposes a strategy to formulate an optimal blend of these supplements. This combination approach will target key processes, including mitochondrial dysfunction, protein misfolding, neuroinflammation, and oxidative stress responsible for neurodegenerative conditions. Additionally, this review examines various models used for both the initial screening and subsequent assessment of candidate supplement combinations.}, } @article {pmid40674898, year = {2025}, author = {Sikirzhytskaya, A and Tyagin, I and Sutton, SS and Wyatt, MD and Safro, I and Shtutman, M}, title = {AI-based mining of biomedical literature: Applications for drug repurposing for the treatment of dementia.}, journal = {Artificial intelligence in medicine}, volume = {168}, number = {}, pages = {103218}, doi = {10.1016/j.artmed.2025.103218}, pmid = {40674898}, issn = {1873-2860}, support = {R01 DA054992/DA/NIDA NIH HHS/United States ; }, mesh = {*Drug Repositioning/methods ; *Data Mining/methods ; Humans ; *Dementia/drug therapy/genetics ; *Artificial Intelligence ; Discriminant Analysis ; }, abstract = {Neurodegenerative diseases like Alzheimer's, Parkinson's, and HIV-associated neurocognitive disorder severely impact patients and healthcare systems. While effective treatments remain limited, researchers are actively developing ways to slow progression and improve patient outcomes, requiring innovative approaches to handle huge volumes of new scientific data. To enable the automatic analysis of biomedical data we introduced AGATHA, an effective AI-based literature mining tool that can navigate massive scientific literature databases. The overarching goal of this effort is to adapt AGATHA for drug repurposing by revealing hidden connections between FDA-approved medications and a health condition of interest. Our tool converts the abstracts of peer-reviewed papers from PubMed into multidimensional space where each gene and health condition are represented by specific metrics. We implemented advanced statistical analysis to reveal distinct clusters of scientific terms within the virtual space created using AGATHA-calculated parameters for selected health conditions and genes. Partial Least Squares Discriminant Analysis was employed for categorizing and predicting samples (122 diseases and 20,889 genes) fitted to specific classes. Advanced statistics were employed to build a discrimination model and extract lists of genes specific to each disease class. We focused on repurposing drugs for dementia by identifying dementia-associated genes highly ranked in other disease classes. The method was developed for detection of genes that shared across multiple conditions and classified them based on their roles in biological pathways. This led to the selection of six primary drugs for further study.}, } @article {pmid40672883, year = {2025}, author = {Zammit, AR and Capuano, AW and Barnes, LL and Schneider, JA and Sperling, RA and Bennett, DA and Grodstein, F}, title = {Cognitive decline across five cognitive batteries: Sample size implications for clinical trials.}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70137}, pmid = {40672883}, issn = {2352-8737}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG022018/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; K01 AG054700/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: We evaluated the statistical power for a theoretical randomized trial of anti-amyloid treatment in preclinical Alzheimer's Disease across five cognitive composites in preclinical Alzheimer's Disease across five cognitive composites: Alzheimer's Prevention Initiative Preclinical Composite Cognitive Test (APCC); Preclinical Alzheimer's Composite with Semantic Processing (PACC5); Preclinical Alzheimer's Cognitive Composite (PACC); and global and episodic memory composites. METHODS: We utilized annual cognitive assessments from 517 decedents (78.2 ± 4.7years; 72% female) with post mortem pathologic Alzheimer's disease (AD) to represent amyloid positivity. We calculated sample sizes to detect 30% reduction in 5-year slopes of cognitive decline for equal size treatment versus placebo groups across composites. RESULTS: Estimated sample sizes for APCC (n = 1633, 95% confidence interval [CI] 1400-1823), PACC (n = 1822, 95% CI 1612-2122), and episodic memory (n = 3141 95%CI 2563-3732) were larger than for PACC5 (n = 1424, 95% CI 1249-1575). Sample size estimates were similar between PACC5 and the global composite (n = 1267, 95%CI 1336-1407). DISCUSSION: Small changes in composites, such as addition of semantic fluency in PACC5, could be considered as part of approaches to improve statistical power. HIGHLIGHTS: We evaluated statistical power of a theoretical 5-year randomized trial testing anti-amyloid treatments in early Alzheimer's across five cognitive composite endpoints.We leveraged annual cognitive assessment in Rush Alzheimer's Disease Center cohorts and used post mortem pathologic AD to represent amyloid positivity.Preclinical Alzheimer's Composite with Semantic Processing (PACC5) required significantly lower sample size to achieve power for a 30% reduction in cognitive slope than Alzheimer's Disease Cooperative Study-Preclinical Alzheimer's Cognitive Composite (PACC).PACC5 had better statistical power than Alzheimer's Prevention Initiative Preclinical Composite Cognitive Test (APCC) and an episodic memory composite.Small changes in cognitive composites can improve detection of cognitive decline.}, } @article {pmid40672873, year = {2025}, author = {Xu, Q and An, L and Yang, H and Hong, KS}, title = {A multi-graph convolutional network method for Alzheimer's disease diagnosis based on multi-frequency EEG data with dual-mode connectivity.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1555657}, pmid = {40672873}, issn = {1662-4548}, abstract = {OBJECTIVE: Alzheimer's disease (AD) is mainly identified by cognitive function deterioration. Diagnosing AD at early stages poses significant challenges for both researchers and healthcare professionals due to the subtle nature of early brain changes. Currently, electroencephalography (EEG) is widely used in the study of neurodegenerative diseases. However, most existing research relies solely on functional connectivity methods to infer inter-regional brain connectivity, overlooking the importance of spatial connections. Moreover, many existing approaches fail to fully integrate multi-frequency EEG features, limiting the comprehensive understanding of dynamic brain activity across different frequency bands. This study aims to address these limitations by developing a novel graph-based deep learning model that fully utilizes both functional and structural information from multi-frequency EEG data. METHODS: This paper introduces a Multi-Frequency EEG data-based Multi-Graph Convolutional Network (MF-MGCN) model for AD diagnosis. This method integrates both functional and structural connectivity to more thoroughly capture the relationships among brain regions. By extracting differential entropy (DE) features from five distinct frequency bands of EEG signals for each segment and using graph convolutional networks (GCNs) to aggregate these features, the model effectively distinguishes between AD and healthy controls (HC). RESULTS: The outcomes show that the developed model outperforms existing methods, achieving 96.15% accuracy and 98.74% AUC in AD and HC classification. CONCLUSION: These findings highlight the potential of the MF-MGCN model as a clinical tool for Alzheimer's disease diagnosis. This approach could help clinicians detect Alzheimer's at earlier stages, enabling timely intervention and personalized treatment plans.}, } @article {pmid40672508, year = {2025}, author = {, and Cao, H and Song, Z and Duggan, MR and Erus, G and Srinivasan, D and Tian, YE and Bai, W and Rafii, MS and Aisen, P and Belsky, DW and Walker, KA and Zalesky, A and Ferrucci, L and Davatzikos, C and Wen, J}, title = {Multi-organ MRI digitizes biological aging clocks across proteomics, metabolomics, and genetics.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40672508}, support = {RF1 AG054409/AG/NIA NIH HHS/United States ; }, abstract = {Leveraging clinical phenotypes[1,2], neuroimaging[3], proteomics[4], metabolomics[5], and epigenetics[6], biological aging clocks across organ systems and tissues have advanced our understanding of human aging and disease. In this study, we expand this biological aging clock framework to multi-organ magnetic resonance imaging (MRI) by developing 7 organ-specific MRI-based biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney, and pancreas. Leveraging imaging, genetic, proteomic, and metabolomic data from 313,645 individuals curated by the MULTI consortium, we link the 7 MRIBAGs to 2,923 plasma proteins, 327 metabolites, and 6,477,810 common genetic variants. These associations reveal organ-specific and cross-organ interconnection landscapes, identifying distinct molecular signatures related to organ aging. Genome-wide associations identify 53 MRIBAG-locus pairs (P<5×10[-8]). Genetic correlation and Mendelian randomization analyses further support organ-specific and cross-organ interconnections with 9 phenotype-based[1,2], 11 proteome-based[7], and 5 metabolome-based aging clocks[5], as well as 525 disease endpoints. Through functional gene mapping and Bayesian colocalization analysis linking evidence from genetics, proteomics, and metabolomics, we prioritize 9 druggable genes as targets for future anti-aging treatments. Finally, we demonstrate the clinical relevance of the 7 MRIBAGs in predicting disease endpoints (e.g., diabetes mellitus), all-cause mortality, and capturing differential and heterogeneous cognitive decline trajectories over 240 weeks of treatment with the Alzheimer's disease drug (Solanezumab). Sex differences are evident across multiple organ systems, manifesting at structural, molecular, and genetic levels. In summary, we developed 7 MRI-based aging clocks that enhance the existing multi-organ biological aging framework, offer multi-scale insights into aging biology, and demonstrate clinical potential to advance future aging research.}, } @article {pmid40672452, year = {2025}, author = {Mei, X and Zhao, Z and Wang, J and Qiu, C and Li, L and Xiong, C and Zhu, S and Zheng, C}, title = {Synergistic effects of surface-enhanced Raman spectroscopy and enzyme-linked immunoassays in diagnosis of Alzheimer's disease, mild cognitive impairment, and late-life depression.}, journal = {Frontiers in neurology}, volume = {16}, number = {}, pages = {1615457}, pmid = {40672452}, issn = {1664-2295}, abstract = {BACKGROUND: Objective tests that can be used to identify neurodegenerative diseases and neuropsychiatric disorders are urgently needed. The primary objective of this study is to evaluate the diagnostic accuracy of surface-enhanced Raman spectroscopy (SERS), a novel blood-based detection method, in differentiating neurodegenerative diseases and neuropsychiatric disorders. Additionally, we aim to assess the synergistic diagnostic performance of combining SERS with enzyme-linked immunosorbent assay (ELISA) technology for Alzheimer's disease (AD), mild cognitive impairment (MCI), and late-life depression (LLD). METHODS: In total, 23 patients with AD, 24 with MCI, 20 with LLD, and 20 cognitively normal (control) individuals were enrolled. ELISA and SERS were used to test various biomarkers in the AD, MCI, LLD, and control groups. RESULTS: Amyloid-β, tau, brain-derived neurotrophic factor, proinflammatory cytokine IL-1β, and growth differentiation factor-15 levels as measured using ELISA significantly differed among the four groups (P < 0.05). SERS peaks at 592 (P = 0.038), 725 (P = 0.001), 1,003 (P = 0.010), 1,331 (P = 0.000), and 165 cm[-1] (P = 0.000) likewise significantly differed among the four groups. The area under the curve was significantly higher after combining multiple blood indicators than that with single-blood indicators. CONCLUSIONS: Combining SERS and ELISA can significantly increase diagnostic accuracy for AD, MCI, and LLD. The findings are expected to provide potential therapeutic targets for precise intervention in these diseases, thereby contributing to improved clinical stratification and personalized treatment strategies. ChiCTR2300076307 (30/09/2023).}, } @article {pmid40672178, year = {2025}, author = {Labra, SR and Compher, J and Prabhavalkar, A and Almaraz, M and Kwong, CC and Baal, C and Talantova, M and Dolatabadi, N and Piña-Sanz, J and Wang, Y and Yoon, L and Ghatak, S and Gao, Z and Zhang, Y and Trudler, D and Massey, L and Lin, W and Balistreri, A and Bula, M and Schork, NJ and Mondala, TS and Head, SR and Kelly, JW and Lipton, SA}, title = {Autophagy activators normalize aberrant Tau proteostasis and rescue synapses in human familial Alzheimer's disease iPSC-derived cortical organoids.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40672178}, issn = {2692-8205}, support = {R35 AG071734/AG/NIA NIH HHS/United States ; R01 AG056259/AG/NIA NIH HHS/United States ; R01 AG073418/AG/NIA NIH HHS/United States ; U01 AG088679/AG/NIA NIH HHS/United States ; TL1 TR002551/TR/NCATS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia worldwide. Despite extensive progress, the cellular and molecular mechanisms of AD remain incompletely understood, partially due to inadequate disease models. To illuminate the earliest changes in hereditary (familial) Alzheimer's disease, we developed an isogenic AD cerebrocortical organoid (CO) model. Our refined methodology produces COs containing excitatory and inhibitory neurons alongside glial cells, utilizing established isogenic wild-type and diseased human induced pluripotent stem cells (hiPSCs) carrying heterozygous familial AD mutations, namely PSEN1[ΔE9/WT], PSEN1[M146V/WT], or APP[swe/WT]. Our CO model reveals time-progressive accumulation of amyloid beta (Aβ) species, loss of monomeric Tau, and accumulation of aggregated high-molecular-weight (HMW) phospho(p)-Tau species. This is accompanied by neuronal hyperexcitability, as observed in early human AD cases on electroencephalography (EEG), and synapse loss. Single-cell RNA-sequencing analyses reveal significant differences in molecular abnormalities in excitatory vs. inhibitory neurons, helping explain AD clinical phenotypes. Finally, we show that chronic dosing with autophagy activators, including a novel CNS-penetrant mTOR inhibitor-independent drug candidate, normalizes pathologic accumulation of Aβ and HMW p-Tau, normalizes hyperexcitability, and rescues synaptic loss in COs. Collectively, our results demonstrate these COs are a useful human AD model suitable for assessing early features of familial AD etiology and for testing drug candidates that ameliorate or prevent molecular AD phenotypes.}, } @article {pmid40671844, year = {2025}, author = {Mohammed, O and Kelemu, T}, title = {Incretin-Based Therapies in Alzheimer's and Parkinson's Disease: Advancing Neuroprotection With Dual and Triple Agonists-A Review.}, journal = {Health science reports}, volume = {8}, number = {7}, pages = {e71065}, pmid = {40671844}, issn = {2398-8835}, abstract = {BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD) are progressive neurodegenerative disorders with significant cognitive and motor impairments, affecting millions globally. Current treatments offer limited efficacy, prompting the exploration of new therapeutic approaches. AIM: To discuss the intricate relationship between incretin and insulin signaling pathways and their relevance to the pathogenesis and treatment of Alzheimer's and Parkinson's diseases. METHODS: A comprehensive literature review was conducted using a variety of search engines, including Google Scholar, PubMed Central, Scopus, Web of Science, and others. RESULTS: Emerging evidence highlights disrupted insulin signaling in AD and, to a lesser extent, in PD, suggesting that insulin plays a key neuroprotective role. Incretins, such as GLP-1 and GIP, which enhance insulin signaling, have shown potential in preclinical and clinical studies. Incretin-based therapies, particularly GLP-1/GIP receptor agonists, have demonstrated promising effects by addressing several pathological processes, including oxidative stress, inflammation, misfolded protein aggregation, and insulin resistance. Dual agonists like DA-CH3, DA5-CH, and DA4-JC have proven superior in crossing the blood-brain barrier and offering improved neuroprotection in comparison with conventional GLP-1 agonists. Triple agonists provide even greater neuroprotective benefits, highlighting their potential as disease-modifying therapies for AD and PD. CONCLUSION: While GLP-1 and GIP analogs hold promise in modulating early neurodegenerative processes, their efficacy likely depends on timely intervention before permanent neuronal damage occurs.}, } @article {pmid40671308, year = {2025}, author = {Creeden, JF and Machiraju, SN and Amin, JB and Stahl, SM}, title = {From betel nuts to Cobenfy: how an ancient recreational drug gave rise to a new class of schizophrenia medications.}, journal = {CNS spectrums}, volume = {30}, number = {1}, pages = {e55}, doi = {10.1017/S1092852925100424}, pmid = {40671308}, issn = {1092-8529}, mesh = {Humans ; *Areca ; *Schizophrenia/drug therapy/history ; *Antipsychotic Agents/therapeutic use/history ; *Arecoline/therapeutic use/pharmacology ; *Illicit Drugs/history ; }, abstract = {The term "betel" most accurately refers to the betel pepper (Piper betle). Confusingly, this term is also frequently used to refer to a street drug that often-but not always-includes the betel leaf as a constituent. This linguistic misdirection only intensifies with terms such as "betel nut," which, in common usage, may refer to this same composite street drug or to a single isolated constituent of that street drug: the nut of the areca palm (Areca catechu), which is otherwise wholly unrelated to the betel pepper. This composite street drug, colloquially referred to as "betel" or "betel nut" or "betel quid," is one of the most frequently used psychoactive substances in the world. It carries a cultural legacy spanning over 10,000 years and a current user base numbering in the hundreds of millions. Its primary psychoactive constituent is arecoline, a well-established parasympathomimetic agent. Early studies exploring arecoline's ability to modulate cholinergic signaling pathways and exert therapeutic psychiatric effects on conditions such as Alzheimer's disease were initially mired by intolerable parasympathetic side effects. Indeed, over the course of its long history, various hints regarding the therapeutic utility of arecoline have been obfuscated by a variety of challenges which have only recently been overcome. Now, developments in psychopharmacology and our growing understanding of neurochemical brain circuitry have unlocked a new mechanism of action by which arecoline-derived medications interact with dopaminergic processes to improve outcomes for schizophrenia patients. One such medication, xanomeline-trospium (Cobenfy), has emerged as the first such agent to receive U.S. Food and Drug Administration (FDA) approval for the treatment of schizophrenia and represents an entirely new class of pro-cholinergic medication within the field of psychiatry. Many in the field believe that this heralds the beginning of a new era of psychopharmacology: the era of muscarinic agonism. This article briefly described the fascinating journey from ancient betel nuts to modern muscarinic therapeutics.}, } @article {pmid40671224, year = {2025}, author = {Wen, J and Hu, J and Yang, X and Luo, F and Zou, G}, title = {Effective Analysis of Alzheimer's Disease and Mechanisms of Methyl-4- Hydroxybenzoate using Network Toxicology, Molecular Docking, and Machine Learning Strategies.}, journal = {Current Alzheimer research}, volume = {22}, number = {6}, pages = {456-475}, pmid = {40671224}, issn = {1875-5828}, support = {20243BCE51028, 310201384304//Science and Technology Department of Jiangxi Province/ ; 81760811, 81960854, 82260911//National Natural Science Foundation of China/ ; S202410412112//Innovation and Entrepreneurship Training Program for College Students/ ; zyyzdxk-2023113//State Administration of Traditional Chinese Medicine has built a high-level key discipline of traditional Chinese medicine/ ; 20192B AB205099, 20202BA206070//Natural Science Foundation of Jiangxi Province/ ; 20204420, SKJP-220210188, 2022B516//Science and Technology Program of Jiangxi Provincial Health Commission/ ; }, mesh = {*Alzheimer Disease/chemically induced/genetics/metabolism ; *Molecular Docking Simulation ; Humans ; *Machine Learning ; *Environmental Pollutants/toxicity ; Gene Regulatory Networks/drug effects ; }, abstract = {INTRODUCTION: Nowadays, the large increase in environmental pollutants has led to the occurrence and development of an increasing number of diseases. Studies have shown that exposure to environmental pollutants, such as methyl-4-hydroxybenzoate (MEP) may lead to Alzheimer's disease (AD). Therefore, the purpose of this study was to elucidate the complex effects and potential molecular mechanisms of environmental pollutants MEP on AD. METHODS: Through exhaustive exploration of databases, such as ChEMBL, STITCH, SwissTarget- Prediction, and Gene Expression Omnibus DataSets (GEO DataSets), we have identified a comprehensive list of 46 potential targets closely related to MEP and AD. After rigorous screening using the STRING platform and Cytoscape software, we narrowed the list to nine candidate targets and ultimately identified six hub targets using three proven machine learning methods (LASSO, RF, and SVM): CREBBP, BCL6, CXCR4, GRIN1, GOT2, and ITGA5. The "clusterProfiler" R package was used to conduct GO and KEGG enrichment analysis. At the same time, we also constructed disease prediction models for core genes. At last, six hub targets were executed molecular docking. RESULTS: We derived 46 key target genes related to MEP and AD and conducted gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. MEP might play a role in AD by affecting the pathways of neuroactive ligand-receptor interaction. Nine genes were screened as pivotal targets, followed by machine learning methods to identify six hub targets. Molecular docking analysis showed a good binding ability between MEP and CREBBP, BCL6, CXCR4, GRIN1, GOT2 and ITGA5. In addition, changes in the immune microenvironment revealed a significant impact of immune status on AD. DISCUSSIONS: This study revealed that MEP may induce AD through multiple mechanisms, such as oxidative stress, neurotoxicity, and immune regulation, and identified six core targets (CREBBP, BCL6, etc.) and found that they are related to changes in the immune microenvironment, such as T cells and B cells, providing new molecular targets for AD intervention. CONCLUSION: Overall, CREBBP, BCL6, CXCR4, GRIN1, GOT2, and ITGA5 have been identified as the crucial targets correlating with AD. Our findings provide a theoretical framework for understanding the complex molecular mechanisms underlying the effects of MEP on AD and provide insights for the development of prevention and treatment of AD caused by exposure to MEP.}, } @article {pmid40671162, year = {2025}, author = {Rodríguez, A and Calero, O and Veiga, S and Menacho-Román, M and Arribas, I and Cano, L and García-Ribas, G and Calero, M}, title = {A novel biochemical analysis for ApoE4 quantification in plasma and discrimination of homozygous and heterozygous APOE ε4 carriers.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {163}, pmid = {40671162}, issn = {1758-9193}, support = {AB-SER1-19-025//Servicio Gallego de Salud (SERGAS) and Fondo Europeo de Desarrollo Regional (FEDER)/ ; CB06/05/0085//CIBER - Consorcio Centro de Investigación Biomédica en Red/ ; }, mesh = {Humans ; *Apolipoprotein E4/blood/genetics ; *Heterozygote ; Homozygote ; Male ; Female ; Aged ; Alzheimer Disease/genetics/blood ; Middle Aged ; ROC Curve ; Genotype ; Aged, 80 and over ; }, abstract = {BACKGROUND: The APOE ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and is associated with increased risk of amyloid-related imaging abnormalities (ARIA) during anti-amyloid therapy. Accurate identification of ε4 carriers, particularly APOE ε4/ε4 individuals, is clinically relevant. This study outlines the development and validation of e4Quant, a novel turbidimetric assay for quantifying plasma ApoE4 as a non-genetic alternative to APOE genotyping. METHODS: The e4Quant test utilizes a proprietary particle-enhanced immunoturbidimetry method, employing an isoform-specific anti-ApoE4 antibody on standard chemistry analyzers. Plasma samples from 160 individuals of known APOE genotype (35 APOE ε4/ε4 homozygotes, 115 APOE ε4 heterozygotes, and 10 APOE ε4 non-carriers) were analyzed for ApoE4 and total ApoE levels. The test's discriminatory performance was assessed by ROC analysis and two-threshold classification algorithms. RESULTS: ApoE4 levels ascertained by the e4Quant test exhibited clear genotype-dependent stratification. ROC analysis indicated 100% sensitivity and specificity in distinguishing APOE ε4 carriers from non-carriers, and 88.6% sensitivity and 90.4% specificity for discriminating homozygous from heterozygous carriers. Normalizing ApoE4 to total ApoE improved classification (sensitivity 94.3%, specificity 93.9%). A combined ratio-plus-concentration approach further enhanced discrimination (sensitivity 91.4%, specificity 100%). Three ε4 homozygous samples with low ApoE4/total ApoE ratios were misclassified. DISCUSSION: The e4Quant assay offers a rapid, cost-effective, and highly accurate biochemical alternative to APOE genotyping, suitable for clinical and research settings, particularly in assessing AD risk and optimizing anti-amyloid therapeutic strategies. One subgroup of APOE ε4/ε4 subjects had unexpectedly low ApoE4 levels, raising questions about potential biological heterogeneity and its impact on Alzheimer's disease biology. CONCLUSION: The e4Quant assay is a novel alternative for genotyping to determine APOE ε4 carrier status, while also providing quantitative measurements of ApoE4 levels. Its high diagnostic accuracy, ease of use in standard clinical laboratories, and potential utility for personalized medicine in AD treatment highlight its translational value. Further studies are warranted to investigate the clinical significance of APOE ε4 expression variability and its impact on disease progression and treatment response.}, } @article {pmid40670451, year = {2025}, author = {Ali, ZH and Hassan, E and Elgamal, S and El-Rashidy, N}, title = {Developing an explainable machine learning and fog computing-based visual rating scale for the prediction of dementia progression.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {25872}, pmid = {40670451}, issn = {2045-2322}, mesh = {Humans ; *Machine Learning ; Aged ; Male ; Female ; *Dementia/diagnosis ; Disease Progression ; Cognitive Dysfunction/diagnosis ; Magnetic Resonance Imaging ; Mental Status and Dementia Tests ; Aged, 80 and over ; Neuropsychological Tests ; Middle Aged ; }, abstract = {Recently, dementia research has primarily concentrated on using Magnetic Resonance Imaging (MRI) to develop learning models in processing and analyzing brain data. However, these models often cannot provide early detection of affected brain regions. Alternatively, mental test scores such as the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) offer valuable insights into the likelihood of dementia and cognitive impairments. The main objective of this study is to introduce an innovative and dependable context-aware health monitoring system based on fog computing to measure mental impairment in the elderly population. The framework provides screening tests utilizing MMSE and MoCA to achieve accurate and real-time monitoring of cognitive function, allowing for early detection and treatment of mental disorders. To assess the effectiveness of our screening test, we evaluated a dataset comprising 450 subjects with Mild Cognitive Impairment (MCI) from Kaferelshikh University. The aggregated dataset is categorized into three classes: (1) 150 patients with MCI, (2) 150 subjects with subcortical diseases, Parkinson's Disease (PD), and (3) 150 subjects with cortical diseases, Alzheimer's Disease (AD). To accurately determine health risks, we employ an ensemble AdaBoost model, providing superior performance in accuracy, precision, recall, F-score, and Area Under the Curve (AUC). To validate the effectiveness of our Machine Learning (ML) model on unseen data, we evaluate an additional 18 subjects using the proposed scoring test, with six subjects from each class. The results indicate that our proposed ML model achieves an impressive accuracy of 0.93, outperforming the MoCA score (0.90) and MMSE score (0.83). Through our research, we demonstrate the potential of our context-aware fog computing approach in significantly enhancing early diagnosis of dementia, leveraging mental test scores as valuable indicators.}, } @article {pmid40668823, year = {2025}, author = {Castelli, V and Cesare, P and Bej, E and d'Angelo, M and Volpe, AR}, title = {Mechanistic insights into the anti-aging effects of Crocus sativus in a D-Gal-induced in vitro neural senescence model.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0320572}, pmid = {40668823}, issn = {1932-6203}, mesh = {*Crocus/chemistry ; *Galactose/pharmacology ; *Cellular Senescence/drug effects ; Animals ; *Plant Extracts/pharmacology ; Reactive Oxygen Species/metabolism ; *Aging/drug effects ; Lipid Peroxidation/drug effects ; Cell Proliferation/drug effects ; Endoplasmic Reticulum Stress/drug effects ; *Neurons/drug effects/metabolism/cytology ; beta-Galactosidase/metabolism ; Glycation End Products, Advanced/metabolism ; Malondialdehyde/metabolism ; Cell Cycle/drug effects ; Humans ; Oxidative Stress/drug effects ; Rats ; }, abstract = {BACKGROUND: The increasing number of elderly individuals has made age-related disorders a significant health concern. Aging is a natural, progressive and gradual phenomenon that leads to irreversible modifications in all molecules, cells, tissues and organs of an organism. Brain senescence is associated with increased risk of developing various neurological diseases, such as Alzheimer's disease, Parkinson's disease, and stroke. Therefore, finding effective strategies to counteract or delay brain senescence is of great importance for improving the quality of life and health span of the elderly population. Previous studies demonstrated that D-galactose is an appropriate agent to induce aging effects in in vivo and in vitro models. PURPOSE: In the present study, we evaluated anti-aging effects of a local Saffron extract (SE from Central Italy) on D-GAL-induced aging model in vitro. Based on promising preliminary results, future studies will focus on testing this specific Crocus sativus stigma preparation in animal models of aging. METHODS: The potential anti-aging effect was evaluated using assessment of cell proliferation, live-cell cytotoxicity, Beta-Galactosidase (β-GAL), lipid peroxidation, intracellular reactive oxygen species (ROS), advanced glycation end products (AGEs) and malondialdehyde (MDA) levels. Additionally, the effects of SE pretreatment were examined on cell cycle and endoplasmic reticulum stress. Additionally, we employed a novel approach to analyze deeper changes upon saffron extract treatment, which is label-free holotomography. RESULTS: Overall, our findings suggested that pretreatment with SE was protective against D-GAL-induced senescence, by counteracting oxidative and endoplasmic reticulum stress and proteins that regulate cell death. CONCLUSION: We obtained interesting results since pre-treatment with SE ameliorated overall condition, and for the first time we observed the strong anti-aging effect of SE not only in term of morphology, but also dynamics and total dry mass of cells. Overall, our work introduces a novel and promising approach to counteract or delay brain senescence, potentially improving the quality of life and health span of the elderly population.}, } @article {pmid40668694, year = {2025}, author = {Padliya, T}, title = {Breaking Barriers With Sound: Focused Ultrasound in the Brain.}, journal = {IEEE pulse}, volume = {16}, number = {3}, pages = {30-35}, doi = {10.1109/MPULS.2025.3572600}, pmid = {40668694}, issn = {2154-2317}, mesh = {Humans ; *Brain/diagnostic imaging ; Magnetic Resonance Imaging ; *Ultrasonic Therapy/methods ; }, abstract = {Focused ultrasound (FUS) is rapidly redefining the landscape of brain therapy, offering a noninvasive, highly precise alternative to traditional neurosurgical techniques. Enabled by advances in phased-array transducer technology, MRI-guided targeting and thermometry, and sophisticated treatment planning software, FUS delivers sub-millimeter accuracy through the skull while sparing surrounding tissue. This article provides a comprehensive yet accessible overview of the core technologies that make FUS possible, including phase correction for skull variability and real-time imaging for safety. We survey the broadening spectrum of clinical applications, from FDA-approved treatments for essential tremor and Parkinson's disease to investigational uses in Alzheimer's, glioblastoma, obsessive-compulsive disorder, and targeted drug delivery. Pioneering trials have demonstrated not only durable tremor control and motor improvement, but also the unique ability to deliver drugs directly to the brain and noninvasively target deep neuropsychiatric circuits.}, } @article {pmid40668687, year = {2025}, author = {Kern, R}, title = {Restoring the Brain's Rhythm: A Physics-Driven Approach to Treating Alzheimer's Disease.}, journal = {IEEE pulse}, volume = {16}, number = {3}, pages = {56-59}, doi = {10.1109/MPULS.2025.3572591}, pmid = {40668687}, issn = {2154-2317}, mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology ; *Brain/physiopathology ; *Gamma Rhythm/physiology ; }, abstract = {Alzheimer's disease (AD) has traditionally been addressed through biochemical interventions targeting amyloid and tau pathologies. However, these approaches are constrained by high costs, limited accessibility, and suboptimal efficacy. This article introduces a novel, physics-based therapeutic modality: noninvasive neuromodulation via synchronized visual and auditory stimulation to restore gamma frequency brain rhythms. The Spectris AD device, developed by Cognito Therapeutics, leverages principles of signal processing and systems engineering to drive gamma oscillations in patients with mild to moderate AD. Early clinical studies, including the OVERTURE and FLICKER trials, demonstrate promising results, such as a 77% reduction in functional decline [Alzheimer's disease co-operative study ADL (ADCS-ADL)], a 76% slowing of cognitive decline [mini mental-state exam (MMSE)], and structural brain preservation without the safety risks associated with monoclonal antibodies. The ongoing HOPE pivotal trial aims to validate these findings in a diverse U.S. population. Spectris AD exemplifies a shift from molecular to network-level interventions, offering a scalable, home-based solution that reimagines neurodegenerative treatment as a systems-engineering challenge. This article presents the engineering, clinical data, and broader implications of this pioneering approach to neurotherapeutics.}, } @article {pmid40667684, year = {2025}, author = {Gueorguieva, I and Chow, K and Chua, L and Shcherbinin, S and Zimmer, JA and Evans, CD and Wang, H and Nery, ESM and Brooks, DA and Sims, JR}, title = {Donanemab exposure-response in early symptomatic Alzheimer's disease.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70491}, pmid = {40667684}, issn = {1552-5279}, support = {//Eli Lilly and Company/ ; }, mesh = {Aged ; Female ; Humans ; Male ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacokinetics ; Disease Progression ; Dose-Response Relationship, Drug ; *Plaque, Amyloid/drug therapy ; Treatment Outcome ; }, abstract = {INTRODUCTION: These analyses aimed to identify factors impacting donanemab exposure, amyloid plaque, and clinical efficacy in early symptomatic Alzheimer's disease using a population pharmacokinetic/pharmacodynamic (PK/PD) approach. METHODS: Analyses included donanemab trial participants (NCT02624778; NCT03367403; NCT04640077; NCT04437511). Dose- and exposure-response relationships were characterized relative to amyloid plaque lowering using indirect response PK/PD and disease progression models. RESULTS: Donanemab population PK was described by a biphasic distribution with an estimated terminal elimination half-life of approximately 12.1 days for a typical participant (72 kg body weight, 1:2560 maximum antidrug antibody [ADA] titer). Amyloid reduction was associated with maintaining median serum donanemab concentrations over 15 µg/mL (95% confidence interval: 8.54, 18.0). After completing active treatment, simulations showed an estimated plaque reaccumulation rate (median, 95% confidence interval) of 2.8 (2.16, 3.11) Centiloids/year. The donanemab disease progression model showed a clear treatment effect. DISCUSSION: These donanemab models can inform dosing strategies in future clinical trials. HIGHLIGHTS: Weight-based and flat dosing had similar exposure metrics; flat dosing was adopted. Donanemab exposure was influenced by weight and titer (not clinically relevant). 2.8 Centiloids/year amyloid reaccumulation rate observed upon donanemab treatment completion. Around 30% reduction in disease progression rate on treatment for integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB).}, } @article {pmid40667349, year = {2025}, author = {Young, JI and Varma, A and Gomez, L and Schmidt, MA and Kunkle, B and Wang, L and Martin, ER}, title = {Sex-Stratified Transcriptomic Meta-Analysis of Alzheimer's Disease Reveal Brain Region and Sex Specific Dysregulation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.25.661596}, pmid = {40667349}, issn = {2692-8205}, abstract = {OBJECTIVE: Alzheimer disease (AD) is a neurodegenerative disorder leading to cognitive decline. Despite growing recognition of sex differences in epidemiology, symptomatology, and clinical outcomes of AD, the molecular mechanisms underlying these variations remain poorly defined. We performed transcriptome association studies of AD aiming to identify sex-specific and sex-dependent transcriptomic profiles that could provide insights into the molecular mechanisms underlying sex differences in AD pathogenesis. METHODS: We conducted a meta-analysis of bulk-RNAseq data derived from human postmortem brain studies. Specifically, we analyzed gene expression differences between individuals diagnosed with AD and non-cognitively impaired (NCI) individuals across two key brain regions: the prefrontal cortex and the temporal lobe. We performed stratified differential expression analyses separately in males and females, alongside combined analyses across sexes. Additionally, we assessed the data in relation to known AD genes, proteomic studies, and drug repurposing opportunities. RESULTS: Beyond the genes commonly dysregulated across both sexes, our meta-analyses identified multiple differentially expressed genes (DEGs) between AD and NCI that are either altered in only one sex or show different effects between sexes. Some genes are known AD genes from genetic studies, but others are novel. Correlation with proteomic data suggests that these transcriptional differences have functional significance, potentially contributing to the biological mechanisms underlying sex differences observed in AD. Finally, we identify drug compounds that are potential candidates for treatment. INTERPRETATION: Our findings enhance our understanding of sex-related differences in disease etiology and progression, and underscore the importance of incorporating sex as a critical variable in transcriptomic studies of AD. These insights help pave the way for more precise, personalized medicine approaches that account for sex-specific molecular mechanisms.}, } @article {pmid40666518, year = {2025}, author = {Liao, Y and Xu, F and Yan, Y and Zhou, S and Liu, N and Dou, B and Srinivasan, N and Wang, W and Zhu, X and Ye, J and Xu, Y}, title = {Chronic ethanol administration exacerbates memory loss by altering N6-methyladenosine-mediated epigenetic signaling.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1455994}, pmid = {40666518}, issn = {1664-3224}, support = {RF1 AG083811/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Adenosine/analogs & derivatives/metabolism ; *Ethanol/administration & dosage/adverse effects/toxicity ; *Epigenesis, Genetic/drug effects ; Mice ; *Memory Disorders/genetics/metabolism/etiology/chemically induced ; Mice, Transgenic ; Signal Transduction/drug effects ; Disease Models, Animal ; Male ; Alzheimer Disease/genetics/metabolism ; }, abstract = {BACKGROUND: Chronic alcohol use disorder (AUD) is recognized as one of the most critical risk factors for the progression of Alzheimer's disease (AD). Epigenetic and neuroimmune alterations are closely associated with the development of memory impairment related to AUD and AD. METHODS: Adult APP/PS1 transgenic mice received intermittently intraperitoneal injections of ethanol (EtOH, 2.5 g/kg, i.p.) or vehicle with two "drug" treatment days, and one and two "drug-free" days every 7 days for 10 weeks. The novel object recognition (NOR) and Y-maze tests were performed to determine whether chronic ethanol treatment exacerbated memory impairment in these mice. The brain tissues were collected for pathological changes through MeRIP/RNA-sequence analyses and molecular biological assays. RESULTS: The results suggested that chronic intermittent ethanol (CIE) treatment for 10 weeks exacerbated sporadic and spatial memory deficits in NOR and Y-maze tests in the APP/PS1 mice. The pathological assays revealed that CIE procedure increased Aβ plaque burden in the brain of the AD mice, which were consistent with memory behavioral deficits. The subsequent MeRIP/RNA sequence analyses showed that two genes, e.g. Rbm15b and Hnrnpa2b1, were related to N6-methyladenosine (m[6]A) methylation that plays an important role in the development of memory loss. These results were further supported by molecular biological and mRNA-microRNA-lncRNA ceRNA network analyses that demonstrated that the increased Rbm15b and decreased Hnrnpa2b1 were involved in synaptic dysfunction and neuroinflammation in CIE-induced memory impairment in these AD mice. CONCLUSIONS: The conclusion is drawn that m[6]A mediated epigenetic dysfunction and immune cells infiltration participate in chronic alcohol use disorder related memory loss in AD mice.}, } @article {pmid40666174, year = {2025}, author = {Arya, P and Sharma, V and Singh, P and Thapliyal, S and Sharma, M}, title = {Bacterial endotoxin-lipopolysaccharide role in inflammatory diseases: An overview.}, journal = {Iranian journal of basic medical sciences}, volume = {28}, number = {5}, pages = {553-564}, pmid = {40666174}, issn = {2008-3866}, abstract = {Despite advancements in antimicrobial and anti-inflammatory treatments, inflammation and its repercussions continue to pose a considerable challenge in medicine. Acute inflammation may cause life-threatening conditions like septic shock, while chronic inflammation leads to tissue degeneration and impaired function. Lipopolysaccharides (LPS), a well-known pathogenic trigger contributing to several dysfunctions, is a crucial part of the outer membrane of gr-negative bacteria. LPS are well-known for eliciting acute inflammatory responses by activating a pathogen-associated molecular pattern (PAMP), which stimulates the innate immune system and triggers local or systemic inflammatory responses. LPS also activate numerous intracellular molecules that modulate the expression of a wide range of inflammatory mediators. These mediators subsequently initiate or exacerbate various inflammatory processes. Beyond immune cells, LPS can also activate non-immune cells, leading to inflammatory reactions. These excessive inflammatory responses are often detrimental and typically result in chronic and progressive inflammatory diseases, including neurodegenerative, cardiovascular diseases, and cancer. This review delves into the mechanisms by which the bacterial endotoxin LPS contribute to multiple inflammatory diseases. These insights into LPS signaling pathways could inform the design of new treatment strategies such as TLR4, NLRP3, HMGA1, MAPK, and NF-kB inhibitors. This enables precise targeting of inflammation-related processes in disease management.}, } @article {pmid40665449, year = {2025}, author = {Chen, BK and Hunsberger, HC and Whye, A and Matthews, LC and Yook, A and Willner, MJ and Logan, RW and Johns, S and Weisblum, E and Denny, CA}, title = {Combinatorial targeting of NMDARs and 5-HT4Rs exerts beneficial effects in a mouse model of Alzheimer's disease.}, journal = {Alzheimer's research & therapy}, volume = {17}, number = {1}, pages = {160}, pmid = {40665449}, issn = {1758-9193}, mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Mice ; Male ; Disease Models, Animal ; Female ; *Receptors, Serotonin, 5-HT4/metabolism ; Mice, Transgenic ; *Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; *Serotonin 5-HT4 Receptor Agonists/pharmacology/administration & dosage ; *Benzofurans/pharmacology/administration & dosage ; *Excitatory Amino Acid Antagonists/pharmacology ; Amyloid beta-Protein Precursor/genetics ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia. There are limited approved medications that delay cognitive decline or lessen neuropsychiatric symptoms. Numerous clinical trials for AD using a single drug administration have failed to meet therapeutic endpoints, which is most likely due to the complexity of AD. A multimodal therapeutic intervention is more likely to improve symptoms by targeting multiple targets implicated in AD. Here, we investigated if targeting both N-Methyl-D-aspartic acid receptors (NMDARs) and serotonin type 4 receptors (5-HT4R) may have beneficial effects in a mouse model of AD, as they have separately been shown to improve cognition and/or mood. METHODS: Male and female control (Ctrl) or APP/PS1 mice were administered single, intermittent, or chronic administration of 1) saline; 2) (R,S)-ketamine, an NMDAR antagonist; 3) prucalopride, a 5-HT4R agonist; or 4) (R,S)-ketamine + prucalopride to simultaneously target co-morbid neuropsychiatric and cognitive deficits. Behavioral assays were then administered to measure cognition, perseverative behavior, hyponeophagia, and/or sleep. Brains were processed for glial fibrillary acidic protein (GFAP) immunohistochemistry. RESULTS: Single and chronic administration of (R,S)-ketamine + prucalopride administration improved cognitive decline by increasing memory retrieval in a contextual fear conditioning (CFC) paradigm in APP/PS1 mice. Drug efficacy was less effective in females than in males and was age dependent. Hippocampal GFAP immunoreactivity was decreased by chronic (R,S)-ketamine + prucalopride treatment in females. CONCLUSIONS: Our results indicate that combined administration of (R,S)-ketamine + prucalopride is a novel multimodal therapeutic strategy to treat cognitive decline in AD. Future work will further characterize these interactions with the goal of clinical development.}, } @article {pmid40665063, year = {2025}, author = {Yu, L and Yang, X and Lei, HP and Hu, YT and Wu, LN and Zhou, SY and Jin, F}, title = {Multiple Mechanisms and Therapeutic Strategies for the Involvement of AMPK in the Development of Alzheimer's Disease.}, journal = {Molecular neurobiology}, volume = {62}, number = {12}, pages = {15390-15409}, pmid = {40665063}, issn = {1559-1182}, support = {ZK [2023]058//the Key Projects of Basic Research Program of the Science and Technology Department of Guizhou Province/ ; 82060727//National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease/enzymology/drug therapy/therapy/pathology/metabolism ; Humans ; *AMP-Activated Protein Kinases/metabolism ; Animals ; Signal Transduction ; Amyloid beta-Peptides/metabolism ; Oxidative Stress ; }, abstract = {Alzheimer's disease (AD) is a major cause of dementia, a life-threatening condition for which there is currently no cure. Currently, the treatment of AD focuses on reducing the accumulation of amyloid β-protein (Aβ) and the phosphorylation of Tau proteins (Tau). However, simply reducing pathological features does not completely improve AD. Therefore, there is an urgent need to explore a target that regulates AD-related pathologies and highlights its potential as a novel therapeutic target. Recent studies suggest that oxidative stress, neuroinflammation, autophagy dysfunction, and energy metabolism alterations are associated with the development of AD. Reviewing previous data, we found that AMP-activated protein kinase (AMPK) not only acts as a cellular energy sensor to influence the progression of AD, but also activation of AMPK affects the pathologic processes above. In this review, we provide an update on activating the AMPK pathway with targeting in AD therapy. Finally, research has shown that compounds can activate the AMPK pathway to affect a series of cellular processes and improve AD. We propose that AMPK activation represents a paradigm-shifting strategy for AD therapy by simultaneously targeting multiple pathological cascades, although challenges in isoform-specific activation and brain delivery warrant further investigation.}, } @article {pmid40665048, year = {2025}, author = {Imam, F and Saloner, R and Vogel, JW and Krish, V and Abdel-Azim, G and Ali, M and An, L and Anastasi, F and Bennett, D and Pichet Binette, A and Boxer, AL and Bringmann, M and Burns, JM and Cruchaga, C and Dage, JL and Farinas, A and Ferrucci, L and Finney, CA and Frasier, M and Hansson, O and Hohman, TJ and Johnson, ECB and Kivimaki, M and Korologou-Linden, R and Ruiz Laza, A and Levey, AI and Liepelt-Scarfone, I and Lu, L and Mattsson-Carlgren, N and Middleton, LT and Nho, K and Oh, HS and Petersen, RC and Reiman, EM and Robinson, O and Rothstein, JD and Saykin, AJ and Shvetcov, A and Slawson, C and Smets, B and Suárez-Calvet, M and Tijms, BM and Timmers, M and Vieira, F and Vilor-Tejedor, N and Visser, PJ and Walker, KA and Winchester, LM and Wyss-Coray, T and Yang, C and Bose, N and Lovestone, S and , }, title = {The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging.}, journal = {Nature medicine}, volume = {31}, number = {8}, pages = {2556-2566}, pmid = {40665048}, issn = {1546-170X}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; U01 AG079847/AG/NIA NIH HHS/United States ; RF1 AG053303/AG/NIA NIH HHS/United States ; R01 AG053960/AG/NIA NIH HHS/United States ; R01 AG057911/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; RF1 AG057471/AG/NIA NIH HHS/United States ; R01 AG061800/AG/NIA NIH HHS/United States ; R01 AG057339/AG/NIA NIH HHS/United States ; R01 AG069453/AG/NIA NIH HHS/United States ; U01 AG058922/AG/NIA NIH HHS/United States ; R01 AG044546/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; U19 AG063911/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; RF1 AG058501/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; RF1 AG062553/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; U01 AG045390/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; U54 NS092089/NS/NINDS NIH HHS/United States ; R01 AG064227/AG/NIA NIH HHS/United States ; RF1 AG057470/AG/NIA NIH HHS/United States ; R01 AG083740/AG/NIA NIH HHS/United States ; R01 AG056477/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/metabolism/blood ; *Proteomics/methods ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Drug Discovery ; *Aging/metabolism/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Parkinson Disease/metabolism ; Alzheimer Disease/metabolism ; Frontotemporal Dementia/metabolism ; }, abstract = {More than 57 million people globally suffer from neurodegenerative diseases, a figure expected to double every 20 years. Despite this growing burden, there are currently no cures, and treatment options remain limited due to disease heterogeneity, prolonged preclinical and prodromal phases, poor understanding of disease mechanisms, and diagnostic challenges. Identifying novel biomarkers is crucial for improving early detection, prognosis, staging and subtyping of these conditions. High-dimensional molecular studies in biofluids ('omics') offer promise for scalable biomarker discovery, but challenges in assembling large, diverse datasets hinder progress. To address this, the Global Neurodegeneration Proteomics Consortium (GNPC)-a public-private partnership-established one of the world's largest harmonized proteomic datasets. It includes approximately 250 million unique protein measurements from multiple platforms from more than 35,000 biofluid samples (plasma, serum and cerebrospinal fluid) contributed by 23 partners, alongside associated clinical data spanning Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This dataset is accessible to GNPC members via the Alzheimer's Disease Data Initiative's AD Workbench, a secure cloud-based environment, and will be available to the wider research community on 15 July 2025. Here we present summary analyses of the plasma proteome revealing disease-specific differential protein abundance and transdiagnostic proteomic signatures of clinical severity. Furthermore, we describe a robust plasma proteomic signature of APOE ε4 carriership, reproducible across AD, PD, FTD and ALS, as well as distinct patterns of organ aging across these conditions. This work demonstrates the power of international collaboration, data sharing and open science to accelerate discovery in neurodegeneration research.}, } @article {pmid40664126, year = {2025}, author = {Jangid, K and Devi, B and Kumar, N and Upadhayay, S and Kumar, V and Thareja, S and Kumar, V}, title = {ML-based prediction to experimental validation: Development of dihydroquinazoline based multi-potent ligands as anti-Alzheimer's agents.}, journal = {Computers in biology and medicine}, volume = {196}, number = {Pt A}, pages = {110762}, doi = {10.1016/j.compbiomed.2025.110762}, pmid = {40664126}, issn = {1879-0534}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Monoamine Oxidase/chemistry/metabolism ; *Monoamine Oxidase Inhibitors/chemistry/pharmacology ; *Quinazolines/chemistry/pharmacology ; Molecular Docking Simulation ; Acetylcholinesterase/chemistry/metabolism ; Amyloid beta-Peptides/chemistry/metabolism/antagonists & inhibitors ; *Machine Learning ; Ligands ; }, abstract = {Alzheimer's disease (AD) is a multifactorial neurological disorder accounting for the cognitive decline in the patients. The disease is linked to numerous pathological factors including hyperactivation of acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B), accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain etc. The single-target medications already available in the market are found to be ineffective and the research focus is shifting towards the development of multitargeting agents. In order to find a multi-potent inhibitor against AChE, MAO-B and Aβ1-42, in the present study we employed a machine learning-based tool, PyRMD, to screen an in-house generated library of dihydroquinazoline derivatives. This screening process identified six promising compounds, KV-271, KV-832, KV-968, KV-1131, KV-1159, KV-1234 with dual inhibition potential against AChE and MAO-B enzymes. In the docking studies, these compounds showed good interactions at the active cavity of the AChE and MAO-B comparable to the standard inhibitors donepezil (AChE) and pargyline (MAO-B). To validate these predictions, the six identified compounds were synthesized and subjected to in vitro enzymatic assays. All the six compounds displayed significant inhibitory activity, with IC50 values below 5 μM for both AChE and MAO-B. Amongst these compounds, KV-1131 and KV-1234 were found to be the most potent inhibitors with IC50 values of 0.93 μM and 0.85 μM against AChE and IC50 values of 1.17 μM and 0.79 μM against MAO-B, respectively. In addition, KV-1131 and KV-1234 exhibited inhibitory activity against Aβ1-42 self-aggregation inhibition of 34.79 % and 45.70 %, respectively, after 48 h of incubation. Both KV-1131 and KV-1234 were found to be non-toxic up to 10 μM concentration and showed neuroprotective potential against 6-hydroxydopamine induced neurotoxicity in the SHSY-5Y cells. Thus, KV-1131 and KV-1234 were identified as potent leads that can be developed as drug candidates for the treatment of Alzheimer's disease.}, } @article {pmid40663501, year = {2025}, author = {Bian, Z and Liu, X and Li, J and Hu, S and Choo, YM and Zhao, Z and Hu, J and Ji, K and Hamann, MT and Wang, X and Wang, X}, title = {Bletistrosides M-X, Anti-Alzheimer's Disease Compounds from the Tubers of Bletilla striata.}, journal = {Journal of natural products}, volume = {88}, number = {7}, pages = {1752-1765}, pmid = {40663501}, issn = {1520-6025}, support = {R01 AT007318/AT/NCCIH NIH HHS/United States ; R01 GM145845/GM/NIGMS NIH HHS/United States ; }, mesh = {*Orchidaceae/chemistry ; *Alzheimer Disease/drug therapy ; Molecular Structure ; *Plant Tubers/chemistry ; Animals ; Amyloid beta-Peptides ; Humans ; Glycosides/pharmacology/chemistry/isolation & purification ; }, abstract = {Twelve new compounds, bletistrosides M-X (1-12), including five glucosyloxybenzyl 2-isobutylmalates (1-5), along with four neolignan glycosides (6-9), two phenanthrene derivatives (10-11), and one bibenzyl derivative (12), were isolated from the tubers of Bletilla striata (B. striata). The structures and absolute configurations of the undescribed compounds were elucidated on the basis of spectroscopic data analysis, experimental and calculated electronic circular dichroism data, chiroptical analysis, and chemical derivatizations. In silico, compounds 2, 3, and 12 bound well to Aβ1-42. Compounds 2, 3, and 12 significantly delayed the paralysis phenotype in CL4176 worms compared to controls. Higher nonparalysis rates were observed in these treatment groups (5 μM for compound 2; 25, 50 μM for compounds 2, 3 and 12), suggesting their potential role in anti-Alzheimer's disease.}, } @article {pmid40662861, year = {2025}, author = {Feng, J and Shi, H and Da, M and Beg, MF and Cao, J}, title = {A Latent-Class Model for Time-To-Event Outcomes and High-Dimensional Imaging Data.}, journal = {Statistics in medicine}, volume = {44}, number = {15-17}, pages = {e70186}, pmid = {40662861}, issn = {1097-0258}, support = {RGPIN-2021-02963//Natural Sciences and Engineering Research Council of Canada/ ; RGPIN-2023-04057//Natural Sciences and Engineering Research Council of Canada/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging ; *Magnetic Resonance Imaging/statistics & numerical data/methods ; Neuroimaging/methods/statistics & numerical data ; Computer Simulation ; Algorithms ; *Latent Class Analysis ; Proportional Hazards Models ; Logistic Models ; Disease Progression ; Brain/diagnostic imaging ; *Models, Statistical ; }, abstract = {Structural magnetic resonance imaging (MRI) is one of the primary predictors of Alzheimer's disease risk, enabling the identification of patients with similar risk profiles for precision medicine treatment. Motivated by the need for flexible modeling in AD research, we propose a latent-class model that addresses the heterogeneity within study populations. This model allows for varying relationships between covariates and survival outcomes, accommodating the dynamics of AD progression. The imaging predictors are characterized by bivariate splines over triangulation to accommodate the irregular domain of the brain images. We develop a generalized expectation-maximization (EM) algorithm that combines the computational methods for logistic regression and penalized proportional hazards models to implement the proposed approach. We demonstrate the advantages of the proposed method through extensive simulation studies and provide an application to the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, which helps to reveal different subtypes or stages of the disease process in Alzheimer's Disease.}, } @article {pmid40662560, year = {2025}, author = {Talluri, S}, title = {Computational Design of Drugs for Epilepsy using a Novel Guided Evolutionary Algorithm for Enhanced Blood Brain Barrier Permeability.}, journal = {Central nervous system agents in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715249385792250709073502}, pmid = {40662560}, issn = {1875-6166}, abstract = {INTRODUCTION: Epilepsy is a common disorder of the Central Nervous System (CNS). The rational design of small-molecule drugs for disorders of the CNS is a difficult process because the majority of small molecules are unable to cross the Blood-Brain-Barrier. An efficient method for the design of inhibitors that have high permeability through the Blood-Brain-Barrier has the potential for application in drug design for CNS disorders such as Addiction, Alzheimer's disease, Bipolar disorder, Depression, Epilepsy, Gliomas, and Tuberculous meningitis. METHOD: Supervised learning was used to model the Blood-Brain-Barrier permeability of drugs like small organic molecules. This information was utilized to guide an evolutionary algorithm for the design of inhibitors with increased affinity for the target as well as higher Blood-Brain-Barrier permeability. RESULTS: The ligands designed with guided evolution were predicted to have higher binding affinity for the target as well as higher permeability across the Blood-Brain-Barrier compared to an evolutionary algorithm without the guidance. The guided evolutionary method was applied to design a set of drug-like ligands that were predicted to bind to GABA-T with high affinity, to be BBB permeable, and to be chemically synthesizable. DISCUSSION: Despite the availability of several drugs that are approved for the treatment of epilepsy, there are many cases that do not respond to available drugs or experience adverse effects. The novel ligands designed as part of this work have the potential to address the limitations of available drugs. CONCLUSION: Guided evolution is an efficient computational approach for the design of CNS drugs. The de novo design of drugs by application of the guided evolution algorithm, developed as part of this work, has resulted in the generation of ligands that are potential drugs for the cure of epilepsy. However, the effectiveness of these drugs for the cure of epilepsy has to be validated experimentally.}, } @article {pmid40662425, year = {2025}, author = {Shen, J and Isenberg, D and Linn, KA and Hubbard, RA}, title = {Integrating Misclassified EHR Outcomes With Validated Outcomes From a Non-Probability Sample.}, journal = {Statistics in medicine}, volume = {44}, number = {15-17}, pages = {e70127}, pmid = {40662425}, issn = {1097-0258}, support = {R21AG075574/AG/NIA NIH HHS/United States ; U19AG066567/AG/NIA NIH HHS/United States ; U01 AG006781/AG/NIA NIH HHS/United States ; U01AG006781/AG/NIA NIH HHS/United States ; R21 AG075574/AG/NIA NIH HHS/United States ; U19 AG066567/AG/NIA NIH HHS/United States ; }, mesh = {*Electronic Health Records/statistics & numerical data ; Humans ; Alzheimer Disease/pathology ; Longitudinal Studies ; Dementia ; Computer Simulation ; Bias ; Models, Statistical ; Selection Bias ; Washington ; *Outcome Assessment, Health Care/statistics & numerical data/methods ; }, abstract = {Although increasingly used for research, electronic health records (EHR) often lack a gold-standard assessment of key data elements. Linking EHRs to other data sources with higher-quality measurements can improve statistical inference, but such analyses must account for selection bias if the linked data source arises from a non-probability sample. We propose a set of novel estimators targeting the average treatment effect (ATE) that combine information from binary outcomes measured with error in a large, population-representative EHR database with gold-standard outcomes obtained from a smaller validation sample subject to selection bias. We evaluate our approach in extensive simulations and an analysis of data from the Adult Changes in Thought (ACT) study, a longitudinal study of incident dementia in a cohort of Kaiser Permanente Washington members with linked EHR data. For a subset of deceased ACT participants who consented to brain autopsy prior to death, gold-standard measures of Alzheimer's disease neuropathology are available. Our proposed estimators reduced bias and improved efficiency for the ATE, facilitating valid inference with EHR data when key data elements are ascertained with error.}, } @article {pmid40662084, year = {2025}, author = {Kunevičius, A and Vijaya, AK and Atzeni, A and Mingaila, J and Šimoliūnė, I and Jamontas, R and Keževičiūtė, E and Gueimonde, M and Meškys, R and Baltriukienė, D and Arboleya, S and Burokas, A}, title = {Intermittent supplementation with Akkermansia muciniphila and galactooligosaccharides modulates Alzheimer's disease progression, gut microbiota, and colon short-chain fatty acid profiles in mice.}, journal = {Frontiers in aging neuroscience}, volume = {17}, number = {}, pages = {1617980}, pmid = {40662084}, issn = {1663-4365}, abstract = {BACKGROUND: Bidirectional communication and mutual regulation between the gastrointestinal tract and the CNS is facilitated through the gut-brain axis. Recent studies have found reduced diversity of the gut microbiota in Alzheimer's disease (AD) patients, and animal models suggest microbial involvement in amyloid beta peptide (Aβ) accumulation. Modulation of the gut microbiota by new-generation probiotics represents a novel treatment strategy to alleviate the symptoms and slow the progression of AD. METHODS: In this study, the therapeutic effect of the probiotic Akkermansia muciniphila and the prebiotic galactooligosaccharides (GOS) was investigated in the APP/PS1 mouse model. After 7 months of triweekly administration, we evaluated physiological parameters, glucose metabolism, and behavioral outcomes. Additionally, we assessed gut microbiota diversity and composition, short-chain fatty acid (SCFA) concentrations in the cecum, Aβ load in the hippocampus and prefrontal cortex, and microglial abundance in the hippocampus. RESULTS: A. muciniphila and GOS administration normalized fasting glucose levels, glucose metabolism, and intestinal transit time to wild-type levels. Furthermore, supplementation reduced anxiety, improved long-and short-term memory, and partially restored activity levels. It also regulated SCFA concentrations in the cecum, improved the richness of the gut microbiota, and normalized abundance of microglia in the hippocampus, indicating reduced neuroinflammation. CONCLUSION: These findings suggest that long-term administration of A. muciniphila and GOS effectively improves metabolic health and modulates symptoms of AD in the APP/PS1 mouse model.}, } @article {pmid40661491, year = {2025}, author = {Santana, RA and McWhirt, JM and Brewer, GJ}, title = {Treatment of age-related decreases in GTP levels restores endocytosis and autophagy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.09.658689}, pmid = {40661491}, issn = {2692-8205}, abstract = {Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimer's model mice and a novel genetically encoded fluorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free-GTP co-localized in the mitochondria decreased with age accompanied by the accumulation of free-GTP labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while bafilomycin inhibition of autophagy raised GTP levels. 24 hr. supplementation of aged neurons with the NAD precursor nicotinamide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endocytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal Aβ aggregates and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy deficits that impair autophagy and endocytosis. GTP deficits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path.}, } @article {pmid40661469, year = {2025}, author = {Khajuria, P and Kour, D and Sharma, K and Singh, L and Banoo, R and Manhas, D and Ramajayan, P and Nandi, U and Bharate, S and Ahmed, Z and Kumar, A}, title = {Bisdemethoxycurcumin mitigates Alzheimer disease pathology through autophagy-mediated reduction of senescence and amyloid beta.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661469}, issn = {2692-8205}, abstract = {AD pathology is accompanied by increased senescence and reduced levels of autophagy in the brain. We investigated whether pharmacologically inducing autophagy could alter the senescent phenotype and help ameliorate AD pathology. We discovered that Bisdemethoxycurcumin (BDMC), a natural compound found in Curcuma longa, stimulates autophagy in primary astrocytes. We found that autophagy and senescence exhibit an inverse relationship in aging astrocytes, with increased expression of senescent proteins and downregulation of autophagic proteins. However, treatment of aged astrocytes with BDMC reversed the senescent phenotype by ameliorating the impaired autophagy. Interestingly, the senescent phenotype persisted when autophagy was downregulated by knockdown of AMPK. Additionally, BDMC-induced autophagy aided in the removal of amyloid beta that was administered externally to the astrocytes. Further, to validate these results in a mouse model of AD, we confirmed that BDMC can significantly penetrate the blood-brain barrier (BBB) in mice. Therefore, we administered 50 and 100 mg/kg b.w. of BDMC to transgenic 3xTg-AD mice for two months. In their hippocampus, the Control 3xTg-AD animals showed more senescent cells and lower autophagy levels. In contrast, autophagic proteins were significantly upregulated while senescence indicators, such as senescence-associated secretory phenotype (SASP) proteins, were sharply downregulated in the brain of treated animals. Additionally, we discovered that the treated mice's hippocampus had a significantly lower amyloid beta load. These molecular changes in the brain were ultimately reflected in the improved working memory and neuromuscular coordination behavior of mice treated with BDMC. This study warrants further evaluation of BDMC for the management of AD.}, } @article {pmid40661460, year = {2025}, author = {Falvey, A and Palandira, SP and Chaudhry, S and Tynan, A and Consolim-Colombo, FM and Metz, CN and Brines, M and Chang, EH and Chavan, SS and Tracey, KJ and Pavlov, VA}, title = {The cholinergic drug galantamine ameliorates acute and subacute peripheral and brain manifestations of acute respiratory distress syndrome in mice.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661460}, issn = {2692-8205}, support = {R01 GM121102/GM/NIGMS NIH HHS/United States ; R01 GM128008/GM/NIGMS NIH HHS/United States ; R35 GM118182/GM/NIGMS NIH HHS/United States ; }, abstract = {Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute lung injury (ALI), which is a common cause of respiratory failure and high mortality in critically ill patients. Long-term mortality and brain dysfunction have been documented in ARDS patients after hospital discharge. Inflammation plays a key role in ALI/ARDS pathogenesis. Neural cholinergic signaling regulates cytokine responses and inflammation. Here, we studied the effects of galantamine, an approved cholinergic drug (for Alzheimer's disease) on ALI/ARDS severity and inflammation in mice, using a clinically relevant mouse model induced by intratracheal administration of hydrochloric acid and lipopolysaccharide. Mice were treated 30 mins prior to each insult with vehicle or galantamine (4 mg/kg, i.p.). Galantamine treatment significantly decreased bronchoalveolar lavage (BAL) and serum TNF, IL-1β, and IL-6 levels, as well as BAL total protein and myeloperoxidase and lung histopathology in ALI/ARDS mice. In addition, galantamine improved the functional state of mice with ALI/ARDS during a 10-day monitoring and attenuated lung injury and indices of brain inflammation at 10 days. These findings support further studies utilizing this approved cholinergic drug in therapeutic strategies for ARDS and its subacute sequelae.}, } @article {pmid40661442, year = {2025}, author = {Jayarathne, H and Manchanayake, DH and Chimienti, N and Kadri, O and Gurdziel, K and Kim, S and Jang, H and Ginsburg, BC and Miller, RA and Yakar, S and Sadagurski, M}, title = {Canagliflozin reprograms the aging hippocampus in genetically diverse UM-HET3 mice and attenuates Alzheimer's-like pathology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.1101/2025.06.10.658747}, pmid = {40661442}, issn = {2692-8205}, abstract = {Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana's potential to combat brain aging and AD through sex-specific mechanisms.}, } @article {pmid40661313, year = {2025}, author = {Mervosh, N and Devi, G}, title = {Estrogen, menopause, and Alzheimer's disease: understanding the link to cognitive decline in women.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1634302}, pmid = {40661313}, issn = {2296-889X}, abstract = {BACKGROUND: Women face a significantly higher lifetime risk of developing Alzheimer's disease (AD) than men. This disparity is often attributed to longer female longevity, but growing evidence suggests a multifactorial origin, including hormonal, vascular, and immunologic contributions. Estrogen plays a critical neuroprotective role across multiple systems implicated in AD pathogenesis, including synaptic plasticity, mitochondrial function, and cerebrovascular integrity. However, clinical trials investigating hormone therapy (HT) for AD prevention have yielded mixed results, in part due to variability in study populations, timing of intervention, and formulation of hormones. AIMS/METHODS: This review examines the biological rationale for estrogen's role in cognitive aging, synthesizes clinical and translational data on hormone therapy and AD risk, and highlights the importance of vascular comorbidity, including cerebral small vessel disease, in mediating AD pathology. CONCLUSION: We propose that estrogen's neuroprotective potential may be best realized in personalized treatment frameworks that account for age, timing, APOE genotype, and vascular burden. Interpretation of estrogen's role in AD is further complicated by variability in diagnostic criteria, which may contribute to conflicting findings across studies. Recognition of menopause-related cognitive impairment as an early, hormonally modulated risk state may offer additional opportunity for timely intervention. Addressing this complexity is essential to refining AD prevention strategies in midlife women.}, } @article {pmid40661291, year = {2025}, author = {Seiger, R and Fierlinger, P}, title = {Predicting conversion from mild cognitive impairment to Alzheimer's disease using a Vision Transformer and hippocampal MRI slices.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40661291}, support = {U19 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Convolutional neural networks (CNNs) have been the standard for computer vision tasks and are frequently applied in medical conditions, such as in Alzheimer's disease (AD). Recently, Vision Transformers (ViTs) have been introduced, which provide a strong alternative to CNNs by discarding the convolution approach in favor of the attention mechanism. This allows modeling global and distant relationships within distinct parts of an image without relying on the strong inductive biases present in CNNs. A common precursor stage of AD is a syndrome called mild cognitive impairment (MCI). However, not all individuals diagnosed with MCI progress to AD. The establishment of reliable classification models that predict converters versus non-converters would be a valuable tool to support clinical decision-making, such as enabling early treatment. Hence, in this investigation a transfer learning approach was used by applying a pretrained ViT model, fine-tuned on the ADNI dataset comprising 575 subjects with MCI. We included baseline T1-weighted structural MRI data from 299 stable MCI and 276 progressive MCI individuals, who developed Alzheimer's disease within 36 months. Inputs to the model were three normalized axial slices covering areas of the hippocampal region, consisting of the combined gray and white matter segmentations. The final model was evaluated over multiple runs to obtain stable performance estimates, yielding an average area under the receiver operating characteristic curve (AUC-ROC) on the test set of 0.74 ± 0.02 (mean ± SD), an accuracy of 0.69 ± 0.03, a sensitivity of 0.65 ± 0.07, a specificity of 0.72 ± 0.06, and a F1-score for the pMCI class of 0.67 ± 0.04. By specifically focusing on axial slices covering the hippocampal region, we aimed to target the brain structure often reported as being the first affected by the disease, while our results indicate that a ViT approach achieves reasonable classification accuracy for predicting the conversion from MCI to AD.}, } @article {pmid40660741, year = {2025}, author = {McCullough, A and Chen, CD and Gordon, BA and Joseph-Mathurin, N and Jack, CR and Koeppe, R and Hornbeck, R and Koudelis, D and McKay, NS and Hobbs, DA and Flores, S and Keefe, SJ and Aggarwal, NT and Allegri, RF and Berman, SB and Bird, T and Black, SE and Brooks, WS and Chhatwal, JP and Day, GS and Farlow, MR and Fox, NC and Gauthier, S and Honig, LS and Hsiung, GY and Jucker, M and Levin, J and Masellis, M and Masters, C and Mendez, PC and Ringman, JM and Snider, BJ and Salloway, S and Schofield, PR and Shimada, H and Suzuki, K and van Dyck, CH and Klein, G and Clifford, DB and Cruchaga, C and Hassenstab, J and Li, Y and McDade, E and Mills, S and Morris, JC and Perrin, RJ and Supnet-Bell, C and Wang, G and Xiong, C and Bateman, RJ and Benzinger, TLS and , }, title = {Regional effects of gantenerumab on neuroimaging biomarkers in the DIAN-TU-001 trial.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70347}, pmid = {40660741}, issn = {1552-5279}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; //F. Hoffman-LaRoche Ltd/ ; T32AG078117-01/GF/NIH HHS/United States ; //F. Hoffman-LaRoche Ltd./ ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01 AG046179/AG/NIA NIH HHS/United States ; R01AG053267-S1/NH/NIH HHS/United States ; R01AG053267-S2/NH/NIH HHS/United States ; R01AG053267/NH/NIH HHS/United States ; A2022013F//BrightFocus Foundation/ ; AARFD-20-681815//N.J.M./ ; U01AG042791/GF/NIH HHS/United States ; //GHR Foundation/ ; AARF-21-722077/ALZ/Alzheimer's Association/United States ; K01 AG080123/AG/NIA NIH HHS/United States ; T32 AG078117/AG/NIA NIH HHS/United States ; 1K01AG080123//N.J.M./ ; R01 AG053267/AG/NIA NIH HHS/United States ; T32AG078117-01/NH/NIH HHS/United States ; //Avid Radiopharmaceuticals/ ; //Eli Lilly and Company/ ; U01AG042791-S1/NH/NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; R01AG046179/NH/NIH HHS/United States ; //Cerveau Technologies, Cogstate, and Signant/ ; U01AG042791/NH/NIH HHS/United States ; U01 AG042791/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/genetics/pathology ; Positron-Emission Tomography ; Male ; Female ; Magnetic Resonance Imaging ; *Brain/diagnostic imaging/drug effects/pathology/metabolism ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Neuroimaging ; Middle Aged ; Biomarkers/metabolism ; Thiazoles ; Fluorodeoxyglucose F18 ; Aniline Compounds ; Aged ; Amyloid beta-Peptides/metabolism ; }, abstract = {INTRODUCTION: Monoclonal anti-amyloid therapies are now accessible, but how these treatments influence changes within the brain is still not clear. We investigated overall and regional change in amyloid removal, glucose metabolism, and atrophy in trial participants with dominantly inherited Alzheimer's disease (DIAD). METHODS: In the DIAN-TU-001 trial, 92 carriers received gantenerumab or placebo and underwent serial neuroimaging assessments including [[11]C]-Pittsburgh compound-B (PiB) positron emission tomography (PET), [[18]F]-fluoro-2-deoxyglucose (FDG) PET, and magnetic resonance imaging (MRI). RESULTS: Gantenerumab significantly reduced PiB-PET uptake overall and in most regions and showed no changes in FDG-PET or MRI measures. Drug effects were associated with baseline PiB-PET uptake, and the largest effects occurred in medial regions. DISCUSSION: Treated DIAD participants, and especially those with higher amyloid burden, showed a decrease in PiB-PET uptake, which was more pronounced in the basal ganglia and medial frontal structures. These results may inform patient response and future drug trial design. HIGHLIGHTS: Gantenerumab unevenly decreased Aβ burden as measured by PiB-PET across brain regions. The strongest decrease in PiB-PET uptake was in basal ganglia and medial frontal structures. Variable drug effect on Aβ was partly due to the amount of burden present before treatment. There was no regional effect on FDG-PET metabolism or MRI volumetrics after 4 years.}, } @article {pmid40660634, year = {2025}, author = {Zhang, Y and Wu, YX and Zhang, XG and Guo, SY and He, J and Hu, NN and Huang, YL and Kong, Y and Li, QF and Sui, AR and Zhu, BH and Piao, H and Zhao, J and Li, S}, title = {Scorpion venom heat-resistant synthetic peptide improves cognitive dysfunction of APP/PS1 mice through microglial retromer complex.}, journal = {British journal of pharmacology}, volume = {182}, number = {21}, pages = {5391-5408}, doi = {10.1111/bph.70124}, pmid = {40660634}, issn = {1476-5381}, support = {LJKQZ2021101//Department of Education of Liaoning Province/ ; LJ222510161002//Department of Education of Liaoning Province/ ; 82101275//National Natural Science Foundation of China/ ; 82471464//National Natural Science Foundation of China/ ; 82101661//National Natural Science Foundation of China/ ; U1908208//National Natural Science Foundation of China/ ; }, mesh = {Animals ; *Microglia/drug effects/metabolism ; *Cognitive Dysfunction/drug therapy/metabolism ; Mice, Transgenic ; Mice ; *Scorpion Venoms/pharmacology/therapeutic use/chemistry ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; Mice, Inbred C57BL ; *Peptides/pharmacology/therapeutic use ; Cells, Cultured ; Disease Models, Animal ; *Alzheimer Disease/drug therapy ; }, abstract = {BACKGROUND AND PURPOSE: The abnormal accumulation of amyloid-β (Aβ) in the brain is a characteristic pathological change observed in patients with Alzheimer's disease (AD). Microglial phagocytosis, dependent on recycling through the retromer complex and cell membrane-bound receptors, plays a vital role in clearing Aβ from the brain. Previous studies have demonstrated the neurotrophic and neuroprotective effects of Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP); however, its impacts on cognitive function remain unclear. The present study aims to investigate the impact of SVHRSP on cognitive function in APP/PS1 transgenic mice and underlying mechanisms associated with microglial retromer complex. EXPERIMENTAL APPROACH: SVHRSP and 3-methyladenine (3-MA) were intraperitoneally injected at 7.5 months to investigate their effects on cognitive dysfunction in APP/PS1 mice. Following behavioural testing, brain samples were harvested 24 h later for electrophysiological recordings, analysis of protein and gene expression, and histological assessment. The role of microglial retromer complex was examined using primary microglia cultures. KEY RESULTS: SVHRSP treatment effectively improved AD-related pathological features, including cognitive impairment, neuronal loss, impaired synaptic plasticity, neuroinflammation, and Aβ deposition in APP/PS1 mice. Both in vivo and in vitro studies revealed that SVHRSP treatment increased expression of retromer complex protein VPS35. 3-MA, a specific class III phosphoinositide 3-kinase (PI3K) inhibitor that prevents autophagosome formation, reduced retromer complex protein expression and hindered the cognitive function improvements of SVHRSP. CONCLUSION AND IMPLICATIONS: Our findings suggest that SVHRSP may enhance microglial phagocytosis by modulating retromer complex activity, thereby alleviating Aβ accumulation and improving cognitive dysfunction in AD.}, } @article {pmid40660446, year = {2025}, author = {Singh, D}, title = {Mitochondrial Dysfunction in Neurodegenerative Disorders: Role of Prototype Targeted Drug Delivery Solutions.}, journal = {Current drug safety}, volume = {}, number = {}, pages = {}, doi = {10.2174/0115748863375490250626163609}, pmid = {40660446}, issn = {2212-3911}, abstract = {Mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Targeted drug delivery to mitochondria represents a promising therapeutic strategy to mitigate neuronal degeneration and preserve mitochondrial function in these devastating conditions. This review provides a comprehensive overview of recent advances in targeted drug delivery solutions for mitochondrial dysfunction in neurodegenerative disorders. The mechanisms underlying mitochondrial dysfunction in AD, PD, HD, and ALS are explored, highlighting the specific challenges and opportunities for therapeutic intervention. Emerging drug delivery technologies are discussed, including mitochondriaresponsive systems, nanoparticles, peptides, and viral vectors, designed to deliver therapeutic agents directly to mitochondria along with suitable case studies. Furthermore, preclinical and clinical studies evaluating the efficacy and safety of mitochondria-targeted therapeutics are reviewed, and future directions and challenges in the field are outlined. By elucidating the intersection of mitochondrial biology and drug delivery, this review aims to inspire further research and innovation toward effective treatments for neurodegenerative diseases.}, } @article {pmid40660381, year = {2025}, author = {Zhang, J and Kong, G and Yang, J and Pang, L and Li, X}, title = {Pathological mechanisms and treatment progression of Alzheimer's disease.}, journal = {European journal of medical research}, volume = {30}, number = {1}, pages = {625}, pmid = {40660381}, issn = {2047-783X}, mesh = {Humans ; *Alzheimer Disease/therapy/pathology/metabolism ; Disease Progression ; Animals ; Biomarkers/metabolism ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder and leading cause of dementia worldwide, with its incidence rising dramatically in aging populations. This progressive disease is neuropathologically characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tau tangles, and chronic neuroinflammation, leading to synaptic dysfunction and neuronal loss. Despite extensive research efforts, the complex and multifactorial nature of AD pathogenesis has prevented the development of truly disease-modifying therapies. Current therapeutic approaches, including recently approved anti-amyloid immunotherapies, demonstrate limited clinical efficacy and significant adverse effects, highlighting the need for alternative treatment strategies. This comprehensive review systematically evaluates recent advances in understanding AD pathophysiology, emphasizing the interplay between genetic risk factors (particularly APOE ε4), proteostasis imbalance, metabolic dysfunction, and neurovascular contributions. We critically analyze emerging diagnostic biomarkers, including novel neuroimaging techniques and cerebrospinal fluid/blood-based biomarkers, that enable earlier and more accurate detection. The review provides an in-depth assessment of both pharmacological interventions (such as tau-targeting therapies, anti-inflammatory agents, and neurotransmitter modulators) and non-pharmacological approaches (including lifestyle modifications and cognitive training). Special attention is given to personalized medicine strategies that account for disease heterogeneity and individual risk profiles. By synthesizing evidence from molecular studies, animal models, and clinical trials, we identify key challenges in therapeutic translation and propose future research directions. Our analysis underscores the importance of multimodal interventions targeting multiple pathological processes simultaneously, combined with early detection methods, to effectively combat this devastating disease. This review aims to provide researchers and clinicians with an updated framework for understanding AD pathogenesis and developing more effective treatment paradigms.}, } @article {pmid40659845, year = {2025}, author = {Ardura-Fabregat, A and Bosch, LFP and Wogram, E and Mossad, O and Sankowski, R and Aktories, P and Kieger, L and Cook, J and Hasavci, D and Ulupinar, H and Brock, D and Wang, F and Iovino, N and Wald, S and Preissl, S and Yilmaz, B and Schnepf, D and Macpherson, AJ and Blank, T and Kierdorf, K and Prinz, M}, title = {Response of spatially defined microglia states with distinct chromatin accessibility in a mouse model of Alzheimer's disease.}, journal = {Nature neuroscience}, volume = {28}, number = {8}, pages = {1688-1703}, pmid = {40659845}, issn = {1546-1726}, mesh = {Animals ; *Microglia/metabolism/pathology ; *Alzheimer Disease/pathology/metabolism/genetics ; Disease Models, Animal ; Mice ; Female ; Plaque, Amyloid/pathology/metabolism ; Mice, Transgenic ; *Chromatin/metabolism ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; }, abstract = {Microglial spatial heterogeneity remains a crucial yet not fully answered question in the context of potential cell-directed therapies for Alzheimer's disease (AD). There is an unclear understanding of the dynamics of distinct microglia states adjacent to or far from amyloid-beta (Aβ) plaques and their contributions to neurodegenerative diseases. Here we combine multicolor fluorescence cell fate mapping, single-cell transcriptional analysis, epigenetic profiling, immunohistochemistry and computational modeling to comprehensively characterize the relation of plaque-associated microglia (PAM) and non-plaque-associated microglia (non-PAM) in a mouse model of AD. We show that non-PAM are a distinct and highly dynamic microglial state, transitioning to PAM after Aβ plaque deposition in female mice. Non-PAM modulate the cell population expansion in response to amyloid deposition and rapidly respond to environmental cues. Indeed, Csf1 signaling modulates non-PAM-to-PAM transition during disease progression. Our data suggest that microglia states and their dynamics between each other can have distinct contributions to disease, and they may be targeted for the treatment of AD.}, } @article {pmid40658838, year = {2025}, author = {Zhang, J and Zhang, HL and Xu, XR and Feng, YL and Zhu, QM and Morisseau, C and Qiu, F and Hammock, BD and Sun, CP}, title = {Targeting PBK with small-molecule 1-O-acetyl-4R,6S-britannilactone for the treatment of neuroinflammation.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {29}, pages = {e2502593122}, pmid = {40658838}, issn = {1091-6490}, support = {P42 ES004699/ES/NIEHS NIH HHS/United States ; R35 ES030443/ES/NIEHS NIH HHS/United States ; 82274069//MOST | National Natural Science Foundation of China (NSFC)/ ; P42 ES04699//superfund basic research program of the national institutes of environmental health sciences/ ; }, mesh = {Animals ; Mice ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Lipopolysaccharides ; Microglia/drug effects/metabolism ; Autophagy/drug effects ; *Lactones/pharmacology ; Humans ; Mice, Inbred C57BL ; Inflammation/drug therapy ; Male ; AMP-Activated Protein Kinases/metabolism ; Epoxide Hydrolases/antagonists & inhibitors/metabolism ; }, abstract = {Neuroinflammation is a complex immunological phenomenon characterized by a dysregulated inflammatory response in the central nervous system (CNS) that can be triggered by various pathological injuries, such as toxins, which are involved in Parkinson's and Alzheimer's diseases (PD and AD), therefore, suppressing neuroinflammation serves as an effective treatment for CNS diseases. Herein, we found that natural soluble epoxide hydrolase (sEH) inhibitor 1-O-acetyl-4R,6S-britannilactone (AB) regulated mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) pathways to suppress the microglial activation by regulating inflammation and autophagy in vitro and in vivo, contributing to the improvement of lipopolysaccharide (LPS)-mediated neuroinflammation. Protein microarray analysis indicated that AB could selectively target PDZ binding kinase (PBK) through covalently binding to C70, exhibiting a dissociation constant (Kd) of 0.62 μM, which was corroborated by subsequent chemical biology experiments. We gained a deeper understanding of the mechanistic by which AB interfered PBK function, specifically by disrupting its interaction with tumor necrosis factor alpha-induced protein-8 like-2 (TIPE2), blocking the serine 3 (S3) phosphorylation-mediated ubiquitylation and degradation of TIPE2. Additionally, our study revealed that PBK genetic deletion alleviated the course of LPS-mediated neuroinflammation in vitro and in vivo, and AB did not exhibit any extra effects in LPS-mediated PBK[-/-] mice. These findings first offered broader prospects for treating neuroinflammation by targeting PBK to repress inflammation and activate autophagy, suggesting that AB had the potential to serve as a direct inhibitor in the PBK-TIPE2 interaction.}, } @article {pmid40658710, year = {2025}, author = {Ji, H and Zhao, Z and Zhao, C}, title = {Unveiling Aducanumab's safety profile: A comprehensive pharmacovigilance analysis.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0328076}, pmid = {40658710}, issn = {1932-6203}, mesh = {Humans ; *Pharmacovigilance ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; *Alzheimer Disease/drug therapy ; Retrospective Studies ; Female ; Male ; Aged ; Adverse Drug Reaction Reporting Systems ; United States ; Middle Aged ; United States Food and Drug Administration ; Aged, 80 and over ; Bayes Theorem ; Adult ; }, abstract = {BACKGROUND: Aducanumab, a monoclonal antibody targeting amyloid-beta plaques, has been introduced as a pivotal therapeutic agent for Alzheimer's disease (AD). Although it offers promising benefits in the treatment of early-stage Alzheimer's disease, a thorough evaluation of its safety profile and potential adverse events (AEs) is essential to ensure patient safety. METHODS: This retrospective pharmacovigilance study analyzed data from the FDA Adverse Event Reporting System (FAERS) database to evaluate AEs associated with Aducanumab. Employing a case/non-case methodology, the study utilized signal detection algorithms, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS), to identify AEs signals related to Aducanumab use. RESULTS: The study encompassed a total of 11517459 reports, with 431 specifically citing Aducanumab. A substantial number of AEs were identified, particularly among the elderly population and those with pre-existing neurological conditions. The most frequently reported AEs were related to the nervous system, including "amyloid-related imaging abnormalities" such as edema/effusion and microhemorrhages. Other affected system organ classes (SOCs) included psychiatric disorders and general disorders and administration site conditions. Specific preferred terms (PTs) linked with Aducanumab included "confusional state," "disorientation," and "cerebral microhemorrhage." Unexpected AEs such as "subdural hematoma" and "head injury" were also noted, indicating a broader safety profile that requires further investigation. CONCLUSIONS: The study's findings underscore the necessity for close monitoring of Aducanumab use, especially in elderly patients with AD. The identification of both expected and unexpected AEs emphasizes the need for ongoing pharmacovigilance and additional research to fully understand the safety profile of Aducanumab in clinical practice. Strength: Utilized multiple signal detection algorithms (ROR, PRR, BCPNN, MGPS) to enhance robustness of pharmacovigilance findings. Limitation: Reliance on spontaneous FAERS reports, which are prone to underreporting, overreporting, and reporting bias.}, } @article {pmid40658276, year = {2025}, author = {Luo, J and Shang, P and Tan, Z and Huang, S and Liu, Y and Wang, Y and Chen, Q and Xie, H}, title = {Effects of accelerated intermittent theta-burst stimulation combined with cognitive training on brain function in amnestic mild cognitive impairment patients.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {46}, number = {10}, pages = {5379-5390}, pmid = {40658276}, issn = {1590-3478}, support = {2018YFC2001700//National Key R&D Program of China/ ; 2019A011//the Special Fund of the Foshan Summit Plan/ ; 20220319//the Medical Scientific Research Project of Foshan Municipal Health Bureau/ ; }, mesh = {Humans ; *Cognitive Dysfunction/therapy/physiopathology/diagnostic imaging ; Male ; Female ; Aged ; Double-Blind Method ; *Transcranial Magnetic Stimulation/methods ; Spectroscopy, Near-Infrared ; Middle Aged ; *Amnesia/therapy/physiopathology ; *Dorsolateral Prefrontal Cortex/physiopathology/diagnostic imaging ; *Theta Rhythm/physiology ; *Brain/physiopathology/diagnostic imaging ; Combined Modality Therapy ; Cognitive Training ; }, abstract = {OBJECTIVE: This double-blinded randomized trial investigated the effects of accelerated intermittent theta-burst stimulation (iTBS) and adaptive cognitive training on brain function in 24 patients with amnestic mild cognitive impairment (aMCI). METHODS: Participants received real (n=12) or sham (n=12) iTBS targeting the left dorsolateral prefrontal cortex (DLPFC) thrice daily alongside cognitive training for 14 days. The Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and functional near-infrared spectroscopy (fNIRS) during rest and N-back tasks, which measure cognitive function and brain activity respectively, were administered pre-and post-intervention. RESULTS: The active group demonstrated significant cognitive improvement. Compared to sham controls, postintervention fNIRS results revealed reduced global brain activation during the 1-back task in the active group, particularly in the left prefrontal cortex, and the brain activation correlated with reaction time. In the 2-back task after treatment, the active group exhibited decreased activation in the right motor cortex, while the sham group showed increased activation in the left motor cortex. The overall brain connectivity in the sham group enhanced following the intervention, with significant differences in the correlations between the left prefrontal cortex and left motor cortex between groups. CONCLUSION: These findings suggest that the combined intervention can effectively promote cognitive performance and brain function in aMCI patients. iTBS causes enhanced functional engagement of the left DLPFC, which further facilitates neural efficiency and restores the capacity to modulate the allocation of neural resources rather than relying on global compensatory hyperactivation. These may be the underlying neural mechanisms for memory improvement in aMCI patients (Chinese Clinical Trial Registry: ChiCTR2400087943).}, } @article {pmid40657643, year = {2025}, author = {Bi, S and Liu, S and Zhu, K and Gao, D and Chen, L and Yu, C and Liang, G}, title = {Preclinical and experimental evidence of salvianolic acid B in the treatment of neurological diseases.}, journal = {Frontiers in pharmacology}, volume = {16}, number = {}, pages = {1606146}, pmid = {40657643}, issn = {1663-9812}, abstract = {BACKGROUND: Neurological diseases such as stroke and Alzheimer's disease pose increasing challenges to global public health. Salvianolic Acid B (SalB), a major active component of Salvia miltiorrhiza, has garnered attention due to its anti-inflammatory, antioxidant, neuroprotective, and pro-angiogenic properties in neurological disease treatment. PURPOSE: This paper aims to review the mechanisms and effects of SalB in the treatment of neurological diseases, exploring its role in improving neurological function, mitigating neuroinflammation, and reducing oxidative stress. RESULTS: SalB demonstrates multifaceted mechanisms in neurological disease management. In animal models of cerebral ischemia/reperfusion injury, SalB reduces infarct size and enhances neurological recovery via anti-inflammatory, anti-oxidative stress, and angiogenic pathways. It protects the blood-brain barrier and inhibits neuronal apoptosis in stroke models. In spinal cord injury models, SalB alleviates edema and promotes motor function recovery. In Alzheimer's disease models, SalB suppresses amyloid-beta formation and neuroinflammation. Additionally, SalB exhibits antidepressant and analgesic effects in pain-depression comorbidity models. These effects are mediated through the regulation of signaling pathways, including NF-κB, AMPK, PI3K/Akt, and Nrf2, highlighting SalB's broad therapeutic potential in neurological diseases. CONCLUSION: SalB exhibits promising prospects in the treatment of neurological diseases. However, its clinical application faces challenges such as chemical stability and bioavailability. Further research on the mechanisms of SalB and innovative drug delivery strategies is needed to advance its application in neurological disease therapy.}, } @article {pmid40657533, year = {2025}, author = {Perez, F and Morisaki, J and Kanakri, H and Rizkalla, M and Abdalla, A}, title = {A Novel Design of a Portable Birdcage via Meander Line Antenna (MLA) to Lower Beta Amyloid (Aβ) in Alzheimer's Disease.}, journal = {IEEE journal of translational engineering in health and medicine}, volume = {13}, number = {}, pages = {158-173}, pmid = {40657533}, issn = {2168-2372}, mesh = {*Alzheimer Disease/therapy/metabolism ; Humans ; *Amyloid beta-Peptides/metabolism ; Brain/metabolism/radiation effects ; Electromagnetic Fields ; Cells, Cultured ; Equipment Design ; }, abstract = {Late Onset Alzheimer's Disease (LOAD) is the most common cause of dementia, characterized by the deposition of plaques primarily of neurotoxic amyloid-[Formula: see text] ([Formula: see text]) peptide and tau protein. Our objective is to develop a noninvasive therapy to decrease the toxic A[Formula: see text] levels, using repeated electromagnetic field stimulation (REMFS) in the brain of Alzheimer's disease patients. We previously examined the effects of REMFS on [Formula: see text] levels in primary human brain (PHB) cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro (DIV7) treated with 64 MHz with a SAR of 0.6 W/Kg, one hour daily for 14 days (DIV 21) had significantly reduced (p =0.001) levels of secreted [Formula: see text]-42 and [Formula: see text]-40 peptide without evidence of toxicity. The EMF frequency and power, and SAR levels used in our work is utilized in MRI's, thus suggesting REMFS can be further developed in clinical settings to lower ([Formula: see text]) levels and improve the memory in AD patients. These findings and numerous studies in rodent AD models prompted us to design a portable RF device, appropriate for human use, that will deliver a homogeneous RF power deposition with a SAR value of 0.4-0.9 W/kg to all human brain memory areas, lower ([Formula: see text]) levels, and potentially improve memory in human AD patients.The research took place at the Indiana University School of Medicine (IUSM) and Purdue University Indianapolis. The first phase was done in PHB cultures at the IUSM. Through this phase, we found that a 64 MHz frequency and an RF power deposition with a SAR of 0.4-0.6 W/kg reduced the (A[Formula: see text]) levels potentially impacting Alzheimer's disease. The second phase of the project was conducted at Purdue University, we used ANSYS HFSS (High Frequency Simulation System) to design the devices that produced an appropriate penetration depth, polarization, and power deposition with a SAR of 0.4-0.9 W/kg to all memory brain areas of several numerical models. In Phase II-B will validate the device in a physical phantom. Phase III will require the FDA approval and application in clinical trials.The research parameters were translated into a designed product that fits comfortably in human head and fed from an external RF source that generates an RF power deposition with a SAR of 0.4-0.9 W/kg to a realistic numerical brain. The engineering design is flexible by varying the leg capacitors of the Meander Line Antenna (MLA) devices. Thermal outcomes of the results guarantee less than 0.5 C temperature increase within one-hour time of exposure, which can be used in clinical trials for AD patients. Design parameters include dimension of the coil, the MLA structure, conducting material, and capacitance values with the produced EM fields. The flexible design was achieved by varying the additive capacitance between conductors, and via a hybrid approach integrating a birdcage with sixteen MLA. A coil antenna size within 16 cm radius and 13 cm length was achieved. A capacitance between 6.9 nF and 9.2 nF were observed when copper materials with 16 conductors were used to achieve the research parameters in focus.The medical project proposed here has three phases: The initial phase of determining the research parameters for reducing A[Formula: see text] levels in human brain cultures and animal studies was completed at the IUSM. The translational engineering design of the REMS device and the numerical head and Antenna devices was successfully completed and presented in this paper by Purdue University and IUSM. Future phases will require manufacture and experimental validation of the REMS device with FDA approval for human application. Clinical impact: Our biological studies in human brain cultures showed that an RF power with a SAR of 0.4-0.9 W/kg at 64 MHz, lowered A[Formula: see text] levels, which potentially will prevent the death of the brain neurons and improve memory in AD. The fact that we found a safe RF power deposition with a SAR value associated with the proposed biological effects in human neurons and that 64 MHz provides a penetration depth of 13.5 cm that reaches all memory areas in a human brain makes the design and manufacture of this device of high clinical impact in the study of these exposures on the treatment of Alzheimer's and other protein associate diseases. Also, 64 MHz and RF power deposition with similar SAR levels are administer routinely in routine MRI for more than 4 decades makes it a safe framework for these novel therapeutic strategy.Clinical and Translational Impact Statement: The basic science work presented previously is both mechanistic and translational, and would advance the field of neuroscience as well as AD. This prompted us to joint efforts between the Indiana University School of Medicine and the electrical and computer engineering at Purdue University to design and develop a suitable EMF device for human treatments. Recently, our engineering team designed a birdcage antenna that generate a homogeneous RF power deposition with the same SAR values of our biological experiments in a realistic numerical human brain. Here, the engineering research has been extended to investigate the design of a portable flexible birdcage antenna that will enable adjustments to fit physical patient's characteristics, such as geometry, head size, and tissue dimensions. This new device is expected to improve SAR uniformity and may reduce the likelihood of untreated regions in the brains of patients during treatments. Also, here we determined that the maximum temperature rise of these exposures was less than 0.5°C, which is a safe level per regulatory agencies. This study considers a portable device system that will achieve the research parameters and patient satisfaction regarding reliability and comfort.}, } @article {pmid40657407, year = {2025}, author = {Prabha, S and Choudhury, A and Jawaid, T and Saeed, MU and Thakur, SC and Hassan, MI}, title = {Multi-targeted approach via apigenin-7-O-glucoside for therapeutic intervention of Tau phosphorylating kinases in Alzheimer's disease.}, journal = {3 Biotech}, volume = {15}, number = {8}, pages = {252}, pmid = {40657407}, issn = {2190-572X}, abstract = {UNLABELLED: Alzheimer's disease (AD) is one of the leading tauopathies in which several kinases phosphorylate Tau in response to Aβ oligomers, inflammation, calcium dysregulation, oxidative stress, mitochondrial dysfunction, or disruption of the key signaling pathways. Tau is phosphorylated by Ser/Thr kinases such as GSK3β, CDK5, MAPK14, and MARK2, as well as Tyr kinases like Fyn. Given the large crosstalk among these kinases, targeting one of these kinases is ineffective in treating tauopathies such as AD, highlighting the need for a multi-targeted approach. In this study, we targeted key kinases involved in Tau hyperphosphorylation using compounds derived from the medicinal plant Berberis lycium (B.ly.), which is reported to have anti-inflammatory, autophagy, and antioxidant properties. We employed virtual screening, ADMET evaluation, PASS analysis, DFT, molecular dynamics (MD) simulation, and MM/PBSA studies to assess the interaction of B.ly. compounds with CDK5, Fyn, GSK3β, MARK2, and MAPK14. Apigenin-7-O-glucoside (A7OG) was selected for its strong binding affinity within the ATP-binding pockets of these kinases. MD simulations demonstrated that A7OG exhibited promising inhibitory effects on CDK5, Fyn, MARK2, and MAPK14, with minimal fluctuation in its interaction with GSK3β. MM/PBSA analyses indicated stable binding energies for all the kinase-A7OG complexes. Our multitargeted investigations revealed that A7OG could be a promising molecule implicated in modulating tau hyperphosphorylating kinases that could lead to the development of therapeutic interventions in AD treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04413-3.}, } @article {pmid40657310, year = {2025}, author = {Langhough, RE and Norton, DL and Cody, KA and Du, L and Jonaitis, EM and Wilson, R and Rea Reyes, RE and Hermann, BP and Zetterberg, H and Johnson, SC}, title = {Use of preclinical Alzheimer's disease trajectories for clinical trial design.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40657310}, support = {P30 AG062715/AG/NIA NIH HHS/United States ; R01 AG021155/AG/NIA NIH HHS/United States ; R01 AG027161/AG/NIA NIH HHS/United States ; }, abstract = {INTRODUCTION: This study uses longitudinal amyloid biomarker and cognitive data to generate sample size estimates for two-armed, pre-clinical amyloid clearance clinical trials. METHODS: PET PiB DVR ranges defined three amyloid groups (positive, "A+"; sub threshold/low positive, "subA+"; and negative, "A-") in cognitively unimpaired Wisconsin Registry for Alzheimer's Prevention participants. Amyloid group trajectories estimated from mixed effects models informed per-treatment-arm sample size estimates to detect plausible treatment effects over 3-year (biomarker) or 6-year (cognition) study windows (80% power). RESULTS: To detect ≥60% slowing in PiB accumulation, ≤40 may be needed per arm for both SubA+ and A+; to detect the same effect sizes in plasma p-tau217 trajectories, ~50-1700 are needed, depending on assay and amyloid subgroup. Among cognitive outcomes, Digit Symbol Substitution and a 5-test Preclinical Alzheimer's Cognitive Composite consistently required fewest (<2000) per arm. DISCUSSION: Early intervention study planning will benefit from selection of outcomes that are most sensitive to AD biomarker-related preclinical change.}, } @article {pmid40655392, year = {2025}, author = {Le, TTM and Pham, HT and Trinh, HTT and Quach, NT and Do, TT and Phi, QT and Chu, HH}, title = {Huperzia javanica as a Novel Source of Huperzine Alkaloids and Huperzine-producing Fungi.}, journal = {Indian journal of microbiology}, volume = {65}, number = {2}, pages = {1201-1208}, pmid = {40655392}, issn = {0046-8991}, abstract = {Huperzine A (HupA) and huperzine B (HupB) are potent acetylcholinesterase inhibitor used widely for clinical treatment of Alzheimer's disease, which are mainly extracrted from natural populations of Huperzia species. This study aimed to the evaluate potential of producing Hup of native Huperzia javanica species collected in Vietnam as well as identify endophytic fungi that produce high Hup or simultaneously produce many types of Hup derived from this plant as a material source for natural Hup production. By HPLC-DAD-MS analysis, H. javanica collected from Ha Giang, Vietnam was found as a novel producer of HupA and HupB with a yield of 0.513 mg/g dry weight (wt) and 0.192 mg/g dry wt, respectively. Inspired by this discovery, a total of 63 endophytic fungi were isolated from healthy tissues of the collected H. javanica plants, including 52 fungal strains belonging to nine genera and 11 unidentified strains based on morphological characteristics. Using HPLC, 9 Hup-producing fungi were identified when compared to the standard HupA and HupB. Surprisingly, 7 fungal strains produced both HupA and HupB, among which strain TLC12 produced the highest HupA and HupB contents of 0.271 and 0.163 mg/g mycelium dry cell weight (gdcw), respectively. Fungal strains TLC19 and TLC22 only yielded a respective amount of 0.305 and 0.135 mg/ gdcw of HupA. Combining with Internal Transcribed Spacer sequence analysis, 9 potent fungi were identified as Neurospora calospora (TLC9, TLC10, TLC11), Schizophyllum commune TLC12, Epicoccum sorghinum TLC13, Alternaria tenuissima TLC14, Cephalotrichum sp. TLC20, Daldinia sp. TLC19, and Schizophyllum sp. TLC22. To the best of our knowledge, this is the first report demonstrating H. javanica as a prolific and novel source of endophytic fungi capable of yielding high HupA and HupB contents. The exploitation of 9 Hup-producing fungi is also valuable for both basic research and industrial Hup manufactures. These findings open new perspectives for industrial production of fungal HupA and HupB and conservation of Huperzia species.}, } @article {pmid40654912, year = {2025}, author = {Song, Z and Huang, X and Jannu, AJ and Johnson, TS and Zhang, J and Huang, K}, title = {Identify Alzheimer's disease subtypes and markers from multi-omic data of human brain and blood with a subspace merging algorithm.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40654912}, issn = {2692-8205}, support = {P30 AG072975/AG/NIA NIH HHS/United States ; U01 AG046152/AG/NIA NIH HHS/United States ; RF1 AG057440/AG/NIA NIH HHS/United States ; U54 AG065181/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; U01 AG061357/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; RC2 AG036547/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; R21 AG075541/AG/NIA NIH HHS/United States ; U01 AG061356/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; R01 AG030146/AG/NIA NIH HHS/United States ; U01 AG046170/AG/NIA NIH HHS/United States ; U24 AG061340/AG/NIA NIH HHS/United States ; R01 AG036042/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; RF1 AG057473/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; U01 AG046161/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; R01 AG048015/AG/NIA NIH HHS/United States ; P50 AG025711/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG036836/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, abstract = {Identifying Alzheimer's disease (AD) subtypes is essential for AD diagnosis and treatment. We integrated multiomics data from brain tissues of the ROSMAP and MSBB studies using a subspace merging algorithm and identified two AD patient clusters with notable cognitive and AD pathology differences. Analysis of differentially expressed genes (DEGs) in brain and blood samples pinpointed the LDLR gene as a potential blood biomarker linked to brain gene expression changes. Furthermore, we conducted PheWAS analysis on All of Us Project's EHR and WGS dataset for 105 eQTLs associated with the DEGs and revealed significant associations between these eQTLs and several phenotypes, shedding light on potential regulatory roles of these genes in diverse physiological processes. Our study successfully integrated multiomics data and proposes LDLR as a candidate blood biomarker for AD subtyping. The identified phenotypic signatures provide valuable insights on molecular mechanisms underlying AD heterogeneity, paving the way for personalized AD treatment.}, } @article {pmid40654760, year = {2025}, author = {Mekkittikul, M and Zhu, C and Danna, BT and Zuo, X and Rios, A and Yang, K and Villanueva, M and Agarwal, D and Castro, D and Gu, X and Strofs, AR and Shirihai, OS and Stiles, L and Frautschy, SA and Oscarsson, J and Esterline, RL and Cole, GM and Divakaruni, AS}, title = {13C tracing in synaptosomes reveals that SGLT2 inhibition with dapagliflozin prevents metabolic deficits in the 5X-FAD model of Alzheimer's Disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40654760}, issn = {2692-8205}, support = {R01 AG066212/AG/NIA NIH HHS/United States ; R35 GM138003/GM/NIGMS NIH HHS/United States ; T32 GM136614/GM/NIGMS NIH HHS/United States ; }, abstract = {Metabolic dysfunction is linked to several forms of age-related neurodegeneration including Alzheimer's Disease (AD), and targeting brain energy metabolism is an increasingly attractive mode of therapeutic intervention. However, commonly used in vitro methods to identify specific metabolic pathways of interest in preclinical models of neurodegenerative disease have considerable limitations. They are prone to subselection of sample material, unable to identify cell type-specific effects, or cannot identify metabolic defects upstream of mitochondria. Here we address these challenges by validating a method for stable isotope tracing with isolated synaptic nerve terminals, or 'synaptosomes'. We further applied this approach to study glucose metabolism in synaptosomes isolated from the 5X-FAD mouse model of AD treated with the antidiabetic sodium-glucose linked transporter-2 (SGLT-2) inhibitor Dapagliflozin. Treatment with Dapagliflozin preserved steady-state levels of synaptosomal metabolites and enrichment from labeled glucose into citrate that was reduced in the 5X-FAD model. These changes correlated with trends towards improved spatial working memory but not amyloid burden. The results highlight the utility of stable isotope tracing in synaptosomes to identify precise sites of metabolic dysfunction and mechanisms of action for metabolic drug candidates in preclinical models of neurodegeneration.}, } @article {pmid40654706, year = {2025}, author = {Meade, J and Mesa, H and Liu, L and Zhang, Q}, title = {Synaptic Toxicity of OGA Inhibitors and the Failure of Ceperognastat.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40654706}, issn = {2692-8205}, support = {R01 AG071865/AG/NIA NIH HHS/United States ; R15 AG085620/AG/NIA NIH HHS/United States ; RF1 AG079569/AG/NIA NIH HHS/United States ; }, abstract = {O-GlcNAcase inhibitors (OGAi) have been proposed as therapeutics for Alzheimer's disease due to their ability to increase O-GlcNAcylation of tau and reduce its aggregation. However, the recent failure of ceperognastat in a Phase II trial-marked by accelerated cognitive decline in the treatment arm-has raised concerns about the safety of this therapeutic class. Here, we evaluated the acute synaptic effects of three structurally distinct OGAi (ceperognastat, ASN90, and MK8719) in mouse hippocampal slices. Electrophysiological recordings revealed that all three compounds impaired both short- and long-term synaptic plasticity, as evidenced by reduced paired-pulse facilitation/depression and suppressed long-term potentiation. Immunohistochemistry showed altered synaptic protein levels, with increased PSD-95 and reduced Synaptophysin 1 in neurons, alongside a biphasic shift in Tau phosphorylation. These findings indicate that OGAi produce rapid and convergent synaptotoxic effects across pre- and postsynaptic compartments, likely reflecting a class-wide mechanism. We argue that electrophysiological screening should be standard in CNS drug development and caution against targeting essential synaptic processes in chronic neurodegenerative conditions.}, } @article {pmid40654371, year = {2025}, author = {Wang, Z and Zhang, K and Huang, M and Shang, D and He, X and Wu, Z and Yan, X and Zhang, X}, title = {Structures and functions of the MICOS: Pathogenesis and therapeutic implications in Alzheimer's disease.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {6}, pages = {2966-2984}, pmid = {40654371}, issn = {2211-3835}, abstract = {Mitochondrial dysfunction is a critical factor in the pathogenesis of Alzheimer's disease (AD). The mitochondrial contact site and cristae organizing system (MICOS) plays a pivotal role in shaping the inner mitochondrial membrane, forming cristae junctions and establishing interaction sites between the inner and outer mitochondrial membranes and thereby serving as a cornerstone of mitochondrial structure and function. In the past decade, MICOS abnormalities have been extensively linked to AD pathogenesis. In particular, dysregulated expression of MICOS subunits and mutations in MICOS-related genes have been identified in AD, often in association with hallmark pathological features such as amyloid-β plaque accumulation, neurofibrillary tangle formation, and neuronal apoptosis. Furthermore, MICOS subunits interact with several etiologically relevant proteins, significantly influencing AD progression. The intricate crosstalk between these proteins and MICOS subunits underscores the relevance of MICOS dysfunction in AD. Therapeutic strategies targeting MICOS subunits or their interacting proteins may offer novel approaches for AD treatment. In the present review, we introduce current understanding of MICOS structures and functions, highlight MICOS pathogenesis in AD, and summarize the available MICOS-targeting drugs potentially useful for AD.}, } @article {pmid40654362, year = {2025}, author = {Ren, L and Ma, X and Ye, J}, title = {Mechanism of Alzheimer's disease treatment by sound and light stimulation.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {6}, pages = {3346-3348}, pmid = {40654362}, issn = {2211-3835}, } @article {pmid40654342, year = {2025}, author = {Madamanchi, K and Zhang, J and Melkani, GC}, title = {Linkage of circadian rhythm disruptions with Alzheimer's disease and therapeutic interventions.}, journal = {Acta pharmaceutica Sinica. B}, volume = {15}, number = {6}, pages = {2945-2965}, pmid = {40654342}, issn = {2211-3835}, support = {R01 AG068550/AG/NIA NIH HHS/United States ; RF1 NS133378/NS/NINDS NIH HHS/United States ; }, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and pathological brain changes. While aging is the primary risk factor, circadian rhythm disruption (CRD) is increasingly recognized as a central driver of AD pathology. CRD exacerbates oxidative stress, systemic inflammation, and gut microbiome dysbiosis, impairing sleep-wake cycles, disrupting metabolic homeostasis, and promoting neuroinflammation, ultimately accelerating disease progression. Oxidative stress, a key factor in neuronal damage, is both a cause and consequence of circadian misalignment, while mitochondrial dysfunction further amplifies oxidative damage, impairing synaptic function and cognitive stability. Additionally, gut microbiome dysbiosis contributes to neuroinflammatory processes, worsening neurodegeneration. Given these complex interactions, this review aims to elucidate the role of CRD in AD pathology and explore potential therapeutic interventions targeting circadian dysfunction. Specifically, it examines the efficacy of time-restricted feeding (TRF), a dietary strategy that aligns food intake with circadian rhythms. TRF has shown promise in restoring circadian function, reducing oxidative stress, improving mitochondrial health, and promoting gut microbiome diversity. By addressing CRD, TRF may offer a novel approach to mitigating AD pathologies. This review also identifies current research gaps and future directions for developing circadian-based interventions in AD prevention and treatment.}, } @article {pmid40653764, year = {2025}, author = {Zhang, J and Wang, C and Chang, K and Peng, T and Liang, C and Cheng, J and Shi, Y and Wang, X and Wang, Z and Tan, Y and Hua, Q}, title = {A novel traditional Chinese medicine formula restores sleep and cognitive function in APP/PS1 mice by targeting glycolytic pathways and neuroinflammatory responses.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {107}, number = {2}, pages = {617-627}, doi = {10.1177/13872877251355596}, pmid = {40653764}, issn = {1875-8908}, mesh = {Animals ; Mice ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Sleep/drug effects ; Mice, Transgenic ; *Glycolysis/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; *Cognition/drug effects ; Amyloid beta-Protein Precursor/genetics ; *Medicine, Chinese Traditional/methods ; Male ; *Neuroinflammatory Diseases/drug therapy/metabolism ; Disease Models, Animal ; *Sleep Wake Disorders/drug therapy ; Presenilin-1/genetics ; Cognitive Dysfunction/drug therapy ; Mice, Inbred C57BL ; }, abstract = {BackgroundAlzheimer's disease (AD) is recognized as a multifactorial neurodegenerative disorder involving numerous cellular and molecular processes, such as sleep disturbance, imbalance in brain glucose metabolism and neuroinflammation; these dysregulations typically precede the onset of symptoms. Hence, the results of mono-target therapy after AD diagnosis are in many cases unsatisfactory.ObjectiveTraditional Chinese medicine (TCM) presents significant potential for treating AD. Sleep disorders are one of the early symptoms of AD; however, there is no effective solution to sleep disorders caused by AD. Some TCMs have been shown to treat sleep disorders by regulating energy metabolism or improving neuroinflammation. This study aims to investigate if XX-F administrated in advance could alleviate AD by improving sleep quality and neuroinflammation.MethodsMice were given Xiexintongfu formula (XX-F) intragastrically for three months. Morris water maze and pentobarbital-induced sleep test were performed to evaluate cognition and sleep. Determine changes in energy metabolism related to glycolysis through western blot and specific assay kits. Using immunofluorescence and western blot to detect neuroinflammation.ResultsShortened sleep duration and cognitive impairment were observed in 6-month-old APP/PS1 mice. XX-F significantly prolonged sleep duration and rescued cognition. In addition, XX-F reduced the number of amyloid-β (Aβ) plaques and ameliorated neuroinflammation, and inhibited glycolysis by reducing pyruvate kinase M2 (PKM2) and lactate levels while rescuing adenosine triphosphate (ATP) deficiency.ConclusionsWe demonstrate that XX-F can improve sleep and cognition of AD mice by regulating energy metabolism and reducing neuroinflammation. This is a potential treatment method for AD and requires further in-depth research.}, } @article {pmid40653095, year = {2025}, author = {Varga, K and Sikur, N and Paszternák, A and Friesenhahn, AL and Zymela, FE and Bagaméry, F and Tábi, T and Wölfl, S}, title = {Resveratrol restores insulin signaling and balances mitochondrial biogenesis and autophagy in streptozotocin-induced neurodegeneration in vitro.}, journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences}, volume = {212}, number = {}, pages = {107202}, doi = {10.1016/j.ejps.2025.107202}, pmid = {40653095}, issn = {1879-0720}, mesh = {Resveratrol ; Animals ; *Autophagy/drug effects ; Signal Transduction/drug effects ; *Insulin/metabolism ; *Mitochondria/drug effects/metabolism ; Streptozocin ; Rats ; *Stilbenes/pharmacology ; Insulin Resistance ; Phosphorylation/drug effects ; *Neurodegenerative Diseases/metabolism/drug therapy/chemically induced ; Insulin Receptor Substrate Proteins/metabolism ; Organelle Biogenesis ; *Neuroprotective Agents/pharmacology ; }, abstract = {Resveratrol, a natural phytoalexin, has been suggested to have beneficial effects in age-related diseases, including Alzheimer's disease. Studies indicate that it may delay memory decline and exert neuroprotective properties in vitro and in vivo. However, the precise mechanisms underlying these effects remain unclear, and the impact of resveratrol on central insulin resistance-a key feature of neurodegenerative disorders-remains insufficiently explored. Given the potential therapeutic significance of targeting insulin sensitivity in neurodegeneration, further investigation into the role of resveratrol in modulating these pathways is warranted. Our aim was to investigate the effects of resveratrol on insulin signaling and mitochondrial function in a previously established streptozotocin-induced in vitro neurodegeneration model. The phosphorylation status of key insulin signaling proteins and regulators of insulin resistance and autophagy markers were analyzed via Western blot and an ELISA-based microarray technique. The effects of resveratrol on mitochondrial biogenesis were evaluated through Mitotracker staining and quantification of mitochondrial mRNA and protein expression. Resveratrol augmented the cytoprotective effect of insulin in a concentration-dependent manner. It reduced the Ser(312) phosphorylation of IRS1, which is commonly linked to insulin resistance, and lowered the IC50 value for Tyr(895) phosphorylation required for activation. Similar insulin-sensitizing effects were observed in downstream signaling components. Resveratrol treatment exerted a caloric restriction mimetic activity through activating the AMPK/PGC1α/SIRT1 pathway and upregulated the expression of mitochondrial transcription factor TFAM and ATP synthase subunit (ATP5B). Despite the activation of mitochondrial biogenesis, the number of mitochondria was not altered, because it simultaneously induced autophagy marked by ULK1 phoshorylation and LC3 lipidation. Our findings indicate that resveratrol can enhance insulin signaling, even at the initial step of IRS1 phosphorylation. Its insulin-sensitizing effects extend beyond metabolic regulation to include survival responses. Resveratrol as a caloric restriction mimetic exerted a balanced effect on mitochondrial biogenesis and autophagy therefore improving mitochondrial quality control.}, } @article {pmid40652712, year = {2025}, author = {Brüge, A and Ponimaskin, E and Labus, J}, title = {Targeting the serotonergic system in the treatment of neurodegenerative diseases-emerging therapies and unmet challenges.}, journal = {Pharmacological reviews}, volume = {77}, number = {5}, pages = {100071}, doi = {10.1016/j.pharmr.2025.100071}, pmid = {40652712}, issn = {1521-0081}, mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Serotonin/metabolism ; Receptors, Serotonin/metabolism ; *Serotonin Agents/therapeutic use/pharmacology ; Molecular Targeted Therapy ; }, abstract = {More than 65 million people worldwide experience neurodegenerative diseases, such as Alzheimer disease, frontotemporal dementia, Parkinson disease, and amyotrophic lateral sclerosis. As the risk of developing these diseases increases with age, increasing life expectancy will further accelerate their prevalence. Despite major advances in the understanding of the molecular mechanisms of neurodegeneration, no curative therapy is available to date. Neurodegenerative diseases are known to be associated with alterations in serotonergic neurotransmission, which might critically contribute to the pathogenesis of these diseases. Therefore, targeting the serotonergic system appears to be a promising therapeutic approach. In this review, we provide a comprehensive overview of pathological changes in serotonergic neurotransmission in different neurodegenerative diseases and discuss novel treatment strategies based on targeted modulation of the serotonergic system. We primarily focus on the therapeutic approaches modulating serotonin homeostasis, its biosynthesis, and the modulation of defined serotonin receptors. SIGNIFICANCE STATEMENT: A common feature of multiple neurodegenerative diseases is dysregulation of the serotonergic system at the cellular, molecular, and genetic levels that strongly contributes to specific pathological phenotypes. Targeting these alterations represents a suitable therapeutic strategy to combat disease-relevant pathomechanisms, slow down disease progression, and overcome pathological consequences.}, } @article {pmid40652586, year = {2025}, author = {Li, X and Li, Z and Chen, H and Guo, H and Ge, Y and Dong, F and Zhang, F and Zhang, F}, title = {Unraveling APOE4: The dual role in CNS and peripheral inflammation in Alzheimer's disease.}, journal = {International immunopharmacology}, volume = {163}, number = {}, pages = {115199}, doi = {10.1016/j.intimp.2025.115199}, pmid = {40652586}, issn = {1878-1705}, mesh = {Humans ; *Alzheimer Disease/immunology/metabolism/genetics ; Animals ; *Apolipoprotein E4/metabolism/genetics/immunology ; *Inflammation/immunology ; *Central Nervous System/immunology ; Microglia/immunology ; T-Lymphocytes/immunology ; }, abstract = {Inflammation in both CNS and peripheral circulation system is known to have a significant impact in AD pathogenesis. In the CNS, AD-related inflammation involves the activation of various types of immune cells, such as microglia, astrocytes, and T cells. Meanwhile, one of the hallmarks of peripheral circulation inflammation in AD is activation of T cells. In addition, Apolipoprotein E4 (APOE4), as a key genetic risk factor for late-onset AD, significantly influences both CNS and peripheral circulation system inflammation in the pathogenesis of AD. Moreover, APOE4 play a key role in various pathological changes in AD, such as Aβ accumulation, tau phosphorylation, lipid metabolism disorders, and BBB dysfunction, resulting in microglia, astrocytes, and T cells activation, as well as the release of inflammatory factors. This comprehensive review aims to elucidate the specific mechanisms through which APOE4 triggers inflammation in both CNS and peripheral circulation system in the context of AD. Furthermore, we also summarize several therapeutic approaches that target APOE for the treatment of AD.}, } @article {pmid40651740, year = {2025}, author = {Zhang, Z and Xue, X and Liu, P and Zhang, C and Li, J and Liu, Y and Jiang, Y and Lv, S and Wang, L and Zhou, H and Shen, W and Yang, S and Wang, F}, title = {The role of photobiomodulation in modulating neural activity and brain function: A systematic bibliometric analysis.}, journal = {Photodiagnosis and photodynamic therapy}, volume = {55}, number = {}, pages = {104712}, doi = {10.1016/j.pdpdt.2025.104712}, pmid = {40651740}, issn = {1873-1597}, mesh = {*Low-Level Light Therapy/methods ; Humans ; Bibliometrics ; *Brain/radiation effects ; *Central Nervous System Diseases/therapy/radiotherapy ; }, abstract = {This systematic bibliometric analysis evaluates the scientific evidence, impact, and trends of photobiomodulation (PBM) for central nervous system (CNS) disorders. Analyzing 150 relevant PubMed-indexed studies (including 46 clinical trials) up to September 2024, we demonstrate PBM's positive effects on the CNS. Key mechanisms include enhanced ATP synthesis, modulated nitric oxide signaling, improved neuronal excitability, suppressed oxidative stress, anti-inflammatory effects, and ion channel modulation. PBM offers therapeutic flexibility: shorter-wavelength, high-irradiance power lasers effectively target deep brain structures, while both modalities suit superficial cortical applications where fine spatial control is nonessential.Crucially, PBM induces long-lasting biological effects, highlighting significant potential for chronic CNS conditions like Alzheimer's disease, Parkinson's disease, and stroke. However, critical challenges hinder translation: optimizing disease-specific wavelengths and light sources (laser vs. LED, continuous vs. pulsed), and establishing standardized, long-term treatment protocols based on robust dose-response relationships. Resolving heterogeneity in parameters (energy density, power, potential thermal effects) is paramount for PBM to become a reliable neuromodulation tool. This analysis provides critical insights for advancing targeted PBM therapies in CNS.}, } @article {pmid40651475, year = {2025}, author = {Bershteyn, M and Zhou, H and Fuentealba, L and Chen, C and Subramanyam, G and Cherkowsky, D and Sevilla, ES and Hampel, P and Salvatierra, J and Sezan, M and Maury, Y and Havlicek, S and Kriks, S and Lee, S and Au, W and Watson, M and Kuzmenko, O and Grimmett, ME and Vogel, A and Porkka, F and Qiu, Y and Nesterova, A and Anderson, D and Feld, BG and Hosford, V and Jung, JH and Kowal, T and Bulfone, A and Banik, G and Priest, C and Palop, JJ and Nicholas, CR}, title = {Human stem cell-derived GABAergic interneuron development reveals early emergence of subtype diversity and gradual electrochemical maturation.}, journal = {Neuron}, volume = {113}, number = {19}, pages = {3162-3184.e10}, doi = {10.1016/j.neuron.2025.06.010}, pmid = {40651475}, issn = {1097-4199}, mesh = {Humans ; Animals ; *Interneurons/physiology/metabolism/cytology ; Mice ; *GABAergic Neurons/physiology/cytology/metabolism ; *Pluripotent Stem Cells/physiology/cytology ; Somatostatin/metabolism ; Parvalbumins/metabolism ; Cell Differentiation/physiology ; Median Eminence/cytology ; }, abstract = {Medial ganglionic eminence-derived inhibitory γ-aminobutyric acid (GABAergic) pallial interneurons (MGE-pINs) are essential regulators of cortical circuits, and their dysfunction is associated with neurological disorders. We developed human MGE-pINs from pluripotent stem cells for the treatment of drug-resistant epilepsy. Here, we analyzed xenografted MGE-pINs from human pluripotent stem cells (hMGE-pINs) over the lifespan of host mice in healthy and epileptic environments using single-nuclei RNA sequencing. Comparative transcriptomics against endogenous human brain datasets revealed that 97% of grafted cells developed into somatostatin (SST) and parvalbumin (PVALB) subtypes, including populations that exhibit selective vulnerability in Alzheimer's disease. Transplanted hMGE-pINs demonstrated rapid emergence of subclass features, progressing through distinct transcriptional states sequentially involving neuronal migration, synapse organization, and membrane maturation. We present molecular, electrophysiological, and morphological data that collectively confirm the derivation of diverse bona fide human SST and PVALB subtypes, providing a high-fidelity model to study hMGE-pIN development as well as a compositional atlas for regenerative cell therapy applications.}, } @article {pmid40651201, year = {2025}, author = {D, C and M, M}, title = {Fusion of bio-inspired optimization and machine learning for Alzheimer's biomarker analysis.}, journal = {Computers in biology and medicine}, volume = {196}, number = {Pt A}, pages = {110746}, doi = {10.1016/j.compbiomed.2025.110746}, pmid = {40651201}, issn = {1879-0534}, mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; Humans ; Biomarkers/metabolism ; *Machine Learning ; *Deep Learning ; Male ; Female ; Magnetic Resonance Imaging ; Brain/diagnostic imaging ; *Image Processing, Computer-Assisted/methods ; }, abstract = {Identification of Alzheimer's Disease (AD), especially in its early phases, presents significant challenges due to the nonexistence of reliable biomarkers and effective treatments. Clinical trials for AD medications also suffer from high failure rates. Accurate diagnosis, prognosis determination, progression monitoring, and treatment effect assessment depend heavily on analysing various brain regions, including the Corpus Callosum (CC), Grey Matter (GM), Hippocampus (HC), Ventricle, and White Matter (WM). Among these, the Hippocampus plays a pivotal role in early detection. This study employs deep learning for classification and optimization techniques for segmenting the HC region to enable the AD diagnosis. The pre-processing of raw images involves histogram equalization and Otsu's thresholding methods. The research focuses on data collection and pre-processing as essential steps for advancing diagnostic methods. Segmentation and classification utilize Elephant Herding Optimization (EHO) and Crow Search Optimization (CSO) techniques in combination with the ResNet50 classifier. The results reveal that Crow Search Optimization achieves superior performance, with an accuracy of 92 %, surpassing Elephant Herding Optimization.}, } @article {pmid40651085, year = {2025}, author = {Aydemi̇r, M and Gacar, G and Halbutoğullari, ZS and Duruksu, G and Öztürk, A and Altuntaş, C and Yazir, Y}, title = {Adipose tissue-derived mesenchymal stem cell extracellular vesicles enhance amyloid-beta degradation in an in vitro Alzheimer's model.}, journal = {Tissue & cell}, volume = {96}, number = {}, pages = {103035}, doi = {10.1016/j.tice.2025.103035}, pmid = {40651085}, issn = {1532-3072}, mesh = {Humans ; *Mesenchymal Stem Cells/metabolism ; *Alzheimer Disease/pathology/metabolism ; *Extracellular Vesicles/metabolism/ultrastructure ; *Amyloid beta-Peptides/metabolism ; *Adipose Tissue/cytology/metabolism ; Cell Differentiation ; Hydrogen Peroxide/pharmacology ; Cell Line, Tumor ; *Models, Biological ; Cytokines ; }, abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder lacking effective treatment. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) have shown promise in degrading amyloid beta (Aβ) plaques due to their low immunogenicity and ability to mediate intercellular communication. This study investigates the therapeutic potential of EVs derived from human adipose tissue MSCs (hAT-MSCs) and preconditioned human adipose tissue MSCs in an in vitro AD model. METHODS: MSCs characterized by flow cytometry and differentiation assays. hAT-MSCs stimulated with hydrogen peroxide (H₂O₂) or a cytokine complex (CC; TNF-α, IL-1β, IFN-γ). EVs were isolated via ultracentrifugation and analyzed by electron microscopy and Zetasizer. An in vitro AD model was established using neural-differentiated SH-SY5Y cells treated with Aβ peptides. Differentiation and Aβ degradation were assessed using immunocytochemistry, qRT-PCR, and ELISA. RESULTS: EVs derived from cytokine complex stimulated hAT-MSCs significantly reduced Aβ plaque size and intensity compared to EVs from unstimulated or H₂O₂-stimulated cells. When immunocytochemistry images were analyzed using ImageJ, Aβ levels were found to be highest in the Alzheimer's group and lowest in the CC-EV group. According to ELISA analyses, no significant difference was observed between the Alzheimer's model (a1) and the hAT-MSC-EVs (a3) groups, whereas both the H₂O₂-EV (a4) and CC-EV (a5) groups showed a significant reduction compared to the control (**** P ≤ 0,0001) CONCLUSION: These findings suggest that cytokine-stimulated hAT-MSC-derived EVs effectively promote Aβ degradation and represent a promising cell-free therapeutic strategy for AD.}, } @article {pmid40650861, year = {2025}, author = {Sil, M and Mukherjee, N and Chatterjee, I and Ghosh, A and Goswami, A}, title = {Glial Cells in Alzheimer's Disease: Pathogenic Mechanisms and Therapeutic Frontiers.}, journal = {Journal of molecular neuroscience : MN}, volume = {75}, number = {3}, pages = {87}, pmid = {40650861}, issn = {1559-1166}, mesh = {*Alzheimer Disease/therapy/metabolism/pathology/drug therapy ; Humans ; Animals ; *Neuroglia/metabolism ; Microglia/metabolism ; Receptors, Immunologic/metabolism ; Membrane Glycoproteins ; }, abstract = {The rising incidence of brain diseases parallels the global trend of an aging population, with Alzheimer's disease (AD) being a leading neurodegenerative disorder characterized by memory loss, dementia, and cognitive decline. Despite extensive research, current treatments for AD remain largely symptomatic and have had limited success in halting disease progression, thereby shifting attention toward glial cells as promising therapeutic targets due to their emerging roles in AD pathogenesis. Astrocytes are involved in both beneficial and pathological processes in AD, such as cytokine secretion, Aβ removal, metabolic support, and tau pathology, with deficiency resulting in neuroinflammation and excitotoxicity. Microglia have dual functions in AD by phagocytosing amyloid plaques and limiting tau spread in initial phases but may develop a pro-inflammatory, neurodegenerative phenotype with progression of the disease. Oligodendrocytes and their precursors are involved in Aβ generation and myelin homeostasis, and their disturbance is responsible for white matter lesions and cognitive impairment, though their exact mechanisms are less clear. This review also examines emerging therapeutic strategies targeting glial cells, including modulating TREM2 pathways and novel drug candidates. These methods highlight the therapeutic value of the glial cells and provide valuable leads for furthering the treatment of AD by elucidating their changing roles in the course of the disease.}, } @article {pmid40650773, year = {2025}, author = {Deepika, and Thakur, A and Panghal, A and Pundir, R and Singh, C and Goyal, M and Namdeo, AG and Kumar, J}, title = {Crosstalk between copper, Alzheimer's disease, and melatonin.}, journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}, volume = {38}, number = {5}, pages = {1381-1420}, pmid = {40650773}, issn = {1572-8773}, mesh = {*Melatonin/metabolism ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Copper/metabolism ; Humans ; Animals ; Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; Antioxidants ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that causes cognitive impairment and loss of neurons. According to the Alzheimer's Association's 2022 US report, the USA saw a 145% increase in AD-related fatalities from 2000 to 2020, with an estimated financial burden of these disorders surpassing $1 trillion annually. Its pathological features include neurofibrillary tangles and amyloid-beta (Aβ) plaques. Although there is presently no treatment that may stop the growth of AD, new clinical trials have suggested that anti-amyloid disease-modifying drugs may reduce the progression of the illness. According to a recent study, Copper (Cu) dysregulation plays a crucial role in AD pathogenesis by causing oxidative stress and encouraging the aggregation of Aβ. Meanwhile, melatonin, a neurohormone with strong neuroprotective, antioxidant, and Cu chelation qualities, has drawn an interest due to its possible use for AD treatment. This review thoroughly summarizes the most recent research, including in vivo, in vitro, and human studies, and also examines the complex relationships among AD, melatonin, and Cu toxicity. We observe how an excess of Cu aggravates AD pathogenesis and how the special qualities of melatonin can counteract these effects. Melatonin is a promising molecule having a dual approach to address pathogenesis of AD by chelating excess Cu and lowering oxidative stress. Comprehending the interplay between Cu dysregulation and the protective mechanisms of melatonin may result in innovative therapies, providing promises for enhanced management of AD.}, } @article {pmid40650273, year = {2025}, author = {Merighi, S and Fernandez, M and Nigro, M and Travagli, A and Caldon, F and Salati, S and Borea, PA and Cadossi, R and Varani, K and Gessi, S}, title = {PEMFs Restore Mitochondrial and CREB/BDNF Signaling in Oxidatively Stressed PC12 Cells Targeting Neurodegeneration.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40650273}, issn = {1422-0067}, support = {R/IGEA/Gessi/01/21//Igea Clinical Biophysics/ ; }, mesh = {Animals ; PC12 Cells ; Rats ; *Brain-Derived Neurotrophic Factor/metabolism ; *Mitochondria/metabolism/radiation effects/drug effects ; *Oxidative Stress/drug effects ; *Cyclic AMP Response Element-Binding Protein/metabolism ; *Signal Transduction/radiation effects ; Amyloid beta-Peptides/toxicity ; Hydrogen Peroxide/toxicity/pharmacology ; *Electromagnetic Fields ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Cell Survival/drug effects ; Phosphorylation ; }, abstract = {Alzheimer's disease (AD), the most prevalent form of neurodegenerative dementia, is characterized by progressive cognitive decline and neuronal loss. Despite advances in pharmacological treatments, current therapies remain limited in efficacy and often induce adverse effects. Increasing evidence highlights oxidative stress, mitochondrial dysfunction, and disrupted neurotrophic signaling as key contributors to AD pathogenesis. Pulsed electromagnetic fields (PEMFs) are emerging as a non-invasive, multifactorial approach with promising biological effects. In this study, we investigated the neuroprotective potential of PEMFs in NGF-differentiated PC12 cells exposed to hydrogen peroxide (H2O2) or amyloid-β peptide (Aβ), both of which model pathological features of AD. PEMF treatment significantly counteracted H2O2- and Aβ-induced cytotoxicity by restoring cell viability, reducing reactive oxygen species production, and improving catalase activity. Furthermore, PEMFs preserved the mitochondrial membrane potential and decreased caspase-3 activation and chromatin condensation. Mechanistically, PEMFs inhibited ERK phosphorylation and enhanced cAMP levels, CREB phosphorylation, and BDNF expression, pathways known to support neuronal survival and plasticity. In conclusion, these findings suggest that PEMFs modulate multiple stress response systems, promoting neuroprotection under oxidative and amyloidogenic conditions.}, } @article {pmid40650049, year = {2025}, author = {Yang, HM}, title = {Recent Advances in Antibody Therapy for Alzheimer's Disease: Focus on Bispecific Antibodies.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40650049}, issn = {1422-0067}, support = {RS-2025-02263992//Patient-Centered Clinical Research Coordinating Center/ ; }, mesh = {Humans ; *Alzheimer Disease/therapy/drug therapy/immunology/metabolism ; *Antibodies, Bispecific/therapeutic use/immunology ; Animals ; Blood-Brain Barrier/metabolism ; *Immunotherapy/methods ; Amyloid beta-Peptides/immunology/metabolism ; tau Proteins/immunology/metabolism ; }, abstract = {Alzheimer's disease (AD) impacts more than half a million people worldwide, with no cure available. The regulatory approval of three anti-amyloid monoclonal antibodies (mAbs), including aducanumab, lecanemab, and donanemab, has established immunotherapy as a therapeutic approach to modify disease progression. Its multifactorial pathology, which involves amyloid-β (Aβ) plaques, tau neurofibrillary tangles, neuroinflammation, and cerebrovascular dysfunction, limits the efficacy of single-target therapies. The restricted blood-brain barrier (BBB) penetration and amyloid-related imaging abnormalities (ARIA), together with small treatment effects, demonstrate the necessity for advanced biologic therapies. Protein engineering advancements have created bispecific antibodies that bind to pathological proteins (e.g., Aβ, tau) and BBB shuttle receptors to boost brain delivery and dual therapeutic effects. This review combines existing information about antibody-based therapy in AD by focusing on bispecific antibody formats and their preclinical and clinical development, as well as biomarker-based patient selection and upcoming combination strategies. The combination of rationally designed bispecific antibodies with fluid and imaging biomarkers could show potential for overcoming existing therapeutic challenges and delivering significant clinical advantages.}, } @article {pmid40650013, year = {2025}, author = {Russo, AP and Pastorello, Y and Dénes, L and Brînzaniuc, K and Krupinski, J and Slevin, M}, title = {The Inflammatory Nexus: Unraveling Shared Pathways and Promising Treatments in Alzheimer's Disease and Schizophrenia.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40650013}, issn = {1422-0067}, mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology/therapy ; *Schizophrenia/metabolism/drug therapy/pathology/therapy ; Signal Transduction ; Animals ; *Inflammation/metabolism/pathology ; Biomarkers/metabolism ; Blood-Brain Barrier/metabolism ; Autophagy ; Receptor for Advanced Glycation End Products/metabolism ; Antipsychotic Agents/therapeutic use ; }, abstract = {Alzheimer's disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, blood-brain barrier (BBB) disruption, and cognitive impairment. We examine key signaling pathways, particularly spleen tyrosine kinase (SYK), the mechanistic (or mammalian) target of rapamycin (mTOR), and the S100 calcium-binding protein B (S100B)/receptor for advanced glycation end-products (RAGE) axis, that link glial activation, excitatory/inhibitory neurotransmitter imbalances, and impaired proteostasis across both disorders. Specific biomarkers such as S100B, matrix metalloproteinase 9 (MMP9), and soluble RAGE show promise for stratifying disease subtypes and predicting treatment response. Moreover, psychiatric symptoms frequently precede cognitive decline in both AD and schizophrenia, suggesting that mood and behavioral disturbances may serve as early diagnostic indicators. The roles of autophagic failure, cellular senescence, and impaired glymphatic clearance are also explored as contributors to chronic inflammation and neurodegeneration. Current treatments, including cholinesterase inhibitors and antipsychotics, primarily offer symptomatic relief, while emerging therapeutic approaches target upstream molecular drivers, such as mTOR inhibition and RAGE antagonism. Finally, we discuss the future potential of personalized medicine guided by genetic, neuroimaging, and biomarker profiles to optimize diagnosis and treatment strategies in both AD and schizophrenia. A greater understanding of the pathophysiological convergence between these disorders may pave the way for cross-diagnostic interventions and improved clinical outcomes.}, } @article {pmid40649980, year = {2025}, author = {Mishra, P and Esfahani, EK and Fernyhough, P and Albensi, BC}, title = {Estradiol Prevents Amyloid Beta-Induced Mitochondrial Dysfunction and Neurotoxicity in Alzheimer's Disease via AMPK-Dependent Suppression of NF-κB Signaling.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40649980}, issn = {1422-0067}, support = {R16 NS134540/NS/NINDS NIH HHS/United States ; 1R16NS134540-01/GF/NIH HHS/United States ; PJT-162144//CIHR/ ; }, mesh = {*Alzheimer Disease/metabolism/prevention & control ; *Amyloid beta-Peptides/pharmacology ; Mice, Inbred C57BL ; Animals ; Mice ; Cells, Cultured ; *Estradiol/pharmacology ; *Mitochondria/drug effects/metabolism ; *AMP-Activated Protein Kinases/metabolism ; *Signal Transduction/drug effects ; NF-kappa B/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Enzyme Activation ; Cell Survival/drug effects ; Electron Transport/drug effects ; Neuroinflammatory Diseases/chemically induced/metabolism ; }, abstract = {Alzheimer's disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. In addition to its two major pathological hallmarks, extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), recent evidence highlights the critical roles of mitochondrial dysfunction and neuroinflammation in disease progression. Aβ impairs mitochondrial function, which, in part, can subsequently trigger inflammatory cascades, creating a vicious cycle of neuronal damage. Estrogen receptors (ERs) are widely expressed throughout the brain, and the sex hormone 17β-estradiol (E2) exerts neuroprotection through both anti-inflammatory and mitochondrial mechanisms. While E2 exhibits neuroprotective properties, its mechanisms against Aβ toxicity remain incompletely understood. In this study, we investigated the neuroprotective effects of E2 against Aβ-induced mitochondrial dysfunction and neuroinflammation in primary cortical neurons, with a particular focus on the role of AMP-activated protein kinase (AMPK). We found that E2 treatment significantly increased phosphorylated AMPK and upregulated the expression of mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α), leading to improved mitochondrial respiration. In contrast, Aβ suppressed AMPK and PGC-1α signaling, impaired mitochondrial function, activated the pro-inflammatory nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and reduced neuronal viability. E2 pretreatment also rescued Aβ-induced mitochondrial dysfunction, suppressed NF-κB activation, and, importantly, prevented the decline in neuronal viability. However, the pharmacological inhibition of AMPK using Compound C (CC) abolished these protective effects, resulting in mitochondrial collapse, elevated inflammation, and cell death, highlighting AMPK's critical role in mediating E2's actions. Interestingly, while NF-κB inhibition using BAY 11-7082 partially restored mitochondrial respiration, it failed to prevent Aβ-induced cytotoxicity, suggesting that E2's full neuroprotective effects rely on broader AMPK-dependent mechanisms beyond NF-κB suppression alone. Together, these findings establish AMPK as a key mediator of E2's protective effects against Aβ-driven mitochondrial dysfunction and neuroinflammation, providing new insights into estrogen-based therapeutic strategies for AD.}, } @article {pmid40649809, year = {2025}, author = {Yoon, SM and Lee, YW and Kim, MJ and Shin, JJ and Bae, GW and Park, S}, title = {Neuroprotective Mechanisms of Porcine Brain Enzyme Hydrolysate in Memory Impairment: Multi-Target Strategy Against Amyloid-β-Induced Neurotoxicity.}, journal = {International journal of molecular sciences}, volume = {26}, number = {13}, pages = {}, pmid = {40649809}, issn = {1422-0067}, support = {RS-2023-00208567//Korea National Research Foundation/ ; }, mesh = {Animals ; *Amyloid beta-Peptides/toxicity/metabolism ; *Neuroprotective Agents/pharmacology ; *Brain/enzymology/metabolism ; Swine ; Humans ; *Memory Disorders/drug therapy/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; *Protein Hydrolysates/pharmacology ; Neurons/drug effects/metabolism ; Cell Survival/drug effects ; Apoptosis/drug effects ; Brain-Derived Neurotrophic Factor/metabolism ; Cell Line, Tumor ; Peptide Fragments/toxicity ; }, abstract = {This study investigated the potential neuroprotective mechanisms of porcine brain enzyme hydrolysate (PBEH) against Alzheimer's disease pathology using differentiated SH-SY5Y cells. Differentiated neuronal cells were treated with 40 μM amyloid-β(1-42; Aβ) to induce neurotoxicity, followed by PBEH treatment (12.5-400 μg/mL), Com-A (peptide-based neuroprotective supplement; 200 μg/mL) treatment, and Com-B (herbal extract known for improving memory function; 100 μg/mL) treatment. Key assessments included cell viability, Aβ aggregation in adding 10 μM Aβ, amyloidogenic proteins (APP, BACE), synaptic markers (BDNF, ERK), apoptotic markers (BAX/BCL-2, caspase-3), oxidative stress (reactive oxygen species (ROS)), cholinergic function (ChAT, AChE), MAPK signaling (JNK, p38), and neuroinflammation (IL-1β). PBEH contained high concentrations of amino acids, including L-lysine (32.3 mg/g), L-leucine (42.4 mg/g), L-phenylalanine (30.0 mg/g) and the PSIS peptide (86.9 μg/g). Treatment up to 400 μg/mL showed no cytotoxicity and had cognitive protection effects up to 152% under Aβ stress (p < 0.05). PBEH significantly attenuated Aβ aggregation, decreased APP (28%) and BACE (51%) expression, enhanced synaptic function through increased BDNF, and restored ERK phosphorylation (p < 0.05). Anti-apoptotic effects included a 76% reduction in the BAX/BCL-2 ratio, a 47% decrease in caspase-3, and a 56% reduction in ROS levels. Cholinergic function showed restoration via increased ChAT activity (p < 0.01) and decreased AChE activity (p < 0.05). PBEH reduced IL-1β levels by 70% and suppressed JNK/p38 phosphorylation (p < 0.05). While Com-A enhanced BDNF and Com-B showed anti-inflammatory effects, PBEH demonstrated activity across multiple pathway markers. In conclusion, these findings suggest that PBEH may enable neuronal preservation through multi-pathway modulation, establishing foundational evidence for further mechanistic investigation in cognitive enhancement applications.}, } @article {pmid40649231, year = {2025}, author = {Calva, J and Cuenca, MB and León, A and Benítez, Á}, title = {Chemical Composition, Acetylcholinesterase-Inhibitory Potential and Antioxidant Activity of Essential Oils from Three Populations of Parthenium hysterophorus L. in Ecuador.}, journal = {Molecules (Basel, Switzerland)}, volume = {30}, number = {13}, pages = {}, pmid = {40649231}, issn = {1420-3049}, support = {VIN-POA-56//Universidad Técnica Particular de Loja/ ; }, mesh = {*Oils, Volatile/chemistry/pharmacology ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Ecuador ; *Antioxidants/chemistry/pharmacology ; *Acetylcholinesterase/chemistry/metabolism ; Plant Leaves/chemistry ; Sesquiterpenes/chemistry ; Gas Chromatography-Mass Spectrometry ; *Asteraceae/chemistry ; Sesquiterpenes, Germacrane/chemistry ; Flowers/chemistry ; Alkenes/chemistry ; Parthenium hysterophorus ; }, abstract = {In this study, we analyzed the essential oils (EOs) extracted by steam distillation from the leaves and flowers of Parthenium hysterophorus L., grown in three different locations in southern Ecuador: Espíndola (ESP), Loja (LOJ) and Quilanga (QUI). Approximately 97.45%, 98.27% and 95.99% of the oil constituents were identified using gas chromatography-mass spectrometry (GC-MS) and gas chromatography-flame ionization detection (GC-FID). Sesquiterpene hydrocarbons were predominant in the EOs. The most representative constituents of the sample from ESP were germacrene D (35.08%), myrcene (11.32%), (E)-β-ocimene (10.21%), (E)-caryophyllene (7.90%), germacra-4(15),5,10(14)-trien-1-α-ol (5.18%) and (E, E)-α-farnesene (4.99%), with an AChE IC50 of 14.78 and with 16.38 and 93.16 µg/mL from ABTS and DPPH, respectively. The EOs from LOJ were characterized by the abundant presence of germacrene D (28.30%), myrcene (13.95%), (E)-β-ocimene (10.51%) and isolongifolan-7-α-ol (8.26%), with an AChE IC50 of 16.65 and with 36.18 and 158.43 µg/mL from ABTS and DPPH, respectively. Finally, the EOs from QUI contained germacrene D (32.20%), myrcene (13.36%), (E)-β-ocimene (8.54%), (E, E)-α-farnesene (6.77%), germacra-4(15),5,10(14)-trien-1-α-ol (5.69%) and (E)-caryophyllene (5.37%), with an AChE IC50 of 10.69 and with 14.50 and 92.98 µg/mL from ABTS and DPPH, respectively. This study identifies chemotypic variation in P. hysterophorus collected from different locations and, for the first time, the AChE inhibitor was evaluated. These findings provide a scientific basis for the clinical application of P. hysterophorus EOs in the future treatment of Alzheimer's disease.}, } @article {pmid40648018, year = {2025}, author = {Ferreira, FDS and de Mattos, JLA and da Silva, PHF and da Costa, CA and Ognibene, DT and Resende, AC and de Bem, GF}, title = {Antioxidant, Anti-Inflammatory, and Antiapoptotic Effects of Euterpe oleracea Mart. (Açaí) in Improving Cognition Deficits: Potential Therapeutic Implications for Alzheimer's Disease.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {13}, pages = {}, pmid = {40648018}, issn = {2223-7747}, abstract = {Euterpe oleracea Martius, also popularly known as açaí palm, is a palm tree of the Aracaceae family widely found in the Amazon region. Traditional plant use reports indicate the beneficial effects of açaí juice on fever, pain, and flu. Moreover, many studies have demonstrated the pharmacological potential of açaí, mainly the pulp and seed of the fruit, due to its chemical composition, which significantly consists of polyphenols. In recent years, there has been a growing interest in investigating the neuroprotective effects of açaí, with the potential for the prevention and treatment of neurodegenerative diseases, such as Alzheimer's disease, mainly due to the increasing aging of the population that has contributed to the increase in the number of individuals affected by this disease that has no cure. Therefore, this review aims to evaluate the potential role of açaí fruit in preventing or treating cognitive deficits, highlighting its potential in Alzheimer's disease therapy. Preclinical in vivo and in vitro pharmacological studies were utilized to investigate the learning and memory effects of the pulp and seed of the açaí fruit, focusing on antioxidant, anti-inflammatory, antiapoptotic, and autophagy restoration actions.}, } @article {pmid40647943, year = {2025}, author = {Lin, GD and Vishwakarma, P and Smith, PN and Li, RW}, title = {The Occurrence and Bioactivities of Amaryllidaceae Alkaloids from Plants: A Taxonomy-Guided Genera-Wide Review.}, journal = {Plants (Basel, Switzerland)}, volume = {14}, number = {13}, pages = {}, pmid = {40647943}, issn = {2223-7747}, abstract = {The distribution of Amaryllidaceae alkaloids, with a focus on their chemodiversity, has been reported previously, but not at a genera-wide diversity level. This review provides a comprehensive survey of the occurrence of Amaryllidaceae alkaloids across the genera of the Amaryllidaceae family. This survey is taxonomically guided by the National Center for Biotechnology Information (NCBI) Taxonomy Browser, with targeted keyword searches conducted in the Chemical Abstracts Service (CAS) SciFinder-n and PubMed. The family Amaryllidaceae comprises over 1214 species across three subfamilies: Agapanthoideae (1 genus, 5 species), Allioideae (3 genera plus 11 subgenera, 617 species), and Amaryllidoideae (58 genera plus 13 subgenera, 592 species). Amaryllidaceae alkaloids have been identified exclusively in 36 of the 58 genera and 6 of the 13 subgenera within the Amaryllidoideae subfamily. To date, more than 600 Amaryllidaceae alkaloids have been isolated, predominantly from this subfamily-hence the designation "Amaryllidaceae alkaloids". These alkaloids display a wide spectrum of biological activities, including acetylcholinesterase inhibition, anti-inflammatory, antioxidant, antimicrobial, antidiabetic, and anticancer effects. A notable example is galanthamine (also known as galantamine), an FDA-approved drug marketed under the brand names Reminyl™ (Janssen Research Foundation, Beerse, Belgium, 2001) and Razadyne™ (Johnson & Johnson Pharmaceutical Research, New Brunswick, NJ, USA, 2004) for the treatment of mild to moderate Alzheimer's disease, due to its potent acetylcholinesterase-inhibitory activity. Galanthamine has been isolated from species belonging to the genera Cyrtanthus, Galanthus, Leucojum, Lycoris, Narcissus, Ungernia, Chlidanthus, Crinum, Eucharis, Eustephia, Pancratium, and Phaedranassa. Lycorine is another widely distributed alkaloid found across multiple genera, and it has been extensively studied for its diverse bioactivities. Given the remarkable chemical diversity and bioactivity of Amaryllidaceae alkaloids, along with the many underexplored genera and species, further research into Amaryllidaceae species and their alkaloids is strongly warranted to support the discovery and development of novel therapeutic agents.}, } @article {pmid40647320, year = {2025}, author = {Varga, P and Lehoczki, A and Fekete, M and Jarecsny, T and Kryczyk-Poprawa, A and Zábó, V and Major, D and Fazekas-Pongor, V and Csípő, T and Varga, JT}, title = {The Role of Magnesium in Depression, Migraine, Alzheimer's Disease, and Cognitive Health: A Comprehensive Review.}, journal = {Nutrients}, volume = {17}, number = {13}, pages = {}, pmid = {40647320}, issn = {2072-6643}, support = {RRF-2.3.1-21-2022-00003//National Cardiovascular Laboratory Program/ ; TKP2021-NKTA-47//Ministry of Innovation and Technology of Hungary/ ; }, mesh = {Humans ; *Alzheimer Disease/physiopathology ; *Magnesium/therapeutic use ; *Migraine Disorders/physiopathology/drug therapy ; *Depression/etiology/drug therapy ; *Cognition/drug effects ; Magnesium Deficiency/complications ; Hypothalamo-Hypophyseal System ; }, abstract = {Magnesium is an essential mineral involved in hundreds of biochemical reactions, with particular relevance to maintaining neural homeostasis, modulating neurotransmitter systems, and regulating inflammatory and oxidative stress mechanisms. This comprehensive review aims to evaluate the potential role of magnesium in the pathophysiology and treatment of three prevalent neurological and psychiatric disorders-depression, migraine, and Alzheimer's disease-as well as its broader implications for cognitive health. Current research suggests that magnesium deficiency is associated with the development of depression, as magnesium influences glutamatergic and GABAergic neurotransmission, as well as the activity of the hypothalamic-pituitary-adrenal (HPA) axis, both of which play critical roles in stress responses and mood regulation. Additionally, magnesium's anti-inflammatory properties may contribute to the alleviation of depressive symptoms. In the context of migraine's pathophysiology, magnesium plays a role in regulating cerebral vascular tone, modulating the trigeminovascular system, and reducing neuronal hyperexcitability, which may explain the observed correlation between magnesium levels and the incidence of migraines. Regarding Alzheimer's disease, preclinical and epidemiological studies suggest that magnesium may contribute to modulating neurodegenerative processes and preserving cognitive function; however, due to the heterogeneity of the current findings, further longitudinal and interventional studies are necessary to determine its precise clinical relevance. This review aims to enhance the understanding of the relationship between magnesium and these disorders through a narrative review of relevant clinical studies. The findings may provide insights into the potential therapeutic applications of magnesium and guide the future directions of the research into the prevention and treatment of depression, migraine, and Alzheimer's disease and overall cognitive health.}, } @article {pmid40646945, year = {2025}, author = {Davì, F and Iaconis, A and Cordaro, M and Di Paola, R and Fusco, R}, title = {Nutraceutical Strategies for Targeting Mitochondrial Dysfunction in Neurodegenerative Diseases.}, journal = {Foods (Basel, Switzerland)}, volume = {14}, number = {13}, pages = {}, pmid = {40646945}, issn = {2304-8158}, abstract = {In neurons, mitochondria generate energy through ATP production, thereby sustaining the high energy demands of the central nervous system (CNS). Mitochondrial dysfunction within the CNS was implicated in the pathogenesis and progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, often involving altered mitochondrial dynamics like fragmentation and functional impairment. Accordingly, mitochondrial targeting represents an alternative therapeutic strategy for the treatment of these disorders. Current standard drug treatments present limitations due to adverse effects associated with their chronic use. Therefore, in recent years, nutraceuticals, natural compounds exhibiting diverse biological activities, have garnered significant attention for their potential to treat these diseases. It has been shown that these compounds represent safe and easily available sources for the development of innovative therapeutics, and by modulating mitochondrial function, nutraceuticals offer a promising approach to address neurodegenerative pathologies. We referred to approximately 200 articles published between 2020 and 2025, identified through a focused search across PubMed, Google Scholar, and Scopus using keywords such as "nutraceutical," "mitochondrial dysfunction," and "neurodegenerative diseases. The purpose of this review is to examine how mitochondrial dysfunction contributes to the genesis and progression of neurodegenerative diseases. Also, we discuss recent advances in mitochondrial targeting using nutraceuticals, focusing on their mechanisms of action related to mitochondrial biogenesis, fusion, fission, bioenergetics, oxidative stress, calcium homeostasis, membrane potential, and mitochondrial DNA stability.}, } @article {pmid40646316, year = {2025}, author = {Phan, DTA and Le, HP and Tran, TH and Van Le, U and Van Le, M and Ly, TH}, title = {Ameliorative role of Polyscias fruticosa leaf extract in aluminum chloride-induced neurotoxicity flies possibly mediated by N-methyl-D-aspartate receptor antagonistic and anticholinesterase active compounds.}, journal = {Journal of natural medicines}, volume = {79}, number = {5}, pages = {1167-1187}, pmid = {40646316}, issn = {1861-0293}, mesh = {Animals ; *Plant Extracts/pharmacology/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemistry ; Aluminum Chloride/toxicity ; Plant Leaves/chemistry ; Drosophila melanogaster/drug effects ; *Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/metabolism ; *Fabaceae/chemistry ; Molecular Docking Simulation ; Acetylcholinesterase/metabolism ; Oxidative Stress/drug effects ; }, abstract = {Polyscias fruticosa leaves have been used in traditional medicine to aid in the therapy of brain and nerve-related disorders, including dementia. However, the evidences for the effects and mechanisms of P. fruticosa leaf extract (PFLE) and its constituents in improving dementia remain unclear. This study aims to evaluate the ameliorative effect of PFLE in aluminum chloride-induced neurotoxicity Drosophila melanogaster model. Simultaneously, the dementia-improving mechanisms of PFLE's compounds were explored by computational pharmacological analysis. Results showed that D. melanogaster exposed to 1.0, 2.0, and 4.0 mg/mL PFLE or 0.1 mg/mL donepezil hydrochloride had significant improvements in lifespan, memory, motor behavior, and oxidative stress markers, including decreased malondialdehyde level and increased glutathione level in flies' homogenates. Also, PFLE had acetylcholinesterase inhibitory ability with an IC50 value of 266.10 µg/mL. Applying the UHPLC-Q-TOF-MS/MS technique, 36 compounds were identified in the PFLE. Among these, 25 compounds, including acid amines, flavonoids, saponins, choline, piperine, and vitamin B1, have been demonstrated potential for supporting the treatment of Alzheimer's disease (AD). Interestingly, molecular docking study indicated that many of the compounds are agents of prominent targets in dementia treatment including N-methyl-D-aspartate (NMDA) receptor and cholinesterase, in which polyscioside A-E are the main components of the PFLE that may be responsible for the NMDA receptor antagonistic and anticholinesterase activities. These compounds have favorable physiochemical properties and drug-likeliness. This study suggested the potential of the PFLE and its compounds in the prophylactic and treatment of neurodegenerative pathologies, including AD, and laid the foundation for further studies.}, } @article {pmid40646278, year = {2025}, author = {Knezovic, A and Hosch, M and Hamann, CS and Popp, S and Ortega, G and Osmanovic-Barilar, J and Grünblatt, E and Monoranu, C and Riederer, P and Salkovic-Petrisic, M and Schmitt-Böhrer, A}, title = {Approaching therapy of Alzheimer's disease via the antidiabetic drug liraglutide-a study with streptozotocin intracerebroventricularly treated Wistar rats.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {132}, number = {10}, pages = {1587-1608}, pmid = {40646278}, issn = {1435-1463}, support = {A/00/200017//German Academic Exchange Service/ ; }, mesh = {Animals ; *Liraglutide/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/chemically induced/metabolism ; *Streptozocin/administration & dosage ; Rats, Wistar ; Male ; *Hypoglycemic Agents/pharmacology/administration & dosage ; Rats ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Maze Learning/drug effects ; Avoidance Learning/drug effects ; Injections, Intraventricular ; Neurogenesis/drug effects ; }, abstract = {Risk factors for developing dementia include type 2 diabetes and obesity. Streptozotocin (STZ) intracerebroventricularly (icv) treated rats are a well-accepted animal model for the sporadic Alzheimer`s disease (sAD). STZ-icv treatment results in an insulin-resistant brain state, cognitive deficits, and reduced hippocampal adult neurogenesis (AN). As the antidiabetic drug liraglutide (LIR) has been shown to improve AN, and spatial learning in an AD mouse model, we have investigated the effects of LIR treatment on spatial and fear-motivated learning, AN, and gene expression profiles in STZ-icv treated rats. Male Wistar rats were injected icv with STZ (f.c. 3 mg/kg) or vehicle. Two months later, four weeks of subcutaneous treatment with LIR (0.3 mg/kg) began. Cognitive abilities were assessed with the Morris water maze (MWM) and passive avoidance (PA) test. We performed quantitative immunohistochemistry to evaluate AN, and quantitative real-time PCR to determine the expression levels of genes involved in insulin signaling, glucose uptake, and neuroinflammation. STZ-icv rats showed significantly impaired spatial learning performance in the MWM and fear-motivated memory deficits in the PA test accompanied by reduced AN, downregulated insulin system- and glucose metabolism-related genes in the hippocampus and prefrontal cortex. LIR treatment did not reverse these cognitive deficits of STZ-icv rats in the MWM, and did even worsen PA performance. However, LIR partially restored dysregulated gene expression, however, additionally stimulated neuroinflammation. Refined experimental designs, e.g., refined dosing, should help to further clarify the therapeutic potential of LIR in the future.}, } @article {pmid40645537, year = {2025}, author = {Bashir, DJ and Bhat, KA and Bashir, M}, title = {Deciphering Alzheimer's disease: Molecular mechanisms, preclinical models and strategies to overcome Blood-Brain-Barrier.}, journal = {Brain research}, volume = {1863}, number = {}, pages = {149828}, doi = {10.1016/j.brainres.2025.149828}, pmid = {40645537}, issn = {1872-6240}, mesh = {*Alzheimer Disease/metabolism/physiopathology/pathology ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; Animals ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; }, abstract = {Neurodegenerative diseases involve a spectrum of diseases, with Alzheimer's being the most prevalent one. Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory loss, and synaptic dysfunction. Despite extensive research, effective therapeutic interventions remain limited, largely due to the complex molecular underpinnings of the disease and the challenge posed by the blood-brain barrier (BBB). This review explores the critical molecular mechanisms implicated in AD pathogenesis, i.e. disruption of cholinergic neurotransmission, aggregation of β-amyloid fragments, tau protein phosphorylation, and oxidative stress. As the establishment of effective treatments remains a major research goal, the present review further gives an insight into the various preclinical in vivo models like chemical, lesion-induced, beta-amyloid, streptozotocin infusion, and transgenic models that have been instrumental in advancing our understanding of disease progression and testing potential treatments. A significant focus is given to emerging strategies designed to circumvent or modulate the BBB, including nanoparticle-based delivery systems, receptor-mediated transport, and focused ultrasound techniques. By integrating insights from molecular biology, experimental modeling, and drug delivery science, this work aims to highlight current challenges and propose comprehensive strategies for improving the diagnosis and treatment of Alzheimer's disease.}, } @article {pmid40645230, year = {2025}, author = {Bayer, TA and DeVone, F and Singh, M and Leeder, C and Garbin, A and Halladay, C and McConeghy, K and Gravenstein, S and Rudolph, JL}, title = {Change in Distressed Behavior in Dementia During the COVID-19 Pandemic in Veterans Affairs Community Living Centers.}, journal = {Journal of the American Medical Directors Association}, volume = {26}, number = {9}, pages = {105752}, doi = {10.1016/j.jamda.2025.105752}, pmid = {40645230}, issn = {1538-9375}, mesh = {Humans ; *COVID-19/epidemiology/psychology ; Male ; Female ; Retrospective Studies ; United States/epidemiology ; Aged ; *Veterans/psychology ; *Dementia/psychology ; United States Department of Veterans Affairs ; Aged, 80 and over ; SARS-CoV-2 ; Pandemics ; }, abstract = {OBJECTIVES: To compare distressed behavior in Veterans with Alzheimer disease and related dementias (ADRD) residing in Veterans Affairs (VA) Community Living Centers (CLCs) during the COVID-19 pandemic to previous years. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Veterans with ADRD and without baseline distressed behavior residing in CLCs in March 2020 (Early-COVID) and March 2018 or March 2019 (Pre-COVID). METHODS: We measured distressed behavior with the Distressed Behaviors in Dementia Indicator. Using a Cox regression, we compared the 180-day hazard of distressed behavior in the Early-COVID group to that in the Pre-COVID group. RESULTS: Of 4383 sampled Veterans, 1190 (27%) had recently taken an antipsychotic medication. In the Pre-COVID (n = 2795) and Early-COVID groups (n = 1588), new distressed behavior occurred in 629 (22.5%) and 313 (19.7%) Veterans, respectively. The adjusted hazard ratio (HR) of new distressed behavior was 0.82 (95% CI 0.71-0.95) for Early-COVID compared with Pre-COVID. Antipsychotic medication was associated with new distressed behavior (HR 1.61, 95% CI 1.40-1.86). CONCLUSIONS AND IMPLICATIONS: New distressed behavior decreased during the first 6 months of the COVID-19 pandemic compared with the previous 2 years. The observed association between antipsychotic medication use and distressed behavior may reflect clinical recognition and treatment of a predisposition toward distressed behavior. Recorded changes in distressed behavior in Veterans with dementia residing in CLCs opposed the trend of decreased well-being in residents of non-VA nursing homes, but changes in resident assessment fidelity during the Early-COVID period could have confounded the study.}, } @article {pmid40644887, year = {2025}, author = {Ghorbian, M and Ghorbian, S}, title = {The potential of machine learning to personalized medicine in Neurogenetics: Current trends and future directions.}, journal = {Computers in biology and medicine}, volume = {196}, number = {Pt A}, pages = {110756}, doi = {10.1016/j.compbiomed.2025.110756}, pmid = {40644887}, issn = {1879-0534}, mesh = {Humans ; *Precision Medicine/methods/trends ; *Machine Learning ; *Nervous System Diseases/genetics/diagnosis ; }, abstract = {Neurogenetic disorders (NeD) are a group of neurological conditions resulting from inherited genetic defects. By affecting the normal functioning of the nervous system, these diseases lead to serious problems in movement, cognition, and other body functions. In recent years, machine learning (ML) approaches have proven highly effective, enabling the analysis and processing of vast amounts of medical data. By analyzing genetic data, medical imaging, and other clinical data, these techniques can contribute to early diagnosis and more effective treatment of NeD. However, using these approaches is challenged by issues including data variability, model explainability, and the requirement for interdisciplinary collaboration. This paper investigates the impact of ML on healthcare diagnosis and care of common NeD, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Multiple Sclerosis disease (MSD). The purpose of this research is to determine the opportunities and challenges of using these techniques in the field of neurogenetic medicine. Our findings show that using ML can increase the detection accuracy by 85 % and reduce the detection time by 60 %. Additionally, the use of these techniques in predicting patient prognosis has been 70 % more accurate than traditional methods. Ultimately, this research will enable medical professionals and researchers to leverage ML approaches in advancing the diagnostic and therapeutic processes of NeD by identifying the opportunities and challenges.}, } @article {pmid40644302, year = {2025}, author = {Stephenson, RA and Sepulveda, J and Johnson, KR and Lita, A and Gopalakrishnan, J and Acri, DJ and Beilina, A and Cheng, L and Yang, LG and Root, JT and Ward, ME and Combs, C and Skarnes, WC and Cookson, MR and Shih, HY and Larion, M and Rebeck, GW and Narayan, PS}, title = {Triglyceride metabolism controls inflammation and microglial phenotypes associated with APOE4.}, journal = {Cell reports}, volume = {44}, number = {7}, pages = {115961}, pmid = {40644302}, issn = {2211-1247}, support = {F99 NS134164/NS/NINDS NIH HHS/United States ; R01 NS100704/NS/NINDS NIH HHS/United States ; ZIA DK075158/ImNIH/Intramural NIH HHS/United States ; }, mesh = {*Microglia/metabolism/pathology ; *Triglycerides/metabolism ; Animals ; Humans ; *Apolipoprotein E4/metabolism/genetics ; *Inflammation/metabolism/pathology ; Mice, Transgenic ; Mice ; Phenotype ; Lipid Droplets/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Phagocytosis ; Alzheimer Disease/metabolism/pathology/genetics ; Lipopolysaccharides/pharmacology ; Cytokines/metabolism ; }, abstract = {Changes to cellular lipids accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimer's disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in the cell state. In fact, both triglyceride biosynthesis and catabolism are critical for the activation-induced transcription and secretion of inflammatory cytokines and chemokines, as well as changes in phagocytosis. In microglia harboring the Alzheimer's disease risk APOE4 genotype, inhibiting triglyceride biosynthesis attenuates disease-associated transcriptional states. Triglyceride biosynthesis inhibition also rescues microglial surveillance defects observed in slices from APOE4 humanized transgenic mice. Together, our findings establish that modulating triglyceride metabolism can tune microglial immune activity in response to extrinsic activation and in APOE4-associated disease.}, } @article {pmid40643478, year = {2025}, author = {Yadav, Y and Anwar, M and Sharma, H and Jain, S and Sharma, U and Haldar, P and Dey, AB and Dey, S}, title = {Anti-Inflammatory Peptide Prevents Aβ25-35-Induced Inflammation in Rats via Lipoxygenase Inhibition.}, journal = {Cells}, volume = {14}, number = {13}, pages = {}, pmid = {40643478}, issn = {2073-4409}, mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; *Peptide Fragments/toxicity ; Rats ; Male ; *Lipoxygenase Inhibitors/pharmacology/therapeutic use ; Alzheimer Disease/drug therapy/pathology ; Hippocampus/drug effects/pathology ; *Inflammation/drug therapy/pathology/chemically induced ; *Lipoxygenase/metabolism ; Rats, Sprague-Dawley ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Humans ; }, abstract = {Neuroinflammation, triggered by lipoxygenase (LOX), contributes to Alzheimer's disease (AD) progression. Overexpression of LOX-5 in patients with AD serum highlights its role. This study assessed the efficacy of the LOX-inhibitor-peptide YWCS in an AD rat model induced by Aβ25-35 injection. Cognitive tests, magnetic resonance imaging (MRI) scans, and molecular analyses were conducted. YWCS treatment significantly improved cognitive function, as evidenced by improved performance in the open field, novel object recognition, elevated plus maze, and Morris water maze tests. MRI scans revealed hippocampal shrinkage in AD rats and no changes were observed from YWCS treatment. Molecular analysis revealed altered expression of LOX-5, LOX-12, Aβ, γ-secretase components, p-Tau[181], Akt, p-Akt, and p53 in AD rats. Immunofluorescence staining confirmed increased expression of LOX, Aβ, and p-Tau[181] in the hippocampus of AD rats, which was reduced by YWCS treatment. Serum LOX levels were elevated in AD rats and significantly decreased after YWCS treatment, aligning with previous findings in human AD patients and AD cell models. YWCS offered improvements in behavioral and inflammatory marker regulation and also prevented progression of the disease, as shown by MRI results. These results suggest that YWCS, by targeting LOX, has the potential to be a promising therapeutic agent for AD.}, } @article {pmid40642909, year = {2025}, author = {Tan, Y and Yang, D and Ke, Z and Hu, Z and Song, W and Tang, L and Zhou, Z and Mo, Y and Huang, L and Xu, Y}, title = {The Effect of APOE ε4 Allele on Dynamic Local Spontaneous Brain Activity and Functional Integration in Alzheimer's Disease.}, journal = {Human brain mapping}, volume = {46}, number = {10}, pages = {e70269}, pmid = {40642909}, issn = {1097-0193}, support = {82130036//National Natural Science Foundation of China/ ; ZDXK202216//Jiangsu Province Key Medical Discipline/ ; 2022ZD0211800//STI 2030 - Major Projects/ ; }, mesh = {Humans ; *Alzheimer Disease/physiopathology/genetics/diagnostic imaging/blood ; *Apolipoprotein E4/genetics ; Male ; Female ; Aged ; Magnetic Resonance Imaging ; Middle Aged ; Amyloid beta-Peptides/blood ; Alleles ; Aged, 80 and over ; *Brain/physiopathology/diagnostic imaging ; }, abstract = {The apolipoprotein E (APOE) ε4 allele is the most important genetic risk factor for sporadic Alzheimer's disease (AD), yet its mechanisms in AD pathology and cognitive decline remain unclear. Using a sliding-time window approach to directly quantify the instantaneous fluctuations of various local metrics based on continuous time series and calculate voxel-wise concordance of these metrics, we explored the impact of APOE ε4 on dynamic local brain activity and functional integration in AD, and its interrelations with plasma biomarkers and cognition. Results showed that APOE ε4 widely affected dALFF, dReHo, dGSCorr, and voxel-wise concordance. For AD patients, APOE ε4 carriers uniquely exhibited correlations between dALFF in the right angular gyrus/supramarginal gyrus and MoCA scores and orientation function, and between voxel-wise concordance in the right caudate nucleus (CAU) and general cognition, attention, language function, orientation function, plasma Aβ42. Critically, APOE ε4-related altered voxel-wise concordance in the right CAU mediated the relationship between plasma Aβ and language cognition in AD. Moreover, the combined model incorporating dynamic metrics, plasma AD biomarkers, and demographic data effectively distinguished AD from NC (AUC = 0.94, sensitivity = 87.69%, specificity = 86.84%). In conclusion, the APOE ε4 allele might play a pivotal role in modulating brain dynamic functional activities in AD, which may contribute to the association between Aβ pathology and cognitive decline. Our findings may provide imaging markers and targets for the diagnosis and treatment of AD.}, } @article {pmid40642529, year = {2025}, author = {Lizcano, F and Sanabria, D and Aviles, E}, title = {Hormonal modulation, mitochondria and Alzheimer's prevention: the role of GLP-1 agonists and estrogens.}, journal = {Frontiers in molecular biosciences}, volume = {12}, number = {}, pages = {1622186}, pmid = {40642529}, issn = {2296-889X}, abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia worldwide, disproportionately affecting women and lacking effective disease-modifying therapies. While traditional approaches have focused on amyloid β (Aβ) plaques and tau pathology, emerging evidence highlights the role of metabolic dysfunction, mitochondrial impairment, and hormonal signaling in the pathogenesis of AD. Estrogens exert neuroprotective effects by modulating synaptic plasticity, enhancing mitochondrial bioenergetics, and reducing oxidative stress and inflammation. Similarly, glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for the treatment of type 2 diabetes, have demonstrated promising cognitive benefits, potentially mediated through improved insulin signaling, neuronal survival, and reduced β-amyloid (Aβ) and tau burden. This review explores the converging mechanisms through which estrogens and GLP-1RAs may act synergistically to prevent or delay the onset of AD. We examine the influence of sex differences in mitochondrial dynamics, estrogen receptor distribution, and GLP-1 signaling pathways, particularly within central nervous system regions implicated in AD. Preclinical studies using GLP-1-estrogen conjugates have shown enhanced metabolic and neuroprotective outcomes, accompanied by reduced systemic hormonal exposure, suggesting a viable therapeutic strategy. As the global prevalence of AD continues to rise, especially among postmenopausal women, dual agonism targeting estrogen and GLP-1 receptors may represent a novel, physiologically informed approach to prevention and intervention. Ongoing clinical trials and future research must consider sex-specific factors, receptor polymorphisms, and brain-region selectivity to optimize the translational potential of this combined strategy.}, } @article {pmid40642320, year = {2025}, author = {}, title = {Correction to "The HOPE4MCI study: AGB101 treatment slows progression of entorhinal cortex atrophy in APOE ε4 non-carriers with mild cognitive impairment due to Alzheimer's disease".}, journal = {Alzheimer's & dementia (New York, N. Y.)}, volume = {11}, number = {3}, pages = {e70131}, doi = {10.1002/trc2.70131}, pmid = {40642320}, issn = {2352-8737}, abstract = {[This corrects the article DOI: 10.1002/trc2.70004.].}, } @article {pmid40642087, year = {2025}, author = {Noor, F and Aslam, S and Piras, IS and Tremblay, C and Beach, TG and Serrano, GE}, title = {Integrative bioinformatics and machine learning approaches reveal oxidative stress and glucose metabolism related genes as therapeutic targets and drug candidates in Alzheimer's disease.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1572468}, pmid = {40642087}, issn = {1664-3224}, mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/drug therapy ; *Oxidative Stress/genetics ; *Machine Learning ; *Glucose/metabolism ; *Computational Biology/methods ; Molecular Docking Simulation ; Gene Regulatory Networks ; Gene Expression Profiling ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; }, abstract = {BACKGROUND: Alzheimer's disease (AD), the most common form of dementia, has treatments that slow but do not stop cognitive decline. Additional treatments are based on its pathogenic mechanisms are needed. Evidence has long highlighted oxidative stress and impaired glucose metabolism as crucial factors in AD pathogenesis. Therefore, in this study we aimed to find key AD pathogenic pathways combining genes involved in oxidative stress and glucose metabolism as well as potential small-molecule therapeutic agents. METHODS: Using autopsy brain RNA sequencing data (GSE125583) derived from the Arizona Study of Aging and Brain and Body Donation Program, AD-related genes were identified via differential gene expression, pathway and coexpression analysis. Oxidative stress and glucose metabolism genes were correlated to pinpoint module genes. GSE173955 was used an independent dataset was used for validation, conducting molecular docking, assessing hub genes for AD, and integrating machine learning approaches. RESULTS: We identified 13,982 differentially expressed genes (DEGs) in AD patients. Through WGCNA coexpression analysis, 1,068 genes were linked to AD-specific modules. Pearson's correlation analysis highlighted 99 genes involved in oxidative stress and glucose metabolism. Overlap analysis of DEGs, module genes, and these metabolic genes revealed 21 key overlapping targets. PPI network and receiving operating curve (ROC) curve analyses then identified AKT1 and PPARGC1A as diagnostic hub genes for AD. Machine learning-based virtual screening of small molecules identified various inhibitors and enhancers with drug-like potential targeting AKT1 (upregulated) and PPARGC1A (downregulated), respectively. Among others, the Random Forest model was the most reliable for predicting molecular activity. Molecular docking further validated the binding affinities of these small molecules (inhibitors/enhancers) to AKT1 and PPARGC1A. CONCLUSION: This study identified AKT1 and PPARGC1A as potential therapeutic targets in AD. We discovered drug candidates with strong binding affinities, offering new avenues for effective AD treatment strategies.}, } @article {pmid40641595, year = {2025}, author = {Delvenne, A and Gobom, J and Reus, LM and Dobricic, V and Ten Kate, M and Schindler, SE and Ramakers, I and Tijms, BM and Vandenberghe, R and Schaeverbeke, J and Martinez-Lage, P and Tainta, M and Teunissen, CE and Popp, J and Peyratout, G and Tsolaki, M and Freund-Levi, Y and Lovestone, S and Streffer, J and Barkhof, F and Bertram, L and Blennow, K and Zetterberg, H and Visser, PJ and Vos, SJB}, title = {Cerebrospinal fluid proteomic profiling of cognitively unimpaired individuals with suspected non-Alzheimer's disease pathophysiology.}, journal = {Brain communications}, volume = {7}, number = {4}, pages = {fcaf253}, pmid = {40641595}, issn = {2632-1297}, support = {K23 AG053426/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; }, abstract = {Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker-based concept describing individuals with abnormal tau and/or neurodegeneration markers but normal amyloid levels. SNAP is common in individuals with normal cognition (NC), but its underlying pathophysiology is understudied, while being relevant for clinical trial design and treatment approaches. We aimed to investigate the pathophysiology of individuals with NC who are amyloid-negative and tau-positive (SNAP) through cerebrospinal fluid (CSF) proteomics. Two hundred and ninety-one individuals with NC were classified based on CSF amyloid β1-42 and phosphorylated tau 181, as amyloid-negative/tau-negative (controls), amyloid-negative/tau-positive (SNAP), amyloid-positive/tau-negative and amyloid-positive/tau-positive. We measured 3102 proteins in CSF using tandem mass tag proteomic analyses. We compared protein abundance between groups using analysis of covariance and identified enriched biological pathways using Gene Ontology. We also examined differences between groups in genetic risk for Alzheimer's disease, estimated using polygenic risk scores based on genome-wide association study data. SNAP individuals with NC showed mostly increased protein levels (n = 360) compared with controls, mainly associated with neuroplasticity, angiogenesis, and protein modification and degradation. The proteomic profile of SNAP was similar to that of amyloid-positive/tau-positive individuals, while distinct from amyloid-positive/tau-negative individuals, who showed mainly decreased proteins associated with neuroplasticity. Higher levels of amyloid β1-40 and amyloid β1-42 were observed in SNAP compared with the three other groups. Polygenic risk scores analyses showed no significant differences between SNAP, amyloid-positive/tau-negative, and amyloid-positive/tau-positive individuals, while SNAP showed some genetic differences from controls, which were driven by APOE. Individuals with NC and SNAP or amyloid-positive/tau-positive status showed similar CSF proteomic profiles, while amyloid-positive/tau-negative individuals showed a distinct CSF proteomic profile. This suggests that tau, rather than amyloid, might be the main driver of the proteomic profiles in SNAP and other amyloid/tau subgroups. This may have implications for future proteomic studies and clinical trial design, as these findings highlight the importance of considering tau status in future studies.}, } @article {pmid40641055, year = {2025}, author = {Le, W and Shen, L and Guo, T and Xie, F}, title = {Spotlight on Alzheimer's disease and related dementias research in East Asia.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {7}, pages = {e70479}, pmid = {40641055}, issn = {1552-5279}, mesh = {Humans ; *Alzheimer Disease/epidemiology/therapy/diagnosis ; Asia, Eastern/epidemiology ; *Dementia/epidemiology/therapy/diagnosis ; Biomarkers/blood ; *Biomedical Research ; Neuroimaging ; }, abstract = {With a burgeoning dementia burden driven by unique demographic, genetic, and socioeconomic factors of East Asia, the region has made significant investments in understanding disease mechanisms, developing biomarkers, and exploring therapeutic approaches. This collection highlights the current landscape of Alzheimer's disease and related dementias research in East Asia, including region-specific epidemiological insights, advances in plasma biomarkers and neuroimaging, and innovative diagnostic and treatment strategies. Despite progress, challenges such as limited access to advanced imaging, cultural barriers to autopsy, and disparities in healthcare persist.}, } @article {pmid40641016, year = {2025}, author = {Dahiya, M and Yadav, M and Kumar, A and Goyal, C}, title = {Tau Pathology in Alzheimer's Disease: Bridging Molecular Mechanisms and Targeted Therapies.}, journal = {CNS & neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/0118715273376581250626003322}, pmid = {40641016}, issn = {1996-3181}, abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by β-amyloid (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau. While Aβ-targeting therapies have been a primary focus of drug development, their long-term efficacy remains uncertain. Emerging evidence suggests that tauopathy is more closely linked to cognitive decline, positioning tau as a promising therapeutic target. Tauopathies, a group of neurodegenerative disorders marked by tau dysfunction and aggregation, were historically attributed to a toxic gain-of-function. However, clinical trials targeting tau have yielded limited success, likely due to the heterogeneity of tau pathology, variable patient responses, and suboptimal therapeutic strategies. Here, we underline the need for a refined understanding of tau biology to develop effective interventions. Advancing precision medicine approaches and identifying optimal tau species for therapeutic intervention could transform tau-targeting therapies into a cornerstone in managing tauopathies. By integrating insights from genetics, pathology, and translational research, future efforts may overcome current challenges and unlock novel treatment avenues, ultimately improving patient outcomes.}, } @article {pmid40640892, year = {2025}, author = {Noh, MY and Kwon, HS and Kwon, MS and Nahm, M and Jin, HK and Bae, JS and Kim, SH}, title = {Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions.}, journal = {Molecular neurodegeneration}, volume = {20}, number = {1}, pages = {82}, pmid = {40640892}, issn = {1750-1326}, support = {RS-2024-00348451//Korea Dementia Research Center/ ; }, mesh = {Humans ; *Microglia/metabolism ; *Neurodegenerative Diseases/metabolism/therapy ; *Biomarkers/metabolism ; Animals ; }, abstract = {Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies-including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data-offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.}, } @article {pmid40640460, year = {2025}, author = {Heimler, SR and Amick, KA and Bergstrom, J and Moliné, M and Mahapatra, G and Craft, S and Molina, AJA}, title = {Nervonic acid and 15-epi-PGA1 mediate systemic mitochondrial dysfunction in AD dementia.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {40640460}, issn = {2509-2723}, support = {R01 AG072734/AG/NIA NIH HHS/United States ; P30 AG068635/AG/NIA NIH HHS/United States ; P30 AG068635/GF/NIH HHS/United States ; R01 AG054523/GF/NIH HHS/United States ; P30 AG 072947/GF/NIH HHS/United States ; R01 AG061805/AG/NIA NIH HHS/United States ; R01 AG061805/GF/NIH HHS/United States ; }, abstract = {Systemic mitochondrial dysfunction is apparent in the pathophysiology of Alzheimer's disease (AD). However, the factors driving bioenergetic decline remain unclear. This study utilized serum samples from older adults with normal cognition, mild cognitive impairment, and dementia to identify circulating molecules that can drive mitochondrial dysfunction in the context of AD. We used mass spectrometry to measure the abundance of lipid metabolites and applied tiered selection criteria to identify candidate "mito-inhibitory" molecules. These criteria were based on correlations with (1) in vitro bioenergetic effects of whole serum samples on naïve cells, (2) the bioenergetic capacity of blood cells from the serum donor, and (3) cognition, as measured by the modified mini-mental state exam. Mito-inhibitory lipid candidates were validated by examining their bioenergetic effects on neurons, myoblasts, and fibroblasts in vitro. Our results indicate that nervonic acid and 15-epi Prostaglandin A1 (15-epi-PGA1) are elevated in participants with dementia compared to those with normal cognition. Importantly, both metabolites inhibited mitochondrial function across multiple cell types in vitro. High resolution respirometric analyses reveal that inhibitory effects from lipid treatment occur via broad inhibition of the electron transfer system (ETS) with no change in overall mitochondrial content. This study provides insights into the mechanisms underlying systemic bioenergetic decline associated with AD dementia. The identification of circulating factors that drive mitochondrial bioenergetic decline may inform the development of mitochondrial therapeutics for AD.}, } @article {pmid40639970, year = {2025}, author = {Franceschi, AM and Keir, G and Benzinger, TLS and Cogswell, PM and Ali, FZ and Petrella, JR and Prescott, JW and Whitlow, CT and Zaharchuk, G and Allen, JW and , }, title = {Clinical Role of Brain PET in Alzheimer Disease in the Era of Disease-Modifying Therapies.}, journal = {AJNR. American journal of neuroradiology}, volume = {46}, number = {8}, pages = {1521-1527}, pmid = {40639970}, issn = {1936-959X}, mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/metabolism/drug therapy/therapy ; *Positron-Emission Tomography/methods ; *Brain/diagnostic imaging/metabolism ; }, abstract = {Alzheimer disease (AD) is the leading cause of dementia, with an estimated 6.9 million Americans aged 65 and older living with Alzheimer dementia today, with this number projected to grow to 13.8 million by 2060. Amyloid and τ accumulation underpin our understanding of the pathophysiology of AD, with the abnormal accumulation of these proteins leading to neurodegeneration. With the recent approval of antiamyloid monoclonal antibody therapies for patients with early-stage Alzheimer disease by the Food and Drug Administration, there is renewed energy and focus on brain imaging for diagnosis, triage, and monitoring of patients with neurodegenerative disease. Furthermore, PET imaging of amyloid and τ has revolutionized our understanding of dementia progression and staging, and influences patient management in the clinical setting. We aim to update radiologists on the evolving role of amyloid and τ PET in clinical practice, emphasizing the need for standardized workflows and the integration of molecular imaging data with other disease biomarkers. We also discuss the clinical implications of amyloid and τ PET, including their impact on diagnosis and treatment decisions, as well as the challenges of reimbursement and workforce capacity. With recent shifts in the AD management landscape, it is crucial for radiologists to keep abreast of recent advances in clinical practice, thereby ensuring effective patient care.}, } @article {pmid40639271, year = {2025}, author = {Mao, Y and Zhang, L and Zhang, C and Qin, L and Liao, X and Zhao, L}, title = {The close relationship between trace elements (Cu, Fe, Zn, Se, Rb, Si, Cr, and V) and Alzheimer's disease: Research progress and insights.}, journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)}, volume = {90}, number = {}, pages = {127692}, doi = {10.1016/j.jtemb.2025.127692}, pmid = {40639271}, issn = {1878-3252}, mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Trace Elements/metabolism ; Iron/metabolism ; Zinc/metabolism ; Silicon/metabolism ; Selenium/metabolism ; Animals ; Copper/metabolism ; Chromium/metabolism ; Vanadium/metabolism ; }, abstract = {Alzheimer's disease (AD) is a typical neurodegenerative disorder primarily characterized by the deposition of β-amyloid (Aβ) plaques and the hyperphosphorylation of tau protein, leading to the formation of neurofibrillary tangles (NFTs). These pathological changes are closely associated with the imbalance of trace element homeostasis. Trace elements are extensively involved in fundamental physiological processes, including DNA synthesis, protein synthesis, energy metabolism, and enzymatic reactions, all of which are essential for cognitive function and brain development. This review summarizes the alterations in homeostasis and the biological roles of trace elements such as copper, iron, zinc, selenium, rubidium, silicon, chromium, and vanadium, as well as their relationship with the onset and progression of AD. Additionally, we discuss recent advancements in therapeutic strategies targeting the balance of trace element ions, including metal chelators, supplements, nanomedicines, and small-molecule drugs, to provide new perspectives for AD research and treatment.}, } @article {pmid40638744, year = {2025}, author = {Keil, SA and Jansson, D and Braun, M and Iliff, JJ}, title = {Glymphatic dysfunction in Alzheimer's disease: A critical appraisal.}, journal = {Science (New York, N.Y.)}, volume = {389}, number = {6756}, pages = {eadv8269}, doi = {10.1126/science.adv8269}, pmid = {40638744}, issn = {1095-9203}, mesh = {Animals ; Humans ; *Alzheimer Disease/genetics/metabolism/physiopathology ; *Glymphatic System/metabolism/pathology/physiopathology ; Disease Models, Animal ; Aquaporin 4/genetics/metabolism ; }, abstract = {Thirteen years after the initial publication defining the glymphatic system, we critically reappraise the role of its dysfunction in Alzheimer's disease (AD). Our understanding of glymphatic function and its involvement in the pathogenesis of AD derives primarily from correlative clinical data and rodent studies. A causal role for glymphatic dysfunction in AD has not yet been established in humans. We review current approaches to assess glymphatic function clinically, which capture different features of perivascular fluid dynamics or their results. The absence of clinically suitable imaging approaches to measuring glymphatic exchange in the human brain is an obstacle to evaluating whether glymphatic function is impaired in AD populations and to developing and evaluating therapeutics to modulate glymphatic function in the treatment and prevention of AD.}, } @article {pmid40637746, year = {2025}, author = {Xu, D and Wu, J and Zhao, X and Shen, J and Lu, Z and Yang, Z}, title = {A bibliometric analysis of the current research status and hotspots regarding Aducanumab treatment for Alzheimer's disease.}, journal = {Naunyn-Schmiedeberg's archives of pharmacology}, volume = {}, number = {}, pages = {}, pmid = {40637746}, issn = {1432-1912}, abstract = {BACKGROUND: The prevalence of Alzheimer's disease is steadily increasing, and Aducanumab has garnered significant attention as a treatment since 2021. There is a growing body of research on Aducanumab and its relationship with Alzheimer's disease; however, there is currently a lack of bibliometric analysis regarding the use of Aducanumab in the treatment of Alzheimer's disease. OBJECTIVE: This study employs bibliometric methods to analyze the current research landscape and hotspots surrounding Alzheimer's disease and Aducanumab, providing a reference for subsequent investigations in this field and the promotion of Aducanumab as a treatment for Alzheimer's disease. METHODS: This study retrieved articles related to Alzheimer's disease and Aducanumab from the WOS core database, covering the period from the establishment of the database until Dec 31, 2024. After a rigorous selection process, analyses were conducted using GraphPad Prism 10, VOSviewer, and CiteSpace to obtain insights into publication and citation metrics, collaboration networks among countries, institutions, and authors, as well as clustering analysis of reference papers and keywords. RESULTS: The number of articles regarding Aducanumab treatment for Alzheimer's disease has been increasing annually, with a notable surge occurring after 2021. The three countries with the highest publication output are the United States, the United Kingdom, and China. The leading institutions in terms of publication volume are Biogen, Harvard Medical School, and the University of California, San Francisco. The top three authors contributing to this body of work are Poul F. Høilund-Carlsen, Abass Alavi, and Mona-Elisabeth Revheim. The journals with the highest publication rates include Alzheimer's & Dementia, the International Journal of Molecular Sciences, and the Journal of Alzheimer's Disease. The most cited article is "Lecanemab in Early Alzheimer's Disease," authored by van Dyck CH et al., published in 2023 in the New England Journal of Medicine. The ten most frequently occurring keywords are Alzheimer's disease, Aducanumab, dementia, amyloid-beta, immunotherapy, tau, a-beta, mouse model, amyloid, and mild cognitive impairment. The keyword and cluster "pharmacokinetics" currently represent a research hotspot in this field. CONCLUSION: This study employs bibliometric methods to reveal the publication trends related to Aducanumab in the context of Alzheimer's disease, examining collaborations among countries, regions, and authors, as well as recent research hotspots. It provides objective data that serves as a reference for scientific research and clinical practice concerning Aducanumab treatment for Alzheimer's disease.}, } @article {pmid40637583, year = {2025}, author = {Bonomi, CG and Motta, C and Di Donna, MG and Poli, M and Koch, G and Martorana, A}, title = {Rethinking dementia in the oldest old: Lessons to learn for the diagnosis and treatment of Alzheimer's disease.}, journal = {Neural regeneration research}, volume = {}, number = {}, pages = {}, doi = {10.4103/NRR.NRR-D-25-00312}, pmid = {40637583}, issn = {1673-5374}, } @article {pmid40637522, year = {2025}, author = {Nonino, F and Colosimo, C and Massacesi, L}, title = {[Lecanemab and Alzheimer-Perusini's disease: between therapeutic hopes and regulatory challenges].}, journal = {Recenti progressi in medicina}, volume = {116}, number = {7-8}, pages = {407-410}, doi = {10.1701/4530.45309}, pmid = {40637522}, issn = {2038-1840}, mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology ; *Amyloid beta-Peptides/metabolism/immunology ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use/administration & dosage ; Aged ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; }, abstract = {Alzheimer-Perusini's disease (AD) represents a growing health crisis. The lack of effective disease-modifying treatments and its increasing prevalence in the elderly population contribute to a major burden for patients and their caregivers, challenging health systems globally. The accumulation of beta-amyloid protein (Aβ) within the brain tissue plays an important pathogenic role in the inflammatory and degenerative mechanisms leading to cognitive and functional impairment. In recent years monoclonal antibodies targeting (Aβ) have been developed and one of them (lecanemab) recently received marketing authorization by the European Medicines Agency (Ema). Although they represent an important innovation in the treatment of AD, their clinical net benefit is uncertain, due to modest efficacy and the threat of potentially severe side effects. Cost, mode od delivery and complexity of programs aimed at minimizing risks for people with AD may limit access to these therapies and pose equity issues within health systems.}, } @article {pmid40636703, year = {2025}, author = {Patricio-Martínez, A and Patricio, F and Macuil-Chapuli, E and Martínez-Juárez, EÁ and Flores-Díaz, S and Cedillo-Ramírez, ML and Limón, ID}, title = {The role of probiotics, prebiotics, and postbiotics: cellular and molecular pathways activated on glial cells in Alzheimer's disease.}, journal = {Frontiers in neuroscience}, volume = {19}, number = {}, pages = {1598011}, pmid = {40636703}, issn = {1662-4548}, abstract = {Supplementation with prebiotics and probiotics can modulate the intestinal microbiota, returning it to a more physiological state; therefore, they can be considered as a possible treatment in many prevalent conditions, including neurodegenerative diseases. Alzheimer's disease (AD) is the most common form of dementia, accounting for 60 to 70% of cases. The neuropathological features of AD include neuritic plaques (extracellular deposits of the beta-amyloid protein, Aβ), neurofibrillary tangles (resulting from hyperphosphorylation of the tau protein), a predominantly cholinergic synaptic decrease, and the presence of inflammatory markers, all these characteristics together trigger the neurodegenerative process and cognitive deterioration. The etiology of AD is multifactorial, however, in recent years evidence has been shown on the significant association between dysbiosis, neuroinflammation, and neurodegeneration. In the present review, we will discuss the role of gut microbiota in the pathogenesis of AD, as well as the underlying mechanisms that trigger the use of probiotics, prebiotics, and postbiotics in neuroinflammation. Our attention will focus on the cellular and molecular mechanisms triggered by astrocytes and microglia, cells involved in mediating neuroinflammation and neurodegeneration in AD.}, } @article {pmid40636522, year = {2025}, author = {Wang, J and Chen, Y and Chen, S and Mu, Z and Chen, J}, title = {How endothelial cell metabolism shapes blood-brain barrier integrity in neurodegeneration.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1623321}, pmid = {40636522}, issn = {1662-5099}, abstract = {BACKGROUND/OBJECTIVE: Endothelial cells, a monolayer of cells adjacent to blood vessels, play a critical role in maintaining vascular function through metabolic pathways such as glycolysis, fatty acid, and amino acid metabolism. Recent studies have revealed their significant involvement in neurodegenerative diseases, although the underlying mechanisms remain unclear. METHODS: By reviewing literature from the past decade, we summarized the metabolic alterations and functional changes of endothelial cells in neurological disorders. RESULTS: In neurodegenerative diseases such as stroke, Alzheimer's disease, multiple sclerosis, and aging, metabolic dysregulation in cerebral vascular endothelial cells disrupts their normal function and is closely associated with blood-brain barrier impairment. CONCLUSION: Aberrant endothelial cell metabolism compromises the integrity of the blood-brain barrier and exacerbates the pathological progression of neurodegenerative diseases. Our review further explores the therapeutic potential of targeting endothelial cell metabolism in various pathological contexts, aiming to provide novel insights for the prevention and treatment of related disorders.}, } @article {pmid40636521, year = {2025}, author = {Sharma, E and Mehta, D and Jadhav, N and Gujrati, G and Dhananya, S and Moorthy, M and Ramaswamy, G and Zhou, Y and Nair, S}, title = {Whole-genome sequencing shows modulation of neurodegenerative genes by Withania somnifera in human SK-N-SH cells.}, journal = {Frontiers in molecular neuroscience}, volume = {18}, number = {}, pages = {1512727}, pmid = {40636521}, issn = {1662-5099}, abstract = {BACKGROUND: Aging is driven by several primary and secondary hallmarks that manifest with age, of which neurodegenerative diseases are important manifestations. The ability to decelerate or reverse aging, and promote healthy aging, has garnered great interest in recent times. In traditional medicine, Withania somnifera (WS) or Ashwagandha has been recognized for its adaptogenic and rejuvenative effects. METHODS: To investigate WS-modulated global gene expression profiles, we performed whole-genome sequencing of WS-treated human neuroblastoma SK-N-SH cells at different doses (50 and 100 μg/mL) and time points (3 h and 9 h) and validation by quantitative real-time PCR (qRT-PCR) and immunoblotting. Disease enrichment analysis for brain-related disorders was performed by DisGeNET. RESULTS: Using differential gene expression analyses, we identified 19,945 WS-modulated genes. Of these, 2,403 and 177 genes were significantly (p ≤ 0.05) upregulated and downregulated, respectively, by WS treatment. Interestingly, different patterns of gene expression were exhibited in dose-dependent (9 upregulated, 1 downregulated, 100 μg/mL 3 h vs. 50 μg/mL 3 h; 21 upregulated, 86 downregulated, 100 μg/mL 9 h vs. 50 μg/mL 9 h) and temporal kinetics (210 upregulated, 6 downregulated, 50 μg/mL 9 h vs. 50 μg/mL 3 h; 8 upregulated, 49 downregulated, 100 μg/mL 9 h vs. 100 μg/mL 3 h). Furthermore, qRT-PCR experiments validated the RNA-seq results. WS-modulated genes were implicated in Alzheimer's disease, migraine, Parkinson's disease, bipolar disorder, cognition, stress, anxiety, forgetfulness, sleep disorders, and substance abuse among others. CONCLUSION: Taken together, our transcriptomic profiling study revealed for the first time that WS may modulate key genes in neurodegenerative disorders with potential beneficial implications for brain-related disorders and healthy aging.}, } @article {pmid40636063, year = {2025}, author = {Armstrong, MJ and Grill, JD and Tropea, TF}, title = {It is time to share Alzheimer biomarker results in dementia with Lewy bodies.}, journal = {Alzheimer's & dementia (Amsterdam, Netherlands)}, volume = {17}, number = {3}, pages = {e70144}, pmid = {40636063}, issn = {2352-8729}, support = {K23 NS114167/NS/NINDS NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; RF1 AG080591/AG/NIA NIH HHS/United States ; }, abstract = {UNLABELLED: There are increasing calls for sharing individual biomarker results with participants in dementia research. No studies investigate returning Alzheimer's disease (AD) biomarker results to individuals with syndromic dementia with Lewy bodies (DLB) even though most of these individuals have both pathologies. This perspective argues that AD biomarkers are valid, interpretable, and actionable, particularly relating to expected prognosis and treatment effects, in people with DLB. Thus, there is an ethical imperative to study AD biomarker result sharing in these patients. This will require revising current disclosure practices. Areas of need include unique pre- and post-test education and careful assessment of the readiness to receive results and post-result responses in people with DLB given the frequency of neuropsychiatric symptoms in this group. Studying responses to sharing AD biomarkers in people with DLB will also inform other dementia settings (e.g., returning synuclein results to individuals with syndromic AD) and neurodegenerative diseases more broadly. HIGHLIGHTS: There are increasing calls for biomarker result sharing in dementia research.No processes exist to guide result sharing in dementia with Lewy bodies (DLB).Alzheimer biomarker results in DLB are valid, interpretable, and actionable.Research is needed on the methods and effects of sharing with people with DLB.Research is needed for sharing evidence of co-pathology across neurodegenerations.}, } @article {pmid40635533, year = {2025}, author = {Tae, WS and Ham, BJ and Pyun, SB and Kim, BJ}, title = {Current Clinical Applications of Structural MRI in Neurological Disorders.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {21}, number = {4}, pages = {277-293}, pmid = {40635533}, issn = {1738-6586}, support = {2022R1F1A1074517/NRF/National Research Foundation of Korea/Korea ; RS-2023-00241730/NRF/National Research Foundation of Korea/Korea ; RS-2025-00515464/NRF/National Research Foundation of Korea/Korea ; }, abstract = {Structural magnetic resonance imaging (sMRI) plays a pivotal role in the evaluation of neurological disorders by providing high-resolution anatomical information. Recent advances in quantitative postprocessing techniques have expanded the utility of sMRI beyond visual assessments by enabling the detection of subtle morphological changes associated with various neurological and psychiatric conditions. This review summarizes current clinical applications of sMRI-based analysis, including brain volumetry, shape analysis, voxel-based morphometry (VBM), surface-based morphometry, source-based morphometry, and voxel-based lesion-symptom mapping (VLSM). Volumetric and shape-based analyses allow for assessments of region-specific atrophy and subregional morphological alterations, while VBM and surface-based morphometry provide complementary insights into tissue volumes and the architecture of the cortical surface. Source-based morphometry reveals network-level patterns of structural covariance, and VLSM directly correlates lesion locations with functional outcomes, particularly in stroke. It has been demonstrated that these methodologies are clinically relevant in conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and major depressive disorder. By quantifying structural brain alterations that are not readily detectable using conventional imaging methods, these tools improve diagnostic accuracy, support prognostication, and facilitate monitoring of treatment effects. This review highlights the growing integration of sMRI postprocessing techniques into clinical neurology.}, } @article {pmid40635531, year = {2025}, author = {Park, KH and Choi, SH and Shim, Y and Youn, YC and Yang, DW and Kim, S}, title = {Use of Amyloid Positron-Emission Tomography to Diagnose Alzheimer's Disease in Clinical Practice in South Korea: Expert Recommendations.}, journal = {Journal of clinical neurology (Seoul, Korea)}, volume = {21}, number = {4}, pages = {251-264}, pmid = {40635531}, issn = {1738-6586}, abstract = {Amyloid positron-emission tomography (PET) is the optimal method for detecting amyloid plaque deposition in patients experiencing cognitive decline, which is essential for diagnosing Alzheimer's disease. However, its clinical application globally has been restricted by the high cost, short radiotracer half-life, and significant accessibility challenges. In particular, the lack of treatment options following diagnosis has been considered the largest obstacle to using amyloid PET as a diagnostic tool. Consequently, the current appropriate-use recommendations for amyloid PET tend to support restricting its use. However, the relatively low cost and superior accessibility of amyloid PET in South Korea have resulted in it being used much more frequently in clinical settings than in other countries. The recent introduction of disease-modifying drugs has increased the importance and frequency of amyloid PET usage. Considering these circumstances, this article presents expert opinions on the appropriate use of amyloid PET in South Korea based on existing recommendations and survey results from dementia experts in South Korea.}, } @article {pmid40635450, year = {2025}, author = {Li, J and Li, Y and Wang, Z and Yao, Y and Yao, D and Chen, K and Xia, Y}, title = {Oxytocin Intervention Mitigates Pathological and Behavioral Impairments in APP/PS1 Mice Subjected to Early Social Isolation.}, journal = {CNS neuroscience & therapeutics}, volume = {31}, number = {7}, pages = {e70511}, pmid = {40635450}, issn = {1755-5949}, support = {2022ZD0208500//STI 2030-Major Project/ ; 2024YFHZ0359//Sichuan Province Science and Technology Support Program/ ; }, mesh = {Animals ; *Oxytocin/pharmacology/therapeutic use ; *Social Isolation/psychology ; Mice ; *Alzheimer Disease/pathology/psychology/drug therapy/genetics/metabolism ; Mice, Transgenic ; Male ; Presenilin-1/genetics ; Gastrointestinal Microbiome/drug effects ; Amyloid beta-Protein Precursor/genetics ; Mice, Inbred C57BL ; Anxiety/drug therapy ; Depression/drug therapy ; Receptors, Oxytocin/metabolism ; Disease Models, Animal ; }, abstract = {BACKGROUND: Neuropsychiatric symptoms, such as anxiety and depression, are prevalent during the prodromal phase of Alzheimer's disease (AD). Social isolation (SI) has been implicated as a potential exacerbating factor for emotional disturbances in AD pathogenesis. Despite the well-established role of oxytocin (OXT) in regulating social behavior and mental health, its function and mechanisms in alleviating AD-related psychiatric symptoms remain poorly understood. MATERIALS AND METHODS: We utilized a 12-week SI model to assess its effects on anxiety, depression-like behaviors, and social cognition in early-stage AD mice. Through immunofluorescence, enzyme-linked immunosorbent assay, and 16S rDNA sequencing, we examined the changes in AD pathology and gut microbiota composition induced by SI, as well as the effects of OXT intervention. RESULTS: Our findings revealed that SI markedly intensified anxiety-like behaviors, depression-like phenotypes, and social cognitive impairments in AD mice. Mechanistically, SI resulted in decreased OXT levels and upregulated OXT receptor expression while also exacerbating AD-related pathological features, including increased Aβ plaque deposition, aberrant microglial proliferation, and reduced PSD-95 expression in the prefrontal cortex. Furthermore, SI induced significant changes in gut microbiota composition. OXT intervention demonstrated therapeutic efficacy by mitigating behavioral deficits, alleviating AD-related pathological damage, and restoring gut microbiota homeostasis in SI AD mice. CONCLUSION: These results underscore OXT as a promising therapeutic avenue for AD, offering novel insights into treatment strategies and identifying potential therapeutic targets through the restoration of gut homeostasis and mitigation of pathological processes.}, } @article {pmid40635217, year = {2025}, author = {Guo, L and Lin, Y and Sun, B}, title = {Highly Efficient and Eco-friendly Synthesis and Bio-activities of 1,3-benzazoles as Cu (II) Chelators in Alzheimer's Disease Therapy.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0109298673371011250612094752}, pmid = {40635217}, issn = {1875-533X}, abstract = {INTRODUCTION: Dyshomeostasis of Cu2+ and abnormal interactions between Cu2+ and β Amyloid peptide (Aβ) can promote Aβ aggregation and oxidative stress, which are considered to trigger Alzheimer's Disease (AD). Metal chelating therapy is a promising approach for the treatment of AD. METHOD: In this study, 2-(2-hydroxyphenyl)benzazoles were synthesized via microwave irradiation promotion. Chelators inhibiting Cu2+-induced Aβ aggregation were determined through turbidity assay and BCA protein assay, while anti-oxidants were detected via HRP/Amplex red assay and fluorescent probe of DCFH-DA. Cell viability was measured by MTT assay. RESULTS: The bio-activity for inhibiting Cu2+ induced-Aβ aggregation of chelators S-1, S-3, S-4, S-5, S-7, S-10, N-5, N-9, N-10 O-2, O-4, X-N-2 was better than that of CQ. The ability of the chelators (S-1, S-10, O-2, O-5, N-9, and X-N-2) to decrease the level of ROS in Aβ+Cu2+ treated SH-SY5Y cells was better than that of CQ. The ability to attenuate Aβ-mediated cytotoxicity in SH-SY5Y cells of S-10 (O-2, O-5, and N-9) was better than that of CQ. CONCLUSION: After the evolution of the bio-activities for the treatment of AD in vitro, it was found that 4 chelators (S-10, O-2, O-5, and N-9) exhibited better bio-activities than CQ in all aspects.}, } @article {pmid40635213, year = {2025}, author = {A Shaldam, M and Carradori, S and Melfi, F and Guglielmi, P and Diomede, F and Piattelli, M and O Tawfik, H}, title = {Potential of MAO-B Inhibitors with Multi-Target Inhibition and Antioxidant Properties for the Treatment of Neurodegenerative Disorders.}, journal = {Mini reviews in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0113895575392491250630195630}, pmid = {40635213}, issn = {1875-5607}, abstract = {Millions of people worldwide are affected by neurodegenerative disorders (NDs), which include a broad range of clinical ailments that affect the brain or peripheral nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, etc. Neuronal cell death in NDs is often linked to oxidative stress; thus, antioxidant treatment can combat oxidative cell damage, and this strategy has been studied in neurodegenerative processes. Over the past 10 years, we have witnessed intense research activity on the biological potential of human monoamine oxidase (hMAO) inhibitors that have been associated with the prevention of oxidative stress and inflammation. These inhibitors have emerged as promising therapeutic agents, especially in the treatment of neurodegenerative diseases (NDs), where their core activity may help mitigate disease progression. An overview of the current state of numerous scaffolds, such as chromones, coumarins, chalcones, propargylamines, benzothiazoles, aminoisoquinolines, and the natural compounds, including ferulic acid, resveratrol, and chrysin, which combine antioxidant capability and hMAO inhibition is given in this review, with particular attention given to each scaffold's mechanism of action and structure-activity relationships (SARs), which are thoroughly discussed. Focusing on the dual mechanism of action, combining inhibition and antioxidant properties, as a potential therapy for neurodegenerative diseases, we have reviewed the different chemical classes of multi-targetdirected ligand (MTDL) inhibitors developed within this framework. Other central nervous system (CNS)-related enzymes, such as cholinesterases, carbonic anhydrases, and BACE-1, have also been explored as targets in the MTDL strategy. By understanding their biological activity, medicinal chemists can better comprehend biological activity and recommend more effective and specific ND treatments.}, } @article {pmid40633621, year = {2025}, author = {Limone, A and Di Napoli, C and De Rosa, G and Bagnoli, S and Izzo, A and Procaccini, C and Matarese, G and Nacmias, B and Lavecchia, A and Sarnataro, D}, title = {Modulation of mitochondrial quality control through autophagic pathway in familial Alzheimer's disease.}, journal = {Biochimica et biophysica acta. Molecular cell research}, volume = {1872}, number = {7}, pages = {120019}, doi = {10.1016/j.bbamcr.2025.120019}, pmid = {40633621}, issn = {1879-2596}, mesh = {Humans ; *Alzheimer Disease/genetics/metabolism/pathology ; *Mitochondria/metabolism/drug effects/pathology/genetics ; *Autophagy/drug effects ; Mitophagy/drug effects ; Fibroblasts/metabolism/drug effects/pathology ; TOR Serine-Threonine Kinases/metabolism/genetics ; Signal Transduction/drug effects ; Protein Kinases/metabolism/genetics ; Ubiquitin-Protein Ligases/metabolism/genetics ; Proto-Oncogene Proteins c-akt/metabolism/genetics ; }, abstract = {Autophagy is a highly conserved cellular catabolic process recognized as an essential pathway for the maintenance of cellular homeostasis. Growing evidence implicates autophagic dysfunction in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease (AD), thus its modulation might represent an interesting therapeutic tool. Searching for a compound that stimulates autophagic pathway, led us to identify the inhibitor of RPSA receptor, NSC47924. In this study, we show that, NSC47924 down-modulated Akt-mTOR-axis pathway, the master regulator of autophagy, which was abnormally hyperactivated in fibroblasts from genetic AD-affected patients. Consistently, by monitoring the conversion of LC3, we found that inhibition of RPSA enhanced and restored the compromised autophagic flux. Moreover, by qRT-PCR analysis we found that inhibitor treatment upregulated the expression of autophagy-linked genes. Importantly, AD-affected fibroblasts exhibited massive mitochondrial network fragmentation and mitophagy defects, which were restored through the stimulation of autophagy induced by RPSA inhibition. Consistent with an efficient elimination of dysfunctional mitochondria, we found that the turnover of both the mitophagy regulators PINK1 and Parkin and the autophagic receptors p62, NDP52, OPTN, was modulated, thus restoring a highly interconnected organelle's network. In addition, the improvement of mitochondrial morphology correlated with a functional recovery, as assessed by Seahorse analysis and mitochondrial ROS production evaluation. Collectively, our findings suggest that RPSA inhibition stimulates an autophagic pathway promoting the efficient removal of damaged mitochondria, favouring the recovery of cellular homeostasis, and counteracting crucial AD pathogenic mechanisms.}, } @article {pmid40633409, year = {2025}, author = {Khaliq, A and Ahmad, F and Rehman, HU and Alanazi, SA and Haleem, H and Junaid, K and Andrikopoulou, E}, title = {Revolutionizing medical imaging: A cutting-edge AI framework with vision transformers and perceiver IO for multi-disease diagnosis.}, journal = {Computational biology and chemistry}, volume = {119}, number = {}, pages = {108586}, doi = {10.1016/j.compbiolchem.2025.108586}, pmid = {40633409}, issn = {1476-928X}, mesh = {Humans ; *Artificial Intelligence ; *Diagnostic Imaging ; Deep Learning ; }, abstract = {The integration of artificial intelligence in medical image classification has significantly advanced disease detection. However, traditional deep learning models face persistent challenges, including poor generalizability, high false-positive rates, and difficulties in distinguishing overlapping anatomical features, limiting their clinical utility. To address these limitations, this study proposes a hybrid framework combining Vision Transformers (ViT) and Perceiver IO, designed to enhance multi-disease classification accuracy. Vision Transformers leverage self-attention mechanisms to capture global dependencies in medical images, while Perceiver IO optimizes feature extraction for computational efficiency and precision. The framework is evaluated across three critical clinical domains: neurological disorders, including Stroke (tested on the Brain Stroke Prediction CT Scan Image Dataset) and Alzheimer's (analyzed via the Best Alzheimer MRI Dataset); skin diseases, covering Tinea (trained on the Skin Diseases Dataset) and Melanoma (augmented with dermoscopic images from the HAM10000/HAM10k dataset); and lung diseases, focusing on Lung Cancer (using the Lung Cancer Image Dataset) and Pneumonia (evaluated with the Pneumonia Dataset containing bacterial, viral, and normal X-ray cases). For neurological disorders, the model achieved 0.99 accuracy, 0.99 precision, 1.00 recall, 0.99 F1-score, demonstrating robust detection of structural brain abnormalities. In skin disease classification, it attained 0.95 accuracy, 0.93 precision, 0.97 recall, 0.95 F1-score, highlighting its ability to differentiate fine-grained textural patterns in lesions. For lung diseases, the framework achieved 0.98 accuracy, 0.97 precision, 1.00 recall, 0.98 F1-score, confirming its efficacy in identifying respiratory conditions. To bridge research and clinical practice, an AI-powered chatbot was developed for real-time analysis, enabling users to upload MRI, X-ray, or skin images for automated diagnosis with confidence scores and interpretable insights. This work represents the first application of ViT and Perceiver IO for these disease categories, outperforming conventional architectures in accuracy, computational efficiency, and clinical interpretability. The framework holds significant potential for early disease detection in healthcare settings, reducing diagnostic errors, and improving treatment outcomes for clinicians, radiologists, and patients. By addressing critical limitations of traditional models, such as overlapping feature confusion and false positives, this research advances the deployment of reliable AI tools in neurology, dermatology, and pulmonology.}, } @article {pmid40633205, year = {2025}, author = {Metzendorf, NG and Godec, A and Petrovic, A and Chourlia, A and Napoleone, A and Syvänen, S and Rofo, F and Hultqvist, G}, title = {Somatostatin therapy, neprilysin activation, and amyloid beta reduction: A novel approach for Alzheimer's treatment.}, journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie}, volume = {189}, number = {}, pages = {118325}, doi = {10.1016/j.biopha.2025.118325}, pmid = {40633205}, issn = {1950-6007}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; *Amyloid beta-Peptides/metabolism ; *Neprilysin/metabolism ; *Somatostatin/pharmacology/therapeutic use/administration & dosage ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Blood-Brain Barrier/metabolism/drug effects ; Mutation ; Amyloid beta-Protein Precursor/genetics/metabolism ; Peptide Fragments/metabolism ; }, abstract = {INTRODUCTION: Neprilysin is the primary enzyme responsible for the degradation of amyloid beta (Aβ), with its levels regulated by the hormone somatostatin (SST). METHODS: We have developed a novel treatment mechanism for Alzheimer's disease (AD) by combining SST with a blood-brain barrier (BBB) transporter and a Fc fragment to extend its half-life. This treatment was tested in a murine AD model overexpressing amyloid precursor protein (APP) with the Arctic mu